Econstudentlog

Oncology (I)

I really disliked the ‘Pocket…’ part of this book, so I’ll sort of pretend to overlook this aspect also in my coverage of the book here. This’ll be a hard thing to do, given the way the book is written – I refer to my goodreads review for details, I’ll include only one illustrative quote from that review here:

“In terms of content, the book probably compares favourably with many significantly longer oncology texts (mainly, but certainly not only, because of the publication date). In terms of readability it compares unfavourably to an Egyptian translation of Alan Sokal’s 1996 article in Social Text, if it were translated by a 12-year old dyslexic girl.”

I don’t yet know in how much detail I’ll blog the book; this may end up being the only post about the book, or I may decide to post a longer sequence of posts. The book is hard to blog, which is an argument against covering it in detail – and also the reason why I haven’t already blogged it – but some of the content included in the book is really, really nice stuff to know, which is a strong argument in favour of covering at least some of the material here. The book has a lot of stuff, so regardless of the level of detail of my future coverage a lot of interesting stuff will of necessity have been left out.

My coverage below includes some observations and links related to the first 100 pages of the book.

“Understanding Radiation Response: The 4 Rs of Radiobiology
Repair of sublethal damage
Reassortment of cells w/in the cell cycle
Repopulation of cells during the course of radiotherapy
Reoxygenation of hypoxic cells […]

*Oxygen enhances DNA damage induced by free radicals, thereby facilitating the indirect action of IR [ionizing radiation, US] *Biologically equivalent dose can vary by a factor of 2–3 depending upon the presence or absence of oxygen (referred to as the oxygen enhancement ratio) *Poorly oxygenated postoperative beds frequently require higher doses of RT than preoperative RT [radiation therapy] […] Chemotherapy is frequently used sequentially or concurrently w/radiotherapy to maximize therapeutic benefit. This has improved pt outcomes although also a/w ↑ overall tox. […] [Many chemotherapeutic agents] show significant synergy with RT […] Mechanisms for synergy vary widely: Include cell cycle effects, hypoxic cell sensitization, & modulation of the DNA damage response”.

“Specific dose–volume relationships have been linked to the risk of late organ tox. […] *Dose, volume, underlying genetics, and age of the pt at the time of RT are critical determinants of the risk for 2° malignancy *The likelihood of 2° CA is correlated w/dose, but there is no threshold dose below which there is no additional risk of 2° malignancy *Latent period for radiation-induced solid tumors is generally between 10 and 60 y […]. Latent period for leukemias […] is shorter — peak between 5 & 7 y.”

“The immune system plays an important role in CA surveillance; Rx’s that modulate & amplify the immune system are referred to as immunotherapies […] tumors escape the immune system via loss of molecules on tumor cells important for immune activation […]; tumors can secrete immunosuppressing cytokines (IL-10 & TGF-β) & downregulate IFN-γ; in addition, tumors often express nonmutated self-Ag, w/c the immune system will, by definition, not react against; tumors can express molecules that inhibit T-cell function […] Ubiquitous CD47 (Don’t eat me signal) with ↑ expression on tumor cells mediates escape from phagocytosis. *Tumor microenvironment — immune cells are found in tumors, the exact composition of these cells has been a/w [associated with, US] pt outcomes; eg, high concentration of tumor-infiltrating lymphocytes (CD8+ cells) are a/w better outcomes & ↑ response to chemotherapy, Tregs & myeloid-derived suppressor cells are a/w worse outcomes, the exact role of Th17 in tumors is still being elucidated; the milieu of cytokines & chemokines also plays a role in outcome; some cytokines (VEGF, IL-1, IL-8) lead to endothelial cell proliferation, migration, & activation […] Expression of PD-L1 in tumor microenvironment can be indicator of improved likelihood of response to immune checkpoint blockade. […] Tumor mutational load correlates w/increased response to immunotherapy (NEJM; 2014;371:2189.).”

“Over 200 hereditary CA susceptibility syndromes, most are rare […]. Inherited CAs arise from highly penetrant germline mts [mutations, US]; “familial” CAss may be caused by interaction of low-penetrance genes, gene–environment interactions, or both. […] Genetic testing should be done based on individual’s probability of being a mt carrier & after careful discussion & informed consent”.

Pharmacogenetics: Effect of heritable genes on response to drugs. Study of single genes & interindividual differences in drug metabolizing enzymes. Pharmacogenomics: Effect of inherited & acquired genetic variation on drug response. Study of the functions & interactions of all genes in the genome & how the overall variability of drug response may be used to predict the right tx in individual pts & to design new drugs. Polymorphisms: Common variations in a DNA sequence that may lead to ↓ or ↑ activity of the encoded gene (SNP, micro- & minisatellites). SNPs: Single nucleotide polymorphisms that may cause an amino acid exchange in the encoded protein, account for >90% of genetic variation in the human genome.”

Tumor lysis syndrome [TLS] is an oncologic emergency caused by electrolyte abnormalities a/w spontaneous and/or tx-induced cell death that can be potentially fatal. […] 4 key electrolyte abnormalities 2° to excessive tumor/cell lysis: *Hyperkalemia *Hyperphosphatemia *Hypocalcemia *Hyperuricemia (2° to catabolism of nucleic acids) […] Common Malignancies Associated with a High Risk of Developing TLS in Adult Patients [include] *Acute leukemias [and] *High-grade lymphomas such as Burkitt lymphoma & DLBCL […] [Disease] characteristics a/w TLS risk: Rapidly progressive, chemosensitive, myelo- or lymphoproliferative [disease] […] [Patient] characteristics a/w TLS risk: *Baseline impaired renal function, oliguria, exposure to nephrotoxins, hyperuricemia *Volume depletion/inadequate hydration, acidic urine”.

Hypercalcemia [affects] ~10–30% of all pts w/malignancy […] Symptoms: Polyuria/polydipsia, intravascular volume depletion, AKI, lethargy, AMS [Altered Mental Status, US], rarely coma/seizures; N/V [nausea/vomiting, US] […] Osteolytic Bone Lesions [are seen in] ~20% of all hyperCa of malignancy […] [Treat] underlying malignancy, only way to effectively treat, all other tx are temporizing”.

“National Consensus Project definition: Palliative care means patient and family-centered care that optimizes quality of life by anticipating, preventing, and treating suffering. Palliative care throughout the continuum of illness involves addressing physical, intellectual, emotional, social, and spiritual needs to facilitate patient autonomy, access to information, and choice.” […] *Several RCTs have supported the integration of palliative care w/oncologic care, but specific interventions & models of care have varied. Expert panels at NCCN & ASCO recently reviewed the data to release evidence-based guidelines. *NCCN guidelines (2016): “Palliative care should be initiated by the primary oncology team and then augmented by collaboration with an interdisciplinary team of palliative care experts… All cancer patients should be screened for palliative care needs at their initial visit, at appropriate intervals, and as clinically indicated.” *ASCO guideline update (2016): “Inpatients and outpatients with advanced cancer should receive dedicated palliative care services, early in the disease course, concurrent with active tx. Referral of patients to interdisciplinary palliative care teams is optimal […] Essential Components of Palliative Care (ASCO) *Rapport & relationship building w/pts & family caregivers *Symptom, distress, & functional status mgmt (eg, pain, dyspnea, fatigue, sleep disturbance, mood, nausea, or constipation) *Exploration of understanding & education about illness & prognosis *Clarification of tx goals *Assessment & support of coping needs (eg, provision of dignity therapy) *Assistance w/medical decision making *Coordination w/other care providers *Provision of referrals to other care providers as indicated […] Useful Communication Tips *Use open-ended questions to elicit pt concerns *Clarify how much information the pt would like to know […] Focus on what can be done (not just what can’t be done) […] Remove the phrase “do everything” from your medical vocabulary […] Redefine hope by supporting realistic & achievable goals […] make empathy explicit”.

Some links:

Radiation therapy.
Brachytherapy.
External beam radiotherapy.
Image-guided radiation therapy.
Stereotactic Radiosurgery.
Total body irradiation.
Cancer stem cell.
Cell cycle.
Carcinogenesis. Oncogene. Tumor suppressor gene. Principles of Cancer Therapy: Oncogene and Non-oncogene Addiction.
Cowden syndrome. Peutz–Jeghers syndrome. Familial Atypical Multiple Mole Melanoma Syndrome. Li–Fraumeni syndrome. Lynch syndrome. Turcot syndrome. Muir–Torre syndrome. Von Hippel–Lindau disease. Gorlin syndrome. Werner syndrome. Birt–Hogg–Dubé syndrome. Neurofibromatosis type I. -ll- type 2.
Knudson hypothesis.
DNA sequencing.
Cytogenetics.
Fluorescence in situ hybridization.
CAR T Cell therapy.
Antimetabolite. Alkylating antineoplastic agentAntimicrotubule agents/mitotic inhibitors. Chemotherapeutic agentsTopoisomerase inhibitorMonoclonal antibodiesBisphosphonatesProteasome inhibitors. [The book covers all of these agents, and others I for one reason or another decided not to include, in great detail, listing many different types of agents and including notes on dosing, pharmacokinetics & pharmacodynamics, associated adverse events and drug interactions etc. These parts of the book were very interesting, but they are impossible to blog – US).
Syndrome of inappropriate antidiuretic hormone secretion.
Acute lactic acidosis (“Often seen w/liver mets or rapidly dividing heme malignancies […] High mortality despite aggressive tx [treatment]”).
Superior vena cava syndrome.

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October 12, 2018 Posted by | Biology, Books, Cancer/oncology, Genetics, Immunology, Medicine, Pharmacology | Leave a comment

Circadian Rhythms (II)

Below I have added some more observations from the book, as well as some links of interest.

“Most circadian clocks make use of a sun-based mechanism as the primary synchronizing (entraining) signal to lock the internal day to the astronomical day. For the better part of four billion years, dawn and dusk has been the main zeitgeber that allows entrainment. Circadian clocks are not exactly 24 hours. So to prevent daily patterns of activity and rest from drifting (freerunning) over time, light acts rather like the winder on a mechanical watch. If the clock is a few minutes fast or slow, turning the winder sets the clock back to the correct time. Although light is the critical zeitgeber for much behaviour, and provides the overarching time signal for the circadian system of most organisms, it is important to stress that many, if not all cells within an organism possess the capacity to generate a circadian rhythm, and that these independent oscillators are regulated by a variety of different signals which, in turn, drive countless outputs […]. Colin Pittendrigh was one of the first to study entrainment, and what he found in Drosophila has been shown to be true across all organisms, including us. For example, if you keep Drosophila, or a mouse or bird, in constant darkness it will freerun. If you then expose the animal to a short pulse of light at different times the shifting (phase shifting) effects on the freerunning rhythm vary. Light pulses given when the clock ‘thinks’ it is daytime (subjective day) will have little effect on the clock. However, light falling during the first half of the subjective night causes the animal to delay the start of its activity the following day, while light exposure during the second half of the subjective night advances activity onset. Pittendrigh called this the ‘phase response curve’ […] Remarkably, the PRC of all organisms looks very similar, with light exposure around dusk and during the first half of the night causing a delay in activity the next day, while light during the second half of the night and around dawn generates an advance. The precise shape of the PRC varies between species. Some have large delays and small advances (typical of nocturnal species) while others have small delays and big advances (typical of diurnal species). Light at dawn and dusk pushes and pulls the freerunning rhythm towards an exactly 24-hour cycle. […] Light can act directly to modify behaviour. In nocturnal rodents such as mice, light encourages these animals to seek shelter, reduce activity, and even sleep, while in diurnal species light promotes alertness and vigilance. So circadian patterns of activity are not only entrained by dawn and dusk but also driven directly by light itself. This direct effect of light on activity has been called ‘masking’, and combines with the predictive action of the circadian system to restrict activity to that period of the light/dark cycle to which the organism has evolved and is optimally adapted.”

“[B]irds, reptiles, amphibians, and fish (but not mammals) have ‘extra-ocular’ photoreceptors located within the pineal complex, hypothalamus, and other areas of the brain, and like the invertebrates, eye loss in many cases has little impact upon the ability of these animals to entrain. […] Mammals are strikingly different from all other vertebrates as they possess photoreceptor cells only within their eyes. Eye loss in all groups of mammals […] abolishes the capacity of these animals to entrain their circadian rhytms to the light/dark cycle. But astonishingly, the visual cells of the retina – the rods and cones – are not required for the detection of the dawn/dusk signal. There exists a third class of photoreceptors within the eye […] Studies in the late 1990s by Russell Foster and his colleagues showed that mice lacking all their rod and cone photoreceptors could still regulate their circadian rhythms to light perfectly normally. But when their eyes were covered the ability to entrain was lost […] work on the rodless/coneless mouse, along with [other] studies […], clearly demonstrated that the mammalian retina contains a small population of photosensitive retinal ganglion cells or pRGCs, which comprise approximately 1-2 per cent of all retinal ganglion cells […] Ophthalmologists now appreciate that eye loss deprives us of both vision and a proper sense of time. Furthermore, genetic diseases that result in the loss of the rods and cones and cause visual blindness, often spare the pRGCs. Under these circumstances, individuals who have their eyes but are visually blind, yet possess functional pRGCs, need to be advised to seek out sufficient light to entrain their circadian system. The realization that the eye provides us with both our sense of space and our sense of time has redefined the diagnosis, treatment, and appreciation of human blindness.”

“But where is ‘the’ circadian clock of mammals? […] [Robert] Moore and [Irving] Zucker’s work pinpointed the SCN as the likely neural locus of the light-entrainable circadian pacemaker in mammals […] and a decade later this was confirmed by definitive experiments from Michael Menaker’s laboratory undertaken at the University of Virginia. […] These experiments established the SCN as the ‘master circadian pacemaker’ of mammals. […] There are around 20,000 or so neurons in the mouse SCN, but they are not identical. Some receive light information from the pRGCs and pass this information on to other SCN neurons, while others project to the thalamus and other regions of the brain, and collectively these neurons secrete more than one hundred different neurotransmitters, neuropeptides, cytokines, and growth factors. The SCN itself is composed of several regions or clusters of neurons, which have different jobs. Furthermore, there is considerable variability in the oscillations of the individual cells, ranging from 21.25 to 26.25 hours. Although the individual cells in the SCN have their own clockwork mechanisms with varying periods, the cell autonomous oscillations in neural activity are synchronized at the system level within the SCN, providing a coherent near 24-hour signal to the rest of the mammal. […] SCN neurons exhibit a circadian rhythm of spontaneous action potentials (SAPs), with higher frequency during the daytime than the night which in turn drives many rhythmic changes by alternating stimulatory and inhibitory inputs to the appropriate target neurons in the brain and neuroendocrine systems. […] The SCN projects directly to thirty-five brain regions, mostly located in the hypothalamus, and particularly those regions of the hypothalamus that regulate hormone release. Indeed, many pituitary hormones, such as cortisol, are under tight circadian control. Furthermore, the SCN regulates the activity of the autonomous nervous system, which in turn places multiple aspects of physiology, including the sensitivity of target tissues to hormonal signals, under circadian control. In addition to these direct neuronal connections, the SCN communicates to the rest of the body using diffusible chemical signals.”

“The SCN is the master clock in mammals but it is not the only clock. There are liver clocks, muscle clocks, pancreas clocks, adipose tissue clocks, and clocks of some sort in every organ and tissue examined to date. While lesioning of the SCN disrupts global behavioural rhythms such as locomotor activity, the disruption of clock function within just the liver or lung leads to circadian disorder that is confined to the target organ. In tissue culture, liver, heart, lung, skeletal muscle, and other organ tissues such as mammary glands express circadian rhythms, but these rhythms dampen and disappear after only a few cycles. This occurs because some individual clock cells lose rhythmicity, but more commonly because the individual cellular clocks become uncoupled from each other. The cells continue to tick, but all at different phases so that an overall 24-hour rhythm within the tissue or organ is lost. The discovery that virtually all cells of the body have clocks was one of the big surprises in circadian rhythms research. […] the SCN, entrained by pRGCs, acts as a pacemaker to coordinate, but not drive, the circadian activity of billions of individual peripheral circadian oscillators throughout the tissues and organs of the body. The signalling pathways used by the SCN to phase-entrain peripheral clocks are still uncertain, but we know that the SCN does not send out trillions of separate signals around the body that target specific cellular clocks. Rather there seems to be a limited number of neuronal and humoral signals which entrain peripheral clocks that in turn time their local physiology and gene expression.”

“As in Drosophilia […], the mouse clockwork also comprises three transcriptional-translational feedback loops with multiple interacting components. […] [T]he generation of a robust circadian rhythm that can be entrained by the environment is achieved via multiple elements, including the rate of transcription, translation, protein complex assembly, phosphorylation, other post-translation modification events, movement into the nucleus, transcriptional inhibition, and protein degradation. […] [A] complex arrangement is needed because from the moment a gene is switched on, transcription and translation usually takes two hours at most. As a result, substantial delays must be imposed at different stages to produce a near 24-hour oscillation. […] Although the molecular players may differ from Drosophilia and mice, and indeed even between different insects, the underlying principles apply across the spectrum of animal life. […] In fungi, plants, and cyanobacteria the clock genes are all different from each other and different again from the animal clock genes, suggesting that clocks evolved independently in the great evolutionary lineages of life on earth. Despite these differences, all these clocks are based upon a fundamental TTFL.”

“Circadian entrainment is surprisingly slow, taking several days to adjust to an advanced or delayed light/dark cycle. In most mammals, including jet-lagged humans, behavioural shifts are limited to approximately one hour (one time zone) per day. […] Changed levels of PER1 and PER2 act to shift the molecular clockwork, advancing the clock at dawn and delaying the clock at dusk. However, per mRNA and PER protein levels fall rapidly even if the animal remains exposed to light. As a result, the effects of light on the molecular clock are limited and entrainment is a gradual process requiring repeated shifting stimuli over multiple days. This phenomenon explains why we get jet lag: the clock cannot move immediately to a new dawn/dusk cycle because there is a ‘brake’ on the effects of light on the clock. […] The mechanism that provides this molecular brake is the production of SLK1 protein. […] Experiments on mice in which SLK1 has been suppressed show very rapid entrainment to simulated jet-lag.”

“We spend approximately 36 per cent of our entire lives asleep, and while asleep we do not eat, drink, or knowingly pass on our genes. This suggests that this aspect of our 24-hour behaviour provides us with something of huge value. If we are deprived of sleep, the sleep drive becomes so powerful that it can only be satisfied by sleep. […] Almost all life shows a 24-hour pattern of activity and rest, as we live on a planet that revolves once every 24 hours causing profound changes in light, temperature, and food availability. […] Life seems to have made an evolutionary ‘decision’ to be active at a specific part of the day/night cycle, and a species specialized to be active during the day will be far less effective at night. Conversely, nocturnal animals that are beautifully adapted to move around and hunt under dim or no light fail miserably during the day. […] no species can operate with the same effectiveness across the 24-hour light/dark environment. Species are adapted to a particular temporal niche just as they are to a physical niche. Activity at the wrong time often means death. […] Sleep may be the suspension of most physical activity, but a huge amount of essential physiology occurs during this time. Many diverse processes associated with the restoration and rebuilding of metabolic pathways are known to be up-regulated during sleep […] During sleep the body performs a broad range of essential ‘housekeeping’ functions without which performance and health during the active phase deteriorates rapidly. But these housekeeping functions would not be why sleep evolved in the first place. […] Evolution has allocated these key activities to the most appropriate time of day. […] In short, sleep has probably evolved as a species-specific response to a 24-hour world in which light, temperature, and food availability change dramatically. Sleep is a period of physical inactivity when individuals avoid movement within an environment to which they are poorly adapted, while using this time to undertake essential housekeeping functions demanded by their biology.”

“Sleep propensity in humans is closely correlated with the melatonin profile but this may be correlation and not causation. Indeed, individuals who do not produce melatonin (e.g. tetraplegic individuals, people on beta-blockers, or pinealectomized patients) still exhibit circadian sleep/wake rhythms with only very minor detectable changes. Another correlation between melatonin and sleep relates to levels of alertness. When melatonin is suppressed by light at night alertness levels increase, suggesting that melatonin and sleep propensity are directly connected. However, increases in alertness occur before a significant drop in blood melatonin. Furthermore, increased light during the day will also improve alertness when melatonin levels are already low. These findings suggest that melatonin is not a direct mediator of alertness and hence sleepiness. Taking synthetic melatonin or synthetic analogues of melatonin produces a mild sleepiness in about 70 per cent of people, especially when no natural melatonin is being released. The mechanism whereby melatonin produces mild sedation remains unclear.”

Links:

Teleost multiple tissue (tmt) opsin.
Melanopsin.
Suprachiasmatic nucleus.
Neuromedin S.
Food-entrainable circadian oscillators in the brain.
John Harrison. Seymour Benzer. Ronald Konopka. Jeffrey C. Hall. Michael Rosbash. Michael W. Young.
Circadian Oscillators: Around the Transcription-Translation Feedback Loop and on to Output.
Period (gene). Timeless (gene). CLOCK. Cycle (gene). Doubletime (gene). Cryptochrome. Vrille Gene.
Basic helix-loop-helix.
The clockwork orange Drosophila protein functions as both an activator and a repressor of clock gene expression.
RAR-related orphan receptor. RAR-related orphan receptor alpha.
BHLHE41.
The two-process model of sleep regulation: a reappraisal.

September 30, 2018 Posted by | Books, Genetics, Medicine, Molecular biology, Neurology, Ophthalmology | Leave a comment

A few diabetes papers of interest

i. Islet Long Noncoding RNAs: A Playbook for Discovery and Characterization.

“This review will 1) highlight what is known about lncRNAs in the context of diabetes, 2) summarize the strategies used in lncRNA discovery pipelines, and 3) discuss future directions and the potential impact of studying the role of lncRNAs in diabetes.”

“Decades of mouse research and advances in genome-wide association studies have identified several genetic drivers of monogenic syndromes of β-cell dysfunction, as well as 113 distinct type 2 diabetes (T2D) susceptibility loci (1) and ∼60 loci associated with an increased risk of developing type 1 diabetes (T1D) (2). Interestingly, these studies discovered that most T1D and T2D susceptibility loci fall outside of coding regions, which suggests a role for noncoding elements in the development of disease (3,4). Several studies have demonstrated that many causal variants of diabetes are significantly enriched in regions containing islet enhancers, promoters, and transcription factor binding sites (5,6); however, not all diabetes susceptibility loci can be explained by associations with these regulatory regions. […] Advances in RNA sequencing (RNA-seq) technologies have revealed that mammalian genomes encode tens of thousands of RNA transcripts that have similar features to mRNAs, yet are not translated into proteins (7). […] detailed characterization of many of these transcripts has challenged the idea that the central role for RNA in a cell is to give rise to proteins. Instead, these RNA transcripts make up a class of molecules called noncoding RNAs (ncRNAs) that function either as “housekeeping” ncRNAs, such as transfer RNAs (tRNAs) and ribosomal RNAs (rRNAs), that are expressed ubiquitously and are required for protein synthesis or as “regulatory” ncRNAs that control gene expression. While the functional mechanisms of short regulatory ncRNAs, such as microRNAs (miRNAs), small interfering RNAs (siRNAs), and Piwi-interacting RNAs (piRNAs), have been described in detail (810), the most abundant and functionally enigmatic regulatory ncRNAs are called long noncoding RNAs (lncRNAs) that are loosely defined as RNAs larger than 200 nucleotides (nt) that do not encode for protein (1113). Although using a definition based strictly on size is somewhat arbitrary, this definition is useful both bioinformatically […] and technically […]. While the 200-nt size cutoff has simplified identification of lncRNAs, this rather broad classification means several features of lncRNAs, including abundance, cellular localization, stability, conservation, and function, are inherently heterogeneous (1517). Although this represents one of the major challenges of lncRNA biology, it also highlights the untapped potential of lncRNAs to provide a novel layer of gene regulation that influences islet physiology and pathophysiology.”

“Although the role of miRNAs in diabetes has been well established (9), analyses of lncRNAs in islets have lagged behind their short ncRNA counterparts. However, several recent studies provide evidence that lncRNAs are crucial components of the islet regulome and may have a role in diabetes (27). […] misexpression of several lncRNAs has been correlated with diabetes complications, such as diabetic nephropathy and retinopathy (2931). There are also preliminary studies suggesting that circulating lncRNAs, such as Gas5, MIAT1, and SENCR, may represent effective molecular biomarkers of diabetes and diabetes-related complications (32,33). Finally, several recent studies have explored the role of lncRNAs in the peripheral metabolic tissues that contribute to energy homeostasis […]. In addition to their potential as genetic drivers and/or biomarkers of diabetes and diabetes complications, lncRNAs can be exploited for the treatment of diabetes. For example, although tremendous efforts have been dedicated to generating replacement β-cells for individuals with diabetes (35,36), human pluripotent stem cell–based β-cell differentiation protocols remain inefficient, and the end product is still functionally and transcriptionally immature compared with primary human β-cells […]. This is largely due to our incomplete knowledge of in vivo differentiation regulatory pathways, which likely include a role for lncRNAs. […] Inherent characteristics of lncRNAs have also made them attractive candidates for drug targeting, which could be exploited for developing new diabetes therapies.”

“With the advancement of high-throughput sequencing techniques, the list of islet-specific lncRNAs is growing exponentially; however, functional characterization is missing for the majority of these lncRNAs. […] Tens of thousands of lncRNAs have been identified in different cell types and model organisms; however, their functions largely remain unknown. Although the tools for determining lncRNA function are technically restrictive, uncovering novel regulatory mechanisms will have the greatest impact on understanding islet function and identifying novel therapeutics for diabetes. To date, no biochemical assay has been used to directly determine the molecular mechanisms by which islet lncRNAs function, which highlights both the infancy of the field and the difficulty in implementing these techniques. […] Due to the infancy of the lncRNA field, most of the biochemical and genetic tools used to interrogate lncRNA function have only recently been developed or are adapted from techniques used to study protein-coding genes and we are only beginning to appreciate the limits and challenges of borrowing strategies from the protein-coding world.”

“The discovery of lncRNAs as a novel class of tissue-specific regulatory molecules has spawned an exciting new field of biology that will significantly impact our understanding of pancreas physiology and pathophysiology. As the field continues to grow, there is growing appreciation that lncRNAs will provide many of the missing components to existing molecular pathways that regulate islet biology and contribute to diabetes when they become dysfunctional. However, to date, most of the experimental emphasis on lncRNAs has focused on large-scale discovery using genome-wide approaches, and there remains a paucity of functional analysis.”

ii. Diabetes and Trajectories of Estimated Glomerular Filtration Rate: A Prospective Cohort Analysis of the Atherosclerosis Risk in Communities Study.

“Diabetes is among the strongest common risk factors for end-stage renal disease, and in industrialized countries, diabetes contributes to ∼50% of cases (3). Less is known about the pattern of kidney function decline associated with diabetes that precedes end-stage renal disease. Identifying patterns of estimated glomerular filtration rate (eGFR) decline could inform monitoring practices for people at high risk of chronic kidney disease (CKD) progression. A better understanding of when and in whom eGFR decline occurs would be useful for the design of clinical trials because eGFR decline >30% is now often used as a surrogate end point for CKD progression (4). Trajectories among persons with diabetes are of particular interest because of the possibility for early intervention and the prevention of CKD development. However, eGFR trajectories among persons with new diabetes may be complex due to the hypothesized period of hyperfiltration by which GFR increases, followed by progressive, rapid decline (5). Using data from the Atherosclerosis Risk in Communities (ARIC) study, an ongoing prospective community-based cohort of >15,000 participants initiated in 1987 with serial measurements of creatinine over 26 years, our aim was to characterize patterns of eGFR decline associated with diabetes, identify demographic, genetic, and modifiable risk factors within the population with diabetes that were associated with steeper eGFR decline, and assess for evidence of early hyperfiltration.”

“We categorized people into groups of no diabetes, undiagnosed diabetes, and diagnosed diabetes at baseline (visit 1) and compared baseline clinical characteristics using ANOVA for continuous variables and Pearson χ2 tests for categorical variables. […] To estimate individual eGFR slopes over time, we used linear mixed-effects models with random intercepts and random slopes. These models were fit on diabetes status at baseline as a nominal variable to adjust the baseline level of eGFR and included an interaction term between diabetes status at baseline and time to estimate annual decline in eGFR by diabetes categories. Linear mixed models were run unadjusted and adjusted, with the latter model including the following diabetes and kidney disease–related risk factors: age, sex, race–center, BMI, systolic blood pressure, hypertension medication use, HDL, prevalent coronary heart disease, annual family income, education status, and smoking status, as well as each variable interacted with time. Continuous covariates were centered at the analytic population mean. We tested model assumptions and considered different covariance structures, comparing nested models using Akaike information criteria. We identified the unstructured covariance model as the most optimal and conservative approach. From the mixed models, we described the overall mean annual decline by diabetes status at baseline and used the random effects to estimate best linear unbiased predictions to describe the distributions of yearly slopes in eGFR by diabetes status at baseline and displayed them using kernel density plots.”

“Because of substantial variation in annual eGFR slope among people with diagnosed diabetes, we sought to identify risk factors that were associated with faster decline. Among those with diagnosed diabetes, we compared unadjusted and adjusted mean annual decline in eGFR by race–APOL1 risk status (white, black– APOL1 low risk, and black–APOL1 high risk) [here’s a relevant link, US], systolic blood pressure […], smoking status […], prevalent coronary heart disease […], diabetes medication use […], HbA1c […], and 1,5-anhydroglucitol (≥10 and <10 μg/mL) [relevant link, US]. Because some of these variables were only available at visit 2, we required that participants included in this subgroup analysis attend both visits 1 and 2 and not be missing information on APOL1 or the variables assessed at visit 2 to ensure a consistent sample size. In addition to diabetes and kidney disease–related risk factors in the adjusted model, we also included diabetes medication use and HbA1c to account for diabetes severity in these analyses. […] to explore potential hyperfiltration, we used a linear spline model to allow the slope to change for each diabetes category between the first 3 years of follow-up (visit 1 to visit 2) and the subsequent time period (visit 2 to visit 5).”

“There were 15,517 participants included in the analysis: 13,698 (88%) without diabetes, 634 (4%) with undiagnosed diabetes, and 1,185 (8%) with diagnosed diabetes at baseline. […] At baseline, participants with undiagnosed and diagnosed diabetes were older, more likely to be black or have hypertension and coronary heart disease, and had higher mean BMI and lower mean HDL compared with those without diabetes […]. Income and education levels were also lower among those with undiagnosed and diagnosed diabetes compared with those without diabetes. […] Overall, there was a nearly linear association between eGFR and age over time, regardless of diabetes status […]. The crude mean annual decline in eGFR was slowest among those without diabetes at baseline (decline of −1.6 mL/min/1.73 m2/year [95% CI −1.6 to −1.5]), faster among those with undiagnosed diabetes compared with those without diabetes (decline of −2.1 mL/min/1.73 m2/year [95% CI −2.2 to −2.0][…]), and nearly twice as rapid among those with diagnosed diabetes compared with those without diabetes (decline of −2.9 mL/min/1.73 m2/year [95% CI −3.0 to −2.8][…]). Adjustment for diabetes and kidney disease–related risk factors attenuated the results slightly, but those with undiagnosed and diagnosed diabetes still had statistically significantly steeper declines than those without diabetes (decline among no diabetes −1.4 mL/min/1.73 m2/year [95% CI −1.5 to −1.4] and decline among undiagnosed diabetes −1.8 mL/min/1.73 m2/year [95% CI −2.0 to −1.7], difference vs. no diabetes of −0.4 mL/min/1.73 m2/year [95% CI −0.5 to −0.3; P < 0.001]; decline among diagnosed diabetes −2.5 mL/min/1.73 m2/year [95% CI −2.6 to −2.4], difference vs. no diabetes of −1.1 mL/min/1.73 m2/ year [95% CI −1.2 to −1.0; P < 0.001]). […] The decline in eGFR per year varied greatly across individuals, particularly among those with diabetes at baseline […] Among participants with diagnosed diabetes at baseline, those who were black, had systolic blood pressure ≥140 mmHg, used diabetes medications, had an HbA1c ≥7% [≥53 mmol/mol], or had 1,5-anhydroglucitol <10 μg/mL were at risk for steeper annual declines than their counterparts […]. Smoking status and prevalent coronary heart disease were not associated with significantly steeper eGFR decline in unadjusted analyses. Adjustment for risk factors, diabetes medication use, and HbA1c attenuated the differences in decline for all subgroups with the exception of smoking status, leaving black race along with APOL1-susceptible genotype, systolic blood pressure ≥140 mmHg, current smoking, insulin use, and HbA1c ≥9% [≥75 mmol/mol] as the risk factors indicative of steeper decline.”

CONCLUSIONS Diabetes is an important risk factor for kidney function decline. Those with diagnosed diabetes declined almost twice as rapidly as those without diabetes. Among people with diagnosed diabetes, steeper declines were seen in those with modifiable risk factors, including hypertension and glycemic control, suggesting areas for continued targeting in kidney disease prevention. […] Few other community-based studies have evaluated differences in kidney function decline by diabetes status over a long period through mid- and late life. One study of 10,184 Canadians aged ≥66 years with creatinine measured during outpatient visits showed results largely consistent with our findings but with much shorter follow-up (median of 2 years) (19). Other studies of eGFR change in a general population have found smaller declines than our results (20,21). A study conducted in Japanese participants aged 40–79 years found a decline of only −0.4 mL/min/1.73 m2/year over the course of two assessments 10 years apart (compared with our estimate among those without diabetes: −1.6 mL/min/1.73 m2/year). This is particularly interesting, as Japan is known to have a higher prevalence of CKD and end-stage renal disease than the U.S. (20). However, this study evaluated participants over a shorter time frame and required attendance at both assessments, which may have decreased the likelihood of capturing severe cases and resulted in underestimation of decline.”

