i. “You can no more make someone tell the truth than you can force someone to love you.” (Philip Roth, Portnoy’s Complaint)

ii. “Every generation laughs at the old fashions, but follows religiously the new.” (Henry David Thoreau, Walden)

iii. “Nature is our kindest friend and best critic in experimental science if we only allow her intimations to fall unbiased on our minds.” (Michael Faraday)

iv. “If you stroke a cat, it will purr; and, as inevitably, if you praise a man, a sweet expression of delight will appear on his face; and even though the praise is a palpable lie, it will be welcome, if the matter is one on which he prides himself.” (Schopenhauer)

v. “Nature answers only when she is questioned.” (Friedrich Gustav Jakob Henle)

vi. “Tyranny and despotism can be exercised by many, more rigorously, more vigorously, and more severely, than by one.” (Andrew Johnson)

vii. “It is hardly in human nature that a man should quite accurately gauge the limits of his own insight; but it is the duty of those who profit by his work to consider carefully where he may have been carried beyond it.” (William Kingdon Clifford, The Ethics of Belief)

viii. “Between two evils, choose neither; between two goods, choose both.” (Tryon Edwards, A Dictionary of Thoughts)

ix. “Any act often repeated soon forms a habit: and habit allowed, steadily gains in strength. — At first it may be but as the spider’s web, easily broken through, but if not resisted it soon binds us with chains of steel.” (-ll-)

x. “The prejudiced and obstinate man does not so much hold opinions, as his opinions hold him.” (-ll-)

xi. “We should be as careful of the books we read, as of the company we keep. The dead very often have more power than the living.” (-ll-)

xii. “Right actions for the future are the best apologies for wrong ones in the past – the best evidence of regret for them that we can offer, or the world receive.” (-ll-)

xiii. “It remains a lesson to all time, that goodness, though the indispensable adjunct to knowledge, is no substitute for it; that when conscience undertakes to dictate beyond its province, the result is only the more monstrous.” (James Anthony Froude)

xiv. “I ask no one who may read this book to accept my views. I ask him to think for himself.” (Henry George, Social Problems)

xv. “The bitterest tears shed over graves are for words left unsaid and deeds left undone.” (Harriet Beecher Stowe)

xvi. “The greater the interest involved in a truth the more careful, self-distrustful, and patient should be the inquiry.” (-ll-)

xvii. “To a person uninstructed in natural history, his country or sea-side stroll is a walk through a gallery filled with wonderful works of art, nine-tenths of which have their faces turned to the wall.” (Thomas Henry Huxley)

xviii. “I can assure you that there is the greatest practical benefit in making a few failures early in life. You learn that which is of inestimable importance — that there are a great many people in the world who are just as clever as you are.” (-ll-)

xix. “Whoever is not in the possession of leisure can hardly be said to possess independence.” (Herman Melville)

xx. “Truth does not need to borrow garments from falsehood.” (José Rizal)

November 19, 2016 Posted by | quotes | Leave a comment

Random stuff

i. Fire works a little differently than people imagine. A great ask-science comment. See also AugustusFink-nottle’s comment in the same thread.


iii. I was very conflicted about whether to link to this because I haven’t actually spent any time looking at it myself so I don’t know if it’s any good, but according to somebody (?) who linked to it on SSC the people behind this stuff have academic backgrounds in evolutionary biology, which is something at least (whether you think this is a good thing or not will probably depend greatly on your opinion of evolutionary biologists, but I’ve definitely learned a lot more about human mating patterns, partner interaction patterns, etc. from evolutionary biologists than I have from personal experience, so I’m probably in the ‘they-sometimes-have-interesting-ideas-about-these-topics-and-those-ideas-may-not-be-terrible’-camp). I figure these guys are much more application-oriented than were some of the previous sources I’ve read on related topics, such as e.g. Kappeler et al. I add the link mostly so that if I in five years time have a stroke that obliterates most of my decision-making skills, causing me to decide that entering the dating market might be a good idea, I’ll have some idea where it might make sense to start.

iv. Stereotype (In)Accuracy in Perceptions of Groups and Individuals.

“Are stereotypes accurate or inaccurate? We summarize evidence that stereotype accuracy is one of the largest and most replicable findings in social psychology. We address controversies in this literature, including the long-standing  and continuing but unjustified emphasis on stereotype inaccuracy, how to define and assess stereotype accuracy, and whether stereotypic (vs. individuating) information can be used rationally in person perception. We conclude with suggestions for building theory and for future directions of stereotype (in)accuracy research.”

A few quotes from the paper:

Demographic stereotypes are accurate. Research has consistently shown moderate to high levels of correspondence accuracy for demographic (e.g., race/ethnicity, gender) stereotypes […]. Nearly all accuracy correlations for consensual stereotypes about race/ethnicity and  gender exceed .50 (compared to only 5% of social psychological findings; Richard, Bond, & Stokes-Zoota, 2003).[…] Rather than being based in cultural myths, the shared component of stereotypes is often highly accurate. This pattern cannot be easily explained by motivational or social-constructionist theories of stereotypes and probably reflects a “wisdom of crowds” effect […] personal stereotypes are also quite accurate, with correspondence accuracy for roughly half exceeding r =.50.”

“We found 34 published studies of racial-, ethnic-, and gender-stereotype accuracy. Although not every study examined discrepancy scores, when they did, a plurality or majority of all consensual stereotype judgments were accurate. […] In these 34 studies, when stereotypes were inaccurate, there was more evidence of underestimating than overestimating actual demographic group differences […] Research assessing the accuracy of  miscellaneous other stereotypes (e.g., about occupations, college majors, sororities, etc.) has generally found accuracy levels comparable to those for demographic stereotypes”

“A common claim […] is that even though many stereotypes accurately capture group means, they are still not accurate because group means cannot describe every individual group member. […] If people were rational, they would use stereotypes to judge individual targets when they lack information about targets’ unique personal characteristics (i.e., individuating information), when the stereotype itself is highly diagnostic (i.e., highly informative regarding the judgment), and when available individuating information is ambiguous or incompletely useful. People’s judgments robustly conform to rational predictions. In the rare situations in which a stereotype is highly diagnostic, people rely on it (e.g., Crawford, Jussim, Madon, Cain, & Stevens, 2011). When highly diagnostic individuating information is available, people overwhelmingly rely on it (Kunda & Thagard, 1996; effect size averaging r = .70). Stereotype biases average no higher than r = .10 ( Jussim, 2012) but reach r = .25 in the absence of individuating information (Kunda & Thagard, 1996). The more diagnostic individuating information  people have, the less they stereotype (Crawford et al., 2011; Krueger & Rothbart, 1988). Thus, people do not indiscriminately apply their stereotypes to all individual  members of stereotyped groups.” (Funder incidentally talked about this stuff as well in his book Personality Judgment).

One thing worth mentioning in the context of stereotypes is that if you look at stuff like crime data – which sadly not many people do – and you stratify based on stuff like country of origin, then the sub-group differences you observe tend to be very large. Some of the differences you observe between subgroups are not in the order of something like 10%, which is probably the sort of difference which could easily be ignored without major consequences; some subgroup differences can easily be in the order of one or two orders of magnitude. The differences are in some contexts so large as to basically make it downright idiotic to assume there are no differences – it doesn’t make sense, it’s frankly a stupid thing to do. To give an example, in Germany the probability that a random person, about whom you know nothing, has been a suspect in a thievery case is 22% if that random person happens to be of Algerian extraction, whereas it’s only 0,27% if you’re dealing with an immigrant from China. Roughly one in 13 of those Algerians have also been involved in a case of ‘body (bodily?) harm’, which is the case for less than one in 400 of the Chinese immigrants.

v. Assessing Immigrant Integration in Sweden after the May 2013 Riots. Some data from the article:

“Today, about one-fifth of Sweden’s population has an immigrant background, defined as those who were either born abroad or born in Sweden to two immigrant parents. The foreign born comprised 15.4 percent of the Swedish population in 2012, up from 11.3 percent in 2000 and 9.2 percent in 1990 […] Of the estimated 331,975 asylum applicants registered in EU countries in 2012, 43,865 (or 13 percent) were in Sweden. […] More than half of these applications were from Syrians, Somalis, Afghanis, Serbians, and Eritreans. […] One town of about 80,000 people, Södertälje, since the mid-2000s has taken in more Iraqi refugees than the United States and Canada combined.”

“Coupled with […] macroeconomic changes, the largely humanitarian nature of immigrant arrivals since the 1970s has posed challenges of labor market integration for Sweden, as refugees often arrive with low levels of education and transferable skills […] high unemployment rates have disproportionately affected immigrant communities in Sweden. In 2009-10, Sweden had the highest gap between native and immigrant employment rates among OECD countries. Approximately 63 percent of immigrants were employed compared to 76 percent of the native-born population. This 13 percentage-point gap is significantly greater than the OECD average […] Explanations for the gap include less work experience and domestic formal qualifications such as language skills among immigrants […] Among recent immigrants, defined as those who have been in the country for less than five years, the employment rate differed from that of the native born by more than 27 percentage points. In 2011, the Swedish newspaper Dagens Nyheter reported that 35 percent of the unemployed registered at the Swedish Public Employment Service were foreign born, up from 22 percent in 2005.”

“As immigrant populations have grown, Sweden has experienced a persistent level of segregation — among the highest in Western Europe. In 2008, 60 percent of native Swedes lived in areas where the majority of the population was also Swedish, and 20 percent lived in areas that were virtually 100 percent Swedish. In contrast, 20 percent of Sweden’s foreign born lived in areas where more than 40 percent of the population was also foreign born.”

vi. Book recommendations. Or rather, author recommendations. A while back I asked ‘the people of SSC’ if they knew of any fiction authors I hadn’t read yet which were both funny and easy to read. I got a lot of good suggestions, and the roughly 20 Dick Francis novels I’ve read during the fall I’ve read as a consequence of that thread.

vii. On the genetic structure of Denmark.

viii. Religious Fundamentalism and Hostility against Out-groups: A Comparison of Muslims and Christians in Western Europe.

“On the basis of an original survey among native Christians and Muslims of Turkish and Moroccan origin in Germany, France, the Netherlands, Belgium, Austria and Sweden, this paper investigates four research questions comparing native Christians to Muslim immigrants: (1) the extent of religious fundamentalism; (2) its socio-economic determinants; (3) whether it can be distinguished from other indicators of religiosity; and (4) its relationship to hostility towards out-groups (homosexuals, Jews, the West, and Muslims). The results indicate that religious fundamentalist attitudes are much more widespread among Sunnite Muslims than among native Christians, even after controlling for the different demographic and socio-economic compositions of these groups. […] Fundamentalist believers […] show very high levels of out-group hostility, especially among Muslims.”

ix. Portal: Dinosaurs. It would have been so incredibly awesome to have had access to this kind of stuff back when I was a child. The portal includes links to articles with names like ‘Bone Wars‘ – what’s not to like? Again, awesome!

x. “you can’t determine if something is truly random from observations alone. You can only determine if something is not truly random.” (link) An important insight well expressed.

xi. Chessprogramming. If you’re interested in having a look at how chess programs work, this is a neat resource. The wiki contains lots of links with information on specific sub-topics of interest. Also chess-related: The World Championship match between Carlsen and Karjakin has started. To the extent that I’ll be following the live coverage, I’ll be following Svidler et al.’s coverage on chess24. Robin van Kampen and Eric Hansen – both 2600+ elo GMs – did quite well yesterday, in my opinion.

xii. Justified by More Than Logos Alone (Razib Khan).

“Very few are Roman Catholic because they have read Aquinas’ Five Ways. Rather, they are Roman Catholic, in order of necessity, because God aligns with their deep intuitions, basic cognitive needs in terms of cosmological coherency, and because the church serves as an avenue for socialization and repetitive ritual which binds individuals to the greater whole. People do not believe in Catholicism as often as they are born Catholics, and the Catholic religion is rather well fitted to a range of predispositions to the typical human.”

November 12, 2016 Posted by | books, Chemistry, Chess, data, dating, demographics, genetics, Geography, immigration, Paleontology, papers, Physics, Psychology, random stuff, religion | 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 | books, cancer, diabetes, genetics, medicine, Neurology, Pharmacology | Leave a comment

Water Supply in Emergency Situations (II)

Here’s my first post about the book. In this post I’ve added a few more quotes from a couple of the last chapters of the book:

“Due to the high complexity of the [water supply] systems, and the innumerable possible points of contaminant insertion, complete prevention of all possible terror attacks (chemical, biological, or radiological) on modern drinking water supplying systems […] seems to be an impossible goal. For example, in the USA there are about 170,000 water systems, with about 8,100 very large systems that serve 90% of the population who get water from a community water system […] The prevailing approach to the problem of drinking water contamination is based on the implementation of surveillance measures and technologies for “risk reduction” such as improvement of physical security measures of critical assets (high-potential vulnerability to attacks), [and] installation of online contaminant monitoring systems (OCMS) with capabilities to detect and warn in real time on relevant contaminants, as part of standard operating procedures for quality control (QC) and supervisory control and data acquisition (SCADA) systems. […] Despite the impressive technical progress in online water monitoring technologies […] detection with complete certainty of pollutants is expensive, and remains problematic.”

“A key component of early warning systems is the availability of a mathematical model for predicting the transport and fate of the spill or contaminant so that downstream utilities can be warned. […] Simulation tools (i.e. well-calibrated hydraulic and water quality models) can be linked to SCADA real-time databases allowing for continuous, high-speed modeling of the pressure, flow, and water quality conditions throughout the water distribution network. Such models provide the operator with computed system status data within the distribution network. These “virtual sensors” complement the measured data. Anomalies between measured and modeled data are automatically observed, and computed values that exceed predetermined alarm thresholds are automatically flagged by the SCADA system.”

“Any given tap receives water, which arrives though a number of pipes in the supply network, the transport route, and ultimately comes from a source […] in order to achieve maximum supply security in case of pipe failures or unusual demand patterns (e.g. fire flows) water supply networks are generally designed as complicated, looped systems, where each tap typically can receive water from several sources and intermediate storage facilities. This means that the water from any given tap can arrive through several different routes and can be a mixture of water from several sources. The routes and sources for a given tap can vary over time […] A model can show: *Which sources (well-fields, reservoirs, and tanks) contribute to the supply of which parts of the city? *Where does the water come from (percentage distribution) at any specific location in the system (any given tap or pipe)? *How long has the water been traveling in the pipe system, before it reaches a specific location?
One way to reduce the risk – and simplify the response to incidents – is by compartmentalizing the water supply system. If each tap receives water from one and only one reservoir pollution of one reservoir will affect one well-defined and relatively smaller part of the city. Compartmentalizing the water supply system will reduce the spreading of toxic substances. On the flip side, it may increase the concentration of the toxic substance. It is also likely to have a negative impact on the supply of water for fire flow and on the robustness of the water supply network in case of failures of pipes or other elements.”

An important point in the context of that part of the coverage is that if you want online (i.e. continuous, all-the-time) monitoring of drinking water, well, that’s going to be expensive regardless of how precisely you’re going to go about doing it. Another related problem is that it’s actually not really a simple matter to figure out what it even makes sense to test for when you’re analyzing the water (you can’t test for ‘everything’ all the time, and so the leading approach in monitoring systems employed today is according to the authors based on the idea of using ‘surrogate parameters’ which may be particularly informative about any significant changes in the quality of the drinking water taking place.

“After the collapse of the Soviet Union, the countries of the South Caucasus gained their independence. However, they faced problems associated with national and transboundary water management. Transboundary water management remains one of the key issues leading to conflict in the region today. The scarcity of water especially in downstream areas is a major problem […] The fresh surface water resources of the South Caucasus mainly consist of runoff from the KuraAraz River basins. […] Being a water-poor region, water supply over the Azerbaijan Republic territory totals about 100,000 /km2, which amounts to an average of about 1,000 of water per person per year. Accordingly, Azerbaijan Republic occupies one of the lowest рlaces in the world in water availability. Water resources of the Republic are distributed very irregularly over administrative districts.”

Water provision [in Azerbaijan] […] is carried out by means of active hydrotechnical constructions, which are old-fashioned and many water intake facilities and treatment systems cannot operate during high flooding, water turbidity, and extreme pollution. […] Tap water satisfies [the] needs of only 50% of the population, and some areas experience lack of drinking water. Due to the lack of water supply networks and deteriorated conditions of those existing, about half of the water is lost within the distribution system. […] The sewage system of the city of Baku covers only 70% of its territory and only about half of sewage is treated […] Owing to rapid growth of turbidity of Kura (and its inflows) during high water the water treatment facilities are rendered inoperable thus causing failures in the water supply of the population of the city of Baku. Such situations mainly take place in autumn and spring on the average 3–5 times a year for 1–2 days. In the system of centralized water supply of the city of Baku about 300 emergency cases occur annually […] Practically nobody works with the population to promote efficient water use practices.”

October 31, 2016 Posted by | books, Engineering, Geography | Leave a comment

Diabetic nephropathies

Bakris et al.‘s text on this topic is the first book I’ve read specifically devoted to the topic of DN. As I pointed out on goodreads, “this is a well-written and interesting work which despite the low page count cover quite a bit of ground. A well-sourced and to-the-point primer on these topics.” Below I have added a few observations from the book.

