Econstudentlog

Respirology

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

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

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

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

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

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

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

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

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

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

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

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

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

3-3

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

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

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

August 22, 2016 Posted by | books, economics, 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):

elife-13410-fig3-v1

(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

Quotes

i. “It wasn’t what was done to you. Life was what you did with what was done to you.” (Kameron Hurley)

ii. “Stepan Arkadyevitch was a truthful man in his relationship with himself. He was incapable of deceiving himself and persuading himself that he repented of his conduct. He could not at this date repent of the fact that he, a handsome, susceptible man of thirty-four, was not in love with his wife, the mother of five living and two dead children, and only a year younger than himself. All he repented of was that he had not succeeded better in hiding it from his wife.” (Tolstoy, Anna Karenina)

iii  “”And is it true the younger Vlassieva girl’s to marry Topov?”
“Yes, they say it’s quite a settled thing.”
“I wonder at the parents! They say it’s a marriage for love.”
“For love? What antediluvian notions you have! Can one talk of love in these days?” said the ambassador’s wife.
“What’s to be done? It’s a foolish old fashion that’s kept up still,” said Vronsky.
“So much the worse for those who keep up the fashion. The only happy marriages I know are marriages of prudence.” (-ll-)

iv. “To be treated with mercy, some must reveal their handicaps, while others must conceal them.” (Yahia Lababidi)

v. “It is only in appearance that time is a river. It is rather a vast landscape and it is the eye of the beholder that moves.” (Thornton Wilder)

vi. “The instinct for self-deception in human beings makes them try to banish from their minds dangers of which at bottom they are perfectly aware by declaring them non-existent.” (Stefan Zweig)

vii. “When one does another person an injustice, in some mysterious way it does one good to discover (or to persuade oneself) that the injured party has also behaved badly or unfairly in some little matter or other; it is always a relief to the conscience if one can apportion some measure of guilt to the person one has betrayed.” (-ll-)

viii. “One can run away from anything but oneself.” (-ll-)

ix. “Nothing is harder than to accept oneself.” (Max Frisch)

x. “To a certain degree we are really the person others have seen in us” (-ll-)

xi. “Time does not change us[,] it just unfolds us” (-ll-)

xii. “I feel fairly certain that my hatred harms me more than the people whom I hate.” (-ll-)

xiii. “A society needs famous people; the question is whom it chooses for that role. Any criticism of its choice is by implication a criticism of that society.” (-ll-)

xiv. “‘You know what most of the milit’ry training is, Perks?’ he went on. […] It’s to turn you into a man who will, on the word of command, stick his blade into some poor sod just like him who happens to be wearing the wrong uniform. He’s like you, you’re like him. He doesn’t really want to kill you, you don’t really want to kill him. But if you don’t kill him first, he’ll kill you. That’s the start and finish of it. It don’t come easy without trainin’.” (Terry Pratchett, Monstrous Regiment)

xv. “Polly felt questing eyes boring into her. She was embarrassed, of course. But not for the obvious reason. It was for the other one, the little lesson that life sometimes rams home with a stick: you are not the only one watching the world. Other people are people; while you watch them they watch you, and they think about you while you think about them. The world isn’t just about you.” (-ll-)

xiv. “Fifty miles away, Lord Lynchknowle’s dinner had been interrupted by the arrival of a police car and the news of his daughter’s death. The fact that it had come between the mackerel pâté and the game pie, and on the wine side, an excellent Montrachet and a Château Lafite 1962, several bottles of which he’d opened to impress the Home Secretary and two old friends from the Foreign Office, particularly annoyed him. Not that he intended to let the news spoil his meal by announcing it before he’d finished, but he could foresee an ugly episode with his wife afterwards for no better reason than that he had come back to the table with the rather unfortunate remark that it was nothing important. Of course, he could always excuse himself on the grounds that hospitality came first, and old Freddie was the Home Secretary after all, and he wasn’t going to let that Lafite ’62 go to waste, but somehow he knew Hilary was going to kick up the devil of a fuss about it afterwards.” (Tom Sharpe, Wilt on High. As I also noted on goodreads I really liked Sharpe’s Wilt series; these books are very funny.)

xvii. “‘England’s ruin, damned Socialists,’ growled Sir Cathcart. ‘Turned the country into a benevolent society. Seem to think you can rule a nation with good intentions. Damned nonsense. Discipline. That’s what the country needs. A good dose of unemployment to bring the working classes to their senses.’ […] ‘It’s the dole. Man can earn more not working than he can at his job. All wrong. A bit of genuine starvation would soon put that right.’
‘I suppose the argument is that the wives and children suffer,’ said the Dean.
‘Can’t see much harm in that,’ the General continued. ‘Nothing like a hungry woman to put some pep into a man.” (Tom Sharpe, Porterhouse Blue. The Cathcart character is funny. He also has in his ’employment’ “A Japanese gardener, a prisoner of war, whom Sir Cathcart kept carefully ignorant of world news and who was, thanks to the language barrier, incapable of learning it for himself…” The book was published in 1974..)

xviii. “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.” (Richard D. Alexander, The Biology of Moral Systems)

xix. “Should a traveller give an account of men who were entirely divested of avarice, ambition, or revenge; who knew no pleasure but friendship, generosity, and public spirit, we should immediately detect the falsehood and prove him a liar with the same certitude as if he had stuffed his narration with centaurs and dragons.” (David Hume, Essays and Treatises, 1772)

xx. “In plucking the fruit of memory one runs the risk of spoiling its bloom.” (Joseph Conrad)

July 10, 2016 Posted by | books, quotes | Leave a comment

The Second World War (IV)

This will be my last post about the book(s). You can read my previous posts about it(/them) here, here, and here. In this post I’ve included some quotes and observations from the last few hundred pages.