“The Baltimore Longitudinal Study of Aging also assessed kidney function over time in a general population of 446 men, ranging in age from 22 to 97 years at baseline, each with up to 14 measurements of creatinine clearance assessed between 1958 and 1981 (21). They also found a smaller decline than we did (−0.8 mL/min/year), although this study also had notable differences. Their main analysis excluded participants with hypertension and history of renal disease or urinary tract infection and those treated with diuretics and/or antihypertensive medications. Without those exclusions, their overall estimate was −1.1 mL/min/year, which better reflects a community-based population and our results. […] In our evaluation of risk factors that might explain the variation in decline seen among those with diagnosed diabetes, we observed that black race, systolic blood pressure ≥140 mmHg, insulin use, and HbA1c ≥9% (≥75 mmol/mol) were particularly important. Although the APOL1 high-risk genotype is a known risk factor for eGFR decline, African Americans with low-risk APOL1 status continued to be at higher risk than whites even after adjustment for traditional risk factors, diabetes medication use, and HbA1c.”

“Our results are relevant to the design and conduct of clinical trials. Hard clinical outcomes like end-stage renal disease are relatively rare, and a 30–40% decline in eGFR is now accepted as a surrogate end point for CKD progression (4). We provide data on patient subgroups that may experience accelerated trajectories of kidney function decline, which has implications for estimating sample size and ensuring adequate power in future clinical trials. Our results also suggest that end points of eGFR decline might not be appropriate for patients with new-onset diabetes, in whom declines may actually be slower than among persons without diabetes. Slower eGFR decline among those with undiagnosed diabetes, who are likely early in the course of diabetes, is consistent with the hypothesis of hyperfiltration. Similar to other studies, we found that persons with undiagnosed diabetes had higher GFR at the outset, but this was a transient phenomenon, as they ultimately experienced larger declines in kidney function than those without diabetes over the course of follow-up (2325). Whether hyperfiltration is a universal aspect of early disease and, if not, whether it portends worse long-term outcomes is uncertain. Existing studies investigating hyperfiltration as a precursor to adverse kidney outcomes are inconsistent (24,26,27) and often confounded by diabetes severity factors like duration (27). We extended this literature by separating undiagnosed and diagnosed diabetes to help address that confounding.”

iii. Saturated Fat Is More Metabolically Harmful for the Human Liver Than Unsaturated Fat or Simple Sugars.

OBJECTIVE Nonalcoholic fatty liver disease (i.e., increased intrahepatic triglyceride [IHTG] content), predisposes to type 2 diabetes and cardiovascular disease. Adipose tissue lipolysis and hepatic de novo lipogenesis (DNL) are the main pathways contributing to IHTG. We hypothesized that dietary macronutrient composition influences the pathways, mediators, and magnitude of weight gain-induced changes in IHTG.

RESEARCH DESIGN AND METHODS We overfed 38 overweight subjects (age 48 ± 2 years, BMI 31 ± 1 kg/m2, liver fat 4.7 ± 0.9%) 1,000 extra kcal/day of saturated (SAT) or unsaturated (UNSAT) fat or simple sugars (CARB) for 3 weeks. We measured IHTG (1H-MRS), pathways contributing to IHTG (lipolysis ([2H5]glycerol) and DNL (2H2O) basally and during euglycemic hyperinsulinemia), insulin resistance, endotoxemia, plasma ceramides, and adipose tissue gene expression at 0 and 3 weeks.

RESULTS Overfeeding SAT increased IHTG more (+55%) than UNSAT (+15%, P < 0.05). CARB increased IHTG (+33%) by stimulating DNL (+98%). SAT significantly increased while UNSAT decreased lipolysis. SAT induced insulin resistance and endotoxemia and significantly increased multiple plasma ceramides. The diets had distinct effects on adipose tissue gene expression.”

CONCLUSIONS NAFLD has been shown to predict type 2 diabetes and cardiovascular disease in multiple studies, even independent of obesity (1), and also to increase the risk of progressive liver disease (17). It is therefore interesting to compare effects of different diets on liver fat content and understand the underlying mechanisms. We examined whether provision of excess calories as saturated (SAT) or unsaturated (UNSAT) fats or simple sugars (CARB) influences the metabolic response to overfeeding in overweight subjects. All overfeeding diets increased IHTGs. The SAT diet induced a greater increase in IHTGs than the UNSAT diet. The composition of the diet altered sources of excess IHTGs. The SAT diet increased lipolysis, whereas the CARB diet stimulated DNL. The SAT but not the other diets increased multiple plasma ceramides, which increase the risk of cardiovascular disease independent of LDL cholesterol (18). […] Consistent with current dietary recommendations (3638), the current study shows that saturated fat is the most harmful dietary constituent regarding IHTG accumulation.”

iv. Primum Non Nocere: Refocusing Our Attention on Severe Hypoglycemia Prevention.

“Severe hypoglycemia, defined as low blood glucose requiring assistance for recovery, is arguably the most dangerous complication of type 1 diabetes as it can result in permanent cognitive impairment, seizure, coma, accidents, and death (1,2). Since the Diabetes Control and Complications Trial (DCCT) demonstrated that intensive intervention to normalize glucose prevents long-term complications but at the price of a threefold increase in the rate of severe hypoglycemia (3), hypoglycemia has been recognized as the major limitation to achieving tight glycemic control. Severe hypoglycemia remains prevalent among adults with type 1 diabetes, ranging from ∼1.4% per year in the DCCT/EDIC (Epidemiology of Diabetes Interventions and Complications) follow-up cohort (4) to ∼8% in the T1D Exchange clinic registry (5).

One the greatest risk factors for severe hypoglycemia is impaired awareness of hypoglycemia (6), which increases risk up to sixfold (7,8). Hypoglycemia unawareness results from deficient counterregulation (9), where falling glucose fails to activate the autonomic nervous system to produce neuroglycopenic symptoms that normally help patients identify and respond to episodes (i.e., sweating, palpitations, hunger) (2). An estimated 20–25% of adults with type 1 diabetes have impaired hypoglycemia awareness (8), which increases to more than 50% after 25 years of disease duration (10).

Screening for hypoglycemia unawareness to identify patients at increased risk of severe hypoglycemic events should be part of routine diabetes care. Self-identified impairment in awareness tends to agree with clinical evaluation (11). Therefore, hypoglycemia unawareness can be easily and effectively screened […] Interventions for hypoglycemia unawareness include a range of behavioral and medical options. Avoiding hypoglycemia for at least several weeks may partially reverse hypoglycemia unawareness and reduce risk of future episodes (1). Therefore, patients with hypoglycemia and unawareness may be advised to raise their glycemic and HbA1c targets (1,2). Diabetes technology can play a role, including continuous subcutaneous insulin infusion (CSII) to optimize insulin delivery, continuous glucose monitoring (CGM) to give technological awareness in the absence of symptoms (14), or the combination of the two […] Aside from medical management, structured or hypoglycemia-specific education programs that aim to prevent hypoglycemia are recommended for all patients with severe hypoglycemia or hypoglycemia unawareness (14). In randomized trials, psychoeducational programs that incorporate increased education, identification of personal risk factors, and behavior change support have improved hypoglycemia unawareness and reduced the incidence of both nonsevere and severe hypoglycemia over short periods of follow-up (17,18) and extending up to 1 year (19).”

“Given that the presence of hypoglycemia unawareness increases the risk of severe hypoglycemia, which is the strongest predictor of a future episode (2,4), the implication that intervention can break the life-threatening and traumatizing cycle of hypoglycemia unawareness and severe hypoglycemia cannot be overstated. […] new evidence of durability of effect across treatment regimen without increasing the risk for long-term complications creates an imperative for action. In combination with existing screening tools and a body of literature investigating novel interventions for hypoglycemia unawareness, these results make the approach of screening, recognition, and intervention very compelling as not only a best practice but something that should be incorporated in universal guidelines on diabetes care, particularly for individuals with type 1 diabetes […] Hyperglycemia is […] only part of the puzzle in diabetes management. Long-term complications are decreasing across the population with improved interventions and their implementation (24). […] it is essential to shift our historical obsession with hyperglycemia and its long-term complications to equally emphasize the disabling, distressing, and potentially fatal near-term complication of our treatments, namely severe hypoglycemia. […] The health care providers’ first dictum is primum non nocere — above all, do no harm. ADA must refocus our attention on severe hypoglycemia as an iatrogenic and preventable complication of our interventions.”

v. Anti‐vascular endothelial growth factor combined with intravitreal steroids for diabetic macular oedema.

“Background

The combination of steroid and anti‐vascular endothelial growth factor (VEGF) intravitreal therapeutic agents could potentially have synergistic effects for treating diabetic macular oedema (DMO). On the one hand, if combined treatment is more effective than monotherapy, there would be significant implications for improving patient outcomes. Conversely, if there is no added benefit of combination therapy, then people could be potentially exposed to unnecessary local or systemic side effects.

Objectives

To assess the effects of intravitreal agents that block vascular endothelial growth factor activity (anti‐VEGF agents) plus intravitreal steroids versus monotherapy with macular laser, intravitreal steroids or intravitreal anti‐VEGF agents for managing DMO.”

“There were eight RCTs (703 participants, 817 eyes) that met our inclusion criteria with only three studies reporting outcomes at one year. The studies took place in Iran (3), USA (2), Brazil (1), Czech Republic (1) and South Korea (1). […] When comparing anti‐VEGF/steroid with anti‐VEGF monotherapy as primary therapy for DMO, we found no meaningful clinical difference in change in BCVA [best corrected visual acuity] […] or change in CMT [central macular thickness] […] at one year. […] There was very low‐certainty evidence on intraocular inflammation from 8 studies, with one event in the anti‐VEGF/steroid group (313 eyes) and two events in the anti‐VEGF group (322 eyes). There was a greater risk of raised IOP (Peto odds ratio (OR) 8.13, 95% CI 4.67 to 14.16; 635 eyes; 8 RCTs; moderate‐certainty evidence) and development of cataract (Peto OR 7.49, 95% CI 2.87 to 19.60; 635 eyes; 8 RCTs; moderate‐certainty evidence) in eyes receiving anti‐VEGF/steroid compared with anti‐VEGF monotherapy. There was low‐certainty evidence from one study of an increased risk of systemic adverse events in the anti‐VEGF/steroid group compared with the anti‐VEGF alone group (Peto OR 1.32, 95% CI 0.61 to 2.86; 103 eyes).”

“One study compared anti‐VEGF/steroid versus macular laser therapy. At one year investigators did not report a meaningful difference between the groups in change in BCVA […] or change in CMT […]. There was very low‐certainty evidence suggesting an increased risk of cataract in the anti‐VEGF/steroid group compared with the macular laser group (Peto OR 4.58, 95% 0.99 to 21.10, 100 eyes) and an increased risk of elevated IOP in the anti‐VEGF/steroid group compared with the macular laser group (Peto OR 9.49, 95% CI 2.86 to 31.51; 100 eyes).”

“Authors’ conclusions

Combination of intravitreal anti‐VEGF plus intravitreal steroids does not appear to offer additional visual benefit compared with monotherapy for DMO; at present the evidence for this is of low‐certainty. There was an increased rate of cataract development and raised intraocular pressure in eyes treated with anti‐VEGF plus steroid versus anti‐VEGF alone. Patients were exposed to potential side effects of both these agents without reported additional benefit.”

vi. Association between diabetic foot ulcer and diabetic retinopathy.

“More than 25 million people in the United States are estimated to have diabetes mellitus (DM), and 15–25% will develop a diabetic foot ulcer (DFU) during their lifetime [1]. DFU is one of the most serious and disabling complications of DM, resulting in significantly elevated morbidity and mortality. Vascular insufficiency and associated neuropathy are important predisposing factors for DFU, and DFU is the most common cause of non-traumatic foot amputation worldwide. Up to 70% of all lower leg amputations are performed on patients with DM, and up to 85% of all amputations are preceded by a DFU [2, 3]. Every year, approximately 2–3% of all diabetic patients develop a foot ulcer, and many require prolonged hospitalization for the treatment of ensuing complications such as infection and gangrene [4, 5].

Meanwhile, a number of studies have noted that diabetic retinopathy (DR) is associated with diabetic neuropathy and microvascular complications [610]. Despite the magnitude of the impact of DFUs and their consequences, little research has been performed to investigate the characteristics of patients with a DFU and DR. […] the aim of this study was to investigate the prevalence of DR in patients with a DFU and to elucidate the potential association between DR and DFUs.”

“A retrospective review was conducted on DFU patients who underwent ophthalmic and vascular examinations within 6 months; 100 type 2 diabetic patients with DFU were included. The medical records of 2496 type 2 diabetic patients without DFU served as control data. DR prevalence and severity were assessed in DFU patients. DFU patients were compared with the control group regarding each clinical variable. Additionally, DFU patients were divided into two groups according to DR severity and compared. […] Out of 100 DFU patients, 90 patients (90%) had DR and 55 (55%) had proliferative DR (PDR). There was no significant association between DR and DFU severities (R = 0.034, p = 0.734). A multivariable analysis comparing type 2 diabetic patients with and without DFUs showed that the presence of DR [OR, 226.12; 95% confidence interval (CI), 58.07–880.49; p < 0.001] and proliferative DR [OR, 306.27; 95% CI, 64.35–1457.80; p < 0.001), higher HbA1c (%, OR, 1.97, 95% CI, 1.46–2.67; p < 0.001), higher serum creatinine (mg/dL, OR, 1.62, 95% CI, 1.06–2.50; p = 0.027), older age (years, OR, 1.12; 95% CI, 1.06–1.17; p < 0.001), higher pulse pressure (mmHg, OR, 1.03; 95% CI, 1.00–1.06; p = 0.025), lower cholesterol (mg/dL, OR, 0.94; 95% CI, 0.92–0.97; p < 0.001), lower BMI (kg/m2, OR, 0.87, 95% CI, 0.75–1.00; p = 0.044) and lower hematocrit (%, OR, 0.80, 95% CI, 0.74–0.87; p < 0.001) were associated with DFUs. In a subgroup analysis of DFU patients, the PDR group had a longer duration of diabetes mellitus, higher serum BUN, and higher serum creatinine than the non-PDR group. In the multivariable analysis, only higher serum creatinine was associated with PDR in DFU patients (OR, 1.37; 95% CI, 1.05–1.78; p = 0.021).

Conclusions

Diabetic retinopathy is prevalent in patients with DFU and about half of DFU patients had PDR. No significant association was found in terms of the severity of these two diabetic complications. To prevent blindness, patients with DFU, and especially those with high serum creatinine, should undergo retinal examinations for timely PDR diagnosis and management.”

August 29, 2018 Posted by | Diabetes, Epidemiology, Genetics, Medicine, Molecular biology, Nephrology, Ophthalmology, Statistics, Studies | Leave a comment

Nephrology Board Review

Some links related to the lecture’s coverage:

Diabetic nephropathy.
Henoch–Schönlein purpura.
Leukocytoclastic Vasculitis.
Glomerulonephritis. Rapidly progressive glomerulonephritis.
Nephrosis.
Analgesic nephropathy.
Azotemia.
Allergic Interstitial Nephritis: Clinical Features and Pathogenesis.
Nonsteroidal anti-inflammatory drugs: effects on kidney function (Whelton & Hamilton, J Clin Pharmacol. 1991 Jul;31(7):588-98).
Goodpasture syndrome.
Creatinine. Limitations of serum creatinine as a marker of renal function.
Hyperkalemia.
U wave.
Nephrolithiasis. Calcium oxalate.
Calcium gluconate.
Bicarbonate.
Effect of various therapeutic approaches on plasma potassium and major regulating factors in terminal renal failure (Blumberg et al., 1988).
Effect of prolonged bicarbonate administration on plasma potassium in terminal renal failure (Blumberg et al., 1992).
Renal tubular acidosis.
Urine anion gap.
Metabolic acidosis.
Contrast-induced nephropathy.
Rhabdomyolysis.
Lipiduria. Urinary cast.
Membranous glomerulonephritis.
Postinfectious glomerulonephritis.

August 28, 2018 Posted by | Cardiology, Chemistry, Diabetes, Lectures, Medicine, Nephrology, Pharmacology, Studies | Leave a comment

Circadian Rhythms (I)

“Circadian rhythms are found in nearly every living thing on earth. They help organisms time their daily and seasonal activities so that they are synchronized to the external world and the predictable changes in the environment. These biological clocks provide a cross-cutting theme in biology and they are incredibly important. They influence everything, from the way growing sunflowers track the sun from east to west, to the migration timing of monarch butterflies, to the morning peaks in cardiac arrest in humans. […] Years of work underlie most scientific discoveries. Explaining these discoveries in a way that can be understood is not always easy. We have tried to keep the general reader in mind but in places perseverance on the part of the reader may be required. In the end we were guided by one of our reviewers, who said: ‘If you want to understand calculus you have to show the equations.’”

The above quote is from the book‘s foreword. I really liked this book and I was close to giving it five stars on goodreads. Below I have added some observations and links related to the first few chapters of the book’s coverage (as noted in my review on goodreads the second half of the book is somewhat technical, and I’ve not yet decided if I’ll be blogging that part of the book in much detail, if at all).

“There have been over a trillion dawns and dusks since life began some 3.8 billion years ago. […] This predictable daily solar cycle results in regular and profound changes in environmental light, temperature, and food availability as day follows night. Almost all life on earth, including humans, employs an internal biological timer to anticipate these daily changes. The possession of some form of clock permits organisms to optimize physiology and behaviour in advance of the varied demands of the day/night cycle. Organisms effectively ‘know’ the time of day. Such internally generated daily rhythms are called ‘circadian rhythms’ […] Circadian rhythms are embedded within the genomes of just about every plant, animal, fungus, algae, and even cyanobacteria […] Organisms that use circadian rhythms to anticipate the rotation of the earth are thought to have a major advantage over both their competitors and predators. For example, it takes about 20–30 minutes for the eyes of fish living among coral reefs to switch vision from the night to daytime state. A fish whose eyes are prepared in advance for the coming dawn can exploit the new environment immediately. The alternative would be to wait for the visual system to adapt and miss out on valuable activity time, or emerge into a world where it would be more difficult to avoid predators or catch prey until the eyes have adapted. Efficient use of time to maximize survival almost certainly provides a large selective advantage, and consequently all organisms seem to be led by such anticipation. A circadian clock also stops everything happening within an organism at the same time, ensuring that biological processes occur in the appropriate sequence or ‘temporal framework’. For cells to function properly they need the right materials in the right place at the right time. Thousands of genes have to be switched on and off in order and in harmony. […] All of these processes, and many others, take energy and all have to be timed to best effect by the millisecond, second, minute, day, and time of year. Without this internal temporal compartmentalization and its synchronization to the external environment our biology would be in chaos. […] However, to be biologically useful, these rhythms must be synchronized or entrained to the external environment, predominantly by the patterns of light produced by the earth’s rotation, but also by other rhythmic changes within the environment such as temperature, food availability, rainfall, and even predation. These entraining signals, or time-givers, are known as zeitgebers. The key point is that circadian rhythms are not driven by an external cycle but are generated internally, and then entrained so that they are synchronized to the external cycle.”

“It is worth emphasizing that the concept of an internal clock, as developed by Richter and Bünning, has been enormously powerful in furthering our understanding of biological processes in general, providing a link between our physiological understanding of homeostatic mechanisms, which try to maintain a constant internal environment despite unpredictable fluctuations in the external environment […], versus the circadian system which enables organisms to anticipate periodic changes in the external environment. The circadian system provides a predictive 24-hour baseline in physiological parameters, which is then either defended or temporarily overridden by homeostatic mechanisms that accommodate an acute environmental challenge. […] Zeitgebers and the entrainment pathway synchronize the internal day to the astronomical day, usually via the light/dark cycle, and multiple output rhythms in physiology and behaviour allow appropriately timed activity. The multitude of clocks within a multicellular organism can all potentially tick with a different phase angle […], but usually they are synchronized to each other and by a central pacemaker which is in turn entrained to the external world via appropriate zeitgebers. […] Most biological reactions vary greatly with temperature and show a Q10 temperature coefficient of about 2 […]. This means that the biological process or reaction rate doubles as a consequence of increasing the temperature by 10°C up to a maximum temperature at which the biological reaction stops. […] a 10°C temperature increase doubles muscle performance. By contrast, circadian rhythms exhibit a Q10 close to 1 […] Clocks without temperature compensation are useless. […] Although we know that circadian clocks show temperature compensation, and that this phenomenon is a conserved feature across all circadian rhythms, we have little idea how this is achieved.”

“The systematic study of circadian rhythms only really started in the 1950s, and the pioneering studies of Colin Pittendrigh brought coherence to this emerging new discipline. […] From [a] mass of emerging data, Pittendrigh had key insights and defined the essential properties of circadian rhythms across all life. Namely that: all circadian rhythms are endogenous and show near 24-hour rhythms in a biological process (biochemistry, physiology, or behaviour); they persist under constant conditions for several cycles; they are entrained to the astronomical day via synchronizing zeitgebers; and they show temperature compensation such that the period of the oscillation does not alter appreciably with changes in environmental temperature. Much of the research since the 1950s has been the translation of these formalisms into biological structures and processes, addressing such questions as: What is the clock and where is it located within the intracellular processes of the cell? How can a set of biochemical reactions produce a regular self-sustaining rhythm that persists under constant conditions and has a period of about 24 hours? How is this internal oscillation synchronized by zeitgebers such as light to the astronomical day? Why is the clock not altered by temperature, speeding up when the environment gets hotter and slowing down in the cold? How is the information of the near 24-hour rhythm communicated to the rest of the organism?”

“There have been hundreds of studies showing that a broad range of activities, both physical and cognitive, vary across the 24-hour day: tooth pain is lowest in the morning; proofreading is best performed in the evening; labour pains usually begin at night and most natural births occur in the early morning hours. The accuracy of short and long badminton serves is higher in the afternoon than in the morning and evening. Accuracy of first serves in tennis is better in the morning and afternoon than in the evening, although speed is higher in the evening than in the morning. Swimming velocity over 50 metres is higher in the evening than in the morning and afternoon. […] The majority of studies report that performance increases from morning to afternoon or evening. […] Typical ‘optimal’ times of day for physical or cognitive activity are gathered routinely from population studies […]. However, there is considerable individual variation. Peak performance will depend upon age, chronotype, time zone, and for behavioural tasks how many hours the participant has been awake when conducting the task, and even the nature of the task itself. As a general rule, the circadian modulation of cognitive functioning results in an improved performance over the day for younger adults, while in older subjects it deteriorates. […] On average the circadian rhythms of an individual in their late teens will be delayed by around two hours compared with an individual in their fifties. As a result the average teenager experiences considerable social jet lag, and asking a teenager to get up at 07.00 in the morning is the equivalent of asking a 50-year-old to get up at 05.00 in the morning.”

“Day versus night variations in blood pressure and heart rate are among the best-known circadian rhythms of physiology. In humans, there is a 24-hour variation in blood pressure with a sharp rise before awakening […]. Many cardiovascular events, such as sudden cardiac death, myocardial infarction, and stroke, display diurnal variations with an increased incidence between 06.00 and 12.00 in the morning. Both atrial and ventricular arrhythmias appear to exhibit circadian patterning as well, with a higher frequency during the day than at night. […] Myocardial infarction (MI) is two to three times more frequent in the morning than at night. In the early morning, the increased systolic blood pressure and heart rate results in an increased energy and oxygen demand by the heart, while the vascular tone of the coronary artery rises in the morning, resulting in a decreased coronary blood flow and oxygen supply. This mismatch between supply and demand underpins the high frequency of onset of MI. Plaque blockages are more likely to occur in the morning as platelet surface activation markers have a circadian pattern producing a peak of thrombus formation and platelet aggregation. The resulting hypercoagulability partially underlies the morning onset of MI.”

“A critical area where time of day matters to the individual is the optimum time to take medication, a branch of medicine that has been termed ‘chronotherapy’. Statins are a family of cholesterol-lowering drugs which inhibit HMGCR-reductase […] HMGCR is under circadian control and is highest at night. Hence those statins with a short half-life, such as simvastatin and lovastatin, are most effective when taken before bedtime. In another clinical domain entirely, recent studies have shown that anti-flu vaccinations given in the morning provoke a stronger immune response than those given in the afternoon. The idea of using chronotherapy to improve the efficacy of anti-cancer drugs has been around for the best part of 30 years. […] In experimental models more than thirty anti-cancer drugs have been found to vary in toxicity and efficacy by as much as 50 per cent as a function of time of administration. Although Lévi and others have shown the advantages to treating individual patients by different timing regimes, few hospitals have taken it up. One reason is that the best time to apply many of these treatments is late in the day or during the night, precisely when most hospitals lack the infrastructure and personnel to deliver such treatments.”

“Flying across multiple time zones and shift work has significant economic benefits, but the costs in terms of ill health are only now becoming clear. Sleep and circadian rhythm disruption (SCRD) is almost always associated with poor health. […] The impact of jet lag has long been known by elite athletes […] even when superbly fit individuals fly across time zones there is a very prolonged disturbance of circadian-driven rhythmic physiology. […] Horses also suffer from jet lag. […] Even bees can get jet lag. […] The misalignments that occur as a result of the occasional transmeridian flight are transient. Shift working represents a chronic misalignment. […] Nurses are one of the best-studied groups of night shift workers. Years of shift work in these individuals has been associated with a broad range of health problems including type II diabetes, gastrointestinal disorders, and even breast and colorectal cancers. Cancer risk increases with the number of years of shift work, the frequency of rotating work schedules, and the number of hours per week working at night [For people who are interested to know more about this, I previously covered a text devoted exclusively to these topics here and here.]. The correlations are so strong that shift work is now officially classified as ‘probably carcinogenic [Group 2A]’ by the World Health Organization. […] the partners and families of night shift workers need to be aware that mood swings, loss of empathy, and irritability are common features of working at night.”

“There are some seventy sleep disorders recognized by the medical community, of which four have been labelled as ‘circadian rhythm sleep disorders’ […] (1) Advanced sleep phase disorder (ASPD) […] is characterized by difficulty staying awake in the evening and difficulty staying asleep in the morning. Typically individuals go to bed and rise about three or more hours earlier than the societal norm. […] (2) Delayed sleep phase disorder (DSPD) is a far more frequent condition and is characterized by a 3-hour delay or more in sleep onset and offset and is a sleep pattern often found in some adolescents and young adults. […] ASPD and DSPD can be considered as pathological extremes of morning or evening preferences […] (3) Freerunning or non-24-hour sleep/wake rhythms occur in blind individuals who have either had their eyes completely removed or who have no neural connection from the retina to the brain. These people are not only visually blind but are also circadian blind. Because they have no means of detecting the synchronizing light signals they cannot reset their circadian rhythms, which freerun with a period of about 24 hours and 10 minutes. So, after six days, internal time is on average 1 hour behind environmental time. (4) Irregular sleep timing has been observed in individuals who lack a circadian clock as a result of a tumour in their anterior hypothalamus […]. Irregular sleep timing is [also] commonly found in older people suffering from dementia. It is an extremely important condition because one of the major factors in caring for those with dementia is the exhaustion of the carers which is often a consequence of the poor sleep patterns of those for whom they are caring. Various protocols have been attempted in nursing homes using increased light in the day areas and darkness in the bedrooms to try and consolidate sleep. Such approaches have been very successful in some individuals […] Although insomnia is the commonly used term to describe sleep disruption, technically insomnia is not a ‘circadian rhythm sleep disorder’ but rather a general term used to describe irregular or disrupted sleep. […] Insomnia is described as a ‘psychophysiological’ condition, in which mental and behavioural factors play predisposing, precipitating, and perpetuating roles. The factors include anxiety about sleep, maladaptive sleep habits, and the possibility of an underlying vulnerability in the sleep-regulating mechanism. […] Even normal ‘healthy ageing’ is associated with both circadian rhythm sleep disorders and insomnia. Both the generation and regulation of circadian rhythms have been shown to become less robust with age, with blunted amplitudes and abnormal phasing of key physiological processes such as core body temperature, metabolic processes, and hormone release. Part of the explanation may relate to a reduced light signal to the clock […]. In the elderly, the photoreceptors of the eye are often exposed to less light because of the development of cataracts and other age-related eye disease. Both these factors have been correlated with increased SCRD.”

“Circadian rhythm research has mushroomed in the past twenty years, and has provided a much greater understanding of the impact of both imposed and illness-related SCRD. We now appreciate that our increasingly 24/7 society and social disregard for biological time is having a major impact upon our health. Understanding has also been gained about the relationship between SCRD and a spectrum of different illnesses. SCRD in illness is not simply the inconvenience of being unable to sleep at an appropriate time but is an agent that exacerbates or causes serious health problems.”

Links:

Circadian rhythm.
Acrophase.
Phase (waves). Phase angle.
Jean-Jacques d’Ortous de Mairan.
Heliotropism.
Kymograph.
John Harrison.
Munich Chronotype Questionnaire.
Chronotype.
Seasonal affective disorder. Light therapy.
Parkinson’s disease. Multiple sclerosis.
Melatonin.

August 25, 2018 Posted by | Biology, Books, Cancer/oncology, Cardiology, Medicine | Leave a comment

Developmental Biology (II)

Below I have included some quotes from the middle chapters of the book and some links related to the topic coverage. As I already pointed out earlier, this is an excellent book on these topics.

Germ cells have three key functions: the preservation of the genetic integrity of the germline; the generation of genetic diversity; and the transmission of genetic information to the next generation. In all but the simplest animals, the cells of the germline are the only cells that can give rise to a new organism. So, unlike body cells, which eventually all die, germ cells in a sense outlive the bodies that produced them. They are, therefore, very special cells […] In order that the number of chromosomes is kept constant from generation to generation, germ cells are produced by a specialized type of cell division, called meiosis, which halves the chromosome number. Unless this reduction by meiosis occurred, the number of chromosomes would double each time the egg was fertilized. Germ cells thus contain a single copy of each chromosome and are called haploid, whereas germ-cell precursor cells and the other somatic cells of the body contain two copies and are called diploid. The halving of chromosome number at meiosis means that when egg and sperm come together at fertilization, the diploid number of chromosomes is restored. […] An important property of germ cells is that they remain pluripotent—able to give rise to all the different types of cells in the body. Nevertheless, eggs and sperm in mammals have certain genes differentially switched off during germ-cell development by a process known as genomic imprinting […] Certain genes in eggs and sperm are imprinted, so that the activity of the same gene is different depending on whether it is of maternal or paternal origin. Improper imprinting can lead to developmental abnormalities in humans. At least 80 imprinted genes have been identified in mammals, and some are involved in growth control. […] A number of developmental disorders in humans are associated with imprinted genes. Infants with Prader-Willi syndrome fail to thrive and later can become extremely obese; they also show mental retardation and mental disturbances […] Angelman syndrome results in severe motor and mental retardation. Beckwith-Wiedemann syndrome is due to a generalized disruption of imprinting on a region of chromosome 7 and leads to excessive foetal overgrowth and an increased predisposition to cancer.”

“Sperm are motile cells, typically designed for activating the egg and delivering their nucleus into the egg cytoplasm. They essentially consist of a nucleus, mitochondria to provide an energy source, and a flagellum for movement. The sperm contributes virtually nothing to the organism other than its chromosomes. In mammals, sperm mitochondria are destroyed following fertilization, and so all mitochondria in the animal are of maternal origin. […] Different organisms have different ways of ensuring fertilization by only one sperm. […] Early development is similar in both male and female mammalian embryos, with sexual differences only appearing at later stages. The development of the individual as either male or female is genetically fixed at fertilization by the chromosomal content of the egg and sperm that fuse to form the fertilized egg. […] Each sperm carries either an X or Y chromosome, while the egg has an X. The genetic sex of a mammal is thus established at the moment of conception, when the sperm introduces either an X or a Y chromosome into the egg. […] In the absence of a Y chromosome, the default development of tissues is along the female pathway. […] Unlike animals, plants do not set aside germ cells in the embryo and germ cells are only specified when a flower develops. Any meristem cell can, in principle, give rise to a germ cell of either sex, and there are no sex chromosomes. The great majority of flowering plants give rise to flowers that contain both male and female sexual organs, in which meiosis occurs. The male sexual organs are the stamens; these produce pollen, which contains the male gamete nuclei corresponding to the sperm of animals. At the centre of the flower are the female sex organs, which consist of an ovary of two carpels, which contain the ovules. Each ovule contains an egg cell.”

“The character of specialized cells such as nerve, muscle, or skin is the result of a particular pattern of gene activity that determines which proteins are synthesized. There are more than 200 clearly recognizable differentiated cell types in mammals. How these particular patterns of gene activity develop is a central question in cell differentiation. Gene expression is under a complex set of controls that include the actions of transcription factors, and chemical modification of DNA. External signals play a key role in differentiation by triggering intracellular signalling pathways that affect gene expression. […] the central feature of cell differentiation is a change in gene expression, which brings about a change in the proteins in the cells. The genes expressed in a differentiated cell include not only those for a wide range of ‘housekeeping’ proteins, such as the enzymes involved in energy metabolism, but also genes encoding cell-specific proteins that characterize a fully differentiated cell: hemoglobin in red blood cells, keratin in skin epidermal cells, and muscle-specific actin and myosin protein filaments in muscle. […] several thousand different genes are active in any given cell in the embryo at any one time, though only a small number of these may be involved in specifying cell fate or differentiation. […] Cell differentiation is known to be controlled by a wide range of external signals but it is important to remember that, while these external signals are often referred to as being ‘instructive’, they are ‘selective’, in the sense that the number of developmental options open to a cell at any given time is limited. These options are set by the cell’s internal state which, in turn, reflects its developmental history. External signals cannot, for example, convert an endodermal cell into a muscle or nerve cell. Most of the molecules that act as developmentally important signals between cells during development are proteins or peptides, and their effect is usually to induce a change in gene expression. […] The same external signals can be used again and again with different effects because the cells’ histories are different. […] At least 1,000 different transcription factors are encoded in the genomes of the fly and the nematode, and as many as 3,000 in the human genome. On average, around five different transcription factors act together at a control region […] In general, it can be assumed that activation of each gene involves a unique combination of transcription factors.”