“Diabetic nephropathy (DN), also known as diabetic kidney disease (DKD), is one of the most important long-term complications of diabetes and the most common cause of endstage renal disease (ESRD) worldwide. DKD […] is defined as structural and functional renal damage manifested as clinically detected albuminuria in the presence of normal or abnormal glomerular filtration rate (GFR). […] Patients with DKD […] account for one-third of patients demanding renal transplantation. […] in the United States, Medicare expenditure on treating ESRD is approximately US $33 billion (as of 2010), which accounts for 8–9 % of the total annual health-care budget […] According to the United States Renal Data System […], the incidence of ESRD requiring RRT [in 2012] was 114,813 patients, with 44 % due to DKD [9]. A registry report from Japan revealed a nearly identical relative incidence, with 44.2 % of the patients with ESRD caused by diabetes”

Be careful not to confuse incidence and prevalence here; the proportion of diabetics diagnosed with ESDR in any given year is almost certainly higher than the proportion of people with ESDR who have diabetes, because diabetics with kidney failure die at a higher rate than do other people with kidney failure. This problem/fact tends to make some questions hard to answer; to give an example, how large a share of the total costs that diabetics contribute to the whole kidney disease component of medical costs seems to me to be far from an easy question to answer, because you in some sense are not really making an apples-to-apples comparison, and a lot might well depend on the chosen discount rate and how to address the excess mortality in the diabetes sample; and even ‘simply’ adding up medical outlays for the diabetes- and non-diabetes samples would require a lot of data (which may not be available) and work. You definitely cannot just combine the estimates provided above, and assume that the 44% incidence translates into 44% of people with ESDR having diabetes; it’s not clear in the text where the ‘one-third of patients’ number above comes from, but if that’s also US data then it should be obvious from the difference between these numbers that there’s a lot of excess mortality here in the diabetes sample (I have included specific data from the publication on these topics below). The book also talks about the fact that the type of dialysis used in a case of kidney failure will to some extent depend on the health status of the patient, and that diabetes is a significant variable in that context; this means that the available/tolerable treatment options for the kidney disease component may not be the same in the case of a diabetic and a case of a patient with, say, lupus nephritis, and it also means that the patient groups most likely are not ‘equally sick’, so basing cost estimates on cost averages might lead to misleading results if severity of disease and (true) treatment costs are related, as they usually are.

“A recent analysis revealed an estimated diabetes prevalence of 12–14 % among adults in the United States […] In the age group ≥65 years, this amounts to more than 20 %”.

It should be emphasized in the context of the above numbers that the prevalence of DKD is highly variable across countries/populations – the authors also include in the book the observation that: “Over a period of 20 years, 32 studies from 16 countries revealed a prevalence ranging from 11 to 83 % of patients with diabetes”. Some more prevalence data:

“DKD affects about 30 % of patients with type 1 diabetes and 25–40 % of the patients with type 2 diabetes. […] The global prevalence of micro- and macroalbuminuria is estimated at 39 % and 10 %, respectively […] (NHANES III) […] reported a prevalence of 35 % (microalbuminuria) and 6 % (macroalbuminuria) in patients with T2DM aged ≥40 years [24]. In another study, this was reported to be 43 % and 12 %, respectively, in a Japanese population [23]. According to the European Diabetes (EURODIAB) Prospective Complications Study Group, in patients with T1DM, the incidence of microalbuminuria was 12.6 % (over 7.3 years) [25]. This prevalence was further estimated at 33 % in an 18-year follow-up study in Denmark […] In the United Kingdom Prospective Diabetes Study (UKPDS), proteinuria [had] a peak incidence after around 15–20 years after diabetes diagnosis.”

I won’t cover the pathophysiology parts in too much detail here, but a few new things I learned does need to be mentioned:

“A natural history of DKD was first described in the 1970s by Danish physicians [32]. It was characterized by a long silent period without overt clinical signs and symptoms of nephropathy and progression through various stages, starting from hyperfiltration, microalbuminuria, macroalbuminuria, and overt renal failure to ESRD. Microalbuminuria (30–300 mg/day of albumin in urine) is a sign of early DKD, whereas macroalbuminuria (>300 mg/day) represents DKD progression. [I knew this stuff. The stuff that follows below was however something I did not know:]
However, this ‘classical’ natural evolution of urinary albumin excretion and change in GFR is not present in many patients with diabetes, especially those with type 2 diabetes [34]. These patients can have reduction or disappearance of proteinuria over time or can develop even overt renal disease in the absence of proteinuria [30, 35]. […] In the Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR) of patients with T2DM, 45.2 % of participants developed albuminuria, and 29 % developed renal impairment over a 15-year follow-up period [37]. Of those patients who developed renal impairment, 61 % did not have albuminuria beforehand, and 39 % never developed albuminuria during the study. Of the patients that developed albuminuria, only 24 % subsequently developed renal impairment during the study. A significant degree of discordance between development of albuminuria and renal impairment is apparent [37]. These data, thus, do not support the classical paradigm of albuminuria always preceding renal impairment in the progression of DKD. […] renal hyperfiltration and rapid GFR decline are considered stronger predictors of nephropathy progression in type 1 diabetes than presence of albuminuria [67]. The annual eGFR loss in patients with DKD is >3 mL/min/1.73 m2 or 3.3 % per year.”

As for the last part about renal hyperfiltration, they however also note later in the coverage in a different chapter that “recent long-term prospective surveys cast doubt on the validity of glomerular hyperfiltration being predictive of renal outcome in patients with type 1 diabetes”. Various factors mentioned in the coverage – some of which are very hard to avoid and some of which are actually diabetes-specific – contribute to measurement error, which may be part of the explanation for the sub-optimal performance of the prognostic markers employed.

An important observation I think I have mentioned before here on the blog is that diabetic nephropathy is not just bad because people who develop this complication may ultimately develop kidney failure, but is also bad because diabetics may die before they even do that; diabetics with even moderate stages of nephropathy have high mortality from cardiovascular disease, so if you only consider diabetics who actually develop kidney failure you may miss some of the significant adverse health effects of this complication; it might be argued that doing this would be a bit like analyzing the health outcomes of smokers while only tallying the cancer cases, and ignoring e.g. the smoking-associated excess deaths from cardiovascular disease. Some observations from the book on this topic:

“Comorbid DM and DKD are associated with high cardiovascular morbidity and mortality. The risk of cardiovascular disease is disproportionately higher in patients with DKD than patients with DM who do not have kidney disease [76]. The incident dialysis rate might even be higher after adjusting for patients dying from cardiovascular disease before reaching ESRD stage [19]. The United States Renal Data System (USRDS) data shows that elderly patients with a triad of DM, chronic kidney disease (CKD), and heart failure have a fivefold higher chance of death than progression to CKD and ESRD [36]. The 5-year survival rate for diabetic patients with ESRD is estimated at 20 % […] This is higher than the mortality rate for many solid cancers (including prostate, breast, or renal cell cancer). […] CVD accounts for more than half of deaths of patients undergoing dialysis […] the 5-year survival rate is much lower in diabetic versus nondiabetic patients undergoing hemodialysis […] Adler et al. tested whether HbA1c levels were associated with death in adults with diabetes starting HD or peritoneal dialysis [38]. Of 3157 patients observed for a median time of 2.7 years, 1688 died. [this example provided, I thought, a neat indication of what sort of data you end up with when you look at samples with a 20% 5-year survival rate] […] Despite modern therapies […] most patients continue to show progressive renal damage. This outcome suggests that the key pathogenic mechanisms involved in the induction and progression of DN remain, at least in part, active and unmodified by the presently available therapies.” (my emphasis)

The link between blood glucose (Hba1c) and risk of microvascular complications such as DN is strong and well-documented, but Hba1c does not explain everything:

“Only a subset of individuals living with diabetes […] develop DN, and studies have shown that this is not just due to poor blood glucose control [50–54]. DN appears to cluster in families […] Several consortia have investigated genetic risk factors […] Genetic risk factors for DN appear to differ between patients with type 1 and type 2 diabetes […] The pathogenesis of DN is complex and has not yet been completely elucidated […] [It] is multifactorial, including both genetic and environmental factors […]. Hyperglycemia affects patients carrying candidate genes associated with susceptibility to DN and results in metabolic and hemodynamic alterations. Hyperglycemia alters vasoactive regulators of glomerular arteriolar tone and causes glomerular hyperfiltration. Production of AGEs and oxidative stress interacts with various cytokines such as TGF-β and angiotensin II to cause kidney damage. Additionally, oxidative stress can cause endothelial dysfunction and systemic hypertension. Inflammatory pathways are also activated and interact with the other pathways to cause kidney damage.”

“An early clinical sign of DN is moderately increased urinary albumin excretion, referred to as microalbuminuria […] microalbuminuria has been shown to be closely associated with an increased risk of cardiovascular morbidity and mortality [and] is [thus] not only a biomarker for the early diagnosis of DN but also an important therapeutic target […] Moderately increased urinary albumin excretion that progresses to severely increased albuminuria is referred to as macroalbuminuria […] Severely increased albuminuria is defined as an ACR≥300 mg/g Cr; it leads to a decline in renal function, which is defined in terms of the GFR [8] and generally progresses to ESRD 6–8 years after the onset of overt proteinuria […] patients with type 1 diabetes are markedly younger than type 2 patients. The latter usually develop ESRD in their mid-fifties to mid-sixties. According to a small but carefully conducted study, both type 1 and type 2 patients take an average of 77–81 months from the stage of producing macroproteinuria with near-normal renal function to developing ESRD [17].”

“Patients with diabetes and kidney disease are at increased risk of hypoglycemia due to decreased clearance of some of the medications used to treat diabetes such as insulin, as well as impairment of renal gluconeogenesis from having a lower kidney mass. As the kidney is responsible for about 30–80 % of insulin removal, reduced kidney function is associated with a prolonged insulin half-life and a decrease in insulin requirements as estimated glomerular filtration rate (eGFR) decline […] Metformin [a first-line drug for treating type 2 diabetes, US] should be avoided in patients with an eGFR < 30 mL/min /1.73 m2. It is recommended that metformin is stopped in the presence of situations that are associated with hypoxia or an acute decline in kidney function such as sepsis/shock, hypotension, acute myocardial infarction, and use of radiographic contrast or other nephrotoxic agents […] The ideal medication regimen is based on the specific needs of the patient and physician experience and should be individualized, especially as renal function changes. […] Lower HbA1c levels are associated with higher risks of hypoglycemia so the HbA1c target should be individualized […] Whereas patients with mild renal insufficiency can receive most antihyperglycemic treatments without any concern, patients with CKD stage 3a and, in particular, with CKD stages 3b, 4, and 5 often require treatment adjustments according to the degree of renal insufficiency […] Higher HbA1c targets should be considered for those with shortened life expectancies, a known history of severe hypoglycemia or hypoglycemia unawareness, CKD, and children.”

“In cases where avoidance of development of DKD has failed, the second approach is slowing disease progression. The most important therapeutic issues at this stage are control of hypertension and hyperglycemia. […] Hypertension is present in up to 85 % of patients with DN/ DKD, depending on the duration and stage (e.g., higher in more progressive cases). […] In a recent meta-analysis, the efficacy and safety of blood pressure-lowering agents in adults with diabetes and kidney disease was analyzed […] In total, 157 studies comprising 43,256 participants, mostly with type 2 diabetes and CKD, were included in the network meta-analysis. No drug regimen was found to be more effective than placebo for reducing all-cause mortality. […] DKD is accompanied by abnormalities in lipid metabolism related to decline in kidney function. The association between higher low-density lipoprotein cholesterol (LDL-C) and risk of myocardial infarction is weaker for people with lower baseline eGFR, despite higher absolute risk of myocardial infarction [53]. Thus, increased LDL-C seems to be less useful as a marker of coronary risk among people with CKD than in the general population.”

“An analysis of the USRDS data revealed an RR of 0.27 (95 % CI, 0.24–0.30) 18 months after transplantation in patients with diabetes in comparison to patients on dialysis on a transplant waiting list [76]. The gain in projected years of life with transplantation amounted to 11 years in patients with DKD in comparison to patients without transplantation.”

October 27, 2016 Posted by | books, diabetes, medicine, Pharmacology | Leave a comment


i. “You will never find time for anything. If you want time, you must make it.” (Charles Buxton)

ii. “When we meet a fact which contradicts a prevailing theory, we must accept the fact and abandon the theory, even when the theory is supported by great names and generally accepted.” (Claude Bernard)

iii. “The cheapest sort of pride is national pride; for if a man is proud of his own nation, it argues that he has no qualities of his own of which he can be proud; otherwise he would not have recourse to those which he shares with so many millions of his fellowmen. The man who is endowed with important personal qualities will be only too ready to see clearly in what respects his own nation falls short, since their failings will be constantly before his eyes. But every miserable fool who has nothing at all of which he can be proud adopts, as a last resource, pride in the nation to which he belongs; he is ready and glad to defend all its faults and follies tooth and nail, thus reimbursing himself for his own inferiority.” (Schopenhauer)

iv. “… whoever attributes no merit to himself because he really has none is not modest, but merely honest.” (-ll-)

v. “It is the possession of a great heart or a great head, and not the mere fame of it, which is worth having, and conducive to happiness. Not fame, but that which deserves to be famous, is what a man should hold in esteem.” (-ll-)

vi. “It is not knowledge, but the act of learning, not the possession of but the act of getting there, which grants the greatest enjoyment.” (Gauss)

vii. “People may flatter themselves just as much by thinking that their faults are always present to other people’s minds, as if they believe that the world is always contemplating their individual charms and virtues.” (Elizabeth Gaskell)

viii. “Fools have a habit of believing that everything written by a famous author is admirable.” (Voltaire)

ix. “One always speaks badly when one has nothing to say.” (-ll-)

x. “He who dares not offend cannot be honest.” (Thomas Paine)

xi. “False opinions are like false money, struck first of all by guilty men and thereafter circulated by honest people who perpetuate the crime without knowing what they are doing.” (Joseph de Maistre)

xii. “Learning is not attained by chance, it must be sought for with ardor and attended to with diligence.” (Abigail Adams)

xiii. “It is not easy to be wise for all times, not even for the present much less for the future; and those who judge the past must recollect that, when it was the present the present was future” (Gouverneur Morris)

xiv. “Praise — actual personal praise — oftener frets and embarrasses than it encourages. It is too small when too near.” (Letitia Elizabeth Landon)

xv. “Everybody is seldom to be believed. “They say” is not proof that they know.” (Samuel Laman Blanchard)

xvi. “Useless laws weaken the necessary laws.” (Montesquieu)

xvii. “Not to be loved is a misfortune, but it is an insult to be loved no longer.” (-ll-)

xviii. “Pithy sentences are like sharp nails which force truth upon our memory.” (Denis Diderot)

xix. “One may demand of me that I should seek truth, but not that I should find it.” (-ll-)

xx. “It is bad policy to fear the resentment of an enemy.” (Ethan Allen)

October 24, 2016 Posted by | quotes | Leave a comment

Water Supply in Emergency Situations (I)

I didn’t think much of this book (here’s my goodreads review), but I did learn some new things from reading it. Some of the coverage in the book overlapped a little bit with stuff I’d read before, e.g. coverage provided in publications such as Rodricks and Fong and Alibek, but I read those books in 2013 and 2014 respectively (so I’ve already forgot a great deal) and most of the stuff in the book was new stuff. Below I’ve added a few observations and data from the first half of the publication.

“Mediterranean basin demands for water are high. Today, the region uses around 300 billion cubic meters per year. Two thirds of Mediterranean countries now use over 500  per year per inhabitant mainly because of heavy use of irrigation. But these per capita demands are irregular and vary across a wide range – from a little over 100 to more than 1,000 per year. Globally, demand has doubled since the beginning of the 20th century and increased by 60% over the last 25 years. […] the Middle East ecosystems […]  populate some 6% of the world population, but have only some 1% of its renewable fresh water. […] Seasonality of both supply and demand due to tourism […] aggravate water resource problems. During the summer months, water shortages become more frequent. Distribution networks left unused during the winter period face overload pressures in the summer. On the other hand, designing the system with excess capability to satisfy tourism-related summer peak demands raises construction and maintenance costs significantly.”

“There are over 30,000 km of mains within London and over 30% of these are over 150 years old, they serve 7.5 million people with 2,500 million liters of water a day.”

“A major flooding of the Seine River would have tremendous consequences and would impact very significantly the daily life of the 10 million people living in the Parisian area. A deep study of the impacts of such a catastrophic natural hazard has recently been initiated by the French authorities. […] The rise of the water level in the Seine during the last two major floods occurred slowly over several weeks which may explain their low number of fatalities: 50 deaths in 1658 and only one death in 1910. The damage and destruction to buildings and infrastructure, and the resulting effect on economic activity were, however, of major proportions […] Dams have been constructed on the rivers upstream from Paris, but their capacity to stock water is only 830 million cubic meters, which would be insufficient when compared to the volume of 4 billion cubic meters of water produced by a big flood. […] The drinkable water supply system in Paris, as well as that of the sewer network, is still constrained by the decisions and orientations taken during the second half of the 19th century during the large public works projects realized under Napoleon III. […] two of the three water plants which treat river water and supply half of Paris with drinkable water existed in 1910. Water treatment technology has radically changed, but the production sites have remained the same. New reservoirs for potable water have been added, but the principles of distribution have not changed […] The average drinking water production in Paris is 615,000 /day.”

They note in the chapter from which the above quotes are taken that a flood comparable to that which took place in 1910 would in 2005 have resulted in 20% of the surface of Paris being flooded, and 600.000 people being without electricity, among other things. The water distribution system currently in place would also be unable to deal with the load, however a plan for how to deal with this problem in an emergency setting does exist. In that context it’s perhaps worth noting that Paris is hardly unique in terms of the structure of the distribution system – elsewhere in the book it is observed that: “The water infrastructure developed in Europe during the 19th century and still applied, is almost completely based on options of centralized systems: huge supply and disposal networks with few, but large waterworks and sewage treatment plants.” Having both centralized and decentralized systems working at the same time/in the same area tends to increase costs, but may also lower risk; it’s observed in the book during the coverage of an Indonesian case-study that in that region the centralized service provider may take a long time to repair broken water pipes, which is … not very nice if you live in a tropical climate and prefer to have drinking water available to you.