“In wartime […] truth is so precious that she should always be attended by a bodyguard of lies.”

“On June 10 [1944] General Montgomery reported that he was sufficiently established ashore to receive a visit. […] Montgomery, smiling and confident, met me at the beach as we scrambled out of our landing craft. His army had already penetrated seven or eight miles inland. There was very little firing or activity. […] The General was in the highest spirits. I asked him how far away was the actual front. He said about three miles. I asked him if he had a continuous line. He said, “No.” “What is there then to prevent an incursion of German armour breaking up our luncheon?” He said he did not think they would come. […] In the first six days 326,000 men, 54,000 vehicles, and 104,000 tons of stores were landed. […] [German] divisions arrived piecemeal, short of equipment, and fatigued by long night marches, and were thrown into the line as they came. […] On June 17, at Margival, near Soissons, Hitler held a conference with Rundstedt and Rommel. His two generals pressed on him strongly the folly of bleeding the German Army to death in Normandy. They urged that before it was destroyed the Seventh Army should make an orderly withdrawal towards the Seine […] Hitler would not agree. Here, as in Russia and Italy, he demanded that no ground should be given up and all should fight where they stood. The generals were of course right. […] by the middle of July thirty Allied divisions were ashore. Half were American and half British and Canadian. Against these the Germans had gathered twenty-seven divisions. But they had already suffered 160,000 casualties, and General Eisenhower estimated their fighting value as no higher than sixteen divisions. […] By August 30 our troops were crossing the Seine at many points. Enemy losses had been tremendous: 400,000 men, half of them prisoners, 1,300 tanks, 20,000 vehicles, 1,500 field guns. […] the Seine was reached six days ahead of the planned time.”

[During a visit to the Italian front:] [General] Alexander had planned an early start and a long day on the front. He had also promised to take me wherever I wanted to go. […] We first climbed by motor up a high outstanding rock pinnacle, upon the top of which a church and village were perched. The inhabitants, men and women, came out to greet us from the cellars in which they had been sheltering. It was at once plain that the place had just been bombarded. Masonry and wreckage littered the single street. “When did this stop?” Alexander asked the small crowd who gathered round us, grinning rather wryly. “About a quarter of an hour ago,” they said. […] Presently Alexander said that we had better not stay any longer, as the enemy would naturally be firing at observation posts like this and might begin again. […] We got into our cars accordingly, and in half an hour were across the river, where the road ran into undulating groves of olives, brightly patched with sunshine. Having got an officer guide from one of the battalions engaged, we pushed on through these glades till the sounds of rifle and machine-gun fire showed we were getting near to the front line. Presently warning hands brought us to a standstill. It appeared there was a minefield, and it was only safe to go where other vehicles had already gone without mishap. […] [We] found a very good place in the stone building, which was in fact an old château overlooking a rather sharp declivity. Here one certainly could see all that was possible. The Germans were firing with rifles and machine-guns from thick scrub on the farther side of the valley, about five hundred yards away. Our front line was beneath us. The firing was desultory and intermittent. But this was the nearest I got to the enemy and the time I heard the most bullets in the Second World War. After about half an hour we went back to our motor-cars and made our way to the river”.

The book has some interesting coverage of the Warsaw Uprising. The short story to people who don’t know it is that the Polish resistance movement started a major uprising in the city of Warsaw when the Soviet forces were very close to the city, a move encouraged by the Soviets [“Soviet broadcasting stations had for a considerable time been urging the Polish population to drop all caution and start a general revolt against the Germans”]. What the Soviets did as a response to the uprising was then to halt their advance rather than keep it going, in order to let the German army help Stalin get rid of the non-communist Polish resistance. Stalin also explicitly refused to allow British and American aircraft providing supplies to the Poles to land on Soviet […Polish…] territory. The tactics changed slightly over time: “On September 10, after six weeks of Polish torment, the Kremlin appeared to change their tactics. […] They wished to have the non-Communist Poles destroyed to the full, but also to keep alive the idea that they were going to their rescue.” So they pretended to try to help, but really did very little. “The struggle in Warsaw had lasted more than sixty days. Of the 40,000 men and women of the Polish Underground Army about 15,000 fell. Out of a population of a million nearly 200,000 had been stricken. […] When the Russians entered the city three months later [they were at points less than 10 miles away from the city when the uprising began] they found little but shattered streets and the unburied dead. Such was their liberation of Poland, where they now rule.” It should perhaps be obvious, but of course Stalin’s deceit did not stop there – this later sequence of events is also illustrative:

