Econstudentlog

Harnessing phenotypic heterogeneity to design better therapies

Unlike many of the IAS lectures I’ve recently blogged this one is a new lecture – it was uploaded earlier this week. I have to say that I was very surprised – and disappointed – that the treatment strategy discussed in the lecture had not already been analyzed in a lot of detail and been implemented in clinical practice for some time. Why would you not expect the composition of cancer cell subtypes in the tumour microenvironment to change when you start treatment – in any setting where a subgroup of cancer cells has a different level of responsiveness to treatment than ‘the average’, that would to me seem to be the expected outcome. And concepts such as drug holidays and dose adjustments as treatment responses to evolving drug resistance/treatment failure seem like such obvious approaches to try out here (…the immunologists dealing with HIV infection have been studying such things for decades). I guess ‘better late than never’.

A few papers mentioned/discussed in the lecture:

Impact of Metabolic Heterogeneity on Tumor Growth, Invasion, and Treatment Outcomes.
Adaptive vs continuous cancer therapy: Exploiting space and trade-offs in drug scheduling.
Exploiting evolutionary principles to prolong tumor control in preclinical models of breast cancer.

June 11, 2017 Posted by | Cancer/oncology, Genetics, Immunology, Lectures, Mathematics, Medicine, Studies | Leave a comment

A few diabetes papers of interest

i. Association Between Blood Pressure and Adverse Renal Events in Type 1 Diabetes.

“The Joint National Committee and American Diabetes Association guidelines currently recommend a blood pressure (BP) target of <140/90 mmHg for all adults with diabetes, regardless of type (13). However, evidence used to support this recommendation is primarily based on data from trials of type 2 diabetes (46). The relationship between BP and adverse outcomes in type 1 and type 2 diabetes may differ, given that the type 1 diabetes population is typically much younger at disease onset, hypertension is less frequently present at diagnosis (3), and the basis for the pathophysiology and disease complications may differ between the two populations.

Prior prospective cohort studies (7,8) of patients with type 1 diabetes suggested that lower BP levels (<110–120/70–80 mmHg) at baseline entry were associated with a lower risk of adverse renal outcomes, including incident microalbuminuria. In one trial of antihypertensive treatment in type 1 diabetes (9), assignment to a lower mean arterial pressure (MAP) target of <92 mmHg (corresponding to ∼125/75 mmHg) led to a significant reduction in proteinuria compared with a MAP target of 100–107 mmHg (corresponding to ∼130–140/85–90 mmHg). Thus, it is possible that lower BP (<120/80 mmHg) reduces the risk of important renal outcomes, such as proteinuria, in patients with type 1 diabetes and may provide a synergistic benefit with intensive glycemic control on renal outcomes (1012). However, fewer studies have examined the association between BP levels over time and the risk of more advanced renal outcomes, such as stage III chronic kidney disease (CKD) or end-stage renal disease (ESRD)”.

“The primary objective of this study was to determine whether there is an association between lower BP levels and the risk of more advanced diabetic nephropathy, defined as macroalbuminuria or stage III CKD, within a background of different glycemic control strategies […] We included 1,441 participants with type 1 diabetes between the ages of 13 and 39 years who had previously been randomized to receive intensive versus conventional glycemic control in the Diabetes Control and Complications Trial (DCCT). The exposures of interest were time-updated systolic BP (SBP) and diastolic BP (DBP) categories. Outcomes included macroalbuminuria (>300 mg/24 h) or stage III chronic kidney disease (CKD) […] During a median follow-up time of 24 years, there were 84 cases of stage III CKD and 169 cases of macroalbuminuria. In adjusted models, SBP in the 2 (95% CI 1.05–1.21), and a 1.04 times higher risk of ESRD (95% CI 0.77–1.41) in adjusted Cox models. Every 10 mmHg increase in DBP was associated with a 1.17 times higher risk of microalbuminuria (95% CI 1.03–1.32), a 1.15 times higher risk of eGFR decline to 2 (95% CI 1.04–1.29), and a 0.80 times higher risk of ESRD (95% CI 0.47–1.38) in adjusted models. […] Because these data are observational, they cannot prove causation. It remains possible that subtle kidney disease may lead to early elevations in BP, and we cannot rule out the potential for reverse causation in our findings. However, we note similar trends in our data even when imposing a 7-year lag between BP and CKD ascertainment.”

CONCLUSIONS A lower BP (<120/70 mmHg) was associated with a substantially lower risk of adverse renal outcomes, regardless of the prior assigned glycemic control strategy. Interventional trials may be useful to help determine whether the currently recommended BP target of 140/90 mmHg may be too high for optimal renal protection in type 1 diabetes.”

It’s important to keep in mind when interpreting these results that endpoints like ESRD and stage III CKD are not the only relevant outcomes in this setting; even mild-stage kidney disease in diabetics significantly increase the risk of death from cardiovascular disease, and a substantial proportion of patients may die from cardiovascular disease before reaching a late-stage kidney disease endpoint (here’s a relevant link).

Identifying Causes for Excess Mortality in Patients With Diabetes: Closer but Not There Yet.

“A number of epidemiological studies have quantified the risk of death among patients with diabetes and assessed the causes of death (26), with highly varying results […] Overall, the studies to date have confirmed that diabetes is associated with an increased risk of all-cause mortality, but the magnitude of this excess risk is highly variable, with the relative risk ranging from 1.15 to 3.15. Nevertheless, all studies agree that mortality is mainly attributable to cardiovascular causes (26). On the other hand, studies of cancer-related death have generally been lacking despite the diabetes–cancer association and a number of plausible biological mechanisms identified to explain this link (8,9). In fact, studies assessing the specific causes of noncardiovascular death in diabetes have been sparse. […] In this issue of Diabetes Care, Baena-Díez et al. (10) report on an observational study of the association between diabetes and cause-specific death. This study involved 55,292 individuals from 12 Spanish population cohorts with no prior history of cardiovascular disease, aged 35 to 79 years, with a 10-year follow-up. […] This study found that individuals with diabetes compared with those without diabetes had a higher risk of cardiovascular death, cancer death, and noncardiovascular noncancer death with similar estimates obtained using the two statistical approaches. […] Baena-Díez et al. (10) showed that individuals with diabetes have an approximately threefold increased risk of cardiovascular mortality, which is much higher than what has been reported by recent studies (5,6). While this may be due to the lack of adjustment for important confounders in this study, there remains uncertainty regarding the magnitude of this increase.”

“[A]ll studies of excess mortality associated with diabetes, including the current one, have produced highly variable results. The reasons may be methodological. For instance, it may be that because of the wide range of age in these studies, comparing the rates of death between the patients with diabetes and those without diabetes using a measure based on the ratio of the rates may be misleading because the ratio can vary by age [it almost certainly does vary by age, US]. Instead, a measure based on the difference in rates may be more appropriate (16). Another issue relates to the fact that the studies include patients with longstanding diabetes of variable duration, resulting in so-called prevalent cohorts that can result in muddled mortality estimates since these are necessarily based on a mix of patients at different stages of disease (17). Thus, a paradigm change may be in order for future observational studies of diabetes and mortality, in the way they are both designed and analyzed. With respect to cancer, such studies will also need to tease out the independent contribution of antidiabetes treatments on cancer incidence and mortality (1820). It is thus clear that the quantification of the excess mortality associated with diabetes per se will need more accurate tools.”

iii. Risk of Cause-Specific Death in Individuals With Diabetes: A Competing Risks Analysis. This is the paper some of the results of which were discussed above. I’ll just include the highlights here:

RESULTS We included 55,292 individuals (15.6% with diabetes and overall mortality of 9.1%). The adjusted hazard ratios showed that diabetes increased mortality risk: 1) cardiovascular death, CSH = 2.03 (95% CI 1.63–2.52) and PSH = 1.99 (1.60–2.49) in men; and CSH = 2.28 (1.75–2.97) and PSH = 2.23 (1.70–2.91) in women; 2) cancer death, CSH = 1.37 (1.13–1.67) and PSH = 1.35 (1.10–1.65) in men; and CSH = 1.68 (1.29–2.20) and PSH = 1.66 (1.25–2.19) in women; and 3) noncardiovascular noncancer death, CSH = 1.53 (1.23–1.91) and PSH = 1.50 (1.20–1.89) in men; and CSH = 1.89 (1.43–2.48) and PSH = 1.84 (1.39–2.45) in women. In all instances, the cumulative mortality function was significantly higher in individuals with diabetes.

CONCLUSIONS Diabetes is associated with premature death from cardiovascular disease, cancer, and noncardiovascular noncancer causes.”

“Summary

Diabetes is associated with premature death from cardiovascular diseases (coronary heart disease, stroke, and heart failure), several cancers (liver, colorectal, and lung), and other diseases (chronic obstructive pulmonary disease and liver and kidney disease). In addition, the cause-specific cumulative mortality for cardiovascular, cancer, and noncardiovascular noncancer causes was significantly higher in individuals with diabetes, compared with the general population. The dual analysis with CSH and PSH methods provides a comprehensive view of mortality dynamics in the population with diabetes. This approach identifies the individuals with diabetes as a vulnerable population for several causes of death aside from the traditionally reported cardiovascular death.”

iv. Disability-Free Life-Years Lost Among Adults Aged ≥50 Years With and Without Diabetes.

RESEARCH DESIGN AND METHODS Adults (n = 20,008) aged 50 years and older were followed from 1998 to 2012 in the Health and Retirement Study, a prospective biannual survey of a nationally representative sample of adults. Diabetes and disability status (defined by mobility loss, difficulty with instrumental activities of daily living [IADL], and/or difficulty with activities of daily living [ADL]) were self-reported. We estimated incidence of disability, remission to nondisability, and mortality. We developed a discrete-time Markov simulation model with a 1-year transition cycle to predict and compare lifetime disability-related outcomes between people with and without diabetes. Data represent the U.S. population in 1998.

RESULTS From age 50 years, adults with diabetes died 4.6 years earlier, developed disability 6–7 years earlier, and spent about 1–2 more years in a disabled state than adults without diabetes. With increasing baseline age, diabetes was associated with significant (P < 0.05) reductions in the number of total and disability-free life-years, but the absolute difference in years between those with and without diabetes was less than at younger baseline age. Men with diabetes spent about twice as many of their remaining years disabled (20–24% of remaining life across the three disability definitions) as men without diabetes (12–16% of remaining life across the three disability definitions). Similar associations between diabetes status and disability-free and disabled years were observed among women.

CONCLUSIONS Diabetes is associated with a substantial reduction in nondisabled years, to a greater extent than the reduction of longevity. […] Using a large, nationally representative cohort of Americans aged 50 years and older, we found that diabetes is associated with a substantial deterioration of nondisabled years and that this is a greater number of years than the loss of longevity associated with diabetes. On average, a middle-aged adult with diabetes has an onset of disability 6–7 years earlier than one without diabetes, spends 1–2 more years with disability, and loses 7 years of disability-free life to the condition. Although other nationally representative studies have reported large reductions in complications (9) and mortality among the population with diabetes in recent decades (1), these studies, akin to our results, suggest that diabetes continues to have a substantial impact on morbidity and quality of remaining years of life.”

v. Association Between Use of Lipid-Lowering Therapy and Cardiovascular Diseases and Death in Individuals With Type 1 Diabetes.

“People with type 1 diabetes have a documented shorter life expectancy than the general population without diabetes (1). Cardiovascular disease (CVD) is the main cause of the excess morbidity and mortality, and despite advances in management and therapy, individuals with type 1 diabetes have a markedly elevated risk of cardiovascular events and death compared with the general population (2).

Lipid-lowering treatment with hydroxymethylglutaryl-CoA reductase inhibitors (statins) prevents major cardiovascular events and death in a broad spectrum of patients (3,4). […] We hypothesized that primary prevention with lipid-lowering therapy (LLT) can reduce the incidence of cardiovascular morbidity and mortality in individuals with type 1 diabetes. The aim of the study was to examine this in a nationwide longitudinal cohort study of patients with no history of CVD. […] A total of 24,230 individuals included in 2006–2008 NDR with type 1 diabetes without a history of CVD were followed until 31 December 2012; 18,843 were untreated and 5,387 treated with LLT [Lipid-Lowering Therapy] (97% statins). The mean follow-up was 6.0 years. […] Hazard ratios (HRs) for treated versus untreated were as follows: cardiovascular death 0.60 (95% CI 0.50–0.72), all-cause death 0.56 (0.48–0.64), fatal/nonfatal stroke 0.56 (0.46–0.70), fatal/nonfatal acute myocardial infarction 0.78 (0.66–0.92), fatal/nonfatal coronary heart disease 0.85 (0.74–0.97), and fatal/nonfatal CVD 0.77 (0.69–0.87).

CONCLUSIONS This observational study shows that LLT is associated with 22–44% reduction in the risk of CVD and cardiovascular death among individuals with type 1 diabetes without history of CVD and underlines the importance of primary prevention with LLT to reduce cardiovascular risk in type 1 diabetes.”

vi. Prognostic Classification Factors Associated With Development of Multiple Autoantibodies, Dysglycemia, and Type 1 Diabetes—A Recursive Partitioning Analysis.

“In many prognostic factor studies, multivariate analyses using the Cox proportional hazards model are applied to identify independent prognostic factors. However, the coefficient estimates derived from the Cox proportional hazards model may be biased as a result of violating assumptions of independence. […] RPA [Recursive Partitioning Analysis] classification is a useful tool that could prioritize the prognostic factors and divide the subjects into distinctive groups. RPA has an advantage over the proportional hazards model in identifying prognostic factors because it does not require risk factor independence and, as a nonparametric technique, makes no requirement on the underlying distributions of the variables considered. Hence, it relies on fewer modeling assumptions. Also, because the method is designed to divide subjects into groups based on the length of survival, it defines groupings for risk classification, whereas Cox regression models do not. Moreover, there is no need to explicitly include covariate interactions because of the recursive splitting structure of tree model construction.”

“This is the first study that characterizes the risk factors associated with the transition from one preclinical stage to the next following a recommended staging classification system (9). The tree-structured prediction model reveals that the risk parameters are not the same across each transition. […] Based on the RPA classification, the subjects at younger age and with higher GAD65Ab [an important biomarker in the context of autoimmune forms of diabetes, US – here’s a relevant link] titer are at higher risk for progression to multiple positive autoantibodies from a single autoantibody (seroconversion). Approximately 70% of subjects with a single autoantibody were positive for GAD65Ab, much higher than for insulin autoantibody (24%) and IA-2A [here’s a relevant link – US] (5%). Our study results are consistent with those of others (2224) in that seroconversion is age related. Previous studies in infants and children at an early age have shown that progression from single to two or more autoantibodies occurs more commonly in children 25). The subjects ≤16 years of age had almost triple the 5-year risk compared with subjects >16 years of age at the same GAD65Ab titer level. Hence, not all individuals with a single islet autoantibody can be thought of as being at low risk for disease progression.”

“This is the first study that identifies the risk factors associated with the timing of transitions from one preclinical stage to the next in the development of T1D. Based on RPA risk parameters, we identify the characteristics of groups with similar 5-year risks for advancing to the next preclinical stage. It is clear that individuals with one or more autoantibodies or with dysglycemia are not homogeneous with regard to the risk of disease progression. Also, there are differences in risk factors at each stage that are associated with increased risk of progression. The potential benefit of identifying these groups allows for a more informed discussion of diabetes risk and the selective enrollment of individuals into clinical trials whose risk more appropriately matches the potential benefit of an experimental intervention. Since the risk levels in these groups are substantial, their definition makes possible the design of more efficient trials with target sample sizes that are feasible, opening up the field of prevention to additional at-risk cohorts. […] Our results support the evidence that autoantibody titers are strong predictors at each transition leading to T1D development. The risk of the development of multiple autoantibodies was significantly increased when the GAD65Ab titer level was elevated, and the risk of the development of dysglycemia was increased when the IA-2A titer level increased. These indicate that better risk prediction on the timing of transitions can be obtained by evaluating autoantibody titers. The results also suggest that an autoantibody titer should be carefully considered in planning prevention trials for T1D in addition to the number of positive autoantibodies and the type of autoantibody.”

May 17, 2017 Posted by | Diabetes, Immunology, Medicine, Nephrology, Statistics, Studies | Leave a comment

Today’s Landscape of Pharmaceutical Research in Cancer

It’s been a while since I watched this lecture so I don’t remember the details very well, but I usually add notes in my bookmarks when I watch lectures so that I know what details to include in my comments here on the blog, and I have added the details from the bookmark notes below.

It is a short lecture, the lecture itself lasts only roughly 30 minutes; it doesn’t really start until roughly the 9 minutes and 30 seconds mark, and it finishes around the 44 min mark (the rest is Q&A – I skipped some of the introduction, but watched the Q&A). The lecture is not very technical, I think the content is perfectly understandable also to people without a medical background. One data point from the lecture which I thought worth including in these comments is this: According to Sigal, “roughly 30 per cent of the biopharmaceutical industry’s portfolio … is focused on research in oncology.”

May 17, 2017 Posted by | Cancer/oncology, Immunology, Lectures, Medicine, Pharmacology | Leave a comment

Standing on the Shoulders of Mice: Aging T-cells

Most of the lecture is not about mice, but rather about stuff like this and this (both papers are covered in the lecture). I’ve read about related topics before (see e.g this), but if you haven’t some parts of the lecture will probably be too technical for you to follow.

May 3, 2017 Posted by | Cancer/oncology, Cardiology, Genetics, Immunology, Lectures, Medicine, Papers | Leave a comment

Biodemography of aging (II)

In my first post about the book I included a few general remarks about the book and what it’s about. In this post I’ll continue my coverage of the book, starting with a few quotes from and observations related to the content in chapter 4 (‘Evidence for Dependence Among Diseases‘).

“To compare the effects of public health policies on a population’s characteristics, researchers commonly estimate potential gains in life expectancy that would result from eradication or reduction of selected causes of death. For example, Keyfitz (1977) estimated that eradication of cancer would result in 2.265 years of increase in male life expectancy at birth (or by 3 % compared to its 1964 level). Lemaire (2005) found that the potential gain in the U.S. life expectancy from cancer eradication would not exceed 3 years for both genders. Conti et al. (1999) calculated that the potential gain in life expectancy from cancer eradication in Italy would be 3.84 years for males and 2.77 years for females. […] All these calculations assumed independence between cancer and other causes of death. […] for today’s populations in developed countries, where deaths from chronic non-communicable diseases are in the lead, this assumption might no longer be valid. An important feature of such chronic diseases is that they often develop in clusters manifesting positive correlations with each other. The conventional view is that, in a case of such dependence, the effect of cancer eradication on life expectancy would be even smaller.”

I think the great majority of people you asked would have assumed that the beneficial effect of hypothetical cancer eradication in humans on human life expectancy would be much larger than this, but that’s just an impression. I’ve seen estimates like these before, so I was not surprised – but I think many people would be if they knew this. A very large number of people die as a result of developing cancer today, but the truth of the matter is that if they hadn’t died from cancer they’d have died anyway, and on average probably not really all that much later. I linked to Richard Alexander’s comments on this topic in my last post about the book, and again his observations apply so I thought I might as well add the relevant quote from the book here:

“In the course of working against senescence, selection will tend to remove, one by one, the most frequent sources of mortality as a result of senescence. Whenever a single cause of mortality, such as a particular malfunction of any vital organ, becomes the predominant cause of mortality, then selection will more effectively reduce the significance of that particular defect (meaning those who lack it will outreproduce) until some other achieves greater relative significance. […] the result will be that all organs and systems will tend to deteriorate together. […] The point is that as we age, and as senescence proceeds, large numbers of potential sources of mortality tend to lurk ever more malevolently just “below the surface,”so that, unfortunately, the odds are very high against any dramatic lengthening of the maximum human lifetime through technology.”

Remove one cause of death and there are plenty of others standing in line behind it. We already knew that; two hundred years ago one out of every four deaths in England was the result of tuberculosis, but developing treatments for tuberculosis and other infectious diseases did not mean that English people stopped dying; these days they just die from cardiovascular disease and cancer instead. Do note in the context of that quote that Alexander is talking about the maximum human lifetime, not average life expectancy; again, we know and have known for a long time that human technology can have a dramatic effect on the latter variable. Of course a shift in one distribution will be likely to have spill-over effects on the other (if more people are alive at the age of 70, the potential group of people also living on to reach e.g. 100 years is higher, even if the mortality rate for the 70-100 year old group did not change) the point is just that these effects are secondary effects and are likely to be marginal at best.

Anyway, some more stuff from the chapter. Just like the previous chapter in the book did, this one also includes analyses of very large data sets:

The Multiple Cause of Death (MCD) data files contain information about underlying and secondary causes of death in the U.S. during 1968–2010. In total, they include more than 65 million individual death certificate records. […] we used data for the period 1979–2004.”

There’s some formal modelling stuff in the chapter which I won’t go into in detail here, this is the chapter in which I encountered the comment about ‘the multivariate lognormal frailty model’ I included in my first post about the book. One of the things the chapter looks at are the joint frequencies of deaths from cancer and other fatal diseases; it turns out that there are multiple diseases that are negatively related with cancer as a cause of death when you look at the population-level data mentioned above. The chapter goes into some of the biological mechanisms which may help explain why these associations look the way they do, and I’ll quote a little from that part of the coverage. A key idea here is (as always..?) that there are tradeoffs at play; some genetic variants may help protect you against e.g. cancer, but at the same time increase the risk of other diseases for the same reason that they protect you against cancer. In the context of the relationship between cancer deaths and deaths from other diseases they note in the conclusion that: “One potential biological mechanism underlying the negative correlation among cancer and other diseases could be related to the differential role of apoptosis in the development of these diseases.” The chapter covers that stuff in significantly more detail, and I decided to add some observations from the chapter on these topics below:

“Studying the role of the p53 gene in the connection between cancer and cellular aging, Campisi (2002, 2003) suggested that longevity may depend on a balance between tumor suppression and tissue renewal mechanisms. […] Although the mechanism by which p53 regulates lifespan remains to be determined, […] findings highlight the possibility that careful manipulation of p53 activity during adult life may result in beneficial effects on healthy lifespan. Other tumor suppressor genes are also involved in regulation of longevity. […] In humans, Dumont et al. (2003) demonstrated that a replacement of arginine (Arg) by proline (Pro) at position 72 of human p53 decreases its ability to initiate apoptosis, suggesting that these variants may differently affect longevity and vulnerability to cancer. Van Heemst et al. (2005) showed that individuals with the Pro/Pro genotype of p53 corresponding to reduced apoptosis in cells had significantly increased overall survival (by 41%) despite a more than twofold increased proportion of cancer deaths at ages 85+, together with a decreased proportion of deaths from senescence related causes such as COPD, fractures, renal failure, dementia, and senility. It was suggested that human p53 may protect against cancer but at a cost of longevity. […] Other biological factors may also play opposing roles in cancer and aging and thus contribute to respective trade-offs […]. E.g., higher levels of IGF-1 [have been] linked to both cancer and attenuation of phenotypes of physical senescence, such as frailty, sarcopenia, muscle atrophy, and heart failure, as well as to better muscle regeneration”.

“The connection between cancer and longevity may potentially be mediated by trade-offs between cancer and other diseases which do not necessarily involve any basic mechanism of aging per se. In humans, it could result, for example, from trade-offs between vulnerabilities to cancer and AD, or to cancer and CVD […] There may be several biological mechanisms underlying the negative correlation among cancer and these diseases. One can be related to the differential role of apoptosis in their development. For instance, in stroke, the number of dying neurons following brain ischemia (and thus probability of paralysis or death) may be less in the case of a downregulated apoptosis. As for cancer, the downregulated apoptosis may, conversely, mean a higher risk of the disease because more cells may survive damage associated with malignant transformation. […] Also, the role of the apoptosis may be different or even opposite in the development of cancer and Alzheimer’s disease (AD). Indeed, suppressed apoptosis is a hallmark of cancer, while increased apoptosis is a typical feature of AD […]. If so, then chronically upregulated apoptosis (e.g., due to a genetic polymorphism) may potentially be protective against cancer, but be deleterious in relation to AD. […] Increased longevity can be associated not only with increased but also with decreased chances of cancer. […] The most popular to-date “anti-aging” intervention, caloric restriction, often results in increased maximal life span along with reduced tumor incidence in laboratory rodents […] Because the rate of apoptosis was significantly and consistently higher in food restricted mice regardless of age, James et al. (1998) suggested that caloric restriction may have a cancer-protective effect primarily due to the upregulated apoptosis in these mice.”

Below I’ll discuss content covered in chapter 5, which deals with ‘Factors That May Increase Vulnerability to Cancer and Longevity in Modern Human Populations’. I’ll start out with a few quotes:

“Currently, the overall cancer incidence rate (age-adjusted) in the less developed world is roughly half that seen in the more developed world […] For countries with similar levels of economic development but different climate and ethnic characteristics […], the cancer rate patterns look much more similar than for the countries that share the same geographic location, climate, and ethnic distribution, but differ in the level of economic development […]. This suggests that different countries may share common factors linked to economic prosperity that could be primarily responsible for the modern increases in overall cancer risk. […] Population aging (increases in the proportion of older people) may […] partly explain the rise in the global cancer burden […]; however, it cannot explain increases in age-specific cancer incidence rates over time […]. Improved diagnostics and elevated exposures to carcinogens may explain increases in rates for selected cancer sites, but they cannot fully explain the increase in the overall cancer risk, nor incidence rate trends for most individual cancers (Jemal et al. 2008, 2013).”