“Water resources management challenges differ enormously in Romania, depending on the type of human settlement. The spectrum of settlement types stretches from the very low-density scattered single dwellings found in rural areas, through villages and small towns, to the much more dense and crowded cities. […] Water resources management will always face the challenge of balancing the needs of different water users. This is the case both in large urban or relatively small rural communities. The water needs of the agricultural production, energy and industrial sectors are often in competition. […] Romania’s water resources are relatively poor and unequally distributed in time and space […] There is a vast differential between urban and rural settlements when it comes to centralized drinking water systems; all the 263 municipalities and towns have such systems, while only 17% of rural communities benefit from this service. […] In Braila and Harghita counties, no village has a sewage network, and Giurgiu and Ialomita counties have only one a piece each. Around 47 of the largest cities which do not have wastewater treatment plants (Bucharest, Braila, Craiova, Turnu Severin Tulcea, etc.) produce ∼20 /s of wastewater, which is directly discharged untreated into surface water.”

There is a difference in quality between water from centralized and decentralized supply systems [in the Ukraine (and likely elsewhere as well)]. Water quality in decentralized systems is the worst (some 30% of samples fail to meet standards, compared to 5.7% in the centralized supply). […] The Sanitary epidemiological stations draw random samples from 1,139 municipal, 6,899 departmental, and 8,179 rural pipes, and from 158,254 points of decentralized water supply, including 152,440 wells, 996 springs, and 4,818 artesian wells. […] From the first day following the accident at Chernobyl Nuclear Power Plant (ChNPP), one of the most serious problems was to prevent general contamination of the Dnieper water system and to guarantee safe water consumption for people living in the affected zone. The water protection and development of monitoring programs for the affected water bodies were among the most important post-accident countermeasures taken by the Government Bodies in Ukraine. […] To solve the water quality problem for Kiev, an emergency water intake at the Desna River was constructed within a very short period. […] During 1986 and the early months of 1987, over 130 special filtration dams […] with sorbing screens containing zeolite (klinoptilolite) were installed for detaining radionuclides while letting the water through. […] After the spring flood of 1987, the construction of new dams was terminated and the decision was made to destroy most of the existing dams. It was found that the 90Sr concentration reduction by the dams studied was insignificant […] Although some countermeasures and cleanup activities applied to radionuclides sources on catchments proved to have positive effects, many other actions were evaluated as ineffective and even useless. […] The most effective measures to reduce radioactivity in drinking water are those, which operate at the water treatment and distribution stage.

“Diversification and redundancy are important technical features to make infrastructure systems less vulnerable to natural and social (man-made) hazards. […] risk management does not only encompass strategies to avoid the occurrence of certain events which might lead to damages or catastrophes, but also strategies of adaptation to limit damages.

The loss of potable water supply typically leads to waterborne diseases, such as typhus and cholera.”

Water velocity in a water supply system is about 1 \s. Therefore, time is a primordial factor in contamination spread along the system. In order to minimize the damage caused by contamination of water, it is essential to act with maximum speed to achieve minimum spread of the contaminant”

October 21, 2016 Posted by | books, Geography | Leave a comment

The Biology of Moral Systems (I)

I have quoted from the book before, but I decided that this book deserves to be blogged in more detail. I’m close to finishing the book at this point (it’s definitely taken longer than it should have), and I’ll probably give it 5 stars on goodreads; I might also add it to my list of favourite books on the site. In this post I’ve added some quotes and ideas from the book, and a few comments. Before going any further I should note that it’s frankly impossible to cover anywhere near all the ideas covered in the book here on the blog, so if you’re even remotely interested in these kinds of things you really should pick up a copy of the book and read all of it.

“I believe that something crucial has been missing from all of the great debates of history, among philosophers, politicians, theologians, and thinkers from other and diverse backgrounds, on the issues of morality, ethics, justice, right and wrong. […] those who have tried to analyze morality have failed to treat the human traits that underlie moral behavior as outcomes of evolution […] for many conflicts of interest, compromises and enforceable contracts represent the only real solutions. Appeals to morality, I will argue, are simply the invoking of such compromises and contracts in particular ways. […] the process of natural selection that has given rise to all forms of life, including humans, operates such that success has always been relative. One consequence is that organisms resulting from the long-term cumulative effects of selection are expected to resist efforts to reveal their interests fully to others, and also efforts to place limits on their striving or to decide for them when their interests are being “fully” satisfied. These are all reasons why we should expect no “terminus” – ever – to debates on moral and ethical issues.” (these comments I also included in the quotes post to which I link at the beginning, but I thought it was worth including them in this post as well even so – US).

“I am convinced that biology can never offer […] easy or direct answers to the questions of what is right and wrong. I explicitly reject the attitude that whatever biology tells us is so is also what ought to be (David Hume’s so-called “naturalistic fallacy”) […] there are within biology no magic solutions to moral problems. […] Knowledge of the human background in organic evolution can [however] provide a deeper self-understanding by an increasing proportion of the world’s population; self-understanding that I believe can contribute to answering the serious questions of social living.”

“If there had been no recent discoveries in biology that provided new ways of looking at the concept of moral systems, then I would be optimistic indeed to believe that I could say much that is new. But there have been such discoveries. […] The central point in these writings [Hamilton, Williams, Trivers, Cavalli-Sforza, Feldman, Dawkins, Wilson, etc. – US] […] is that natural selection has apparently been maximizing the survival by reproduction of genes, as they have been defined by evolutionists, and that, with respect to the activities of individuals, this includes effects on copies of their genes, even copies located in other individuals. In other words, we are evidently evolved not only to aid the genetic materials in our own bodies, by creating and assisting descendants, but also to assist, by nepotism, copies of our genes that reside in collateral (nondescendant) relatives. […] ethics, morality, human conduct, and the human psyche are to be understood only if societies are seen as collections of individuals seeking their own self-interests […] In some respects these ideas run contrary to what people have believed and been taught about morality and human values: I suspect that nearly all humans believe it is a normal part of the functioning of every human individual now and then to assist someone else in the realization of that person’s own interests to the actual net expense of those of the altruist. What [the above-mentioned writings] tells us is that, despite our intuitions, there is not a shred of evidence to support this view of beneficence, and a great deal of convincing theory suggests that any such view will eventually be judged false. This implies that we will have to start all over again to describe and understand ourselves, in terms alien to our intuitions […] It is […] a goal of this book to contribute to this redescription and new understanding, and especially to discuss why our intuitions should have misinformed us.”

“Social behavior evolves as a succession of ploys and counterploys, and for humans these ploys are used, not only among individuals within social groups, but between and among small and large groups of up to hundreds of millions of individuals. The value of an evolutionary approach to human sociality is thus not to determine the limits of our actions so that we can abide by them. Rather, it is to examine our life strategies so that we can change them when we wish, as a result of understanding them. […] my use of the word biology in no way implies that moral systems have some kind of explicit genetic background, are genetically determined, or cannot be altered by adjusting the social environment. […] I mean simply to suggest that if we wish to understand those aspects of our behavior commonly regarded as involving morality or ethics, it will help to reconsider our behavior as a product of evolution by natural selection. The principal reason for this suggestion is that natural selection operates according to general principles which make its effects highly predictive, even with respect to traits and circumstances that have not yet been analyzed […] I am interested […] not in determining what is moral and immoral, in the sense of what people ought to be doing, but in elucidating the natural history of ethics and morality – in discovering how and why humans initiated and developed the ideas we have about right and wrong.”

I should perhaps mention here that sort-of-kind-of related stuff is covered in Aureli et al. (see e.g. this link), and that some parts of that book will probably make you understand Alexander’s ideas a lot better even if perhaps he didn’t read those specific authors – mainly because it gets a lot easier to imagine the sort of mechanisms which might be at play here if you’ve read this sort of literature. Here’s one relevant quote from the coverage of that book, which also deals with the question Alexander discusses above, and in a lot more detail throughout his book, namely ‘where our morality comes from?’

“we make two fundamental assertions regarding the evolution of morality: (1) there are specific types of behavior demonstrated by both human and nonhuman primates that hint at a shared evolutionary background to morality; and (2) there are theoretical and actual connections between morality and conflict resolution in both nonhuman primates and human development. […] the transition from nonmoral or premoral to moral is more gradual than commonly assumed. No magic point appears in either evolutionary history or human development at which morality suddenly comes into existence. In both early childhood and in animals closely related to us, we can recognize behaviors (and, in the case of children, judgments) that are essential building blocks of the morality of the human adult. […] the decision making and emotions underlying moral judgments are generated within the individual rather than being simply imposed by society. They are a product of evolution, an integrated part of the human genetic makeup, that makes the child construct a moral perspective through interactions with other members of its species. […] Much research has shown that children acquire morality through a social-cognitive process; children make connections between acts and consequences. Through a gradual process, children develop concepts of justice, fairness, and equality, and they apply these concepts to concrete everyday situations […] we assert that emotions such as empathy and sympathy provide an experiential basis by which children construct moral judgments. Emotional reactions from others, such as distress or crying, provide experiential information that children use to judge whether an act is right or wrong […] when a child hits another child, a crying response provides emotional information about the nature of the act, and this information enables the child, in part, to determine whether and why the transgression is wrong. Therefore, recognizing signs of distress in another person may be a basic requirement of the moral judgment process. The fact that responses to distress in another have been documented both in infancy and in the nonhuman primate literature provides initial support for the idea that these types of moral-like experiences are common to children and nonhuman primates.”

Alexander’s coverage is quite different from that found in Aureli et al.,, but some of the contributors to the latter work deal with similar questions to the ones in which he’s interested, using approaches not employed in Alexander’s book – so this is another place to look if you’re interested in these topics. Margalit’s The Emergence of Norms is also worth mentioning. Part of the reason why I mention these books here is incidentally that they’re not talked about in Alexander’s coverage (for very natural reasons, I should add, in the case of the former book at least; Natural Conflict Resolution was published more than a decade after Alexander wrote his book…).

“In the hierarchy of explanatory principles governing the traits of living organisms, evolutionary reductionism – the development of principles from the evolutionary process – tends to subsume all other kinds. Proximate-cause reductionism (or reduction by dissection) sometimes advances our understanding of the whole phenomena. […] When evolutionary reduction becomes trivial in the study of life it is for a reason different from incompleteness; rather, it is because the breadth of the generalization distances it too significantly from the particular problem that may be at hand. […] the greatest weakness of reduction by generalization is not that it is likely to be trivial but that errors are probable through unjustified leaps from hypothesis to conclusion […] Critics such as Gould and Lewontin […] do not discuss the facts that (a) all students of human behavior (not just those who take evolution into account) run the risk of leaping unwarrantedly from hypothesis to conclusion and (b) just-so stories were no less prevalent and hypothesis-testing no more prevalent in studies of human behavior before evolutionary biologists began to participate. […] I believe that failure by biologists and others to distinguish proximate- or partial-cause and evolutionary- or ultimate-cause reductionism […] is in some part responsible for the current chasm between the social and the biological sciences and the resistance to so-called biological approaches to understanding humans. […] Both approaches are essential to progress in biology and the social sciences, and it would be helpful if their relationship, and that of their respective practitioners, were not seen as adversarial.”

(Relatedly, love is motivationally prior to sugar. This one also seems relevant, though in a different way).

“Humans are not accustomed to dealing with their own strategies of life as if they had been tuned by natural selection. […] People are not generally aware of what their lifetimes have been evolved to accomplish, and, even if they are roughly aware of this, they do not easily accept that their everyday activities are in any sense means to that end. […] The theory of lifetimes most widely accepted among biologists is that individuals have evolved to maximize the likelihood of survival of not themselves, but their genes, and that they do this by reproducing and tending in various ways offspring and other carriers of their own genes […] In this theory, survival of the individual – and its growth, development, and learning – are proximate mechanisms of reproductive success, which is a proximate mechanism of genic survival. Only the genes have evolved to survive. […] To say that we are evolved to serve the interests of our genes in no way suggests that we are obliged to serve them. […] Evolution is surely most deterministic for those still unaware of it. If this argument is correct, it may be the first to carry us from is to ought, i.e., if we desire to be the conscious masters of our own fates, and if conscious effort in that direction is the most likely vehicle of survival and happiness, then we ought to study evolution.”

“People are sometimes comfortable with the notion that certain activities can be labeled as “purely cultural” because they also believe that there are behaviors that can be labeled “purely genetic.” Neither is true: the environment contributes to the expression of all behaviors, and culture is best described as part of the environment.”

“Happiness and its anticipation are […] proximate mechanisms that lead us to perform and repeat acts that in the environments of history, at least, would have led to greater reproductive success.”

“The remarkable difference between the patterns of senescence in semelparous (one-time breeding) and iteroparous (repeat-breeding) organisms is probably one of the best simple demonstrations of the central significance of reproduction in the individual’s lifetime. How, otherwise, could we explain the fact that those who reproduce but once, like salmon and soybeans, tend to die suddenly right afterward, while those like ourselves who have residual reproductive possibilities after the initial reproductive act decline or senesce gradually? […] once an organism has completed all possibilities of reproducing (through both offspring production and assistance, and helping other relatives), then selection can no longer affect its survival: any physiological or other breakdown that destroys it may persist and even spread if it is genetically linked to a trait that is expressed earlier and is reproductively beneficial. […] selection continually works against senescence, but is just never able to defeat it entirely. […] senescence leads to a generalized deterioration rather than one owing to a single effect or a few effects […] 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. […] natural selection maximizes the likelihood of genetic survival, which is incompatible with eliminating senescence. […] Senescence, and the finiteness of lifetimes, have evolved as incidental effects […] Organisms compete for genetic survival and the winners (in evolutionary terms) are those who sacrifice their phenotypes (selves) earlier when this results in greater reproduction.”

“altruism appears to diminish with decreasing degree of relatedness in sexual species whenever it is studied – in humans as well as nonhuman species”

October 5, 2016 Posted by | anthropology, biology, books, genetics, philosophy | Leave a comment

A Cooperative Species

“In the pages that follow we advance two propositions.
First, people cooperate not only for self-interested reasons but also because they are genuinely concerned about the well-being of others, try to uphold social norms, and value behaving ethically for its own sake. People punish those who exploit the cooperative behavior of others for the same reasons. Contributing to the success of a joint project for the benefit of one’s group, even at a personal cost, evokes feelings of satisfaction, pride, even elation. Failing to do so is often a source of shame or guilt.
Second, we came to have these “moral sentiments” because our ancestors lived in environments, both natural and socially constructed, in which groups of individuals who were predisposed to cooperate and uphold ethical norms tended to survive and expand relative to other groups, thereby allowing these prosocial motivations to proliferate. The first proposition concerns proximate motivations for prosocial behavior, the second addresses the distant evolutionary origins and ongoing perpetuation of these cooperative dispositions.”

Here’s my goodreads review of the book – I gave the book five stars on goodreads. In the post I have included some illustrative quotes below, but really you should read all of it if you find this sort of stuff interesting and you’re not mathematically illiterate (and as the authors note early on, they have given the way they present their ideas some thought: “We have presented technical material in verbal as well as mathematical form wherever possible, and avoided mathematical formulations entirely where that was possible without sacrificing clarity.” Even so, the book is somewhat dense and it takes some work to get through).

“In short, humans became the cooperative species that we are because cooperation was highly beneficial to the members of groups that practiced it, and we were able to construct social institutions that minimized the disadvantages of those with social preferences in competition with fellow group members, while heightening the group-level advantages associated with the high levels of cooperation that these social preferences allowed. These institutions proliferated because the groups that adopted them secured high levels of within-group cooperation, which in turn favored the groups’ survival as a biological and cultural entity in the face of environmental, military and other challenges.”

The regulation of social interactions by group-level institutions plays no less a role than altruistic individual motives in understanding how this cooperative species came to be. Institutions affect the rewards and penalties associated with particular behaviors, often favoring the adoption of cooperative actions over others, so that even the self-regarding are often induced to act in the interest of the group. […] the individual motives and group-level institutions that account for cooperation among humans include not only the most elevated, including a concern for others, fair-mindedness, and democratic accountability of leaders, but also the most wicked, such as vengeance, racism, religious bigotry, and hostility toward outsiders.

“Optimizing models are commonly used to describe behavior not because they mimic the cognitive processes of the actors, which they rarely do, but because they capture important influences on individual behavior in a succinct and analytically tractable way.”

“Culture is an evolutionary force in its own right, not simply an effect of the interaction of genes and natural environments. […] human preferences and beliefs are the product of a dynamic whereby genes affect cultural evolution and culture affects genetic evolution, the two being tightly intertwined in the evolution of our species. [I have of course talked about gene-culture coevolution before here on the blog and I don’t like to repeat myself, but this idea/notion really is unknown to many people who should know better, and so is perhaps worth repeating here even so – US] […] The idea of treating culture as a form of epigenetic transmission was pioneered by Cavalli-Sforza and Feldman (1973), Karl Popper (1979), and Richard Dawkins, who coined the term “meme” […] to represent an integral unit of information that could be transmitted phenotypically. There quickly followed several major contributions to a biological approach to culture, all based on the notion that culture, like genes, could evolve through replication (intergenerational transmission), mutation, and selection […] Richard Dawkins added a second fundamental mechanism of epigenetic information transmission in The Extended Phenotype (1982), noting that organisms can directly transmit environmental artifacts to the next generation […] Creating a fitness-relevant aspect of an environment and stably transmitting this environment across generations, known as niche construction, is a widespread form of epigenetic transmission […] niche construction gives rise to what might be called a gene-environment coevolutionary process, since a genetically induced environmental regularity becomes the basis for genetic selection, and genetic mutations that give rise to mutant niches will tend to survive if they are fitness enhancing for their constructors. […] Human cultures, along with the institutional structures they support, are instances of niche construction”.