“Stem cells involve some special features in relation to differentiation. A single stem cell can divide to produce two daughter cells, one of which remains a stem cell while the other gives rise to a lineage of differentiating cells. This occurs in our skin and gut all the time and also in the production of blood cells. It also occurs in the embryo. […] Embryonic stem (ES) cells from the inner cell mass of the early mammalian embryo when the primitive streak forms, can, in culture, differentiate into a wide variety of cell types, and have potential uses in regenerative medicine. […] it is now possible to make adult body cells into stem cells, which has important implications for regenerative medicine. […] The goal of regenerative medicine is to restore the structure and function of damaged or diseased tissues. As stem cells can proliferate and differentiate into a wide range of cell types, they are strong candidates for use in cell-replacement therapy, the restoration of tissue function by the introduction of new healthy cells. […] The generation of insulin-producing pancreatic β cells from ES cells to replace those destroyed in type 1 diabetes is a prime medical target. Treatments that direct the differentiation of ES cells towards making endoderm derivatives such as pancreatic cells have been particularly difficult to find. […] The neurodegenerative Parkinson disease is another medical target. […] To generate […] stem cells of the patient’s own tissue type would be a great advantage, and the recent development of induced pluripotent stem cells (iPS cells) offers […] exciting new opportunities. […] There is [however] risk of tumour induction in patients undergoing cell-replacement therapy with ES cells or iPS cells; undifferentiated pluripotent cells introduced into the patient could cause tumours. Only stringent selection procedures that ensure no undifferentiated cells are present in the transplanted cell population will overcome this problem. And it is not yet clear how stable differentiated ES cells and iPS cells will be in the long term.”

“In general, the success rate of cloning by body-cell nuclear transfer in mammals is low, and the reasons for this are not yet well understood. […] Most cloned mammals derived from nuclear transplantation are usually abnormal in some way. The cause of failure is incomplete reprogramming of the donor nucleus to remove all the earlier modifications. A related cause of abnormality may be that the reprogrammed genes have not gone through the normal imprinting process that occurs during germ-cell development, where different genes are silenced in the male and female parents. The abnormalities in adults that do develop from cloned embryos include early death, limb deformities and hypertension in cattle, and immune impairment in mice. All these defects are thought to be due to abnormalities of gene expression that arise from the cloning process. Studies have shown that some 5% of the genes in cloned mice are not correctly expressed and that almost half of the imprinted genes are incorrectly expressed.”

“Organ development involves large numbers of genes and, because of this complexity, general principles can be quite difficult to distinguish. Nevertheless, many of the mechanisms used in organogenesis are similar to those of earlier development, and certain signals are used again and again. Pattern formation in development in a variety of organs can be specified by position information, which is specified by a gradient in some property. […] Not surprisingly, the vascular system, including blood vessels and blood cells, is among the first organ systems to develop in vertebrate embryos, so that oxygen and nutrients can be delivered to the rapidly developing tissues. The defining cell type of the vascular system is the endothelial cell, which forms the lining of the entire circulatory system, including the heart, veins, and arteries. Blood vessels are formed by endothelial cells and these vessels are then covered by connective tissue and smooth muscle cells. Arteries and veins are defined by the direction of blood flow as well as by structural and functional differences; the cells are specified as arterial or venous before they form blood vessels but they can switch identity. […] Differentiation of the vascular cells requires the growth factor VEGF (vascular endothelial growth factor) and its receptors, and VEGF stimulates their proliferation. Expression of the Vegf gene is induced by lack of oxygen and thus an active organ using up oxygen promotes its own vascularization. New blood capillaries are formed by sprouting from pre-existing blood vessels and proliferation of cells at the tip of the sprout. […] During their development, blood vessels navigate along specific paths towards their targets […]. Many solid tumours produce VEGF and other growth factors that stimulate vascular development and so promote the tumour’s growth, and blocking new vessel formation is thus a means of reducing tumour growth. […] In humans, about 1 in 100 live-born infants has some congenital heart malformation, while in utero, heart malformation leading to death of the embryo occurs in between 5 and 10% of conceptions.”

“Separation of the digits […] is due to the programmed cell death of the cells between these digits’ cartilaginous elements. The webbed feet of ducks and other waterfowl are simply the result of less cell death between the digits. […] the death of cells between the digits is essential for separating the digits. The development of the vertebrate nervous system also involves the death of large numbers of neurons.”

Links:

Budding.
Gonad.
Down Syndrome.
Fertilization. In vitro fertilisation. Preimplantation genetic diagnosis.
SRY gene.
X-inactivation. Dosage compensation.
Cellular differentiation.
MyoD.
Signal transduction. Enhancer (genetics).
Epigenetics.
Hematopoiesis. Hematopoietic stem cell transplantation. Hemoglobin. Sickle cell anemia.
Skin. Dermis. Fibroblast. Epidermis.
Skeletal muscle. Myogenesis. Myoblast.
Cloning. Dolly.
Organogenesis.
Limb development. Limb bud. Progress zone model. Apical ectodermal ridge. Polarizing region/Zone of polarizing activity. Sonic hedgehog.
Imaginal disc. Pax6. Aniridia. Neural tube.
Branching morphogenesis.
Pistil.
ABC model of flower development.

July 16, 2018 Posted by | Biology, Books, Botany, Cancer/oncology, Diabetes, Genetics, Medicine, Molecular biology, Ophthalmology | Leave a comment

100 Cases in Orthopaedics and Rheumatology (II)

Below I have added some links related to the last half of the book’s coverage, as well as some more observations from the book.

Scaphoid fracture. Watson’s test. Dorsal intercalated segment instability. (“Non-union is not uncommon as a complication after scaphoid fractures because the blood supply to this bone is poor. Smokers have a higher incidence of non-union. Occasionally, the blood supply is poor enough to lead to avascular necrosis. If non-union is not detected, subsequent arthritis in the wrist can develop.”)
Septic arthritis. (“Septic arthritis is an orthopaedic emergency. […] People with septic arthritis are typically unwell with fevers and malaise and the joint pain is severe. […] Any acutely hot or painful joint is septic arthritis until proven otherwise.”)
Rheumatoid arthritis. (“[RA is] the most common of the inflammatory arthropathies. […] early-morning stiffness and pain, combined with soft-tissue rather than bony swelling, are classic patterns for inflammatory disease. Although […] RA affects principally the small joints of the hands (and feet), it may progress to involve any synovial joint and may be complicated by extra-articular features […] family history [of the disease] is not unusual due to the presence of susceptibility genes such as HLA-DR. […] Not all patients with RA have rheumatoid factor (RF), and not all patients with RF have RA; ACPA has greater specificity for RA than rheumatoid factor. […] Medical therapy focuses on disease-modifying anti-rheumatic drugs (DMARDs) such as methotrexate, sulphasalazine, leflunomide and hydroxychloroquine which may be used individually or in combination. […] Disease activity in RA is measured by the disease activity score (DAS), which is a composite score of the clinical evidence of synovitis, the current inflammatory response and the patient’s own assessment of their health. […] Patients who have high disease activity as determined by the DAS and have either failed or failed to tolerate standard disease modifying therapy qualify for biologic therapy – monoclonal antibodies that are directed against key components of the inflammatory response. […] TNF-α blockade is highly effective in up to 70 per cent of patients, reducing both inflammation and the progressive structural damage associated with severe active disease.”)
Ankylosing spondylitis. Ankylosis. Schober’s index. Costochondritis.
Mononeuritis multiplex. (“Mononeuritis multiplex arises due to interruption of the vasa nervorum, the blood supply to peripheral nerves […] Mononeuritis multiplex is commonly caused by diabetes or vasculitis. […] Vasculitis – inflammation of blood vessels and subsequent obstruction to blood flow – can be primary (idiopathic) or secondary, in which case it is associated with an underlying condition such as rheumatoid arthritis. The vasculitides are classified according to the size of the vessel involved. […] Management of mononeuritis multiplex is based on potent immunosuppression […] and the treatment of underlying infections such as hepatitis.”)
Multiple myeloma. Bence-Jones protein. (“The combination of bone pain and elevated ESR and calcium is suggestive of multiple myeloma.”)
Osteoporosis. DEXA scan. T-score. (“Postmenopausal bone loss is the most common cause of osteoporosis, but secondary osteoporosis may occur in the context of a number of medical conditions […] Steroid-induced osteoporosis is a significant problem in medical practice. […] All patients receiving corticosteroids should have bone protection […] Pharmacological treatment in the form of calcium supplementation and biphosphonates to reduce osteoclast activity is effective but compliance is typically poor.”)
Osteomalacia. Rickets. Craniotabes.
Paget’s disease (see also this post). (“In practical terms, the main indication to treat Paget’s disease is pain […] although bone deformity or compression syndromes (or risk thereof) would also prompt therapy. The treatment of choice is a biphosphonate to diminish osteoclast activity”).
Stress fracture. Female athlete triad. (“Stress fractures are overuse injuries and occur when periosteal resorption exceeds bone formation. They are commonly seen in two main patient groups: soldiers may suffer so-called march fractures in the metatarsals, while athletes may develop them in different sites according to their sporting activity. Although the knee is a common site in runners due to excess mechanical loading, stress fractures may also result in non-weight-bearing sites due to repetitive and excessive traction […]. The classic symptom […] is of pain that occurs throughout running and crucially persists with rest; this is in contrast to shin splints, a traction injury to the tibial periosteum in which the pain diminishes somewhat with continued activity […] The crucial feature of rehabilitation is a graded return to sport to prevent progression or recurrence.”)
Psoriatic arthritis. (“Arthropathy and rash is a common combination in rheumatology […] Psoriatic arthritis is a common inflammatory arthropathy that affects up to 15 per cent of those with psoriasis. […] Nail disease is very helpful in differentiating psoriatic arthritis from other forms of inflammatory arthropathy.”)
Ehlers–Danlos syndromes. Marfan syndrome. Beighton (hypermobility) score.
Carpal tunnel syndrome. (“Carpal tunnel syndrome is the most common entrapment neuropathy […] The classic symptoms are of tingling in the sensory distribution of the median nerve (i.e. the lateral three and a half digits); loss of thumb abduction is a late feature. Symptoms are often worse at night (when the hand might be quite painful) and in certain postures […] The majority of cases are idiopathic, but pregnancy and rheumatoid arthritis are very common precipitating causes […] The majority of patients will respond well to conservative management […] If these measures fail, corticosteroid injection into the carpal tunnel can be very effective in up to 80 per cent of patients. Surgical decompression should be reserved for those with persistent disabling symptoms or motor loss.”)
Mixed connective tissue disease.
Crystal arthropathy. Tophus. Uric acid nephropathyChondrocalcinosis. (“In any patient presenting with an acutely painful and swollen joint, the most important diagnoses to consider are septic arthritis and crystal arthropathy. Crystal arthropathy such as gout is more common than septic arthritis […] Gout may be precipitated by diuretics, renal impairment and aspirin use”).
Familial Mediterranean fever. Amyloidosis.
Systemic lupus erythematosus (see also this). Jaccoud arthropathy. Lupus nephritis. (“Renal disease is the most feared complication of SLE.”)
Scleroderma. Raynaud’s phenomenon. (“Scleroderma is an uncommon disorder characterized by thickening of the skin and, to a greater or lesser degree, fibrosis of internal organs.”)
Henoch-Schönlein purpura. Cryoglobulinemia. (“Purpura are the result of a spontaneous extravasation of blood from the capillaries into the skin. If small they are known as petechiae, when they are large they are termed ecchymoses. There is an extensive differential diagnosis for purpura […] The combination of palpable purpura (distributed particularly over the buttocks and extensor surfaces of legs), abdominal pain, arthritis and renal disease is a classic presentation of Henoch–Schönlein purpura (HSP). HSP is a distinct and frequently self-limiting small-vessel vasculitis that can affect any age; but the majority of cases present in children aged 2–10 years, in whom the prognosis is more benign than the adult form, often remitting entirely within 3–4 months. The abdominal pain may mimic a surgical abdomen and can presage intussusception, haemorrhage or perforation. The arthritis, in contrast, is relatively mild and tends to affect the knees and ankles.”)
Rheumatic fever.
Erythema nodosum. (“Mild idiopathic erythema nodosum […] needs no specific treatment”).
Rheumatoid lung disease. Bronchiolitis obliterans. Methotrexate-induced pneumonitis. Hamman–Rich syndrome.
Antiphospholipid syndrome. Sapporo criteria. (“Antiphospholipid syndrome is a hypercoagulable state characterized by recurrent arteriovenous thrombosis and/or pregnancy morbidity in the presence of either a lupus anticoagulant or anticardiolipin antibody (both phospholipid-related proteins). […] The most common arteriovenous thrombotic events in antiphospholipid syndrome are deep venous thrombosis and pulmonary embolus […], but any part of the circulation may be involved, with arterial events such as myocardial infarction and stroke carrying a high mortality rate. Poor placental circulation is thought to be responsible for the high pregnancy morbidity, with recurrent first- and second-trimester loss and a higher rate of pre-eclampsia being typical clinical features.”)
Still’s disease. (“Consider inflammatory disease in cases of pyrexia of unknown origin.”)
Polymyalgia rheumatica. Giant cell arteritis. (“[P]olymyalgia rheumatica (PMR) [is] a systemic inflammatory syndrome affecting the elderly that is characterized by bilateral pain and stiffness in the shoulders and hip girdles. The stiffness can be profound and limits mobility although true muscle weakness is not a feature. […] The affected areas are diffusely tender, with movements limited by pain. […] care must be taken not to attribute joint inflammation to PMR until other diagnoses have been excluded; for example, a significant minority of RA patients may present with a polymyalgic onset. […] The treatment for PMR is low-dose corticosteroids. […] Many physicians would consider a dramatic response to low-dose prednisolone as almost diagnostic for PMR, so if a patients symptoms do not improve rapidly it is wise to re-evaluate the original diagnosis.”)
Relapsing polychondritis. (“Relapsing polychondritis is characterized histologically by inflammatory infiltration and later fibrosis of cartilage. Any cartilage, in any location, is at risk. […] Treatment of relapsing polychondritis is with corticosteroids […] Surgical reconstruction of collapsed structures is not an option as the deformity tends to continue postoperatively.”)
Dermatomyositis. Gottron’s Papules.
Enteropathic arthritis. (“A seronegative arthritis may develop in up to 15 per cent of patients with any form of inflammatory bowel disease, including ulcerative colitis (UC), Crohn’s disease or microscopic and collagenous colitis. The most common clinical presentations are a peripheral arthritis […] and spondyloarthritis.”)
Reflex sympathetic dystrophy.
Whipple’s disease. (“Although rare, consider Whipple’s disease in any patient presenting with malabsorption, weight loss and arthritis.”)
Wegener’s granulomatosis. (“Small-vessel vasculitis may cause a pulmonary-renal syndrome. […] The classic triad of Weneger’s granulomatosis is the presence of upper and lower respiratory tract disease and renal impairment.”)
Reactive arthritis. Reiter’s syndrome. (“Consider reactive arthritis in any patient presenting with a monoarthropathy. […] Reactive arthritis is generally benign, with up to 80 per cent making a full recovery.”)
Sarcoidosis. Löfgren syndrome.
Polyarteritis nodosa. (“Consider mesenteric ischaemia in any patient presenting with a systemic illness and postprandial abdominal pain.”)
Sjögren syndrome. Schirmer’s test.
Behçet syndrome.
Lyme disease. Erythema chronicum migrans. (“The combination of rash leading to arthralgia and cranial neuropathy is a classic presentation of Lyme disease.”)
Takayasu arteritis. (“Takayasu’s arteritis is an occlusive vasculitis leading to stenoses of the aorta and its principal branches. The symptoms and signs of the disease depend on the distribution of the affected vessel but upper limbs are generally affected more commonly than the iliac tributaries. […] the disease is a chronic relapsing and remitting condition […] The mainstay of treatment is high-dose corticosteroids plus a steroid-sparing agent such as methotrexate. […] Cyclophosphamide is reserved for those patients who do not achieve remission with standard therapy. Surgical intervention such as bypass or angioplasty may improve ischaemic symptoms once the inflammation is under control.”)
Lymphoma.
Haemarthrosis. (“Consider synovial tumours in a patient with unexplained haemarthrosis.”)
Juvenile idiopathic arthritis.
Drug-induced lupus erythematosus. (“Drug-induced lupus (DIL) generates a different spectrum of clinical manifestations from idiopathic disease. DIL is less severe than idiopathic SLE, and nephritis or central nervous system involvement is very rare. […] The most common drugs responsible for a lupus-like syndrome are procainamide, hydralazine, quinidine, isoniazid, methyldopa, chlorpromazine and minocycline. […] Treatment involves stopping the offending medication and the symptoms will gradually resolve.”)
Churg–Strauss syndrome.

July 8, 2018 Posted by | Books, Cancer/oncology, Cardiology, Gastroenterology, Immunology, Medicine, Nephrology, Neurology, Ophthalmology, Pharmacology | Leave a comment

A few diabetes papers of interest

i. Clinical Inertia in Type 2 Diabetes Management: Evidence From a Large, Real-World Data Set.

Despite clinical practice guidelines that recommend frequent monitoring of HbA1c (every 3 months) and aggressive escalation of antihyperglycemic therapies until glycemic targets are reached (1,2), the intensification of therapy in patients with uncontrolled type 2 diabetes (T2D) is often inappropriately delayed. The failure of clinicians to intensify therapy when clinically indicated has been termed “clinical inertia.” A recently published systematic review found that the median time to treatment intensification after an HbA1c measurement above target was longer than 1 year (range 0.3 to >7.2 years) (3). We have previously reported a rather high rate of clinical inertia in patients uncontrolled on metformin monotherapy (4). Treatment was not intensified early (within 6 months of metformin monotherapy failure) in 38%, 31%, and 28% of patients when poor glycemic control was defined as an HbA1c >7% (>53 mmol/mol), >7.5% (>58 mmol/mol), and >8% (>64 mmol/mol), respectively.

Using the electronic health record system at Cleveland Clinic (2005–2016), we identified a cohort of 7,389 patients with T2D who had an HbA1c value ≥7% (≥53 mmol/mol) (“index HbA1c”) despite having been on a stable regimen of two oral antihyperglycemic drugs (OADs) for at least 6 months prior to the index HbA1c. This HbA1c threshold would generally be expected to trigger treatment intensification based on current guidelines. Patient records were reviewed for the 6-month period following the index HbA1c, and changes in diabetes therapy were evaluated for evidence of “intensification” […] almost two-thirds of patients had no evidence of intensification in their antihyperglycemic therapy during the 6 months following the index HbA1c ≥7% (≥53 mmol/mol), suggestive of poor glycemic control. Most alarming was the finding that even among patients in the highest index HbA1c category (≥9% [≥75 mmol/mol]), therapy was not intensified in 44% of patients, and slightly more than half (53%) of those with an HbA1c between 8 and 8.9% (64 and 74 mmol/mol) did not have their therapy intensified.”

“Unfortunately, these real-world findings confirm a high prevalence of clinical inertia with regard to T2D management. The unavoidable conclusion from these data […] is that physicians are not responding quickly enough to evidence of poor glycemic control in a high percentage of patients, even in those with HbA1c levels far exceeding typical treatment targets.

ii. Gestational Diabetes Mellitus and Diet: A Systematic Review and Meta-analysis of Randomized Controlled Trials Examining the Impact of Modified Dietary Interventions on Maternal Glucose Control and Neonatal Birth Weight.

“Medical nutrition therapy is a mainstay of gestational diabetes mellitus (GDM) treatment. However, data are limited regarding the optimal diet for achieving euglycemia and improved perinatal outcomes. This study aims to investigate whether modified dietary interventions are associated with improved glycemia and/or improved birth weight outcomes in women with GDM when compared with control dietary interventions. […]

From 2,269 records screened, 18 randomized controlled trials involving 1,151 women were included. Pooled analysis demonstrated that for modified dietary interventions when compared with control subjects, there was a larger decrease in fasting and postprandial glucose (−4.07 mg/dL [95% CI −7.58, −0.57]; P = 0.02 and −7.78 mg/dL [95% CI −12.27, −3.29]; P = 0.0007, respectively) and a lower need for medication treatment (relative risk 0.65 [95% CI 0.47, 0.88]; P = 0.006). For neonatal outcomes, analysis of 16 randomized controlled trials including 841 participants showed that modified dietary interventions were associated with lower infant birth weight (−170.62 g [95% CI −333.64, −7.60]; P = 0.04) and less macrosomia (relative risk 0.49 [95% CI 0.27, 0.88]; P = 0.02). The quality of evidence for these outcomes was low to very low. Baseline differences between groups in postprandial glucose may have influenced glucose-related outcomes. […] we were unable to resolve queries regarding potential concerns for sources of bias because of lack of author response to our queries. We have addressed this by excluding these studies in the sensitivity analysis. […] after removal of the studies with the most substantial methodological concerns in the sensitivity analysis, differences in the change in fasting plasma glucose were no longer significant. Although differences in the change in postprandial glucose and birth weight persisted, they were attenuated.”

“This review highlights limitations of the current literature examining dietary interventions in GDM. Most studies are too small to demonstrate significant differences in our primary outcomes. Seven studies had fewer than 50 participants and only two had more than 100 participants (n = 125 and 150). The short duration of many dietary interventions and the late gestational age at which they were started (38) may also have limited their impact on glycemic and birth weight outcomes. Furthermore, we cannot conclude if the improvements in maternal glycemia and infant birth weight are due to reduced energy intake, improved nutrient quality, or specific changes in types of carbohydrate and/or protein. […] These data suggest that dietary interventions modified above and beyond usual dietary advice for GDM have the potential to offer better maternal glycemic control and infant birth weight outcomes. However, the quality of evidence was judged as low to very low due to the limitations in the design of included studies, the inconsistency between their results, and the imprecision in their effect estimates.”

iii. Lifetime Prevalence and Prognosis of Prediabetes Without Progression to Diabetes.

Impaired fasting glucose, also termed prediabetes, is increasingly prevalent and is associated with adverse cardiovascular risk (1). The cardiovascular risks attributed to prediabetes may be driven primarily by the conversion from prediabetes to overt diabetes (2). Given limited data on outcomes among nonconverters in the community, the extent to which some individuals with prediabetes never go on to develop diabetes and yet still experience adverse cardiovascular risk remains unclear. We therefore investigated the frequency of cardiovascular versus noncardiovascular deaths in people who developed early- and late-onset prediabetes without ever progressing to diabetes.”

“We used data from the Framingham Heart Study collected on the Offspring Cohort participants aged 18–77 years at the time of initial fasting plasma glucose (FPG) assessment (1983–1987) who had serial FPG testing over subsequent examinations with continuous surveillance for outcomes including cause-specific mortality (3). As applied in prior epidemiological investigations (4), we used a case-control design focusing on the cause-specific outcome of cardiovascular death to minimize the competing risk issues that would be encountered in time-to-event analyses. To focus on outcomes associated with a given chronic glycemic state maintained over the entire lifetime, we restricted our analyses to only those participants for whom data were available over the life course and until death. […] We excluded individuals with unknown age of onset of glycemic impairment (i.e., age ≥50 years with prediabetes or diabetes at enrollment). […] We analyzed cause-specific mortality, allowing for relating time-varying exposures with lifetime risk for an event (4). We related glycemic phenotypes to cardiovascular versus noncardiovascular cause of death using a case-control design, where cases were defined as individuals who died of cardiovascular disease (death from stroke, heart failure, or other vascular event) or coronary heart disease (CHD) and controls were those who died of other causes.”

“The mean age of participants at enrollment was 42 ± 7 years (43% women). The mean age at death was 73 ± 10 years. […] In our study, approximately half of the individuals presented with glycemic impairment in their lifetime, of whom two-thirds developed prediabetes but never diabetes. In our study, these individuals had lower cardiovascular-related mortality compared with those who later developed diabetes, even if the prediabetes onset was early in life. However, individuals with early-onset prediabetes, despite lifelong avoidance of overt diabetes, had greater propensity for death due to cardiovascular or coronary versus noncardiovascular disease compared with those who maintained lifelong normal glucose status. […] Prediabetes is a heterogeneous entity. Whereas some forms of prediabetes are precursors to diabetes, other types of prediabetes never progress to diabetes but still confer increased propensity for death from a cardiovascular cause.”

iv. Learning From Past Failures of Oral Insulin Trials.

Very recently one of the largest type 1 diabetes prevention trials using daily administration of oral insulin or placebo was completed. After 9 years of study enrollment and follow-up, the randomized controlled trial failed to delay the onset of clinical type 1 diabetes, which was the primary end point. The unfortunate outcome follows the previous large-scale trial, the Diabetes Prevention Trial–Type 1 (DPT-1), which again failed to delay diabetes onset with oral insulin or low-dose subcutaneous insulin injections in a randomized controlled trial with relatives at risk for type 1 diabetes. These sobering results raise the important question, “Where does the type 1 diabetes prevention field move next?” In this Perspective, we advocate for a paradigm shift in which smaller mechanistic trials are conducted to define immune mechanisms and potentially identify treatment responders. […] Mechanistic trials will allow for better trial design and patient selection based upon molecular markers prior to large randomized controlled trials, moving toward a personalized medicine approach for the prevention of type 1 diabetes.

“Before a disease can be prevented, it must be predicted. The ability to assess risk for developing type 1 diabetes (T1D) has been well documented over the last two decades (1). Using genetic markers, human leukocyte antigen (HLA) DQ and DR typing (2), islet autoantibodies (1), and assessments of glucose tolerance (intravenous or oral glucose tolerance tests) has led to accurate prediction models for T1D development (3). Prospective birth cohort studies Diabetes Autoimmunity Study in the Young (DAISY) in Colorado (4), Type 1 Diabetes Prediction and Prevention (DIPP) study in Finland (5), and BABYDIAB studies in Germany have followed genetically at-risk children for the development of islet autoimmunity and T1D disease onset (6). These studies have been instrumental in understanding the natural history of T1D and making T1D a predictable disease with the measurement of antibodies in the peripheral blood directed against insulin and proteins within β-cells […]. Having two or more islet autoantibodies confers an ∼85% risk of developing T1D within 15 years and nearly 100% over time (7). […] T1D can be predicted by measuring islet autoantibodies, and thousands of individuals including young children are being identified through screening efforts, necessitating the need for treatments to delay and prevent disease onset.”

“Antigen-specific immunotherapies hold the promise of potentially inducing tolerance by inhibiting effector T cells and inducing regulatory T cells, which can act locally at tissue-specific sites of inflammation (12). Additionally, side effects are minimal with these therapies. As such, insulin and GAD have both been used as antigen-based approaches in T1D (13). Oral insulin has been evaluated in two large randomized double-blinded placebo-controlled trials over the last two decades. First in the Diabetes Prevention Trial–Type 1 (DPT-1) and then in the TrialNet clinical trials network […] The DPT-1 enrolled relatives at increased risk for T1D having islet autoantibodies […] After 6 years of treatment, there was no delay in T1D onset. […] The TrialNet study screened, enrolled, and followed 560 at-risk relatives over 9 years from 2007 to 2016, and results have been recently published (16). Unfortunately, this trial failed to meet the primary end point of delaying or preventing diabetes onset.”

“Many factors influence the potency and efficacy of antigen-specific therapy such as dose, frequency of dosing, route of administration, and, importantly, timing in the disease process. […] Over the last two decades, most T1D clinical trial designs have randomized participants 1:1 or 2:1, drug to placebo, in a double-blind two-arm design, especially those intervention trials in new-onset T1D (18). Primary end points have been delay in T1D onset for prevention trials or stimulated C-peptide area under the curve at 12 months with new-onset trials. These designs have served the field well and provided reliable human data for efficacy. However, there are limitations including the speed at which these trials can be completed, the number of interventions evaluated, dose optimization, and evaluation of mechanistic hypotheses. Alternative clinical trial designs, such as adaptive trial designs using Bayesian statistics, can overcome some of these issues. Adaptive designs use accumulating data from the trial to modify certain aspects of the study, such as enrollment and treatment group assignments. This “learn as we go” approach relies on biomarkers to drive decisions on planned trial modifications. […] One of the significant limitations for adaptive trial designs in the T1D field, at the present time, is the lack of validated biomarkers for short-term readouts to inform trial adaptations. However, large-scale collaborative efforts are ongoing to define biomarkers of T1D-specific immune dysfunction and β-cell stress and death (9,22).”

T1D prevention has proven much more difficult than originally thought, challenging the paradigm that T1D is a single disease. T1D is indeed a heterogeneous disease in terms of age of diagnosis, islet autoantibody profiles, and the rate of loss of residual β-cell function after clinical onset. Children have a much more rapid loss of residual insulin production (measured as C-peptide area under the curve following a mixed-meal tolerance test) after diagnosis than older adolescents and adults (23,24), indicating that childhood and adult-onset T1D are not identical. Further evidence for subtypes of T1D come from studies of human pancreata of T1D organ donors in which children (0–14 years of age) within 1 year of diagnosis had many more inflamed islets compared with older adolescents and adults aged 15–39 years old (25). Additionally, a younger age of T1D onset (<7 years) has been associated with higher numbers of CD20+ B cells within islets and fewer insulin-containing islets compared with an age of onset ≥13 years associated with fewer CD20+ islet infiltrating cells and more insulin-containing islets (26,27). This suggests a much more aggressive autoimmune process in younger children and distinct endotypes (a subtype of a condition defined by a distinct pathophysiologic mechanism), which has recently been proposed for T1D (27).”

“Safe and specific therapies capable of being used in children are needed for T1D prevention. The vast majority of drug development involves small biotechnology companies, specialty pharmaceutical firms, and large pharmaceutical companies, more so than traditional academia. A large amount of preclinical and clinical research (phase 1, 2, and 3 studies) are needed to advance a drug candidate through the development pipeline to achieve U.S. Food and Drug Administration (FDA) approval for a given disease. A recent analysis of over 4,000 drugs from 835 companies in development during 2003–2011 revealed that only 10.4% of drugs that enter clinical development at phase 1 (safety studies) advance to FDA approval (32). However, the success rate increases 50% for the lead indication of a drug, i.e., a drug specifically developed for one given disease (32). Reasons for this include strong scientific rationale and early efficacy signals such as correlating pharmacokinetic (drug levels) to pharmacodynamic (drug target effects) tests for the lead indication. Lead indications also tend to have smaller, better-defined “homogenous” patient populations than nonlead indications for the same drug. This would imply that the T1D field needs more companies developing drugs specifically for T1D, not type 2 diabetes or other autoimmune diseases with later testing to broaden a drug’s indication. […] In a similar but separate analysis, selection biomarkers were found to substantially increase the success rate of drug approvals across all phases of drug development. Using a selection biomarker as part of study inclusion criteria increased drug approval threefold from 8.4% to 25.9% when used in phase 1 trials, 28% to 46% when transitioning from a phase 2 to phase 3 efficacy trial, and 55% to 76% for a phase 3 trial to likelihood of approval (33). These striking data support the concept that enrichment of patient enrollment at the molecular level is a more successful strategy than heterogeneous enrollment in clinical intervention trials. […] Taken together, new drugs designed specifically for children at risk for T1D and a biomarker selecting patients for a treatment response may increase the likelihood for a successful prevention trial; however, experimental confirmation in clinical trials is needed.”

v. Metabolic Karma — The Atherogenic Legacy of Diabetes: The 2017 Edwin Bierman Award Lecture.

“Cardiovascular (CV) disease remains the major cause of mortality and is associated with significant morbidity in both type 1 and type 2 diabetes (14). Despite major improvements in the management of traditional risk factors, including hypertension, dyslipidemia, and glycemic control prevention, retardation and reversal of atherosclerosis, as manifested clinically by myocardial infarction, stroke, and peripheral vascular disease, remain a major unmet need in the population with diabetes. For example, in the Steno-2 study and in its most recent report of the follow-up phase, at least a decade after cessation of the active treatment phase, there remained a high risk of death, primarily from CV disease despite aggressive control of the traditional risk factors, in this originally microalbuminuric population with type 2 diabetes (5,6). In a meta-analysis of major CV trials where aggressive glucose lowering was instituted […] the beneficial effect of intensive glycemic control on CV disease was modest, at best (7). […] recent trials with two sodium–glucose cotransporter 2 inhibitors, empagliflozin and canagliflozin (11,12), and two long-acting glucagon-like peptide 1 agonists, liraglutide and semaglutide (13,14), have reported CV benefits that have led in some of these trials to a decrease in CV and all-cause mortality. However, even with these recent positive CV outcomes, CV disease remains the major burden in the population with diabetes (15).”

“This unmet need of residual CV disease in the population with diabetes remains unexplained but may occur as a result of a range of nontraditional risk factors, including low-grade inflammation and enhanced thrombogenicity as a result of the diabetic milieu (16). Furthermore, a range of injurious pathways as a result of chronic hyperglycemia previously studied in vitro in endothelial cells (17) or in models of microvascular complications may also be relevant and are a focus of this review […] [One] major factor that is likely to promote atherosclerosis in the diabetes setting is increased oxidative stress. There is not only increased generation of ROS from diverse sources but also reduced antioxidant defense in diabetes (40). […] vascular ROS accumulation is closely linked to atherosclerosis and vascular inflammation provide the impetus to consider specific antioxidant strategies as a novel therapeutic approach to decrease CV disease, particularly in the setting of diabetes.”

“One of the most important findings from numerous trials performed in subjects with type 1 and type 2 diabetes has been the identification that previous episodes of hyperglycemia can have a long-standing impact on the subsequent development of CV disease. This phenomenon known as “metabolic memory” or the “legacy effect” has been reported in numerous trials […] The underlying explanation at a molecular and/or cellular level for this phenomenon remains to be determined. Our group, as well as others, has postulated that epigenetic mechanisms may participate in conferring metabolic memory (5153). In in vitro studies initially performed in aortic endothelial cells, transient incubation of these cells in high glucose followed by subsequent return of these cells to a normoglycemic environment was associated with increased gene expression of the p65 subunit of NF-κB, NF-κB activation, and expression of NF-κB–dependent proteins, including MCP-1 and VCAM-1 (54).

In further defining a potential epigenetic mechanism that could explain the glucose-induced upregulation of genes implicated in vascular inflammation, a specific histone methylation mark was identified in the promoter region of the p65 gene (54). This histone 3 lysine 4 monomethylation (H3K4m1) occurred as a result of mobilization of the histone methyl transferase, Set7. Furthermore, knockdown of Set7 attenuated glucose-induced p65 upregulation and prevented the persistent upregulation of this gene despite these endothelial cells returning to a normoglycemic milieu (55). These findings, confirmed in animal models exposed to transient hyperglycemia (54), provide the rationale to consider Set7 as an appropriate target for end-organ protective therapies in diabetes. Although specific Set7 inhibitors are currently unavailable for clinical development, the current interest in drugs that block various enzymes, such as Set7, that influence histone methylation in diseases, such as cancer (56), could lead to agents that warrant testing in diabetes. Studies addressing other sites of histone methylation as well as other epigenetic pathways including DNA methylation and acetylation have been reported or are currently in progress (55,57,58), particularly in the context of diabetes complications. […] As in vitro and preclinical studies increase our knowledge and understanding of the pathogenesis of diabetes complications, it is likely that we will identify new molecular targets leading to better treatments to reduce the burden of macrovascular disease. Nevertheless, these new treatments will need to be considered in the context of improved management of traditional risk factors.”

vi. Perceived risk of diabetes seriously underestimates actual diabetes risk: The KORA FF4 study.