“[W]e propose that the association between the overall cancer risk and the economic progress and spread of the Western lifestyle could in part be explained by the higher proportion of individuals more susceptible to cancer in the populations of developed countries, and discuss several mechanisms of such an increase in the proportion of the vulnerable. […] mechanisms include but are not limited to: (i) Improved survival of frail individuals. […] (ii) Avoiding or reducing traditional exposures. Excessive disinfection and hygiene typical of the developed world can diminish exposure to some factors that were abundant in the past […] Insufficiently or improperly trained immune systems may be less capable of resisting cancer. (iii) Burden of novel exposures. Some new medicines, cleaning agents, foods, etc., that are not carcinogenic themselves may still affect the natural ways of processing carcinogens in the body, and through this increase a person’s susceptibility to established carcinogens. [If this one sounds implausible to you, I’ll remind you that drug metabolism is complicatedUS] […] (iv) Some of the factors linked to economic prosperity and the Western lifestyle (e.g., delayed childbirth and food enriched with growth factors) may antagonistically influence aging and cancer risk.”

They provide detailed coverage of all of these mechanisms in the chapter, below I have included a few select observations from that part of the coverage.

“There was a dramatic decline in infant and childhood mortality in developed countries during the last century. For example, the infant mortality rate in the United States was about 6 % of live births in 1935, 3 % in 1950, 1.3 % in 1980, and 0.6 % in 2010. That is, it declined tenfold over the course of 75 years […] Because almost all children (including those with immunity deficiencies) survive, the proportion of the children who are inherently more vulnerable could be higher in the more developed countries. This is consistent with a typically higher proportion of children with chronic inflammatory immune disorders such as asthma and allergy in the populations of developed countries compared to less developed ones […] Over-reduction of such traditional exposures may result in an insufficiently/improperly trained immune system early in life, which could make it less able to resist diseases, including cancer later in life […] There is accumulating evidence of the important role of these effects in cancer risk. […] A number of studies have connected excessive disinfection and lack of antigenic stimulation (especially in childhood) of the immune system in Westernized communities with increased risks of both chronic inflammatory diseases and cancer […] The IARC data on migrants to Israel […] allow for comparison of the age trajectories of cancer incidence rates between adult Jews who live in Israel but were born in other countries […] [These data] show that Jews born in less developed regions (Africa and Asia) have overall lower cancer risk than those born in the more developed regions (Europe and America).  The discrepancy is unlikely to be due to differences in cancer diagnostics because at the moment of diagnosis all these people were citizens of the same country with the same standard of medical care. These results suggest that surviving childhood and growing up in a less developed country with diverse environmental exposures might help form resistance to cancer that lasts even after moving to a high risk country.”

I won’t go much into the ‘burden of novel exposures’ part, but I should note that exposures that may be relevant include factors like paracetamol use and antibiotics for treatment of H. pylori. Paracetamol is not considered carcinogenic by the IARC, but we know from animal studies that if you give rats paratamol and then expose them to an established carcinogen (with the straightforward name N-nitrosoethyl-N-hydroxyethylamine), the number of rats developing kidney cancer goes up. In the context of H. pylori, we know that these things may cause stomach cancer, but when you treat rats with metronidazol (which is used to treat H. pylori) and expose them to an established carcinogen, they’re more likely to develop colon cancer. The link between colon cancer and antibiotics use has been noted in other contexts as well; decreased microbial diversity after antibiotics use may lead to suppression of the bifidobacteria and promotion of E. coli in the colon, the metabolic products of which may lead to increased cancer risk. Over time an increase in colon cancer risk and a decrease in stomach cancer risk has been observed in developed societies, but aside from changes in diet another factor which may play a role is population-wide exposure to antibiotics. Colon and stomach cancers are incidentally not the only ones of interest in this particular context; it has also been found that exposure to chloramphenicol, a broad-spectrum antibiotic used since the 40es, increases the risk of lymphoma in mice when the mice are exposed to a known carcinogen, despite the drug itself again not being clearly carcinogenic on its own.

Many new exposures aside from antibiotics are of course relevant. Two other drug-related ones that might be worth mentioning are hormone replacement therapy and contraceptives. HRT is not as commonly used today as it was in the past, but to give some idea of the scope here, half of all women in the US aged 50-65 are estimated to have been on HRT at the peak of its use, around the turn of the millennium, and HRT is assumed to be partly responsible for the higher incidence of hormone-related cancers observed in female populations living in developed countries. It’s of some note that the use of HRT dropped dramatically shortly after this peak (from 61 million prescriptions in 2001 to 21 million in 2004), and that the incidence of estrogen-receptor positive cancers subsequently dropped. As for oral contraceptives, these have been in use since the 1960s, and combined hormonal contraceptives are known to increase the risk of liver- and breast cancer, while seemingly also having a protective effect against endometrial cancer and ovarian cancer. The authors speculate that some of the cancer incidence changes observed in the US during the latter half of the last century, with a decline in female endometrial and ovarian cancer combined with an increase in breast- and liver cancer, could in part be related to widespread use of these drugs. An estimated 10% of all women of reproductive age alive in the world, and 16% of those living in the US, are estimated to be using combined hormonal contraceptives. In the context of the protective effect of the drugs, it should perhaps be noted that endometrial cancer in particular is strongly linked to obesity so if you are not overweight you are relatively low-risk.

Many ‘exposures’ in a cancer context are not drug-related. For example women in Western societies tend to go into menopause at a higher age, and higher age of menopause has been associated with hormone-related cancers; but again the picture is not clear in terms of how the variable affects longevity, considering that later menopause has also been linked to increased longevity in several large studies. In the studies the women did have higher mortality from the hormone-related cancers, but on the other hand they were less likely to die from some of the other causes, such as pneumonia, influenza, and falls. Age of childbirth is also a variable where there are significant differences between developed countries and developing countries, and this variable may also be relevant to cancer incidence as it has been linked to breast cancer and melanoma; in one study women who first gave birth after the age of 35 had a 40% increased risk of breast cancer compared to mothers who gave birth before the age of 20 (good luck ‘controlling for everything’ in a context like that, but…), and in a meta-analysis the relative risk for melanoma was 1.47 for women in the oldest age group having given birth, compared to the youngest (again, good luck controlling for everything, but at least it’s not just one study). Lest you think this literature only deals with women, it’s also been found that parental age seems to be linked to cancers in the offspring (higher parental age -> higher cancer risk in the offspring), though the effect sizes are not mentioned in the coverage.

Here’s what they conclude at the end of the chapter:

“Some of the factors associated with economic prosperity and a Western lifestyle may influence both aging and vulnerability to cancer, sometimes oppositely. Current evidence supports a possibility of trade-offs between cancer and aging-related phenotypes […], which could be influenced by delayed reproduction and exposures to growth factors […]. The latter may be particularly beneficial at very old age. This is because the higher levels of growth factors may attenuate some phenotypes of physical senescence, such as decline in regenerative and healing ability, sarcopenia, frailty, elderly fractures and heart failure due to muscles athrophy. They may also increase the body’s vulnerability to cancer, e.g., through growth promoting and anti-apoptotic effects […]. The increase in vulnerability to cancer due to growth factors can be compatible with extreme longevity because cancer is a major contributor to mortality mainly before age 85, while senescence-related causes (such as physical frailty) become major contributors to mortality at oldest old ages (85+). In this situation, the impact of growth factors on vulnerability to death could be more deleterious in middle-to-old life (~before 85) and more beneficial at older ages (85+).

The complex relationships between aging, cancer, and longevity are challenging. This complexity warns against simplified approaches to extending longevity without taking into account the possible trade-offs between phenotypes of physical aging and various health disorders, as well as the differential impacts of such tradeoffs on mortality risks at different ages (e.g., Ukraintseva and Yashin 2003a; Yashin et al. 2009; Ukraintseva et al. 2010, 2016).”

March 7, 2017 Posted by | Books, Cancer/oncology, Epidemiology, Genetics, Immunology, Medicine, Pharmacology | Leave a comment

The Ageing Immune System and Health (II)

Here’s the first post about the book. I finished it a while ago but I recently realized I had not completed my intended coverage of the book here on the blog back then, and as some of the book’s material sort-of-kind-of relates to material encountered in a book I’m currently reading (Biodemography of Aging) I decided I might as well finish my coverage of the book now in order to review some things I might have forgot in the meantime, by providing coverage here of some of the material covered in the second half of the book. It’s a nice book with some interesting observations, but as I also pointed out in my first post it is definitely not an easy read. Below I have included some observations from the book’s second half.

Lungs:

“The aged lung is characterised by airspace enlargement similar to, but not identical with acquired emphysema [4]. Such tissue damage is detected even in non-smokers above 50 years of age as the septa of the lung alveoli are destroyed and the enlarged alveolar structures result in a decreased surface for gas exchange […] Additional problems are that surfactant production decreases with age [6] increasing the effort needed to expand the lungs during inhalation in the already reduced thoracic cavity volume where the weakened muscles are unable to thoroughly ventilate. […] As ageing is associated with respiratory muscle strength reduction, coughing becomes difficult making it progressively challenging to eliminate inhaled particles, pollens, microbes, etc. Additionally, ciliary beat frequency (CBF) slows down with age impairing the lungs’ first line of defence: mucociliary clearance [9] as the cilia can no longer repel invading microorganisms and particles. Consequently e.g. bacteria can more easily colonise the airways leading to infections that are frequent in the pulmonary tract of the older adult.”

“With age there are dramatic changes in neutrophil function, including reduced chemotaxis, phagocytosis and bactericidal mechanisms […] reduced bactericidal function will predispose to infection but the reduced chemotaxis also has consequences for lung tissue as this results in increased tissue bystander damage from neutrophil elastases released during migration […] It is currently accepted that alterations in pulmonary PPAR profile, more precisely loss of PPARγ activity, can lead to inflammation, allergy, asthma, COPD, emphysema, fibrosis, and cancer […]. Since it has been reported that PPARγ activity decreases with age, this provides a possible explanation for the increasing incidence of these lung diseases and conditions in older individuals [6].”

Cancer:

“Age is an important risk factor for cancer and subjects aged over 60 also have a higher risk of comorbidities. Approximately 50 % of neoplasms occur in patients older than 70 years […] a major concern for poor prognosis is with cancer patients over 70–75 years. These patients have a lower functional reserve, a higher risk of toxicity after chemotherapy, and an increased risk of infection and renal complications that lead to a poor quality of life. […] [Whereas] there is a difference in organs with higher cancer incidence in developed versus developing countries [,] incidence increases with ageing almost irrespective of country […] The findings from Surveillance, Epidemiology and End Results Program [SEERincidentally I likely shall at some point discuss this one in much more detail, as the aforementioned biodemography textbook covers this data in a lot of detail.. – US] [6] show that almost a third of all cancer are diagnosed after the age of 75 years and 70 % of cancer-related deaths occur after the age of 65 years. […] The traditional clinical trial focus is on younger and healthier patient, i.e. with few or no co-morbidities. These restrictions have resulted in a lack of data about the optimal treatment for older patients [7] and a poor evidence base for therapeutic decisions. […] In the older patient, neutropenia, anemia, mucositis, cardiomyopathy and neuropathy — the toxic effects of chemotherapy — are more pronounced […] The correction of comorbidities and malnutrition can lead to greater safety in the prescription of chemotherapy […] Immunosenescence is a general classification for changes occurring in the immune system during the ageing process, as the distribution and function of cells involved in innate and adaptive immunity are impaired or remodelled […] Immunosenescence is considered a major contributor to cancer development in aged individuals“.

Neurodegenerative diseases:

“Dementia and age-related vision loss are major causes of disability in our ageing population and it is estimated that a third of people aged over 75 are affected. […] age is the largest risk factor for the development of neurodegenerative diseases […] older patients with comorbidities such as atherosclerosis, type II diabetes or those suffering from repeated or chronic systemic bacterial and viral infections show earlier onset and progression of clinical symptoms […] analysis of post-mortem brain tissue from healthy older individuals has provided evidence that the presence of misfolded proteins alone does not correlate with cognitive decline and dementia, implying that additional factors are critical for neural dysfunction. We now know that innate immune genes and life-style contribute to the onset and progression of age-related neuronal dysfunction, suggesting that chronic activation of the immune system plays a key role in the underlying mechanisms that lead to irreversible tissue damage in the CNS. […] Collectively these studies provide evidence for a critical role of inflammation in the pathogenesis of a range of neurodegenerative diseases, but the factors that drive or initiate inflammation remain largely elusive.”

“The effect of infection, mimicked experimentally by administration of bacterial lipopolysaccharide (LPS) has revealed that immune to brain communication is a critical component of a host organism’s response to infection and a collection of behavioural and metabolic adaptations are initiated over the course of the infection with the purpose of restricting the spread of a pathogen, optimising conditions for a successful immune response and preventing the spread of infection to other organisms [10]. These behaviours are mediated by an innate immune response and have been termed ‘sickness behaviours’ and include depression, reduced appetite, anhedonia, social withdrawal, reduced locomotor activity, hyperalgesia, reduced motivation, cognitive impairment and reduced memory encoding and recall […]. Metabolic adaptation to infection include fever, altered dietary intake and reduction in the bioavailability of nutrients that may facilitate the growth of a pathogen such as iron and zinc [10]. These behavioural and metabolic adaptions are evolutionary highly conserved and also occur in humans”.

“Sickness behaviour and transient microglial activation are beneficial for individuals with a normal, healthy CNS, but in the ageing or diseased brain the response to peripheral infection can be detrimental and increases the rate of cognitive decline. Aged rodents exhibit exaggerated sickness and prolonged neuroinflammation in response to systemic infection […] Older people who contract a bacterial or viral infection or experience trauma postoperatively, also show exaggerated neuroinflammatory responses and are prone to develop delirium, a condition which results in a severe short term cognitive decline and a long term decline in brain function […] Collectively these studies demonstrate that peripheral inflammation can increase the accumulation of two neuropathological hallmarks of AD, further strengthening the hypothesis that inflammation i[s] involved in the underlying pathology. […] Studies from our own laboratory have shown that AD patients with mild cognitive impairment show a fivefold increased rate of cognitive decline when contracting a systemic urinary tract or respiratory tract infection […] Apart from bacterial infection, chronic viral infections have also been linked to increased incidence of neurodegeneration, including cytomegalovirus (CMV). This virus is ubiquitously distributed in the human population, and along with other age-related diseases such as cardiovascular disease and cancer, has been associated with increased risk of developing vascular dementia and AD [66, 67].”

Frailty:

“Frailty is associated with changes to the immune system, importantly the presence of a pro-inflammatory environment and changes to both the innate and adaptive immune system. Some of these changes have been demonstrated to be present before the clinical features of frailty are apparent suggesting the presence of potentially modifiable mechanistic pathways. To date, exercise programme interventions have shown promise in the reversal of frailty and related physical characteristics, but there is no current evidence for successful pharmacological intervention in frailty. […] In practice, acute illness in a frail person results in a disproportionate change in a frail person’s functional ability when faced with a relatively minor physiological stressor, associated with a prolonged recovery time […] Specialist hospital services such as surgery [15], hip fractures [16] and oncology [17] have now begun to recognise frailty as an important predictor of mortality and morbidity.

I should probably mention here that this is another area where there’s an overlap between this book and the biodemography text I’m currently reading; chapter 7 of the latter text is about ‘Indices of Cumulative Deficits’ and covers this kind of stuff in a lot more detail than does this one, including e.g. detailed coverage of relevant statistical properties of one such index. Anyway, back to the coverage:

“Population based studies have demonstrated that the incidence of infection and subsequent mortality is higher in populations of frail people. […] The prevalence of pneumonia in a nursing home population is 30 times higher than the general population [39, 40]. […] The limited data available demonstrates that frailty is associated with a state of chronic inflammation. There is also evidence that inflammageing predates a diagnosis of frailty suggesting a causative role. […] A small number of studies have demonstrated a dysregulation of the innate immune system in frailty. Frail adults have raised white cell and neutrophil count. […] High white cell count can predict frailty at a ten year follow up [70]. […] A recent meta-analysis and four individual systematic reviews have found beneficial evidence of exercise programmes on selected physical and functional ability […] exercise interventions may have no positive effect in operationally defined frail individuals. […] To date there is no clear evidence that pharmacological interventions improve or ameliorate frailty.”

Exercise:

“[A]s we get older the time and intensity at which we exercise is severely reduced. Physical inactivity now accounts for a considerable proportion of age-related disease and mortality. […] Regular exercise has been shown to improve neutrophil microbicidal functions which reduce the risk of infectious disease. Exercise participation is also associated with increased immune cell telomere length, and may be related to improved vaccine responses. The anti-inflammatory effect of regular exercise and negative energy balance is evident by reduced inflammatory immune cell signatures and lower inflammatory cytokine concentrations. […] Reduced physical activity is associated with a positive energy balance leading to increased adiposity and subsequently systemic inflammation [5]. […] Elevated neutrophil counts accompany increased inflammation with age and the increased ratio of neutrophils to lymphocytes is associated with many age-related diseases including cancer [7]. Compared to more active individuals, less active and overweight individuals have higher circulating neutrophil counts [8]. […] little is known about the intensity, duration and type of exercise which can provide benefits to neutrophil function. […] it remains unclear whether exercise and physical activity can override the effects of NK cell dysfunction in the old. […] A considerable number of studies have assessed the effects of acute and chronic exercise on measures of T-cell immunesenescence including T cell subsets, phenotype, proliferation, cytokine production, chemotaxis, and co-stimulatory capacity. […] Taken together exercise appears to promote an anti-inflammatory response which is mediated by altered adipocyte function and improved energy metabolism leading to suppression of pro-inflammatory cytokine production in immune cells.”

February 24, 2017 Posted by | Biology, Books, Cancer/oncology, Epidemiology, Immunology, Medicine, Neurology | Leave a comment

Diabetes and the Brain (II)

Here’s my first post about the book, which I recently finished – here’s my goodreads review. I added the book to my list of favourite books on goodreads, it’s a great textbook. Below some observations from the first few chapters of the book.

“Several studies report T1D [type 1 diabetes] incidence numbers of 0.1–36.8/100,000 subjects worldwide (2). Above the age of 15 years ketoacidosis at presentation occurs on average in 10% of the population; in children ketoacidosis at presentation is more frequent (3, 4). Overall, publications report a male predominance (1.8 male/female ratio) and a seasonal pattern with higher incidence in November through March in European countries. Worldwide, the incidence of T1D is higher in more developed countries […] After asthma, T1D is a leading cause of chronic disease in children. […]  twin studies show a low concordant prevalence of T1D of only 30–55%. […] Diabetes mellitus type 1 may be sporadic or associated with other autoimmune diseases […] The latter has been classified as autoimmune polyglandular syndrome type II (APS-II). APS-II is a polygenic disorder with a female preponderance which typically occurs between the ages of 20 and 40 years […] In clinical practice, anti-thyroxine peroxidase (TPO) positive hypothyroidism is the most frequent concomitant autoimmune disease in type 1 diabetic patients, therefore all type 1 diabetic patients should annually be screened for the presence of anti-TPO antibodies. Other frequently associated disorders are atrophic gastritis leading to vitamin B12 deficiency (pernicious anemia) and vitiligo. […] The normal human pancreas contains a superfluous amount of β-cells. In T1D, β-cell destruction therefore remains asymptomatic until a critical β-cell reserve is left. This destructive process takes months to years […] Only in a minority of type 1 diabetic patients does the disease begin with diabetic ketoacidosis, the majority presents with a milder course that may be mistaken as type 2 diabetes (7).”

“Insulin is the main regulator of glucose metabolism by stimulating glucose uptake in tissues and glycogen storage in liver and muscle and by inhibiting gluconeogenesis in the liver (11). Moreover, insulin is a growth factor for cells and cell differentiation, and acting as anabolic hormone insulin stimulates lipogenesis and protein synthesis. Glucagon is the counterpart of insulin and is secreted by the α-cells in the pancreatic islets in an inversely proportional quantity to the insulin concentration. Glucagon, being a catabolic hormone, stimulates glycolysis and gluconeogenesis in the liver as well as lipolysis and uptake of amino acids in the liver. Epinephrine and norepinephrine have comparable catabolic effects […] T1D patients lose the glucagon response to hypoglycemia after several years, when all β-cells are destructed […] The risk of hypoglycemia increases with improved glycemic control, autonomic neuropathy, longer duration of diabetes, and the presence of long-term complications (17) […] Long-term complications are prevalent in any population of type 1 diabetic patients with increasing prevalence and severity in relation to disease duration […] The pathogenesis of diabetic complications is multifactorial, complicated, and not yet fully elucidated.”

“Cataract is much more frequent in patients with diabetes and tends to become clinically significant at a younger age. Glaucoma is markedly increased in diabetes too.” (I was unaware of this).

“T1D should be considered as an independent risk factor for atherosclerosis […] An older study shows that the cumulative mortality of coronary heart disease in T1D was 35% by the age 55 (34). In comparison, the Framingham Heart Study showed a cardiovascular mortality of 8% of men and 4% of women without diabetes, respectively. […] Atherosclerosis is basically a systemic disease. Patients with one clinically apparent localization are at risk for other manifestations. […] Musculoskeletal disease in diabetes is best viewed as a systemic disorder with involvement of connective tissue. Potential pathophysiological mechanisms that play a role are glycosylation of collagen, abnormal cross-linking of collagen, and increased collagen hydration […] Dupuytren’s disease […] may be observed in up to 42% of adults with diabetes mellitus, typically in patients with long-standing T1D. Dupuytren’s is characterized by thickening of the palmar fascia due to fibrosis with nodule formation and contracture, leading to flexion contractures of the digits, most commonly affecting the fourth and fifth digits. […] Foot problems in diabetes are common and comprise ulceration, infection, and gangrene […] The lifetime risk of a foot ulcer for diabetic patients is about 15% (42). […] Wound depth is an important determinant of outcome (46, 47). Deep ulcers with cellulitis or abscess formation often involve osteomyelitis. […] Radiologic changes occur late in the course of osteomyelitis and negative radiographs certainly do not exclude it.”

“Education of people with diabetes is a comprehensive task and involves teamwork by a team that comprises at least a nurse educator, a dietician, and a physician. It is, however, essential that individuals with diabetes assume an active role in their care themselves, since appropriate self-care behavior is the cornerstone of the treatment of diabetes.” (for much more on these topics, see Simmons et al.)

“The International Diabetes Federation estimates that more than 245 million people around the world have diabetes (4). This total is expected to rise to 380 million within 20 years. Each year a further 7 million people develop diabetes. Diabetes, mostly type 2 diabetes (T2D), now affects 5.9% of the world’s adult population with almost 80% of the total in developing countries. […] According to […] 2007 prevalence data […] [a]lmost 25% of the population aged 60 years and older had diabetes in 2007. […] It has been projected that one in three Americans born in 2000 will develop diabetes, with the highest estimated lifetime risk among Latinos (males, 45.4% and females, 52.5%) (6). A rise in obesity rates is to blame for much of the increase in T2D (7). Nearly two-thirds of American adults are overweight or obese (8). [my bold, US]

“In the natural history of progression to diabetes, β-cells initially increase insulin secretion in response to insulin resistance and, for a period of time, are able to effectively maintain glucose levels below the diabetic range. However, when β-cell function begins to decline, insulin production is inadequate to overcome the insulin resistance, and blood glucose levels rise. […] Insulin resistance, once established, remains relatively stable over time. […] progression of T2D is a result of worsening β-cell function with pre-existing insulin resistance.”

“Lifestyle modification (i.e., weight loss through diet and increased physical activity) has proven effective in reducing incident T2D in high-risk groups. The Da Qing Study (China) randomly allocated 33 clinics (557 persons with IGT) to 1 of 4 study conditions: control, diet, exercise, or diet plus exercise (23). Compared with the control group, the incidence of diabetes was reduced in the three intervention groups by 31, 46, and 42%, respectively […] The Finnish Diabetes Prevention Study evaluated 522 obese persons with IGT randomly allocated on an individual basis to a control group or a lifestyle intervention group […] During the trial, the incidence of diabetes was reduced by 58% in the lifestyle group compared with the control group. The US Diabetes Prevention Program is the largest trial of primary prevention of diabetes to date and was conducted at 27 clinical centers with 3,234 overweight and obese participants with IGT randomly allocated to 1 of 3 study conditions: control, use of metformin, or intensive lifestyle intervention […] Over 3 years, the incidence of diabetes was reduced by 31% in the metformin group and by 58% in the lifestyle group; the latter value is identical to that observed in the Finnish Study. […] Metformin is recommended as first choice for pharmacologic treatment [of type 2 diabetes] and has good efficacy to lower HbA1c […] However, most patients will eventually require treatment with combinations of oral medications with different mechanisms of action simultaneously in order to attain adequate glycemic control.”