“while genetic transmission of information plays a central role in our account, the genetics of non-pathological social behavior is for the most part unknown. […] No “gene for cooperation” has been discovered. Nor is it likely that one will ever be found, for the idea of a one-to-one mapping between genes and behavior is unlikely given what is now known about gene expression, and is implausible in light of the complexity and cultural variation of cooperative behaviors. […] an explanation of the evolution of human cooperation must hinge on the empirical evidence. The question is not “Which model works?” They all work, if mathematical coherence is the bar. The question we are asking is about something that actually happened in the human past. Thus we measure the empirical plausibility of alternative explanations against the conditions under which early humans lived during the Pleistocene, roughly 1.6 million years before the present, until the advent of agriculture beginning about 12,000 years ago, and especially the last 100 or so millennia of this period.”

“in small-scale societies punishment can be highly effective even when it takes the form of ridicule or gossip and it inflicts no material costs on its targets. […] People are sensitive to others’ evaluation of their moral worth or intentions and will cooperate in social dilemmas when the punishment for free-riding takes the form of criticism by peers rather than a reduction in material payoffs. […] People punish not only those who have hurt them, but also those who hurt others. […] even self-regarding individuals may engage in third-party punishment if they believe that this will induce other-regarding individuals to behave favorably toward them. […] recent experimental results are consistent with the view that the social preferences that become salient in a population depend critically on the manner in which a people’s institutions and livelihood frame social interactions and shape the process of social learning. An expected result, confirmed by a growing body of international comparative evidence, is substantial cross-cultural differences in the nature and extent of social preferences.”

In experimental and natural settings, people often behave differently toward others, depending on the organizational, linguistic, ethnic, and religious groups to which they belong. People choose to associate with others who are similar to themselves in some salient respect […] Among the salient characteristics on which this choice operates are racial and ethnic identification, and religion […] Conversely, people often seek to avoid interactions with those who are different from themselves. […] Those who condition their behavior on the group membership of the other may do this because group membership is thought to provide information about the other’s likely behavior. Or group membership may matter because people would like to help or to interact with members of some groups more than others. In the first case the actor’s beliefs are involved. In the second case, group-sensitive preferences are at work. […] a series of experiments by Toshio Yamagishi and his associates […] show that experimental subjects’ allocations favor in-group members not because of altruistic sentiments toward those who are similar to themselves, but because they expected reciprocation from in-groupers and not from out-groupers. […] taking account of ethnic, racial and other characteristics of those with whom one interacts appears to be a quite common human trait. We seem quite attuned to noticing and treating as salient the ascriptive markers of group difference. For example, Americans of European and African origin are better at recognizing faces of their own ancestral group, and faces of their own group induce greater activation in the part of the brain associated with face recognition.” (my bold)

“The most parsimonious and compelling proximate explanation of behavior in the ultimatum game, public goods game, and other social dilemma experiments is that people think that cooperating is the right thing to do and enjoy doing it, and that they dislike unfair treatment and enjoy punishing those who violate norms of fairness. […] Recent studies of brain functioning provide some support for this hedonic view of cooperative behavior.

Differential group success […] plays a central role in the evolution of human behaviors and institutions, members of less successful groups copying the more successful or being eliminated by them. […] the speed of an evolutionary process is proportional to the differences on which it works […] reduction in within-group differences slows down the selection against altruistic individuals. Insider biases and individual preferences to interact with like individuals lead to large between-group differences in behavior and, to a lesser but not negligible extent, in genotypes too […] insider biases result in frequent between-group conflicts as well as high levels of positive assortment in interactions both within and between groups. […] All of these aspects of human social life enhance the force of between-group selection relative to within-group selection.” (my bold)

“The fact that helping behaviors are […] motivated by [a] wide range of proximate motives, from maternal love, to enlightened self-interest, to solidarity with one’s coethnics or conationals, is consistent with our view that in all likelihood each of the mechanisms […] has played a significant role in human evolution, the importance of each depending on the forms of cooperation under consideration and the ecological and social conditions under which ancestral humans interacted. […] what can be known or reasonably conjectured from genetic, archaeological and other data about [the] ancestral human conditions suggests that neither helping close family members nor reciprocal altruism provides an adequate account of the emergence of [our] cooperative species. […] multi-level selection models based on gene culture coevolution [however] contribute substantially to a convincing explanation.

As mentioned, if you find this kind of stuff interesting you should strongly consider reading the book.

September 29, 2016 Posted by | anthropology, books | Leave a comment

Human Drug Metabolism (III)

This is my third post about this book. You can read my previous posts here and here. In this post I have covered material from chapter 7, dealing with ‘factors affecting drug metabolism’.

“Data from animal studies in one country are usually comparable with that of another, provided the animal species and strain are the same. This provides a consistent picture of the basic pharmacological and toxicological actions of a candidate drug in a living organism […] it has been obvious since animal testing began that there would be large differences in the way a drug might perform in man compared with animal species […]. Unfortunately, there is no experimental model yet designed that can not only consider human biochemistry and physiology, but also the effects of age, smoking, legal and illegal drug usage, gender, diet, environment, disease and finally genetic variation. Indeed, many clinical studies have revealed enormous differences in drug clearance and pharmacological effect even in age, sex and ethnically matched individuals. In effect, this means that the first year or so of a drug’s clinical life is a vast, but monitored experiment, involving hundreds of thousands of patients and there is no guarantee of success.”

“Most biotransformational polymorphisms that might potentially cause a problem clinically are due to an inability of those with defective enzymes to remove the drug from the system. Drug failure can occur if the agent is administered as a pro-drug and requires some metabolic conversion to an active metabolite. Drug accumulation can lead to unpleasant side effects and loss of patient tolerance for the agent. […] Overall, there are a large number of factors that can influence drug metabolism, either by increasing clearance to cause drug failure, or by preventing clearance to lead to toxicity. In the real world, it is often impossible to delineate the different conflicting factors which result in net changes in drug clearance which cause a drug to fall out of, or climb above, the therapeutic window. It may only be possible clinically in many cases to try to change what appears to be the major cause to bring about a resolution of the situation to restore curative and non-toxic drug levels.”

“Most population studies of human polymorphisms list the allelic frequency, that is, how many of an ethnic group contain the alleles in question. […] The actual haplotypes in the population, that is, which individuals express which combinations of alleles, are not the same as the population allelic frequency. […] If an SNP or a combination of SNPs is a fairly mild defect in the enzyme when it is homozygously expressed, then the heterozygotes will show little impairment and the polymorphism may be clinically irrelevant. With other SNPs, the enzyme produced may be completely non-functional.  Homozygotes will be virtually unable to clear the drug and heterozygotes will show impairment also. There are also smaller populations of UMs, or ultra rapid metabolizers which may have a feature of their enzyme which either makes it super efficient or expressed in abnormally high amounts. […] Phenotyping will group patients in very broad EMs [extensive metabolizers], IMs [intermediate metabolizers] or PM [poor metabolizers] categories, but will be unable to distinguish between heterozygous and homozygous EMs. Although genotyping may be very helpful in dosage estimation in the initiation of therapy, there is no substitute for the normal process of therapeutic monitoring, which is effectively phenotyping the individual in the real world in terms of maximizing response and minimizing toxicity.”

“it is clear that there is a vast amount of genetic variation across humanity in terms of biotransformational capability and so the idea that in therapeutics, ‘one size fits all’ is not only outdated, but fabulously naïve. […] Unfortunately, detecting and responding successfully to human biotransformational polymorphisms has proved to be extremely problematic. In terms of polymorphism detection, this area is a classic illustration of how the exploration of the human genome with powerful molecular biological tools may unearth many apparently marked polymorphic defects that may not necessarily translate into a measurable clinical impact in terms of efficacy and toxicity. In reality, many more scientists have the opportunity to discover and publish such polymorphisms in vitro, than there are clinical scientists, resources and indeed cooperative volunteers or patients in sufficient quantity to determine practical clinical relevance.”

the CYP3A group (chromosome 7) metabolize around half of all drugs […] variation in the metabolism of CYP3A substrates […] can be up to ten-fold in terms of drug clearances and up to 90-fold in liver protein expression. […] It is likely that the full extent of the variation in CYP3A4 is still to be discovered […] While it is thought that CYP3A4 is not subject to an obvious major polymorphism, CYP3A5 definitely is. […] *3/*3 individuals form no serviceable CYP3A5. Functional CYP3A5 is found in around 20 per cent of Caucasians, half of Chinese/Japanese, 70 per cent of Hispanics and more than 80 per cent of African Americans.”

“A particularly dangerous polymorphism clinically was identified in the 1980s for one of the methyltransferases. The endogenous role of S-methylating thiopurine S-methyltransferase (TPMT) is not that clear, but […] [t]hese drugs are […] effective in some childhood leukaemias […] TPMT highlights the genotyping/phenotyping issue mentioned earlier in the management of patients with polymorphisms. Genotyping will reveal the level of TPMT expression that should be expected in the otherwise healthy patient. However, there are many factors which impact day-to-day TPMT expression during thiopurine therapy. […] Hence, what might be predicted from a genotype test may bear little resemblance to how the enzyme is performing on a particular day in a treatment cycle. So clinically, it is preferred to test actual TPMT activity.”

“Understanding of sulphonation and its roles in endogenous as well as xenobiotic metabolism is not as advanced compared with that of CYPs; however, the role of SULTs in the activation of carcinogens is becoming more apparent. One of the major influences on SULT activity is their polymorphic nature; in the case of one of the most important toxicologically relevant SULTs, SULT1A1, this isoform exists as three variants, SULT1A1*1 (wild-type), SULT1A1*2 and SULT1A1*3. The *1 variant allele is found in the majority of Caucasians (around 65 per cent), whilst the *2 variant differs only in the exchange of one amino acid for another. This single amino acid change has profound effects on the stability and catalytic activity of the isoform. The *2 variant is found in approximately 32 per cent of Caucasians and catalytically faulty […] About 9 in 10 Chinese people have the *1 allele and about 8 per cent have allele *2. About half of African-Americans have *1 and a third have *2. Interestingly, there is a *3 which is rare in most races but accounts for more than 22 per cent of African Americans. There is also considerable variation in SULT2A1 and SULT2B1, which are the major hydroxysteroid sulphators in the body, which may have implications for sex steroid and cholesterol handling. […] from the cancer-risk viewpoint, a highly active SULT1A1 *1 is usually an advantage in that it usually removes reactive species rapidly as stable sulphates. With some agents it is problematic as certain carcinogens such as acetylfluorene are indirectly activated to reactive species by SULTs. In addition, protective dietary flavonoids […] are also rapidly cleared by SULT1A1 *1, so there is a combination of production of toxins and loss of protective dietary agents. In terms of carcinogenesis risk, SULT1A1*2 could be a liability as potentially damaging substrates such as electrophilic toxins cannot be cleared rapidly. However, in some circumstances the *2 allele can be rather protective as […] it also allows protective agents [to] remain in tissues for longer periods. The combinations are endless and so it is often extremely difficult to predict risks of carcinogenicity for individuals and toxin exposures.”

GSTs are polymorphic and much research has been directed at linking increased predisposition to cytotoxicity and carcinogenicity with defective GST phenotypes. Active wild-type GSTMu-1 is found in around 60 per cent of Caucasians, but a non-functional version of the isoform is found in the remainder. […] GST-M1 null (non-functional alleles) can predispose to risks of prostate abnormalities and GST Pi is subject to several SNPs and many attempts have been made to link these SNPs with the consequences of failure to detoxify reactive species, such as the risk of lung cancer. […] Carcinogenesis may be due to a complex mix of factors, where different enzyme expression and activities may combine with particular reactive species from specific parent xenobiotics that lead to DNA damage only in certain individuals. Resolving specific risk factors may be extremely difficult in such circumstances. […] in cancer chemotherapy, there is evidence that the presence of GST-M1 and GST-T1 null (non-functional) alleles predisposes children to a six-fold higher level of adverse events usually seen with antineoplastic drugs, such as bone marrow damage, nephrotoxicity and neurotoxicity.”

“The effects of age on drug clearance and metabolism have been known since the 1950s, but they have been extensively investigated in the last 20 or so years. It is now generally accepted that at the extremes of life, neonatal and geriatric, drug clearance can be significantly different from the rest of humanity. In general, neonates, i.e. those less than four weeks old, cannot clear certain agents due to immaturity of drug metabolizing systems. Those over retirement age cannot clear the drugs due to loss of efficiency in their metabolizing systems. Either way, the net result can be toxicity due to drug accumulation. […] It seems that the inability of older people to clear drugs is not necessarily related to the efficacy of their CYP-mediated oxidations, which are often not much different from that of younger individuals. Studies with the major CYPs in vitro have revealed that CYP2D6 is unaffected by age, as are most other CYPs, with the exception of CYP1A2, which does decline in activity in the elderly. […] In general, there is little significant change in the inducibility in most CYPs, or in the capability of conjugation systems in vitro. […] there are significant changes in the liver itself, as it decreases in mass and its blood flow is reduced as we age. This occurs at the rate of around 0.5–1.5 per cent per year, so by the time we hit 60–70, we may have up to a 40 per cent decline in liver blood flow compared with a 30-year-old. Other factors include gradual decline in renal function, increased fat deposits and reduction in gut blood flow, which affects absorption. […] The problem arises that the drug’s bioavailability increases due to lack of first-pass clearance; this means that from a standard dose, blood levels can be considerably higher than would be expected in a 40-year-old. This can be a serious problem in drugs with a narrow TI, such as antiarrhythmics. In addition, average doses of warfarin required to provide therapeutic anticoagulation in the elderly are less than half those required for younger people. The person’s lifelong smoking and drinking habits, as well as older individuals ’ sometimes erratic diet also complicate this situation. Among the drugs cleared more slowly in older people are antipsychotics, paracetamol, antidepressants, benzodiazepines, warfarin, beta-blockers and indomethicin.”

“Thousands of polyphenols are found in plants, vegetables, fruit, as well as tea, coffee, wine and fruit juices. […] Flavonoids such as quercetin and fisetin are excellent substrates for COMT, so competitively inhibiting the metabolism of endogenous catecholamine and catechol oestrogens. Quercetin and other polyphenols are found in various foods such as soy (genestein) and they are potent inhibitors of SULT1A1 which sulphate endogenous oestrogens, so potentiating the effects of oestrogens in the body. Many of these flavonoids and isoflavonoids are manufactured and sold as cancer preventative agents; however, it is more likely that their elevation of oestrogen levels may have the opposite effect in the long term. It is also likely that various polyphenols influence other endogenous substrates of sulphotransferases, such as thyroid hormones and various catecholamines. It is gradually becoming apparent that polyphenols can induce UGTs, indeed; it would be surprising if they did not. […] Overall, it is likely that there are a large number of polyphenols that are potent modulators of CYPs and conjugative enzymes. […] It is clear that diet can substantially modulate biotransformation […] As to the effects on prescription drugs, […] abrupt changes in a person’s diet may significantly alter the clearance of drugs and lead to loss of efficacy or toxicity.”

In general, experimental or ‘probe’ drugs […] which are used to study the activities of a number of CYPs, are metabolized more quickly by women than men. This is allowing for differences in weight, fat distribution (body mass index) and volume of distribution […] It appears that CYP expression is linked to growth hormone (GH) and about the same amount is secreted over 24 hours in both sexes. In animals the pattern of release of the hormone is crucial to the effects on the CYPs; in females, GH is secreted in small but more or less continuous pulses, while males secrete large pulses, then periods of no secretion. The system is thought to be similar in humans. […] Little is known of the effects of the menopause and hormone replacement, where steroid metabolism changes dramatically. It is highly likely that these events could have profound effects on female drug clearance. […] females in general are more susceptible to drug adverse reactions than males, especially hepatotoxic effects.”

“For those chronically dependent on ethanol their CYP2E1 levels can be ten-fold higher than non-drinkers and they would clear CYP2E1 substrates extremely quickly if they chose to be sober for a period of time. This may lead to the accumulation of metabolites of the substrates. It is apparent that alcoholics who are sober can suffer paracetamol (acetaminophen)-induced liver toxicity at overdoses of around half that of non-drinkers, which is due to CYP2E1 induction. […]  the vast variation in ADH [alcohol dehydrogenase] catalytic activity across the human race is mainly due to just a few SNPs that profoundly change the efficiency of the isoforms. ADH1B/*1 is the most effective variant and is the ADH wild-type […] Part of a ‘successful’ career as an alcoholic depends possessing the ADH1B/*1 isoform. The other defective isoforms are found in low frequencies in alcoholics and cirrhotics. […] in the vast majority of individuals, whatever their variant of ADH, they are able to process acetaldehyde to acetate and water, as the consequences of failing to do this are severe. With ALDH, the wild-type and gold standard is ALDH2*1/*1, which has the highest activity of all these isoforms and is the second essential component for an alcoholic career. […] the variant ALDH2*1/*2 has less than a quarter of the wild-type’s capacity and is found predominantly in Eastern races. The variant ALDH2*2/*2 is completely useless and renders the individuals very sensitive to acetaldehyde poisoning, although the toxin is removed eventually by ALDH1A1 which does not seem to be affected by polymorphisms. In a survey of 1300 Japanese alcoholics, there was nobody at all with the ALDH2*2/*2 variant. […] Women are much more vulnerable to ethanol damage and on average die in half the time it generally takes for a male alcoholic to drink himself to death. Women drink much less than men also – one study indicated that a group of women consumed about 14,000 drinks to induce cirrhosis, whilst men required more than 44,000 to achieve the same effect. Ethanol distributes in total body water only, so in women their greater fat content means that blood ethanol levels are higher than men of similar weight and age.