“According to the International Diabetes Federation (IDF), almost half of the people with diabetes worldwide are unaware of having the disease, and even in high-income countries, about one in three diabetes cases is not diagnosed [1,2]. In the USA, 28% of diabetes cases are undiagnosed [3]. In DEGS1, a recent population-based German survey, 22% of persons with HbA1c ≥ 6.5% were unaware of their disease [4]. Persons with undiagnosed diabetes mellitus (UDM) have a more than twofold risk of mortality compared to persons with normal glucose tolerance (NGT) [5,6]; many of them also have undiagnosed diabetes complications like retinopathy and chronic kidney disease [7,8]. […] early detection of diabetes and prediabetes is beneficial for patients, but may be delayed by patients´ being overly optimistic about their own health. Therefore, it is important to address how persons with UDM or prediabetes perceive their diabetes risk.”

“The proportion of persons who perceived their risk of having UDM at the time of the interview as “negligible”, “very low” or “low” was 87.1% (95% CI: 85.0–89.0) in NGT [normal glucose tolerance individuals], 83.9% (81.2–86.4) in prediabetes, and 74.2% (64.5–82.0) in UDM […]. The proportion of persons who perceived themselves at risk of developing diabetes in the following years ranged from 14.6% (95% CI: 12.6–16.8) in NGT to 20.6% (17.9–23.6) in prediabetes to 28.7% (20.5–38.6) in UDM […] In univariate regression models, perceiving oneself at risk of developing diabetes was associated with younger age, female sex, higher school education, obesity, self-rated poor general health, and parental diabetes […] the proportion of better educated younger persons (age ≤ 60 years) with prediabetes, who perceived themselves at risk of developing diabetes was 35%, whereas this figure was only 13% in less well educated older persons (age > 60 years).”

The present study shows that three out of four persons with UDM [undiagnosed diabetes mellitus] believed that the probability of having undetected diabetes was low or very low. In persons with prediabetes, more than 70% believed that they were not at risk of developing diabetes in the next years. People with prediabetes were more inclined to perceive themselves at risk of diabetes if their self-rated general health was poor, their mother or father had diabetes, they were obese, they were female, their educational level was high, and if they were younger. […] People with undiagnosed diabetes or prediabetes considerably underestimate their probability of having or developing diabetes. […] perceived diabetes risk was lower in men, lower educated and older persons. […] Our results showed that people with low and intermediate education strongly underestimate their risk of diabetes and may qualify as target groups for detection of UDM and prediabetes.”

“The present results were in line with results from the Dutch Hoorn Study [18,19]. Adriaanse et al. reported that among persons with UDM, only 28.3% perceived their likeliness of having diabetes to be at least 10% [18], and among persons with high risk of diabetes (predicted from a symptom risk questionnaire), the median perceived likeliness of having diabetes was 10.8% [19]. Again, perceived risk did not fully reflect the actual risk profiles. For BMI, there was barely any association with perceived risk of diabetes in the Dutch study [19].”

July 2, 2018 Posted by | Cardiology, Diabetes, Epidemiology, Genetics, Immunology, Medicine, Molecular biology, Pharmacology, Studies | Leave a comment

100 Cases in Orthopaedics and Rheumatology (I)

This book was decent, but it’s not as good as some of the books I’ve previously read in this series; in some of the books in the series the average length of the answer section is 2-3 pages, which is a format I quite like, whereas in this book the average is more like 1-2 pages – which is a bit too short in my opinion.

Below I have added some links related to the first half of the book’s coverage and a few observations from the book.

Acute haematogenous osteomyelitis. (“There are two principal types of acute osteomyelitis: •haematogenous osteomyelitis •direct or contiguous inoculation osteomyelitis. Acute haematogenous osteomyelitis is characterized by an acute infection of the bone caused by the seeding of the bacteria within the bone from a remote source. This condition occurs primarily in children. […] In general, osteomyelitis has a bimodal age distribution. Acute haematogenous osteomyelitis is primarily a disease in children. Direct trauma and contiguous focus osteomyelitis are more common among adults and adolescents than in children. Spinal osteomyelitis is more common in individuals older than 45 years.”)
Haemophilic arthropathy. (“Haemophilic arthropathy is a condition associated with clotting disorder leading to recurrent bleeding in the joints. Over time this can lead to joint destruction.”)
Avascular necrosis of the femoral head. Trendelenburg’s sign. Gaucher’s disease. Legg–Calvé–Perthes disease. Ficat and Arlet classification of avascular necrosis of femoral head.
Osteosarcoma. Codman triangle. Enneking Classification. (“A firm, irregular mass fixed to underlying structures is more suspicious of a malignant lesion.”)
Ewing’s sarcomaHaversian canal. (“This condition [ES] typically occurs in young patients and presents with pain and fever. [It] is the second most common primary malignant bone tumour (the first being osteosarcoma). The tumour is more common in males and affects children and young adults. The majority develop this between the ages of 10 and 20 years. […] The earliest symptom is pain, which is initially intermittent but becomes intense. Rarely, a patient may present with a pathological fracture. Eighty-five per cent of patients have chromosomal translocations associated with the 11/22 chromosome. Ewing’s sarcoma is potentially the most aggressive form of the primary bone tumours. […] Patients are usually assigned to one of two groups, the tumour being classified as either localized or metastatic disease. Tumours in the pelvis typically present late and are therefore larger with a poorer prognosis. Treatment comprises chemotherapy, surgical resection and/or radiotherapy. […] With localized disease, wide surgical excision of the tumour is preferred over radiotherapy if the involved bone is expendable (e.g. fibular, rib), or if radiotherapy would damage the growth plate. […] Non-metastatic disease survival rates are 55–70 per cent, compared to 22–33 per cent for metastatic disease. Patients require careful follow-up owing to the risk of developing osteosarcoma following radiotherapy, particularly in children in whom it can occur in up to 20 per cent of cases.”
Clavicle Fracture. Floating Shoulder.
Proximal humerus fractures.
Lateral condyle fracture of the humerus. Salter-Harris fracture. (“Humeral condyle fractures occur most commonly between 6 and 10 years of age. […] fractures often appear subtle on radiographs. […] Operative management is essential for all displaced fractures“).
Distal radius fracture. (“Colles’ fractures account for over 90 per cent of distal radius fractures. Any injury to the median nerve can produce paraesthesia in the thumb, index finger, and middle and radial border of the ring finger […]. There is a bimodal age distribution of fractures to the distal radius with two peaks occurring. The first peak occurs in people aged 18–25 years, and a second peak in older people (>65 years). High-energy injuries are more common in the younger group and low-energy injuries in the older group. Osteoporosis may play a role in the occurrence of this later fracture. In the group of patients between 60 and 69 years, women far outnumber men. […] Assessment with plain radiographs is all that is needed for most fractures. […] The majority of distal radius fractures can be treated conservatively.”)
Gamekeeper’s thumb. Stener lesion.
Subtrochanteric Hip Fracture.
Supracondylar Femur Fractures. (“There is a bimodal distribution of fractures based on age and gender. Most high-energy distal femur fractures occur in males aged between 15 and 50 years, while most low-energy fractures occur in osteoporotic women aged 50 or above. The most common high-energy mechanism of injury is a road traffic accident (RTA), and the most common low-energy mechanism is a fall. […] In general, […] non-operative treatment does not work well for displaced fractures. […] Operative intervention is also indicated in the presence of open fractures and injuries associated with vascular injury. […] Total knee replacement is effective in elderly patients with articular fractures and significant osteoporosis, or pre-existing arthritis that is not amenable to open reduction and internal fixation. Low-demand elderly patients with non- or minimally displaced fractures can be managed conservatively. […] In general, this fracture can take a minimum of 3-4 months to unite.”)
Supracondylar humerus fracture. Gartland Classification of Supracondylar Humerus Fractures. (“Prior to the treatment of supracondylar fractures, it is essential to identify the type. Examination of the degree of swelling and deformity as well as a neurological and vascular status assessment of the forearm is essential. A vascular injury may present with signs of an acute compartment syndrome with pain, paraesthesia, pallor, and pulseless and tight forearm. Injury to the brachial artery may present with loss of the distal pulse. However, in the presence of a weak distal pulse, major vessel injury may still be present owing to the collateral circulation. […] Vascular insult can lead to Volkmann ischaemic contracture of the forearm. […] Malunion of the fracture may lead to cubitus varus deformity.”)
Femoral Shaft Fractures.
Femoral Neck Fractures. Garden’s classification. (“Hip fractures are the most common reason for admission to an orthopaedic ward, usually caused by a fall by an elderly person. The average age of a person with a hip fracture is 77 years. Mortality is high: about 10 per cent of people with a hip fracture die within 1 month, and about one-third within 12 months. However, fewer than half of deaths are attributable to the fracture, reflecting the high prevalence of comorbidity. The mental status of the patient is also important: senility is associated with a three-fold increased risk of sepsis and dislocation of prosthetic replacement when compared with mentally alert patients. The one-year mortality rate in these patients is considerable, being reported as high as 50 per cent.”)
Tibia Shaft Fractures. (“The tibia is the most frequent site of a long-bone fracture in the body. […] Open fractures are surgical emergencies […] Most closed tibial fractures can be treated conservatively using plaster of Paris.”)
Tibial plateau fracture. Schatzker classification.
Compartment syndrome. (“This condition is an orthopaedic emergency and can be limb- and life-threatening. Compartment syndrome occurs when perfusion pressure falls below tissue pressure in a closed fascial compartment and results in microvascular compromise. At this point, blood flow through the capillaries stops. In the absence of flow, oxygen delivery stops. Hypoxic injury causes cells to release vasoactive substances (e.g. histamine, serotonin), which increase endothelial permeability. Capillaries allow continued fluid loss, which increases tissue pressure and advances injury. Nerve conduction slows, tissue pH falls due to anaerobic metabolism, surrounding tissue suffers further damage, and muscle tissue suffers necrosis, releasing myoglobin. In untreated cases the syndrome can lead to permanent functional impairment, renal failure secondary to rhabdomyolysis, and death. Patients at risk of compartment syndrome include those with high-velocity injuries, long-bone fractures, high-energy trauma, penetrating injuries such as gunshot wounds and stabbing, and crush injuries, as well as patients on anticoagulants with trauma. The patient usually complains of severe pain that is out of proportion to the injury. An assessment of the affected limb may reveal swelling which feels tense, or hard compartments. Pain on passive range of movement of fingers or toes of the affected limb is a typical feature. Late signs comprise pallor, paralysis, paraesthesia and a pulseless limb. Sensory nerves begin to lose conductive ability, followed by motor nerves. […] Fasciotomy is the definitive treatment for compartment syndrome. The purpose of fasciotomy is to achieve prompt and adequate decompression so as to restore the tissue perfusion.”)
Talus fracture. Hawkins sign. Avascular necrosis.
Calcaneal fracture. (“The most common situation leading to calcaneal fracture is a young adult who falls from a height and lands on his or her feet. […] Patients often sustain occult injuries to their lumbar or cervical spine, and the proximal femur. A thorough clinical and radiological investigation of the spine area is mandatory in patients with calcaneal fracture.”)
Idiopathic scoliosis. Adam’s forward bend test. Romberg test. Cobb angle.
Cauda equina syndrome. (“[Cauda equina syndrome] is an orthopaedic emergency. The condition is characterized by the red-flag signs comprising low back pain, unilateral or bilateral sciatica, saddle anaesthesia with sacral sparing, and bladder and bowel dysfunctions. Urinary retention is the most consistent finding. […] Urgent spinal orthopaedic or neurosurgical consulation is essential, with transfer to a unit capable of undertaking any definitive surgery considered necessary. In the long term, residual weakness, incontinence, impotence and/or sensory abnormalities are potential problems if therapy is delayed. […] The prognosis improves if a definitive cause is identified and appropriate surgical spinal decompression occurs early. Late surgical compression produces varying results and is often associated with a poorer outcome.”)
Developmental dysplasia of the hip.
OsteoarthritisArthroplasty. OsteotomyArthrodesis. (“Early-morning stiffness that gradually diminishes with activity is typical of osteoarthritis. […] Patients with hip pathology can sometimes present with knee pain without any groin or thigh symptoms. […] Osteoarthritis most commonly affects middle-aged and elderly patients. Any synovial joint can develop osteoarthritis. This condition can lead to degeneration of articular cartilage and is often associated with stiffness.”)
Prepatellar bursitis.
Baker’s cyst.
Meniscus tear. McMurray test. Apley’s test. Lachman test.
Anterior cruciate ligament injury.
Achilles tendon rupture. Thompson Test.
Congenital Talipes EquinovarusPonseti method. Pirani score. (“Club foot is bilateral in about 50 per cent of cases and occurs in approximately 1 in 800 births.”)
Charcot–Marie–Tooth disease. Pes cavus. Claw toe deformity. Pes planus.
Hallux valgus. Hallux Rigidus.
Mallet toe deformity. Condylectomy. Syme amputation. (“Mallet toes are common in diabetics with peripheral neuropathy. […] Pain and/or a callosity is often the presenting complaint. This may also lead to nail deformity on the toe. Most commonly the deformity is present in the second toe. […] Footwear modification […] should be tried first […] Surgical management of mallet toe is indicated if the deformity becomes painful.”)
Hammer Toe.
Lisfranc injury. Fleck sign. (“The Lisfranc joint, which represents the articulation between the midfoot and forefoot, is composed of the five TMT [tarsometatarsal] joints. […] A Lisfranc injury encompasses everything from a sprain to a complete disruption of normal anatomy through the TMT joints. […] Lisfranc injuries are commonly undiagnosed and carry a high risk of chronic secondary disability.”)
Charcot joint. (“Charcot arthropathy results in progressive destruction of bone and soft tissues at weight-bearing joints. In its most severe form it may cause significant disruption of the bony architecture, including joint dislocations and fractures. Charcot arthropathy can occur at any joint but most commonly affects the lower regions: the foot and ankle. Bilateral disease occurs in fewer than 10 per cent of patients. Any condition that leads to a sensory or autonomic neuropathy can cause a Charcot joint. Charcot arthropathy can occur as a complication of diabetes, syphilis, alcoholism, leprosy, meningomyleocele, spinal cord injury, syringomyelia, renal dialysis and congenital insensitivity to pain. In the majority of cases, non-operative methods are preferred. The principles of management are to provide immobilization of the affected joint and reduce any areas of stress on the skin. Immobilization is usually accomplished by casting.”)
Lateral epicondylitis (tennis elbow). (“For work-related lateral epicondylitis, a systematic review identified three risk factors: handling tools heavier than 1 kg, handling loads heavier than 20 kg at least ten times per day, and repetitive movements for more than two hours per day. […] Up to 95 per cent of patients with tennis elbow respond to conservative measures.”)
Medial Epicondylitis.
De Quervain’s tenosynovitis. Finkelstein test. Intersection syndrome. Wartenberg’s syndrome.
Trigger finger.
Adhesive capsulitis (‘frozen shoulder’). (“Frozen shoulder typically has three phases: the painful phase, the stiffening phase and the thawing phase. During the initial phase there is a gradual onset of diffuse shoulder pain lasting from weeks to months. The stiffening phase is characterized by a progressive loss of motion that may last up to a year. The majority of patients lose glenohumeral external rotation, internal rotation and abduction during this phase. The final, thawing phase ranges from weeks to months and constitutes a period of gradual motion improvement. Once in this phase, the patient may require up to 9 months to regain a fully functional range of motion. There is a higher incidence of frozen shoulder in patients with diabetes compared with the general population. The incidence among patients with insulin-dependent diabetes is even higher, with an increased frequency of bilateral frozen shoulder. Adhesive capsulitis has also been reported in patients with hyperthyroidism, ischaemic heart disease, and cervical spondylosis. Non-steroidal anti-inflammatory drugs (NSAIDs) are recommended in the initial treatment phase. […] A subgroup of patients with frozen shoulder syndrome often fail to improve despite conservative measures. In these cases, interventions such as manipulation, distension arthrography or open surgical release may be beneficial.” [A while back I covered some papers on adhesive capsulitis and diabetes here (part iii) – US].
Dupuytren’s Disease. (“Dupuytren’s contracture is a benign, slowly progressive fibroproliferative disease of the palmar fascia. […] The disease presents most commonly in the ring and little fingers and is bilateral in 45 per cent of cases. […] Dupuytren’s disease is more common in males and people of northern European origin. It can be associated with prior hand trauma, alcoholic cirrhosis, epilepsy (due to medications such as phenytoin), and diabetes. [“Dupuytren’s disease […] may be observed in up to 42% of adults with diabetes mellitus, typically in patients with long-standing T1D” – I usually don’t like such unspecific reported prevalences (what does ‘up to’ really mean?), but the point is that this is not a 1 in a 100 complication among diabetics; it seems to be a relatively common complication in type 1 DM – US] The prevalence increases with age. Mild cases may not need any treatment. Surgery is indicated in progressive contractures and established deformity […] Recurrence or extension of the disease after operation is not uncommon”).

July 1, 2018 Posted by | Books, Cancer/oncology, Diabetes, Medicine, Neurology | Leave a comment

Gastrointestinal complications of diabetes (I)

I really liked this book. It covered a lot of stuff also covered in Horowitz & Samsom’s excellent book on these topics, but it’s shorter and so probably easier for the relevant target group to justify reading. I recommend the book if you want to know more about these topics but don’t quite feel like reading a long textbook on these topics.

Below I’ve added some observations from the first half of the book. In the quotes below I’ve added some links and highlighted some key observations by the use of bold text.

Gastrointestinal (GI) symptoms occur more commonly in patients with diabetes than in the general population [2]. […] GI symptoms such as nausea, abdominal pain, bloating, diarrhea, constipation, and delayed gastric emptying occur in almost 75 % of patients with diabetes [3]. A majority of patients with GI symptoms stay undiagnosed or undertreated due to a lack of awareness of these complications among clinicians. […] Diabetes can affect the entire GI tract from the oral cavity and esophagus to the large bowel and anorectal region, either in isolation or in a combination. The extent and the severity of the presenting symptoms may vary widely depending upon which part of the GI tract is involved. In patients with long-term type 1 DM, upper GI symptoms seem to be particularly common [4]. Of the different types […] gastroparesis seems to be the most well known and most serious complication, occurring in about 50 % of patients with diabetes-related GI complications [5].”

The enteric nervous system (ENS) is an independent network of neurons and glial cells that spread from the esophagus up to the internal anal sphincter. […] the ENS regulates GI tract functions including motility, secretion, and participation in immune regulation [12, 13]. GI complications and their symptoms in patients with diabetes arise secondary to both abnormalities of gastric function (sensory and motor modality), as well as impairment of GI hormonal secretion [14], but these abnormalities are complex and incompletely understood. […] It has been known for a long time that diabetic autonomic neuropathy […] leads to abnormalities in the GI motility, sensation, secretion, and absorption, serving as the main pathogenic mechanism underlying GI complications. Recently, evidence has emerged to suggest that other processes might also play a role. Loss of the pacemaker interstitial cells of Cajal, impairment of the inhibitory nitric oxide-containing nerves, abnormal myenteric neurotransmission, smooth muscle dysfunction, and imbalances in the number of excitatory and inhibitory enteric neurons can drastically alter complex motor functions causing dysfunction of the enteric system [7, 11, 15, 16]. This dysfunction can further lead to the development of dysphagia and reflux esophagitis in the esophagus, gastroparesis, and dyspepsia in the stomach, pseudo-obstruction of the small intestine, and constipation, diarrhea, and incontinence in the colon. […] Compromised intestinal vascular flow arising due to ischemia and hypoxia from microvascular disease of the GI tract can also cause abdominal pain, bleeding, and mucosal dysfunction. Mitochondrial dysfunction has been implicated in the pathogenesis of gastric neuropathy. […] Another possible association between DM and the gastrointestinal tract can be infrequent autoimmune diseases associated with type I DM like autoimmune chronic pancreatitis, celiac disease (2–11 %), and autoimmune gastropathy (2 % prevalence in general population and three- to fivefold increase in patients with type 1 DM) [28, 29]. GI symptoms are often associated with the presence of other diabetic complications, especially autonomic and peripheral neuropathy [2, 30, 31]. In fact, patients with microvascular complications such as retinopathy, nephropathy, or neuropathy should be presumed to have GI abnormalities until proven otherwise. In a large cross-sectional questionnaire study of 1,101 subjects with DM, 57 % of patients reported at least one GI complication [31]. Poor glycemic control has also been found to be associated with increased severity of the upper GI symptoms. […] management of DM-induced GI complications is challenging, is generally suboptimal, and needs improvement.

Diabetes mellitus (DM) has multiple clinically important effects on the esophagus. Diabetes results in several esophageal motility disturbances, increases the risk of esophageal candidiasis, and increases the risk of Barrett’s esophagus and esophageal carcinoma. Finally, “black esophagus,” or acute esophageal necrosis, is also associated with DM. […] Esophageal dysmotility has been shown to be associated with diabetic neuropathy; however, symptomatic esophageal dysmotility is not often considered an important complication of diabetes. […] In general, the manometric effects of diabetes on the esophagus are not specific and mostly related to speed and strength of peristalsis. […] The pathological findings which amount to loss of cholinergic stimulation are consistent with the manometric findings in the esophagus, which are primarily related to slowed or weakened peristalsis. […] The association between DM and GERD is complex and conflicting. […] A recent meta-analysis suggests an overall positive association in Western countries [12]. […] The underlying pathogenesis of DM contributing to GERD is not fully elucidated, but is likely related to reduced acid clearance due to slow, weakened esophageal peristalsis. The association between DM and gastroesophageal reflux (GER) is well established, but the link between DM and GERD, which requires symptoms or esophagitis, is more complex because sensation may be blunted in diabetics with neuropathy. Asymptomatic gastroesophageal reflux (GER) confirmed by pH studies is significantly more frequent in diabetic patients than in healthy controls [13]. […] long-standing diabetics with neuropathy are at higher risk for GERD even if they have no symptoms. […] Abnormal pH and motility studies do not correlate very well with the GI symptoms of diabetics, possibly due to DM-related sensory dysfunction.”

Gastroparesis is defined as a chronic disorder characterized by delayed emptying of the stomach occurring in the absence of mechanical obstruction. It is a well-known and potentially serious complication of diabetes. […] Diabetic gastroparesis affects up to 40 % of patients with type 1 diabetes and up to 30 % of patients with type 2 diabetes [1, 2]. Diabetic gastroparesis generally affects patients with longstanding diabetes mellitus, and patients often have other diabetic complications […] For reasons that remain unclear, approximately 80 % of patients with gastroparesis are women [3]. […] In diabetes, delayed gastric emptying can often be asymptomatic. Therefore, the term gastroparesis should only be reserved for patients that have both delayed gastric emptying and upper gastrointestinal symptoms. Additionally, discordance between the pattern and type of symptoms and the magnitude of delayed gastric emptying is a well-established phenomenon. Accelerating gastric emptying may not improve symptoms, and patients can have symptomatic improvement while gastric emptying time remains unchanged. Furthermore, patients with severe symptoms can have mild delays in gastric emptying. Clinical features of gastroparesis include nausea, vomiting, bloating, abdominal pain, and malnutrition. […] Gastroparesis affects oral drug absorption and can cause hyperglycemia that is challenging to manage, in addition to unexplained hypoglycemia. […] Nutritional and caloric deficits are common in patients with gastroparesis […] Possible complications of gastroparesis include volume depletion with renal failure, malnutrition, electrolyte abnormalities, esophagitis, Mallory–Weiss tear (from vomiting), or bezoar formation. […] Unfortunately, there is a dearth of medications available to treat gastroparesis. Additionally, many of the medications used are based on older trials with small sample sizes […and some of them have really unpleasant side effects – US]. […] Gastroparesis can be associated with abdominal pain in as many as 50 % of patients with gastroparesis at tertiary care centers. There are no trials to guide the choice of agents. […] Abdominal pain […] is often difficult to treat [3]. […] In a subset of patients with diabetes [less than 10%, according to Horowitz & Samsom – US], gastric emptying can be abnormally accelerated […]. Symptoms are often difficult to distinguish from those with delayed gastric emptying. […] Worsening symptoms with a prokinetic agent can be a sign of possible accelerated emptying.”

“Diabetic enteropathy encompasses small intestinal and colorectal dysfunctions such as diarrhea, constipation, and/or fecal incontinence. It is more commonly seen in patients with long-standing diabetes, especially in those with gastroparesis. Development of diabetic enteropathy is complex and multifactorial. […] gastrointestinal symptoms and complications do not always correlate with the duration of diabetes, glycemic control, or with the presence of autonomic neuropathy, which is often assumed to be the major cause of many gastrointestinal symptoms. Other pathophysiologic processes operative in diabetic enteropathy include enteric myopathy and neuropathy; however, causes of these abnormalities are unknown [1]. […] Collectively, the effects of diabetes on several targets cause aberrations in gastrointestinal function and regulation. Loss of ICC, autonomic neuropathy, and imbalances in the number of excitatory and inhibitory enteric neurons can drastically alter complex motor functions such as peristalsis, reflexive relaxation, sphincter tone, vascular flow, and intestinal segmentation [5]. […] Diarrhea is a common complaint in DM. […] Etiologies of diarrhea in diabetes are multifactorial and include rapid intestinal transit, drug-induced diarrhea, small-intestine bacterial overgrowth, celiac disease, pancreatic exocrine insufficiency, dietary factors, anorectal dysfunction, fecal incontinence, and microscopic colitis [1]. […] It is important to differentiate whether diarrhea is caused by rapid intestinal transit vs. SIBO. […] This differentiation has key clinical implications with regard to the use of antimotility agents or antibiotics in a particular case. […] Constipation is a common problem seen with long-standing DM. It is more common than in general population, where the incidence varies from 2 % to 30 % [30]. It affects 60 % of the patients with DM and is more common than diarrhea [14]. […] There are no specific treatments for diabetes-associated constipation […] In most cases, patients are treated in the same way as those with idiopathic chronic constipation. […] Colorectal cancer is the third most common cancer in men and the second in women [33]. Individuals with type 2 DM have an increased risk of colorectal cancer when compared with their nondiabetic counterparts […] According to a recent large observational population-based cohort study, type 2 DM was associated with a 1.3-fold increased risk of colorectal cancer compared to the general population.”

Nonalcoholic fatty liver disease (NAFLD) is the main hepatic complication of obesity, insulin resistance, and diabetes and soon to become the leading cause for end-stage liver disease in the United States [1]. […] NAFLD is a spectrum of disease that ranges from steatosis (hepatic fat without significant hepatocellular injury) to nonalcoholic steatohepatitis (NASH; hepatic fat with hepatocellular injury) to advanced fibrosis and cirrhosis. As a direct consequence of the obesity epidemic, NAFLD is the most common cause of chronic liver disease, while NASH is the second leading indication for liver transplantation [1]. NAFLD prevalence is estimated at 25 % globally [2] and up to 30 % in the United States [3–5]. Roughly 30 % of individuals with NAFLD also have NASH, the progressive subtype of NAFLD. […] NASH is estimated at 22 % among patients with diabetes, compared to 5 % of the general population [4, 14]. […] Insulin resistance is strongly associated with NASH. […] Simple steatosis (also known as nonalcoholic fatty liver) is characterized by the presence of steatosis without ballooned hepatocytes (which represents hepatocyte injury) or fibrosis. Mild inflammation may be present. Simple steatosis is associated with a very low risk of progressive liver disease and liver-related mortality. […] Patients with NASH are at risk for progressive liver fibrosis and liver-related mortality, cardiovascular complications, and hepatocellular carcinoma (HCC) even in the absence of cirrhosis [26]. Liver fibrosis stage progresses at an estimated rate of one stage every 7 years [27]. Twenty percent of patients with NASH will eventually develop liver cirrhosis [9]. […] The risk of cardiovascular disease is increased across the entire NAFLD spectrum. […] Cardiovascular risk reduction should be aggressively managed in all patients.

 

June 17, 2018 Posted by | Books, Cancer/oncology, Cardiology, Diabetes, Gastroenterology, Medicine, Neurology | Leave a comment

Robotics

“This book is not about the psychology or cultural anthropology of robotics, interesting as those are. I am an engineer and roboticist, so I confine myself firmly to the technology and application of real physical robots. […] robotics is the study of the design, application, and use of robots, and that is precisely what this Very Short Introduction is about: what robots do and what roboticists do.”

The above quote is from the book‘s preface; the book is quite decent and occasionally really quite fascinating. Below I have added some sample quotes and links to topics/stuff covered in the book.

“Some of all of […] five functions – sensing, signalling, moving, intelligence, and energy, integrated into a body – are present in all robots. The actual sensors, motors, and behaviours designed into a particular robot body shape depend on the job that robot is designed to do. […] A robot is: 1. an artificial device that can sense its environment and purposefully act on or in that environment; 2. an embodied artificial intelligence; or 3. a machine that can autonomously carry out useful work. […] Many real-world robots […] are not autonomous but remotely operated by humans. […] These are also known as tele-operated robots. […] From a robot design point of view, the huge advantage of tele-operated robots is that the human in the loop provides the robot’s ‘intelligence’. One of the most difficult problems in robotics — the design of the robot’s artificial intelligence — is therefore solved, so it’s not surprising that so many real-world robots are tele-operated. The fact that tele-operated robots alleviate the problem of AI design should not fool us into making the mistake of thinking that tele-operated robots are not sophisticated — they are. […] counter-intuitively, autonomous robots are often simpler than tele-operated robots […] When roboticists talk about autonomous robots they normally mean robots that decide what to do next entirely without human intervention or control. We need to be careful here because they are not talking about true autonomy, in the sense that you or I would regard ourselves as self-determining individuals, but what I would call ‘control autonomy’. By control autonomy I mean that the robot can undertake its task, or mission, without human intervention, but that mission is still programmed or commanded by a human. In fact, there are very few robots in use in the real world that are autonomous even in this limited sense. […] It is helpful to think about a spectrum of robot autonomy, from remotely operated at one end (no autonomy) to fully autonomous at the other. We can then place robots on this spectrum according to their degree of autonomy. […] On a scale of autonomy, a robot that can react on its own in response to its sensors is highly autonomous. A robot that cannot react, perhaps because it doesn’t have any sensors, is not.”

“It is […] important to note that autonomy and intelligence are not the same thing. A robot can be autonomous but not very smart, like a robot vacuum cleaner. […] A robot vacuum cleaner has a small number of preprogrammed (i.e. instinctive) behaviours and is not capable of any kind of learning […] These are characteristics we would associate with very simple animals. […] When roboticists describe a robot as intelligent, what they mean is ‘a robot that behaves, in some limited sense, as if it were intelligent’. The words as if are important here. […] There are basically two ways in which we can make a robot behave as if it is more intelligent: 1. preprogram a larger number of (instinctive) behaviours; and/or 2. design the robot so that it can learn and therefore develop and grow its own intelligence. The first of these approaches is fine, providing that we know everything there is to know about what the robot must do and all of the situations it will have to respond to while it is working. Typically we can only do this if we design both the robot and its operational environment. […] For unstructured environments, the first approach to robot intelligence above is infeasible simply because it’s impossible to anticipate every possible situation a robot might encounter, especially if it has to interact with humans. The only solution is to design a robot so that it can learn, either from its own experience or from humans or other robots, and therefore adapt and develop its own intelligence: in effect, grow its behavioural repertoire to be able to respond appropriately to more and more situations. This brings us to the subject of learning robots […] robot learning or, more generally, ‘machine learning’ — a branch of AI — has proven to be very much harder than was expected in the early days of Artificial Intelligence.”

“Robot arms on an assembly line are typically programmed to go through a fixed sequence of moves over and over again, for instance spot-welding car body panels, or spray-painting the complete car. These robots are therefore not intelligent. In fact, they often have no exteroceptive sensors at all. […] when we see an assembly line with multiple robot arms positioned on either side along a line, we need to understand that the robots are part of an integrated automated manufacturing system, in which each robot and the line itself have to be carefully programmed in order to coordinate and choreograph the whole operation. […] An important characteristic of assembly-line robots is that they require the working environment to be designed for and around them, i.e. a structured environment. They also need that working environment to be absolutely predictable and repeatable. […] Robot arms either need to be painstakingly programmed, so that the precise movement required of each joint is worked out and coded into a set of instructions for the robot arm or, more often (and rather more easily), ‘taught’ by a human using a control pad to move its end-effector (hand) to the required positions in the robot’s workspace. The robot then memorizes the set of joint movements so that they can be replayed (over and over again). The human operator teaching the robot controls the trajectory, i.e. the path the robot arm’s end-effector follows as it moves through its 3D workspace, and a set of mathematical equations called the ‘inverse kinematics’ converts the trajectory into a set of individual joint movements. Using this approach, it is relatively easy to teach a robot arm to pick up an object and move it smoothly to somewhere else in its workspace while keeping the object level […]. However […] most real-world robot arms are unable to sense the weight of the object and automatically adjust accordingly. They are simply designed with stiff enough joints and strong enough motors that, whatever the weight of the object (providing it’s within the robot’s design limits), it can be lifted, moved, and placed with equal precision. […] The robot arm and gripper are a foundational technology in robotics. Not only are they extremely important as […] industrial assembly-line robot[s], but they have become a ‘component’ in many areas of robotics.”