CVD [cardiovascular disease, US] is the cause of 65% of deaths in patients with T2D (31). Epidemiologic studies have shown that the risk of a myocardial infarction (MI) or CVD death in a diabetic individual with no prior history of CVD is comparable to that of an individual who has had a previous MI (32, 33). […] Stroke is the second leading cause of long-term disability in high-income countries and the second leading cause of death worldwide. […] Stroke incidence is highly age-dependent. The median stroke incidence in persons between 15 and 49 years of age is 10 per 100,000 per year, whereas this is 2,000 per 100,000 for persons aged 85 years or older. […] In Western communities, about 80% of strokes are caused by focal cerebral ischemia, secondary to arterial occlusion, 15% by intracerebral hemorrhage, and 5% by subarachnoid hemorrhage (2). […] Patients with ischemic stroke usually present with focal neurological deficit of sudden onset. […] Common deficits include dysphasia, dysarthria, hemianopia, weakness, ataxia, sensory loss, and cognitive disorders such as spatial neglect […] Mild-to-moderate headache is an accompanying symptom in about a quarter of all patients with ischemic stroke […] The risk of symptomatic intracranial hemorrhage after thrombolysis is higher with more severe strokes and higher age (21). [worth keeping in mind when in the ‘I-am-angry-and-need-someone-to-blame-for-the-death-of-individual-X-phase’ – if the individual died as a result of the treatment, the prognosis was probably never very good to start with..] […] Thirty-day case fatality rates for ischemic stroke in Western communities generally range between 10 and 17% (2). Stroke outcome strongly depends not only on age and comorbidity, but also on the type and cause of the infarct. Early case fatality can be as low as 2.5% in patients with lacunar infarcts (7) and as high as 78% in patients with space-occupying hemispheric infarction (8).”

“In the previous 20 years, ten thousands of patients with acute ischemic stroke have participated in hundreds of clinical trials of putative neuroprotective therapies. Despite this enormous effort, there is no evidence of benefit of a single neuroprotective agent in humans, whereas over 500 have been effective in animal models […] the failure of neuroprotective agents in the clinic may […] be explained by the fact that most neuroprotectants inhibit only a single step in the broad cascade of events that lead to cell death (9). Currently, there is no rationale for the use of any neuroprotective medication in patients with acute ischemic stroke.”

“Between 5 and 10% of patients with ischemic stroke suffer from epileptic seizures in the first week and about 3% within the first 24 h […] Post-stroke seizures are not associated with a higher mortality […] About 1 out of every 11 patient with an early epileptic seizure develops epilepsy within 10 years after stroke onset (51) […] In the first 12 h after stroke onset, plasma glucose concentrations are elevated in up to 68% of patients, of whom more than half are not known to have diabetes mellitus (53). An initially high blood glucose concentration in patients with acute stroke is a predictor of poor outcome (53, 54). […] Acute stroke is associated with a blood pressure higher than 170/110 mmHg in about two thirds of patients. Blood pressure falls spontaneously in the majority of patients during the first week after stroke. High blood pressure during the acute phase of stroke has been associated with a poor outcome (56). It is unclear how blood pressure should be managed during the acute phase of ischemic stroke. […] routine lowering of the blood pressure is not recommended in the first week after stroke, except for extremely elevated values on repeated measurements […] Urinary incontinence affects up to 60% of stroke patients admitted to hospital, with 25% still having problems on hospital discharge, and around 15% remaining incontinent at 1 year. […] Between 22 and 43% of patients develop fever or subfebrile temperatures during the first days after stroke […] High body temperature in the first days after stroke is associated with poor outcome (42, 67). There is currently no evidence from randomized trials to support the routine lowering of body temperature above 37◦C.”

December 28, 2016 Posted by | Books, Cardiology, Diabetes, Epidemiology, Immunology, Medicine, Neurology | Leave a comment

The Ageing Immune System and Health (I)

as we age, we observe a greater heterogeneity of ability and health. The variation in, say, walking speed is far greater in a group of 70 year olds, than in a group on 20 year olds. This makes the study of ageing and the factors driving that heterogeneity of health and functional ability in old age vital. […] The study of the immune system across the lifespan has demonstrated that as we age the immune system undergoes a decline in function, termed immunosenescence. […] the decline in function is not universal across all aspects of the immune system, and neither is the magnitude of functional loss similar between individuals. The theory of inflammageing, which represents a chronic low grade inflammatory state in older people, has been described as a major consequence of immunosenescence, though lifestyle factors such as reduced physical activity and increased adiposity also play a major role […] In poor health, older people accumulate disease, described as multimorbidity. This in turn means traditional single system based health care becomes less valid as each system affected by disease impacts on other systems. This leads some older people to be at greater risk of adverse events such as disability and death. The syndrome of this increased vulnerability is described as frailty, and increasing fundamental evidence is emerging that suggests immunosenescence and inflammageing may underpin frailty […] Thus frailty is seen as one clinical manifestation of immunosenescence.”

The above quotes are from the book‘s preface. I gave it 3 stars on goodreads. I should probably, considering that this topic is mentioned in the preface, mention explicitly that the book doesn’t actually go into a lot of details about the downsides of ‘traditional single system based health care’; the book is mainly about immunology and related topics, and although it provides coverage of intervention studies etc., it doesn’t really provide detailed coverage about issues like the optimization of organizational structures/systems analysis etc.. The book I was currently reading while I started out writing this post – Integrated Diabetes Care – A Multidisciplinary Approach (blog coverage here) – is incidentally pretty much exclusively devoted to providing coverage of these sorts of topics (and it did a fine job).

If you have never read any sort of immunology text before the book will probably be unreadable to you – “It is aimed at fundamental scientists and clinicians with an interest in ageing or the immune system.” In my coverage below I have not made any efforts towards picking out quotes which would be particularly easy for the average reader to read and understand; this is another way of saying that the post is mainly written for my own benefit, perhaps even more so than is usually the case, not for the benefit of potential readers reading along here.

“Physiological ageing is associated with significant re-modelling of the immune system. Termed immunosenescence, age-related changes have been described in the composition, phenotype and function of both the innate and adaptive arms of the immune system. […] Neutrophils are the most abundant leukocyte in circulation […] The first step in neutrophil anti-microbial defence is their extravasation from the bloodstream and migration to the site of infection. Whilst age appears to have no effect upon the speed at which neutrophils migrate towards chemotactic signals in vitro [15], the directional accuracy of neutrophil migration to inflammatory agonists […] as well as bacterial peptides […] is significantly reduced [15]. […] neutrophils from older adults clearly exhibit defects in several key defensive mechanisms, namely chemotaxis […], phagocytosis of opsonised pathogens […] and NET formation […]. Given this near global impairment in neutrophil function, alterations to a generic signalling element rather than defects in molecules specific to each anti-microbial defence strategy is likely to explain the aberrations in neutrophil function that occur with age. In support of this idea, ageing in rodents is associated with a significant increase in neutrophil membrane fluidity, which coincides with a marked reduction in neutrophil function […] ageing results in a reduction in NK cell production and proliferation […] Numerous studies have examined the impact of age […], with the general consensus that at the single cell level, NK cell cytotoxicity (NKCC) is reduced with age […] retrospective and prospective studies have reported relationships between low NK cell activity in older adults and (1) a past history of severe infection, (2) an increased risk of future infection, (3) a reduced probability of surviving infectious episodes and (4) infectious morbidity [49–51]. Related to this increased risk of infection, reduced NKCC prior to and following influenza vaccination in older adults has been shown to be associated with reduced protective anti-hemagglutinin titres, worsened health status and an increased incidence of respiratory tract infection […] Whilst age has no effect upon the frequency or absolute number of monocytes [54, 55], the composition of the monocyte pool is markedly different in older adults, who present with an increased frequency of non-classical and intermediate monocytes, and fewer classical monocytes when compared to their younger counterparts”.

“Via their secretion of growth factors, pro-inflammatory cytokines, and proteases, senescent cells compromise tissue homeostasis and function, and their presence has been causally implicated in the development of such age-associated conditions as sarcopenia and cataracts [92]. Several studies have demonstrated a role for innate immune cells in the recognition and clearance of senescent cells […] ageing is associated with a low-grade systemic up-regulation of circulating inflammatory mediators […] Results from longitudinal-based studies suggest inflammageing is deleterious to human health with studies in older cohorts demonstrating that low-grade increases in the circulating levels of TNF-α [103], IL-6 […] and CRP [105] are associated with both all-cause […] and cause-specific […] mortality. Furthermore, inflammageing is a predictor of frailty [106] and is considered a major factor in the development of several age-related pathologies, such as atherosclerosis [107], Alzheimer’s disease [100] and sarcopenia [108].”

“Persistent viral infections, reduced vaccination responses, increased autoimmunity, and a rise in inflammatory syndromes all typify immune ageing. […] These changes can be in part attributed to the accumulation of highly differentiated senescent T cells, characterised by their decreased proliferative capacity and the activation of senescence signaling pathways, together with alterations in the functional competence of regulatory cells, allowing inflammation to go unchecked. […] Immune senescence results from defects in different leukocyte populations, however the dysfunction is most profound in T cells [6, 7]. The responses of T cells from aged individuals are typically slower and of a lower magnitude than those of young individuals […] while not all equally affected by age, the overall T cell number does decline dramatically as a result of thymic atrophy […] T cell differentiation is a highly complex process controlled not only by costimulation but also by the strength and duration of T cell receptor (TCR) signalling [34]. Nearly all TCR signalling pathways have been found altered during ageing […] two phenotypically distinct subsets of B cells […] have been demonstrated to exert immunosuppressive functions. The frequency and function of both these Breg subsets declines with age”.

“The immune impairments in patients with chronic hyperglycemia resemble those seen during ageing, namely poor control of infections and reduced vaccination response [99].” [This is hardly surprising. ‘Hyperglycemia -> accelerated ageing’ seems generally to be a good (over-)simplified model in many contexts. To give another illustrative example from Czernik & Fowlkes text, “approximately 4–6 years of diabetes exposure in some children may be sufficient to increase skin AGEs to levels that would naturally accumulate only after ~25 years of chronological aging”].

“The term “immunosenescence” is commonly taken to mean age-associated changes in immune parameters hypothesized to contribute to increased susceptibility and severity of the older adult to infectious disease, autoimmunity and cancer. In humans, it is characterized by lower numbers and frequencies of naïve T and B cells and higher numbers and frequencies of late-differentiated T cells, especially CD8+ T cells, in the peripheral blood. […] Low numbers of naïve cells render the aged highly susceptible to pathogens to which they have not been previously exposed, but are not otherwise associated with an “immune risk profile” predicting earlier mortality. […] many of the changes, or most often, differences, in immune parameters of the older adult relative to the young have not actually been shown to be detrimental. The realization that compensatory changes may be developing over time is gaining ground […] Several studies have now shown that lower percentages and absolute numbers of naïve CD8+ T cells are seen in all older subjects whereas the accumulation of very large numbers of CD8+ late-stage differentiated memory cells is seen in a majority but not in all older adults [2]. The major difference between this majority of subjects with such accumulations of memory cells and those without is that the former are infected with human herpesvirus 5 (Cytomegalovirus, CMV). Nevertheless, the question of whether CMV is associated with immunosenescence remains so far uncertain as no causal relationship has been unequivocally established [5]. Because changes are seen rapidly after primary infection in transplant patients [6] and infants [7], it is highly likely that CMV does drive the accumulation of CD8+ late-stage memory cells, but the relationship of this to senescence remains unclear. […] In CMV-seropositive people, especially older people, a remarkably high fraction of circulating CD8+ T lymphocytes is often found to be specific for CMV. However, although the proportion of naïve CD8+ T cells is lower in the old than the young whether or not they are CMV-infected, the gross accumulation of late-stage differentiated CD8+ T cells only occurs in CMV-seropositive individuals […] It is not clear whether this is adaptive or pathological […] The total CMV-specific T-cell response in seropositive subjects constitutes on average approximately 10 % of both the CD4+ and CD8+ memory compartments, and can be far greater in older people. […] there are some published data suggesting that that in young humans or young mice, CMV may improve immune responses to some antigens and to influenza virus, probably by way of increased pro-inflammatory responses […] observations suggest that the effect of CMV on the immune system may be highly dependent also on an individuals’ age and circumstances, and that what is viewed as ageing is in fact later collateral damage from immune reactivity that was beneficial in earlier life [47, 48]. This is saying nothing more than that the same immune pathology that always accompanies immune responses to acute viruses is also caused by CMV, but over a chronic time scale and usually subclinical. […] data suggest that the remodeling of the T-cell compartment in the presence of a latent infection with CMV represents a crucial adaptation of the immune system towards the chronic challenge of lifelong CMV.”

The authors take issue with using the term ‘senescence’ to describe some of the changes discussed above, because this term by definition should be employed only in the context of changes that are demonstrably deleterious to health. It should be kept in mind in this context that insufficient immunological protection against CMV in old age could easily be much worse than the secondary inflammatory effects, harmful though these may well be; CMV in the context of AIDS, organ transplantation (“CMV is the most common and single most important viral infection in solid organ transplant recipients” – medscape) and other disease states involving compromised immune systems can be really bad news (“Disease caused by human herpesviruses tends to be relatively mild and self-limited in immunocompetent persons, although severe and quite unusual disease can be seen with immunosuppression.” Holmes et al.)

“The role of CMV in the etiology of […] age-associated diseases is currently under intensive investigation […] in one powerful study, the impact of CMV infection on mortality was investigated in a cohort of 511 individuals aged at least 65 years at entry, who were then followed up for 18 years. Infection with CMV was associated with an increased mortality rate in healthy older individuals due to an excess of vascular deaths. It was estimated that those elderly who were CMV- seropositive at the beginning of the study had a near 4-year reduction in lifespan compared to those who were CMV-seronegative, a striking result with major implications for public health [59]. Other data, such as those from the large US NHANES-III survey, have shown that CMV seropositivity together with higher than median levels of the inflammatory marker CRP correlate with a significantly lower 10-year survival rate of individuals who were mostly middle-aged at the start of the study [63]. Further evidence comes from a recently published Newcastle 85+ study of the immune parameters of 751 octogenarians investigated for their power to predict survival during a 65-month follow-up. It was documented that CMV-seropositivity was associated with increased 6-year cardiovascular mortality or death from stroke and myocardial infarction. It was therefore concluded that CMV-seropositivity is linked to a higher incidence of coronary heart disease in octogenarians and that senescence in both the CD4+ and CD8+ T-cell compartments is a predictor of overall cardiovascular mortality”.

“The incidence and severity of many infections are increased in older adults. Influenza causes approximately 36,000 deaths and more than 100,000 hospitalizations in the USA every year […] Vaccine uptake differs tremendously between European countries with more than 70 % of the older population being vaccinated against influenza in The Netherlands and the United Kingdom, but below 10 % in Poland, Latvia and Estonia during the 2012–2013 season […] several systematic reviews and meta-analyses have estimated the clinical efficacy and/or effectiveness of a given influenza vaccine, taking into consideration not only randomized trials, but also cohort and case-control studies. It can be concluded that protection is lower in the old than in young adults […] [in one study including “[m]ore than 84,000 pneumococcal vaccine-naïve persons above 65 years of age”] the effect of age on vaccine efficacy was studied and the statistical model showed a decline of vaccine efficacy for vaccine-type CAP and IPD [Invasive Pneumococcal Disease] from 65 % (95 % CI 38–81) in 65-year old subjects, to 40 % (95 % CI 17–56) in 75-year old subjects […] The most effective measure to prevent infectious disease is vaccination. […] Over the last 20–30 years tremendous progress has been achieved in developing novel/improved vaccines for children, but a lot of work still needs to be done to optimize vaccines for the elderly.”

December 12, 2016 Posted by | Books, Cardiology, Diabetes, Epidemiology, Immunology, Infectious disease, Medicine, Microbiology | Leave a comment

Role of Biomarkers in Medicine

“The use of biomarkers in basic and clinical research has become routine in many areas of medicine. They are accepted as molecular signatures that have been well characterized and repeatedly shown to be capable of predicting relevant disease states or clinical outcomes. In Role of Biomarkers in Medicine, expert researchers in their individual field have reviewed many biomarkers or potential biomarkers in various types of diseases. The topics address numerous aspects of medicine, demonstrating the current conceptual status of biomarkers as clinical tools and as surrogate endpoints in clinical research.”

The above quote is from the preface of the book. Here’s my goodreads review. I have read about biomarkers before – for previous posts on this topic, see this link. I added the link in part because the coverage provided in this book is in my opinion generally of a somewhat lower quality than is the coverage that has been provided in some of the other books I’ve read on these topics. However the fact that the book is not amazing should probably not keep me from sharing some observations of interest from the book, which I have done in this post.

we suggest more precise studies to establish the exact role of this hormone […] additional studies are necessary […] there are conflicting results […] require further investigation […] more intervention studies with long-term follow-up are required. […] further studies need to be conducted […] further research is needed (There are a lot of comments like these in the book, I figured I should include a few in my coverage…)

“Cancer biomarkers (CB) are biomolecules produced either by the tumor cells or by other cells of the body in response to the tumor, and CB could be used as screening/early detection tool of cancer, diagnostic, prognostic, or predictor for the overall outcome of a patient. Moreover, cancer biomarkers may identify subpopulations of patients who are most likely to respond to a given therapy […] Unfortunately, […] only very few CB have been approved by the FDA as diagnostic or prognostic cancer markers […] 25 years ago, the clinical usefulness of CB was limited to be an effective tool for patient’s prognosis, surveillance, and therapy monitoring. […] CB have [since] been reported to be used also for screening of general population or risk groups, for differential diagnosis, and for clinical staging or stratification of cancer patients. Additionally, CB are used to estimate tumor burden and to substitute for a clinical endpoint and/or to measure clinical benefit, harm or lack of benefit, or harm [4, 18, 30]. Among commonly utilized biomarkers in clinical practice are PSA, AFP, CA125, and CEA.”

“Bladder cancer (BC) is the second most common malignancy in the urologic field. Preoperative predictive biomarkers of cancer progression and prognosis are imperative for optimizing […] treatment for patients with BC. […] Approximately 75–85% of BC cases are diagnosed as nonmuscle-invasive bladder cancer (NMIBC) […] NMIBC has a tendency to recur (50–70%) and may progress (10–20%) to a higher grade and/or muscle-invasive BC (MIBC) in time, which can lead to high cancer-specific mortality [2]. Histological tumor grade is one of the clinical factors associated with outcomes of patients with NMIBC. High-grade NMIBC generally exhibits more aggressive behavior than low-grade NMIBC, and it increases the risk of a poorer prognosis […] Cystoscopy and urine cytology are commonly used techniques for the diagnosis and surveillance of BC. Cystoscopy can identify […] most papillary and solid lesions, but this is highly invasive […] urine cytology is limited by examiner experience and low sensitivity. For these reasons, some tumor markers have been investigated […], but their sensitivity and specificity are limited [5] and they are unable to predict the clinical outcome of BC patients. […] Numerous efforts have been made to identify tumor markers. […] However, a serum marker that can serve as a reliable detection marker for BC has yet to be identified.”

“Endometrial cancer (EmCa) is the most common type of gynecological cancer. EmCa is the fourth most common cancer in the United States, which has been linked to increased incidence of obesity. […] there are no reliable biomarker tests for early detection of EmCa and treatment effectiveness. […] Approximately 75% of women with EmCa are postmenopausal; the most common symptom is postmenopausal bleeding […] Approximately 15% of women diagnosed with EmCa are younger than 50 years of age, while 5% are diagnosed before the age of 40 [29]. […] Roughly, half of the EmCa cases are linked to obesity. Obese women are four times more likely to develop EmCa when compared to normal weight women […] Obese individuals oftentimes exhibit resistance to leptin and show high levels of the adipokine in blood, which is known as leptin resistance […] prolonged exposure of leptin damages the hypothalamus causing it to become insensitive to the effects of leptin […] Evidence shows that leptin is an important pro-inflammatory, pro-angiogenic, and mitogenic factor for cancer. Leptin produced by cancer cells acts in an autocrine and paracrine manner to promote tumor cell proliferation, migration and invasion, pro-inflammation, and angiogenesis [58, 70]. High levels of leptin […] are associated with metastasis and decreased survival rates in breast cancer patients [58]. […] Metabolic syndrome including obesity, hypertension, insulin resistance, diabetes, and dyslipidemia increase the risk of developing multiple malignancies, particularly EmCa [30]. Younger women diagnosed with EmCa are usually obese, and their carcinomas show a well-differentiated histology [20].

“Normally, tumor suppressor genes act to inhibit or arrest cell proliferation and tumor development [37]. However; when mutated, tumor suppressors become inactive, thus permitting tumor growth. For example, mutations in p53 have been determined in various cancers such as breast, colon, lung, endometrium, leukemias, and carcinomas of many tissues. These p53 mutations are found in approximately 50% of all cancers [38]. Roughly 10–20% of endometrial carcinomas exhibit p53 mutations [37]. […] overexpression of mutated tumor suppressor p53 has been associated with Type II EmCa (poor histologic grade, non-endometrioid histology, advanced stage, and poor survival).”

“Increasing data indicate that oxidative stress is involved in the development of DR [diabetic retinopathy] [16–19]. The retina has a high content of polyunsaturated fatty acids and has the highest oxygen uptake and glucose oxidation relative to any other tissue. This phenomenon renders the retina more susceptible to oxidative stress [20]. […] Since long-term exposure to oxidative stress is strongly implicated in the pathogenesis of diabetic complications, polymorphic genes of detoxifying enzymes may be involved in the development of DR. […] A meta-analysis comprising 17 studies, including type 1 and type 2 diabetic patients from different ethnic origins, implied that the C (Ala) allele of the C47T polymorphism in the MnSOD gene had a significant protective effect against microvascular complications (DR and diabetic nephropathy) […] In the development of DR, superoxide levels are elevated in the retina, antioxidant defense system is compromised, MnSOD is inhibited, and mitochondria are swollen and dysfunctional [77,87–90]. Overexpression of MnSOD protects [against] diabetes-induced mitochondrial damage and the development of DR [19,91].”

Continuous high level of blood glucose in diabetes damages micro and macro blood vessels throughout the body by altering the endothelial cell lining of the blood vessels […] Diabetes threatens vision, and patients with diabetes develop cataracts at an earlier age and are nearly twice as likely to get glaucoma compared to non-diabetic[s] [3]. More than 75% of patients who have had diabetes mellitus for more than 20 years will develop diabetic retinopathy (DR) [4]. […] DR is a slow progressive retinal disease and occurs as a consequence of longstanding accumulated functional and structural impairment of the retina by diabetes. It is a multifactorial condition arising from the complex interplay between biochemical and metabolic abnormalities occurring in all cells of the retina. DR has been classically regarded as a microangiopathy of the retina, involving changes in the vascular wall leading to capillary occlusion and thereby retinal ischemia and leakage. And more recently, the neural defects in the retina are also being appreciated […]. Recently, various clinical investigators [have detected] neuronal dysfunction at very early stages of diabetes and numerous abnormalities in the retina can be identified even before the vascular pathology appears [76, 77], thus suggesting a direct effect of diabetes on the neural retina. […] An emerging issue in DR research is the focus on the mechanistic link between chronic low-grade inflammation and angiogenesis. Recent evidence has revealed that extracellular high-mobility group box-1 (HMGB1) protein acts as a potent proinflammatory cytokine that triggers inflammation and recruits leukocytes to the site of tissue damage, and exhibits angiogenic effects. The expression of HMGB1 is upregulated in epiretinal membranes and vitreous fluid from patients with proliferative DR and in the diabetic retina. […] HMGB1 may be a potential biomarker [for diabetic retinopathy] […] early blockade of HMGB1 may be an effective strategy to prevent the progression of DR.”

“High blood pressure is one of the leading risk factors for global mortality and is estimated to have caused 9.4 million deaths in 2010. A meta‐analysis which includes 1 million individuals has indicated that death from both CHD [coronary heart disease] and stroke increase progressively and linearly from BP levels as low as 115 mmHg systolic and 75 mmHg diastolic upwards [138]. The WHO [has] pointed out that a “reduction in systolic blood pressure of 10 mmHg is associated with a 22% reduction in coronary heart disease, 41% reduction in stroke in randomized trials, and a 41–46% reduction in cardiometabolic mortality in epidemiological studies” [139].”

Several reproducible studies have ascertained that individuals with autism demonstrate an abnormal brain 5-HT system […] peripheral alterations in the 5-HT system may be an important marker of central abnormalities in autism. […] In a recent study, Carminati et al. [129] tested the therapeutic efficacy of venlafaxine, an antidepressant drug that inhibits the reuptake of 5-HT, and [found] that venlafaxine at a low dose [resulted in] a substantial improvement in repetitive behaviors, restricted interests, social impairment, communication, and language. Venlafaxine probably acts via serotonergic mechanisms  […] OT [Oxytocin]-related studies in autism have repeatedly reported lower blood OT level in autistic patients compared to age- and gender-matched control subjects […] autistic patients demonstrate an altered neuroinflammatory response throughout their lives; they also show increased astrocyte and microglia inflammatory response in the cortex and the cerebellum  [47, 48].”

November 3, 2016 Posted by | autism, Books, Cancer/oncology, Cardiology, Diabetes, Epidemiology, Genetics, Immunology, Medicine, Neurology, Pharmacology | Leave a comment

Respirology

I was debating whether to blog this book at all, as it’s neither very long nor very good, but I decided it was worth adding a few observations from the book here. You can read my goodreads review of the publication here. Whenever quotes look a bit funny in the coverage below (i.e. when you see things like words in brackets or strangely located ‘[…]’, assume that the reason for this is that I tried to improve upon the occasionally frankly horrible language of some of the contributors to the publication. If you want to know exactly what they wrote, rather than what they presumably meant to write (basic grammar errors due to the authors having trouble with the English language are everywhere in this publication, and although I did choose to do so here I do feel a bit uncomfortable quoting a publication like this one verbatim on my blog), read the book.