September 15, 2016 Posted by | books, genetics, medicine, Pharmacology | Leave a comment

Some US immigration data

I have had a look at two sources, the Office of Refugee Resettlement’s annual reports to Congress for the financial years 2013 and 2014. I have posted some data from the reports below. In the cases where the page numbers are not included directly in the screen-caps, all page numbers given below are the page numbers of the pdf version of the documents.

I had some trouble with how to deal with the images included in the post; I hope it looks okay now, at least it does on my laptop – but if it doesn’t, I’m not sure I care enough to try to figure out how to resolve the problem. Anyway, to the data!

The one above is the only figure/chart from the 2014 report, but I figured it was worth including here. It’s from page 98 of the report. It’s of some note that, despite the recent drop, 42.8% of the 2014 US arrivals worked/had worked during the year they arrived; in comparison, only 494 of Sweden’s roughly 163.000 asylum seekers who arrived during the year 2015 landed a job that year (link).

All further images/charts below are from the 2013 report.

(p. 75)


It’s noteworthy here how different the US employment gap is to e.g. the employment gap in Denmark. In Denmark the employment rate of refugees with fugitive status who have stayed in the country for 5 years is 34%, and the employment rate of refugees with fugitive status who have stayed in the country for 15 years is 37%, compared to a native employment rate of ~74% (link). But just like in Denmark, in the US it matters a great deal where the refugees are coming from:


“Since their arrival in the U.S., 59 percent of refugees in the five-year population worked at one point. This rate was highest for refugees from Latin America (85 percent) and lowest for refugees from the Middle East (48 percent), while refugees from South/Southeast Asia (61 percent) and Africa (59 percent) were positioned in between. […] The highest disparity between male and female labor force participation rates was found for respondents from  the Middle East (64.1 percent for males vs. 34.5 percent for females, a gap of 30 points). A sizeable gender gap  was also found among refugees from South/Southeast Asia (24 percentage points) and Africa (18 percentage  points), but there was hardly any gap among Latin American refugees (3 percentage points).  Among all refugee  groups, 71 percent of males were working or looking for work at the time of the 2013 survey, compared with 49  percent of females.” (p.94)

Two tables (both are from page 103 of the 2013 report):



When judged by variables such as home ownership and the proportion of people who survive on public assistance, people who have stayed longer do better (Table II-16). But if you consider table II-17, a much larger proportion of the refugees surveyed in 2013 than in 2008 are partially dependent on public assistance, and it seems that a substantially smaller proportion of the refugees living in the US in the year 2013 was totally self-reliant than was the case 5 years earlier. Fortunately the 2013 report has a bit more data on this stuff (p. 107):


The table has more information on page 108, with more details about specific public assistance programs.Table II-22 includes data on how public assistance utilization has developed over time (it’s clear that utilization rates increased substantially during the half-decade observed):


Some related comments from the report:

“Use of non-cash assistance was generally higher than cash assistance. This is probably because Medicaid, the Supplemental Nutrition Assistance Program (SNAP), and housing assistance programs, though available to cash assistance households, also are available more broadly to households without children. SNAP utilization was lowest among Latin Americans (37 percent) but much higher for the other groups, reaching 89 to 91 percent among the refugees from Africa and the Middle East. […] Housing assistance varied by refugee group — as low as 4 percent for Latin American refugees and as high as 32 percent for refugees from South/Southeast Asia in the 2013 survey. In the same period, other refugee groups averaged use of housing assistance between 19 and 31 percent.” (pp. 107-108)

The report includes some specific data on Iraqi refugees – here’s one table from that section:


The employment rate of the Iraqis increased from 29.8% in the 2009 survey to 41.3% in 2013. However the US female employment rate is still actually not much different from the female employment rates you observe when you look at European data on these topics – just 29%, up from 18.8% in 2009. As a comparison, in the year 2010 the employment rate of Iraqi females living in Denmark was 28% (n=10163) (data from p.55 of the Statistics Denmark publication Indvandrere i Danmark 2011), almost exactly the same as the employment rate of female Iraqis in the US.

Of note in the context of the US data is perhaps also the fact that despite the employment rate going up for females in the time period observed, the labour market participation rate of this group actually decreased between 2009 and 2013, as it went from 42.2% to 38.1%. So more than 3 out of 5 Iraqi female refugees living in the US are outside the labour market, and almost one in four of those that are not are unemployed. A few observations from the report:

“The survey found that the overall EPR [employment rate, US] for the 2007 to 2009 Iraqi refugee group in the 2013 survey9 was 41 percent (55 percent for males and 29 percent for females), a steady increase in the overall rate from 39 percent in the 2012 survey, 36 percent in the 2011 survey, 31 percent in the 2010 survey, and 30 percent in the 2009 survey. As a point of further reference, the EPR for the general U.S. population was 58.5 percent in 2013, about 17 percentage points higher than that of the 2007 to 2009 Iraqi refugee group (41.3 percent). The U.S. male population EPR was nine percentage points higher than the rate for Iraqi males who arrived in the U.S. in 2007 to 2009 (64 percent versus 55 percent), while the rate for the Iraqi females who arrived in the U.S. in 2007 to 2009 was 24 points higher for all U.S. women (53 percent versus 29 percent). The difference between the male and female EPRs among the same group of Iraqi refugees (26 percentage points) also was much larger than the gap between male and female EPRs in the general U.S. population (11 points) […] The overall unemployment rate for the 2007 to 2009 Iraqi refugee group was 22.9 percent in the 2013 survey, about four times higher than that of the general U.S. population (6.5 percent) in 2013” (pp. 114-115).

September 10, 2016 Posted by | data, demographics, economics, immigration | Leave a comment

Diabetes and the Metabolic Syndrome in Mental Health (II)

Here’s my first post about the book. This will be my last post about the book. In the coverage below I’ll include some quotes from the second half of the publication, as well as some comments.

“To date, no prospective study has directly compared the efficacy and tolerability of selective serotonin reuptake inhibitors (SSRIs), serotonin/ norepinephrine reuptake inhibitors (SNRIs), or other second-generation antidepressants in patients with diabetes versus patients without diabetes.”

“Weight is a common and well-known adverse effect of short-term and long-term treatment with TCAs, primarily as a result of excessive appetite. […] weight gain is the most common cause for premature discontinuation of all TCAs. […] TCAs are […] likely to impair diabetes control, because they increase serum glucose levels by up to 150%, increase appetite (particularly carbohydrate craving), and reduce the metabolic rate. […] SSRIs have been associated with both weight gain and weight loss. […] Weight gain is less likely with SSRIs when they are used short term — for 6 months or less. Contradictory evidence exists about whether an increase in body weight occurs in patients using SSRIs for 1 year or longer. […] The mean incidence of weight gain across comparative randomized controlled trials ranges from 4.1% for fluoxetine, 7.6% for sertraline, and 9.6% for paroxetine. […] SSRIs may reduce serum glucose by up to 30% and cause appetite suppression, resulting in weight loss. Fluoxetine should be used cautiously in patients with diabetes, because of its increased potential for hypoglycemia […]. Its side effects of tremor, nausea, sweating, and anxiety may also be misinterpreted as due to hypoglycemia.”

“Prior to the development of the second-generation antipsychotics (SGAs), or atypical antipsychotics, phenothiazines were the dominant therapy for schizophrenia. Numerous studies at this time began documenting that the use of phenothiazines led to aggravation of preexisting diabetes and the development of new-onset type 2 diabetes. […] high-potency neuroleptics […] appeared to be less implicated in the development of diabetes. These drugs eventually became the predominant form of therapy for schizophrenia […] Unfortunately, the high-potency neuroleptics are also associated with a high rate of occurrence of extrapyramidal symptoms, tardive dyskinesia, and subsequent noncompliance […]  In the late 1980s, a new class of antipsychotics, the thiobenzodiazepines or “atypical antipsychotics,” was introduced. […] One major advantage of these agents was a marked reduction in the occurrence of extrapyramidal symptoms. […] However, the atypical antipsychotics have also proven to carry their own unique side-effect profile. Side effects include substantial weight gain […] lipid abnormalities […] Hyperglycemia and diabetes are strongly associated with some of the newer atypical antipsychotics […] Thus, many psychiatrists are finding themselves in the difficult position of trading efficacy in the treatment of schizophrenia for an array of adverse metabolic side effects.”

“Weight gain is one of the more noticeable effects of all of the psychotropics. Although the SGAs appear to be a major culprit, TCAs, lithium, and mood stabilizers such as valproic acid or divalproex sodium and carbamazepine are also associated with weight gain. […] A range of evidence suggests that treatment with certain antipsychotic medications is associated with an increased risk of insulin resistance, hyperglycemia, and type 2 diabetes, compared with no treatment or treatment with alternative antipsychotics. […] A growing body of evidence supports the key observation that treatments producing the greatest increases in body weight and adiposity are also associated with a consistent pattern of clinically significant adverse effects on insulin resistance and changes in blood glucose and lipid levels. However, there are a growing number of cases of antipsychotic-associated hyperglycemia that involve patients without substantial weight gain, and reports that involve patients who improve when the offending agent is discontinued or who experience deterioration of glycemic control when re-challenged with the drug. […] Antipsychotics may lead to diabetes in susceptible individuals by causing decreased insulin secretion, increased insulin resistance, or a combination of both. Data suggest, however, that insulin resistance is primarily the responsible mechanism. […] The mechanism through which antipsychotics lead to insulin resistance is not clear.

“Many drugs may influence glucose insulin homeostasis. Commonly prescribed drugs that may have adverse effects on carbohydrate metabolism, especially in patients with diabetes mellitus or those at risk of developing glucose intolerance, include diuretics, beta-blockers, sympathomimetics, corticosteroids, and sex hormones”.

The book’s Table 4.11 include a really nice list of drugs, or drug classes, that can increase blood glucose levels, which includes quite a few commonly used drugs. A couple of to me surprising culprits on that list were marijuana and oral contraceptives; the oral contraceptives one certainly makes a lot of sense in retrospect (I don’t really know much about the metabolism of marijuana/cannabis, all I’ve ever learned about that stuff includes what was covered in the appendix of Coleman’s excellent textbook – and I have no personal experience…), I just hadn’t thought about the fact that very commonly used drugs like these may also have side effects of this nature).

“Patients with depression or bipolar depression may lack interest in their well-being and suffer from difficulty maintaining focus. Furthermore, many depressed patients suffer from decreased energy, psychomotor retardation, and changes in appetite, which may further promote weight gain. All of these make it very challenging to successfully implement a weight loss program in depressed patients. […] In addition, many patients with mental illnesses such as depression […] often state that eating is one of the few highlights of their day.” (So it’s probably a good idea to avoid giving these people drugs which will cause them to gain a substantial amount of weight/increase appetite/increase carbohydrate cravings, to the extent that this is possible…)

“Diabetes is considered a coronary artery disease equivalent by the National Cholesterol Education Panel (NCEP) […] Aspirin therapy is considered a routine part of secondary prevention in people with diabetes and a history of cardiovascular disease, and it is also recommended as part of primary prevention for cardiovascular disease in all patients with diabetes older than 40 years of age; additionally treatment with 75 to 325 mg/day of aspirin should be considered in patients 30 to 40 years of age with one additional cardiovascular risk factor.1,13 […] for all people older than 40 years of age with diabetes, statin therapy is recommended to lower the LDL by 30% to 40%, regardless of baseline levels.14 […] Lowering triglycerides to levels less than 150 mg/dL also confers cardiovascular benefit.1,14 However, hyperglycemia and hypertriglyceridemia are intricately linked, likely through elevations of free fatty acids. Free fatty acids are potent inhibitors of insulin action and transport, and act to disrupt glucose transport into skeletal muscle. Thus, triglyceride goals are often difficult to attain in uncontrolled diabetes.”

In some weird way some aspects of the last part of the book’s coverage was quite funny. So you have a diabetic whose disease has caused extensive damage to the nervous system leading to painful neuropathy. How do you treat the (in general difficult to treat) symptoms of neuropathy? Why, you give him tricyclic antidepressants (which will of course make his diabetes harder to treat, and cause him to gain weight). No, I’m not making this up:

“The most widely used medical treatments for symptoms of diabetic neuropathy include gabapentin and tricyclic antidepressants.”

Or how about this one – you have a type 2 diabetic who’s most likely overweight and who could probably benefit quite a bit from losing weight; why, let’s treat his diabetes with a drug that causes him to gain weight! People actually do this: “Thiazolidinediones (rosiglitazone, pioglitazone) act as agonists of the peroxisome proliferator-activator receptor gamma and improve insulin sensitivity at the tissue level. These agents are contraindicated in patients with heart failure and can worsen peripheral edema. Unfortunately, a common side effect of the glitazone class of agents is weight gain.” They’re not first-line agents, but they are used in diabetics. Just to make things even better, these drugs also seem to increase the risk of osteoporosis, a risk which is already somewhat elevated in type 2 diabetics: “Additionally, these drugs [thiazolidinediones] appear to decrease appendicular bone mass with associated increased risk of fractures.34

…or perhaps now some people might start thinking here: ‘Is stuff like this actually part of the explanation for Vestergaard’s findings described in the link above?’ I should add to these people that this is unlikely to be the case, especially considering the big difference between the (really quite substantial) type 1- and (significantly lower) type 2 fracture risk elevation; thiazolidinediones are not used in the treatment of type 1, and it’s not even a first-line treatment of type 2 – other explanations, such as those covered in Czernik & Fowlkes’s text, seem much more likely to matter (though in the context of a few individuals these drugs may still be of relevance).

“In addition to glycemic goals, nonglycemic treatment goals of blood pressure control, lipid management, and initiation of aspirin therapy are often necessary. For many patients, the diagnosis of diabetes results in multidrug therapy. For patients with mental illness who are likely to already be on multiple medications, the addition of several new agents can be difficult. Several studies have suggested that medication adherence in patients with psychiatric illness is poor at baseline,38 and may worsen when an increasing number of medications are prescribed.”

It’s also worth remembering here that “asymptomatic and chronic diseases needing long-term treatment […] result in poorer compliance”, although on the other hand “patient-controlled non-compliance [is] lower in treatment for diseases in which the relationship between non-compliance and recurrence is very clear, such as diabetes, compared to treatment for diseases in which this relationship is less clear” (Kermani and Davies). Combine psychiatric disease with chronic illnesses of a different kind and potential polypharmacy and non-compliance certainly becomes an issue worth taking into account when considering what might be the optimal treatment regime. It’s also worth keeping in mind that even in people without psychiatric problems adherence tends to be low in the case of antihypertensives and lipid-lowering drugs – again I refer to Kermani and Davies’ text:

“Chapman et al. (2005) recently examined compliance with concomitant antihypertensive and lipid-lowering drug therapy in 8406 enrollees in a US-managed care plan […] Less than half of patients (44.7 per cent) were adherent with both therapies three months after medication initiation, a figure that decreased to 35.8 per cent at 12 months.”

September 7, 2016 Posted by | books, diabetes, medicine | Leave a comment

Promoting the unknown

No other interpretation of this piece even comes close to Zimerman’s, in my opinion. This is as good as it gets.


September 3, 2016 Posted by | music | Leave a comment


A few days ago I decided to have a closer look at goodreads’ quotes and how that part of the site worked. I have now added a little more than 1000 quotes to my personal quote collection on the site, many (literally hundreds) of which are quotes I have added myself to the goodreads quote library. Most of them are naturally quotes taken from the blog – the quote collection I have here is still far larger than is my goodreads collection, but at least in terms of the ‘better than average quotes’ posted here on the blog I do believe I’ve transferred/duplicated a rather substantial proportion of those quotes to goodreads by now.

Although some aspects of the site’s functionality is nice, I thoroughly dislike other aspects of the way the goodreads site works and handles specific problems. Wikiquote has for a long time been my go-to place for quotes, and it’ll remain so for the foreseeable future, barring any sudden unexpected changes of a profoundly negative nature. A really huge problem I have with the way goodreads handles these things is that if a specific quote contains an error, e.g. is missing a comma or is attributed to the wrong person, you cannot correct the error yourself, even if you know it’s an error and you literally sit there with the book in front of you, and to make matters (much) worse you often cannot even add a new quote with correct attribution; if a new quote you add is ‘sufficiently similar’ to an erroneous/misattributed quote already added to the site, you trying to add a correct quote will only lead to you automatically ‘liking’ the original flawed quote you were annoyed about and the corrected quote you tried to add will not be added. I’m still quite annoyed that one of Marie von Ebner-Eschenbach‘s really nice maxims on goodreads have been attributed by some ignorant £$@! to Jane Austen, but that’s just one of several examples I’ve encountered. There are multiple cases where I have decided not to add a specific quote because I refuse on principle to ‘like’ a quote containing an error, and/but there are also a few cases where I have bit the metaphorical bullet, after some thought, and liked a quote despite it not matching perfectly the version of the quote with which I was myself familiar (this has mostly been in the case of quotes by non-English speaking individuals, where at least some leeway can be argued to exist on account of issues pertaining to translation). I found it somewhat irritating that some really quite notable people seem to not be considered notable on goodreads (notability is a requirement for quotation, and goodreads does not allow anonymous quotes/proverbs etc. in the quotes section); for example I found myself trying in vain to add a quote by a Nobel Prize winner in Physics at some point, but the guy hadn’t written any books added to the site and so when trying to add the name after having written out the quote I realized I couldn’t do that; at least it was not immediately obvious to me how to handle this problem, and so I let it go on account of it being just one quote. Books with multiple authors also cause some problems (one specific one of which I’ve now at least partially figured out how to handle, fortunately), and books with many contributors still pose questions to which I do not know the answer; it doesn’t seem to me like the goodreads site in its current format even enables you theoretically in any way to attribute quotes taken from such books correctly – at least I haven’t found out how to do it.