“At the beginning of March 1945 the Polish Underground were invited by the Russian Political Police to send a delegation to Moscow to discuss the formation of a united Polish Government along the lines of the Yalta agreement. This was followed by a written guarantee of personal safety and it was understood that the party would later be allowed if the negotiations were successful to travel to London for talks with the Polish Government in exile. On March 27 General Leopold Okulicki, the successor of General Bor-Komorowski in command of the Underground Army, two other leaders, and an interpreter had a meeting in the suburbs of Warsaw with a Soviet representative. They were joined the following day by eleven leaders representing the major political parties in Poland. One other Polish leader was already in Russian hands. No one returned from the rendezvous. On April 6 the Polish Government in exile issued a statement in London giving the outline of this sinister episode. The most valuable representatives of the Polish Underground had disappeared without a trace in spite of the formal Russian offer of safe-conduct. Questions were asked in Parliament and stories have since spread of the shooting of local Polish leaders in the areas at this time occupied by the Soviet armies […] On May 18 Stalin publicly denied that the arrested Polish leaders had ever been invited to Moscow […] The prisoners were accused of subversion, terrorism, and espionage, and all except one admitted wholly or in part the charges against them. […] This was in fact the judicial liquidation of the leadership of the Polish Underground which had fought so heroically against Hitler. The rank and file had already died in the ruins of Warsaw.”

“In the autumn of 1942 only three American aircraft-carriers were afloat; a year later there were fifty; by the end of the war there were more than a hundred. This achievement had been matched by an increase in aircraft production which was no less remarkable.”

“The number of divisions that could be sustained [in Europe, 1944], and the speed and range of their advance, depended […] entirely on harbours, transport, and supplies. Relatively little ammunition was being used, but food, and above all petrol, governed every movement.”

“You are responsible for maintaining order in Athens and for neutralising or destroying all E.A.ME.L.A.S. bands approaching the city. […] Naturally E.L.A.S will try to put women and children in the van where shooting may occur. You must be clever about this and avoid mistakes. But do not hesitate to fire at any armed male in Athens who assails the British authority or Greek authority with which we are working. Do not […] hesitate to act as if you were in a conquered city where a local rebellion is in progress.” (Telegram to General Scobie. Here’s a related wiki link. Churchill observes in the book that: “I felt grave concern about the whole business, but I was sure that there should be no room for doubts or hedging. I had in my mind Arthur Balfour’s celebrated telegram in the eighties to the British authorities in Ireland: “Don’t hesitate to shoot.” […] There was a furious storm about it in the House of Commons of those days, but it certainly prevented loss of life.”)

“I saw quite plainly that Communism would be the peril civilization would have to face after the defeat of Nazism and Fascism. It did not fall to us to end the task in Greece. […] I told the President [Roosevelt] that we ought to occupy as much of Austria as possible, as it was “undesirable that more of Western Europe than necessary should be occupied by the Russians.”” [Churchill’s subsequent italics] […] “I deem it highly important that we should shake hands with the Russians as far to the east as possible.” [telegram from Churchill to Eisenhower sent in the late stage of the war.]

“Poland was discussed at no fewer than seven out of the eight plenary meetings of the Yalta Conference, and the British record contains an interchange on this topic of nearly eighteen thousand words between Stalin, Roosevelt, and myself. […] A large body of opinion in Great Britain was shocked at the idea of moving millions of people by force. Great success had been achieved in disentangling the Greek and Turkish populations after the last war […] but in that case under a couple of millions of people had been moved. […] I was not afraid of the problem of transferring populations, so long as it was proportionate to what the Poles could manage and to what could be put into Germany. But it was a matter which required study, not as a question of principle, but of the numbers which would have to be handled.”

“As war waged by a coalition draws to its end political aspects have a mounting importance. […] At this time the points at issue did not seem to the United States Chiefs of Staff to be of capital importance. They were of course unnoticed by and unknown to the public, and were all soon swamped, and for the time being effaced, by the flowing tide of victory. Nevertheless, as will not now be disputed, they played a dominating part in the destiny of Europe […] The indispensable political direction was lacking [due to Roosevelt’s illness and death] at the moment when it was most needed. The United States stood on the scene of victory, master of world fortunes, but without a true and coherent design. Britain, though still very powerful, could not act decisively alone. I could at this stage only warn and plead. Thus the climax of apparently measureless success was to me a most unhappy time. I moved amid cheering crowds, or sat at a table adorned with congratulations and blessings from every part of the Grand Alliance, with an aching heart and a mind oppressed by forebodings.
The destruction of German military power had brought with it a fundamental change in the relations between Communist Russia and the Western democracies. They had lost their common enemy, which was almost their sole bond of union. […] Apprehension for the future and many perplexities filled my mind as I moved among the cheering crowds of Londoners in their hour of well-won rejoicing after all they had gone through. […] Japan was still unconquered. The atomic bomb was still unborn. The world was in confusion. […] The Soviet menace, to my eyes, had already replaced the Nazi foe. But no comradeship against it existed. […] I had seen it all before. I remembered that other joy-day nearly thirty years before, when I had driven with my wife from the Ministry of Munitions through similar multitudes convulsed with enthusiasm to Downing Street to congratulate the Prime Minister. Then, as at this time, I understood the world situation as a whole. But then at least there was no mighty army that we need fear […] How stands the scene after eight years have passed? The Russian occupation line in Europe runs from Lübeck to Linz. Czechoslovakia has been engulfed. The Baltic states, Poland, Roumania, and Bulgaria have been reduced to satellite States under totalitarian Communist rule. Yugoslavia has broken loose. Greece alone is saved. Our armies are gone, and it will be a long time before even sixty divisions can be again assembled opposite Russian forces, which in armour and manpower are in overwhelming strength. This also takes no account of all that has happened in the Far East. The danger of a third World War, under conditions at the outset of grave disadvantage, casts its lurid shadow over the free nations of the world.” [The last quote in the above paragraph was written in 1953.]