I went off on a tangent towards the end of the post and I ended up adding some general remarks about medical cost, insurance and various other topics. So the post may have something of interest even to people who may not be highly interested in any of the stuff covered in the book itself.

“Despite intensive recommendations, [the] influenza vaccination rate in medical staff in Poland ranges from about 20 % in physicians to 10 % in nurses. […] It has been demonstrated that vaccination of health care workers against influenza significantly decreases mortality of elderly people remaining under [long-term care]. […] Vaccinating health care workers also substantially reduces sickness absenteeism, especially in emergency units […] Concerning physicians, vaccination avoidance stemmed from the lack of knowledge of protective value of vaccine (33 %), lack of time to get vaccinated (29 %), and Laziness (24 %). In nurses, these figures amounted to 55 %, 12 %, and 5 %, respectively (Zielonka et al. 2009).”

I just loved the fact that ‘laziness’ was included here as an explanatory variable, but on the other hand the fact that one-third of doctors cited lack of knowledge about the protective value of vaccination as a reason for not getting vaccinated is … well, let’s use the word ‘interesting’. But it gets even better:

“The questions asked and opinions expressed by physicians or nurses on vaccinations showed that their knowledge in this area was far from the current evidence-based medicine recommendations. Nurses, in particular, commonly presented opinions similar to those which can be found in anti-vaccination movements and forums […] The attitude of physicians toward influenza vaccination vary greatly. In many a ward, a majority of physicians were vaccinated (70–80 %). However, in the neurology and intensive care units the proportion of vaccinated physicians amounted only to 20 %. The reason for such a small yield […] was a critical opinion about the effectiveness and safety of vaccination. Similar differences, depending on medical specialty, were observed in Germany (4–71% of vaccines) (Roggendorf et al. 2011) […] It is difficult to explain the fear of influenza vaccination among the staff of intensive care units, since these are exactly the units where many patients with most severe cases of influenza are admitted and often die (Ayscue et al. 2014). In this group of health care workers, high efficiency of influenza vaccination has been clearly demonstrated […] In the present study a strong difference between the proportion of vaccinated physicians (55 %) and nurses (21 %) was demonstrated, which is in line with some data coming from other countries. In the US, 69 % of physicians and 46 % of nurses get a vaccine shot […] and in Germany the respective percentages are 39 % and 17 % […] In China, 21 % of nurses and only 13 % of physicians are vaccinated against influenza (Seale et al. 2010a), and in [South] Korea, 91 % and 68 % respectively (Lee et al. 2008).”

“[A] survey was conducted among Polish (243) and foreign (80) medical students at the Pomeranian Medical University in Szczecin, Poland. […] The survey results reveal that about 40 % of students were regular or occasional smoker[s]. […] 60 % of students declared themselves to be non-smokers, 20 % were occasional smokers, and 20 % were regular smokers”

40 % of medical students in a rather large sample turned out to be smokers. Wow. Yeah, I hadn’t seen that one coming. I’d probably expect a few alcoholics and I would probably not have been surprised about a hypothetical higher-than-average alcohol consumption in a sample like that (they don’t talk about alcohol so I don’t have data on this, I’m just saying I wouldn’t be surprised – after all I do know that doctors are high-risk for suicide), but such a large proportion smoking? That’s unexpected. It probably shouldn’t have been, considering that this is very much in line with the coverage included in Thirlaway & Upton’s book. I include some remarks about their coverage about smoking in my third post about the book here. The important observation of note from that part of the book’s coverage is probably that most smokers want to quit and yet very few manage to actually do it. “Although the majority of smokers want to stop smoking and predict that they will have stopped in twelve months, only 2–3 per cent actually stops permanently a year (Taylor et al. 2006).” If those future Polish doctors know that smoking is bad for them, but they assume that they can just ‘stop in time’ when ‘the time’ comes – well, some of those people are probably in for a nasty surprise (and they should have studied some more, so that they’d known this?).

A prospective study of middle-aged British men […] revealed that the self-assessment of health status was strongly associated with mortality. Men who reported poor health had an eight-fold increase in total mortality compared with those reporting excellent health. Those who assessed their health as poor were manual workers, cigarette smokers, and often heavy drinkers. Half of those with poor health suffered from chest pain on exertion and other chronic diseases. Thus, self-assessment of health status appears to be a good measure of current physical health and risk of death“.

It is estimated that globally 3.1 million people die each year due to chronic obstructive pulmonary disease (COPD). According to the World Health Organization (WHO 2014), the disease was the third leading cause of death worldwide in 2012. [In the next chapter of the book they state that: “COPD is currently the fourth leading cause of death among adult patients globally, and it is projected that it will be the third most common cause of death by 2020.” Whether it’s the third or fourth most common cause of death, it definitely kills a lot of people…] […] Approximately 40–50 % of lifelong smokers will go on to develop COPD […] the number of patients with a primary diagnosis of COPD […] constitutes […] 1.33 % of the total population of Poland. This result is consistent with that obtained during the Polish Spirometry Day in 2011 (Dabrowiecki et al. 2013) when 1.1 % of respondents declared having had a diagnosed COPD, while pulmonary function tests showed objectively the presence of obstruction in 12.3 % of patients.”

Based on numbers like these I feel tempted to conclude that the lungs may be yet another organ in which a substantial proportion of people of advanced age experience low-level organ dysfunction arguably not severe enough to lead to medical intervention. The kidneys are similar, as I also noted when I covered Longmore et al.‘s text.

“Generally, the costs of treatment of patients with COPD are highly variable […] estimates suggest […] that the costs of treatment of moderate stages of COPD may be 3–4-fold higher in comparison with the mild form of the disease, and in the severe form they reach up to 6–10 times the basic cost […] every second person with COPD is of working age […] Admission rates for COPD patients differ as much as 10-fold between European countries (European Lung White Book 2013).”

“In the EU, the costs of respiratory diseases are estimated at 6 % of the budget allocated to health care. Of this amount, 56 % is allocated for the treatment of COPD patients. […] Studies show that one per ten Poles over 30 year of age have COPD symptoms. Each year, around 4 % of all hospitalizations are due to COPD. […] One of the most important parameters regarding pharmacoeconomics is the hospitalization rate […] a high number of hospitalizations due to COPD exacerbations in Poland dramatically increase direct medical costs.”

I bolded the quote above because I knew this but had never seen it stated quite as clearly as it’s stated here, and I may be tempted to quote that one later on. Hospitalizations are often really expensive compared to drugs people who are not hospitalized take for their various health conditions, for example you can probably buy a year’s worth of anti-diabetic drugs, or more, for the costs of just one hospital admission due to drug mis-dosing. Before you get the idea that this might have ‘obvious implications’ for how ‘one’ should structure medical insurance arrangements in terms of copay structures etc., do however keep in mind that the picture here is really confusing:

3-3

Here’s the link, with more details – the key observation is that: “There is no consistency […] in the direction of change in costs resulting from changes in compliance”. That’s not diabetes, that’s ‘stuff in general’.

It would be neat if you could e.g. tell a story about how high costs of a drug always lead to non-compliance, which lead to increased hospitalization rates, which lead to higher costs than if the drugs had been subsidized. That would be a very strong case for subsidization. Or it would be neat if you could say that it doesn’t matter whether you subsidize a drug or not, because the costs of drugs are irrelevant in terms of usage patterns – people are told to take one pill every day by their doctor, and by golly that’s what they’re doing, regardless of what those pills cost. I know someone personally who wrote a PhD thesis about a drug where that clearly wasn’t the case, and the price elasticity was supposed to be ‘theoretically low’ in that case, so that one’s obviously out ‘in general’, but the point is that people have looked at this stuff, a lot. I’m assuming you might be able to spot a dynamic like this in some situations, and different dynamics in the case of other drugs. It gets even better when you include complicating phenomena like cost-switching; perhaps the guy/organization responsible for potentially subsidizing the drug is not the same guy(/-…) as the guy who’s supposed to pay for the medical admissions (this depends on the insurance structure/setup). But that’s not always the case, and the decision as to who pays for what is not necessarily a given; it may depend e.g. on health care provider preferences, and those preferences may themselves depend upon a lot of things unrelated to patient preferences or -incentives. A big question even in the relatively simple situation where the financial structure is – for these purposes at least – simple, is also the extent to which relevant costs are even measured, and/or how they’re measured (if a guy dies due to a binding budget constraint resulting in no treatment for a health condition that would have been treatable with a drug, is that outcome supposed to be ‘very cheap’ (he didn’t pay anything for  drugs, so there were no medical outlays) or very expensive (he could have worked for another two decades if he’d been treated, and those productivity losses need to be included in the calculation somehow; to focus solely on medical outlays is thus to miss the point)? An important analytical point here is that if you don’t explicitly make those deaths/productivity losses expensive, they are going to look very cheap, because the default option will always be to have them go unrecorded and untallied.

A problem not discussed in the coverage was incidentally the extent to which survey results pertaining to the cost of vaccination are worth much. You ask doctors why they didn’t get vaccinated, and they tell you it’s because it’s too expensive. Well, how many of them would you have expected to tell you they did not get vaccinated because the vaccines were too cheap? This is more about providing people with a perceived socially acceptable out than it is about finding stuff out about their actual reasons for behaving the way they do. If the price of vaccination does not vary across communities it’s difficult to estimate the price elasticity, true (if it does, you probably got an elasticity estimate right there), but using survey information to implicitly assess the extent to which the price is too high? Allow the vaccination price to vary next year/change it/etc. (or even simpler/cheaper, if those data exist; look at price variation which happened in the past and observe how the demand varied), and see if/how the doctors and nurses respond. That’s how you do this, you don’t ask people. Asking people is also actually sort of risky; I’m pretty sure a smart doctor could make an argument that if you want doctors to get vaccinated you should pay them for getting the shot – after all, getting vaccinated is unpleasant, and as mentioned there are positive externalities here in terms of improved patient outcomes, which might translate into specific patients not dying, which is probably a big deal, for those patients at least. The smart doctor wouldn’t necessarily be wrong; if the price of vaccination was ‘sufficiently low’, i.e. a ‘large’ negative number (‘if you get vaccinated, we give you $10.000’), I’m pretty sure coverage rates would go up a lot. That doesn’t make it a good idea. (Or a bad idea per se, for that matter – it depends upon the shape of the implicit social welfare function we’re playing around with. Though I must add – so that any smart doctors potentially reading along here don’t get any ideas – that a ‘large’ negative price of vaccination for health care workers is a bad idea if a cheaper option which achieves the same outcome is potentially available to the decision makers in question, which seems highly likely to me. For example vaccination rates of medical staff would also go up a lot if regular vaccinations were made an explicit condition of their employment, the refusal of which would lead to termination of their employment… There would be implicit costs of such a scheme, in terms of staff selection effects, but if you’re comparing solely those options and you’re the guy who makes the financial decisions..?)

August 22, 2016 Posted by | Books, Economics, Immunology, Medicine | Leave a comment

Eating disorders (II)

You can read my first post about the book, which lead to a brief comment exchange which may be of interest to people curious about diagnostics aspects, here. The book has a lot of stuff; in this post I’ll discuss the immune system, covered in chapter 5 of the book, as well as some ways that eating disorders may affect the skin (many of the remaining chapters of the book cover this topic). This will be my last post about the book.

In chapter 5 the authors start out by noting that adequate nutrition is an important factor in terms of maintaining immunocompetence and that malnutrition increases the risk of infection. Quite a few details are known about how specific aspects of nutritional deficiencies affect specific parts of the immune system. When both energy- and protein intake is insufficient (protein-energy malnutrition, PEM) this state of affairs is associated with atrophy of immune organs such as the thymus and spleen, as well as impairments in T cell populations (likely a natural consequence of thymus atrophy – the ‘T’ in ‘T cell’ stands for thymus…). Cytokine prodution (e.g. IL-1, IL-2, interferon-γ) is down-regulated in PEM, and the ability of T cells to respond appropriately to those cytokines is decreased. Impairments in macrophage phagocytotic function and neutrophils have been observed in malnourished individuals.

The authors note in the coverage that there now “seems to be consensus accepting that, overall, the manifestations of the immunocompromised status of ED patients are less frequent and severe than in PEM [3]. In general, the immune function seems to be better preserved than would be expected, considering the highly defective nutritional status of the patients. […] [some of] the most frequent findings described are leukopenia [white blood cell deficiency] with relative lymphocytosis [increased proportion of lymphocytes in the blood], [and] thrombocytopenia [platelet deficiency] […] immunocompetence and particularly T cell subsets are useful tools to follow-up the nutritional status in patients with ED. This asseveration applies also to BN patients, since T cell subsets seem to reflect their subclinical malnutrition, which is not evident from their weight status. […] Vomiting as a purging strategy is associated with a more deleterious effect on T cells […] Complement-system proteins […] have been found decreased in AN [anorexia nervosa] and BN [bulimia nervosa] [6,79] [and] seem to depend also on white adipose tissue mass. […] These proteins might be useful in the follow-up of AN patients, since C3 and C4 falls seem to occur when treated patients resume their restricting habits increasing their risk of relapse [81].”

Despite eating disorders having significant effects on the immune system, infection risk in people with eating disorders seems surprisingly to not be elevated, at least not until an advanced stage of the disease has been reached. There are multiple explanations offered for this observation, but the answer as to why this is is not completely clear. One reason might be that people with eating disorders tend to maintain relatively high protein and vitamin intake in a manner dissimilar from the intake patterns associated with classic starvation, mediating the effects of energy deficiency. Two other reasons offered both relate to the fact that the immune system does not respond normally to pathogens, and so to the extent that symptoms relate to immune responses to infection people with eating disorders have fewer symptoms; this relates to both down-regulation of memory T-cells and suppressed capacity to mount the classic acute-phase response to infection; a reduced febrile response to bacterial infection has been observed in anorexics. In the context of muted responses to infection, the hormone leptin (‘the satiety hormone’) may also be implicated; “there is a function for leptin as an up-regulator factor of inflammatory immune responses. Moreover, leptin production is acutely increased during infection and inflammation […] an impairment in this acute increase in leptin production in AN patients might be related to the lack of infection symptoms in these patients [26].” Interestingly leptin also seems to be downregulated in BN.

Okay, let’s move on and talk a little bit about how eating disorders may affect the skin. The book has a lot of stuff about this so this will not be an exhaustive review of the material covered in the book – but I did think I ought to talk a little bit about this stuff. Skin signs are important in a diagnostic context: “As most patients with eating disorders tend to minimize or even deny their disorder, the skin changes are sometimes the only indication that the patient has an eating disorder.” Some of the skin signs described in the book relate quite directly to specific behaviours (e.g. vomiting in purging subtypes), whereas others are of a more generalized nature and are rather due to the fact that the body does not get enough energy/micronutrients/etc. to handle all the tasks it’s supposed to handle. Some skin signs are considered ‘guiding signs’ of eating disorders, in the sense that they’re signs often found in an eating disorder context but are not usually found in the differential diagnoses natural to consider in the given clinical context, so they can be used as guiding tools in a diagnostic context. Examples of guiding signs include “lanugo-like body hair [very fine, soft, and usually unpigmented, downy hair] due to starvation, Russell’s sign [calluses on the knuckles or back of the hand] and [tooth] enamel erosions due to self-induced vomiting, and self-induced dermatoses due to psychiatric comorbidity.”

Frequent skin signs in eating disorders include dry, scaly skin; orange discolouration of the skin due to excessive consumption of beta carotene (carrots); the aforementioned lanugo-like body hair; coldness of the extremities (feet, toes) and bluish/purplish colouring of the hands and feet, caused by slow circulation (acrocyanosis); hair loss; inflammation of the lips and nail changes. “With a BMI between 17.5 and 16, the skin is usually pale or yellowish and cold, but no specific signs are found.” They note in the book that “Russell sign, dental enamel erosion, and salivary gland enlargement [elsewhere in the coverage they also dub this phenomenon ‘“chipmunk” cheeks of the bulimic’] are pathognomonic of purging behavior”. Dry skin is reported in 70% of people with anorexia nervosa (-AN), and acne is reported in 47–59% of patients – these are very common symptoms/consequences of AN. The same is the case for lanugo; in one study of AN patients (n=62), 77% had lanugo. In one study, alopecia was present in 67% of bulimics (n=122) and 61% of anorexics (n=62).

Observing the hands may be important: “Strumia [1], observing the hand of the patients with anorexia nervosa (AN), noticed that many peculiar skin signs, such as xerosis, acrocyanosis, carotenoderma, evident blood vessels due to decreased subcutaneous tissue, cold hand, nail dystrophy [“Brittle nails affect approximately 30% of patients with anorexia nervosa and bulimia nervosa”], Russell’s sign and artefacta, were located on the hands. Strumia used the term “anorectic’s hand” and suggested that, by examining the hand of a young patient, one can reasonably suspect an eating disorder. Only Russell’s sign is pathognomonic of eating disorders, but at least three signs, excluding Russell’s sign, are required for the diagnosis of “anorectic’s hand”, for example, xerosis, carotenoderma and cold hand. A perspicacious dermatologist should pay attention to this important sign when it appears in young females that show signs of reduced self-esteem and distorted perception of body weight.”

It is noted in the book that classical deficiency syndromes such as scurvy are very rare in AN because “AN is not commonly associated with vitamin deficiencies” – rather it’s the case that many anorectics over-supplement on vitamin supplements, which can paradoxically induce or worsen some skin complaints, such as e.g. xerosis (dry skin).

“the progression of anorexic pathology is accompanied by changing patterns in dietary habits [5]. These patterns include periods of low or no carbohydrate intake and an avoidance of dietary fats. They can also include patterns in which the primary foods consumed are fruits and vegetables. During this period, meat is often avoided. Changes in relative amounts of heavy to light isotopes [of nitrogen] in the hair indicate changes in the body’s metabolic state and dietary intake. […] By definition, individuals with anorexia or anorexia and bulimia are losing weight and do not get adequate nutrition. These individuals get their nitrogen largely from plants, and/or do not get sufficient nitrogen in their diet and are in nitrogen imbalance. By contrast, individuals diagnosed with only bulimia are maintaining their weight, and therefore get adequate nutrition and are likely not to be in nitrogen imbalance. […] Hatch et al. […] suggest that a distinction may be possible between anorexia and bulimia nervosa using 15N/14N and 13C/12C ratios in hair.”

“A reduced pain sensitivity has been found in eating disorder (ED) patients, but it is unclear what physiological and psychological factors are associated with this abnormality.”

January 26, 2016 Posted by | Books, Epidemiology, Immunology, Medicine | Leave a comment

Oxford Handbook of Clinical Medicine (II)

Here’s my first post about the book. I’ve read roughly 75% of the book at this point (~650 pages). The chapters I’ve read so far have dealt with the topics of: ‘thinking about medicine’ (an introductory chapter), ‘history and examination’, cardiovascular medicine, chest medicine, endocrinology, gastroenterology, renal medicine, haematology, infectious diseases, neurology, oncology and palliative care, rheumatology, and surgery (this last one is a long chapter – ~100 pages – which I have not yet finished). In my first post I (…mostly? I can’t recall if I included one or two observations made later in the coverage as well…) talked about observations included in the first 140 pages of the book, which relate only to the first three topics mentioned above; the chapter about chest medicine starts at page 154. In this post I’ll move on and discuss stuff covered in the chapters about cardiovascular medicine, chest medicine, and endocrinology.

In the previous post I talked a little bit about heart failure, acute coronary syndromes and a few related topics, but there’s a lot more stuff in the chapter about cardiovascular medicine and I figured I should add a few more observations – so let’s talk about aortic stenosis. The most common cause is ‘senile calcification’. The authors state that one should think of aortic stenosis in any elderly person with problems of chest pain, shortness of breath during exercise (exertional dyspnoea), and fainting episodes (syncope). Symptomatic aortic stenosis tends to be bad news; “If symptomatic, prognosis is poor without surgery: 2–3yr survival if angina/syncope; 1–2yr if cardiac failure. If moderate-to-severe and treated medically, mortality can be as high as 50% at 2yrs”. Surgery can improve the prognosis quite substantially; they note elsewhere in the coverage that a xenograft (e.g. from a pig) aortic valve replacement can last (“may require replacement at…”) 8-10 years, whereas a mechanical valve lasts even longer than that. Though it should also be noted in that context that the latter type requires life-long anticoagulation, whereas the former only requires this if there is atrial fibrilation.

Next: Infective endocarditis. Half of all cases of endocarditis occur on normal heart valves; the presentation in that case is one of acute heart failure. So this is one of those cases where your heart can be fine one day, and not many days later it’s toast and you’ll die unless you get treatment (often you’ll die even if you do get treatment as mortality is quite high: “Mortality: 5–50% (related to age and embolic events)”; mortality relates to which organism we’re dealing with: “30% with staphs [S. Aureus]; 14% if bowel organisms; 6% if sensitive streptococci.”). Multiple risk factors are known, but some of those are not easily preventable (renal failure, dermatitis, organ transplantation…); don’t be an IV drug (ab)user, and try to avoid getting (type 2) diabetes.. The authors note that: “There is no proven association between having an interventional procedure (dental or non-dental) and the development of IE”, and: “Antibiotic prophylaxis solely to prevent IE is not recommended”.

Speaking of terrible things that can go wrong with your heart for no good reason, hypertrophic cardiomyopathy (-HCM) is the leading cause of sudden cardiac death in young people, with an estimated prevalence of 1 in 500. “Sudden death may be the first manifestation of HCM in many patients”. Yeah…

The next chapter in the book as mentioned covers chest medicine. At the beginning of the chapter there’s some stuff about what the lungs look like and some stuff about how to figure out whether they’re working or not, or why they’re not working – I won’t talk about that here, but I would note that lung problems can relate to stuff besides ‘just’ lack of oxygen; they can also for example be related to retention of carbon dioxide and associated acidosis. In general I won’t talk much about this chapter’s coverage as I’m aware that I have covered many of the topics included in the book before here on the blog in other posts. It should perhaps be noted that whereas the chapter has two pages about lung tumours and two pages about COPD, it has 6 pages about pneumonia; this is still a very important disease and a major killer. Approximately one in five (the number 21% is included in the book) patients with pneumonia in a hospital setting die. Though it should perhaps also be observed that maybe one reason why more stuff is not included about lung cancer in that chapter is that this disease is just depressing and doctors can’t really do all that much. Carcinoma of the bronchus make up ~19% of all cancers and 27% of cancer deaths in the UK. In terms of prognosis, non-small cell lung cancer has a 50% 2-year mortality in cases where the cancer was not spread at presentation and a 90% 2-year mortality in cases with spread. That’s ‘the one you would prefer’: Small cell lung cancer is worse as small cell tumours “are nearly always disseminated at presentation” – here the untreated median survival is 3 months, increasing to 1-1,5 years if treated. The authors note that only 5% (of all cases, including both types) are ‘cured’ (they presumably use those citation marks for a reason). Malignant mesothelioma, a cancer strongly linked to asbestos exposure most often developing in the pleura, incidentally also has a terrible prognosis (”

5-8% of people in the UK have asthma; I was surprised the number was that high. Most people who get it during childhood either grow out of it or suffer much less as adults, but on the other hand there are also many people who develop chronic asthma late in life. In 2009 approximately 1000 people in the UK died of asthma – unless this number is a big underestimate, it would seem to me that asthma at least in terms of mortality is a relatively mild disease (if 5% of the UK population has asthma, that’s 3 million people – and 1000 deaths among 3 million people is not a lot, especially not considering that half of those deaths were in people above the age of 65). COPD is incidentally another respiratory disease which is more common than I had thought; they note that the estimated prevalence in people above the age of 40 in the UK is 10-20%.

The endocrinology chapter has 10 pages about diabetes, and I won’t talk much about that coverage here as I’ve talked about many of these things before on the blog – however a few observations are worth including and discussing here. The authors note that 4% of all pregnancies are complicated by diabetes, with the large majority of cases (3.5%) being new-onset gestational diabetes. In a way the 0,5% could be considered ‘good news’ because they reflect the fact that outcomes have improved so much that a female diabetic can actually carry a child to term without risking her own life or running a major risk that the fetus dies (“As late as 1980, physicians were still counseling diabetic women to avoid pregnancy” – link). But the 3,5%? That’s not good: “All forms [of diabetes] carry an increased risk to mother and foetus: miscarriage, pre-term labour, pre-eclampsia, congenital malformations, macrosomia, and a worsening of diabetic complications”. I’m not fully convinced this statement is actually completely correct, but there’s no doubt that diabetes during pregnancy is not particularly desirable. As to which part of the statement I’m uncertain about, I think gestational diabetes ‘ought to’ have somewhat different effects than type 1 especially in the context of congenial malformations. Based on my understanding of these things, gestational diabetes should be less likely to cause congenital malformations than type 1 diabetes in the mother; diabetes-related congenital malformations tend to happen/develop very early in pregnancy (for details, see the link above) and gestational pregnancy is closely related to hormonal changes and changing metabolic demands which happen over time during pregnancy. Hormonal changes which occur during pregnancy play a key role in the pathogenesis of gestational diabetes, as the hormonal changes in general increase insulin resistance significantly, which is what causes some non-diabetic women to become diabetic during pregnancy; these same processes incidentally also causes the insulin demands of diabetic pregnant women to increase a lot during pregnancy. You’d expect the inherently diabetogenic hormonal and metabolic processes which happen in pregnancy to play a much smaller role in the beginning of the pregnancy than they do later on, especially as women who develop gestational diabetes during their pregnancy would be likely to be able to compensate early in pregnancy, where the increased metabolic demands are much less severe than they are later on. So I’d expect the risk contribution from ‘classic gestational diabetes’ to be larger in the case of macrosomia than in the case of neural tube defects, where type 1s should probably be expected to dominate – a sort of ‘gestational diabetics don’t develop diabetes early enough in pregnancy for the diabetes to be very likely to have much impact on organogenesis’-argument. This is admittedly not a literature I’m intimately familiar with and maybe I’m wrong, but from my reading of their diabetes-related coverage I sort of feel like the authors shouldn’t be expected to be intimately familiar with the literature either, and I’m definitely not taking their views on these sorts of topics to be correct ‘by default’ at this point. This NHS site/page incidentally seems to support my take on this, as it’s clear that the first occasion for even testing for gestational diabetes is at week 8-12, which is actually after a substantial proportion of diabetes-related organ damage would already be expected to have occurred in the type 1 diabetes context (“There is an increased prevalence of congenital anomalies and spontaneous abortions in diabetic women who are in poor glycemic control during the period of fetal organogenesis, which is nearly complete by 7 wk postconception.” – Sperling et al., see again the link provided above. Note that that entire textbook is almost exclusively about type 1 diabetes, so ‘diabetes’ in the context of that quote equals T1DM), and a glucose tolerance test/screen does not in this setting take place until weeks 24-28.