So all in all I’m not particularly impressed with the site in terms of how it handles quotes, but on the other hand if you’re less interested in adding obscure quotes by people almost nobody alive today have ever heard about than I am, and would rather just like an easy way to collect/manage/remember quotes you happen to like, the site’s probably not really bad at all; it’s very easy to add new quotes to your collection if the quote is already in the goodreads library (it takes a little bit of work if it’s not). You can let my collection be a starting point if you like the sort of quotes I do; I know a few people in the past have said that they liked the quotes I’ve posted on the blog and now you have a quite easy way to just ‘grab’ those of ‘my’ quotes (quotes are posted anonymously on goodreads, so the quotes I have added are no more my quotes than they are yours) you like, and leave the rest.

Below I’ve added the 20 new quotes I usually post in my regular quotes posts, all of which (as far as I have been able to ascertain) have not been posted here before.

i. “Though what we accept be true, it is a prejudice unless we ourselves have considered and understood why and how it is true.” (John Lancaster Spalding)

ii. “However firmly thou holdest to thy opinions, if truth appears on the opposite side, throw down thy arms at once.” (-ll-)

iii. “The ultimate result of shielding men from the effects of folly, is to fill the world with fools.” (Herbert Spencer)

iv. “We often do not see what we do not expect to see.” (Alan Lightman)

v. “The past and future are veiled; but the past wears the widow’s veil; the future, the virgin’s.” (Jean Paul Richter)

vi. “There is no duty we so much underrate as the duty of being happy.” (Robert Louis Stevenson)

vii. “Science may be described as the art of systematic over-simplification — the art of discerning what we may with advantage omit.” (Karl Popper)

viii. “I hold that he who teaches that not reason but love should rule opens up the way for those who rule by hate.” (-ll-)

ix. “You cannot have a rational discussion with a man who prefers shooting you to being convinced by you.” (-ll-)

x. “There is an almost universal tendency, perhaps an inborn tendency, to suspect the good faith of a man who holds opinions that differ from our own opinions.” (-ll-)

xi. “Always remember that it is impossible to speak in such a way that you cannot be misunderstood: there will always be some who misunderstand you.” (-ll-)

xii. “The more we learn about the world, and the deeper our learning, the more conscious, specific, and articulate will be our knowledge of what we do not know, our knowledge of our ignorance.” (-ll-)

xiii. “Methodological rules are for science what rules of law and custom are for conduct.” (Émile Durkheim)

xiv. “Men apt to promise, are apt to forget.” (Thomas Fuller)

xv. “Since people of necessity see things from their own perspective, much of what they say adds up to comforting ideas or outright propaganda for themselves and the groups to which they belong.” (Patricia Crone, Pre-Industrial Societies: Anatomy of the Pre-Modern World)

xvi. “… humans are animals. It would not occur to an ethologist studying ants, lions, wolves or giraffes to argue that ‘ultimately’ it is the animal’s need for food which determines the type of society in which it lives, or its need to reproduce, or its mechanisms of defence against predators, or whatever. On the contrary, he will see the society in question as the outcome of a compromise between a variety of fundamental needs and the environment in which it is set. Precisely the same is true of human societies. […] all attempts to explain human history in terms of a single factor are misguided.” (-ll-)

xvii. “Science doesn’t purvey absolute truth. Science is a mechanism. It’s a way of trying to improve your knowledge of nature. It’s a system for testing your thoughts against the universe and seeing whether they match.” (Isaac Asimov)

xviii. “Where any answer is possible, all answers are meaningless.” (-ll-)

xix. “There are no happy endings in history, only crisis points that pass.” (-ll-)

xx. “To write is to read one’s own self” (Max Frisch)

August 30, 2016 Posted by | books, quotes | Leave a comment


I recently read Nick Middleton’s short publication on this topic and decided it was worth blogging it here. I gave the publication 3 stars on goodreads; you can read my goodreads review of the book here.

In this post I’ll quote a bit from the book and add some details I thought were interesting.

“None of [the] approaches to desert definition is foolproof. All have their advantages and drawbacks. However, each approach delivers […] global map[s] of deserts and semi-deserts that [are] broadly similar […] Roughly, deserts cover about one-quarter of our planet’s land area, and semi-deserts another quarter.”

“High temperatures and a paucity of rainfall are two aspects of climate that many people routinely associate with deserts […] However, desert climates also embrace other extremes. Many arid zones experience freezing temperatures and snowfall is commonplace, particularly in those situated outside the tropics. […] For much of the time, desert skies are cloud-free, meaning deserts receive larger amounts of sunshine than any other natural environment. […] Most of the water vapour in the world’s atmosphere is supplied by evaporation from the oceans, so the more remote a location is from this source the more likely it is that any moisture in the air will have been lost by precipitation before it reaches continental interiors. The deserts of Central Asia illustrate this principle well: most of the moisture in the air is lost before it reaches the heart of the continent […] A clear distinction can be made between deserts in continental interiors and those on their coastal margins when it comes to the range of temperatures experienced. Oceans tend to exert a moderating influence on temperature, reducing extremes, so the greatest ranges of temperature are found far from the sea while coastal deserts experience a much more limited range. […] Freezing temperatures occur particularly in the mid-latitude deserts, but by no means exclusively so. […] snowfall occurs at the Algerian oasis towns of Ouagla and Ghardaia, in the northern Sahara, as often as once every 10 years on average.”

“[One] characteristic of rainfall in deserts is its variability from year to year which in many respects makes annual average statistics seem like nonsense. A very arid desert area may go for several years with no rain at all […]. It may then receive a whole ‘average’ year’s rainfall in just one storm […] Rainfall in deserts is also typically very variable in space as well as time. Hence, desert rainfall is frequently described as being ‘spotty’. This spottiness occurs because desert storms are often convective, raining in a relatively small area, perhaps just a few kilometres across. […] Climates can vary over a wide range of spatial scales […] Changes in temperature, wind, relative humidity, and other elements of climate can be detected over short distances, and this variability on a small scale creates distinctive climates in small areas. These are microclimates, different in some way from the conditions prevailing over the surrounding area as a whole. At the smallest scale, the shade given by an individual plant can be described as a microclimate. Over larger distances, the surface temperature of the sand in a dune will frequently be significantly different from a nearby dry salt lake because of the different properties of the two types of surface. […] Microclimates are important because they exert a critical control over all sorts of phenomena. These include areas suitable for plant and animal communities to develop, the ways in which rocks are broken down, and the speed at which these processes occur.”

“The level of temperature prevailing when precipitation occurs is important for an area’s water balance and its degree of aridity. A rainy season that occurs during the warm summer months, when evaporation is greatest, makes for a climate that is more arid than if precipitation is distributed more evenly throughout the year.”

“The extremely arid conditions of today[‘s Sahara Desert] have prevailed for only a few thousand years. There is lots of evidence to suggest that the Sahara was lush, nearly completely covered with grasses and shrubs, with many lakes that supported antelope, giraffe, elephant, hippopotamus, crocodile, and human populations in regions that today have almost no measurable precipitation. This ‘African Humid Period’ began around 15,000 years ago and came to an end around 10,000 years later. […] Globally, at the height of the most recent glacial period some 18,000 years ago, almost 50% of the land area between 30°N and 30°S was covered by two vast belts of sand, often called ‘sand seas’. Today, about 10% of this area is covered by sand seas. […] Around one-third of the Arabian subcontinent is covered by sandy deserts”.

“Much of the drainage in deserts is internal, as in Central Asia. Their rivers never reach the sea, but take water to interior basins. […] Salt is a common constituent of desert soils. The generally low levels of rainfall means that salts are seldom washed away through soils and therefore tend to accumulate in certain parts of the landscape. Large amounts of common salt (sodium chloride, or halite), which is very soluble in water, are found in some hyper-arid deserts.”

“Many deserts are very rich in rare and unique species thanks to their evolution in relative geographical isolation. Many of these plants and animals have adapted in remarkable ways to deal with the aridity and extremes of temperature. Indeed, some of these adaptations contribute to the apparent lifelessness of deserts simply because a good way to avoid some of the harsh conditions is to hide. Some small creatures spend hot days burrowed beneath the soil surface. In a similar way, certain desert plants spend most of the year and much of their lives dormant, as seeds waiting for the right conditions, brought on by a burst of rainfall. Given that desert rainstorms can be very variable in time and in space, many activities in the desert ecosystem occur only sporadically, as pulses of activity driven by the occasional cloudburst. […] The general scarcity of water is the most important, though by no means the only, environmental challenge faced by desert organisms. Limited supplies of food and nutrients, friable soils, high levels of solar radiation, high daytime temperatures, and the large diurnal temperature range are other challenges posed by desert conditions. These conditions are not always distributed evenly across a desert landscape, and the existence of more benign microenvironments is particularly important for desert plants and animals. Patches of terrain that are more biologically productive than their surroundings occur in even the most arid desert, geographical patterns caused by many factors, not only the simple availability of water.”

A small side note here: The book includes brief coverage of things like crassulacean acid metabolism and related topics covered in much more detail in Beer et al. I’m not going to go into that stuff here as this stuff was in my opinion much better covered in the latter book (some people might disagree, but people who would do that would at least have to admit that the coverage in Beer et al. is/was much more comprehensive than is Middleton’s coverage in this book). There are quite a few other topics included in the book which I did not include coverage of here in the post but I mention this topic in particular in part because I thought it was actually a good example underscoring how this book is very much just a very brief introduction; you can write book chapters, if not books, about some of the topics Middleton devotes a couple of paragraphs to in his coverage, which is but to be expected given the nature and range of coverage of the publication.

Plants aren’t ‘smart’ given any conventional definition of the word, but as I’ve talked about before here on the blog (e.g. here) when you look closer at the way they grow and ‘behave’ over the very long term, some of the things they do are actually at the very least ‘not really all that stupid’:

“The seeds of annuals germinate only when enough water is available to support the entire life cycle. Germinating after just a brief shower could be fatal, so mechanisms have developed for seeds to respond solely when sufficient water is available. Seeds germinate only when their protective seed coats have been broken down, allowing water to enter the seed and growth to begin. The seed coats of many desert species contain chemicals that repel water. These compounds are washed away by large amounts of water, but a short shower will not generate enough to remove all the water-repelling chemicals. Other species have very thick seed coats that are gradually worn away physically by abrasion as moving water knocks the seeds against stones and pebbles.”

What about animals? One thing I learned from this publication is that it turns out that being a mammal will, all else equal, definitely not give you a competitive edge in a hot desert environment:

“The need to conserve water is important to all creatures that live in hot deserts, but for mammals it is particularly crucial. In all environments mammals typically maintain a core body temperature of around 37–38°C, and those inhabiting most non-desert regions face the challenge of keeping their body temperature above the temperature of their environmental surrounds. In hot deserts, where environmental temperatures substantially exceed the body temperature on a regular basis, mammals face the reverse challenge. The only mechanism that will move heat out of an animal’s body against a temperature gradient is the evaporation of water, so maintenance of the core body temperature requires use of the resource that is by definition scarce in drylands.”

Humans? What about them?

“Certain aspects of a traditional mobile lifestyle have changed significantly for some groups of nomadic peoples. Herders in the Gobi desert in Mongolia pursue a way of life that in many ways has changed little since the times of the greatest of all nomadic leaders, Chinggis Khan, 750 years ago. They herd the same animals, eat the same foods, wear the same clothes, and still live in round felt-covered tents, traditional dwellings known in Mongolian as gers. Yet many gers now have a set of solar panels on the roof that powers a car battery, allowing an electric light to extend the day inside the tent. Some also have a television set.” (these remarks incidentally somehow reminded me of this brilliant Gary Larson cartoon)

“People have constructed dams to manage water resources in arid regions for thousands of years. One of the oldest was the Marib dam in Yemen, built about 3,000 years ago. Although this structure was designed to control water from flash floods, rather than for storage, the diverted flow was used to irrigate cropland. […] Although groundwater has been exploited for desert farmland using hand-dug underground channels for a very long time, the discovery of reserves of groundwater much deeper below some deserts has led to agricultural use on much larger scales in recent times. These deep groundwater reserves tend to be non-renewable, having built up during previous climatic periods of greater rainfall. Use of this fossil water has in many areas resulted in its rapid depletion.”

“Significant human impacts are thought to have a very long history in some deserts. One possible explanation for the paucity of rainfall in the interior of Australia is that early humans severely modified the landscape through their use of fire. Aboriginal people have used fire extensively in Central Australia for more than 20,000 years, particularly as an aid to hunting, but also for many other purposes, from clearing passages to producing smoke signals and promoting the growth of preferred plants. The theory suggests that regular burning converted the semi-arid zone’s mosaic of trees, shrubs, and grassland into the desert scrub seen today. This gradual change in the vegetation could have resulted in less moisture from plants reaching the atmosphere and hence the long-term desertification of the continent.” (I had never heard about this theory before, and so I of course have no idea if it’s correct or not – but it’s an interesting idea).

A few wikipedia links of interest:
Karakum Canal.
Atacama Desert.
Salar de Uyuni.
Taklamakan Desert.
Dust Bowl.
Namib Desert.


August 27, 2016 Posted by | anthropology, biology, books, Botany, Geography, Zoology | Leave a comment


i. “The more I write, the more I am convinced that the only way to write a popular story is to split it up into scenes, and have as little stuff between the scenes as possible.” (P. G. Wodehouse, Performing Flea. A long time ago I was working on a blog post covering this book, but I realized I’m probably not going to finish that one so I decided to include some of the quotes from the post here instead. He emphasizes the point made in this quote more than once in his letters, for example he writes in another letter that: “The longer I write, the more I realize the necessity for telling a story as far as possible in scenes, especially at the start.”)

ii. “The principle I always go on in writing a long story is to think of the characters in terms of actors in a play. I say to myself, when I invent a good character for an early scene: ‘If this were a musical comedy we should have to get somebody like Leslie Henson to play this part, and if he found that all he had was a short scene in act one, he would walk out. How, therefore, can I twist the story so as to give him more to do and keep him alive till the fall of the curtain?’ This generally works well and improves the story.” (P. G. Wodehouse, Performing Flea)

iii. “The absolute cast-iron good rule, I’m sure, in writing a story, is to introduce all your characters as early as possible – especially if they are going to play important parts later.” (-ll-)

iv. “I think the success of every novel depends largely on one or two high spots. The thing to do is to say to yourself ‘Which are my big scenes?’ and then get every drop of juice out of them.” (-ll-)

v. “I sometimes wonder if I really am a writer. When I look at the sixty-odd books in the shelf with my name on them, and reflect that ten million of them have been sold, it amazes me that I can have done it. I don’t know anything, and I seem incapable of learning … I feel like I’ve been fooling the public for fifty years.” (-ll-)

vi. “I don’t suppose that anything you say or anything I say will make the slightest damn bit of difference. You need dynamite to dislodge an idea that has got itself firmly rooted in the public mind.” (-ll-)

vii. “The day after graduating from college, I found fifty dollars in the foyer of my Chicago apartment building. The single bill had been folded into eighths and was packed with cocaine. It occurred to me then that if I played my cards right, I might never have to find a job. People lost things all the time. They left class rings on the sinks of public bathrooms and dropped gem-studded earrings at the doors of the opera house. My job was to keep my eyes open and find these things. I didn’t want to become one of those coots who combed the beaches of Lake Michigan with a metal detector, but if I paid attention and used my head, I might never have to work again.
The following afternoon, hung over from cocaine, I found twelve cents and an unopened tin of breath mints. Figuring in my previous fifty dollars, that amounted to an average of twenty-five dollars and six cents per day, which was still a decent wage. The next morning I discovered two pennies and a comb matted with short curly hairs. The day after that I found a peanut. It was then that I started to worry.” (David Sedaris, Naked)

viii. “If she’d had it her way, we would never have known about the cancer. It was our father’s idea to tell us, and she had fought it, agreeing only when he threatened to tell us himself. Our mother worried that once we found out, we would treat her differently, delicately. We might feel obliged to compliment her cooking and laugh at all her jokes, thinking always of the tumor she was trying so hard to forget. And that is exactly what we did. […] We were no longer calling our mother. Now we were picking up the telephone to call our mother with cancer.” (-ll-)

ix. “It was rather annoying to hear how kind she’d been; it entailed putting tiresome qualifications on his dislike for her.” (Kingsley Amis, Lucky Jim)

x. “the most noticeable characteristic of the past, as seen by him, at least, was that there was so much more of it now than formerly, with bits that were longer ago than had once seemed possible.” (Kingsley Amis, The Old Devils)

xi. “Why, you might wonder, should prisoners wear themselves out, working hard, ten years on end, in the camps? You’d think they’d say: No thank you, and that’s that. […] But that didn’t work. To outsmart you they thought up work-teams – but not teams like the ones in freedom, where every man is paid his separate wage. Everything was so arranged in the camp that the prisoners egged one another on. It was like this: either you got a bit extra or you all croaked.” (Aleksandr Solzhenitsyn, One Day in the Life of Ivan Denisovich)

xii. “‘Well, brothers, good-bye,’ said the captain with an embarrassed nod to his team-mates, and followed the guard out.
A few voices shouted: ‘Keep your pecker up.’ But what could you really say to him? They knew the cells, the 104th did, they’d built them. Brick walls, cement floor, no windows, a stove they lit only to melt the ice on the walls and make pools on the floor. You slept on bare boards, and if you’d any teeth left to eat with after all the chattering they’d be doing, they gave you three hundred grammes of bread day after day and hot skilly only on the third, sixth, and ninth.
Ten days. Ten days ‘hard’ in the cells – if you sat them out to the end your health would be ruined for the rest of your life. […] As for those who got fifteen ‘hard’ and sat them out – they went straight into a hole in the cold earth.” (-ll-)

xiii. “Shukhov gazed at the ceiling in silence. Now he didn’t know either whether he wanted freedom or not. At first he’d longed for it. Every night he’d counted the days of his stretch – how many had passed, how many were coming. And then he’d grown bored with counting. And then it became clear that men of his like wouldn’t ever be allowed to return home, that they’d be exiled. And whether his life would be any better there than here – who could tell?
Freedom meant one thing to him – home.
But they wouldn’t let him go home.” (-ll-)

xiv. “You want to know what I do? All right. Some guy comes in with a bandage around his head. We don’t mess about. We’ll soon have that off. He’s got a hole in his head. So what do we do. We stick a nail in it. Get the nail – a good rusty one – from the trash or wherever. And lead him out to the Waiting Room where he’s allowed to linger and holler for a while before we ferry him back to the night. […] Because I am a healer, everything I do heals, somehow. The thing called society is, I believe, insane. In the locker room the steel grilles are pasted with letters that say, Thanks for your kindness for making a tough time much easier to bear, and, If it wasn’t for all of you there at the hospital I don’t know how we would have survived. The doctors read these thankyou notes with tears in their eyes, especially when gratitude is expressed in a childish hand. Not Johnny Young, though. Perhaps he knows, as I do, that the letters are propitiatory. The children (‘7 yrs’) haven’t been here yet. They won’t be so grateful when we’re through.” (Martin Amis, Time’s Arrow.)