“Over a million prisoners were taken in the first three weeks of April”.

“there never was a moment’s discussion as to whether the atomic bomb should be used or not. […] the decision whether or not to use the atomic bomb to compel the surrender of Japan was never even an issue. There was unanimous, automatic, unquestioned agreement around our table; nor did I ever hear the slightest suggestion that we should do otherwise.”

“In sixty-eight months of fighting 781 German U-boats were lost. For more than half this time the enemy held the initiative. […] In the final count British and British-controlled forced destroyed 500 out of the 632 submarines known to have been sunk at sea by the Allies. In the First World War eleven million tons of shipping were sunk, and in the second fourteen and a half million tons, by U-boats alone. If we add the loss from other causes the totals become twelve and three-quarter million and twenty-one and a half million. Of this the British bore over 60 per cent. in the first war and over half in the second. […] It would be a mistake to suppose that the fate of Japan was settled by the atomic bomb. Her defeat was certain before the first bomb fell, and was brought about by overwhelming maritime power. […] Her shipping had been destroyed. She had entered the war with over five and a half million tons, later much augmented by captures and new construction, but her convoy system and escorts were inadequate and ill-organised. Over eight and a half million tons of Japanese shipping were sunk, of which five million fell to submarines. We, an island power, equally dependent on the sea, can read the lesson and understand our own fate had we failed to master the U-boats.”

June 25, 2016 Posted by | books, history | Leave a comment

Quotes

i. “Disgrace does not consist in the punishment, but in the crime.” (Vittorio Alfieri)

ii. “In countries and epochs in which communication is impeded, soon all other liberties wither; discussion dies by inanition, ignorance of the opinion of others becomes rampant, imposed opinions triumph. […] Intolerance is inclined to censor, and censorship promotes ignorance of the arguments of others and thus intolerance itself: a rigid, vicious circle that is hard to break.” (Primo Levi)

iii. “A good listener is not only popular everywhere, but after a while he gets to know something.” (Wilson Mizner)

iv. “Any author who uses mathematics should always express in ordinary language the meaning of the assumptions he admits, as well as the significance of the results obtained. The more abstract his theory, the more imperative this obligation.” (Maurice Allais)

v. “There are no small number of people in this world who, solitary by nature, always try to go back into their shell like a hermit crab or a snail.” (Anton Chekhov)

vi. “Love, friendship, respect, do not unite people as much as a common hatred for something.” (-ll-)

vii. “Although you may tell lies, people will believe you, if only you speak with authority.” (-ll-)

viii. “What seems to us serious, significant and important will, in future times, be forgotten or won’t seem important at all.” (-ll-)

ix. “Future me is a great guy. He deals with all my problems which allows me to just relax and not worry about anything. Sometimes I worry I’m giving him too much work, but he needs the motivation.” (‘Batmaners’, here)

x. “You’re not raising a child, you’re raising an adult.” (u/DankJemo, reddit, unknown original source)

xi. “She was a good woman, a good mother, a woman of quality and character. The fact that she had left him after twenty years to marry her lover did not, could not, change those facts. For at this moment, now that the months had passed, Jordan saw clearly the justice of her decision. She had a right to be happy. […] Not that he had been a bad husband. Just an inadequate one. He had been a good father. He had done his duty in every way. His only fault was that after twenty years he no longer made his wife happy.” (Fools Die, Mario Puzo)

xii. “There warn’t nothing to do now but to look out sharp for the town, and not pass it without seeing it. He said he’d be mighty sure to see it, because he’d be a free man the minute he seen it, but if he missed it he’d be in a slave country again and no more show for freedom. […] I begun to get it through my head that he WAS most free — and who was to blame for it? Why, ME. I couldn’t get that out of my conscience, no how nor no way. It got to troubling me so I couldn’t rest; I couldn’t stay still in one place. It hadn’t ever come home to me before, what this thing was that I was doing. But now it did; and it stayed with me, and scorched me more and more. I tried to make out to myself that I warn’t to blame, because I didn’t run Jim off from his rightful owner; but it warn’t no use, conscience up and says, every time, “But you knowed he was running for his freedom, and you could a paddled ashore and told somebody.” That was so — I couldn’t get around that noway. That was where it pinched. Conscience says to me, “What had poor Miss Watson done to you that you could see her nigger go off right under your eyes and never say one single word? What did that poor old woman do to you that you could treat her so mean?” (Mark Twain, The Adventures of Huckleberry Finn)

xiii. “In Detroit, Mrs Dorothy Van Dorn, suing for divorce, complained that her husband 1) put all their food in a freezer, 2) kept the freezer locked, 3) made her pay for any food she ate, and 4) charged her the 3% Michigan sales tax.” (Time magazine, 10 December 1951. I came across the quote while reading The Life and Times of the Thunderbolt Kid, by Bill Bryson).

xiv. “The trouble with the rat race is that even if you win, you’re still a rat.” (Jane Wagner)

xv. “Don’t be afraid of missing opportunities. Behind every failure is an opportunity somebody wishes they had missed.” (-ll-)

xvi. “A man has only one escape from his old self: to see a different self — in the mirror of some woman’s eyes.” (Clare Luce)

xvii. “What is success? It is a toy balloon among children armed with pins.” (Gene Fowler)

xviii. “Writing is easy. All you do is stare at a blank sheet of paper until drops of blood form on your forehead.” (-ll-)

xix. “The best way to become a successful writer is to read good writing, remember it, and then forget where you remember it from.” (-ll-)

xx. “Just because you’re living in blissful oblivion doesn’t mean you’re not responsible.” (Arthur M. Jolly)