The two main modifiable risk factors in the context of gestational diabetes are weight and age of pregnancy; the risk of developing gestational diabetes  increases with weight and is higher in women above the age of 25. One other sex/gender-related observation to make in the context of diabetes is incidentally that female diabetics are at much higher risk of cardiovascular disease than are non-diabetic females: “DM [diabetes mellitus] removes the vascular advantage conferred by the female sex”. Relatedly, “MI is 4-fold commoner in DM and is more likely to be ‘silent’. Stroke is twice as common.” On a different topic in which I’ve been interested they provided an observation which did not help much: “The role of aspirin prophylaxis […] is uncertain in DM with hypertension.”

They argue in the section about thyroid function tests (p. 209) that people with diabetes mellitus should be screened for abnormalities in thyroid function on the annual review; I’m not actually sure this is done in Denmark and I think it’s not – the DDD annual reports I’ve read have not included this variable, and if it is done I know for a fact that doctors do not report the results to the patient. I’m almost certain they neglected to include a ‘type 1’ in that recommendation, because it makes close to zero sense to screen type 2 diabetics for comorbid autoimmune conditions, and I’d say I’m probably also a little skeptical, though much less skeptical, about annual screenings of all type 1s being potentially cost-effective. Given that autoimmune comorbidities (e.g. Graves’ disease and Hashimoto’s) are much more common in women than in men and that they often present in middle-aged individuals (and given that they’re more common in people who develop diabetes relatively late, unlike me – see Sperling) I would assume I’m relatively low risk and that it would probably not make sense to screen someone like me annually from a cost-benefit/cost-effectiveness perspective; but it might make sense to ask the endocrinologist at my next review about how this stuff is actually being done in Denmark, if only to satisfy my own curiosity. Annual screening of *female*, *type 1* diabetics *above (e.g.) the age of 30* might be a great idea and perhaps less restrictive criteria than that can also be justified relatively easily, but this is an altogether very different recommendation from the suggestion that you should screen all diabetics annually for thyroid problems, which is what they recommend in the book – I guess you can add this one to the list of problems I have with the authors’ coverage of diabetes-related topics (see also my comments in the previous post). The sex- and age-distinction is likely much less important than the ‘type’ restriction and maybe you can justify screening all type 1 diabetics (For example: “Hypothyroid or hyperthyroid AITD [autoimmune thyroid disease] has been observed in 10–24% of patients with type 1 diabetes” – Sperling. Base rates are important here: Type 1 diabetes is rare, and Graves’ disease is rare, but if the same HLA mutation causes both in many cases then the population prevalence is not informative about the risk an individual with diabetes and an HLA mutation has of developing Graves’) – but most diabetics are not type 1 diabetics, and it doesn’t make sense to screen a large number of people without autoimmune disease for autoimmune comorbidities they’re unlikely to have (autoimmunity in diabetes is complicated – see the last part of this comment for a few observations of interest on that topic – but it’s not that complicated; most type 2 diabetics are not sick because of autoimmunity-related disease processes, and type 2 diabetics make up the great majority of people with diabetes mellitus in all patient populations around the world). All this being said, it is worth keeping in mind that despite overt thyroid disease being relatively rare in general, subclinical hypothyroidism is common in middle-aged and elderly individuals (“~10% of those >55yrs”); and the authors recommend treating people in this category who also have DM because they are more likely to develop overt disease (…again it probably makes sense to add a ‘T1’ in front of that DM).

Smoking is sexy, right? (Or at least it used to be…). And alcohol makes other people look sexy, right? In a way I find it a little amusing that alcohol and smoking are nevertheless two of the three big organic causes of erectile dysfunction (the third is diabetes).

How much better does it feel to have sex, compared to how it feels to masturbate? No, they don’t ask that question in the book (leave that to me…) but they do provide part of the answer because actually there are ways to quantify this, sort of: “The prolactin increase ( and ) after coitus is ~400% greater than after masturbation; post-orgasmic prolactin is part of a feedback loop decreasing arousal by inhibiting central dopaminergic processes. The size of post-orgasmic prolactin increase is a neurohormonal index of sexual satisfaction.”

November 1, 2015 Posted by | Books, Cancer/oncology, Cardiology, Diabetes, Epidemiology, Immunology, Medicine | Leave a comment

A couple of lectures and a little bit of random stuff

i. Two lectures from the Institute for Advanced Studies:

The IAS has recently uploaded a large number of lectures on youtube, and the ones I blog here are a few of those where you can actually tell from the title what the lecture is about; I find it outright weird that these people don’t include the topic covered in the lecture in their lecture titles.

As for the video above, as usual for the IAS videos it’s annoying that you can’t hear the questions asked by the audience, but the sound quality of this video is at least quite a bit better than the sound quality of the video below (which has a couple of really annoying sequences, in particular around the 15-16 minutes mark (it gets better), where the image is also causing problems, and in the last couple of minutes of the Q&A things are also not exactly optimal as the lecturer leaves the area covered by the camera in order to write something on the blackboard – but you don’t know what he’s writing and you can’t see the lecturer, because the camera isn’t following him). I found most of the above lecture easier to follow than I did the lecture posted below, though in either case you’ll probably not understand all of it unless you’re an astrophysicist – you definitely won’t in case of the latter lecture. I found it helpful to look up a few topics along the way, e.g. the wiki articles about the virial theorem (/also dealing with virial mass/radius), active galactic nucleus (this is the ‘AGN’ she refers to repeatedly), and the Tully–Fisher relation.

Given how many questions are asked along the way it’s really annoying that you in most cases can’t hear what people are asking about – this is definitely an area where there’s room for improvement in the context of the IAS videos. The lecture was not easy to follow but I figured along the way that I understood enough of it to make it worth watching the lecture to the end (though I’d say you’ll not miss much if you stop after the lecture – around the 1.05 hours mark – and skip the subsequent Q&A). I’ve relatively recently read about related topics, e.g. pulsar formation and wave- and fluid dynamics, and if I had not I probably would not have watched this lecture to the end.

ii. A vocabulary.com update. I’m slowly working my way up to the ‘Running Dictionary’ rank (I’m only a walking dictionary at this point); here’s some stuff from my progress page:

Vocab
I recently learned from a note added to a list that I’ve actually learned a very large proportion of all words available on vocabulary.com, which probably also means that I may have been too harsh on the word selection algorithm in past posts here on the blog; if there aren’t (/m)any new words left to learn it should not be surprising that the algorithm presents me with words I’ve already mastered, and it’s not the algorithm’s fault that there aren’t more words available for me to learn (well, it is to the extent that you’re of the opinion that questions should be automatically created by the algorithm as well, but I don’t think we’re quite there yet at this point). The aforementioned note was added in June, and here’s the important part: “there are words on your list that Vocabulary.com can’t teach yet. Vocabulary.com can teach over 12,000 words, but sadly, these aren’t among them”. ‘Over 12.000’ – and I’ve mastered 11.300. When the proportion of mastered words is this high, not only will the default random word algorithm mostly present you with questions related to words you’ve already mastered; but it actually also starts to get hard to find lists with many words you’ve not already mastered – I’ll often load lists with one hundred words and then realize that I’ve mastered every word on the list. This is annoying if you have a desire to continually be presented with both new words as well as old ones. Unless vocabulary.com increases the rate with which they add new words I’ll run out of new words to learn, and if that happens I’m sure it’ll be much more difficult for me to find motivation to use the site.

With all that stuff out of the way, if you’re not a regular user of the site I should note – again – that it’s an excellent resource if you desire to increase your vocabulary. Below is a list of words I’ve encountered on the site in recent weeks(/months?):

Copaceticfrumpyelisiontermagantharridanquondam, funambulist, phantasmagoriaeyelet, cachinnate, wilt, quidnunc, flocculent, galoot, frangible, prevaricate, clarion, trivet, noisome, revenant, myrmidon (I have included this word once before in a post of this type, but it is in my opinion a very nice word with which more people should be familiar…), debenture, teeter, tart, satiny, romp, auricular, terpsichorean, poultice, ululation, fusty, tangy, honorarium, eyas, bumptious, muckraker, bayou, hobble, omphaloskepsis, extemporize, virago, rarefaction, flibbertigibbet, finagle, emollient.

iii. I don’t think I’d do things exactly the way she’s suggesting here, but the general idea/approach seems to me appealing enough for it to be worth at least keeping in mind if I ever decide to start dating/looking for a partner.

iv. Some wikipedia links:

Tarrare (featured). A man with odd eating habits and an interesting employment history (“Dr. Courville was keen to continue his investigations into Tarrare’s eating habits and digestive system, and approached General Alexandre de Beauharnais with a suggestion that Tarrare’s unusual abilities and behaviour could be put to military use.[9] A document was placed inside a wooden box which was in turn fed to Tarrare. Two days later, the box was retrieved from his excrement, with the document still in legible condition.[9][17] Courville proposed to de Beauharnais that Tarrare could thus serve as a military courier, carrying documents securely through enemy territory with no risk of their being found if he were searched.” Yeah…).

Cauda equina syndromeCastleman’s disease, Astereognosis, Familial dysautonomia, Homonymous hemianopsia, Amaurosis fugax. All of these are of course related to content covered in the Handbook.

1740 Batavia massacre (featured).

v. I am also fun.

October 30, 2015 Posted by | Astronomy, History, Immunology, language, Lectures, Medicine, Neurology, Personal, Physics, Random stuff, Wikipedia | Leave a comment

Random stuff

It’s been a while since I posted anything here so I figured I should at least post something…

i. A few Khan Academy videos I watched a while back:

(No comments)

(Bookmark remark: (‘Not completely devoid of slight inaccuracies as usual – e.g. in meningitis, neck stiffness is not as much as symptom as it is a clinical sign (see Chamberlain’s symptoms and signs…))’

(Bookmark remark: ‘Very simplified, but not terrible’)

(No comments)

ii. I previously read the wiki on strategic bombing during WW2, but the article did not really satisfy my curiosity and it turns out that the wiki also has a great (featured) article about Air raids on Japan (a topic not covered in a great amount of detail in the aforementioned wiki article). A few random observations from the article:

“Overall, the attacks in May destroyed 94 square miles (240 km2) of buildings, which was equivalent to one seventh of Japan’s total urban area.”

“In Tokyo, Osaka, Nagoya, Yokohama, Kobe, and Kawasaki, “over 126,762 people were killed … and a million and a half dwellings and over 105 square miles (270 km2) of urban space were destroyed.”[136] In Tokyo, Osaka and Nagoya, “the areas leveled (almost 100 square miles (260 km2)) exceeded the areas destroyed in all German cities by both the American and English air forces (approximately 79 square miles (200 km2)).”[136]

“In financial terms, the Allied air campaign and attacks on merchant ships destroyed between one third and a quarter of Japan’s wealth.[289]

“Approximately 40 percent of the urban area of the 66 cities subjected to area attacks were destroyed.[290] This included the loss of about 2.5 million housing units, which rendered 8.5 million people homeless.”

iii. A few longer lectures I’ve watched recently but did not think were particularly good: The Fortress (GM Akobian, Chess), Safety in the Nuclear Industry (Philip Thomas, Gresham College), War, Health and Medicine: The medical lessons of World War I (Mark Harrison, Gresham College – topic had potential, somehow did not like ‘the delivery’; others may find it worth watching).

iv. I play a lot of (too much) chess these days, so I guess it makes sense to post a little on this topic as well. Here’s a list of some of my recent opponents on the ICC: GM Zurab Azmaiparashvili, IM Jerzy Slaby, IM Petar Gojkovic, GM Goran Kosanovic, IM Jeroen Bosch, WGM Alla Grinfeld. I recall encountering a few titled players when I started out on the ICC and my rating was still adjusting and stabilizing, but now I’ve sort of fixed at a level around 1700-1800 in both the 1, 3 and 5 minute pools – sometimes a bit higher, sometimes a bit lower (and I’ve played relatively few 5 minute games so far)). This is a level where at least in bullet some of the semi-regular opponents I’ll meet in the rating pool are guys like these. I was quite dissatisfied with my play when I started out on the ICC because I hadn’t realized how tough it is to maintain a high rating there; having a closer look at which sort of opponents I was actually facing gradually made me realize I was probably doing quite well, all things considered. Lately I’ve been thinking that I have probably even been doing quite a bit better than I’d thought I had. See also this and this link. I’ve gradually concluded that I’m probably never ‘going back’ now that I’ve familiarized myself with the ICC server.

And yes, I do occasionally win against opposition like that, also on position – below an example from a recent game against a player not on the list above (there are quite a few anonymous title-holders as well on the server):

easy-e
Click to view full size – the list to the lower left is a list of other players online on the server at that point in time, ordered by rating; as should be clear, lots of title-holders have relatively low ratings (I’m not completely sure which rating pool was displayed in the sidebar at that time, but the defaults on display for me are 5- or 3-minutes, so for example the international master ‘softrain’ thus had either a 3 or 5 minute rating of 1799 at that time. Do note that ICC requires proof for titles to display on the server; random non-titled players do not display as titleholders on the ICC (actually the formally approved titled accounts obviously do not account for all accounts held by title-holders as some titled players on the server use accounts which do not give away the fact that they have a title).

Here’s another very nice illustration of how tough the X-minute pools are (/how strong the players playing on the ICC are):

Wang Hao
Again, click to view in full size. This is Chinese Grandmaster Wang Hao‘s ICC account. Wang Hao is currently #39 on the FIDE list of active chess players in the world, with a FIDE rating above 2700. Even his 5-minute rating on the ICC, based on more than a thousand games, is below 2300, and his current 3 minute rating is barely above 2000. With numbers like those, I currently feel quite satisfied with my 1700-1800 ratings (although I know I should be spending less time on chess than I currently do).

v. A few words I’ve recently encountered on vocabulary.com: Anaphora, usufruct, mimesis, amanuensis, peculate, elide, ataraxia, myrmidon, velleity.

vi. A few other wiki links: Fritz Haber, Great Stink (featured), Edward Low (a really nice guy, it seems – “A story describes Low burning a French cook alive, saying he was a “greasy fellow who would fry well”, and another tells he once killed 53 Spanish captives with his cutlass.[6]“), 1940 Soviet ultimatum to Lithuania (‘good article’).

vii. A really cute paper from the 2013 Christmas edition of the British Medical Journal: Were James Bond’s drinks shaken because of alcohol induced tremor? Here’s the abstract:

Objective To quantify James Bond’s consumption of alcohol as detailed in the series of novels by Ian Fleming.

Design Retrospective literature review.

Setting The study authors’ homes, in a comfy chair.

Participants Commander James Bond, 007; Mr Ian Lancaster Fleming.

Main outcome measures Weekly alcohol consumption by Commander Bond.

Methods All 14 James Bond books were read by two of the authors. Contemporaneous notes were taken detailing every alcoholic drink taken. Predefined alcohol unit levels were used to calculate consumption. Days when Bond was unable to consume alcohol (such as through incarceration) were noted.

Results After exclusion of days when Bond was unable to drink, his weekly alcohol consumption was 92 units a week, over four times the recommended amount. His maximum daily consumption was 49.8 units. He had only 12.5 alcohol free days out of 87.5 days on which he was able to drink.

Conclusions James Bond’s level of alcohol intake puts him at high risk of multiple alcohol related diseases and an early death. The level of functioning as displayed in the books is inconsistent with the physical, mental, and indeed sexual functioning expected from someone drinking this much alcohol. We advise an immediate referral for further assessment and treatment, a reduction in alcohol consumption to safe levels, and suspect that the famous catchphrase “shaken, not stirred” could be because of alcohol induced tremor affecting his hands.”

viii. A couple of other non-serious links which I found hilarious:
1) The Prof(essor) or Hobo quiz (via SSC).
2) Today’s SMBC. I’ll try to remember the words in the votey in the highly unlikely case I’ll ever have use for them – in my opinion it would be a real tragedy if one were to miss an opportunity to make a statement like that, given that it was at all suitable to the situation at hand..

July 6, 2015 Posted by | Chess, Diabetes, Epidemiology, History, Immunology, Infectious disease, Khan Academy, Lectures, Medicine, Personal | Leave a comment

Chlamydia and gonorrhea…

Below some observations from Holmes et al.‘s chapters about the sexually transmitted bacterial infections chlamydia and gonorrhea. A few of these chapters covered some really complicated stuff, but I’ve tried to keep the coverage reasonably readable by avoiding many of the technical details. I’ve also tried to make the excerpts easier to read by adding relevant links and by adding brief explanations of specific terms in brackets where this approach seemed like it might be helpful.

“Since the early 1970s, Chlamydia trachomatis has been recognized as a genital pathogen responsible for an increasing variety of clinical syndromes, many closely resembling infections caused by Neisseria gonorrhoeae […]. Because many practitioners have lacked access to facilities for laboratory testing for chlamydia, these infections often have been diagnosed and treated without benefit of microbiological confirmation. Newer, molecular diagnostic tests have in part now addressed this problem […] Unfortunately, many chlamydial infections, particularly in women, are difficult to diagnose clinically and elude detection because they produce few or no symptoms and because the symptoms and signs they do produce are nonspecific. […] chlamydial infections tend to follow a fairly self-limited acute course, resolving into a low-grade persistent infection which may last for years. […] The disease process and clinical manifestations of chlamydial infections probably represent the combined effects of tissue damage from chlamydial replication and inflammatory responses to chlamydiae and the necrotic material from destroyed host cells. There is an abundant immune response to chlamydial infection (in terms of circulating antibodies or cell-mediated responses), and there is evidence that chlamydial diseases are diseases of immunopathology. […] A common pathologic end point of chlamydial infection is scarring of the affected mucous membranes. This is what ultimately leads to blindness in trachoma and to infertility and ectopic pregnancy after acute salpingitis. There is epidemiologic evidence that repeated infection results in higher rates of sequelae.”

“The prevalence of chlamydial urethral infection has been assessed in populations of men attending general medical clinics, STD clinics, adolescent medicine clinics, and student health centers and ranges from 3–5% of asymptomatic men seen in general medical settings to 15–20% of all men seen in STD clinics. […] The overall incidence of C. trachomatis infection in men has not been well defined, since in most countries these infections are not officially reported, are not microbiologically
confirmed, and often may be asymptomatic, thus escaping detection. […] The prevalence of chlamydial infection has been studied in pregnant women, in women attending gynecology or family planning clinics, in women attending STD clinics, in college students, and in women attending general medicine or family practice clinics in school-based clinics and more recently in population-based studies. Prevalence of infection in these studies has ranged widely from 3% in asymptomatic women in community-based surveys to over 20% in women seen in STD clinics.[31–53] During pregnancy, 3–7% of women generally have been chlamydia positive […] Several studies in the United States indicate that approximately 5% of neonates acquire chlamydial infection perinatally, yet antibody prevalence in later childhood before onset of sexual activity may exceed 20%.”

“Clinically, chlamydia-positive and chlamydia-negative NGU [Non-Gonococcal Urethritis] cannot be differentiated on the basis of signs or symptoms.[76] Both usually present after a 7–21-day incubation period with dysuria and mild-to-moderate whitish or clear urethral discharge. Examination reveals no abnormalities other than the discharge in most cases […] Clinical recognition of chlamydial cervicitis depends on a high index of suspicion and a careful cervical examination. There are no genital symptoms that are specifically correlated with chlamydial cervical infection. […] Although urethral symptoms may develop in some women with chlamydial infection, the majority of female STD clinic patients with urethral chlamydial infection do not have dysuria or frequency. […] the majority of women with chlamydial infection cannot be distinguished from uninfected women either by clinical examination or by […] simple tests and thus require the use of specific diagnostic testing. […] Since many chlamydial infections are asymptomatic, it has become clear that effective control must involve periodic testing of individuals at risk.[168] As the cost of extensive screening may be prohibitive, various approaches to defining target populations at increased risk of infection have been evaluated. One strategy has been to designate patients attending specific high prevalence clinic populations for universal testing. Such clinics would include STD, juvenile detention, and some family planning clinics. This approach, however, fails to account for the majority of asymptomatic infections, since attendees at high prevalence clinics often attend because of symptoms or suspicion of infection. Consequently, selective screening criteria have been developed for use in various clinical settings.[204–208] Among women, young age (generally,

If you’re a woman who’s decided not to have children and so aren’t terribly worried about infertility, it should be emphasized that untreated chlamydia can cause other really unpleasant stuff as well, like chronic pelvic pain from pelvic inflammatory disease, or ectopic pregnancy, which may be life-threatening. This is the sort of infection you’ll want to get treated even if you’re not bothered by symptoms.

Neisseria gonorrhoeae (gonococci) is the etiologic agent of gonorrhea and its related clinical syndromes (urethritis, cervicitis, salpingitis, bacteremia, arthritis, and others). It is closely related to Neisseria meningitidis (meningococci), the etiologic agent of one form of bacterial meningitis, and relatively closely to Neisseria lactamica, an occasional human pathogen. The genus Neisseria includes a variety of other relatively or completely nonpathogenic organisms that are principally important because of their occasional diagnostic confusion with gonococci and meningococci. […] Many dozens of specific serovars have been defined […] By a combination of auxotyping and serotyping […] gonococci can be divided into over 70 different strains; the number may turn out to be much larger.”

“Humans are the only natural host for gonococci. Gonococci survive only a short time outside the human body. Although gonococci can be cultured from a dried environment such as a toilet seat up to 24 hours after being artificially inoculated in large numbers onto such a surface, there is virtually no evidence that natural transmission occurs from toilet seats or similar objects. Gonorrhea is a classic example of an infection spread by contact: immediate physical contact with the mucosal surfaces of an infected person, usually a sexual partner, is required for transmission. […] Infection most often remains localized to initial sites of inoculation. Ascending genital infections (salpingitis, epididymitis) and bacteremia, however, are relatively common and account for most of the serious morbidity due to gonorrhea.”

“Consideration of clinical manifestations of gonorrhea suggests many facets of the pathogenesis of the infection. Since gonococci persist in the male urethra despite hydrodynamic forces that would tend to wash the organisms from the mucosal surface, they must be able to adhere effectively to mucosal surfaces. Similarly, since gonococci survive in the urethra despite close attachment to large numbers of neutrophils, they must have mechanisms that help them to survive interactions with polymorphonuclear neutrophils. Since some gonococci are able to invade and persist in the bloodstream for many days at least, they must be able to evade killing by normal defense mechanisms of plasma […] Invasion of the bloodstream also implies that gonococci are able to invade mucosal barriers in order to gain access to the bloodstream. Repeated reinfections of the same patient by one strain strongly suggest that gonococci are able to change surface antigens frequently and/or to escape local immune mechanisms […] The considerable tissue damage of fallopian tubes consequent to gonococcal salpingitis suggests that gonococci make at least one tissue toxin or gonococci trigger an immune response that results in damage to host tissues.[127] There is evidence to support many of these inferences. […] Since the mid-1960s, knowledge of the molecular basis of gonococcal–host interactions and of gonococcal epidemiology has increased to the point where it is amongst the best described of all microbial pathogens. […] Studies of pathogenesis are [however] complicated by the absence of a suitable animal model. A variety of animal models have been developed, each of which has certain utility, but no animal model faithfully reproduces the full spectrum of naturally acquired disease of humans.”

“Gonococci are inherently quite sensitive to antimicrobial agents, compared with many other gram-negative bacteria. However, there has been a gradual selection for antibioticresistant mutants in clinical practice over the past several decades […] The consequence of these events has been to make penicillin and tetracycline therapy ineffective in most areas. Antibiotics such as spectinomycin, ciprofloxacin, and ceftriaxone generally are effective but more expensive than penicillin G and tetracycline. Resistance to ciprofloxacin emerged in SE Asia and Africa in the past decade and has spread gradually throughout much of the world […] Streptomycin (Str) is not frequently used for therapy of gonorrhea at present, but many gonococci exhibit high-level resistance to Str. […] Resistance to fluoroquinolones is increasing, and now has become a general problem in many areas of the world.”