Planetary rovers are tele-operated mobile robots that present the designer and operator with a number of very difficult challenges. One challenge is power: a planetary rover needs to be energetically self-sufficient for the lifetime of its mission, and must either be launched with a power source or — as in the case of the Mars rovers — fitted with solar panels capable of recharging the rover’s on-board batteries. Another challenge is dependability. Any mechanical fault is likely to mean the end of the rover’s mission, so it needs to be designed and built to exceptional standards of reliability and fail-safety, so that if parts of the rover should fail, the robot can still operate, albeit with reduced functionality. Extremes of temperature are also a problem […] But the greatest challenge is communication. With a round-trip signal delay time of twenty minutes to Mars and back, tele-operating the rover in real time is impossible. If the rover is moving and its human operator in the command centre on Earth reacts to an obstacle, it’s likely to be already too late; the robot will have hit the obstacle by the time the command signal to turn reaches the rover. An obvious answer to this problem would seem to be to give the rover a degree of autonomy so that it could, for instance, plan a path to a rock or feature of interest — while avoiding obstacles — then, when it arrives at the point of interest, call home and wait. Although path-planning algorithms capable of this level of autonomy have been well developed, the risk of a failure of the algorithm (and hence perhaps the whole mission) is deemed so high that in practice the rovers are manually tele-operated, at very low speed, with each manual manoeuvre carefully planned. When one also takes into account the fact that the Mars rovers are contactable only for a three-hour window per Martian day, a traverse of 100 metres will typically take up one day of operation at an average speed of 30 metres per hour.”

“The realization that the behaviour of an autonomous robot is an emergent property of its interactions with the world has important and far-reaching consequences for the way we design autonomous robots. […] when we design robots, and especially when we come to decide what behaviours to programme the robot’s AI with, we cannot think about the robot on its own. We must take into account every detail of the robot’s working environment. […] Like all machines, robots need power. For fixed robots, like the robot arms used for manufacture, power isn’t a problem because the robot is connected to the electrical mains supply. But for mobile robots power is a huge problem because mobile robots need to carry their energy supply around with them, with problems of both the size and weight of the batteries and, more seriously, how to recharge those batteries when they run out. For autonomous robots, the problem is acute because a robot cannot be said to be truly autonomous unless it has energy autonomy as well as computational autonomy; there seems little point in building a smart robot that ‘dies’ when its battery runs out. […] Localization is a[nother] major problem in mobile robotics; in other words, how does a robot know where it is, in 2D or 3D space. […] [One] type of robot learning is called reinforcement learning. […] it is a kind of conditioned learning. If a robot is able to try out several different behaviours, test the success or failure of each behaviour, then ‘reinforce’ the successful behaviours, it is said to have reinforcement learning. Although this sounds straightforward in principle, it is not. It assumes, first, that a robot has at least one successful behaviour in its list of behaviours to try out, and second, that it can test the benefit of each behaviour — in other words, that the behaviour has an immediate measurable reward. If a robot has to try every possible behaviour or if the rewards are delayed, then this kind of so-called ‘unsupervised’ individual robot learning is very slow.”

“A robot is described as humanoid if it has a shape or structure that to some degree mimics the human form. […] A small subset of humanoid robots […] attempt a greater degree of fidelity to the human form and appearance, and these are referred to as android. […] It is a recurring theme of this book that robot intelligence technology lags behind robot mechatronics – and nowhere is the mismatch between the two so starkly evident as it is in android robots. The problem is that if a robot looks convincingly human, then we (not unreasonably) expect it to behave like a human. For this reason whole-body android robots are, at the time of writing, disappointing. […] It is important not to overstate the case for humanoid robots. Without doubt, many potential applications of robots in human work- or living spaces would be better served by non-humanoid robots. The humanoid robot to use human tools argument doesn’t make sense if the job can be done autonomously. It would be absurd, for instance, to design a humanoid robot in order to operate a vacuum cleaner designed for humans. Similarly, if we want a driverless car, it doesn’t make sense to build a humanoid robot that sits in the driver’s seat. It seems that the case for humanoid robots is strongest when the robots are required to work alongside, learn from, and interact closely with humans. […] One of the most compelling reasons why robots should be humanoid is for those applications in which the robot has to interact with humans, work in human workspaces, and use tools or devices designed for humans.”

“…to put it bluntly, sex with a robot might not be safe. As soon as a robot has motors and moving parts, then assuring the safety of human-robot interaction becomes a difficult problem and if that interaction is intimate, the consequences of a mechanical or control systems failure could be serious.”

“All of the potential applications of humanoid robots […] have one thing in common: close interaction between human and robot. The nature of that interaction will be characterized by close proximity and communication via natural human interfaces – speech, gesture, and body language. Human and robot may or may not need to come into physical contact, but even when direct contact is not required they will still need to be within each other’s body space. It follows that robot safety, dependability, and trustworthiness are major issues for the robot designer. […] making a robot safe isn’t the same as making it trustworthy. One person trusts another if, generally speaking, that person is reliable and does what they say they will. So if I were to provide a robot that helps to look after your grandmother and I claim that it is perfectly safe — that it’s been designed to cover every risk or hazard — would you trust it? The answer is probably not. Trust in robots, just as in humans, has to be earned. […for more on these topics, see this post – US] […] trustworthiness cannot just be designed into the robot — it has to be earned by use and by experience. Consider a robot intended to fetch drinks for an elderly person. Imagine that the person calls for a glass of water. The robot then needs to fetch the drink, which may well require the robot to find a glass and fill it with water. Those tasks require sensing, dexterity, and physical manipulation, but they are problems that can be solved with current technology. The problem of trust arises when the robot brings the glass of water to the human. How does the robot give the glass to the human? If the robot has an arm so that it can hold out the glass in the same way a human would, how would the robot know when to let go? The robot clearly needs sensors in order to see and feel when the human has taken hold of the glass. The physical process of a robot handing something to a person is fraught with difficulty. Imagine, for instance, that the robot holds out its arm with the glass but the human can’t reach the glass. How does the robot decide where and how far it would be safe to bring its arm toward the person? What if the human takes hold of the glass but then the glass slips; does the robot let it fall or should it — as a human would — renew its grip on the glass? At what point would the robot decide the transaction has failed: it can’t give the glass of water to the person, or they won’t take it; perhaps they are asleep, or simply forgotten they wanted a glass of water, or confused. How does the robot sense that it should give up and perhaps call for assistance? These are difficult problems in robot cognition. Until they are solved, it’s doubtful we could trust a robot sufficiently well to do even a seemingly simple thing like handing over a glass of water.”

“The fundamental problem with Asimov’s laws of robotics, or any similar construction, is that they require the robot to make judgments. […] they assume that the robot is capable of some level of moral agency. […] No robot that we can currently build, or will build in the foreseeable future, is ‘intelligent’ enough to be able to even recognize, let alone make, these kinds of choices. […] Most roboticists agree that for the foreseeable future robots cannot be ethical, moral agents. […] precisely because, as we have seen, present-day ‘intelligent’ robots are not very intelligent, there is a danger of a gap between what robot users believe those robots to be capable of and what they are actually capable of. Given humans’ propensity to anthropomorphize and form emotional attachments to machines, there is clearly a danger that such vulnerabilities could be either unwittingly or deliberately exploited. Although robots cannot be ethical, roboticists should be.”

“In robotics research, the simulator has become an essential tool of the roboticist’s trade. The reason for this is that designing, building, and testing successive versions of real robots is both expensive and time-consuming, and if part of that work can be undertaken in the virtual rather than the real world, development times can be shortened, and the chances of a robot that works first time substantially improved. A robot simulator has three essential features. First, it must provide a virtual world. Second, it must offer a facility for creating a virtual model of the real robot. And third, it must allow the robot’s controller to be installed and ‘run’ on the virtual robot in the virtual world; the controller then determines how the robot behaves when running in the simulator. The simulator should also provide a visualization of the virtual world and simulated robots in it so that the designer can see what’s going on. […] These are difficult challenges for developers of robot simulators.”

“The next big step in miniaturization […] requires the solution of hugely difficult problems and, in all likelihood, the use of exotic approaches to design and fabrication. […] It is impossible to shrink mechanical and electrical components, or MEMS devices, in order to reduce total robot size to a few micrometres. In any event, the physics of locomotion through a fluid changes at the microscale and simply shrinking mechanical components from macro to micro — even if it were possible — would fail to address this problem. A radical approach is to leave behind conventional materials and components and move to a bioengineered approach in which natural bacteria are modified by adding artificial components. The result is a hybrid of artificial and natural (biological) components. The bacterium has many desirable properties for a microbot. By selecting a bacterium with a flagellum, we have locomotion perfectly suited to the medium. […] Another hugely desirable characteristic is that the bacteria are able to naturally scavenge for energy, thus avoiding the otherwise serious problem of powering the microbots. […] Whatever technology is used to create the microbots, huge problems would have to be overcome before a swarm of medical microbots could become a practical reality. The first is technical: how do surgeons or medical technicians reliably control and monitor the swarm while it’s working inside the body? Or, assuming we can give the microbots sufficient intelligence and autonomy (also a very difficult challenge), do we forgo precise control and human intervention altogether by giving the robots the swarm intelligence to be able to do the job, i.e. find the problem, fix it, then exit? […] these questions bring us to what would undoubtedly represent the greatest challenge: validating the swarm of medical microbots as effective, dependable, and above all safe, then gaining approval and public acceptance for its use. […] Do we treat the validation of the medical microbot swarm as an engineering problem, and attempt to apply the same kinds of methods we would use to validate safety-critical systems such as air traffic control systems? Or do we instead regard the medical microbot swarm as a drug and validate it with conventional and (by and large) trusted processes, including clinical trials, leading to approval and licensing for use? My suspicion is that we will need a new combination of both approaches.”

Links:

E-puck mobile robot.
Jacques de Vaucanson’s Digesting Duck.
Cybernetics.
Alan Turing. W. Ross Ashby. Norbert Wiener. Warren McCulloch. William Grey Walter.
Turtle (robot).
Industrial robot. Mechanical arm. Robotic arm. Robot end effector.
Automated guided vehicle.
Remotely operated vehicle. Unmanned aerial vehicle. Remotely operated underwater vehicle. Wheelbarrow (robot).
Robot-assisted surgery.
Lego Mindstorms NXT. NXT Intelligent Brick.
Biomimetic robots.
Artificial life.
Braitenberg vehicle.
Shakey the robot. Sense-Plan-Act. Rodney Brooks. A robust layered control system for a mobile robot.
Toto the robot.
Slugbot. Ecobot. Microbial fuel cell.
Scratchbot.
Simultaneous localization and mapping (SLAM).
Programming by demonstration.
Evolutionary algorithm.
NASA Robonaut. BERT 2. Kismet (robot). Jules (robot). Frubber. Uncanny valley.
AIBO. Paro.
Cronos Robot. ECCEROBOT.
Swarm robotics. S-bot mobile robot. Swarmanoid project.
Artificial neural network.
Symbrion.
Webots.
Kilobot.
Microelectromechanical systems. I-SWARM project.
ALICE (Artificial Linguistic Internet Computer Entity). BINA 48 (Breakthrough Intelligence via Neural Architecture 48).

June 15, 2018 Posted by | Books, Computer science, Engineering, Medicine | Leave a comment

Blood (II)

Below I have added some quotes from the chapters of the book I did not cover in my first post, as well as some supplementary links.

Haemoglobin is of crucial biological importance; it is also easy to obtain safely in large quantities from donated blood. These properties have resulted in its becoming the most studied protein in human history. Haemoglobin played a key role in the history of our understanding of all proteins, and indeed the science of biochemistry itself. […] Oxygen transport defines the primary biological function of blood. […] Oxygen gas consists of two atoms of oxygen bound together to form a symmetrical molecule. However, oxygen cannot be transported in the plasma alone. This is because water is very poor at dissolving oxygen. Haemoglobin’s primary function is to increase this solubility; it does this by binding the oxygen gas on to the iron in its haem group. Every haem can bind one oxygen molecule, increasing the amount of oxygen able to dissolve in the blood.”

“An iron atom can exist in a number of different forms depending on how many electrons it has in its atomic orbitals. In its ferrous (iron II) state iron can bind oxygen readily. The haemoglobin protein has therefore evolved to stabilize its haem iron cofactor in this ferrous state. The result is that over fifty times as much oxygen is stored inside the confines of the red blood cell compared to outside in the watery plasma. However, using iron to bind oxygen comes at a cost. Iron (II) can readily lose one of its electrons to the bound oxygen, a process called ‘oxidation’. So the same form of iron that can bind oxygen avidly (ferrous) also readily reacts with that same oxygen forming an unreactive iron III state, called ‘ferric’. […] The complex structure of the protein haemoglobin is required to protect the ferrous iron from oxidizing. The haem iron is held in a precise configuration within the protein. Specific amino acids are ideally positioned to stabilize the iron–oxygen bond and prevent it from oxidizing. […] the iron stays ferrous despite the presence of the nearby oxygen. Having evolved over many hundreds of millions of years, this stability is very difficult for chemists to mimic in the laboratory. This is one reason why, desirable as it might be in terms of cost and convenience, it is not currently possible to replace blood transfusions with a simple small chemical iron oxygen carrier.”

“Given the success of the haem iron and globin combination in haemoglobin, it is no surprise that organisms have used this basic biochemical architecture for a variety of purposes throughout evolution, not just oxygen transport in blood. One example is the protein myoglobin. This protein resides inside animal cells; in the human it is found in the heart and skeletal muscle. […] Myoglobin has multiple functions. Its primary role is as an aid to oxygen diffusion. Whereas haemoglobin transports oxygen from the lung to the cell, myoglobin transports it once it is inside the cell. As oxygen is so poorly soluble in water, having a chain of molecules inside the cell that can bind and release oxygen rapidly significantly decreases the time it takes the gas to get from the blood capillary to the part of the cell—the mitochondria—where it is needed. […] Myoglobin can also act as an emergency oxygen backup store. In humans this is trivial and of questionable importance. Not so in diving mammals such as whales and dolphins that have as much as thirty times the myoglobin content of the terrestrial equivalent; indeed those mammals that dive for the longest duration have the most myoglobin. […] The third known function of myoglobin is to protect the muscle cells from damage by nitric oxide gas.”

“The heart is the organ that pumps blood around the body. If the heart stops functioning, blood does not flow. The driving force for this flow is the pressure difference between the arterial blood leaving the heart and the returning venous blood. The decreasing pressure in the venous side explains the need for unidirectional valves within veins to prevent the blood flowing in the wrong direction. Without them the return of the blood through the veins to the heart would be too slow, especially when standing up, when the venous pressure struggles to overcome gravity. […] normal [blood pressure] ranges rise slowly with age. […] high resistance in the arterial circulation at higher blood pressures [places] additional strain on the left ventricle. If the heart is weak, it may fail to achieve the extra force required to pump against this resistance, resulting in heart failure. […] in everyday life, a low blood pressure is rarely of concern. Indeed, it can be a sign of fitness as elite athletes have a much lower resting blood pressure than the rest of the population. […] the effect of exercise training is to thicken the muscles in the walls of the heart and enlarge the chambers. This enables more blood to be pumped per beat during intense exercise. The consequence of this extra efficiency is that when an athlete is resting—and therefore needs no more oxygen than a more sedentary person—the heart rate and blood pressure are lower than average. Most people’s experience of hypotension will be reflected by dizzy spells and lack of balance, especially when moving quickly to an upright position. This is because more blood pools in the legs when you stand up, meaning there is less blood for the heart to pump. The immediate effect should be for the heart to beat faster to restore the pressure. If there is a delay, the decrease in pressure can decrease the blood flow to the brain and cause dizziness; in extreme cases this can lead to fainting.”

“If hypertension is persistent, patients are most likely to be treated with drugs that target specific pathways that the body uses to control blood pressure. For example angiotensin is a protein that can trigger secretion of the hormone aldosterone from the adrenal gland. In its active form angiotensin can directly constrict blood vessels, while aldosterone enhances salt and water retention, so raising blood volume. Both these effects increase blood pressure. Angiotensin is converted into its active form by an enzyme called ‘Angiotensin Converting Enzyme’ (ACE). An ACE inhibitor drug prevents this activity, keeping angiotensin in its inactive form; this will therefore drop the patient’s blood pressure. […] The metal calcium controls many processes in the body. Its entry into muscle cells triggers muscle contraction. Preventing this entry can therefore reduce the force of contraction of the heart and the ability of arteries to constrict. Both of these will have the effect of decreasing blood pressure. Calcium enters muscle cells via specific protein-based channels. Drugs that block these channels (calcium channel blockers) are therefore highly effective at treating hypertension.”

Autoregulation is a homeostatic process designed to ensure that blood flow remains constant [in settings where constancy is desirable]. However, there are many occasions when an organism actively requires a change in blood flow. It is relatively easy to imagine what these are. In the short term, blood supplies oxygen and nutrients. When these are used up rapidly, or their supply becomes limited, the response will be to increase blood flow. The most obvious example is the twenty-fold increase in oxygen and glucose consumption that occurs in skeletal muscle during exercise when compared to rest. If there were no accompanying increase in blood flow to the muscle the oxygen supply would soon run out. […] There are hundreds of molecules known that have the ability to increase or decrease blood flow […] The surface of all blood vessels is lined by a thin layer of cells, the ‘endothelium’. Endothelial cells form a barrier between the blood and the surrounding tissue, controlling access of materials into and out of the blood. For example white blood cells can enter or leave the circulation via interacting with the endothelium; this is the route by which neutrophils migrate from the blood to the site of tissue damage or bacterial/viral attack as part of the innate immune response. However, the endothelium is not just a selective barrier. It also plays an active role in blood physiology and biochemistry.”

“Two major issues [related to blood transfusions] remained at the end of the 19th century: the problem of clotting, which all were aware of; and the problem of blood group incompatbility, which no one had the slightest idea even existed. […] For blood transfusions to ever make a recovery the key issues of blood clotting and adverse side effects needed to be resolved. In 1875 the Swedish biochemist Olof Hammarsten showed that adding calcium accelerated the rate of blood clotting (we now know the mechanism for this is that key enzymes in blood platelets that catalyse fibrin formation require calcium for their function). It therefore made sense to use chemicals that bind calcium to try to prevent clotting. Calcium ions are positively charged; adding negatively charged ions such as oxalate and citrate neutralized the calcium, preventing its clot-promoting action. […] At the same time as anticoagulants were being discovered, the reason why some blood transfusions failed even when there were no clots was becoming clear. It had been shown that animal blood given to humans tended to clump together or agglutinate, eventually bursting and releasing free haemoglobin and causing kidney damage. In the early 1900s, working in Vienna, Karl Landsteiner showed the same effect could occur with human-to-human transfusion. The trick was the ability to separate blood cells from serum. This enabled mixing blood cells from a variety of donors with plasma from a variety of participants. Using his laboratory staff as subjects, Landsteiner showed that only some combinations caused the agglutination reaction. Some donor cells (now known as type O) never clumped. Others clumped depending on the nature of the plasma in a reproducible manner. A careful study of Landsteiner’s results revealed the ABO blood type distinctions […]. Versions of these agglutination tests still form the basis of checking transfused blood today.”

“No blood product can be made completely sterile, no matter how carefully it is processed. The best that can be done is to ensure that no new bacteria or viruses are added during the purification, storage, and transportation processes. Nothing can be done to inactivate any viruses that are already present in the donor’s blood, for the harsh treatments necessary to do this would inevitably damage the viability of the product or be prohibitively expensive to implement on the industrial scale that the blood market has become. […] In the 1980s over half the US haemophiliac population was HIV positive.”

“Three fundamentally different ways have been attempted to replace red blood cell transfusions. The first uses a completely chemical approach and makes use of perfluorocarbons, inert chemicals that, in liquid form, can dissolve gasses without reacting with them. […] Perfluorocarbons can dissolve oxygen much more effectively than water. […] The problem with their use as a blood substitute is that the amount of oxygen dissolved in these solutions is linear with increasing pressure. This means that the solution lacks the advantages of the sigmoidal binding curve of haemoglobin, which has evolved to maximize the amount of oxygen captured from the limited fraction found in air (20 per cent oxygen). However, to deliver the same amount of oxygen as haemoglobin, patients using the less efficient perfluorocarbons in their blood need to breathe gas that is almost 100 per cent pure oxygen […]; this restricts the use of these compounds. […] The second type of blood substitute makes use of haemoglobin biology. Initial attempts used purified haemoglobin itself. […] there is no haemoglobin-based blood substitute in general use today […] The problem for the lack of uptake is not that blood substitutes cannot replace red blood cell function. A variety of products have been shown to stay in the vasculature for several days, provide volume support, and deliver oxygen. However, they have suffered due to adverse side effects, most notably cardiac complications. […] In nature the plasma proteins haptoglobin and haemopexin bind and detoxify any free haemoglobin and haem released from red blood cells. The challenge for blood substitute research is to mimic these effects in a product that can still deliver oxygen. […] Despite ongoing research, these problems may prove to be insurmountable. There is therefore interest in a third approach. This is to grow artificial red blood cells using stem cell technology.”

Links:

Porphyrin. Globin.
Felix Hoppe-Seyler. Jacques Monod. Jeffries Wyman. Jean-Pierre Changeux.
Allosteric regulation. Monod-Wyman-Changeux model.
Structural Biochemistry/Hemoglobin (wikibooks). (Many of the topics covered in this link – e.g. comments on affinity, T/R-states, oxygen binding curves, the Bohr effect, etc. – are also covered in the book, so although I do link to some of the other topics also covered in this link below it should be noted that I did in fact leave out quite a few potentially relevant links on account of those topics being covered in the above link).
1,3-Bisphosphoglycerate.
Erythrocruorin.
Haemerythrin.
Hemocyanin.
Cytoglobin.
Neuroglobin.
Sickle cell anemia. Thalassaemia. Hemoglobinopathy. Porphyria.
Pulse oximetry.
Daniel Bernoulli. Hydrodynamica. Stephen Hales. Karl von Vierordt.
Arterial line.
Sphygmomanometer. Korotkoff sounds. Systole. Diastole. Blood pressure. Mean arterial pressure. Hypertension. Antihypertensive drugs. Atherosclerosis Pathology. Beta blocker. Diuretic.
Autoregulation.
Guanylate cyclase. Glyceryl trinitrate.
Blood transfusion. Richard Lower. Jean-Baptiste Denys. James Blundell.
Parabiosis.
Penrose Inquiry.
ABLE (Age of Transfused Blood in Critically Ill Adults) trial.
RECESS trial.

June 7, 2018 Posted by | Biology, Books, Cardiology, Chemistry, History, Medicine, Molecular biology, Pharmacology, Studies | Leave a comment

Molecular biology (III)

Below I have added a few quotes and links related to the last few chapters of the book‘s coverage.

“Normal ageing results in part from exhaustion of stem cells, the cells that reside in most organs to replenish damaged tissue. As we age DNA damage accumulates and this eventually causes the cells to enter a permanent non-dividing state called senescence. This protective ploy however has its downside as it limits our lifespan. When too many stem cells are senescent the body is compromised in its capacity to renew worn-out tissue, causing the effects of ageing. This has a knock-on effect of poor intercellular communication, mitochondrial dysfunction, and loss of protein balance (proteostasis). Low levels of chronic inflammation also increase with ageing and could be the trigger for changes associated with many age-related disorders.”

“There has been a dramatic increase in ageing research using yeast and invertebrates, leading to the discovery of more ‘ageing genes’ and their pathways. These findings can be extrapolated to humans since longevity pathways are conserved between species. The major pathways known to influence ageing have a common theme, that of sensing and metabolizing nutrients. […] The field was advanced by identification of the mammalian Target Of Rapamycin, aptly named mTOR. mTOR acts as a molecular sensor that integrates growth stimuli with nutrient and oxygen availability. Small molecules such as rapamycin that reduce mTOR signalling act in a similar way to severe dietary restriction in slowing the ageing process in organisms such as yeast and worms. […] Rapamycin and its derivatives (rapalogs) have been involved in clinical trials on reducing age-related pathologies […] Another major ageing pathway is telomere maintenance. […] Telomere attrition is a hallmark of ageing and studies have established an association between shorter telomere length (TL) and the risk of various common age-related ailments […] Telomere loss is accelerated by known determinants of ill health […] The relationship between TL and cancer appears complex.”

“Cancer is not a single disease but a range of diseases caused by abnormal growth and survival of cells that have the capacity to spread. […] One of the early stages in the acquisition of an invasive phenotype is epithelial-mesenchymal transition (EMT). Epithelial cells form skin and membranes and for this they have a strict polarity (a top and a bottom) and are bound in position by close connections with adjacent cells. Mesenchymal cells on the other hand are loosely associated, have motility, and lack polarization. The transition between epithelial and mesenchymal cells is a normal process during embryogenesis and wound healing but is deregulated in cancer cells. EMT involves transcriptional reprogramming in which epithelial structural proteins are lost and mesenchymal ones acquired. This facilitates invasion of a tumour into surrounding tissues. […] Cancer is a genetic disease but mostly not inherited from the parents. Normal cells evolve to become cancer cells by acquiring successive mutations in cancer-related genes. There are two main classes of cancer genes, the proto-oncogenes and the tumour suppressor genes. The proto-oncogenes code for protein products that promote cell proliferation. […] A mutation in a proto-oncogene changes it to an ‘oncogene’ […] One gene above all others is associated with cancer suppression and that is TP53. […] approximately half of all human cancers carry a mutated TP53 and in many more, p53 is deregulated. […] p53 plays a key role in eliminating cells that have either acquired activating oncogenes or excessive genomic damage. Thus mutations in the TP53 gene allows cancer cells to survive and divide further by escaping cell death […] A mutant p53 not only lacks the tumour suppressor functions of the normal or wild type protein but in many cases it also takes on the role of an oncogene. […] Overall 5-10 per cent of cancers occur due to inherited or germ line mutations that are passed from parents to offspring. Many of these genes code for DNA repair enzymes […] The vast majority of cancer mutations are not inherited; instead they are sporadic with mutations arising in somatic cells. […] At least 15 per cent of cancers are attributable to infectious agents, examples being HPV and cervical cancer, H. pylori and gastric cancer, and also hepatitis B or C and liver cancer.”

“There are about 10 million different sites at which people can vary in their DNA sequence withing the 3 billion bases in our DNA. […] A few, but highly variable sequences or minisatellites are chosen for DNA profiling. These give a highly sensitive procedure suitable for use with small amounts of body fluids […] even shorter sequences called microsatellite repeats [are also] used. Each marker or microsatellite is a short tandem repeat (STR) of two to five base pairs of DNA sequence. A single STR will be shared by up to 20 per cent of the population but by using a dozen or so identification markers in profile, the error is miniscule. […] Microsatellites are extremely useful for analysing low-quality or degraded DNA left at a crime scene as their short sequences are usually preserved. However, DNA in specimens that have not been optimally preserved persists in exceedingly small amounts and is also highly fragmented. It is probably also riddled by contamination and chemical damage. Such sources of DNA sources of DNA are too degraded to obtain a profile using genomic STRs and in these cases mitochondrial DNA, being more abundant, is more useful than nuclear DNA for DNA profiling. […]  Mitochondrial DNA profiling is the method of choice for determining the identities of missing or unknown people when a maternally linked relative can be found. Molecular biologists can amplify hypervariable regions of mitochondrial DNA by PCR to obtain enough material for analysis. The DNA products are sequenced and single nucleotide differences are sought with a reference DNA from a maternal relative. […] It has now become possible for […] ancient DNA to reveal much more than genotype matches. […] Pigmentation characteristics can now be determined from ancient DNA since skin, hair, and eye colour are some of the easiest characteristics to predict. This is due to the limited number of base differences or SNPs required to explain most of the variability.”

“A broad range of debilitating and fatal conditions, non of which can be cured, are associated with mitochondrial DNA mutations. […] [M]itochondrial DNA mutates ten to thirty times faster than nuclear DNA […] Mitochondrial DNA mutates at a higher rate than nuclear DNA due to higher numbers of DNA molecules and reduced efficiency in controlling DNA replication errors. […] Over 100,000 copies of mitochondrial DNA are present in the cytoplasm of the human egg or oocyte. After fertilization, only maternal mitochondria survive; the small numbers of the father’s mitochondria in the zygote are targeted for destruction. Thus all mitochondrial DNA for all cell types in the resulting embryo is maternal-derived. […] Patients affected by mitochondrial disease usually have a mixture of wild type (normal) and mutant mitochondrial DNA and the disease severity depends on the ratio of the two. Importantly the actual level of mutant DNA in a mother’s heteroplas[m]y […curiously the authors throughout the coverage insist on spelling this ‘heteroplasty’, which according to google is something quite different – I decided to correct the spelling error (?) here – US] is not inherited and offspring can be better or worse off than the mother. This also causes uncertainty since the ratio of wild type to mutant mitochondria may change during development. […] Over 700 mutations in mitochondrial DNA have been found leading to myopathies, neurodegeneration, diabetes, cancer, and infertility.”

Links:

Dementia. Alzheimer’s disease. Amyloid hypothesis. Tau protein. Proteopathy. Parkinson’s disease. TP53-inducible glycolysis and apoptosis regulator (TIGAR).
Progeria. Progerin. Werner’s syndrome. Xeroderma pigmentosum. Cockayne syndrome.
Shelterin.
Telomerase.
Alternative lengthening of telomeres: models, mechanisms and implications (Nature).
Coats plus syndrome.
Neoplasia. Tumor angiogenesis. Inhibitor protein MDM2.
Li–Fraumeni syndrome.
Non-coding RNA networks in cancer (Nature).
Cancer stem cell. (“The reason why current cancer therapies often fail to eradicate the disease is that the CSCs survive current DNA damaging treatments and repopulate the tumour.” See also this IAS lecture which covers closely related topics – US.)
Imatinib.
Restriction fragment length polymorphism (RFLP).
CODIS.
MC1R.
Archaic human admixture with modern humans.
El Tor strain.
DNA barcoding.
Hybrid breakdown/-inviability.
Trastuzumab.
Digital PCR.
Pearson’s syndrome.
Mitochondrial replacement therapy.
Synthetic biology.
Artemisinin.
Craig Venter.
Genome editing.
Indel.
CRISPR.
Tyrosinemia.

June 3, 2018 Posted by | Biology, Books, Cancer/oncology, Genetics, Medicine, Molecular biology | Leave a comment

Blood (I)

As I also mentioned on goodreads I was far from impressed with the first few pages of this book – but I read on, and the book actually turned out to include a decent amount of very reasonable coverage. Taking into consideration the way the author started out the three star rating should be considered a high rating, and in some parts of the book the author covers very complicated stuff in a really very decent manner, considering the format of the book and its target group.

Below I have added some quotes and some links to topics/people/ideas/etc. covered in the first half of the book.

“[Clotting] makes it difficult to study the components of blood. It also [made] it impossible to store blood for transfusion [in the past]. So there was a need to find a way to prevent clotting. Fortunately the discovery that the metal calcium accelerated the rate of clotting enabled the development of a range of compounds that bound calcium and therefore prevented this process. One of them, citrate, is still in common use today [here’s a relevant link, US] when blood is being prepared for storage, or to stop blood from clotting while it is being pumped through kidney dialysis machines and other extracorporeal circuits. Adding citrate to blood, and leaving it alone, will result in gravity gradually separating the blood into three layers; the process can be accelerated by rapid spinning in a centrifuge […]. The top layer is clear and pale yellow or straw-coloured in appearance. This is the plasma, and it contains no cells. The bottom layer is bright red and contains the dense pellet of red cells that have sunk to the bottom of the tube. In-between these two layers is a very narrow layer, called the ‘buffy coat’ because of its pale yellow-brown appearance. This contains white blood cells and platelets. […] red cells, white cells, and platelets […] define the primary functions of blood: oxygen transport, immune defence, and coagulation.”

“The average human has about five trillion red blood cells per litre of blood or thirty trillion […] in total, making up a quarter of the total number of cells in the body. […] It is clear that the red cell has primarily evolved to perform a single function, oxygen transportation. Lacking a nucleus, and the requisite machinery to control the synthesis of new proteins, there is a limited ability for reprogramming or repair. […] each cell [makes] a complete traverse of the body’s circulation about once a minute. In its three- to four-month lifetime, this means every cell will do the equivalent of 150,000 laps around the body. […] Red cells lack mitochondria; they get their energy by fermenting glucose. […] A prosaic explanation for their lack of mitochondria is that it prevents the loss of any oxygen picked up from the lungs on the cells’ journey to the tissues that need it. The shape of the red cell is both deformable and elastic. In the bloodstream each cell is exposed to large shear forces. Yet, due to the properties of the membrane, they are able to constrict to enter blood vessels smaller in diameter than their normal size, bouncing back to their original shape on exiting the vessel the other side. This ability to safely enter very small openings allows capillaries to be very small. This in turn enables every cell in the body to be close to a capillary. Oxygen consequently only needs to diffuse a short distance from the blood to the surrounding tissue; this is vital as oxygen diffusion outside the bloodstream is very slow. Various pathologies, such as diabetes, peripheral vascular disease, and septic shock disturb this deformability of red blood cells, with deleterious consequences.”

“Over thirty different substances, proteins and carbohydrates, contribute to an individual’s blood group. By far the best known are the ABO and Rhesus systems. This is not because the proteins and carbohydrates that comprise these particular blood group types are vitally important for red cell function, but rather because a failure to account for these types during a blood transfusion can have catastrophic consequences. The ABO blood group is sugar-based […] blood from an O person can be safely given to anyone (with no sugar antigens this person is a ‘universal’ donor). […] As all that is needed to convert A and B to O is to remove a sugar, there is commercial and medical interest in devising ways to do this […] the Rh system […] is protein-based rather than sugar based. […] Rh proteins sit in the lipid membrane of the cell and control the transport of molecules into and out of the cell, most probably carbon dioxide and ammonia. The situation is complex, with over thirty different subgroups relating to subtle differences in the protein structure.”

“Unlike the red cells, all white cell subtypes contain nuclei. Some also contain on their surface a set of molecules called the ‘major histocompatibility complex’ (MHC). In humans, these receptors are also called ‘human leucocyte antigens’ (HLA). Their role is to recognize fragments of protein from pathogens and trigger the immune response that will ultimately destroy the invaders. Crudely, white blood cells can be divided into those that attack ‘on sight’ any foreign material — whether it be a fragment of inanimate material such as a splinter or an invading microorganism — and those that form part of a defence mechanism that recognizes specific biomolecules and marshals a slower, but equally devastating response. […] cells of the non-specific (or innate) immune system […] are divided into those that have nuclei with multiple lobed shapes (polymorphonuclear leukocytes or PMN) and those that have a single lobe nucleus ([…] ‘mononuclear leucocytes‘ or ‘MN’). PMN contain granules inside them and so are sometimes called ‘granulocytes‘.”