June 18, 2016 Posted by | books, quotes | Leave a comment

Random stuff

i. A very long but entertaining chess stream by Peter Svidler was recently uploaded on the Chess24 youtube account – go watch it here, if you like that kind of stuff. The fact that it’s five hours long is a reason to rejoice, not a reason to think that it’s ‘too long to be watchable’ – watch it in segments…

People interested in chess might also be interested to know that Magnus Carlsen has made an account on the ICC on which he has played, which was a result of his recent participation in the ICC Open 2016 (link). A requirement for participation in the tournament was that people had to know whom they were playing against (so there would be no ultra-strong GMs playing using anonymous accounts in the finals – they could use accounts with strange names, but people had to know whom they were playing), so now we know that Magnus Carlsen has played under the nick ‘stoptryharding’ on the ICC. Carlsen did not win the tournament as he lost to Grischuk in the semi-finals. Some very strong players were incidentally kicked out in the qualifiers, including Nepomniachtchi, the current #5 in the world on the FIDE live blitz ratings.

ii. A lecture:

iii. Below I have added some new words I’ve encountered, most of them in books I’ve read (I have not spent much time on vocabulary.com recently). I’m sure if I were to look all of them up on vocabulary.com some (many?) of them would not be ‘new’ to me, but that’s not going to stop me from including them here (I included the word ‘inculcate’ below for a reason…). Do take note of the spelling of some of these words – some of them are tricky ones included in Bryson’s Dictionary of Troublesome Words: A Writer’s Guide to Getting It Right, which people often get wrong for one reason or another:

Conurbation, epizootic, equable, circumvallation, contravallation, exiguous, forbear, louche, vituperative, thitherto, congeries, inculcate, obtrude, palter, idiolect, hortatory, enthalpy (see also wiki, or Khan Academy), trove, composograph, indite, mugginess, apodosis, protasis, invidious, inveigle, inflorescence, kith, anatopism, laudation, luxuriant, maleficence, misogamy (I did not know this was a word, and I’ll definitely try to remember it/that it is…), obsolescent, delible, overweening, parlay (this word probably does not mean what you think it means…), perspicacity, perspicuity, temblor, precipitous, quinquennial, razzmatazz, turpitude, vicissitude, vitriform.

iv. Some quotes from this excellent book review, by Razib Khan:

“relatively old-fashioned anti-religious sentiments […] are socially acceptable among American Left-liberals so long as their targets are white Christians (“punching up”) but more “problematic” and perhaps even “Islamophobic” when the invective is hurled at Muslim “people of color” (all Muslims here being tacitly racialized as nonwhite). […] Muslims, as marginalized people, are now considered part of a broader coalition on the progressive Left. […] most Left-liberals who might fall back on the term Islamophobia, don’t actually take Islam, or religion generally, seriously. This explains the rapid and strident recourse toward a racial analogy for Islamic identity, as that is a framework that modern Left-liberals and progressives have internalized and mastered. The problem with this is that Islam is not a racial or ethnic identity, it is a set of beliefs and practices. Being a Muslim is not about being who you are in a passive sense, but it is a proactive expression of a set of ideas about the world and your behavior within the world. This category error renders much of Left-liberal and progressive analysis of Islam superficial, and likely wrong.”

“To get a genuine understanding of a topic as broad and boundless as Islam one needs to both set aside emotional considerations, as Ben Affleck can not, and dig deeply into the richer and more complex empirical texture, which Sam Harris has not.”

“One of the most obnoxious memes in my opinion during the Obama era has been the popularization of the maxim that “The arc of the moral universe is long, but it bends towards justice.” It is smug and self-assured in its presentation. […] too often it becomes an excuse for lazy thinking and shallow prognostication. […] Modern Western liberals have a particular idea of what a religion is, and so naturally know that Islam is in many ways just like United Methodism, except with a hijab and iconoclasm. But a Western liberalism that does not take cultural and religious difference seriously is not serious, and yet all too often it is what we have on offer. […] On both the American Left and Right there is a tendency to not even attempt to understand Islam. Rather, stylized models are preferred which lead to conclusions which are already arrived at.”

“It’s fine to be embarrassed by reality. But you still need to face up to reality. Where Hamid, Harris, and I all start is the fact that the vast majority of the world’s Muslims do not hold views on social issues that are aligned with the Muslim friends of Hollywood actors. […] Before the Green Revolution I told people to expect there to be a Islamic revival, as 86 percent of Egyptians polled agree with the killing of apostates. This is not a comfortable fact for me, as I am technically an apostate.* But it is a fact. Progressives who exhibit a hopefulness about human nature, and confuse majoritarian democracy with liberalism and individual rights, often don’t want to confront these facts. […] Their polar opposites are convinced anti-Muslims who don’t need any survey data, because they know that Muslims have particular views a priori by virtue of them being Muslims. […] There is a glass half-full/half-empty aspect to the Turkish data. 95 percent of Turks do not believe apostates should be killed. This is not surprising, I know many Turkish atheists personally. But, 5 percent is not a reassuring fraction as someone who is personally an apostate. The ideal, and frankly only acceptable, proportion is basically 0 percent.”