xv. “Like all of my friends, she’s a lousy judge of character.” (David Sedaris, Me Talk Pretty One Day)

xvi. “Nobody dreams of the things he already has.” (-ll-)

xvii. “The word phobic has its place when properly used, but lately it’s been declawed by the pompous insistence that most animosity is based upon fear rather than loathing. No credit is given for distinguishing between these two very different emotions. I fear snakes. I hate computers. My hatred is entrenched, and I nourish it daily. I’m comfortable with it, and no community outreach program will change my mind.” (-ll-)

xviii. “Of all the stumbling blocks inherent in learning this language [French], the greatest for me is the principle that each noun has a corresponding sex that affects both its articles and its adjectives. Because it is a female and lays eggs, a chicken is masculine. Vagina is masculine as well, while the word masculinity is feminine. Forced by the grammar to take a stand one way or the other, hermaphrodite is male and indecisiveness female. I spent months searching for some secret code before I realized that common sense has nothing to do with it. Hysteria, psychosis, torture, depression: I was told that if something is unpleasant, it’s probably feminine. This encouraged me, but the theory was blown by such masculine nouns as murder, toothache, and Rollerblade.” (-ll-)

xix. “By the time I reached my thirties, my brain had been strip-mined by a combination of drugs, alcohol, and the chemical solvents used at the refinishing company where I worked. Still, there were moments when, against all reason, I thought I might be a genius. These moments were provoked not by any particular accomplishment but by cocaine and crystal methamphetamine — drugs that allow you to lean over a mirror with a straw up your nose, suck up an entire week’s paycheck, and think, “God, I’m smart.”” (-ll-)

xx. “As youngsters, we participated in all the usual seaside activities — which were fun, until my father got involved and systematically chipped away at our pleasure. Miniature golf was ruined with a lengthy dissertation on impact, trajectory, and wind velocity, and our sand castles were critiqued with stifling lectures on the dynamics of the vaulted ceiling. We enjoyed swimming, until the mystery of tides was explained in such a way that the ocean seemed nothing more than an enormous saltwater toilet, flushing itself on a sad and predictable basis. […] [“]The goal is to better yourself. Meet some intellectuals. Read a book!” After all these years our father has never understood that we, his children, tend to gravitate toward the very people he’s spent his life warning us about.” (-ll-. There were several reasons why I really enjoyed Sedaris’ book, but the fact that here in this book was actually a character who in some respects seemed to find it natural to behave in a manner similar to the way I could see myself behave – in a setting where the behaviour in question might by some people be considered unusual, that is – was definitely one of them. (Though I’m also slightly conflicted here; I don’t like children very much, and there’s no conceivable universe in which I’d ever have six of them; in such a universe ‘I’ would not be ‘me‘. I’d also on a related note be much more inclined to warn children to stay away from ‘intellectuals’, rather than the opposite…)).

August 25, 2016 Posted by | books, quotes | Leave a comment


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:


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, medicine | Leave a comment

Random Stuff

i. On the youtube channel of the Institute for Advanced Studies there has been a lot of activity over the last week or two (far more than 100 new lectures have been uploaded, and it seems new uploads are still being added at this point), and I’ve been watching a few of the recently uploaded astrophysics lectures. They’re quite technical, but you can watch them and follow enough of the content to have an enjoyable time despite not understanding everything:

This is a good lecture, very interesting. One major point made early on: “the take-away message is that the most common planet in the galaxy, at least at shorter periods, are planets for which there is no analogue in the solar system. The most common kind of planet in the galaxy is a planet with a radius of two Earth radii.” Another big take-away message is that small planets seem to be quite common (as noted in the conclusions, “16% of Sun-like stars have an Earth-sized planet”).

Of the lectures included in this post this was the one I liked the least; there are too many (‘obstructive’) questions/interactions between lecturer and attendants along the way, and the interactions/questions are difficult to hear/understand. If you consider watching both this lecture and the lecture below, I would say that it would probably be wise to watch the lecture below this one before you watch this one; I concluded that in retrospect some of the observations made early on in the lecture below would have been useful to know about before watching this lecture. (The first half of the lecture below was incidentally to me somewhat easier to follow than was the second half, but especially the first half hour of it is really quite good, despite the bad start (which one can always blame on Microsoft…)).

ii. Words I’ve encountered recently (…or ‘recently’ – it’s been a while since I last posted one of these lists): Divagationsperiphrasis, reedy, architravesettpedipalp, tout, togs, edentulous, moue, tatty, tearaway, prorogue, piscine, fillip, sop, panniers, auxology, roister, prepossessing, cantle, catamite, couth, ordure, biddy, recrudescence, parvenu, scupper, husting, hackle, expatiate, affray, tatterdemalion, eructation, coppice, dekko, scull, fulmination, pollarding, grotty, secateurs, bumf (I must admit that I like this word – it seems fitting, somehow, to use that word for this concept…), durophagy, randy, (brief note to self: Advise people having children who ask me about suggestions for how to name them against using this name (or variants such as Randi), it does not seem like a great idea), effete, apricity, sororal, bint, coition, abaft, eaves, gadabout, lugubriously, retroussé, landlubber, deliquescence, antimacassar, inanition.

iii. “The point of rigour is not to destroy all intuition; instead, it should be used to destroy bad intuition while clarifying and elevating good intuition. It is only with a combination of both rigorous formalism and good intuition that one can tackle complex mathematical problems; one needs the former to correctly deal with the fine details, and the latter to correctly deal with the big picture. Without one or the other, you will spend a lot of time blundering around in the dark (which can be instructive, but is highly inefficient). So once you are fully comfortable with rigorous mathematical thinking, you should revisit your intuitions on the subject and use your new thinking skills to test and refine these intuitions rather than discard them. One way to do this is to ask yourself dumb questions; another is to relearn your field.” (Terry Tao, There’s more to mathematics than rigour and proofs)

iv. A century of trends in adult human height. A figure from the paper (Figure 3 – Change in adult height between the 1896 and 1996 birth cohorts):


(Click to view full size. WordPress seems to have changed the way you add images to a blog post – if this one is even so annoyingly large, I apologize, I have tried to minimize it while still retaining detail, but the original file is huge). An observation from the paper:

“Men were taller than women in every country, on average by ~11 cm in the 1896 birth cohort and ~12 cm in the 1996 birth cohort […]. In the 1896 birth cohort, the male-female height gap in countries where average height was low was slightly larger than in taller nations. In other words, at the turn of the 20th century, men seem to have had a relative advantage over women in undernourished compared to better-nourished populations.”

I haven’t studied the paper in any detail but intend to do so at a later point in time.

v. I found this paper, on Exercise and Glucose Metabolism in Persons with Diabetes Mellitus, interesting in part because I’ve been very surprised a few times by offhand online statements made by diabetic athletes, who had observed that their blood glucose really didn’t drop all that fast during exercise. Rapid and annoyingly large drops in blood glucose during exercise have been a really consistent feature of my own life with diabetes during adulthood. It seems that there may be big inter-individual differences in terms of the effects of exercise on glucose in diabetics. From the paper:

“Typically, prolonged moderate-intensity aerobic exercise (i.e., 30–70% of one’s VO2max) causes a reduction in glucose concentrations because of a failure in circulating insulin levels to decrease at the onset of exercise.12 During this type of physical activity, glucose utilization may be as high as 1.5 g/min in adolescents with type 1 diabetes13 and exceed 2.0 g/min in adults with type 1 diabetes,14 an amount that quickly lowers circulating glucose levels. Persons with type 1 diabetes have large interindividual differences in blood glucose responses to exercise, although some intraindividual reproducibility exists.15 The wide ranging glycemic responses among individuals appears to be related to differences in pre-exercise blood glucose concentrations, the level of circulating counterregulatory hormones and the type/duration of the activity.2

August 13, 2016 Posted by | astronomy, demographics, diabetes, language, Lectures, mathematics, Physics, random stuff | Leave a comment

Diabetes and the Metabolic Syndrome in Mental Health (I)

As I stated in my goodreads review, ‘If you’re a schizophrenic and/or you have a strong interest in e.g. the metabolic effects of various anti-psychotics, the book is a must-read’. If that’s not true, it’s a different matter. One reason why I didn’t give the book a higher rating is that many of the numbers in there are quite dated, which is a bit annoying because it means you might feel somewhat uncertain about how valid the estimates included still are at this point.

As pointed out in my coverage of the human drug metabolism text there are a lot of things that can influence the way that drugs are metabolized, and this text includes some details about a specific topic which may help to illustrate what I meant by stating in that post that people ‘self-experimenting’ may be taking on risks they may not be aware of. Now, diabetics who need insulin injections are taking a drug with a narrow therapeutic index, meaning that even small deviations from the optimal dose may have serious repercussions. A lot of things influence what is actually the optimal dose in a specific setting; food (“food is like a drug to a person with diabetes”, as pointed out in Matthew Neal’s endocrinology text, which is yet another text I, alas, have yet to cover here), sleep patterns, exercise (sometimes there may be an impact even days after you’ve exercised), stress, etc. all play a role, and even well-educated diabetics may not know all the details.

A lot of drugs also affect glucose metabolism and insulin sensitivity, one of the best known drug types of this nature probably being the corticosteroids because of their widespread use in a variety of disorders, including autoimmune disorders which tend to be more common in autoimmune forms of diabetes (mainly type 1). However many other types of drugs can also influence blood glucose, and on the topic of antidepressants and antipsychotics we actually know some stuff about these things and about how various medications influence glucose levels; it’s not a big coincidence that people have looked at this, they’ve done that because it has become clear that “[m]any medications, in particular psychotropics, including antidepressants, antipsychotics, and mood stabilizers, are associated with elevations in blood pressure, weight gain, dyslipidemias, and/or impaired glucose homeostasis.” (p. 49). Which may translate into an increased risk of type 2 diabetes, and impaired glucose control in diabetics. Incidentally the authors of this text observes in the text that: “Our research group was among the first in the field to identify a possible link between the development of obesity, diabetes, and other metabolic derangements (e.g., lipid abnormalities) and the use of newer, second-generation antipsychotic medications.” Did the people who took these drugs before this research was done/completed know that their medications might increase their risk of developing diabetes? No, because the people prescribing it didn’t know, nor did the people who developed the drugs. Some probably still don’t know, including some of the medical people prescribing these medications. But the knowledge is out there now, and the effect size is in the case of some drugs argued to be large enough to be clinically relevant. In the context of a ‘self-experimentation’-angle the example is also interesting because the negative effect in question here is significantly delayed; type 2 diabetes takes time to develop, and this is an undesirable outcome which you’re not going to spot the way you might link a headache the next day to a specific drug you just started out with (another example of a delayed adverse event is incidentally cancer). You’re not going to spot dyslipidemia unless you keep track of your lipid levels on your own or e.g. develop xanthomas as a consequence of it, leading you to consult a physician. It helps a lot if you have proper research protocols and large n studies with sufficient power when you want to discover things like this, and when you want to determine whether an association like this is ‘just an association’ or if the link is actually causal (and then clarifying what we actually mean by that, and whether the causal link is also clinically relevant and/or for whom it might be clinically relevant). Presumably many people taking all kinds of medical drugs these days are taking on risks which might in a similar manner be ‘hidden from view’ as was the risk of diabetes in people taking second-generation antipsychotics in the near-past; over time epidemiological studies may pick up on some of these risks, but many will probably remain hidden from view on account of the amount of complexity involved. Even if a drug ‘works’ as intended in the context of the target variable in question, you can get into a lot of trouble if you only focus on the target variable (“if a drug has no side effects, then it is unlikely to work“). People working in drug development know this.

The book has a lot of blog-worthy stuff so I decided to include some quotes in the coverage below. The quotes are from the first half of the book, and this part of the coverage actually doesn’t talk much about the effects of drugs; it mainly deals with epidemiology and cost estimates. I thus decided to save the ‘drug coverage’ to a later post. It should perhaps be noted that some of the things I’d hoped to learn from Ru-Band Lu et al.’s book (blog coverage here) was actually included in this one, which was nice.

“Those with mental illness are at higher risk and are more likely to suffer the severe consequences of comorbid medical illness. Adherence to treatment is often more difficult, and other factors such as psychoneuroendocrine interactions may complicate already problematic treatments. Additionally, psychiatric medications themselves often have severe side effects and can interact with other medications, rendering treatment of the mental illness more complicated. Diabetes is one example of a comorbid medical illness that is seen at a higher rate in people with mental illness.”

“Depression rates have been studied and are increased in type 1 and type 2 diabetes. In a meta-analysis, Barnard et al. reviewed 14 trials in which patients with type 1 diabetes were surveyed for rates of depression.16 […] subjects with type 1 diabetes had a 12.0% rate of depression compared with a rate of 3.4% in those without diabetes. In noncontrolled trials, they found an even higher rate of depression in patients with type 1 diabetes (13.4%). However, despite these overall findings, in trials that were considered of an adequate design, and with a substantially rigorous depression screening method (i.e., use of structured clinical interview rather than patient reported surveys), the rates were not statistically significantly increased (odds ratio [OR] 2.36, 95% confidence interval [CI] 0.69–5.4) but had such substantial variation that it was not sufficient to draw a conclusion regarding type 1 diabetes. […] When it comes to rates of depression, type 2 diabetes has been studied more extensively than type 1 diabetes. Anderson et al. compiled a large metaanalysis, looking at 42 studies involving more than 21,000 subjects to assess rates of depression among patients with type 1 versus type 2 diabetes mellitus.18 Regardless of how depression was measured, type 1 diabetes was associated with lower rates of depression than type 2 diabetes. […] Depression was significantly increased in both type 1 and type 2 diabetes, with increased ORs for subjects with type 1 (OR = 2.9, 95% CI 1.6 –5.5, […] p=0.0003) and type 2 disease (OR = 2.9, 95% CI 2.3–3.7, […] p = 0.0001) compared with controls. Overall, with multiple factors controlled for, the risk of depression in people with diabetes was approximately twofold. In another large meta-analysis, Ali et al. looked at more than 51,000 subjects in ten different studies to assess rates of depression in type 2 diabetes mellitus. […] the OR for comorbid depression among the diabetic patients studied was higher for men than for women, indicating that although women with diabetes have an overall increased prevalence of depression (23.8 vs. 12.8%, p = 0.0001), men with diabetes have an increased risk of developing depression (men: OR = 1.9, 95% CI = 1.7–2.1 vs. women: OR = 1.3, 95% CI = 1.2–1.4). […] Research has shown that youths 12–17 years of age with type 1 diabetes had double the risk of depression compared with a teenage population without diabetes.21 This amounted to nearly 15% of children meeting the criteria for depression.

As many as two-thirds of patients with diabetes and major depression have been ill with depression for more than 2 years.44 […] Depression has been linked to decreased adherence to self-care regimens (exercise, diet, and cessation of smoking) in patients with diabetes, as well as to the use of diabetes control medications […] Patients with diabetes and depression are twice as likely to have three or more cardiac risk factors such as smoking, obesity, sedentary lifestyle, or A1c > 8.0% compared with patients with diabetes alone.47 […] The costs for individuals with both major depression and diabetes are 4.5 times greater than for those with diabetes alone.53

“A 2004 cross-sectional and longitudinal study of data from the Health and Retirement Study demonstrated that the cumulative risk of incident disability over an 8-year period was 21.3% for individuals with diabetes versus 9.3% for those without diabetes. This study examined a cohort of adults ranging in age from 51 to 61 years from 1992 through 2000.”

Although people with diabetes comprise just slightly more than 4% of the U.S. population,3 19% of every dollar spent on health care (including hospitalizations, outpatient and physician visits, ambulance services, nursing home care, home health care, hospice, and medication/glucose control agents) is incurred by individuals with diabetes” (As I noted in the margin, these are old numbers, and prevalence in particular is definitely higher today than it was when that chapter was written, so diabetics’ proportion of the total cost is likely even higher today than it was when that chapter was written. As observed multiple times previously on this blog, most of these costs are unrelated to the costs of insulin treatment and oral anti-diabetics like metformin, and indirect costs make out a quite substantial proportion of the total costs).