“The efficiency of gonorrhea transmission depends on anatomic sites infected and exposed as well as the number of exposures. The risk of acquiring urethral infection for a man following a single episode of vaginal intercourse with an infected woman is estimated to be 20%, rising to an estimated 60–80% following four exposures.[16] The prevalence of infection in women named as secondary sexual contacts of men with gonococcal urethritis has been reported to be 50–90%,[16,17] but no published studies have carefully controlled for number of exposures. It is likely that the single-exposure transmission rate from male to female is higher than that from female to male […] Previous reports saying that 80% of women with gonorrhea were asymptomatic were most often based on studies of women who were examined in screening surveys or referred to STD clinics because of sexual contact with infected men.[23] Symptomatic infected women who sought medical attention were thus often excluded from such surveys. However […] more than 75% of women with gonorrhea attending acute care facilities such as hospital emergency rooms are symptomatic.[24] The true proportion of infected women who remain asymptomatic undoubtedly lies between these extremes […] Asymptomatic infections occur in men as well as women […] Asymptomatically infected males and females contribute disproportionately to gonorrhea transmission, because symptomatic individuals are more likely to cease sexual activity and seek medical care.”

“the incidence of asymptomatic urethral gonococcal infection in the general population also has been estimated at approximately 1–3%.[27] The prevalence of asymptomatic infection may be much higher, approaching 5% in some studies, because untreated asymptomatic infections may persist for considerable periods. […] The prevalence of gonorrhea within communities tends to be dynamic, fluctuating over time, and influenced by a number of interactive factors. Mathematical models for gonorrhea within communities suggest that gonorrhea prevalence is sustained not only through continued transmission by asymptomatically infected patients but also by “core group” transmitters who are more likely than members of the general population to become infected and transmit gonorrhea to their sex partners. […] At present, gonorrhea prevention and control efforts are heavily invested in the concept of vigorous pursuit and treatment of infected core-group members and asymptomatically infected individuals.”

“Relatively large numbers (>50) of gonococcal A/S [auxotype/serotype] classes usually are present in most communities simultaneously […] and new strains can be detected over time. The distribution of isolates within A/S classes tends to be uneven, with a few A/S classes contributing disproportionately to the total number of isolates. These predominant A/S classes generally persist within communities for months or years. […] Interviews of the patients infected by [a specific] strain early in [an] outbreak identified one infected female who acknowledged over 100 different sexual partners over the preceding 2 months, suggesting that she may have played an important role in the introduction and establishment of this gonococcal strain in the community. Thus the Proto/IB-3 strain may have become common in Seattle not because of specific biologic factors but because of its chance of transmission to members of a core population by a high-frequency transmitter.” [100+ partners over a 2 month period! I was completely dumbstruck when I’d read that.]

“clinical gonorrhea is manifested by a broad spectrum of clinical presentations including asymptomatic and symptomatic local infections, local complicated infections, and systemic dissemination. […] Acute anterior urethritis is the most common manifestation of gonococcal infection in men. The incubation period ranges from 1 to 14 days or even longer; however, the majority of men develop symptoms within 2–5 days […] The predominant symptoms are urethral discharge or dysuria [pain on urination]. […] Without treatment, the usual course of gonococcal urethritis is spontaneous resolution over a period of several weeks, and before the development of effective antimicrobial therapy, 95% of untreated patients became asymptomatic within 6 months.[43] […] The incubation period for urogenital gonorrhea in women is less certain and probably more variable than in men, but most who develop local symptoms apparently do so within 10 days of infection.[51,52] The most common symptoms are those of most lower genital tract infections in women […] and include increased vaginal discharge, dysuria, intermenstrual uterine bleeding, and menorrhagia [abnormally heavy and prolonged menstrual period], each of which may occur alone or in combination and may range in intensity from minimal to severe. […] The clinical assessment of women for gonorrhea is often confounded […] by the nonspecificity of these signs and symptoms and by the high prevalence of coexisting cervical or vaginal infections with Chlamydia trachomatis, Trichomonas vaginalis, Candida albicans, herpes simplex virus, and a variety of other organisms […] Among coinfecting agents for patients with gonorrhea in the United States, C. trachomatis [chlamydia] is preeminent. Up to 10–20% of men and 20–30% of women with acute urogenital gonorrhea are coinfected with C. trachomatis.[10,46,76,139–141] In addition, substantial numbers of women with acute gonococcal infection have simultaneous T. vaginalis infections.”

“Among patients with gonorrhea, pharyngeal infection occurs in 3–7% of heterosexual men, 10–20% of heterosexual women, and 10–25% of homosexually active men. […] Gonococcal infection is transmitted to the pharynx by orogenital sexual contact and is more efficiently acquired by fellatio than by cunnilingus.[63]”

“In men, the most common local complication of gonococcal urethritis is epididymitis […], a syndrome that occurred in up to 20% of infected patients prior to the availability of modern antimicrobial therapy. […] Postinflammatory urethral strictures were common complications of untreated gonorrhea in the preantibiotic era but are now rare […] In acute PID [pelvic inflammatory disease], the clinical syndrome comprised primarily of salpingitis, and frequently including endometritis, tubo-ovarian tuboovarian abscess, or pelvic peritonitis is the most common complication of gonorrhea in women, occurring in an estimated 10–20% of those with acute gonococcal infection.[75,76] PID is the most common of all complications of gonorrhea, as well as the most important in terms of public-health impact, because of both its acute manifestations and its longterm sequelae (infertility, ectopic pregnancy, and chronic pelvic pain).”

“A major impediment to use of culture for gonorrhea diagnosis in many clinical settings are the time, expense, and logistical limitations such as specimen transport to laboratories for testing, a process that may take several days and result in temperature variation or other circumstances that can jeopardize culture viability.[111] In recent years, reliable nonculture assays for gonorrhea detection have become available and are being used increasingly. […] recently, nucleic acid amplification tests (NAATs) for gonorrhea diagnosis have become widely available.[116,117] Assays based on polymerase chain reaction (PCR), transcription-mediated amplification (TMA), and other nucleic acid amplification technologies have been developed. As a group, commercially available NAATs are more sensitive than culture for gonorrhea diagnosis and specificities are nearly as high as for culture. […] Emerging data suggest that most currently available NAATs are substantially more sensitive for gonorrhea detection than conventional culture.”

“Prior to the mid-1930s, when sulfanilamide was introduced, gonorrhea therapy involved local genital irrigation with antiseptic solutions such as silver nitrate […] By 1944 […] many gonococci had become sulfanilamide resistant […] Fortunately, in 1943 the first reports of the near 100% utility of penicillin for gonorrhea therapy were published,[127] and by the end of World War II, as penicillin became available to the general public, it quickly became the therapy of choice. Since then, continuing development of antimicrobial resistance by N. gonorrhoeae[128,129] led to regular revisions of recommended gonorrhea therapy. From the 1950s until the mid-1970s, gradually increasing chromosomal penicillin resistance led to periodic increases in the amount of penicillin required for reliable therapy. […] by the late 1980s, penicillins and tetracyclines were no longer recommended for gonorrhea therapy.
In addition to resistance to penicillin, tetracyclines, and erythromycin, in 1987, clinically significant chromosomally mediated resistance to spectinomycin — another drug recommended for gonorrhea therapy — was described in U.S. military personnel in Korea.[132] In Korea, because of the high prevalence of PPNG [spectinomycin-resistant Penicillinase-Producing Neisseria Gonorrhoeae], in 1981, spectinomycin had been adopted as the drug of choice for gonorrhea therapy. By 1983, however, spectinomycin treatment failures were beginning to occur in patients with gonorrhea […] Following recognition of the outbreak of spectinomycin-resistant gonococci in Korea, ceftriaxone became the drug of choice for treatment of gonorrhea in U.S. military personnel in that country.[132] […] Beginning in 1993, fluoroquinolone antibiotics were recommended for therapy of uncomplicated gonorrhea in the United States […] [However] in 2007 the CDC opted to no longer recommend fluoroquinolone antibiotics for therapy of uncomplicated gonorrhea. This change meant that ceftriaxone and other cephalosporin antibiotics had become the sole class of antibiotics recommended as first-line therapy for gonorrhea. […] For over two decades, ceftriaxone — a third-generation cephalosporin—has been the most reliable single-dose regimen used for gonorrhea worldwide. […] there are currently few well-studied therapeutic alternatives to ceftriaxone for gonorrhea treatment.”

November 1, 2014 Posted by | Books, Epidemiology, Immunology, Infectious disease, Medicine, Microbiology, Pharmacology | Leave a comment

100 Cases in Clinical Pathology

This book is another publication from the 100 Cases … series which I’ve talked about before – I refer to these posts for some general comments about what this series is like and some talk about the other books in the series which I’ve read. The book is much like the others, though of course the specific topics covered are different in the various publications. I liked this book and gave it 3 stars on goodreads. The book has three sections: a section dealing with ‘chemical pathology, immunology and genetics’; a section dealing with ‘histopathology’; and a section dealing with ‘haematology’. As usual I knew a lot more about some of the topics covered than I did about some of the others. Some cases were quite easy, others were not. Some of the stuff covered in Greenstein & Wood’s endocrinology text came in handy along the way and enabled me for example to easily identify a case of Cushing’s syndrome and a case of Graves’ disease. I don’t think I’ll spoil anything by noting that two of the cases in this book involved these disorders, but if you plan on reading it later on you may want to skip the coverage below, as I have included some general comments from the answer sections of the book in this post.

As someone who’s not working in the medical field and who will almost certainly never need to know how to interpret a water deprivation test (also covered in detail in Greenstein and Wood, incidentally), there are some parts of books like this one which are not particularly ‘relevant’ to me; however I’d argue that far from all the stuff included in a book like this one is ‘stuff you don’t need to know’, as there are also for example a lot of neat observations included about how specific symptoms (and symptom complexes) are linked to specific disorders, some related ideas about which other medical conditions might cause similar health problems, and which risk factors are potentially important to have in mind in specific contexts. If you’ve had occasional fevers, night sweats and experienced weight loss over the last few months, you should probably have seen a doctor a while ago – knowledge included in books like this one may make the reader perhaps a bit less likely to overlook an important and potentially treatable health problem, and/or increase awareness of potential modifiable risk factors in specific contexts. A problem is however that the book will be hard to read if you have not read any medical textbooks before, and in that case I would probably advise you against reading it as it’s almost certainly not worth the effort.

I have added a few observations from the book below.

“After a bone marrow transplant (and any associated chemotherapy), the main risks are infection (from low white cell counts and the use of immunosuppressants, such as cyclosporin), bleeding (from low platelet counts) and graft versus host disease (GVHD). […] An erythematous rash that develops on the palms or soles of the feet of a patient 10–30 days after a bone marrow transplant is characteristic of GVHD. […] GVHD is a potentially life-threatening problem that can occur in up to 80% of successful allogeneic bone marrow transplants. […] Clinically, GVHD manifests like an autoimmune disease with a macular-papular rash, jaundice and hepatosplenomegaly and ultimately organ fibrosis. It classically involves the skin, gastrointestinal tract and the liver. […] Depending on severity, treatment of acute GVHD may involve topical and intravenous steroid therapy, immunosuppression (e.g. cyclosporine), or biologic therapies targeting TNF-α […], a key inflammatory cytokine. […] Prognosis is related to response to treatment. The mortality of patients who completely respond can still be around 20%, and the mortality in those who do not respond is as high as 75%.”

“The leading indication for a liver transplant is alcoholic cirrhosis in adults and biliary atresia in children. […] The overall one-year survival of a liver transplant is over 90%, with 10-year survival of around 70%. […] Transplant rejection can be classified by time course, which relates to the underlying immune mechanism: • Hyperacute organ rejection occurs within minutes of the graft perfusion in the operating theatre. […] The treatment for hyperacute rejection is immediate removal of the graft. • Acute organ rejection take place a number of weeks after the transplant […] The treatment for acute rejection includes high dose steroids. • Chronic organ rejection can take place months to years after the transplant. […] As it is irreversible, treatment for chronic rejection is difficult, and may include re-transplantation.”

“Chronic kidney disease (CKD) is characterized by a reduction in GFR over a period of 3 or more months (normal GFR is >90–120 mL/min). It arises from a progressive impairment of renal function with a decrease in the number of functioning nephrons; generally, patients remain asymptomatic until GFR reduces to below 15 mL/min (stage V CKD). Common causes of CKD are (1) diabetes mellitus, (2) hypertension, (3) glomerulonephritis, (4) renovascular disease, (5) chronic obstruction or interstitial nephritis, and (6) hereditary or cystic renal disease”

“The definition of an aneurysm is an abnormal permanent focal dilatation of all the layers of a blood vessel. An AAA [abdominal aortic aneurysm] is defined when the aortic diameter, as measured below the level of the renal arteries, is one and a half times normal. Women have smaller aortas, but for convenience, more than 3 cm qualifies as aneurysmal. The main risk factors for aneurysm formation are male gender, smoking, hypertension, Caucasian/European descent and atherosclerosis. Although atherosclerosis is a risk factor and both diseases share common predisposing factors, there are also differences. Atherosclerosis is primarily a disease of the intima, the innermost layer of the vessel wall, whereas in aneurysms there is degeneration of the media, the middle layer. […] The annual risk of rupture equals and begins to outstrip the risk of dying from surgery when the aneurysm exceeds 5.5 cm. This is the size above which surgical repair is recommended, comorbidities permitting. […] Catastrophic rupture, as in this case, presents with hypovolaemic shock and carries a dismal prognosis.” [The patient in the case history died soon after having arrived at the hospital]

“Stroke refers to an acquired focal neurological deficit caused by an acute vascular event. The neurological deficit persists beyond 24 hours, in contrast to a transient ischaemic attack (TIA) where symptoms resolve within 24 hours, although the distinction is now blurred with the advent of thrombolysis. […] Strokes are broadly categorized into ischaemic and haemorrhagic types, the majority being ischaemic. The pathophysiology in a haemorrhagic stroke is rupture of a blood vessel causing extravasation of blood into the brain substance with tissue damage and disruption of neuronal connections. The resulting haematoma also compresses surrounding normal tissue. In most ischaemic strokes, there is thromboembolic occlusion of vessels due to underlying atherosclerosis of the aortic arch and carotid arteries. In 15–20% of cases, there is atherosclerotic disease of smaller intrinsic blood vessels within the brain[…]. A further 15–20% are due to emboli from the heart. […] The territory and the extent of the infarct influences the prognosis; [for example] expressive dysphasia and right hemiparesis are attributable to infarcts in Broca’s area and the motor cortex, both frontal lobe territories supplied by the left middle cerebral artery.”

“The stereotypical profile of a gallstone patient is summed up by the 4Fs: female, fat, fertile and forty. However, while gallstones are twice as common in females, increasing age is a more important risk factor. Above the age of 60, 10–20% of the Western population have gallstones. […] Most people with cholelithiasis are asymptomatic, but there is a 1–4% annual risk of developing symptoms or complications. […] Complications depend on the size of the stones. Smaller stones may escape into the common bile duct, but may lodge at the narrowing of the hepatopancreatic sphincter (sphincter of Oddi), obstructing the common bile duct and pancreatic duct, leading to obstructive jaundice and pancreatitis respectively. […] In most series, alcohol and gallstones each account for 30–35% of cases [of acute pancreatitis]. […] Once symptomatic, the definitive treatment of gallstone disease is generally surgical via a cholecystectomy.”

“Breast cancer affects 1 in 8 women (lifetime risk) in the UK. […] Between 10 and 40% of women who are found to have a mass by mammography will have breast cancer. […] The presence of lymphovascular invasion indicates the likelihood of spread of tumour cells beyond the breast, thereby conferring a poorer outlook. Without lymph node involvement, the 10-year disease-free survival is close to 70–80% but falls progressively with the number of involved nodes.”

“Melanoma is a cancer of melanocytes, the pigmented cells in the skin, and is caused by injury to lightly pigmented skin by excessive exposure to ultraviolet (UV) radiation […] The change in colour of a pre-existing pigmented lesion with itching and bleeding and irregular margins on examination are indicators of transformation to melanoma. Melanomas progress through a radial growth phase to a vertical growth phase. In the radial growth phase, the lesion expands horizontally within the epidermis and superficial dermis often for a long period of time. Progression to the vertical phase is characterized by downward growth of the lesion into the deeper dermis and with absence of maturation of cells at the advancing front. During this phase, the lesion acquires the potential to metastasize through lymphovascular channels. The probability of this happening increases with increasing depth of invasion (Breslow thickness) by the melanoma cells. […] The ABCDE mnemonic aids in the diagnosis of melanoma: Asymmetry – melanomas are likely to be irregular or asymmetrical. Border – melanomas are more likely to have an irregular border with jagged edges. Colour – melanomas tend to be variegated in colour […]. Diameter – melanomas are usually more than 7 mm in diameter. Evolution – look for changes in the size, shape or colour of a mole.”

“CLL [chronic lymphocytic leukaemia] is the most common leukaemia in the Western world. Typically, it is picked up via an incidental lymphocytosis in an asymptomatic individual. […] The disease is staged according to the Binet classification. Typically, patients with Binet stage A disease require no immediate treatment. Symptomatic stage B and all stage C patients receive chemotherapy. […] cure is rare and the aim is to achieve periods of remission and symptom control. […] The median survival in CLL is between four and six years, though some patients survive a decade or more. […] There is […] a tendency of CLL to transform into a more aggressive leukaemia, typically a prolymphocytic transformation (in 15–30% of patients) or, less commonly (<10% of cases), transformation into a diffuse large B-cell lymphoma (a so-called Richter transformation). Appearance of transformative disease is an ominous sign, with few patients surviving for more than a year with such disease.”

“Pain, swelling, warmth, tenderness and immobility are the five cardinal signs of acute inflammation.”

“Osteomyelitis is an infection of bone that is characterized by progressive inflammatory destruction with the formation of sequestra (dead pieces of bone within living bone), which if not treated leads to new bone formation occurring on top of the dead and infected bone. It can affect any bone, although it occurs most commonly in long bones. […] Bone phagocytes engulf the bacteria and release osteolytic enzymes and toxic oxygen free radicals, which lyse the surrounding bone. Pus raises intraosseus pressure and impairs blood flow, resulting in thrombosis of the blood vessels. Ischaemia results in bone necrosis and devitalized segments of bone (known as sequestra). These sequestra are important in the pathogenesis of non-resolving infection, acting as an ongoing focus of infection if not removed. Osteomyelitis is one of the most difficult infections to treat. Treatment may require surgery in addition to antibiotics, especially in chronic osteomyelitis where sequestra are present. […] Poorly controlled diabetics are at increased risk of infections, and having an infection leads to poor control of diabetes via altered physiology occurring during infection. Diabetics are prone to developing foot ulcers, which in turn are prone to becoming infected, which then act as a source of bacteria for infecting the contiguous bones of the feet. This process is exacerbated in patients with peripheral neuropathy, poor diabetic control and peripheral vascular disease, as these all increase the risk of development of skin breakdown and subsequent osteomyelitis.” [The patient was of course a diabetic…]

“Recent onset fever and back pain suggest an upper UTI [urinary tract infection]. UTIs are classified by anatomy into lower and upper UTIs. Lower UTIs refer to infections at or below the level of the bladder, and include cystitis, urethritis, prostatitis, and epididymitis (the latter three being more often sexually transmitted). Upper UTIs refer to infection above the bladder, and include the ureters and kidneys. Infection of the urinary tract above the bladder is known as pyelonephritis [which] may be life threatening or lead to permanent kidney damage if not promptly treated. UTIs are also classified as complicated or uncomplicated. UTIs in men, the elderly, pregnant women, those who have an indwelling catheter, and anatomic or functional abnormality of the urinary tract are considered to be complicated. A complicated UTI will often receive longer courses of broader spectrum antibiotics. Importantly, the clinical history alone of dysuria and frequency (without vaginal discharge) is associated with more than 90% probability of a UTI in healthy women. […] In women, a UTI develops when urinary pathogens from the bowel or vagina colonize the urethral mucosa, and ascend via the urethra into the bladder. During an uncomplicated symptomatic UTI in women, it is rare for infection to ascend via the ureter into the kidney to cause pyelonephritis. […] Up to 40% of uncomplicated lower UTIs in women will resolve spontaneously without antimicrobial therapy. The use of antibiotics in this cohort is controversial when taking into account the side effects of antibiotics and their effect on normal flora. If prescribed, antibiotics for uncomplicated lower UTIs should be narrow-spectrum […] Most healthcare-associated UTIs are associated with the use of urinary catheters. Each day the catheter remains in situ, the risk of UTI rises by around 5%. Thus inserting catheters only when absolutely needed, and ensuring they are removed as soon as possible, can prevent these.”

September 24, 2014 Posted by | alcohol, Books, Cancer/oncology, Cardiology, Diabetes, Immunology, Medicine, Microbiology, Nephrology, Neurology | Leave a comment

The Endocrine System at a Glance (I)

3152(Smbc – click to view full size).

Compare with the book:

Adrenal steroid synthesis

(There are other diagrams in the book which look quite a bit more like the SMBC one than does the table above, but none of them deal with 17α-hydroxylase, progesterone, androstenedione and their friends and acquaintances…).

No, I didn’t get all of the stuff covered in this book, but this would probably also be a bit much to expect. There were however more than a few principles presented here which I’d sort of come across elsewhere which I now have a much better understanding of than I used to do. Many of the things covered (but far from all of them) were things I’d read about before, e.g. in McPhee et al. and Sperling et al. But there was also some new stuff in there.

The book has ~118 pages, plus some pages with reading comprehension questions in the back, but the page count is a very deceptive metric if you want to estimate the amount of work required to get through the book; I may be wrong, but I think most people will find it very hard to read even close to 10 pages per hour, certainly ‘in the long run’ (after the first couple of hours) and certainly if they want to understand the stuff and do not have a medical background. You probably need to be willing to look stuff up every now and then to follow what’s going on. I basically read the book two to four pages at a time, with lots of short breaks. Actually I’m not sure this is a good book to read at all if you do not have some medical knowledge – as they state in the introduction: “The book is aimed at undergraduate medical students […] it should also be a useful source of information for clinical medical students and junior doctors”.

The book belongs in the same series as the nutrition text by Barasi I read a while back (another book covering topics which were also looked at in the book, e.g. stuff like energy homeostasis), and it suffers from the same main problem I had with that publication; there’s not a single source provided in the publication. Actually that’s not entirely true as I think one of the graphs were described in the text and so you were told where the numbers came from in that case; but almost all numbers provided are provided without any indication of where they come from, and you have no way to figure out what kind of research they are based on. “Diabetics are three times more likely to have a stroke and 15 times more likely to undergo lower limb amputation than non-diabetic subjects”, they write in the text, yet the latter number is likely to be an underestimate as: “The relative risk of an individual with diabetes undergoing a lower extremity amputation was 20.3 in 2004 and 21.2 in 2008, compared with that of individuals without diabetes.” (link). Given that some of the other numbers included in the book clearly have not been updated since the previous editions – there’s a particularly hilarious forecast of obesity in the UK which provides a linear forecast (using OLS) of what’s likely to happen (?) to the obesity rate from the year 1998 and forward, based on the numbers observed during the previous two decades… (the third edition of the book which I read was published in 2011) – I find it highly unlikely that the mismatch between the relative risk numbers is the result of outcome improvements observed since 2008. The authors are incidentally British, which is why I refer to the specific ~20 RR estimate – I’m assuming they’re relying on UK/British numbers when providing their estimates, even though even that is actually unclear, so relying on such numbers seemed the most fair way to evaluate the accuracy of the estimate. The discrepancy in question is not one of a kind – for example elsewhere they write that: “Macrovascular complications are the major cause of death in people with Type 2 diabetes, accounting for 50% of deaths in this group” – which again seems to be a significant underestimate: “Subjects with both type 1 and type 2 diabetes are at increased risk of developing cardiovascular disease, with approximately three-quarters of patients with diabetes ultimately dying from vascular causes” and: Mortality from CVD accounts for more than 60% of deaths in patients with type 2 diabetes mellitus”. (Quotes from Betteridge and Nicholls’ Managing Cardiovascular Complications in Diabetesblog link here. 50% is way too low).

I assume most of the numbers included in the book are reasonably in line with the evidence, and there aren’t many numbers to begin with as the book deals almost exclusively with key principles etc., but I do find it annoying and slightly troubling that the numbers seem to be a little bit off in areas where I actually know something about those things they talk about, and regardless of whether they’re wrong or not you should provide a damn source anyway. I don’t think it would be that hard to add a few sources without making drastic changes to the format of the book, as one could just add a number in the text and a source in the back. I should make clear that to the extent the estimates provided in the publication are ‘wrong’ I believe them to be wrong on account of being based on old data; I don’t think any inaccuracies in the book are due to the authors ‘not knowing what they’re talking about’.

As might be inferred from the screenshot above the book is very technical, and so it’s a bit difficult to blog. There are many  chapters where most of the coverage consists of complicated diagrams as well as verbal coverage of the same stuff dealt with in those diagrams, and little else. I have tried in my coverage below to mostly cover stuff from the book which I thought might at least be reasonably easy to understand for people reading along here.