“Harris would give a simple explanation for why Islam sanctions the death penalty for apostates. To be reductive and hyperbolic, his perspective seems to be that Islam is a totalitarian cult, and its views are quite explicit in the Quran and the Hadith. Harris is correct here, and the views of the majority of Muslims in Egypt (and many other Muslim nations) has support in Islamic law. The consensus historical tradition is that apostates are subject to the death penalty. […] the very idea of accepting atheists is taboo in most Arab countries”.

“Christianity which Christians hold to be fundamental and constitutive of their religion would have seemed exotic and alien even to St. Paul. Similarly, there is a much smaller body of work which makes the same case for Islam.

A précis of this line of thinking is that non-Muslim sources do not make it clear that there was in fact a coherent new religion which burst forth out of south-central Arabia in the 7th century. Rather, many aspects of Islam’s 7th century were myths which developed over time, initially during the Umayyad period, but which eventually crystallized and matured into orthodoxy under the Abbasids, over a century after the death of Muhammad. This model holds that the Arab conquests were actually Arab conquests, not Muslim ones, and that a predominantly nominally Syrian Christian group of Arab tribes eventually developed a new religion to justify their status within the empire which they built, and to maintain their roles within it. The mawali (convert) revolution under the Abbasids in the latter half of the 8th century transformed a fundamentally Arab ethnic sect, into a universal religion. […] The debate about the historical Jesus only emerged when the public space was secularized enough so that such discussions would not elicit violent hostility from the populace or sanction form the authorities. [T]he fact is that the debate about the historical Muhammad is positively dangerous and thankless. That is not necessarily because there is that much more known about Muhammad than Jesus, it is because post-Christian society allows for an interrogation of Christian beliefs which Islamic society does not allow for in relation to Islam’s founding narratives.”

“When it comes to understanding religion you need to start with psychology. In particular, cognitive psychology. This feeds into the field of evolutionary anthropology in relation to the study of religion. Probably the best introduction to this field is Scott Atran’s dense In Gods We Trust: The Evolutionary Landscape of Religion. Another representative work is Theological Incorrectness: Why Religious People Believe What They Shouldn’t. This area of scholarship purports to explain why religion is ubiquitous, and, why as a phenomenon it tends to exhibit a particular distribution of characteristics.

What cognitive psychology suggests is that there is a strong disjunction between the verbal scripts that people give in terms of what they say they believe, and the internal Gestalt mental models which seem to actually be operative in terms of informing how they truly conceptualize the world. […] Muslims may aver that their god is omniscient and omnipresent, but their narrative stories in response to life circumstances seem to imply that their believe god may not see or know all things at all moments.

The deep problem here is understood [by] religious professionals: they’ve made their religion too complex for common people to understand without their intermediation. In fact, I would argue that theologians themselves don’t really understand what they’re talking about. To some extent this is a feature, not a bug. If the God of Abraham is transformed into an almost incomprehensible being, then religious professionals will have perpetual work as interpreters. […] even today most Muslims can not read the Quran. Most Muslims do not speak Arabic. […] The point isn’t to understand, the point is that they are the Word of God, in the abstract. […] The power of the Quran is that the Word of God is presumably potent. Comprehension is secondary to the command.”

“the majority of the book […] is focused on political and social facts in the Islamic world today. […] That is the best thing about Islamic Exceptionalism, it will put more facts in front of people who are fact-starved, and theory rich. That’s good.”

“the term ‘fundamentalist’ in the context of islam isn’t very informative.” (from the comments).

Below I have added some (very) superficially related links of my own, most of them ‘data-related’ (in general I’d say that I usually find ‘raw data’ more interesting than ‘big ideas’):

*My short review of Theological Correctness, one of the books Razib mentions.

*Of almost 163,000 people who applied for asylum in Sweden last year, less than 500 landed a job (news article).

*An analysis of Danish data conducted by the Rockwool Foundation found that for family-reunificated spouses/relatives etc. to fugitives, 22 % were employed after having lived in Denmark for five years (the family-reunificated individuals, that is, not the fugitives themselves). Only one in three of the family-reunificated individuals had managed to find a job after having stayed here for fifteen years. The employment rate of family-reunificated to immigrants is 49 % for people who have been in the country for 5 years, and the number is below 60 % after 15 years. In Denmark, the employment rate of immigrants from non-Western countries was 47,7 % in November 2013, compared to 73,8 % for people of (…’supposedly’, see also my comments and observations here) Danish origin, according to numbers from Statistics Denmark (link). When you look at the economic performance of the people with fugitive status themselves, 34 % are employed after 5 years, but that number is almost unchanged a decade later – only 37 % are employed after they’ve stayed in Denmark for 15 years.
Things of course sometimes look even worse at the local level than these numbers reflect, because those averages are, well, averages; for example of the 244 fugitives and family-reunificated who had arrived in the Danish Elsinore Municipality within the last three years, exactly 5 of them were in full-time employment.

*Rotherham child sexual exploitation scandal (“The report estimated that 1,400 children had been sexually abused in the town between 1997 and 2013, predominantly by gangs of British-Pakistani Muslim men […] Because most of the perpetrators were of Pakistani heritage, several council staff described themselves as being nervous about identifying the ethnic origins of perpetrators for fear of being thought racist […] It was reported in June 2015 that about 300 suspects had been identified.”)