“Neutrophils are by far the most abundant PMN, making up over half of the total white blood cell count. The primary role of a neutrophil is to engulf a foreign object such as an invading microorganism. […] Eosinophils and basophils are the least abundant PMN cell type, each making up less than 2 per cent of white blood cells. The role of basophils is to respond to tissue injury by triggering an inflammatory response. […] When activated, basophils and mast cells degranulate, releasing molecules such as histamine, leukotrienes, and cytokines. Some of these molecules trigger an increase in blood flow causing redness and heat in the damaged site, others sensitize the area to pain. Greater permeability of the blood vessels results in plasma leaking out of the vessels and into the surrounding tissue at an increased rate, causing swelling. […] This is probably an evolutionary adaption to prevent overuse of a damaged part of the body but also helps to bring white cells and proteins to the damaged, inflamed area. […] The main function of eosinophils is to tackle invaders too large to be engulfed by neutrophils, such as the multicellular parasitic tapeworms and nematodes. […] Monocytes are a type of mononuclear leucocyte (MN) making up about 5 per cent of white blood cells. They spend even less tiem in the circulation than neutrophils, generally less than ten hours, but their time in the blood circulation does not end in death. Instead, they are converted into a cell called a ‘macrophage‘ […] Their role is similar to the neutrophil, […] the ultimate fate of both the red blood cell and the neutrophil is to be engulfed by a macrophage. An excess of monocytes in a blood count (monocytosis) is an indicator of chronic inflammation”.

“Blood has to flow freely. Therefore, the red cells, white cells, and platelets are all suspended in a watery solution called ‘plasma’. But plasma is more than just water. In fact if it were only water all the cells would burst. Plasma has to have a very similar concentration of molecules and ions as the cells. This is because cells are permeable to water. So if the concentration of dissolved substances in the plasma was significantly higher than that in the cells, water would flow from the cells to the plasma in an attempt to equalize this gradient by diluting the plasma; this would result in cell shrinkage. Even worse, if the concentration in the plasma was lower than in the cells, water would flow into the cells from the plasma, and the resulting pressure increase would burst the cells, releasing all their contents into the plasma in the process. […] Plasma contains much more than just the ions required to prevent cells bursting or shrinking. It also contains key components designed to assist in cellular function. The protein clotting factors that are part of the coagulation cascade are always present in low concentrations […] Low levels of antibodies, produced by the lymphocytes, circulate […] In addition to antibodies, the plasma contains C-reactive proteins, Mannose-binding lectin and complement proteins that function as ‘opsonins‘ […] A host of other proteins perform roles independent of oxygen delivery or immune defence. By far the most abundant protein in serum is albumin. […] Blood is the transport infrastructure for any molecule that needs to be moved around the body. Some, such as the water-soluble fuel glucose, and small hormones like insulin, dissolve freely in the plasma. Others that are less soluble hitch a ride on proteins [….] Dangerous reactive molecules, such as iron, are also bound to proteins, in this case transferrin.”

Immunoglobulins are produced by B lymphocytes and either remain bound on the surface of the cell (as part of the B cell receptor) or circulate freely in the plasma (as antibodies). Whatever their location, their purpose is the same – to bind to and capture foreign molecules (antigens). […] To perform the twin role of binding the antigen and the phagocytosing cell, immunoglobulins need to have two distinct parts to their structure — one that recognizes the foreign antigen and one that can be recognized — and destroyed — by the host defence system. The host defence system does not vary; a specific type of immunoglobulin will be recognized by one of the relatively few types of immune cells or proteins. Therefore this part of the immunoglobulin structure is not variable. But the nature of the foreign antigen will vary greatly; so the antigen-recognizing part of the structure must be highly variable. It is this that leads to the great variety of immunoglobulins. […] within the blood there is an army of potential binding sites that can recognize and bind to almost any conceivable chemical structure. Such variety is why the body is able to adapt and kill even organisms it has never encountered before. Indeed the ability to make an immunoglobulin recognize almost any structure has resulted in antibody binding assays being used historically in diagnostic tests ranging from pregnancy to drugs testing.”

“[I]mmunoglobulins consist of two different proteins — a heavy chain and a light chain. In the human heavy chain there are about forty different V (variable) segments, twenty-five different D (Diversity) segments, and six J (Joining) segments. The light chain also contains variable V and J segments. A completed immunoglobulin has a heavy chain with only one V, D, and J segment, and a light chain with only one V and D segment. It is the shuffling of these segments during development of the mature B lymphocyte that creates the diversity required […] the hypervariable regions are particularly susceptible to mutation during development. […] A separate class of immunoglobulin-like molecules also provide the key to cell-to-cell communication in the immune system. In humans, with the exception of the egg and sperm cells, all cells that possess a nucleus also have a protein on their surface called ‘Human Leucocyte Antigen (HLA) Class I’. The function of HLA Class I is to display fragments (antigens) of all the proteins currently being made inside the cell. It therefore acts like a billboard displaying the current highlights of cellular activity. Any proteins recognized as non-self by cytotoxic T cell lymphocytes will result in the whole cell being targeted for destruction […]. Another form of HLA, Class II, is only present on the surface of specialized cells of the immune system termed antigen presenting cells. In contrast to HLA Class I, the surface of HLA Class II cells displays antigens that originate from outside of the cell.”

Galen.
Bloodletting.
Marcello Malpighi.
William Harvey. De Motu Cordis.
Andreas Vesalius. De humani corporis fabrica.
Ibn al-Nafis. Michael Servetus. Realdo Colombo. Andrea Cesalpino.
Pulmonary circulation.
Hematopoietic stem cell. Bone marrow. Erythropoietin.
Hemoglobin.
Anemia.
Peroxidase.
Lymphocytes. NK cells. Granzyme. B lymphocytes. T lymphocytes. Antibody/Immunoglobulin. Lymphoblast.
Platelet. Coagulation cascade. Fibrinogen. Fibrin. Thrombin. Haemophilia. Hirudin. Von Willebrand disease. Haemophilia A. -ll- B.
Tonicity. Colloid osmotic pressure.
Adaptive immune system. Vaccination. VariolationAntiserum. Agostino Bassi. Muscardine. Louis Pasteur. Élie Metchnikoff. Paul Ehrlich.
Humoral immunity. Membrane attack complex.
Niels Kaj Jerne. David Talmage. Frank Burnet. Clonal selection theory. Peter Medawar.
Susumu Tonegawa.

June 2, 2018 Posted by | Biology, Books, Immunology, Medicine, Molecular biology | Leave a comment

A few diabetes papers of interest

i. Reevaluating the Evidence for Blood Pressure Targets in Type 2 Diabetes.

“There is general consensus that treating adults with type 2 diabetes mellitus (T2DM) and hypertension to a target blood pressure (BP) of <140/90 mmHg helps prevent cardiovascular disease (CVD). Whether more intensive BP control should be routinely targeted remains a matter of debate. While the American Diabetes Association (ADA) BP guidelines recommend an individualized assessment to consider different treatment goals, the American College of Cardiology/American Heart Association BP guidelines recommend a BP target of <130/80 mmHg for most individuals with hypertension, including those with T2DM (13).

In large part, these discrepant recommendations reflect the divergent results of the Action to Control Cardiovascular Risk in Diabetes-BP trial (ACCORD-BP) among people with T2DM and the Systolic Blood Pressure Intervention Trial (SPRINT), which excluded people with diabetes (4,5). Both trials evaluated the effect of intensive compared with standard BP treatment targets (<120 vs. <140 mmHg systolic) on a composite CVD end point of nonfatal myocardial infarction or stroke or death from cardiovascular causes. SPRINT also included unstable angina and acute heart failure in its composite end point. While ACCORD-BP did not show a significant benefit from the intervention (hazard ratio [HR] 0.88; 95% CI 0.73–1.06), SPRINT found a significant 25% relative risk reduction on the primary end point favoring intensive therapy (0.75; 0.64–0.89).”

“To some extent, CVD mechanisms and causes of death differ in T2DM patients compared with the general population. Microvascular disease (particularly kidney disease), accelerated vascular calcification, and diabetic cardiomyopathy are common in T2DM (1315). Moreover, the rate of sudden cardiac arrest is markedly increased in T2DM and related, in part, to diabetes-specific factors other than ischemic heart disease (16). Hypoglycemia is a potential cause of CVD mortality that is specific to diabetes (17). In addition, polypharmacy is common and may increase CVD risk (18). Furthermore, nonvascular causes of death account for approximately 40% of the premature mortality burden experienced by T2DM patients (19). Whether these disease processes may render patients with T2DM less amenable to derive a mortality benefit from intensive BP control, however, is not known and should be the focus of future research.

In conclusion, the divergent results between ACCORD-BP and SPRINT are most readily explained by the apparent lack of benefit of intensive BP control on CVD and all-cause mortality in ACCORD-BP, rather than differences in the design, population characteristics, or interventions between the trials. This difference in effects on mortality may be attributable to differential mechanisms underlying CVD mortality in T2DM, to chance, or to both. These observations suggest that caution should be exercised extrapolating the results of SPRINT to patients with T2DM and support current ADA recommendations to individualize BP targets, targeting a BP of <140/90 mmHg in the majority of patients with T2DM and considering lower BP targets when it is anticipated that individual benefits outweigh risks.”

ii. Modelling incremental benefits on complications rates when targeting lower HbA1c levels in people with Type 2 diabetes and cardiovascular disease.

“Glucose‐lowering interventions in Type 2 diabetes mellitus have demonstrated reductions in microvascular complications and modest reductions in macrovascular complications. However, the degree to which targeting different HbA1c reductions might reduce risk is unclear. […] Participant‐level data for Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS) participants with established cardiovascular disease were used in a Type 2 diabetes‐specific simulation model to quantify the likely impact of different HbA1c decrements on complication rates. […] The use of the TECOS data limits our findings to people with Type 2 diabetes and established cardiovascular disease. […] Ten‐year micro‐ and macrovascular rates were estimated with HbA1c levels fixed at 86, 75, 64, 53 and 42 mmol/mol (10%, 9%, 8%, 7% and 6%) while holding other risk factors constant at their baseline levels. Cumulative relative risk reductions for each outcome were derived for each HbA1c decrement. […] Of 5717 participants studied, 72.0% were men and 74.2% White European, with a mean (sd) age of 66.2 (7.9) years, systolic blood pressure 134 (16.9) mmHg, LDL‐cholesterol 2.3 (0.9) mmol/l, HDL‐cholesterol 1.13 (0.3) mmol/l and median Type 2 diabetes duration 9.6 (5.1–15.6) years. Ten‐year cumulative relative risk reductions for modelled HbA1c values of 75, 64, 53 and 42 mmol/mol, relative to 86 mmol/mol, were 4.6%, 9.3%, 15.1% and 20.2% for myocardial infarction; 6.0%, 12.8%, 19.6% and 25.8% for stroke; 14.4%, 26.6%, 37.1% and 46.4% for diabetes‐related ulcer; 21.5%, 39.0%, 52.3% and 63.1% for amputation; and 13.6%, 25.4%, 36.0% and 44.7 for single‐eye blindness. […] We did not investigate outcomes for renal failure or chronic heart failure as previous research conducted to create the model did not find HbA1c to be a statistically significant independent risk factor for either condition, therefore no clinically meaningful differences would be expected from modelling different HbA1c levels 11.”

“For microvascular complications, the absolute median estimates tended to be lower than for macrovascular complications at the same HbA1c level, but cumulative relative risk reductions were greater. For amputation the 10‐year absolute median estimate for a modelled constant HbA1c of 86 mmol/mol (10%) was 3.8% (3.7, 3.9), with successively lower values for each modelled 1% HbA1c decrement. Compared with the 86 mmol/mol (10%) HbA1c level, median relative risk reductions for amputation were 21.5% (21.1, 21.9) at 75 mmol/mol (9%) increasing to 52.3% (52.0, 52.6) at 53 mmol/mol (7%). […] Relative risk reductions in micro‐ and macrovascular complications for each 1% HbA1c reduction were similar for each decrement. The exception was all‐cause mortality, where the relative risk reductions for 1% HbA1c decrements were greater at higher baseline HbA1c levels. These simulated outcomes differ from the Diabetes Control and Complications Trial outcome in people with Type 1 diabetes, where lowering HbA1c from higher baseline levels had a greater impact on microvascular risk reduction 18.”

iii. Laser photocoagulation for proliferative diabetic retinopathy (Cochrane review).

“Diabetic retinopathy is a complication of diabetes in which high blood sugar levels damage the blood vessels in the retina. Sometimes new blood vessels grow in the retina, and these can have harmful effects; this is known as proliferative diabetic retinopathy. Laserphotocoagulation is an intervention that is commonly used to treat diabetic retinopathy, in which light energy is applied to the retinawith the aim of stopping the growth and development of new blood vessels, and thereby preserving vision. […] The aim of laser photocoagulation is to slow down the growth of new blood vessels in the retina and thereby prevent the progression of visual loss (Ockrim 2010). Focal laser photocoagulation uses the heat of light to seal or destroy abnormal blood vessels in the retina. Individual vessels are treated with a small number of laser burns.

PRP [panretinal photocoagulation, US] aims to slow down the growth of new blood vessels in a wider area of the retina. Many hundreds of laser burns are placed on the peripheral parts of the retina to stop blood vessels from growing (RCOphth 2012). It is thought that the anatomic and functional changes that result from photocoagulation may improve the oxygen supply to the retina, and so reduce the stimulus for neovascularisation (Stefansson 2001). Again the exact mechanisms are unclear, but it is possible that the decreased area of retinal tissue leads to improved oxygenation and a reduction in the levels of anti-vascular endothelial growth factor. A reduction in levels of anti-vascular endothelial growth factor may be important in reducing the risk of harmful new vessels forming. […] Laser photocoagulation is a well-established common treatment for DR and there are many different potential strategies for delivery of laser treatment that are likely to have different effects. A systematic review of the evidence for laser photocoagulation will provide important information on benefits and harms to guide treatment choices. […] This is the first in a series of planned reviews on laser photocoagulation. Future reviews will compare different photocoagulation techniques.”

“We identified a large number of trials of laser photocoagulation of diabetic retinopathy (n = 83) but only five of these studies were eligible for inclusion in the review, i.e. they compared laser photocoagulation with currently available lasers to no (or deferred) treatment. Three studies were conducted in the USA, one study in the UK and one study in Japan. A total of 4786 people (9503 eyes) were included in these studies. The majority of participants in four of these trials were people with proliferative diabetic retinopathy; one trial recruited mainly people with non-proliferative retinopathy.”

“At 12 months there was little difference between eyes that received laser photocoagulation and those allocated to no treatment (or deferred treatment), in terms of loss of 15 or more letters of visual acuity (risk ratio (RR) 0.99, 95% confidence interval (CI) 0.89 to1.11; 8926 eyes; 2 RCTs, low quality evidence). Longer term follow-up did not show a consistent pattern, but one study found a 20% reduction in risk of loss of 15 or more letters of visual acuity at five years with laser treatment. Treatment with laser reduced the risk of severe visual loss by over 50% at 12 months (RR 0.46, 95% CI 0.24to 0.86; 9276 eyes; 4 RCTs, moderate quality evidence). There was a beneficial effect on progression of diabetic retinopathy with treated eyes experiencing a 50% reduction in risk of progression of diabetic retinopathy (RR 0.49, 95% CI 0.37 to 0.64; 8331 eyes; 4 RCTs, low quality evidence) and a similar reduction in risk of vitreous haemorrhage (RR 0.56, 95% CI 0.37 to 0.85; 224 eyes; 2RCTs, low quality evidence).”

“Overall there is not a large amount of evidence from RCTs on the effects of laser photocoagulation compared to no treatment or deferred treatment. The evidence is dominated by two large studies conducted in the US population (DRS 1978; ETDRS 1991). These two studies were generally judged to be at low or unclear risk of bias, with the exception of inevitable unmasking of patients due to differences between intervention and control. […] In current clinical guidelines, e.g. RCOphth 2012, PRP is recommended in high-risk PDR. The recommendation is that “as retinopathy approaches the proliferative stage, laser scatter treatment (PRP) should be increasingly considered to prevent progression to high risk PDR” based on other factors such as patients’ compliance or planned cataract surgery.

These recommendations need to be interpreted while considering the risk of visual loss associated with different levels of severity of DR, as well as the risk of progression. Since PRP reduces the risk of severe visual loss, but not moderate visual loss that is more related to diabetic maculopathy, most ophthalmologists judge that there is little benefit in treating non-proliferative DR at low risk of severe visual damage, as patients would incur the known adverse effects of PRP, which, although mild, include pain and peripheral visual field loss and transient DMO [diabetic macular oedema, US]. […] This review provides evidence that laser photocoagulation is beneficial in treating diabetic retinopathy. […] based on the baseline risk of progression of the disease, and risk of visual loss, the current approach of caution in treating non-proliferative DR with laser would appear to be justified.

By current standards the quality of the evidence is not high, however, the effects on risk of progression and risk of severe visual loss are reasonably large (50% relative risk reduction).”

iv. Immune Recognition of β-Cells: Neoepitopes as Key Players in the Loss of Tolerance.

I should probably warn beforehand that this one is rather technical. It relates reasonably closely to topics covered in the molecular biology book I recently covered here on the blog, and if I had not read that book quite recently I almost certainly would not have been able to read the paper – so the coverage below is more ‘for me’ than ‘for you’. Anyway, some quotes:

“Prior to the onset of type 1 diabetes, there is progressive loss of immune self-tolerance, evidenced by the accumulation of islet autoantibodies and emergence of autoreactive T cells. Continued autoimmune activity leads to the destruction of pancreatic β-cells and loss of insulin secretion. Studies of samples from patients with type 1 diabetes and of murine disease models have generated important insights about genetic and environmental factors that contribute to susceptibility and immune pathways that are important for pathogenesis. However, important unanswered questions remain regarding the events that surround the initial loss of tolerance and subsequent failure of regulatory mechanisms to arrest autoimmunity and preserve functional β-cells. In this Perspective, we discuss various processes that lead to the generation of neoepitopes in pancreatic β-cells, their recognition by autoreactive T cells and antibodies, and potential roles for such responses in the pathology of disease. Emerging evidence supports the relevance of neoepitopes generated through processes that are mechanistically linked with β-cell stress. Together, these observations support a paradigm in which neoepitope generation leads to the activation of pathogenic immune cells that initiate a feed-forward loop that can amplify the antigenic repertoire toward pancreatic β-cell proteins.”

“Enzymatic posttranslational processes that have been implicated in neoepitope generation include acetylation (10), citrullination (11), glycosylation (12), hydroxylation (13), methylation (either protein or DNA methylation) (14), phosphorylation (15), and transglutamination (16). Among these, citrullination and transglutamination are most clearly implicated as processes that generate neoantigens in human disease, but evidence suggests that others also play a role in neoepitope formation […] Citrulline, which is among the most studied PTMs in the context of autoimmunity, is a diagnostic biomarker of rheumatoid arthritis (RA). […] Anticitrulline antibodies are among the earliest immune responses that are diagnostic of RA and often correlate with disease severity (18). We have recently documented the biological consequences of citrulline modifications and autoimmunity that arise from pancreatic β-cell proteins in the development of T1D (19). In particular, citrullinated GAD65 and glucose-regulated protein (GRP78) elicit antibody and T-cell responses in human T1D and in NOD diabetes, respectively (20,21).”

Carbonylation is an irreversible, iron-catalyzed oxidative modification of the side chains of lysine, arginine, threonine, or proline. Mitochondrial functions are particularly sensitive to carbonyl modification, which also has detrimental effects on other intracellular enzymatic pathways (30). A number of diseases have been linked with altered carbonylation of self-proteins, including Alzheimer and Parkinson diseases and cancer (27). There is some data to support that carbonyl PTM is a mechanism that directs unstable self-proteins into cellular degradation pathways. It is hypothesized that carbonyl PTM [post-translational modification] self-proteins that fail to be properly degraded in pancreatic β-cells are autoantigens that are targeted in T1D. Recently submitted studies have identified several carbonylated pancreatic β-cell neoantigens in human and murine models of T1D (27). Among these neoantigens are chaperone proteins that are required for the appropriate folding and secretion of insulin. These studies imply that although some PTM self-proteins may be direct targets of autoimmunity, others may alter, interrupt, or disturb downstream metabolic pathways in the β-cell. In particular, these studies indicated that upstream PTMs resulted in misfolding and/or metabolic disruption between proinsulin and insulin production, which provides one explanation for recent observations of increased proinsulin-to-insulin ratios in the progression of T1D (31).”

“Significant hypomethylation of DNA has been linked with several classic autoimmune diseases, such as SLE, multiple sclerosis, RA, Addison disease, Graves disease, and mixed connective tissue disease (36). Therefore, there is rationale to consider the possible influence of epigenetic changes on protein expression and immune recognition in T1D. Relevant to T1D, epigenetic modifications occur in pancreatic β-cells during progression of diabetes in NOD mice (37). […] Consequently, DNMTs [DNA methyltransferases] and protein arginine methyltransferases are likely to play a role in the regulation of β-cell differentiation and insulin gene expression, both of which are pathways that are altered in the presence of inflammatory cytokines. […] Eizirik et al. (38) reported that exposure of human islets to proinflammatory cytokines leads to modulation of transcript levels and increases in alternative splicing for a number of putative candidate genes for T1D. Their findings suggest a mechanism through which alternative splicing may lead to the generation of neoantigens and subsequent presentation of novel β-cell epitopes (39).”

“The phenomenon of neoepitope recognition by autoantibodies has been shown to be relevant in a variety of autoimmune diseases. For example, in RA, antibody responses directed against various citrullinated synovial proteins are remarkably disease-specific and routinely used as a diagnostic test in the clinic (18). Appearance of the first anticitrullinated protein antibodies occurs years prior to disease onset, and accumulation of additional autoantibody specificities correlates closely with the imminent onset of clinical arthritis (44). There is analogous evidence supporting a hierarchical emergence of autoantibody specificities and multiple waves of autoimmune damage in T1D (3,45). Substantial data from longitudinal studies indicate that insulin and GAD65 autoantibodies appear at the earliest time points during progression, followed by additional antibody specificities directed at IA-2 and ZnT8.”

“Multiple autoimmune diseases often cluster within families (or even within one person), implying shared etiology. Consequently, relevant insights can be gleaned from studies of more traditional autoantibody-mediated systemic autoimmune diseases, such as SLE and RA, where inter- and intramolecular epitope spreading are clearly paradigms for disease progression (47). In general, early autoimmunity is marked by restricted B- and T-cell epitopes, followed by an expanded repertoire coinciding with the onset of more significant tissue pathology […] Akin to T1D, other autoimmune syndromes tend to cluster to subcellular tissues or tissue components that share biological or biochemical properties. For example, SLE is marked by autoimmunity to nucleic acid–bearing macromolecules […] Unlike other systemic autoantibody-mediated diseases, such as RA and SLE, there is no clear evidence that T1D-related autoantibodies play a pathogenic role. Autoantibodies against citrulline-containing neoepitopes of proteoglycan are thought to trigger or intensify arthritis by forming immune complexes with this autoantigen in the joints of RA patients with anticitrullinated protein antibodies. In a similar manner, autoantibodies and immune complexes are hallmarks of tissue pathology in SLE. Therefore, it remains likely that autoantibodies or the B cells that produce them contribute to the pathogenesis of T1D.”

“In summation, the existing literature demonstrates that oxidation, citrullination, and deamidation can have a direct impact on T-cell recognition that contributes to loss of tolerance.”

“There is a general consensus that the pathogenesis of T1D is initiated when individuals who possess a high level of genetic risk (e.g., susceptible HLA, insulin VNTR, PTPN22 genotypes) are exposed to environmental factors (e.g., enteroviruses, diet, microbiome) that precipitate a loss of tolerance that manifests through the appearance of insulin and/or GAD autoantibodies. This early autoimmunity is followed by epitope spreading, increasing both the number of antigenic targets and the diversity of epitopes within these targets. These processes create a feed-forward loop antigen release that induces increasing inflammation and increasing numbers of distinct T-cell specificities (64). The formation and recognition of neoepitopes represents one mechanism through which epitope spreading can occur. […] mechanisms related to neoepitope formation and recognition can be envisioned at multiple stages of T1D pathogenesis. At the level of genetic risk, susceptible individuals may exhibit a genetically driven impairment of their stress response, increasing the likelihood of neoepitope formation. At the level of environmental exposure, many of the insults that are thought to initiate T1D are known to cause neoepitope formation. During the window of β-cell destruction that encompasses early autoimmunity through dysglycemia and diagnosis of T1D it remains unclear when neoepitope responses appear in relation to “classic” responses to insulin and GAD65. However, by the time of onset, neoepitope responses are clearly present and remain as part of the ongoing autoimmunity that is present during established T1D. […] The ultimate product of both direct and indirect generation of neoepitopes is an accumulation of robust and diverse autoimmune B- and T-cell responses, accelerating the pathological destruction of pancreatic islets. Clearly, the emergence of sophisticated methods of tissue and single-cell proteomics will identify novel neoepitopes, including some that occur at near the earliest stages of disease. A detailed mechanistic understanding of the pathways that lead to specific classes of neoepitopes will certainly suggest targets of therapeutic manipulation and intervention that would be hoped to impede the progression of disease.”

v. Diabetes technology: improving care, improving patient‐reported outcomes and preventing complications in young people with Type 1 diabetes.

“With the evolution of diabetes technology, those living with Type 1 diabetes are given a wider arsenal of tools with which to achieve glycaemic control and improve patient‐reported outcomes. Furthermore, the use of these technologies may help reduce the risk of acute complications, such as severe hypoglycaemia and diabetic ketoacidosis, as well as long‐term macro‐ and microvascular complications. […] Unfortunately, diabetes goals are often unmet and people with Type 1 diabetes too frequently experience acute and long‐term complications of this condition, in addition to often having less than ideal psychosocial outcomes. Increasing realization of the importance of patient‐reported outcomes is leading to diabetes care delivery becoming more patient‐centred. […] Optimal diabetes management requires both the medical and psychosocial needs of people with Type 1 diabetes and their caregivers to be addressed. […] The aim of this paper was to demonstrate how, by incorporating technology into diabetes care, we can increase patient‐centered care, reduce acute and chronic diabetes complications, and improve clinical outcomes and quality of life.”

[The paper’s Table 2 on page 422 of the pdf-version is awesome, it includes a lot of different Hba1c estimates from various patient populations all across the world. The numbers included in the table are slightly less awesome, as most populations only achieve suboptimal metabolic control.]

“The risks of all forms of complications increase with higher HbA1c concentration, increasing diabetes duration, hypertension, presence of other microvascular complications, obesity, insulin resistance, hyperlipidaemia and smoking 6. Furthermore, the Diabetes Research in Children (DirecNet) study has shown that individuals with Type 1 diabetes have white matter differences in the brain and cognitive differences compared with individuals without Type 1 diabetes. These studies showed that the degree of structural differences in the brain were related to the degree of chronic hyperglycaemia, hypoglycaemia and glucose variability 7. […] In addition to long‐term complications, people with Type 1 diabetes are also at risk of acute complications. Severe hypoglycaemia, a hypoglycaemic event resulting in altered/loss of consciousness or seizures, is a serious complication of insulin therapy. If unnoticed and untreated, severe hypoglycaemia can result in death. […] The incidence of diabetic ketoacidosis, a life‐threatening consequence of diabetes, remains unacceptably high in children with established diabetes (Table 5). The annual incidence of ketoacidosis was 5% in the Prospective Diabetes Follow‐Up Registry (DPV) in Germany and Austria, 6.4% in the National Paediatric Diabetes Audit (NPDA), and 7.1% in the Type 1 Diabetes Exchange (T1DX) registry 10. Psychosocial factors including female gender, non‐white race, lower socio‐economic status, and elevated HbA1c all contribute to increased risk of diabetic ketoacidosis 11.”

“Depression is more common in young people with Type 1 diabetes than in young people without a chronic disease […] Depression can make it more difficult to engage in diabetes self‐management behaviours, and as a result, contributes to suboptimal glycaemic control and lower rates of self‐monitoring of blood glucose (SMBG) in young people with Type 1 diabetes 15. […] Unlike depression, diabetes distress is not a clinical diagnosis but rather emotional distress that comes from the burden of living with and managing diabetes 16. A recent systematic review found that roughly one‐third of young people with Type 1 diabetes (age 10–20 years) have some level of diabetes distress and that diabetes distress was consistently associated with higher HbA1c and worse self‐management 17. […] Eating and weight‐related comorbidities also exist for individuals with Type 1 diabetes. There is a higher incidence of obesity in individuals with Type 1 diabetes on intensive insulin therapy. […] Adolescent girls and young adult women with Type 1 diabetes are more likely to omit insulin for weight loss and have disordered eating habits 20.”

“In addition to screening for and treating depression and diabetes distress to improve overall diabetes management, it is equally important to assess quality of life as well as positive coping factors that may also influence self‐management and well‐being. For example, lower scores on the PROMIS® measure of global health, which assesses social relationships as well as physical and mental well‐being, have been linked to higher depression scores and less frequent blood glucose checks 13. Furthermore, coping strategies such as problem‐solving, emotional expression, and acceptance have been linked to lower HbA1c and enhanced quality of life 21.”

“Self‐monitoring of blood glucose via multiple finger sticks for capillary blood samples per day has been the ‘gold standard’ for glucose monitoring, but SMBG only provides glucose measurements as snapshots in time. Still, the majority of young people with Type 1 diabetes use SMBG as their main method to assess glycaemia. Data from the T1DX registry suggest that an increased frequency of SMBG is associated with lower HbA1c levels 23. The development of continuous glucose monitoring (CGM) provides more values, along with the rate and direction of glucose changes. […] With continued use, CGM has been shown to decrease the incidence of hypoglycaemia and HbA1c levels 26. […] Insulin can be administered via multiple daily injections or continuous subcutaneous insulin infusion (insulin pumps). Over the last 30 years, insulin pumps have become smaller with more features, making them a valuable alternative to multiple daily injections. Insulin pump use in various registries ranges from as low as 5.9% among paediatric patients in the New Zealand national register 28 to as high as 74% in the German/Austrian DPV in children aged <6 years (Table 2) 29. Recent data suggest that consistent use of insulin pumps can result in improved HbA1c values and decreased incidence of severe hypoglycaemia 30, 31. Insulin pumps have been associated with improved quality of life 32. The data on insulin pumps and diabetic ketoacidosis are less clear.”

“The majority of Type 1 diabetes management is carried out outside the clinical setting and in individuals’ daily lives. People with Type 1 diabetes must make complex treatment decisions multiple times daily; thus, diabetes self‐management skills are central to optimal diabetes management. Unfortunately, many people with Type 1 diabetes and their caregivers are not sufficiently familiar with the necessary diabetes self‐management skills. […] Parents are often the first who learn these skills. As children become older, they start receiving more independence over their diabetes care; however, the transition of responsibilities from caregiver to child is often unstructured and haphazard. It is important to ensure that both individuals with diabetes and their caregivers have adequate self‐management skills throughout the diabetes journey.”

“In the developed world (nations with the highest gross domestic product), 87% of the population has access to the internet and 68% report using a smartphone 39. Even in developing countries, 54% of people use the internet and 37% own smartphones 39. In many areas, smartphones are the primary source of internet access and are readily available. […] There are >1000 apps for diabetes on the Apple App Store and the Google Play store. Many of these apps have focused on nutrition, blood glucose logging, and insulin dosing. Given the prevalence of smartphones and the interest in having diabetes apps handy, there is the potential for using a smartphone to deliver education and decision support tools. […] The new psychosocial position statement from the ADA recommends routine psychosocial screening in clinic. These recommendations include screening for: 1) depressive symptoms annually, at diagnosis, or with changes in medical status; 2) anxiety and worry about hypoglycaemia, complications and other diabetes‐specific worries; 3) disordered eating and insulin omission for purposes of weight control; 4) and diabetes distress in children as young as 7 or 8 years old 16. Implementation of in‐clinic screening for depression in young people with Type 1 diabetes has already been shown to be feasible, acceptable and able to identify individuals in need of treatment who may otherwise have gone unnoticed for a longer period of time which would have been having a detrimental impact on physical health and quality of life 13, 40. These programmes typically use tablets […] to administer surveys to streamline the screening process and automatically score measures 13, 40. This automation allows psychologists and social workers to focus on care delivery rather than screening. In addition to depression screening, automated tablet‐based screening for parental depression, distress and anxiety; problem‐solving skills; and resilience/positive coping factors can help the care team understand other psychosocial barriers to care. This approach allows the development of patient‐ and caregiver‐centred interventions to improve these barriers, thereby improving clinical outcomes and complication rates.”

“With the advent of electronic health records, registries and downloadable medical devices, people with Type 1 diabetes have troves of data that can be analysed to provide insights on an individual and population level. Big data analytics for diabetes are still in the early stages, but present great potential for improving diabetes care. IBM Watson Health has partnered with Medtronic to deliver personalized insights to individuals with diabetes based on device data 48. Numerous other systems […] allow people with Type 1 diabetes to access their data, share their data with the healthcare team, and share de‐identified data with the research community. Data analysis and insights such as this can form the basis for the delivery of personalized digital health coaching. For example, historical patterns can be analysed to predict activity and lead to pro‐active insulin adjustment to prevent hypoglycaemia. […] Improvements to diabetes care delivery can occur at both the population level and at the individual level using insights from big data analytics.”

vi. Route to improving Type 1 diabetes mellitus glycaemic outcomes: real‐world evidence taken from the National Diabetes Audit.

“While control of blood glucose levels reduces the risk of diabetes complications, it can be very difficult for people to achieve. There has been no significant improvement in average glycaemic control among people with Type 1 diabetes for at least the last 10 years in many European countries 6.

The National Diabetes Audit (NDA) in England and Wales has shown relatively little change in the levels of HbA1c being achieved in people with Type 1 diabetes over the last 10 years, with >70% of HbA1c results each year being >58 mmol/mol (7.5%) 7.

Data for general practices in England are published by the NDA. NHS Digital publishes annual prescribing data, including British National Formulary (BNF) codes 7, 8. Together, these data provide an opportunity to investigate whether there are systematic associations between HbA1c levels in people with Type 1 diabetes and practice‐level population characteristics, diabetes service levels and use of medication.”