“Endocrinology is the study of endocrine hormones and of the organs involved in endocrine hormone release. Classically, hormones have been described as chemical messengers, released and having their actions at distant sites. It is now clear, however, that there is a close relationship between hormones and other factors such as neurotransmitters and growth factors acting in a paracrine or autocrine fashion. Hormones are essential for the maintenance of normal physiological function and hormonal disorders occur at all stages of human life. Clinical endocrinologists thus look after patients of all ages and with a very wide range of disorders”

“Hormones are chemical messengers. They may be classified several ways […]: 1 Autocrine: acting on the cells that synthesized them […] 2 Paracrine: acting on neighbouring cells. An example is insulin, secreted by pancreatic β cells and affecting secretion of glucagon by pancreatic α cells. 3 Endocrine: acting on cells or organs to which they are carried in the bloodstream or through another aqueous ducting system, such as lymph. Examples include insulin, estradiol and cortisol. 4 Neuroendocrine: this is really paracrine or endocrine, except that the hormones are synthesized in a nerve cell (neurone) which releases the hormone adjacent to the target cell (paracrine), or releases it into the bloodstream, which carries it to the target cell […] 5 Neural: this is neurotransmission, when a chemical is released by one neurone and acts on an adjacent neurone […]. These chemicals are termed neurotransmitters. […] 6 Pheromonal transmission is the release of volatile hormones, called pheromones, into the atmosphere, where they are transmitted to another individual and are recognized as an olfactory signal.”

“The movement of chemicals between cells and organs is usually tightly controlled. Diffusion is the movement of molecules in a fluid phase, in random thermal (Brownian) motion […] Facilitated transport is the transport of chemicals across membranes by carrier proteins. The process does not require energy and cannot, therefore, transport chemicals against a concentration gradient. […] Active transport uses energy in the form of adenosine triphosphate (ATP) or other metabolic fuels. Therefore chemicals can be transported across the membrane against a concentration gradient […] Ion channels mediate active transport, and consist of proteins containing charged amino acids that may form activation and inactivation ‘gates’. Ion channels may be activated by receptors, or by voltage changes through the cell membrane. Channels of the ion Ca2+ can be activated by these two methods. Osmosis is the passive movement of water through a semipermeable membrane, from a compartment of low solute concentration to one which has a greater concentration of the solute.”

“Hormones interact with target cells through a primary interaction with receptors which recognize the hormones selectively. There are several different receptor systems, which vary in mechanism and timing […] Receptor antagonism is an important aspect of endocrinology and drug use generally […] antagonists play a large part in the treatment of endocrine disease. The molecule which binds to the receptor and elicits the normal cellular response is termed the agonist. The ligand which binds, but elicits no response, is the antagonist. Antagonists act at the membrane in different ways. For example the β-receptor blocker propranolol competes with epinephrine at its binding site. The anticonvulsant phenytoin blocks ion channels.”

“Living systems possess their own internal environment, which has to survive within an external environment. […] Internal control is achieved through integration of the different systems: neural, biochemical and physical. In all cases, the fundamental components of these systems are: (i) signals; (ii) transducers; (iii) sensors; and (iv) responders. […] Integration of endocrine systems is achieved through a complex interplay of regulatory feedback mechanisms operated through both hormonal and neural communication networks. The most important mechanisms are those commonly called feedback, whereby systems limit each other’s activity around a preset oscillator. […] In endocrinology, the brain–pituitary–target gland axes provide examples of feedback mechanisms in action […]. For virtually every anterior pituitary hormone, a corresponding hypothalamic releasing hormone has been discovered, and in some cases a corresponding inhibitory hypothalamic hormone has been found […]. Feedback systems may involve more than two hormones […] Understanding basic feedback mechanisms is vital in clinical endocrinology where it forms the basis of diagnostic testing. […] Characteristically, endocrine disorders disrupt normal feedback mechanisms and this feature is exploited in the interpretation of a number of endocrine function tests. Furthermore, certain hormones rise in response to stressful stimuli and this too can be utilized for diagnostic purposes. […] Most hormones: • Are subject to diurnal or ultradian rhythms • Are secreted in a pulsatile fashion • Are controlled by feedback from target organs (usually negative) • Develop autonomous secretion in pathological states […] As a general rule: • If the clinical suspicion is of hormone excess then suppression tests are used • If the clinical suspicion is of hormone deficiency then stimulation tests are used”

“Many endocrine conditions have an autoimmune aetiology and patients frequently exhibit antibodies to multiple endocrine organs and have evidence of associated autoimmune disease […] Autoimmunity may be defined as an attack by the host’s immune system on the host’s own tissues. These attacks may be transient immune reactions to infection, for example, which resolve spontaneously. They may, however, become chronic, with pathological consequences. Endocrine autoimmunity often involves an immune attack on specific endocrine glands, for example Addison’s disease, Graves’ disease, Hashimoto’s thyroiditis and insulin-dependent diabetes mellitus, where the gland is damaged or destroyed altogether [‘type 1 diabetes mellitus’ is much better than ‘insulin-dependent diabetes mellitus’ [IDDM] in this context – I dislike the unfortunate naming convention applied, given that many type 2 diabetics, as mentioned before here on this blog, will require insulin-injections over time. I’ve previously seen an estimate which I reported here on the blog which indicated that half of type 2 diabetics will need insulin within 6 years of diagnosis, but the original source for that quote has been taken down and I didn’t write down who the authors were so I can’t find the original estimate. I don’t really trust wikipedia on these things, but the article on insulin includes the (likewise unsourced) observation that: “Over 40% of those with Type 2 diabetes require insulin as part of their diabetes management plan”. As something like ~85% of all diabetics are type 2 diabetics, type 2’s make up a substantial majority of all IDDM cases if that estimate can be trusted. Regardless of precisely how many type 2 diabetics are treated with insulin it’s a very substantial number of patients, and the relevant distinction here, when thinking about autoimmunity-mediated organ damage, is between type 1 and type 2, though that distinction is admittedly also not perfect. This post has more about specific subtypes of diabetes, as does this commentas the remarks included in the latter link in particular illustrates, this stuff is complicated and none of the applied diagnostic conventions really distinguish 100 percent between auto-immune and not-autoimmune, though the type 1/2 distinction comes much closer than does the IDDM/NIDDM distinction, which is one of the reasons why the latter distinction is these years rarely used in lieu of the type 1/2 categorization convention]. These are examples of mainly organ-specific autoimmune diseases […]. In systemic autoimmune disease, on the other hand, the immune system attacks several tissues that may be anatomically distant from each other. Examples of systemic autoimmune disease include rheumatoid arthritis, scleroderma and systemic lupus erythematosus (SLE). There may be both organ-specific and systemic components in most, if not all, autoimmune diseases.”

September 10, 2014 Posted by | Books, Diabetes, Immunology, Medicine | Leave a comment

Sexually Transmitted Viral Pathogens

The stuff below covers material from the last half of part V in Holmes et al. This previous post also dealt with this topic (the title of this post is the title of part 5 of the book, which if not hidden away in a 2000+ page textbook might well have been a book of its own; I’m quite sure you can find entire books on these topics which go into much less detail than does part 5 of this book). Some of the stuff was really hard to read; I’ve tried to include in this post mainly stuff people who have not read the rest of the coverage might be expected to understand without too much difficulty.

“Antibody to EBV [Epstein-Barr Virus] can be detected in 90-95% of the population by adulthood.10 Primary exposure often occurs in the first years of life, with seroconversion evident before the age of 5 years in 50% of children studied in the United States and Great Britain.22,23 In economically advantaged communities, primary infection may be delayed until adolescence or early adulthood,24 at which time acquisition of virus produces the clinical syndrome acute infectious mononucleosis. […] Primary EBV infection in infancy or early childhood is usually subclinical, but when delayed until the second decade of life, it manifests as infectious mononucleosis in up to 50% of patients. A self-limiting lymphoproliferative disease, the syndrome consists of fever, headache, pharyngitis, lymphadenopathy, and general malaise. Resolution of symptoms may take weeks to months, but primary infection is always followed by the establishment of a permanent viral carrier state.”

“a highly significant correlation between seropositivity for EBV, sexual intercourse, and an increasing number of sexual partners was found in a cross-sectional analysis of 1006 new University students.50 In this study, two-thirds of infectious mononucleosis cases were statistically attributable to sexual intercourse, whereas only a tenth of asymptomatic primary infections were linked to sexual activity.” [This is of course just a cross-sectional analysis, but even so – ‘kissing disease‘ may perhaps be a slightly inaccurate term…]

“The overall size of the EBV-infected B cell reservoir is largely controlled by CD8+, HLA class I-restricted, EBV-specific cytotoxic T lymphocytes (CTLs). Up to 5% of the total circulating CD8+ T cell pool may be committed to this single virus in the EBV-carrier state,110 indicating the critical role for T-cell surveillance in maintaining the host: virus balance. Impaired CTL responses in immunosuppressed patients such as transplant recipients or HIV-1-infected individuals32,111 leads to an expansion of the infected B cell population and potentially fatal lymphoproliferative disease. The contribution of virus-specific CTLs in immune regulation of EBV-induced lymphoproliferation has been made clear by recent therapeutic interventions involving adoptive transfer of virus-specific T lymphocytes to restore immunity against EBV infection in bone marrow transplant recipients.112, 113, 114

Non-Hodgkin’s lymphoma, an AIDS-defining cancer some 60 times more common in AIDS patients than in the general population,122 can be divided morphologically into Burkitt-like and immunoblastic lymphomas […]. Both have a higher association with EBV (30-40% and 75-80%, respectively) in AIDS than in non-AIDS groups.123,124 […] Burkitt’s lymphomas appear early in the course of AIDS, prior to profound immunosuppression, whereas immunoblastic lymphomas typically occur in late-stage AIDS when cellular immunity is compromised. […] Hodgkin’s lymphomas in the setting of AIDS contain EBV in 75-90% of the cases,140,141 reflecting the unusually high frequency in the HIV-infected population of mixed-cellularity and lymphocyte-depletion subtypes142 known to be most closely associated with EBV in the general population.15,16 Although not considered an AIDS-defining illness, Hodgkin’s lymphoma occurs with increased frequency in the setting of HIV infection. […] Our understanding of the precise role of EBV in the biology of each malignancy remains rudimentary.”

“Papillomaviruses are a group of small DNA viruses that primarily induce epithelial cell proliferation, or papillomas, in higher vertebrates. Infections are strictly genus or species specific and there is considerable tropism among the viruses for particular anatomic sites. […] The genomes of over 100 human papillomavirus (HPV) types have been molecularly cloned and completely sequenced and partial sequences for potentially up to another hundred types have been detected by PCR-based assays.9,10

[You can skip this part without missing out on anything important:] “A basal level of transcription from the p97/p105 promoter is regulated by the keratinocyte-dependent enhancer in the NCR and can be repressed by binding of E2 to its cognate recognition sequences located adjacent to the p97/p105 TATA boxes.82,87 E2 has a role in repressing transcription from the viral promoter and its loss on viral DNA integration allows increased expression of the oncogenic proteins E6 and E7. E2 also activates transcription under some circumstances.88 Variations in binding to four different E2 binding sites may contribute to transcriptional regulation.89 Interestingly, the E8E2C protein of HPV-31 had an ability to repress transcription from a single promoter-distal E2 binding site. This activity was lacking in the full-length E2, suggesting that E8E2C has a role in regulating transcription.90 E2 binds the general transcription factor TFIIB91 and is thought to directly inhibit HPV transcription at a step subsequent to binding of TBP or TFIID to the TATA box.92 It interacts with numerous other transcription factors and chromatin modification factors including CBP,93 p/CAF,94 C/EBP,95 nucleosome assembly protein 1,96 and Top BP1.97 An interaction between bromodomain protein 4 and E2 is required for transcriptional activation by E2.98 Two crystal structure studies of the amino terminal transcription activation domain of E2 suggested that dimerization of E2 helps recruit distal transcription factors to the viral transcription complex99 …” [I decided to include a quote like this as well to indicate what kind of stuff the book is also full of, and illustrate why it was hard to read. There’s a lot of stuff in some of these chapters which I had a really hard time following.]

“Predictions about the role of HPV in neoplasia obtained from experimental studies are consistent with the natural history of cervical cancer. Among women who develop squamous intraepithelial lesions, the time from first detection of viral DNA to lesions is short, ~2 years, though factors like number of partners and infection with other STDs may influence the interval […]. Even mildly dysplastic lesions show an increase in proliferation and polyploidization. These changes result as a direct consequence of expression of E6/E7. The median age of carcinoma in situ (CIS) in the United States is 29,223,224 indicating that approximately a decade has elapsed between the initial infection and severe dysplasia. CIS lesions are characterized by their aneuploid DNA content and thus reflect the genetic instability that accompanies prolonged expression of E6/E7. The preneoplastic lesions can regress spontaneously. One principle explanation for their regression is likely to be an effective immune response, and generalized T-cell deficiency has been associated with increased dysplasia […]. Other explanations may include the fact that some, perhaps most, alterations will be deleterious, resulting in cell death. The median age of invasive cervical cancer in the United States is 49, indicating that additional changes required for invasion and metastasis are acquired slowly over time.”

“All HPV types are linked to the development of low-grade cervical SILs [squamous intraepithelial lesions],16 whereas high-grade cervical SILs are usually positive for oncogenic HPV types.272 In a cohort of young women in the United States, Moscicki et al.155 reported that 15% developed LSIL within 3 years after initial HPV infection, and in the UK, Woodman et al.70 reported that the 3-year cumulative incidence of any cytologic abnormality after initial infection was 33%. In another cohort of young women in the United States, Winer et al.132 reported that approximately 50% developed a low-grade lesion within 3 years after initial HPV infection […]. The latter study also reported that rates of lesion detection tend to increase with increased screening frequency, due to spontaneous regression of most low-grade lesions. Therefore, the shorter interval between follow-up visits (4 vs. 6 months) may explain why that study detected LSIL in a higher proportion of women. Half of newly detected low-grade lesions appear to regress within 6-9 months.70,132,273 It also appears that vaginal SIL is not uncommon among women with incident HPV infections. While less commonly detected than cervical SIL, one study reported that almost 30% of women with incident HPV infections developed vaginal SIL within 3 years (Fig. 28-3B), and the median duration of these lesions was less than 5 months.132

Results from natural history studies suggest that LSILs are transient manifestations of productive HPV infections, whereas HSILs are cervical cancer precursor lesions. This is in contrast to the previously held theory that cervical carcinogenesis always follows a progression from persistent HPV infection to development of low- and then high-grade lesions. Several recent studies have shown that cervical highgrade lesions are a relatively early manifestation of HPV infections in young women. Woodman et al.70 reported that the risk of high-grade lesions was highest in the first 6 months after initial HPV infection. It has also been shown that histologically confirmed high-grade lesions are common after infection with HPV 16 and 18 infections,132,274 with one study reporting that 27% of women with incident HPV 16 or 18 infections developed histologically confirmed CIN grade 2 or 3 within 3 years […] and that the median time to development was 14 months.132

“Although viral hepatitis is unquestionably an ancient disease, it is only in the past 40 years that an appreciation has emerged of the diversity of infectious agents capable of causing the clinical syndrome of acute hepatitis. […] at least five distinctly different human viruses (classified as hepatitis A through E) are now generally recognized to be causative agents of acute and/or chronic viral hepatitis […].

Hepatitis A virus (HAV), hepatitis B virus (HBV), hepatitis C virus (HCV), hepatitis delta virus (HDV), and hepatitis E virus (HEV) all share a remarkable tropism for the liver despite profound differences in their physical structure, pathobiology, and epidemiology. Each of these viruses is a cause of clinically overt acute hepatitis associated with frank jaundice. The severity of the liver disease, which frequently accompanies acute infection with these viruses, generally distinguishes them from cytomegalovirus and Epstein-Barr virus, which typically cause much milder liver dysfunction during primary infections. Within the United States, almost all cases of acute hepatitis are caused by infection with HAV (51%), HBV (40%), or HCV (9%).3 These acute hepatitis virus infections cannot be distinguished from each other without serologic testing. Acute hepatitis represents a considerable disease burden within the United States, with an estimated 40,000-60,000 clinical cases occurring annually during the past 5 years. Only a fraction of these cases are reported to public health authorities, and a substantial number of additional infections do not come to medical attention because they are asymptomatic. Fulminant hepatic failure and death occur in a very small proportion of patients with acute hepatitis A or B, but these clinical endpoints are rarely associated with acute HCV infection in the United States.4,5

“The major burden of disease due to hepatitis virus infections stems from the chronic liver damage that occurs in individuals who develop persistent infections. The proportion of persons who become persistently infected is highly dependent on the infecting virus. Persistent infections with HAV are not well documented and may never occur. On the other hand, more than 50% of persons infected with HCV fail to clear the virus and most eventually develop biochemical and histologic evidence of chronic liver disease.6 HBV has an intermediate tendency to establish persistence, with the risk of persistent infection being highly dependent on the age at the time of infection and immunologic competence of the individual.

It is appropriate to focus attention on the hepatitis viruses in a textbook concerned with sexually transmitted diseases (STDs). Although these are systemic infections that are also commonly transmitted by other means, HBV is a sexually transmitted infection, and sexual activity may profoundly influence the risks for acquisition of HAV. To a lesser extent, sexual behavior may also influence the risk of infection with HCV and HDV.”

“Several factors account for the high risk of HBV infection among MSM [Males who have Sex with Males], which was noted in […] early studies. One of the most important factors was the number of sexual partners. The typical homosexually active male frequenting Denver’s steam baths in the late 1970s had eight different male sexual contacts per month.206 These contacts were largely anonymous and could total as many as 1000 over the lifetime of a gay man.”

“The endemicity of HBV infection varies greatly worldwide and is influenced primarily by the predominant age at which infection occurs.121,190 Endemicity of infection is considered high in those parts of the world where at least 8% of the population is HBsAg positive, and 70-90% of the population has serological evidence of previous HBV infection. Almost all infections occur during either the perinatal period or early in childhood, which accounts for the high rates of chronic HBV infection in these populations. Risk of HBV infection continues after the first 5 years of life, but its eventual contribution to the high rate of chronic infection is less significant. Chronic infection with HBV is strongly associated with HCC [liver cancer], and areas with a high endemicity of chronic HBV infection have the highest death rates from this neoplasm. […]

In most developed parts of the world, including the United States and Western Europe, the prevalence of chronic HBV infection is <1%, and the overall infection rate is 5-7%. The highest incidence of acute hepatitis B is among young adults, and high-risk sexual activity and injectable drug use account for most cases of newly acquired hepatitis B.191, 192, 193, 194 In the United States, heterosexual activity accounts for 40% of new hepatitis B cases, while MSM represent 15% of new cases.”

“HCV infection accounts for 15% of acute viral hepatitis cases within the United States. However, it is by far the leading cause of chronic viral hepatitis and is present in over 40% of persons with chronic liver disease. The morbidity and mortality associated with HCV infection are due to its unique propensity to cause persistent infection in most persons, a feature that distinguishes this virus from other hepatitis viruses. The specific mechanisms underlying viral persistence are not known.

Although it has been controversial, the balance of evidence now favors the occasional sexual transmission of HCV. The risk of infection with HCV, like HBV, has been independently related to numbers of sexual partners in some STD clinic studies.226,285 Although the risk of HCV infection has been shown to correlate with numbers of partners and/or specific sexual practices in some studies of homosexual men,286,287 the risk of infection is overwhelmingly more closely tied to injection drug use. […] About 60-85% of all infections lead to virus persistence, and this is often associated with evidence of chronic liver disease […]. After many years, this process may culminate in cirrhosis and liver failure, or the development of hepatocellular carcinoma. These end-stage events in chronic hepatitis C may claim as many as 10,000 lives annually in the United States.326 […] As many as a third of patients found to have chronic hepatitis C will ultimately develop cirrhosis6,284,333,334; although it is not well defined, the fraction of all patients who are infected with the virus and progress to cirrhosis is undoubtedly far lower. Cirrhosis may be present within as little as 60 months of the initial infection but is identified typically in persons who have been infected for decades. Factors associated with disease progression include age at infection, regular alcohol consumption, coinfection with HIV or HBV, and more recently obesity and insulin resistance.335, 336 Some patients, usually with well-established cirrhosis, develop primary hepatocellular carcinoma.283 Chronic HCV infection is the most important etiology of hepatocellular carcinoma in western countries.

The major challenge to clinical investigators has been the discovery of specific markers that are predictive of progression of chronic hepatitis C to a clinically significant disease state. This remains an exceptionally difficult problem. There is no good correlation between biochemical markers and the extent of fibrosis or the presence or absence of cirrhosis. Indeed, many patients with cirrhosis have no obvious laboratory abnormalities.333 In addition, quantitative measurements of the viremia (“virus load”) are not useful in determining the extent of disease resistance.335, 336

July 20, 2014 Posted by | Books, Cancer/oncology, Epidemiology, Immunology, Infectious disease, Medicine | Leave a comment

Infectious Agents and Cancer

“[H]uman papilloma virus, hepatitis B virus, hepatitis C virus, Epstein-Barr virus, human herpes virus 8, human T-cell lymphotropic virus 1, human immunodeficiency virus, Merkel cell polyomavirus, Helicobacter pylori, Opisthorchis viverrini, Clonorchis sinensis, Schistosoma haematobium […] are recognized as carcinogens and probable carcinogens by [the] International Agency for Research on Cancer (IARC). They are not considered in this book […] The aim of this monograph is to analyze associations of other infectious agents with cancer risk […] virology is not considered in our monograph: although there are some viruses that can be connected with cancer but are not included into the IARC list (John Cunningham virus, herpes simplex virus-1 and -2, human cytomegalovirus, simian virus 40, xenotropic murine leukemia virus-related virus), we decided to leave them for the virologists and to concentrate our efforts on other infectious agents (bacteria, protozoa, helminths and fungi) […] To the best of our knowledge, this is the first book devoted to this problem”

Here’s what I wrote on goodreads:

“This book is written by three Russian researchers, and you can tell; the language is occasionally hilariously bad, but it’s not too difficult to figure out what they’re trying to say. The content partially made up for the poor language, as the book covers quite a bit of ground considering the low page count.”

I gave the book two stars. I’m glad they wrote the book, because it covered some stuff I didn’t know much about. I think I’m closer to one star than three, but it’s mostly because it’s terribly written, not because I have major objections to the coverage as such. What I mean by this is that they talk about a lot of studies and they include a lot of data – they’re scientists who write about scientific research, they just happen to be Russian scientists who are not very good at English. It’s terribly written, but the stuff is interesting.

As mentioned above there are quite a few viruses which we know may lead to cancer in humans. I’ve recently read a lot of stuff about this topic as it was covered in both Boffetta at el. and also rather extensively in part 5 of the Sexually Transmitted Diseases text, which covered sexually transmitted viral pathogens (that section of the book was with its 230 pages actually a ‘book-length section’; it was significantly longer than this book is..). I’ve even covered some of that stuff here on the blog, e.g. here. I may incidentally write more about these things and related stuff later, as I’m quite far behind in terms of my intended coverage of the STD book at the moment.

Anyway, viruses aren’t the only bad guys around. So these guys decided to write a book about some other infectious diseases affecting humans, and how these infectious diseases may relate to cancer risk. As they point out in the book, “there is only one bacterium, Helicobacter pylori, which is recognized by IARC as an established human carcinogen.” After reading this book you’ll realize that there are some others which perhaps look a bit suspicious as well. In some cases a lot of studies have been done and you have both animal-models, lab-analyses, case-control studies, cohort studies, … In other cases you have just a few small studies to judge from. As is always the case when people have a close look at epidemiological research, this stuff is messy. Sometimes studies that looked really convincing turn out to not replicate in larger samples, sometimes dramatically different effect sizes are found in different areas of the world (which may of course both be interpreted as an indicator that the ‘true’ effect sizes are different in the different subpopulations, or it may be interpreted as a result e.g. of faulty study design which makes those Swedish data look really fishy..), sometimes different results can be explained by differences in data quality/type of data applied/etc. (classic cases are different effects based on whether you rely on self reports or biological disease markers, and different results from analyses of bacterial cultures vs PCR analyses), and so on and so forth. There are a lot of details, and they cover them in the book. I occasionally see people criticize epidemiological research online on the grounds that many (‘all?’) results published in this area are just random correlations without any deeper meaning. Sometimes this criticism may well be warranted, and the authors of this book certainly in some cases seem to go quite a bit further than I would do based on the same data. But there’s another part of the story here. When you start out with a couple of case-control studies indicating that guys with cancer type X are more likely to have positive lab cultures for this specific micro-organism, that may not be a big deal. But perhaps then a few microbiologists show up and tell you that it would actually make a lot of sense if there was a connection here (and they might start talking about fancy stuff like various ‘modulations of host immune responses’, ‘inflammatory markers’, ‘the role of nitric oxides’, …). They conduct some studies as well and perhaps one of the things they find is that the observed cancer grades in the patients seem to depend quite a lot upon which of the pathogen subtypes the individual happen to be infected with (perhaps suddenly also providing an explanation for some previously surprising negative results in specific cases). And then perhaps you get a couple of animal studies that show that these animals get cancer when you infect them with these bugs and don’t treat the infection. Perhaps you have a few more studies as well in different populations, because Chinese people get cancer too, and you start seeing that people around the world who happen to be infected with these bugs are all more likely to get cancer, compared to the locals who are not infected (…or perhaps not, and then it just gets more fun…). This process goes on for a while, until at some point it starts getting really hard to think these positive correlations are all just the result of random p-value hunting done by bored researchers who don’t know what else to do with their time, and you start asking yourself if perhaps this idea is not as stupid as it was when you first encountered it. Most of the time the process stops before then because the proposed link isn’t there, but modern epidemiology is not just random collections of correlations.