*A memorial service for the terrorist and murderer Omar El-Hussein who went on a shooting rampage in Copenhagen last year (link) gathered 1500 people, and 600-700 people also participated at the funeral (Danish link).

*Pew asked muslims in various large countries whether they thought ‘Suicide Bombing of Civilian Targets to Defend Islam [can] be Justified?’ More than a third of French muslims think that it can, either ‘often/sometimes’ (16 %) or ‘rarely’ (19 %). Roughly a fourth of British muslims think so as well (15 % often/sometimes, 9 % rarely). Of course in countries like Jordan, Nigeria, and Egypt the proportion of people who do not reply ‘never’ is above 50 %. In such contexts people often like to focus on what the majorities think, but I found it interesting to note that in only 2 of 11 countries (Germany – 7 %, & the US – 8 %) queried was it less than 10 % of muslims who thought suicide bombings were not either ‘often’ or ‘sometimes’ justified. Those numbers are some years old. Newer numbers (from non-Western countries only, unfortunately) tell us that e.g. fewer than two out of five Egyptians (38%) and fewer than three out of five (58%) Turks would answer ‘never’ when asked this question just a couple of years ago, in 2014.

*A few non-data related observations here towards the end. I do think Razib is right that cognitive psychology is a good starting point if you want to ‘understand religion’, but a more general point I would make is that there are many different analytical approaches to these sorts of topics which one might employ, and I think it’s important that one does not privilege any single analytical framework over the others (just to be clear, I’m not saying that Razib’s doing this); different approaches may yield different insights, perhaps at different analytical levels, and combining different approaches is likely to be very useful in order to get ‘the bigger picture’, or at least to not overlook important details. ‘History’, broadly defined, may provide one part of the explanatory model, cognitive psychology another part, mathematical anthropology (e.g. stuff like this) probably also has a role to play, etc., etc.. Survey data, economic figures, scientific literatures on a wide variety of topics like trust, norms, migration analysis, and conflict studies, e.g. those dealing with civil wars, may all help elucidate important questions of interest, if not by adding relevant data then by providing additional methodological approaches/scaffoldings which might be fruitfully employed to make sense of the data that is available.

v. Statistical Portrait of Hispanics in the United States.

vi. The Level and Nature of Autistic Intelligence. Autistics may be smarter than people have been led to believe:

“Autistics are presumed to be characterized by cognitive impairment, and their cognitive strengths (e.g., in Block Design performance) are frequently interpreted as low-level by-products of high-level deficits, not as direct manifestations of intelligence. Recent attempts to identify the neuroanatomical and neurofunctional signature of autism have been positioned on this universal, but untested, assumption. We therefore assessed a broad sample of 38 autistic children on the preeminent test of fluid intelligence, Raven’s Progressive Matrices. Their scores were, on average, 30 percentile points, and in some cases more than 70 percentile points, higher than their scores on the Wechsler scales of intelligence. Typically developing control children showed no such discrepancy, and a similar contrast was observed when a sample of autistic adults was compared with a sample of nonautistic adults. We conclude that intelligence has been underestimated in autistics.”

I recall that back when I was diagnosed I was subjected to a battery of different cognitive tests of various kinds, and a few of those tests I recall thinking were very difficult, compared to how difficult they somehow ‘ought to be’ – it was like ‘this should be an easy task for someone who has the mental hardware to solve this type of problem, but I don’t seem to have that piece of hardware; I have no idea how to manipulate these objects in my head so that I might answer that question’. This was an at least somewhat unfamiliar feeling to me in a testing context, and I definitely did not have this experience when doing the Mensa admissions test later on, which was based on Raven’s matrices. Despite the fact that all IQ tests are supposed to measure pretty much the same thing I do not find it hard to believe that there are some details here which may complicate matters a bit in specific contexts, e.g. for people whose brains may not be structured quite the same way ‘ordinary brains’ are (to put it very bluntly). But of course this is just one study and a few personal impressions – more research is needed, etc. (Even though the effect size is huge.)

Slightly related to the above is also this link – I must admit that I find the title question quite interesting. I find it very difficult to picture characters featuring in books I’m reading in my mind, and so usually when I read books I don’t form any sort of coherent mental image of what the character looks like. It doesn’t matter to me, I don’t care. I have no idea if this is how other people read (fiction) books, or if they actually imagine what the characters look like more or less continuously while those characters are described doing the things they might be doing; to me it would be just incredibly taxing to keep even a simplified mental model of the physical attributes of a character in my mind for even a minute. I can recall specific traits like left-handedness and similar without much difficulty if I think the trait might have relevance to the plot, which has helped me while reading e.g. Agatha Christie novels before, but actively imagining what people look like in my mind I just find very difficult. I find it weird to think that some people might do something like that almost automatically, without thinking about it.

vii. Computer Science Resources. I recently shared the link with a friend, but of course she was already aware of the existence of this resource. Some people reading along here may not be, so I’ll include the link here. It has a lot of stuff.