In 1997, only 8% of the population with a medical claim of diabetes was treated for diabetes alone. Other conditions influenced health care spending, with 13.8% of the population with one other condition, 11.2% with two comorbidities, and 67% with three or more related conditions.6 Patients with diabetes who suffer from comorbid conditions related to diabetes have a greater impact on health services compared with those patients who do not have comorbid conditions. […] Overall, comorbid conditions and complications are responsible for 75% of total medical expenditures for diabetes.” (Again, these are old numbers)

“Heart disease and stroke are the largest contributors to mortality for individuals with diabetes; these two conditions are responsible for 65% of deaths. Death rates from heart disease in adults with diabetes are two to four times higher than in adults without diabetes. […] Adults with diabetes are more than twice as likely to have multiple diagnoses related to macrovascular disease compared to patients without diabetes […] Although the prevalence of cardiovascular disease increases with age for both diabetics and nondiabetics, adults with diabetes have a significantly higher rate of disease. […] The management of macrovascular disease, such as heart attacks and strokes, represents the largest factor driving medical service use and related costs, accounting for 52% of costs to treat diabetes over a lifetime. The average costs of treating macrovascular disease are $24,330 of a total of $47,240 per person (in year 2000 dollars) over the course of a lifetime.17 Moreover, macrovascular disease is an important determinant of cost at an earlier time than other complications, accounting for 85% of the cumulative costs during the first 5 years following diagnosis and 77% over the initial decade. [Be careful here: This is completely driven by type 2 diabetics; a 10-year old newly diagnosed type 1 diabetic does not develop heart disease in the first decade of disease – type 1s are also at high risk of cardiovascular disease, but the time profile here is completely different] […] Cardiovascular disease in the presence of diabetes affects not only cost but also the allocation of health care resources. Average annual individual costs attributed to the treatment of diabetes with cardiovascular disease were $10,172. Almost 51% of costs were for inpatient hospitalizations, 28% were for outpatient care, and 21% were for pharmaceuticals and related supplies. In comparison, the average annual costs for adults with diabetes and without cardiovascular disease were $4,402 for management and treatment of diabetes. Only 31.2% of costs were for inpatient hospitalizations, 40.3% were for outpatient care, and 28.6% were for pharmaceuticals.16

Of individuals with diabetes, 2% to 3% develop a foot ulcer during any given year. The lifetime incidence rate of lower extremity ulcers is 15% in the diabetic population.20 […] The rate of amputation in individuals with diabetes is ten times higher than in those without diabetes.5 Diabetic lower-extremity ulcers are responsible for 92,000 amputations each year,21 accounting for more than 60% of all nontraumatic amputations.5 The 10-year cumulative incidence of lower-extremity amputation is 7% in adults older than 30 years of age who are diagnosed with diabetes.22 […] Following amputation, the 5-year survival rate is 27%.23 […] The majority of annual costs associated with treating diabetic peripheral neuropathy are associated with treatment of ulcers […] Overall, inpatient hospitalization is a major driver of cost, accounting for 77% of expenditures associated with individual episodes of lower-extremity ulcers.24

By 2003, diabetes accounted for 37% of individuals being treated for renal disease in the United States. […] Diabetes is the leading cause of kidney failure, accounting for 44% of all newly diagnosed cases. […] The amount of direct medical costs for ESRD attributed to diabetes is substantial. The total adjusted costs in a 24-month period were 76% higher among ESRD patients with diabetes compared with those without diabetes. […] Nearly one half of the costs of ESRD are due to diabetes.27” [How much did these numbers change since the book was written? I’m not sure, but these estimates do provide some sort of a starting point, which is why I decided to include the numbers even though I assume some of them may have changed since the publication of the book]

Every percentage point decrease in A1c levels reduces the risk of microvascular complications such as retinopathy, neuropathy, and nephropathy by 40%.5 However, the trend is for A1c to drift upward at an average of 0.15% per year, increasing the risk of complications and costs.17 […] A1c levels also affect the cost of specific complications associated with diabetes. Increasing levels affect overall cost and escalate more dramatically when comorbidities are present. A1c along with cardiovascular disease, hypertension, and depression are significant independent predictors of health care
costs in adults with diabetes.”

August 10, 2016 Posted by | books, diabetes, economics, medicine, Pharmacology | Leave a comment

Human Drug Metabolism (II)

My first post covering Coleman’s excellent book can be found here, and here you can read my goodreads review of the book; I think it makes sense to read those things before reading this post, if you have not already done that. As I believe I’ve previously mentioned (?) most non-fiction books I read, including those I do not blog, usually get a goodreads review, and actually I’m much more active on goodreads these days than I am on this blog. I have considered cross-posting goodreads reviews here on the blog, but I decided it might be best to just keep these things separate for the time being. I might change my mind about this, though; I don’t like how inactive the blog has become during the last few months, and goodreads reviews I’ve already written take almost no work to cross-post, so this would be an easy way to at least get some ‘activity’ here.

The book includes a lot of information that really pretty much everybody would be likely to benefit from knowing (how many people for example live their entire lives without consuming any alcohol, tobacco, or medical drugs? If you’ve ever consumed any of these things, the book has material of relevance included in the coverage…). I repeat myself here, but  some of the general observations included in the following seem to me to be important takeaways from the book: Drugs work (sometimes very) differently in different people, they interact with different things, including innocuous things like what you eat and drink and whether you exercise or not; drugs may interact with each other, in a very confusing variety of ways; some drugs are metabolized differently in people who have taken the drug for a while (‘induction’), compared to how the drug might be metabolized in someone who’s not taken the drug before (drug-naïve), and sometimes the ability to metabolize the drug faster/more efficiently may be lost (inhibition) because of a third factor, such as e.g. another drug or a dietary factor, which can be very dangerous (an improved ability to metabolize the drug because of habituation may also be lost due to non-consumption of the drug for some time, leading to a ‘reset’ of the metabolic pathway of relevance, an important factor in an abuse context where this can lead to overdose); there are huge racial and genetic differences in terms of how specific drugs are metabolized; the consequences of getting too much of a specific drug (toxicity) tend to be foreseeably different from the consequences of getting not enough of a drug (drug failure); efficient metabolism of a drug may depend upon the body’s ability not just to transform the xenobiotic compound into something useful, but also the ability to get rid of sometimes really quite toxic metabolites which might be created along the way as the body tries to get rid of that thing you just injected/ingested/etc. Many people don’t consider herbal remedies to be ‘real drugs’ and so neglect to tell their medical practitioner that they’re taking them/have recently stopped taking them, despite some of these having the potential to cause quite serious drug interactions (even if nothing is taken but herbal remedies; St. John’s Wort + kava kava = acute hepatitis? As noted in the book, “One point important to emphasize, is that assuming various herbal remedies do contain active and potent substituents, there is virtually nothing known clinically about what effects mixing herbal remedies might have, in terms of pharmacology and toxicity. This area is unfortunately left for patients to discover for themselves”).

This book is not ‘the whole story’ about drug metabolism and related stuff, it just scratches the surface, but the coverage serves to make it clear to you just how much stuff is to be found ‘below the surface’, and this is something I really like about the book. It makes you appreciate how little you know and how complex this stuff is. People write 500+ page textbooks like this one simply about CYP subtypes (I came across a different 1000+ page textbook also about a CYP subtype while reading the book so I know this one is hardly unique, but unfortunately I did not bookmark the book and I didn’t find the book after a brief search for it – but take my word for it, those books are out there…) and alcohol metabolism, they write 700 page textbooks about the side effects of psychiatric drugs (not the intended effects, that is – the side effects!) they write 800 page textbooks about aspirin and related drugs and about how drugs affect the liver… I know that in some circles it’s somewhat common for people to ‘experiment’ with various drugs and substances, illicit or otherwise; I also assume that most people who do this sort of thing have little idea what they’re actually doing and are likely taking a lot of risks the very existence of which they’re likely not aware of. Simply because there’s just so much stuff you need to know to even have a proper concept of what you’re doing when you’re dealing with how the human body works and how it responds to foreign substances we might choose to introduce into it. It might be that they wouldn’t care even if they knew because you’re probably rather low in risk aversion if you engage in that sort of experimentation in the first place (I incidentally am highly risk averse), but I do find it curious.

I have added some observations from the middle of the book below.

“Although there is growing awareness of the clinical problems posed by P-gp [P-glycoprotein] inhibition on drug bioavailability and toxicity, until recently it was very difficult to generalize and predict which classes of drug might be inhibitors of P-gp. […] There are dozens of drugs which are known inhibitors of P-gp […] it is often difficult to establish what contribution cellular transport systems make to bioavailability. Indeed, it is emerging that one of the reasons for the very wide variety of drug bioavailability in modern medicine could be the sheer number of possible inhibitors and substrates that exist for P-gp in the diet, such as a number of natural products like the flavonols, which can be as potent as cyclosporine or verapamil as P-gp inhibitors. Natural dietary inhibitors have advantages in their general lack of toxicity, but the basic problem of a lack of predictability in their effects on P-gp substrates remains. Since no two people’s diets are identical, the impact of P-gp modulation on drug absorption could be simply too complex to unravel.”

“the objectives of metabolizing systems could be summed up thus:
• To terminate the pharmacological effect of the molecule.
• Make the molecule so water-soluble that it cannot escape clearance, preferably by more than one route to absolutely guarantee its removal.
These objectives could be accomplished by:
• Changing the molecular shape so it no longer binds to its receptors.
• Changing the molecular lipophilicity to hydrophilicity to ensure high water solubility.
• Making the molecule larger and heavier, so it can be eliminated in bile as well as urine.
• Efflux pump systems, which ensure that a highly water-soluble metabolite actually leaves the cell to enter the bloodstream, before it is excreted in bile and urine. […]
CYP-mediated metabolism can increase hydrophilicity, but it does not always increase it enough and it certainly does not make the molecule any bigger and heavier, indeed, sometimes the molecule becomes lighter […] CYP-mediated metabolism does not always alter the pharmacological effects of the drug either […] However, CYPs do perform two essential tasks: the initial destabilization of the molecule, creating a ‘handle’ on it. […] CYPs also ‘unmask’ groups that could be more reactive for further metabolism. […] CYP-mediated preparation can make the molecule vulnerable to the attachment of a very water-soluble and plentiful agent to the drug or steroid, which accomplishes the objectives of metabolism. This is achieved through the attachment of a modified glucose molecule (glucuronidation), or a soluble salt such as a sulphate (sulphation) [see also this] to the prepared site. Both adducts usually make the drug into a stable, heavier and water-soluble ex-drug. […] with many drugs, their stability and lipophilicity mean that their clearance must take more than one metabolic operation to make them water-soluble.”

PXR [Pregnane X receptor], CAR [constitutive androstane receptor] and FXR [Farnesoid X receptor] are […] part of the process whereby the liver can sense whether its own metabolic capacity and physical size is sufficient to respond to homeostatic demands. Hence, alongside various growth factors, the NRs [nuclear receptors] facilitate the amazing process whereby the liver regenerates itself after areas of the organ are removed or damaged. […] As CYPs, UGTs [Glucuronosyltransferases], other biotransforming systems and efflux transporters are meeting the same xenobiotic or endobiotic stimuli in different tissues and degrees of exposure, it is logical that the […] receptor systems integrate and coordinate their responses. […] These multi-receptor mechanisms enable levels of induction to be customized for individual tissues to deal with different chemical threats. Essentially, according to diet, chemical and drug exposure, each individual will possess a unique expression array of UGTs and CYPs which will be constantly fine-tuned throughout life.”

“Sulphonation is accomplished by a set of enzyme systems known as sulphotransferases (SULTs) and they are found in most tissues to varying degrees of activity. […] The general aim of sulphonation is to make the substrate more water-soluble and usually less active pharmacologically. Sulphonated molecules are more readily eliminated in bile and urine. […] All SULTs are subject to genetic polymorphisms, with a high degree of individual variation in their expression and catalytic activities […] Regarding classification of the superfamily of SULTs, it is assumed that 47 per cent amino acid sequence homology is indicative of same family members and 60 per cent homology for subfamily members. To date, there are 47 mammalian SULT isoforms so far discovered, which are derived from ten human sulphotransferase gene families […] knowledge of the role of NRs and AhR [Aryl hydrocarbon receptor] in human SULT expression has progressed in animals but not really in humans. This is partly due to the fact that rodent SULT profiles are quite different to ours […] Many studies have been carried out in rodents, which have produced rather contradictory results […] It seems that whilst SULTs in general are not as responsive to inducers as CYPs and UGTs, their basal expression is much higher, although interindividual expression does vary considerably and this may have severe toxicological consequences, in terms of xenobiotic toxicity and carcinogenicity. There is also some evidence that diet is a strong influence on individual SULT profiles.”

“One of the main problems with the oxidation of various molecules by CYP enzymes is that they are often destabilized and sometimes form highly reactive products. […] CYPs occasionally form metabolites so reactive that they immediately destroy the enzyme by reacting with it, changing its structure and, therefore, its function. […] The most dangerous forms of reactive species are those that evade UGTs and SULT enzymes, or are inadvertently created by conjugation processes. These species escape into the cytosol and even into the nucleus, where potentially carcinogenic events may result. […] CYPs are not the only source of reactive species generated within cells. Around 75 per cent of our food intake is directed at maintaining our body temperature and a great deal of energy must be liberated from the food to accomplish this. Cells derive the vast majority of their energy through oxidative phosphorylation and this takes place in […] the mitochondria. […] In cells almost all the oxygen we breathe is consumed in oxidative phosphorylation, forming ATP, heat and reactive oxidant species in the mitochondria that could cause severe damage to the structure and function of the cell if they were allowed to escape. So all cells, particularly hepatocytes, have evolved a separate system to accommodate such reactive toxic products and this is based on a three amino acid (cysteine, glycine and glutamate) thiol known as glutathione, or GSH. Thiols in general are extremely effective at reducing and thus ‘quenching’ highly reactive, electrophilic species. […] if cells are depleted of GSH by blocking its synthesis (by using buthionine sulphoxime), cell death follows and the organism itself will die in a few days, due to uncontrolled activity of endogenous radicals. […] If GSH levels are not maintained in the cell over a long period of time, the cell wears out more quickly; for example, diabetic complications and HIV infection are linked with poor GSH maintenance.” [I did not know this…]

“There are several enzymes that promote and catalyze the reaction of GSH with potential toxins to ensure that reactive species are actively dealt with, rather than just passive GSH-mediated reduction. Probably the most important from the standpoint of drug metabolism are the GSH-S-transferases [‘GSTs’, which] are the key cellular defence against electrophilic agents formed from endogenous or xenobiotic oxidative metabolism. […] The GSTs are found in humans in several major classes. […] The classes contain several subfamilies […] These enzymes are polymorphic […] and their individual expression ranges from complete absence in some isoforms to overabundance as a response to anticancer therapy. […] The upregulation of GST is a serious problem within cancer therapeutics and resistance to a range of drugs including melphalan and doxorubicin is linked with GST detoxification. Much research has been directed at inhibitors of GST isoforms to reverse or even prevent the development of resistance to anti-neoplastic agents. Unfortunately this strategy has not been successful”

“once xenobiotics have been converted into low-toxicity, higher-molecular-weight and high-water-solubility metabolites by the combination of CYPs, UGTs, SULTs and GSTs, this appears at first sight to be ‘mission accomplished’. However, these conjugates must be transported against a concentration gradient out of the cell into the interstitial space between cells. Then they will enter the capillary system and thence to the main bloodstream and filtration by the kidneys. The biggest hurdle is the transport out of the cell, which is a tall order, as once a highly water-soluble entity has been created, it will effectively be ‘ion-trapped’ in the cell, as the cell membrane is highly lipophilic and is an effective barrier to the exit as well as entry of most hydrophilic molecules. […] failure to remove the hydrophilic products of conjugation reactions [from the cells] can lead to:
• toxicity of conjugates to various cell components;
• hydrolysis of conjugates back to the original reactive species;
• inhibition of conjugating enzymes.
If the cell can manage to transport them out, then they should be excreted in urine or bile and detoxification can proceed at a maximal rate. […] Consequently, an impressive array of multi-purpose membrane bound transport carrier systems has evolved which can actively remove hydrophilic metabolites and many other low molecular weight drugs and toxins from cells. The relatively recent […] term of Phase III metabolism has been applied to the study of this essential arm of the detoxification process. […] The main thrust of research into efflux transporters has been directed at the ABC-type transporters [this link actually has quite a bit of content, unlike some of the other wiki articles on these topics], of which there are 48 genes that code of a variety of ATP-powered pumps.”

“it is clear that the whole process of detection, metabolism and elimination of endobiotic and xenobiotic agents is minutely coordinated and is responsive to changes in load in individual tissues. The CYPs, UGTs, MRPs [Multidrug Resistance Proteins] and P-gp are all tightly regulated through the NR system of PXR, CAR, FXE, PPAR α, LXR etc, as well as the AhR receptor system [does it even make sense to keep adding links here? I’m not sure it does…]. Some enzyme/pump processes are closely linked, such as CYP3A4 and P-gp, as inducers powerfully increase both systems capacity. The reactive species protection ‘arm’ of biotransformation is also controlled through a separate but almost certainly ‘cross-talking’ Nrf2/Keap1 system which coordinates not only the interception of reactive species by GSTs, but also the supply of their GSH substrate, UGTs and the MRPs. This latter coordination is particularly relevant in resistance to cancer chemotherapy and happens because overexpression of any one entity alone cannot rid the cell of the toxin. […] The MRPs, GSH production and GST/UGT activity must be induced in concert. […] much of the integration and coordination of detoxification processes remains to be uncovered”.

Chapter 7, about ‘factors affecting drug metabolism’, has some very interesting stuff, but I think this post is quite long enough as it is. I might talk about that stuff in detail later on, but I make no promises.

August 9, 2016 Posted by | books, medicine, Pharmacology | Leave a comment