In the context of the specific infectious diseases covered in the book the people who have in some sense the final say in these things (the IARC) think we’re not quite there yet, but you have some cases where some different lines of evidence all seem to indicate that a link may be present and relevant. It would be highly surprising to me if in 20 years time we’d have realized that none of the infectious diseases they talk about in this book are at all involved in cancer pathogenesis. A related point is that most likely we’ve missed some ‘true connections’ along the way, and will continue to do so in the future, because even if a link is there, it’s sometimes really hard to find it and easy to overlook it, for many different reasons.

I have quoted a bit from the book below and added some comments here and there. I have corrected some of the spelling/language errors the authors made to ease reading; if a word is placed in brackets, it’s an indicator that I’ve replaced a misspelled word by the correct one (‘they meant to use’). The authors do not even have any clue how and when to use the word ‘the’, often using it when it’s not needed and forgetting to use it in cases where it is needed, which made quoting from the book painful. Read it for the content.

“Chronic inflammation substantially increases the probability of neoplastic transformation of the surrounding cells, inducing mutations and epigenetic alterations by the activity of inflammatory molecules […] through the formation of free radicals and DNA damage […] Since infectious agents persisting in the organism may cause chronic inflammation, they can also promote local carcinogenesis. […] Chronic inflammation can also specifically affect the functioning of [an] organ, for instance, promoting cholelithiasis and urolithiasis that increase the time of exposure of the gallbladder, bile ducts, urinary bladder and ureters to chemical carcinogens and carcinogenic bacteria. […] In addition to […] metabolic and immune mechanisms, a number of bacteria […] and protozoa […] [produce] or [contain] in their cell wall their own toxins […] possessing [carcinogenic] activity, affecting cell-cell interactions, intracellular signal transduction or induction of mutations and epigenetic alterations that can influence vital cell processes (apoptosis, proliferation, survival, growth, differentiation, invasion). Intracellular protozoan (Toxoplasma gondii) may induce resistance to multiple mechanisms of apoptosis […]. So, bacterial and [protozoan toxins] may function like initiating or like promoting agents.”

“Typhoid fever, which is a systemic infection caused by Salmonella enterica serovar Typhi (S. typhi), is a major health problem in developing countries. There are approximately 21.6 million cases of typhoid fever worldwide and an estimated 200,000 deaths every year. It is known that S. typhi may colonize the gallbladder, causing […] chronic inflammation. Welton et al. (1979) were the very first to [establish] an association between the typhoid-carrier state and death due to malignancies of the hepatobiliary tract. They recruited 471 U.S. carriers of [S. typhi] , matched them with 942 controls and demonstrated that chronic typhoid carriers died of hepatobiliary cancer six times more often than the controls. […] The absence of basic research analyzing the carcinogenic properties of S. typhi does not allow placing it in the short list of the infectious agents that may be a cause of cancer development but are not included in the IARC roster, but this bacterium undoubtedly should be [on] the extended list. If [basic] studies on cell lines and animal models [support] the results of [the] epidemiological investigations, S. typhi can be placed [on] the short list.” [I included this in part because it is one of several examples in the book of how even strong correlations and high relative risks are not considered sufficient on their own by epidemiologists to settle matters. Some relative risks in other studies have been even higher – a study on gall-bladder cancer found an RR of 12.7].

“Tuberculosis (TB), a destructive disease [affecting] the lungs […] is a major global health burden, with about nine million of new cases and 1.1 million deaths annually. When the host protective immunity fails to control M. tuberculosis growth, progression to active disease occurs. […] According to the data of the last comprehensive systematic review and [meta-analysis] published by Brenner et al. (2011), there were 30 studies […] conducted in North America, Europe and Asia, which investigated the association of tuberculosis on lung cancer risk with adjustment for smoking. The relative risk (RR) of lung cancer development among patients with TB history was 1.76 (95% CI = 1.49–2.08).”

“22 studies from North America, Europe and East Asia [have] investigated the association between pneumonia and lung cancer risk while adjusting for smoking […] A significant increase in lung cancer risk was observed among all studies (RR = 1.43, 95% CI = 1.22–1.68). […] To sum up, there are basic as well as extensive epidemiological evidence that С. pneumoniae may cause lung cancer” [However effect sizes seem to be different in different countries. I was skeptical about this one in part because a non-smoker’s absolute risk of getting lung cancer is very low, meaning that relative risks in the neighbourhood reported above although statistically significant probably are clinically insignificant. How pneumonia and smoking interact seems to me a much more important question. Then again we haven’t got an explanation for all of the non-smoking-related lung cancers yet, and they are caused by something, so it’s also not like researching this is a complete waste of time.]

“Primary infection with C. trachomatis [Chlamydia], the most prevalent sexually transmitted bacterium worldwide with an estimated 90 million new cases occurring each year, is often asymptomatic and may persist for several months or years. The first study analyzing possible association of C. trachomatis with cervical cancer was carried out by Schachter et al. (1975) who assessed the prevalence of antibodies to TRIC (trachoma-inclusion conjunctivitis) agents in women with cervical dysplasia and in women attending selected clinics […]. According to this investigation, antibodies to chlamydiae were identified in 77.6% of the women with dysplasia or cervical cancer whereas antichlamydial antibodies were less prevalent in the other clinic populations. Four years later, Paavonen et al. (1979) obtained [similar] results in 93 of patients with cervical dysplasia comparing them to the controls. […] Smith et al. (2001, 2002) examined 499 women with incident invasive cervical cancer cases and 539 control patients from Brazil and the Philippines, detecting that C. trachomatis increased risk of squamous cervical cancer among HPV-positive women (OR=2.1; 95% CI=1.1–4.0). The results were similar in both countries.” [As I recently pointed out elsewhere, “Chronic infection with HPV is a necessary cause of cervical cancer. Using sensitive molecular techniques, virtually all tumours are positive for the virus.” But as this finding (and other related findings) indicate, other infectious processes may play a role as well in HPV-related cancers. Synergistic effects are common in this area (recall for example also the herpes simplex virus-HIV link).]

Trichomonas vaginalis (T. vaginalis), a protozoan parasite, is the causative agent of trichomoniasis, the most common nonviral sexually transmitted disease in humans. This parasite has a worldwide distribution and it infects 250–350 million people worldwide. [wiki says ~150 mil, but these guesstimates should always be taken with a grain of salt. Either way it affects a lot of people] […] Zhang et al. (1995) observed a relationship between T. vaginalis infection and cervical cancer in [their] prospective study in a cohort of 16,797 Chinese women. T. vaginalis-infection correlated with higher cervical cancer risk (RR=3.3, 95% CI=1.5–7.4). In a large cohort study conducted in Finland by Viikki et al. (2000) T. vaginalis was associated with a high RR of cervical cancer, 6.4 (95% CI = 3.7–10) and SIR [standardized incidence ratio]=5.5 (95% CI=4.2–7.2s), respectively. […] Mekki and Ivić (1979), detected that T. vaginalis were of a significantly smaller diameter in invasive carcinoma and carcinoma in situ in comparison with dysplasia. In the control group with trichomoniasis alone, the diameter of T. vaginalis was twice as large as that in carcinoma and larger compared to dysplasia, indicating that small forms of T. vaginalis are more carcinogenic than large ones. […] To sum up, there are basic as well as epidemiological evidence that T. vaginalis may be a cause of cervical and prostate cancer […] For cervical cancer it is evident, for prostate cancer it is arguable. According to our criteria, it is possible to include it in the short list of the infectious agents that may be a cause of cancer development but are not placed in the IARC roster.”

“At the moment of publication, IARC [recognizes] Schistosoma haematobium [and] [S. mansoni], Opisthorchis viverrini, and Clonorchis sinensis as causative agents of cancer, leaving a possibility to enlarge this list by [Schistosoma japonicum] [and] Opisthorchis felineus.” [The authors think the list should be enlarged even more, but I did not find their helmith data/coverage very convincing (not much research has been done in this area), so I decided not to cover these things here].

July 12, 2014 Posted by | Books, Cancer/oncology, Epidemiology, Immunology, Infectious disease, Medicine, Microbiology | Leave a comment

Sexually Transmitted Diseases (4th edition) (IV)

Here’s a link to a previous post about the book, which includes links to the first two posts I wrote about it.

I was not super impressed with the coverage in part 3, although there was a lot of interesting stuff as well. However the level of coverage and amount of detail included is high in part four and five. There were a lot of details which evaded me in some of the recent chapters, but I also learned a great deal. There’s quite a lot of coverage of various ‘related topics’ (microbiology, biochemistry, immunology, oncology) in the parts of the book I’ve read recently, and like many other medical texts this book will help you realize that many things you in your mind had thought of as unrelated actually are connected in various interesting ways. It’s worth noting that given how many aspects of these things the book covers (again, 2000+ pages…) you actually get to know a lot of stuff about a lot of other things besides just ‘classic STDs’. It turns out that in Jamaica and Trinidad, over 70% of all lymphoid malignancies are attributable to exposure to a specific herpes virus most people probably haven’t heard about, HTLV-1 (prevalence is also high in other parts of the world, e.g. southern Japan). I didn’t expect to learn this from a book about sexually transmitted diseases, but there we are.

I hope that I’ve picked out stuff from this part of the coverage which is also intelligible to people who didn’t read the 95+% of those chapters I didn’t quote (I always like feedback on such aspects).

“At the simplest level, infection of a cell by a virus or bacterium may lead to cell death. In the case of viruses, specific disease syndromes may be caused by destruction of certain subsets of cells that express essential differentiated functions. A classic example of this is the development of the AIDS following HIV-1 mediated depletion of the CD4 lymphocyte population. Virus-induced cell death may result from one or more specific mechanisms. Many viruses express specific proteins that have as their major function the induction of a blockade in normal host cell metabolism (cellular translation and transcription) such that the metabolic machinery of the cell is subverted preferentially to viral replication. For obvious reasons, the expression of such proteins is usually highly toxic to the cell. Cellular destruction or “direct cytopathic effect” is considered responsible for the disease manifestations of many lytic viruses, including, for example, HSV and poliovirus. On the other hand, many cells may respond to the presence of an invading virus by the induction of apoptosis and the initiation of programmed cell death. Some viruses appear to have evolved mechanisms to prevent or delay apoptosis, thus potentially prolonging productive infection and maximizing replication. For example, HSV-1 infection induces apoptosis at multiple metabolic checkpoints but has also evolved mechanisms to block apoptosis at each point.28 Importantly, the inhibition of apoptosis by HSV-1 also prevents apoptosis induced by virus-specific cytotoxic T lymphocytes, thereby conferring on the infected cell a certain measure of resistance to the host’s cell-mediated immune responses.29

However, many viruses are not intrinsically cytopathic. HBV is a prime example, as many infected HBsAg carriers are asymptomatic and without overt evidence of active liver disease. Despite this, such carriers may be very infectious […] The presence or absence of liver disease is largely determined by the T-cell response to the virus.30 Thus, chronic hepatitis B results from a relatively vigorous but unsuccessful attempt on the part of the host to eliminate the infection. […] chronic liver inflammation and the occurrence of hepatocellular carcinoma reflect the immune response to the virus, rather than specific virus effects. Similar indirect mechanisms may contribute to the progressive immune destruction of infected CD4-positive lymphocytes in patients with HIV-1 infection.

Some bacterial disease processes may also be caused largely to immunopathologic responses. For instance, there is substantial evidence that complications of genital chlamydia infections (salpingitis, Reiter’s syndrome) are correlated with and may be owing to stimulation of antibodies against a heatshock protein (hsp60).33,34 […] In contrast, gonococcal tissue damage appears to be caused by the direct toxic effects of lipid A and peptidoglycan fragments”

“Some viruses are capable of altering differentiated cellular functions, resulting in the production of disease by mechanisms that do not exist among bacteria. A prime example is the altered cellular growth that follows infections by molluscum contagiosum virus (MCV) […]. A more extreme example is the proliferation of epithelial cells that is induced by infection with HPVs. HPV-related epithelial malignancies and cellular transformation are related to the expression of two specific HPV proteins, the E6 and E7 oncoproteins, by high-risk HPV subtypes.22 These proteins interact with p53 and pRb, both promoting cellular proliferation and cell survival. Oncogenic transformation is usually associated with high-level expression of E7 from integrated HPV DNA. The Kaposi’s sarcoma-associated herpes virus (KSHV) also expresses a number of proteins that mimic important host regulators of cellular proliferation and survival […] Expression of these proteins may result in deregulation of cell growth, with changes in the cellular morphology and/or acquisition of the ability of the cells to form colonies in soft agar, changes that are indicative of transformation.

On the other hand, hepatocellular cancers occurring in the context of chronic viral hepatitis are likely to have an alternative explanation. Although it is possible that integration of HBV DNA may be responsible for altered cellular growth control in some hepatitis B-associated cases, liver cancer in this setting may be primarily immunopathogenic.30,32 Chronic inflammation accompanied by oxidative stress and cellular DNA damage are likely to pla[y] important roles.”

“The human immunodeficiency viruses (HIV-1 and HIV-2) and the simian immunodeficiency viruses (SIV) (with a subscript indicating the species of origin) are members of the lentivirus genus of the Retroviridae family, commonly called retroviruses. […] Retroviruses are divided into two subfamilies: Orthoretrovirinae and Spumaretrovirinae […] The spumaretroviruses have distinctive features of their replication cycle that require this more distant classification. They have been isolated from primates, but not humans, and are not associated with any known disease. The orthoretroviruses are divided into six genera and represent viruses that infect snakes, fish, birds, and mammals. […] Human infections occur with viruses from two of these genera. The Deltaretrovirus genus includes human T-cell leukemia virus type I (HTLV-I), the causative agent of adult T-cell leukemia,5, 6, 7 and human T-cell leukemia virus type II (HTLV-II), which is not known to be associated with any disease syndrome. HTLV-I is also associated with another syndrome called HTLV-associated myelopathy (HAM). HTLV-I and HTLV-II are related to viruses found in primates and more distantly related to bovine leukemia virus. The lentivirus genus includes HIV-18 and HIV-29 as well as viruses found in a variety of mammals ranging from primates to sheep. Viruses within these different genera vary widely in the diseases they cause and the mechanisms of disease induction, in contrast to the many common features of their replication cycle. […] In its DNA form the viral genome is inserted into the host genome […]. This step in the virus life cycle has important implications for several features of virus-host interactions. For example, viral DNA that integrates into the genome of a cell but is not expressed becomes silently carried in the descendents of that cell. When this happens in a germline cell, or in the cell of an early embryo that becomes a germline cell, this copy of viral DNA becomes a linked physical part of the host genome, is present in every cell in the body, and is passed on to subsequent generations. Such a genetic element is called an endogenous retrovirus. Most of the elements that become fixed are defective, as there is probably a strong selective pressure against elements that can activate to produce infectious virus. Thus, they represent an archive within the host genome of previous waves of retroviral infections. In fact, the human genome carries a record of retroviral infections over the last 40 million years of primate evolution. These are viruses that we do not recognize as active in the human population at present but are represented by 110,000 genomic inserts of gammaretroviruses, 10,000 inserts of betaretroviruses, and 80,000 inserts of a genus that may be distantly related to spumaretroviruses or may represent an uncharacterized lineage.10 Most of these elements contain large deletions; however, if these deletions had been retained, our genomes would be 40% endogenous retroviruses by mass and outnumber our normal genes 7 to 1.”

“Most histories of retroviruses start with the dramatic discovery by Peyton Rous in 1911 that a virus, Rous sarcoma virus (RSV), could cause cancer. […] The isolation of other tumor-causing retroviruses followed and in time it became apparent that there were two broad classes of agents: one class of viruses caused cancer after a long latency period […], while the other class caused tumors that appeared rapidly […]. We now know that the acutely transforming retroviruses carry a cell-derived oncogene that is responsible for the transforming activity,14 while the slowly transforming retroviruses act by the chance integration of viral DNA near these cellular oncogenes in the host genome to induce their expression and promote tumor formation.15,16 Importantly, many of these same genes can be mutated or overexpressed in human cancers, and the proteins they encode are now the targets of new generations of specific antitumor therapies […] One can confidently surmise that the remnants of the beta- and gammaretroviruses littered in our genomes had such oncogenic effects when they were active. Ironically, for the active human retroviruses, HTLV-I causes tumors by a different but still poorly understood mechanism, and HIV is involved in tumor formation only indirectly through immune suppression. […] There are two fundamental differences between lentiviruses and most other retroviruses: Lentiviruses do not cause cancer [directly…] and they establish chronic infections that result in a long incubation period followed by a chronic symptomatic disease. The “slow” (lenti is Latin for slow), chronic nature of these viral infections was first appreciated for a disease of sheep called maedi-visna (maedi = labored breathing, visna = paralysis and wasting).”

“Using the current sequence diversity in the HIV-1 population, the 1959 sequence, and estimates of the rate of sequence change per year, it has been possible to suggest that the cross-species transmission event that gave rise to the M group of HIV-1 occurred early in the twentieth century.38 If we accept that SIVcpz [HIV in chimps…] has entered the human population three times in the last century (the three groups N,O, and M), then it follows that this virus likely has been transmitted to humans any number of times over the last 10,000 years. Only in the last century the human institutions of large cities and efficient transportation corridors have given these transmission events access to a human environment that could support an epidemic.”

“Over 100 herpesviruses have been identified, with at least eight infecting humans [I had no idea there were that many of them, and I had no clue some of the ones mentioned were actually herpes viruses…]. All human herpesviruses are well adapted to their natural host, being endemic in all human populations studied and carried by a significant fraction of persons in each population. The human herpesviruses include herpes simplex viruses types 1 and 2 (HSV-1 and HSV-2), varicella-zoster virus (VZV), Epstein-Barr virus (EBV), cytomegalovirus (CMV), human herpesvirus 6 (HHV-6), human herpesvirus 7 (HHV-7), and human herpesvirus 8 (HHV-8) or Kaposi’s sarcoma (KS)-associated herpesvirus. Disease caused by human herpesviruses tends to be relatively mild and self-limited in immunocompetent persons, although severe and quite unusual disease can be seen with immunosuppression. […] all herpesviruses share biologic traits. These include expression of a large number of viral enzymes, assembly of the nucleocapsid in the cell nucleus, cytopathic effects on the cell during productive infection, and ability to establish latent infections in an infected host.”

“Vaccine development poses great challenges in the case of herpesviruses because recovery from natural disease is not associated with elimination of virus and does not always protect against another episode of disease.
Live-attenuated, killed, and recombinant subunit herpesvirus vaccines have all been studied. Whole-virus vaccines have the advantage of exposing the immune system to all viral antigens. Live-attenuated vaccines have tended to produce longer-lasting immunity than killed preparations. However, live-attenuated herpesvirus vaccines may be capable of establishing latent infections. The risks are not clear and there is concern that vaccine recipients who subsequently become immunosuppressed may develop disease caused by reactivated virus. Two avirulent HSV strains have been shown to generate lethal recombinants in mice.127 Thus, recombination between an attenuated vaccine strain and a superinfecting wild-type strain could occur. Because several herpesviruses have been associated with malignancies in humans, the long-term safety of any live-attenuated vaccine needs careful study.”

“In the most recent data from NHANES, the prevalence of HSV-1 appears to have fallen slightly from 62% in the years 1988-1994 to 57.7% in the years 1999-2004 in the general population.30 In Western Europe, the prevalence of HSV-1 infection in young adults remains 10-20% higher than that in the United States.31 In STD clinics in the United States, about 60% of attendees have HSV-1 antibodies. In Asia and Africa, HSV-1 infection remains almost universal […] The cumulative lifetime incidence of HSV-2 reaches 25% in white women, 20% in white men, 80% in African American women and 60% in African American men […] Transmission of HSV between sexual partners has been addressed most often in prospective studies of serologically discordant couples, i.e., in couples in whom one partner has and the other does not have HSV-2. Longitudinal studies of such couples have shown that the transmission rate varies from 3% to 12% per year. […] Unlike other STDs, persons usually acquire genital HSV-1 and genital HSV-2 in the context of a steady rather than casual relationship.91 Women have higher rates of acquisition than men; in one study the attack rate among seronegative women approached 30% per year.88 […] Subclinical or asymptomatic viral shedding is an important aspect of the clinical and epidemiologic understanding of genital herpes, as most episodes of sexual and vertical transmission appear to occur during such shedding. […] the risk of HSV transmission is likely similar regardless of the presence of lesions, supporting the epidemiologic observation that most HSV is acquired from asymptomatic partners. […] Subclinical HSV reactivation is highest in the first year after acquisition of infection. During this time period, HSV can be detected from genital sites by PCR on a mean of 25-30% of days […]. This is about 1.5 times higher than patients sampled later in their disease course.”

“The major morbidity of recurrent genital herpes is its frequent reactivation rate. Most likely, all HSV-2 seropositive persons reactivate HSV-2 in the genital region. Moreover, because of the extensive area enervated by the sacral nerve root ganglia, reactivation of HSV-2 is widespread over a large anatomic area.

A prospective study of 457 patients with documented first-episode genital herpes infection has shown that 90% of patients with genital HSV-2 developed recurrences in the first 12 months of infection.93 The median recurrence rate was 0.33 recurrences/month. Most patients experienced multiple clinical reactivations. After primary HSV-2 infection, 38% of patients had at least 6 recurrences and 20% had more than 10 recurrences in the first year of infection. Men had slightly more frequent recurrences than women, median 5 per year compared with 4 recurrences per year [it’s important to note that the recurrence rate is substantial even in patients on suppressive therapy: “About 25% of persons on suppressive therapy will develop a breakthrough recurrence each 3-month period”] […] Recently, long-term cohort studies indicate that the frequency of symptomatic recurrences gradually decreases over time. In the initial years of infection, reported recurrence rate decreases by a median of 1 recurrence per year. […] subclinical shedding episodes account for one-third to one-half of the total episodes of HSV reactivation as measured by viral isolation and for 50-75% of reactivations as measured by PCR. […] Rather than regarding HSV-2 as a predominantly silent infection with occasional clinical outbreaks with marked viral shedding, HSV is a dynamic infection, with very frequent reactivation, mostly subclinical, and active effort on the part of the immune system of the host is required to control mucosal viral replication. […] Immunocompromised patients have frequent and prolonged mucocutaneous HSV infections.226, 227, 228 Over 70% of renal and bone marrow transplant recipients who have serologic evidence of HSV infection reactivate HSV infection clinically within the first month after transplantation […] Recurrent genital herpes in immunosuppressed patients often results in the development of large numbers of vesicles which coalesce into extensive deep, often necrotic, ulcerative lesions.228 […] about 70% of HIV-infected persons in the developed world and 95% in the developing world have HSV-2 antibody. […] The epidemiologic interactions between HIV and HSV-2 have led to calculation of potential population-level impact of these intersecting epidemics. […] The population attributable risk will depend on the prevalence of HSV-2 in the population at risk; at 50% HSV-2 prevalence, common among MSM [Males who have Sex with Males, US], or African Americans in the United States, or general population in sub-Saharan Africa, 35% of HIV infections will be attributable to HSV-2. […] the risk of transmitting HSV [from the mother] to the neonate is 30-50% in women with newly acquired HSV [during the last part of the pregnancy] versus <1% in women with established infection.” [This is relevant not only because herpes sucks, but also because it sucks even more when a newborn child gets it].

“More than 50% of individuals in most populations throughout the world demonstrate serological evidence of prior CMV infection.6 The coevolution with and adaptation to its human host over millions of years may account for the observation that in most cases, CMV infection causes few if any symptoms.5 However, in immunocompromised individuals, primary infection or reactivation of latent virus can be life-threatening. As well, congenital infections are common and can result in serious lifelong sequelae. […] Although CMV does not typically come to medical attention as a result of genital tract lesions or disease, it can be transmitted sexually and has important consequences for the sexually active, child-bearing population. […] As with many viruses that cause chronic infection, CMV seems to have coevolved with humans to a balanced state in which the virus persists but generally causes little clinical illness. The host’s innate and adaptive immune responses are usually successful at limiting CMV infection as is evident by the clear association of immune system dysfunction with CMV disease. In the absence of prophylactic antiviral treatment, CMV often reactivates in seropositive individuals who undergo hematopoietic stem cell transplantation (HSCT).41 Immunosuppression resulting from drugs used to treat cancer and autoimmune disorders, and from impaired T-cell function that occurs with advanced AIDS, is also associated with reactivation of CMV. […] The development of primary CMV infection has been noted in up to 79% of liver transplants and 58% of kidney or heart transplants in which the donor is seropositive and the recipient is seronegative.134,135 In the setting of HSCT, several studies have documented that CMV seropositivity of the recipient results in significantly increased overall posttransplant mortality compared to CMV seronegative recipients with a seronegative donor.136 When the recipient is CMV seronegative, overall mortality is increased when the donor is seropositive compared to the situation where the donor is seronegative.137 […] the transplant recipient is at particularly high risk of CMV reactivation during periods of potent immunosuppression that accompany graft rejection or graft-versus-host disease.”

July 7, 2014 Posted by | Books, Epidemiology, Evolutionary biology, Genetics, Immunology, Infectious disease, Medicine, Microbiology | Leave a comment