“The Quality and Outcomes Framework (a payment system for general practice performance) provided a baseline list of all general practices in England for each year, the practice list size and number of people (both with Type 1 and Type 2 diabetes) on their diabetes register. General practice‐level data of participating practices were taken from the NDA 2013–2014, 2014–2015 and 2015–2016 (5455 practices in the last year). They include Type 1 diabetes population characteristics, routine review checks and the proportions of people achieving target glycaemic control and/or being at higher glycaemic risk.

Diabetes medication data for all people with diabetes were taken from the general practice prescribing in primary care data for 2013–2014, 2014–2015 and 2015–2016, including insulin and blood glucose monitoring (BGM) […] A total of 20 indicators were created that covered the epidemiological, service, medication, technological, costs and outcomes performance for each practice and year. The variance in these indicators over the 4‐year period and among general practices was also considered. […] The values of the indicators found to be in the 90th percentile were used to quantify the potential of highest performing general practices. […] In total 13 085 practice‐years of data were analysed, covering 437 000 patient‐years of management.”

“There was significant variation among the participating general practices (Fig. 3) in the proportion of people achieving target glycaemic control target [percentage of people with HbA1c ≤58 mmol/mol (7.5%)] and in the proportion at high glycaemic risk [percentage of people with HbA1c >86 mmol/mol (10%)]. […] Our analysis showed that, at general practice level, the median target glycaemic control attainment was 30%, while the 10th percentile was 16%, and the 90th percentile was 45%. The corresponding median for the high glycaemic risk percentage was 16%, while the 10th percentile (corresponding to the best performing practices) was 6% and the 90th percentile (greatest proportion of Type 1 diabetes at high glycaemic risk) was 28%. Practices in the deciles for both lowest target glycaemic control and highest high glycaemic risk had 49% of the results in the 58–86 mmol/mol range. […] A very wide variation was found in the percentage of insulin for presumed pump use (deduced from prescriptions of fast‐acting vial insulin), with a median of 3.8% at general practice level. The 10th percentile was 0% and the 90th percentile was 255% of the median inferred pump usage.”

“[O]ur findings suggest that if all practices optimized service and therapies to the levels achieved by the top decile then 16 100 (7%) more people with Type 1 diabetes would achieve the glycaemic control target of 58 mmol/mol (7.5%) and 11 500 (5%) fewer people would have HbA1c >86 mmol/mol (10%). Put another way, if the results for all practices were at the top decile level, 36% vs 29% of people with Type 1 diabetes would achieve the glycaemic control target of HbA1c ≤ 58 mmol/mol (7.5%), and as few as 10% could have HbA1c levels > 86 mmol/mol (10%) compared with 15% currently (Fig. 6). This has significant implications for the potential to improve the longer‐term outcomes of people with Type 1 diabetes, given the close link between glycaemia and complications in such individuals 5, 10, 11.”

“We found that the significant variation among the participating general practices (Fig. 2) in terms of the proportion of people with HbA1c ≤58 mmol/mol (7.5%) was only partially related to a lower proportion of people with HbA1c >86 mmol/mol (10%). There was only a weak relationship between level of target glycaemia achieved and avoidance of very suboptimal glycaemia. The overall r2 value was 0.6. This suggests that there is a degree of independence between these outcomes, so that success factors at a general practice level differ for people achieving optimal glycaemia vs those factors affecting avoiding a level of at risk glycaemia.”

May 30, 2018 Posted by | Cardiology, Diabetes, Epidemiology, Genetics, Immunology, Medicine, Molecular biology, Ophthalmology, Studies | Leave a comment

Molecular biology (II)

Below I have added some more quotes and links related to the book’s coverage:

“[P]roteins are the most abundant molecules in the body except for water. […] Proteins make up half the dry weight of a cell whereas DNA and RNA make up only 3 per cent and 20 per cent respectively. […] The approximately 20,000 protein-coding genes in the human genome can, by alternative splicing, multiple translation starts, and post-translational modifications, produce over 1,000,000 different proteins, collectively called ‘the proteome‘. It is the size of the proteome and not the genome that defines the complexity of an organism. […] For simple organisms, such as viruses, all the proteins coded by their genome can be deduced from its sequence and these comprise the viral proteome. However for higher organisms the complete proteome is far larger than the genome […] For these organisms not all the proteins coded by the genome are found in any one tissue at any one time and therefore a partial proteome is usually studied. What are of interest are those proteins that are expressed in specific cell types under defined conditions.”

“Enzymes are proteins that catalyze or alter the rate of chemical reactions […] Enzymes can speed up reactions […] but they can also slow some reactions down. Proteins play a number of other critical roles. They are involved in maintaining cell shape and providing structural support to connective tissues like cartilage and bone. Specialized proteins such as actin and myosin are required [for] muscular movement. Other proteins act as ‘messengers’ relaying signals to regulate and coordinate various cell processes, e.g. the hormone insulin. Yet another class of protein is the antibodies, produced in response to foreign agents such as bacteria, fungi, and viruses.”

“Proteins are composed of amino acids. Amino acids are organic compounds with […] an amino group […] and a carboxyl group […] In addition, amino acids carry various side chains that give them their individual functions. The twenty-two amino acids found in proteins are called proteinogenic […] but other amino acids exist that are non-protein functioning. […] A peptide bond is formed between two amino acids by the removal of a water molecule. […] each individual unit in a peptide or protein is known as an amino acid residue. […] Chains of less than 50-70 amino acid residues are known as peptides or polypeptides and >50-70 as proteins, although many proteins are composed of more than one polypeptide chain. […] Proteins are macromolecules consisting of one or more strings of amino acids folded into highly specific 3D-structures. Each amino acid has a different size and carries a different side group. It is the nature of the different side groups that facilitates the correct folding of a polypeptide chain into a functional tertiary protein structure.”

“Atoms scatter the waves of X-rays mainly through their electrons, thus forming secondary or reflected waves. The pattern of X-rays diffracted by the atoms in the protein can be captured on a photographic plate or an image sensor such as a charge coupled device placed behind the crystal. The pattern and relative intensity of the spots on the diffraction image are then used to calculate the arrangement of atoms in the original protein. Complex data processing is required to convert the series of 2D diffraction or scatter patterns into a 3D image of the protein. […] The continued success and significance of this technique for molecular biology is witnessed by the fact that almost 100,000 structures of biological molecules have been determined this way, of which most are proteins.”

“The number of proteins in higher organisms far exceeds the number of known coding genes. The fact that many proteins carry out multiple functions but in a regulated manner is one way a complex proteome arises without increasing the number of genes. Proteins that performed a single role in the ancestral organism have acquired extra and often disparate functions through evolution. […] The active site of an enzyme employed in catalysis is only a small part of the protein, leaving spare capacity for acquiring a second function. […] The glycolytic pathway is involved in the breakdown of sugars such as glucose to release energy. Many of the highly conserved and ancient enzymes from this pathway have developed secondary or ‘moonlighting’ functions. Proteins often change their location in the cell in order to perform a ‘second job’. […] The limited size of the genome may not be the only evolutionary pressure for proteins to moonlight. Combining two functions in one protein can have the advantage of coordinating multiple activities in a cell, enabling it to respond quickly to changes in the environment without the need for lengthy transcription and translational processes.”

Post-translational modifications (PTMs) […] is [a] process that can modify the role of a protein by addition of chemical groups to amino acids in the peptide chain after translation. Addition of phosphate groups (phosphorylation), for example, is a common mechanism for activating or deactivating an enzyme. Other common PTMs include addition of acetyl groups (acetylation), glucose (glucosylation), or methyl groups (methylation). […] Some additions are reversible, facilitating the switching between active and inactive states, and others are irreversible such as marking a protein for destruction by ubiquitin. [The difference between reversible and irreversible modifications can be quite important in pharmacology, and if you’re curious to know more about these topics Coleman’s drug metabolism text provide great coverage of related topics – US.] Diseases caused by malfunction of these modifications highlight the importance of PTMs. […] in diabetes [h]igh blood glucose lead to unwanted glocosylation of proteins. At the high glucose concentrations associated with diabetes, an unwanted irreversible chemical reaction binds the gllucose to amino acid residues such as lysines exposed on the protein surface. The glucosylated proteins then behave badly, cross-linking themselves to the extracellular matrix. This is particularly dangerous in the kidney where it decreases function and can lead to renal failure.”

“Twenty thousand protein-coding genes make up the human genome but for any given cell only about half of these are expressed. […] Many genes get switched off during differentiation and a major mechanism for this is epigenetics. […] an epigenetic trait […] is ‘a stably heritable phenotype resulting from changes in the chromosome without alterations in the DNA sequence’. Epigenetics involves the chemical alteration of DNA by methyl or other small molecular groups to affect the accessibility of a gene by the transcription machinery […] Epigenetics can […] act on gene expression without affecting the stability of the genetic code by modifying the DNA, the histones in chromatin, or a whole chromosome. […] Epigenetic signatures are not only passed on to somatic daughter cells but they can also be transferred through the germline to the offspring. […] At first the evidence appeared circumstantial but more recent studies have provided direct proof of epigenetic changes involving gene methylation being inherited. Rodent models have provided mechanistic evidence. […] the importance of epigenetics in development is highlighted by the fact that low dietary folate, a nutrient essential for methylation, has been linked to higher risk of birth defects in the offspring.” […on the other hand, well…]

The cell cycle is divided into phases […] Transition from G1 into S phase commits the cell to division and is therefore a very tightly controlled restriction point. Withdrawal of growth factors, insufficient nucleotides, or energy to complete DNA replication, or even a damaged template DNA, would compromise the process. Problems are therefore detected and the cell cycle halted by cell cycle inhibitors before the cell has committed to DNA duplication. […] The cell cycle inhibitors inactive the kinases that promote transition through the phases, thus halting the cell cycle. […] The cell cycle can also be paused in S phase to allow time for DNA repairs to be carried out before cell division. The consequences of uncontrolled cell division are so catastrophic that evolution has provided complex checks and balances to maintain fidelity. The price of failure is apoptosis […] 50 to 70 billion cells die every day in a human adult by the controlled molecular process of apoptosis.”

“There are many diseases that arise because a particular protein is either absent or a faulty protein is produced. Administering a correct version of that protein can treat these patients. The first commercially available recombinant protein to be produced for medical use was human insulin to treat diabetes mellitus. […] (FDA) approved the recombinant insulin for clinical use in 1982. Since then over 300 protein-based recombinant pharmaceuticals have been licensed by the FDA and the European Medicines Agency (EMA) […], and many more are undergoing clinical trials. Therapeutic proteins can be produced in bacterial cells but more often mammalian cells such as the Chinese hamster ovary cell line and human fibroblasts are used as these hosts are better able to produce fully functional human protein. However, using mammalian cells is extremely expensive and an alternative is to use live animals or plants. This is called molecular pharming and is an innovative way of producing large amounts of protein relatively cheaply. […] In plant pharming, tobacco, rice, maize, potato, carrots, and tomatoes have all been used to produce therapeutic proteins. […] [One] class of proteins that can be engineered using gene-cloning technology is therapeutic antibodies. […] Therapeutic antibodies are designed to be monoclonal, that is, they are engineered so that they are specific for a particular antigen to which they bind, to block the antigen’s harmful effects. […] Monoclonal antibodies are at the forefront of biological therapeutics as they are highly specific and tend not to induce major side effects.”

“In gene therapy the aim is to restore the function of a faulty gene by introducing a correct version of that gene. […] a cloned gene is transferred into the cells of a patient. Once inside the cell, the protein encoded by the gene is produced and the defect is corrected. […] there are major hurdles to be overcome for gene therapy to be effective. One is the gene construct has to be delivered to the diseased cells or tissues. This can often be difficult […] Mammalian cells […] have complex mechanisms that have evolved to prevent unwanted material such as foreign DNA getting in. Second, introduction of any genetic construct is likely to trigger the patient’s immune response, which can be fatal […] once delivered, expression of the gene product has to be sustained to be effective. One approach to delivering genes to the cells is to use genetically engineered viruses constructed so that most of the viral genome is deleted […] Once inside the cell, some viral vectors such as the retroviruses integrate into the host genome […]. This is an advantage as it provides long-lasting expression of the gene product. However, it also poses a safety risk, as there is little control over where the viral vector will insert into the patient’s genome. If the insertion occurs within a coding gene, this may inactivate gene function. If it integrates close to transcriptional start sites, where promoters and enhancer sequences are located, inappropriate gene expression can occur. This was observed in early gene therapy trials [where some patients who got this type of treatment developed cancer as a result of it. A few more details hereUS] […] Adeno-associated viruses (AAVs) […] are often used in gene therapy applications as they are non-infectious, induce only a minimal immune response, and can be engineered to integrate into the host genome […] However, AAVs can only carry a small gene insert and so are limited to use with genes that are of a small size. […] An alternative delivery system to viruses is to package the DNA into liposomes that are then taken up by the cells. This is safer than using viruses as liposomes do not integrate into the host genome and are not very immunogenic. However, liposome uptake by the cells can be less efficient, resulting in lower expression of the gene.”

Links:

One gene–one enzyme hypothesis.
Molecular chaperone.
Protein turnover.
Isoelectric point.
Gel electrophoresis. Polyacrylamide.
Two-dimensional gel electrophoresis.
Mass spectrometry.
Proteomics.
Peptide mass fingerprinting.
Worldwide Protein Data Bank.
Nuclear magnetic resonance spectroscopy of proteins.
Immunoglobulins. Epitope.
Western blot.
Immunohistochemistry.
Crystallin. β-catenin.
Protein isoform.
Prion.
Gene expression. Transcriptional regulation. Chromatin. Transcription factor. Gene silencing. Histone. NF-κB. Chromatin immunoprecipitation.
The agouti mouse model.
X-inactive specific transcript (Xist).
Cell cycle. Cyclin. Cyclin-dependent kinase.
Retinoblastoma protein pRb.
Cytochrome c. CaspaseBcl-2 family. Bcl-2-associated X protein.
Hybridoma technology. Muromonab-CD3.
Recombinant vaccines and the development of new vaccine strategies.
Knockout mouse.
Adenovirus Vectors for Gene Therapy, Vaccination and Cancer Gene Therapy.
Genetically modified food. Bacillus thuringiensis. Golden rice.

 

May 29, 2018 Posted by | Biology, Books, Chemistry, Diabetes, Engineering, Genetics, Immunology, Medicine, Molecular biology, Pharmacology | Leave a comment

Alcohol and Aging (II)

I gave the book 3 stars on goodreads.

As is usual for publications of this nature, the book includes many chapters that cover similar topics and so the coverage can get a bit repetitive if you’re reading it from cover to cover the way I did; most of the various chapter authors obviously didn’t read the other contributions included in the book, and as each chapter is meant to stand on its own you end up with a lot of chapter introductions which cover very similar topics. If you can disregard such aspects it’s a decent book, which covers a wide variety of topics.

Below I have added some observations from some of the chapters of the book which I did not cover in my first post.

It is widely accepted that consuming heavy amounts of alcohol and binge drinking are detrimental to the brain. Animal studies that have examined the anatomical changes that occur to the brain as a consequence of consuming alcohol indicate that heavy alcohol consumption and binge drinking leads to the death of existing neurons [10, 11] and prevents production of new neurons [12, 13]. […] While animal studies indicate that consuming even moderate amounts of alcohol is detrimental to the brain, the evidence from epidemiological studies is less clear. […] Epidemiological studies that have examined the relationship between late life alcohol consumption and cognition have frequently reported that older adults who consume light to moderate amounts of alcohol are less likely to develop dementia and have higher cognitive functioning compared to older adults who do not consume alcohol. […] In a meta-analysis of 15 prospective cohort studies, consuming light to moderate amounts of alcohol was associated with significantly lower relative risk (RR) for Alzheimer’s disease (RR=0.72, 95% CI=0.61–0.86), vascular dementia (RR=0.75, 95% CI=0.57–0.98), and any type of dementia (RR=0.74, 95% CI=0.61–0.91), but not cognitive decline (RR=0.28, 95 % CI=0.03–2.83) [31]. These findings are consistent with a previous meta-analysis by Peters et al. [33] in which light to moderate alcohol consumption was associated with a decreased risk for dementia (RR=0.63, 95 % CI=0.53–0.75) and Alzheimer’s disease (RR=0.57, 95 % CI=0.44–0.74), but not vascular dementia (RR=0.82, 95% CI=0.50–1.35) or cognitive decline RR=0.89, 95% CI=0.67–1.17). […] Mild cognitive impairment (MCI) has been used to describe the prodromal stage of Alzheimer’s disease […]. There is no strong evidence to suggest that consuming alcohol is protective against MCI [39, 40] and several studies have reported non-significant findings [41–43].”

The majority of research on the relationship between alcohol consumption and cognitive outcomes has focused on the amount of alcohol consumed during old age, but there is a growing body of research that has examined the relationship between alcohol consumption during middle age and cognitive outcomes several years or decades later. The evidence from this area of research is mixed with some studies not detecting a significant relationship [17, 58, 59], while others have reported that light to moderate alcohol consumption is associated with preserved cognition [60] and decreased risk for cognitive impairment [31, 61, 62]. […] Several epidemiological studies have reported that light to moderate alcohol consumption is associated with a decreased risk for stroke, diabetes, and heart disease [36, 84, 85]. Similar to the U-shaped relationship between alcohol consumption and dementia, heavy alcohol consumption has been associated with poor health [86, 87]. The decreased risk for several metabolic and vascular health conditions for alcohol consumers has been attributed to antioxidants [54], greater concentrations of high-density lipoprotein cholesterol in the bloodstream [88], and reduced blood clot formation [89]. Stroke, diabetes, heart disease, and related conditions have all been associated with lower cognitive functioning during old age [90, 91]. The reduced prevalence of metabolic and vascular health conditions among light to moderate alcohol consumers may contribute to the decreased risk for dementia and cognitive decline for older adults who consume alcohol. A limitation of the hypothesis that the reduced risk for dementia among light and moderate alcohol consumers is conferred through the reduced prevalence of adverse health conditions associated with dementia is the possibility that this relationship is confounded by reverse causality. Alcohol consumption decreases with advancing age and adults may reduce their alcohol consumption in response to the onset of adverse health conditions […] the higher prevalence of dementia and lower cognitive functioning among abstainers may be due in part to their worse health rather than their alcohol consumption.”

A limitation of large cohort studies is that subjects who choose not to participate or are unable to participate are often less healthy than those who do participate. Non-response bias becomes more pronounced with age because only subjects who have survived to old age and are healthy enough to participate are observed. Studies on alcohol consumption and cognition are sensitive to non-response bias because light and moderate drinkers who are not healthy enough to participate in the study will not be observed. Adults who survive to old age despite consuming very high amounts of alcohol represent an even more select segment of the general population because they may have genetic, behavioral, health, social, or other factors that protect them against the negative effects of heavy alcohol consumption. As a result, the analytic sample of epidemiological studies is more likely to be comprised of “healthy” drinkers, which biases results in favor of finding a positive effect of light to moderate alcohol consumption for cognition and health in general. […] The incidence of Alzheimer’s disease doubles every 5 years after 65 years of age [94] and nearly 40% of older adults aged 85 and over are diagnosed with Alzheimer’s disease [7]. The relatively old age of onset for most dementia cases means the observed protective effect of light to moderate alcohol consumption for dementia may be due to alcohol consumers being more likely to die or drop out of a study as a result of their alcohol consumption before they develop dementia. This bias may be especially strong for heavy alcohol consumers. Not properly accounting for death as a competing outcome has been observed to artificially increase the risk of dementia among older adults with diabetes [95] and the effect that death and other competing outcomes may have on the relationship between alcohol consumption and dementia risk is unclear. […] The majority of epidemiological studies that have studied the relationship between alcohol consumption and cognition treat abstainers as the reference category. This can be problematic because often times the abstainer or non-drinking category includes older adults who stopped consuming alcohol because of poor health […] Not differentiating former alcohol consumers from lifelong abstainers has been found to explain some but not all of the benefit of alcohol consumption for preventing mortality from cardiovascular causes [96].”

“It is common for people to engage in other behaviors while consuming alcohol. This complicates the relationship between alcohol consumption and cognition because many of the behaviors associated with alcohol consumption are positively and negatively associated with cognitive functioning. For example, alcohol consumers are more likely to smoke than non-drinkers [104] and smoking has been associated with an increased risk for dementia and cognitive decline [105]. […] The relationship between alcohol consumption and cognition may also differ between people with or without a history of mental illness. Depression reduces the volume of the hippocampus [106] and there is growing evidence that depression plays an important role in dementia. Depression during middle age is recognized as a risk factor for dementia [107], and high depressive symptoms during old age may be an early symptom of dementia [108]. Middle aged adults with depression or other mental illness who self-medicate with alcohol may be at especially high risk for dementia later in life because of synergistic effects that alcohol and depression has on the brain. […] While current evidence from epidemiological studies indicates that consuming light to moderate amounts of alcohol, in particular wine, does not negatively affect cognition and in many cases is associated with cognitive health, adults who do not consume alcohol should not be encouraged to increase their alcohol consumption until further research clarifies these relationships. Inconsistencies between studies on how alcohol consumption categories are defined make it difficult to determine the “optimal” amount of alcohol consumption to prevent dementia. It is likely that the optimal amount of alcohol varies according to a person’s gender, as well as genetic, physiological, behavioral, and health characteristics, making the issue extremely complex.”

Falls are the leading cause of both fatal and nonfatal injuries among older adults, with one in three older adults falling each year, and 20–30% of people who fall suffer moderate to severe injuries such as lacerations, hip fractures, and head traumas. In fact, falls are the foremost cause of both fractures and traumatic brain injury (TBI) among older adults […] In 2013, 2.5 million nonfatal falls among older adults were treated in ED and more than 734,000 of these patients were hospitalized. […] Our analysis of the 2012 Nationwide Emergency Department Sample (NEDS) data set show that fall-related injury was a presenting problem among 12% of all ED visits by those aged 65+, with significant differences among age groups: 9% among the 65–74 age group, 12 % among the 75–84 age group, and 18 % among the 85+ age group [4]. […] heavy alcohol use predicts fractures. For example, among those 55+ years old in a health survey in England, men who consumed more than 8 units of alcohol and women who consumed more than 6 units on their heaviest drinking day in the past week had significantly increased odds of fractures (OR =1.65, 95% CI =1.37–1.98 for men and OR=2.07, 95% CI =1.28–3.35 for women) [63]. […] The 2008–2009 Canadian Community Health Survey-Healthy Aging also showed that consumption of at least one alcoholic drink per week increased the odds of falling by 40 % among those 65+ years [57].”

I at first was not much impressed by the effect sizes mentioned above because there are surely 100 relevant variables they didn’t account for/couldn’t account for, but then I thought a bit more about it. An important observation here – they don’t mention it in the coverage, but it sprang to mind – is that if sick or frail elderly people consume less alcohol than their more healthy counterparts, and are more likely to not consume alcohol (which they do, and which they are, we know this), and if frail or sick(er) elderly people are more likely to suffer a fall/fracture than are people who are relatively healthy (they are, again, we know this), well, then you’d expect consumption of alcohol to be found to have a ‘protective effect’ simply due to confounding by (reverse) indication (unless the researchers were really careful about adjusting for such things, but no such adjustments are mentioned in the coverage, which makes sense as these are just raw numbers being reported). The point is that the null here should not be that ‘these groups should be expected to have the same fall rate/fracture rate’, but rather ‘people who drink alcohol should be expected to be doing better, all else equal’ – but they aren’t, quite the reverse. So ‘the true effect size’ here may be larger than what you’d think.

I’m reasonably sure things are a lot more complicated than the above makes it appear (because of those 100 relevant variables we were talking about…), but I find it interesting anyway. Two more things to note: 1. Have another look at the numbers above if they didn’t sink in the first time. This is more than 10% of emergency department visits for that age group. Falls are a really big deal. 2. Fractures in the elderly are also a potentially really big deal. Here’s a sample quote: “One-fifth of hip fracture victims will die within 6 months of the injury, and only 50% will return to their previous level of independence.” (link). In some contexts, a fall is worse news than a cancer diagnosis, and they are very common events in the elderly. This also means that even relatively small effect sizes here can translate into quite large public health effects, because baseline incidence is so high.

The older adult population is a disproportionate consumer of prescription and over-the-counter medications. In a nationally representative sample of community-dwelling adults aged 57–84 years from the National Social Life, Health, and Aging Project (NSHAP) in 2005–2006, 81 % regularly used at least one prescription medication on a regular basis and 29% used at least five prescription medications. Forty-two percent used at least one nonprescription medication and concurrent use with a prescription medication was common, with 46% of prescription medication users also using OTC medications [2]. Prescription drug use by older adults in the U.S. is also growing. The percentage of older adults taking at least one prescription drug in the last 30 days increased from 73.6% in 1988–1994 to 89.7 % in 2007–2010 and the percentage taking five or more prescription drugs in the last 30 days increased from 13.8% in 1988–1994 to 39.7 % in 2007–2010 [3].”

The aging process can affect the response to a medication by altering its pharmacokinetics and pharmacodynamics [9, 10]. Reduced gastrointestinal motility and gastric acidity can alter the rate or extent of drug absorption. Changes in body composition, including decreased total body water and increased body fat can alter drug distribution. For alcohol, changes in body composition result in higher blood alcohol levels in older adults compared to younger adults after the same dose or quantity  of alcohol consumed. Decreased size of the liver, hepatic blood flow, and function of Phase I (oxidation, reduction, and hydrolysis) metabolic pathways result in reduced drug metabolism and increased drug exposure for drugs that undergo Phase I metabolism. Phase II hepatic metabolic pathways are generally preserved with aging. Decreased size of the kidney, renal blood flow, and glomerular filtration result in slower elimination of medications and metabolites by the kidney and increased drug exposure for medications that undergo renal elimination. Age-related impairment of homeostatic mechanisms and changes in receptor number and function can result in changes in pharmacodynamics as well. Older adults are generally more sensitive to the effects of medications and alcohol which act on the central nervous system for example. The consequences of these physiologic changes with aging are that older adults often experience increased drug exposure for the same dose (higher drug concentrations over time) and increased sensitivity to medications (greater response at a given drug concentration) than their younger counterparts.”

“Aging-related changes in physiology are not the only sources of variability in pharmacokinetics and pharmacodynamics that must be considered for an individual person. Older adults experience more chronic diseases that may decrease drug metabolism and renal elimination than younger cohorts. Frailty may result in further decline in drug metabolism, including Phase II metabolic pathways in the liver […] Drug interactions must also be considered […] A drug interaction is defined as a clinically meaningful change in the effect of one drug when coadministered with another drug [12]. Many drugs, including alcohol, have the potential for a drug interaction when administered concurrently, but whether a clinically meaningful change in effect occurs for a specific person depends on patient-specifc factors including age. Drug interactions are generally classified as pharmacokinetic interactions, where one drug alters the absorption, distribution, metabolism, or elimination of another drug resulting in increased or decreased drug exposure, or pharmacodynamic interactions, where one drug alters the response to another medication through additive or antagonistic pharmacologic effects [13]. An adverse drug event occurs when a pharmacokinetic or pharmacodynamic interaction or combination of both results in changes in drug exposure or response that lead to negative clinical outcomes. The adverse drug event could be a therapeutic failure if drug exposure is decreased or the pharmacologic response is antagonistic. The adverse drug event could be drug toxicity if the drug exposure is increased or the pharmacologic response is additive or synergistic. The threshold for experiencing an adverse event is often lower in older adults due to physiologic changes with aging and medical comorbidities, increasing their risk of experiencing an adverse drug event when medications are taken concurrently.”

“A large number of potential medication–alcohol interactions have been reported in the literature. Mechanisms of these interactions range from pharmacokinetic interactions affecting either alcohol or medication exposure to pharmacodynamics interactions resulting in exaggerated response. […] Epidemiologic evidence suggests that concurrent use of alcohol and medications among older adults is common. […] In a nationally representative U.S. sample of community-dwelling older adults in the National Social Life, Health and Aging Project (NSHAP) 2005–2006, 41% of participants reported consuming alcohol at least once per week and 20% were at risk for an alcohol–medication interaction because they were using both alcohol and alcohol-interacting medications on a regular basis [17]. […] Among participants in the Pennsylvania Assistance Contract for the Elderly program (aged 65–106 years) taking at least one prescription medication, 77% were taking an alcohol-interacting medication and 19% of the alcohol-interacting medication users reported concurrent use of alcohol [18]. […] Although these studies do not document adverse outcomes associated with alcohol–medication interactions, they do document that the potential exists for many older adults. […] High prevalence of concurrent use of alcohol and alcohol-interacting medications have also been reported in Australian men (43% of sedative or anxiolytic users were daily drinkers) [19], in older adults in Finland (42% of at-risk alcohol users were also taking alcohol-interacting medications) [20], and in older Irish adults (72% of participants were exposed to alcohol-interacting medications and 60% of these reported concurrent alcohol use) [21]. Drinking and medication use patterns in older adults may differ across countries, but alcohol–medication interactions appear to be a worldwide concern. […] Polypharmacy in general, and psychotropic burden specifically, has been associated with an increased risk of experiencing a geriatric syndrome such as falls or delirium, in older adults [26, 27]. Based on its pharmacology, alcohol can be considered as a psychotropic drug, and alcohol use should be assessed as part of the medication regimen evaluation to support efforts to prevent or manage geriatric syndromes. […] Combining alcohol and CNS active medications can be particularly problematic […] Older adults suffering from sleep problems or pain may be a particular risk for alcohol–medication interaction-related adverse events.”

In general, alcohol use in younger couples has been found to be highly concordant, that is, individuals in a relationship tend to engage in similar drinking behaviors [67,68]. Less is known, however, about alcohol use concordance between older couples. Graham and Braun [69] examined similarities in drinking behavior between spouses in a study of 826 community-dwelling older adults in Ontario, Canada. Results showed high concordance of drinking between spouses — whether they drank at all, how much they drank, and how frequently. […] Social learning theory suggests that alcohol use trajectories are strongly influenced by attitudes and behaviors of an individual’s social networks, particularly family and friends. When individuals engage in social activities with family and friends who approve of and engage in drinking, alcohol use, and misuse are reinforced [58, 59]. Evidence shows that among older adults, participation in social activities is correlated with higher levels of alcohol consumption [34, 60]. […] Brennan and Moos [29] […] found that older adults who reported less empathy and support from friends drank more alcohol, were more depressed, and were less self-confident. More stressors involving friends were associated with more drinking problems. Similar to the findings on marital conflict […], conflict in close friendships can prompt alcohol-use problems; conversely, these relationships can suffer as a result of alcohol-related problems. […] As opposed to social network theory […], social selection theory proposes that alcohol consumption changes an individual’s social context [33]. Studies among younger adults have shown that heavier drinkers chose partners and friends who approve of heavier drinking [70] and that excessive drinking can alienate social networks. The Moos study supports the idea that social selection also has a strong influence on drinking behavior among older adults.”

Traditionally, treatment studies in addiction have excluded patients over the age of 65. This bias has left a tremendous gap in knowledge regarding treatment outcomes and an understanding of the neurobiology of addiction in older adults.

Alcohol use causes well-established changes in sleep patterns, such as decreased sleep latency, decreased stage IV sleep, and precipitation or aggravation of sleep apnea [101]. There are also age-associated changes in sleep patterns including increased REM episodes, a decrease in REM length, a decrease in stage III and IV sleep, and increased awakenings. Age-associated changes in sleep can all be worsened by alcohol use and depression. Moeller and colleagues [102] demonstrated in younger subjects that alcohol and depression had additive effects upon sleep disturbances when they occurred together [102]. Wagman and colleagues [101] also have demonstrated that abstinent alcoholics did not sleep well because of insomnia, frequent awakenings, and REM fragmentation [101]; however, when these subjects ingested alcohol, sleep periodicity normalized and REM sleep was temporarily suppressed, suggesting that alcohol use could be used to self-medicate for sleep disturbances. A common anecdote from patients is that alcohol is used to help with sleep problems. […] The use of alcohol to self-medicate is considered maladaptive [34] and is associated with a host of negative outcomes. […] The use of alcohol to aid with sleep has been found to disrupt sleep architecture and cause sleep-related problems and daytime sleepiness [35, 36, 46]. Though alcohol is commonly used to aid with sleep initiation, it can worsen sleep-related breathing disorders and cause snoring and obstructive sleep apnea [36].”

Epidemiologic studies have clearly demonstrated that comorbidity between alcohol use and other psychiatric symptoms is common in younger age groups. Less is known about comorbidity between alcohol use and psychiatric illness in late life [88]. […] Blow et al. [90] reviewed the diagnosis of 3,986 VA patients between ages 60 and 69 presenting for alcohol treatment [90]. The most common comorbid psychiatric disorder was an affective disorder found in 21 % of the patients. […] Blazer et al. [91] studied 997 community dwelling elderly of whom only 4.5% had a history of alcohol use problems [91]; […] of these subjects, almost half had a comorbid diagnosis of depression or dysthymia. Comorbid depressive symptoms are not only common in late life but are also an important factor in the course and prognosis of psychiatric disorders. Depressed alcoholics have been shown to have a more complicated clinical course of depression with an increased risk of suicide and more social dysfunction than non-depressed alcoholics [9296]. […]  Alcohol use prior to late life has also been shown to influence treatment of late life depression. Cook and colleagues [94] found that a prior history of alcohol use problems predicted a more severe and chronic course for depression [94]. […] The effect of past heavy alcohol use is [also] highlighted in the findings from the Liverpool Longitudinal Study demonstrating a fivefold increase in psychiatric illness among elderly men who had a lifetime history of 5 or more years of heavy drinking [24]. The association between heavy alcohol consumption in earlier years and psychiatric morbidity in later life was not explained by current drinking habits. […] While Wernicke-Korsakoff’s syndrome is well described and often caused by alcohol use disorders, alcohol-related dementia may be difficult to differentiate from Alzheimer’s disease. Clinical diagnostic criteria for alcohol-related dementia (ARD) have been proposed and now validated in at least one trial, suggesting a method for distinguishing ARD, including Wernicke-Korsakoff’s syndrome, from other types of dementia [97, 98]. […] Finlayson et al. [100] found that 49 of 216 (23%) elderly patients presenting for alcohol treatment had dementia associated with alcohol use disorders [100].”

 

May 24, 2018 Posted by | Books, Demographics, Epidemiology, Medicine, Neurology, Pharmacology, Psychiatry, Statistics | Leave a comment

Alcohol and Aging

I’m currently reading this book. Below I have added some observations from the first five chapters. The book has 17 chapters in total, covering a wide variety of topics. I like the coverage so far. All the highlighted observations below were highlighted by me; they were not written in bold in the book.

“Alcohol consumption and alcohol-related deaths or problems have recently increased among older age groups in many developed countries […]. This increase in consumption, in combination with the ageing of populations worldwide, means that the absolute number of older people with alcohol problems is on the increase and a real danger exists that a “silent epidemic” may be evolving [2]. Although there is growing recognition of this public health problem, clinicians consistently under-detect alcohol problems and under-deliver behaviour change interventions to older people [8, 9] […] While older adults historically demonstrate much lower rates of alcohol use compared with younger adults [4, 5] and present to substance abuse treatment programs less frequently than their younger counterparts [6], substantial evidence suggests that at-risk alcohol use and alcohol use disorder (AUD) among older adults has been under-identified for decades [7, 8]. […] Individuals who have had alcohol-related problems over several decades and have survived into old age tend to be referred to as early onset drinkers. It is estimated that two-thirds of older drinkers fall into this category [2]. […] Late-onset drinking accounts for the remaining one-third of older people who use alcohol excessively [2]. Late-onset drinkers usually begin drinking in their 50s or 60s and tend to be of a higher socio-economic status than early onset drinkers with higher levels of education and income [2]. Stressful life events, such as bereavement or retirement, may trigger late-onset drinking […]. One study demonstrated that 70 % of late-onset drinkers had experienced stressful life events, compared with 25 % of early onset drinkers [17]. Those whose alcohol problems are of late onset tend to have fewer health problems and are more receptive to treatment than those with early onset problems […] Our data highlighted that losing a parent or partner was often pinpointed as an event that had prompted an escalation in alcohol use […] A recent systematic review which examined the relationship between late-life spousal bereavement and changes in routine health behaviour over 32 different studies [however] found only moderate evidence for increased alcohol consumption [41].”

“Understanding alcohol use among older adults requires a life course perspective [2] […]. Broadly speaking, to understand alcohol consumption patterns and associated risks among older adults, one must consider both biopsychosocial processes that emerge earlier in life and aging-specific processes, such as multimorbidity and retirement. […] In the population overall, older adulthood is a life stage in which overall alcohol consumption decreases, binge drinking becomes less common, and individuals give up drinking. […] data collected internationally supports the assertion that older adulthood is a period of declining drinking. […] Two forces specific to later life may be at work in decreasing levels of alcohol consumption in late life. First, the “sick-quitter” hypothesis [12, 13] suggests that changes in health during the aging process limit alcohol consumption. With declines in health, older adults decrease the quantity and frequency of their drinking leading to lower average consumption in the overall older adult population [11, 14]. Similarly, differential mortality of heavy drinkers may lead to decreases in alcohol use among cohorts of older adults; these changes in average drinking may be a function of early mortality of heavy drinkers [15]. Although alcohol use generally declines throughout the course of older adulthood, the population of older adults exhibits a great deal of variability in drinking patterns. […] longitudinal research studies have found that older men tend to consume alcohol at higher levels than women, and their consumption levels decline more slowly than women’s [6]. […] National survey data [from the UK] estimate that approximately 40–45% of older adults (65+) drank alcohol in the past year […] Numerous studies suggest that lifetime nondrinkers are more likely to be female, display greater religiosity (e.g., attend religious services), and have lower levels of education than their moderate drinking peers [20, 21]. […] Older adult nondrinkers are a heterogeneous population, and as such, lifetime nondrinkers and former drinkers should be studied separately. This is especially important when considering the issue of health and drinking because the context for abstinence may be different in these two groups [23, 24].”

“[V]ersion 5 of the DSM manual abandoned separate alcohol abuse and alcohol dependence diagnoses, and combined them into a single diagnosis: alcohol use disorder (AUD). […] The NSDUH survey estimated a past-year prevalence rate of alcohol abuse or dependence of 6.1 % among those aged 50–54 and 2.2 % among those ages 65 and older. […] AUD is the most severe manifestation of alcohol-related pathology among older adults, but most alcohol-related harm is not a function of disordered drinking [55]. […] older adults commonly take medications that interact with alcohol. A recent study of community-dwelling older adults (aged 57+) found that 41% consumed alcohol regularly and among regular alcohol consumers, 51 % used at least one alcohol interacting medication [57]. An analysis of the Irish Longitudinal Study on Ageing identified a high prevalence of alcohol use (60 %) among individuals taking alcohol interacting medications [58]. Falls are also a common health concern for older adults, and there is evidence of increased risk of falls among older adults who drink more than 14 drinks per week [59] […] a study by Holahan and colleagues [44] explored longitudinal outcomes for individuals who were moderate drinkers (below the weekly at-risk threshold) but who engaged in heavy episodic drinking (exceeded day threshold). Individuals were first surveyed between the ages of 55 and 65 and followed for 20 years. Episodic heavy drinkers were twice as likely to have died in the 20-year follow-up period compared with those who were not episodic heavy drinkers […to clarify, none of the episodic heavy drinkers in that study would qualify for a diagnosis of AUD, US] […] Alcohol use in the aging population has been defined through various thresholds of risk. Each approach brings certain advantages and problems. Using alcohol related disorders as a benchmark misses many older adults who may experience alcohol-related consequences to their health and well-being even though they do not meet criteria for disordered drinking. More conservative measures of alcohol risk may identify at-risk drinking in those for whom alcohol use may never compromise their health. […] among light to moderate drinkers, the level of risk is uncertain.

Among adults 65 years old and older in 2000–2001, just under 49.6% reported lifetime use [of tobacco] and 14% reported use in the last 12 months [30]. […] Data collected by the Centers for Disease Control in 2008 revealed that only 9% of individuals aged 65 and older reported being current smokers [42]. […] data from the 2001–2002 NESARC reveal a strong relationship between AUDs and tobacco use […] in 2012, 19.3% of adults 65 and older reported having ever used illicit drugs in their lifetime, whereas 47.6% of adults between the ages 60 and 64 reported lifetime drug use. […] In the 2005–2006 NSDUH […] 3.9% of adults aged 50–64, the bulk of the Baby Boomers at that time, reported past year marijuana use, compared to only 0.7% of those 65 years old and older [53]. Among those aged 50 and older reporting marijuana use, 49% reported using marijuana more than 30 days in the past year, with a mean of 81 days. […] The increasingly widespread, legal availability and acceptance of cannabis, for both medicinal and recreational use, may pose unique risks in an aging population. Across age groups, cannabis is known to impair short-term memory, increase one’s heart and respiratory rate, and elevate blood pressure [56]. […] For older adults, these risks may be particularly pronounced, especially for those whose cognitive or cardiovascular systems may already be compromised. […] Most researchers generally consider existing estimations of mental health and substance use disorders to be underestimations among older adults. […] Assumptions that older adults do not drink or use illicit substances should not be made.

“Although several studies in the United States and elsewhere have shown that moderate alcohol consumption is associated with reduced risk for heart disease [16–20] and that heavy intake is associated with increased risk of CVD incidence [6, 21] and all-cause mortality in various populations […], data specific to effects of alcohol in elderly populations remain scant. The few studies available, e.g., the Cardiovascular Health Study, suggest that moderate alcohol use is beneficial and may be associated with reduced Medicare costs among individuals with CVD [25]. The benefits and risks of alcohol consumption are dose dependent with a consistent cut-point for cardiovascular benefits being 1 drink per day for women and about 2 drinks per day for men [21]. These cut-points have also been observed for associations between alcohol consumption and all-cause mortality [21, 26]. Although there are many similarities in the effects of alcohol on CVD across many populations, the magnitude and significance of the association between amount of alcohol consumed and CVD risk remain inconsistent, especially within countries, regions, age, sex, race, and other population strata […] As shown in a recent review [33], a drinking pattern characterized by moderate drinking without episodes of heavy drinking may be more beneficial for CVD protection when compared to patterns that include heavy drinking episodes. […] In additional to amount of alcohol consumed per se, the pattern of alcohol consumption, commonly defined as the number of drinking days per week is also associated with CVD outcomes independent of the amount of alcohol consumed [18, 24, 34–37]. In general, a drinking pattern characterized by alcohol consumption on 4 or more days of the week is inversely associated with MI, stroke, and CVD risk factors“.

“The relation between moderate alcohol consumption and intermediate CVD markers was summarized in two recent reviews [6, 42]. Overall, moderate alcohol consumption is associated with improved concentrations of CVD risk markers, particularly HDL-C concentrations [18, 31, 43, 44]. Whether HDL-C resulting from moderate alcohol intake is functional and beneficial for cardioprotection remains unknown […] While moderate alcohol consumption shows no appreciable benefit on LDL-C, it is associated with significant improvement in insulin sensitivity […] Alcohol intake may also influence CVD markers through its effects on absorption and metabolism of nutrients in the body. This is critical especially in the elderly who may have deficiencies or insufficiencies of nutrients such as folate, vitamin B12, vitamin D, magnesium, and iron. Indeed, moderate alcohol consumption has been shown to improve status of nutrients associated with cardiovascular effects. For example, it improves iron absorption in humans [52, 53] and is associated with higher vitamin D levels in men [54]. […] heavy alcohol consumption [on the other hand] leads to deficiencies of magnesium [55], zinc, folate [56], and other nutrients and damages the intestinal lining and the liver impairing nutrient absorption and metabolism [57]. These effects of alcohol are likely to be worse in the elderly. […] chronic heavy drinking lowers magnesium [55], a nutrient needed for proper metabolism of vitamin D [58], implying that supplementation with vitamin D in heavy drinkers may not be as effective as intended. These effects of alcohol could also extend to prescription medications that are in common use among the elderly. […] Taken together, moderate alcohol seems to protect against cardiovascular disease across the whole life span but the data on older age groups are scanty. Theoretical considerations as well as emerging data on intermediate outcomes such as lipids, suggest that moderate alcohol could beneficially interact with medications such as statins to improve cardiovascular health but heavy alcohol could worsen CVD risk, especially in the elderly.”

Alcohol is one of the main risk factors for cancer, with alcohol use attributed to up to 44% of some cancers [2, 3] and between 3.2 and 3.7 % of all cancer deaths [4, 5]. Since 1988, alcohol has been classified as a carcinogen [6]. Types of cancers linked to alcohol use include cancers of the liver, pancreas, esophagus, breast, pharynx, and larynx with most convincing evidence for alcohol-related cancers of the upper aerodigestive tract, stomach, colorectum, liver, and the lungs [2, 7]. All of these cancers have a much higher incidence and mortality rate in older adults […] For alcohol-associated cancers, 66–95% of new cases appear in those 55 years of age or older [8, 9]. For alcohol-associated cancers, other than breast cancer, 75–95 % of new cases occur in those 55 years of age or older [8, 10, 11]. […] Four countries with a decline in alcohol use (France, the UK, Sweden, and US) have […] demonstrated a stabilization or decline in the incidence and mortality rates for types of cancers closely associated with alcohol use [12]. […] The increased risk for cancer related to alcohol use is based on a combination of both quantity/frequency and duration of use, with those consuming alcohol for 20 or more years at increased risk [14]. […] consumption of alcohol at lower levels may also increase the risk for alcohol-related cancers. Nelson et al. reported that daily consumption of 1.5 drinks or greater accounted for 26–35% of alcohol-attributable deaths [5]. Thus, the evidence is growing that daily drinking, even at lower levels, increases the risk for developing cancer in later life with the conclusion that there may be no safe threshold level for alcohol consumption below which there is no risk for cancer [6, 16, 17].”

The risk for developing alcohol-related cancer is increased among those who have a history of concurrent tobacco use and at-risk alcohol use […] Among individuals who have a history of smoking two or more packs of cigarettes and consuming more than four alcoholic drinks per day, the risk of head and neck cancer is increased greater than 35-fold [22]. […] At least 75 % of head and neck cancer is associated with alcohol and tobacco use[9]. […] There are gender differences in alcohol attributable cancer deaths with over half (56–66 %) of all alcohol-attributable cancer deaths in females resulting from breast cancer [5]. […] For women, even low-risk alcohol use (5–14.9 g/day or one standard drink of alcohol or less) increases the risk of cancer, mainly breast cancer [18]. […] Alcohol use during cancer treatment can complicate the treatment regimen and lead to poor long-term outcomes. […] Alcohol use is correlated with poor survival outcomes in oncology patients. […] Another issue for patients during cancer treatment is quality of life. Alcohol consumption at higher levels […] or patients who screened positive for a possible AUD during cancer treatment experienced worse quality of life outcomes, including problems with pain, sleep, dyspnea, total distress, anxiety, coping, shortness of breath, diarrhea, poor emotional functioning, fatigue, and poor appetite [58, 59]. Current alcohol use has also been associated with higher pain scores and long-term use of opioids [48, 49].”

May 14, 2018 Posted by | Books, Cancer/oncology, Cardiology, Epidemiology, Medicine | Leave a comment

100 cases in emergency medicine and critical care (II)

In this post I’ve added some links to topics covered in the second half of the book, as well as some quotes.

Flexor tenosynovitis. Kanavel’s cardinal signs.
Pelvic Fracture in Emergency Medicine. (“Pelvic injuries may be associated with significant haemorrhage. […] The definitive management of pelvic fractures is surgical.”)
Femur fracture. Girdlestone-Taylor procedure. (“A fall from standing can result in occult cervical spine fractures. If there is any doubt, then the patient should be immobilized and imaged to exclude injury.”)
Anterior Cruciate Ligament Injury. Anterior drawer test. Segond fracture. (“[R]upture of the anterior cruciate ligament (ACL) […] is often seen in younger patients and is associated with high-energy sports such as skiing, football or cycling. […] Take a careful history of all knee injuries including the mechanism of injury and the timing of swelling.”)
Tibial plateau fracture. Schatzker classification of tibial plateau fractures. (“When assessing the older patient with minor trauma resulting in fracture, always investigate the possibility that this may be a pathological fracture (e.g. osteoporosis, malignancy.”))
Ankle Fracture. Maisonneuve fracture.
Acute cholecystitis. Murphy’s sign. Mirizzi syndrome. (“Most patients with gallstones are asymptomatic. However, complications of gallstones range from biliary colic, whereby gallstones irritate or temporarily block the biliary tract, to acute cholecystitis, which is an infection of the gallbladder sometimes due to obstruction of the cystic duct. Gallstones can also become trapped in the common bile duct (choledocholithiasis) causing jaundice and potential ascending cholangitis, which refers to infection of the biliary tree. Ascending cholangitis classically presents with Charcot’s triad of fever, right upper quadrant (RUQ) pain and jaundice. It can be life-threatening. […] Acute cholecystitis requires antibiotic therapy and admission under general surgery, who should decide whether to perform a ‘hot’ emergency cholecystectomy within 24-72 hours of admission. This shortens the hospital stay but can be associated with more surgical complications.”)
Small-Bowel Obstruction. (“SBO is defined as a mechanical obstruction to the passage of contents in the bowel lumen. There can be complete or incomplete obstruction. […] There are many causes of SBO. […] The commonest cause of SBO worldwide is incarcerated herniae, whereas the commonest cause in the Western world is adhesion secondary to previous abdominal surgery. […] A strangulated hernia is […] a surgical emergency associated with a high mortality.”)
Pneumothorax. Flail chest.
Perforated peptic ulcer. (“Immediate onset pain usually signifies a rupture or occlusion of an organ, whereas more insidious onset tends to be infective or inflammatory in origin.” […] A perforated peptic ulcer is a surgical emergency that presents with upper abdominal pain, decreased or absent bowel sounds and signs of septic shock.”)
Diverticulitis.
Acute appendicitisMcBurney’s point. Rovsing’s sign. Psoas signObturator sign. (“The lifetime risk of developing appendicitis is 5-10%, and it is the commonest cause of emergency abdominal surgery in the Western world. […] in appendicitis, pain classically precedes vomiting, whereas the opposite occurs in gastroenteritis. […] Appendicitis is the commonest general surgical emergency in pregnant women and may have an atypical presentation with pain anywhere in the right side of the abdomen […] It is estimated that 25% of appendicitis will perforate 24 hours from the onset of symptoms, and 75% by 48 hours.”)
Abdominal aortic aneurysm. (“A ruptured AAA is a surgical emergency with 100% mortality if not immediately repaired. It classically presents with abdominal pain, pulsatile abdominal mass and hypotension. It should be ruled out in all patients over 65 years of age presenting with abdominal, loin or groin pain, especially if they have risk factors including smoking, hypertension, COPD or peripheral vascular disease. […] Do not be lured into a diagnosis of renal colic in an older patient, without definitive imaging to rule out an AAA rupture.”)
Nephrolithiasis. (“up to 30% of patients with kidney stones have a recurrence within 5 years”)
Acute Otitis Media. Mastoiditis. Bezold’s abscess.
Malignant otitis externa. (“Despite the term ‘malignant’, this is not a cancerous process. Rather, it refers to temporal bone (skull base) osteomyelitis. This is an ENT emergency associated with serious morbidity and mortality including cranial nerve palsies. […] The defining features of MOE are severe otalgia, often exceeding oral analgesics, in the older diabetic patient. Other symptoms such as hearing loss, otorrhoea, vertigo and tinnitus may also be present”)
Post-tonsillectomy hemorrhage. (Post-tonsillectomy bleeding (PTB) is a common but potentially serious complication occurring in around 5%-10% of patients undergoing tonsillectomy. The majority are self-limiting but around 1% require a return to theatre to stop the bleeding. All patients must be assessed immediately and admitted for observation as a self-limiting bleed can preclude a larger bleed within 24 hours. […] [PTB] should be treated as an airway emergency due to the possibility of obstruction.”)
Acute rhinosinusitis. (“Periorbital cellulitis is a potentially sight-threatening emergency. It is often precipitated by an upper respiratory tract infection, rhinosinusitis or local trauma (injury, insect bite).”)
Corneal Foreign Body. Seidel test. (“Pain with photosensitivity, watery discharge and foreign body sensation are cardinal features of corneal irritation. […] Abnormal pupil shape, iris defect and shallow anterior chamber are red flags for possible ocular perforation or penetrating ocular injury. […] Most conjunctival foreign bodies can be removed by simply irrigating the eye […] Removing a corneal foreign body […] requires more skill and an experienced operator should be sought. […] Iron, steel, copper and wood are known to cause severe ocular reactions”)
Acanthamoeba Keratitis. Bacterial Keratitis. Fungal keratitis. (“In patients with red eyes, reduced vision with severe to moderate pain should be prompted to an early ophthalmology review. Pre-existing ocular surface disease and contact lens wear are high risk factors for microbial keratitis.”)
Globe ruptureAcute orbital compartment syndromeLateral Canthotomy and Cantholysis. (Thirty percent of all facial fractures involve the orbit […] In open globe injuries with visible penetrating objects, it may be tempting to remove the object; however, avoid this as it may cause the globe to collapse.”)
Mandibular fracture. Guardsman fracture. (“Jaw pain, altered bite, numbness of lower lip, trismus or difficulty moving the jaw are the cardinal symptoms of possible mandibular fracture or dislocation.”)
Bronchiolitis. (“This is an acute respiratory condition, resulting in inflammation of the bronchioles. […] Bronchiolitis occurs in children under 2 years of age and most commonly presents in infants aged 3 to 6 months. […] Around 3% of all infants under 1 year old are admitted to hospital with bronchiolitis. […] Not all patients require hospital admission.”)
Fever of Unknown Origin. (“Fever is a very common presentation in the Emergency Department, and in the immunocompetent child is usually caused by a simple infection […] it is important to look for concerning features. Tachycardia is a particular feature that should not be ignored […] red-flag signs for serious illness [include:] • Grunting, tachypneoa or other signs of respiratory distress • Mottled, pale skin with cool peripheries […] Irritability […] not responding to social cues • Difficulty to rouse […] Consider Kawasaki disease in fever lasting more than 5 days.”)
Pediatric gastroenteritis. Rotavirus.
Acute Pyelonephritis. (“Female infants have a two- to-fourfold higher prevalence of UTI than male infants”)
Gastroesophageal Reflux Disease. (“Reflux describes the passage of gastric contents into the oesophagus with or without regurgitation and vomiting. This is a very common, normal, physiological process and occurs in 5% of babies up to six times per day. GORD presents when reflux causes troublesome symptoms or complications. This has a prevalence of 10%– 20% […] No investigations are required in the Emergency Department if there is a suspicion of GORD; this is usually a clinical diagnosis alone.”)
Head injury. (“Head injuries are common in children […] Clinical features of concern in head injuries include multiple episodes of vomiting […] significant scalp haematoma, prolonged loss of consciousness, confusion and seizures.”)
Pertussis. (“In the twentieth century, pertussis was one of the most common childhood diseases and a major cause of childhood mortality. Since use of the immunisation began, incidence has decreased more than 75%.”)
Hyperemesis gravidarum. ([HG] is defined as severe or long-lasting nausea and vomiting, appearing for the first time within the first trimester of pregnancy, and is so severe that weight loss, dehydration and electrolyte imbalance may occur. It affects less than 4% of pregnant women, although up to 80% of women suffer from some degree of nausea and vomiting throughout their pregnancy. […] Classically, patents present with a long history of nausea and vomiting that becomes progressively worse, despite treatment with simple antiemetics.”)
Ectopic pregnancy. (“Abdominal pain and collapse with a positive pregnancy test must be treated as a ruptured ectopic pregnancy until proven otherwise. […] In cases where the patient is stable and an intact ectopic is suspected, this is not an emergency and patients can be brought back the next day […] if seen out of hours”)
Recurrent miscarriage. Antiphospholipid syndrome. (“Bleeding in early pregnancy is common and does not necessarily lead to miscarriage.”)
Ovarian torsion. (“Torsion of the ovary and/ or fallopian tube account for between 2.4% and 7.4% of all gynaecological emergencies, and rapid intervention is required in order to preserve ovarian function. […] Ovarian torsion is unfortunately often misdiagnosed due to its non-specific symptoms and lack of diagnostic tools. […] Suspect ovarian torsion in women with severe sudden onset unilateral pelvic pain.”)
Pelvic Inflammatory Disease. Fitz-Hugh–Curtis syndrome.
Ovarian hyperstimulation syndrome. (“OHSS is an iatrogenic complication of fertility treatment with exogenous gonadotrophins to promote oocyte formation. Hyperstimulation of the ovaries leads to ovarian enlargement, and subsequent exposure to human chorionic gonadotrophin (hCG) causes production of proinflammatory mediators, primarily vascular endothelial growth factor (VEGF). The effects of proinflammatory mediators lead to increased vascular permeability and a loss of fluid from intravascular to third space compartments. This gives rise to ascites, pleural effusions and in some cases pericardial effusions. Women with severe OHSS can typically lose up to 20% of their circulating volume in the acute phase […] OHSS patients are also at high risk of developing a thromboembolism […] In conventional IVF, around one-third of cycles are affected by mild OHSS. The combined incidence of moderate or severe OHSS is reported as between 3.1% and 8%.”)
Pulmonary embolism. (“The overall prevalence of PE in pregnancy is between 2% and 6%. Pregnancy increases the risk of developing a venous thromboembolism by four to five times, compared to non-pregnant women of the same age.”)
Postpartum psychosis.
Informed consent. Gillick competency and Fraser guidelines.
Duty of candour. Never events.

May 8, 2018 Posted by | Books, Gastroenterology, Infectious disease, Medicine, Nephrology, Ophthalmology | Leave a comment

Molecular biology (I?)

“This is a great publication, considering the format. These authors in my opinion managed to get quite close to what I’d consider to be ‘the ideal level of coverage’ for books of this nature.”

The above was what I wrote in my short goodreads review of the book. In this post I’ve added some quotes from the first chapters of the book and some links to topics covered.

Quotes:

“Once the base-pairing double helical structure of DNA was understood it became apparent that by holding and preserving the genetic code DNA is the source of heredity. The heritable material must also be capable of faithful duplication every time a cell divides. The DNA molecule is ideal for this. […] The effort then concentrated on how the instructions held by the DNA were translated into the choice of the twenty different amino acids that make up proteins. […] George Gamov [yes, that George Gamov! – US] made the suggestion that information held in the four bases of DNA (A, T, C, G) must be read as triplets, called codons. Each codon, made up of three nucleotides, codes for one amino acid or a ‘start’ or ‘stop’ signal. This information, which determines an organism’s biochemical makeup, is known as the genetic code. An encryption based on three nucleotides means that there are sixty-four possible three-letter combinations. But there are only twenty amino acids that are universal. […] some amino acids can be coded for by more than one codon.”

“The mechanism of gene expression whereby DNA transfers its information into proteins was determined in the early 1960s by Sydney Brenner, Francois Jacob, and Matthew Meselson. […] Francis Crick proposed in 1958 that information flowed in one direction only: from DNA to RNA to protein. This was called the ‘Central Dogma‘ and describes how DNA is transcribed into RNA, which then acts as a messenger carrying the information to be translated into proteins. Thus the flow of information goes from DNA to RNA to proteins and information can never be transferred back from protein to nucleic acid. DNA can be copied into more DNA (replication) or into RNA (transcription) but only the information in mRNA [messenger RNA] can be translated into protein”.

“The genome is the entire DNA contained within the forty-six chromosomes located in the nucleus of each human somatic (body) cell. […] The complete human genome is composed of over 3 billion bases and contain approximately 20,000 genes that code for proteins. This is much lower than earlier estimates of 80,000 to 140,000 and astonished the scientific community when revealed through human genome sequencing. Equally surprising was the finding that genomes of much simpler organisms sequenced at the same time contained a higher number of protein-coding genes than humans. […] It is now clear that the size of the genome does not correspond with the number of protein-coding genes, and these do not determine the complexity of an organism. Protein-coding genes can be viewed as ‘transcription units’. These are made up of sequences called exons that code for amino acids, and separated by by non-coding sequences called introns. Associated with these are additional sequences termed promoters and enhancers that control the expression of that gene.”

“Some sections of the human genome code for RNA molecules that do not have the capacity to produce proteins. […] it is now becoming apparent that many play a role in controlling gene expression. Despite the importance of proteins, less than 1.5 per cent of the genome is made up of exon sequences. A recent estimate is that about 80 per cent of the genome is transcribed or involved in regulatory functions with the rest mainly composed of repetitive sequences. […] Satellite DNA […] is a short sequence repeated many thousands of times in tandem […] A second type of repetitive DNA is the telomere sequence. […] Their role is to prevent chromosomes from shortening during DNA replication […] Repetitive sequences can also be found distributed or interspersed throughout the genome. These repeats have the ability to move around the genome and are referred to as mobile or transposable DNA. […] Such movements can be harmful sometimes as gene sequences can be disrupted causing disease. […] The vast majority of transposable sequences are no longer able to move around and are considered to be ‘silent’. However, these movements have contributed, over evolutionary time, to the organization and evolution of the genome, by creating new or modified genes leading to the production of proteins with novel functions.”

“A very important property of DNA is that it can make an accurate copy of itself. This is necessary since cells die during the normal wear and tear of tissues and need to be replenished. […] DNA replication is a highly accurate process with an error occurring every 10,000 to 1 million bases in human DNA. This low frequency is because the DNA polymerases carry a proofreading function. If an incorrect nucleotide is incorporated during DNA synthesis, the polymerase detects the error and excises the incorrect base. Following excision, the polymerase reinserts the correct base and replication continues. Any errors that are not corrected through proofreading are repaired by an alternative mismatch repair mechanism. In some instances, proofreading and repair mechanisms fail to correct errors. These become permanent mutations after the next cell division cycle as they are no longer recognized as errors and are therefore propagated each time the DNA replicates.”

DNA sequencing identifies the precise linear order of the nucleotide bases A, C, G, T, in a DNA fragment. It is possible to sequence individual genes, segments of a genome, or whole genomes. Sequencing information is fundamental in helping us understand how our genome is structured and how it functions. […] The Human Genome Project, which used Sanger sequencing, took ten years to sequence and cost 3 billion US dollars. Using high-throughput sequencing, the entire human genome can now be sequenced in a few days at a cost of 3,000 US dollars. These costs are continuing to fall, making it more feasible to sequence whole genomes. The human genome sequence published in 2003 was built from DNA pooled from a number of donors to generate a ‘reference’ or composite genome. However, the genome of each individual is unique and so in 2005 the Personal Genome Project was launched in the USA aiming to sequence and analyse the genomes of 100,000 volunteers across the world. Soon after, similar projects followed in Canada and Korea and, in 2013, in the UK. […] To store and analyze the huge amounts of data, computational systems have developed in parallel. This branch of biology, called bioinformatics, has become an extremely important collaborative research area for molecular biologists drawing on the expertise of computer scientists, mathematicians, and statisticians.”

“[T]he structure of RNA differs from DNA in three fundamental ways. First, the sugar is a ribose, whereas in DNA it is a deoxyribose. Secondly, in RNA the nucleotide bases are A, G, C, and U (uracil) instead of A, G, C, and T. […] Thirdly, RNA is a single-stranded molecule unlike double-stranded DNA. It is not helical in shape but can fold to form a hairpin or stem-loop structure by base-pairing between complementary regions within the same RNA molecule. These two-dimensional secondary structures can further fold to form complex three-dimensional, tertiary structures. An RNA molecule is able to interact not only with itself, but also with other RNAs, with DNA, and with proteins. These interactions, and the variety of conformations that RNAs can adopt, enables them to carry out a wide range of functions. […] RNAs can influence many normal cellular and disease processes by regulating gene expression. RNA interference […] is one of the main ways in which gene expression is regulated.”

“Translation of the mRNA to a protein takes place in the cell cytoplasm on ribosomes. Ribosomes are cellular structures made up primarily of rRNA and proteins. At the ribosomes, the mRNA is decoded to produce a specific protein according to the rules defined by the genetic code. The correct amino acids are brought to the mRNA at the ribosomes by molecules called transfer RNAs (tRNAs). […] At the start of translation, a tRNA binds to the mRNA at the start codon AUG. This is followed by the binding of a second tRNA matching the adjacent mRNA codon. The two neighbouring amino acids linked to the tRNAs are joined together by a chemical bond called the peptide bond. Once the peptide bond forms, the first tRNA detaches leaving its amino acid behind. The ribosome then moves one codon along the mRNA and a third tRNA binds. In this way, tRNAs sequentially bind to the mRNA as the ribosome moves from codon to codon. Each time a tRNA molecule binds, the linked amino acid is transferred to the growing amino acid chain. Thus the mRNA sequence is translated into a chain of amino acids connected by peptide bonds to produce a polypeptide chain. Translation is terminated when the ribosome encounters a stop codon […]. After translation, the chain is folded and very often modified by the addition of sugar or other molecules to produce fully functional proteins.”

“The naturally occurring RNAi pathway is now extensively exploited in the laboratory to study the function of genes. It is possible to design synthetic siRNA molecules with a sequence complementary to the gene under study. These double-stranded RNA molecules are then introduced into the cell by special techniques to temporarily knock down the expression of that gene. By studying the phenotypic effects of this severe reduction of gene expression, the function of that gene can be identified. Synthetic siRNA molecules also have the potential to be used to treat diseases. If a disease is caused or enhanced by a particular gene product, then siRNAs can be designed against that gene to silence its expression. This prevents the protein which drives the disease from being produced. […] One of the major challenges to the use of RNAi as therapy is directing siRNA to the specific cells in which gene silencing is required. If released directly into the bloodstream, enzymes in the bloodstream degrade siRNAs. […] Other problems are that siRNAs can stimulate the body’s immune response and can produce off-target effects by silencing RNA molecules other than those against which they were specifically designed. […] considerable attention is currently focused on designing carrier molecules that can transport siRNA through the bloodstream to the diseased cell.”

“Both Northern blotting and RT-PCR enable the expression of one or a few genes to be measured simultaneously. In contrast, the technique of microarrays allows gene expression to be measured across the full genome of an organism in a single step. This massive scale genome analysis technique is very useful when comparing gene expression profiles between two samples. […] This can identify gene subsets that are under- or over-expressed in one sample relative to the second sample to which it is compared.”

Links:

Molecular biology.
Charles Darwin. Alfred Wallace. Gregor Mendel. Wilhelm Johannsen. Heinrich Waldeyer. Theodor Boveri. Walter Sutton. Friedrich Miescher. Phoebus Levene. Oswald Avery. Colin MacLeod. Maclyn McCarty. James Watson. Francis Crick. Rosalind Franklin. Andrew Fire. Craig Mello.
Gene. Genotype. Phenotype. Chromosome. Nucleotide. DNA. RNA. Protein.
Chargaff’s rules.
Photo 51.
Human Genome Project.
Long interspersed nuclear elements (LINEs). Short interspersed nuclear elements (SINEs).
Histone. Nucleosome.
Chromatin. Euchromatin. Heterochromatin.
Mitochondrial DNA.
DNA replication. Helicase. Origin of replication. DNA polymeraseOkazaki fragments. Leading strand and lagging strand. DNA ligase. Semiconservative replication.
Mutation. Point mutation. Indel. Frameshift mutation.
Genetic polymorphism. Single-nucleotide polymorphism (SNP).
Genome-wide association study (GWAS).
Molecular cloning. Restriction endonuclease. Multiple cloning site (MCS). Bacterial artificial chromosome.
Gel electrophoresis. Southern blot. Polymerase chain reaction (PCR). Reverse transcriptase PCR (RT-PCR). Quantitative PCR (qPCR).
GenBank. European Molecular Biology Laboratory (EMBL). Encyclopedia of DNA Elements (ENCODE).
RNA polymerase II. TATA box. Transcription factor IID. Stop codon.
Protein biosynthesis.
SmRNA (small nuclear RNA).
Untranslated region (/UTR sequences).
Transfer RNA.
Micro RNA (miRNA).
Dicer (enzyme).
RISC (RNA-induced silencing complex).
Argonaute.
Lipid-Based Nanoparticles for siRNA Delivery in Cancer Therapy.
Long non-coding RNA.
Ribozyme/catalytic RNA.
RNA-sequencing (RNA-seq).

May 5, 2018 Posted by | Biology, Books, Chemistry, Genetics, Medicine, Molecular biology | Leave a comment