June 8, 2016 Posted by | books, Chess, Computer science, data, demographics, Psychology, random stuff, religion | Leave a comment

Quotes

i. “The lucky man is he who knows how much to leave to chance.” (C. S. Forester)

ii. “even the meanest person has still at his disposition high-sounding words wherewith to mask his real character.” (Henryk Sienkiewicz)

iii. “Fine, large, meaningless, general terms like romance and business can always be related. They take the place of thinking, and are highly useful to optimists and lecturers.” (Sinclair Lewis)

iv. “Indians, of course, have no ‘theology,’ and indeed no word for the system of credulity in which the white priests arrange for God, who must be entirely bewildered by it, a series of excuses for his failures.” (-ll-)

v. “Believe those who seek the truth, doubt those who find it” (André Gide)

vi. “The surest defense against Evil is extreme individualism, originality of thinking, whimsicality, even — if you will — eccentricity. That is, something that can’t be feigned, faked, imitated; something even a seasoned imposter couldn’t be happy with. […] Evil is a sucker for solidity. It always goes for big numbers, for confident granite, for ideological purity, for drilled armies and balanced sheets. Its proclivity for such things has to do with its innate insecurity, but this realization, again, is of small comfort when Evil triumphs.” (Joseph Brodsky)

vii. “None of us can help the things life has done to us. They’re done before you realize it, and once they’re done they make you do other things until at last everything comes between you and what you’d like to be, and you’ve lost your true self forever.” (Eugene O’Neill)

viii. “Intelligence is almost useless to the person whose only quality it is.” (Alexis Carrel)

ix. “The value of a sentiment is the amount of sacrifice you are prepared to make for it.” (John Galsworthy)

x. “Vulgarized knowledge characteristically gives birth to a feeling that everything is understandable and explained. It is like a system of bridges built over chasms. One can travel boldly ahead over these bridges, ignoring the chasms. It is forbidden to look down into them; but that, alas, does not alter the fact that they exist.” (Czesław Miłosz)

xi. “The more the universe seems comprehensible, the more it also seems pointless.” (Steven Weinberg)

xii. “Most men resemble great deserted palaces: the owner occupies only a few rooms and has closed off wings where he never ventures.” (François Mauriac)

xiii. “You may turn a bad idea into a good idea — don’t kill the bad idea prematurely. A bad idea can evolve into a good idea.” (Martin Lewis Perl)

xiv. “When, as we must often do, we fear science, we really fear ourselves. Human dignity is better served by embracing knowledge.” (John Polanyi)

xv. “Authority in science exists to be questioned, since heresy is the spring from which new ideas flow.” (-ll-)

xvi. “no one of mature age cares to make a complete confession of his past life.” (W. B. Maxwell, The Devil’s Garden)

xvii. “Whenever a government feels the need of promising peace and prosperity to its citizens by means of a proclamation, it is time to be on guard and expect the opposite.” (Ivo Andrić)

xviii. “When we lose one we love, our bitterest tears are called forth by the memory of hours when we loved not enough.” (Maurice Maeterlinck)

xix. “War is the outcome, not mainly of evil intentions, but on the whole, of good intentions which miscarry or are frustrated. It is made, not usually by evil men knowing themselves to be wrong, but is the outcome of policies pursued by good men usually passionately convinced that they are right.” (Norman Angell)

xx. “The real point of honor [for a scientist] is not to be always right. It is to dare to propose new ideas, and then to check them.” (Pierre-Gilles de Gennes)

May 24, 2016 Posted by | books, quotes | Leave a comment

The Second World War (III)

You can read my previous posts about the book here and here. I gave the book 5 stars on goodreads. Below I have added some more quotes from the stuff in the middle, on various topics. I expect to post at least one more post about the book later on; there’s a lot of interesting stuff in here, and in order for me to have at least some chance of remembering some of that stuff later on I think I need to blog it.

“The battle [of Crete] began on the morning of May 20 [1941] […] It was the first large-scale airborne attack in the annals of war. […] When the battle joined we did not know what were the total resources of Germany in parachute troops. The 11th Air Corps might have been only one of half a dozen such units. It was not till many months afterwards that we were sure it was the only one.” (This quote highlights, I think, one aspect of the war which is easy to miss for people who ‘wasn’t there’; how much uncertainty there was, about a lot of things that the enemy might be doing, or might not be doing, or might be planning to do. Espionage will get you only so far).

“Prime Minister to Stafford Cripps               3 Apr 41

Following from me to M. Stalin, provided it can be personally delivered by you:
I have sure information from a trusted agent that when the Germans thought they had got Yugoslavia in the net – that is to say, after March 20 – they began to move three out of the five Panzer divisions from Roumania to Southern Poland. The moment they heard of the Serbian revolution this movement was countermanded. Your Excellency will readily appreciate the significance of these facts.”

(If the significance of these facts is not clear to people unfamiliar with the scene at the time, here’s what Churchill thought: “This shuffling and reversal of about sixty trains could not be concealed from our agents on the spot. To me it illuminated the whole Eastern scene like a lightning-flash. The sudden movement to Cracow of so much armour needed in the Balkan sphere could only mean Hitler’s intention to invade Russia in May. […] The fact that the Belgrade revolution had required their return to Roumania involved perhaps a delay from May to June. I cast about for some means of warning Stalin […] I made the message short and cryptic, hoping that this very fact, and that it was the first message I had sent him since my formal telegram of June 25, 1940, commending Sir Stafford Cripps as Ambassador, would arrest his attention and make him ponder. […] This was the only message before the attack that I sent Stalin direct.” When Churchill and Stalin later briefly discussed the warning during their 1942 Moscow conference, Stalin remarked that he remembered the warning, and added: “I did not need any warnings. I knew war would come, but I thought I might gain another six months or so.”)

“Almost all responsible military opinion held that the Russian armies would soon be defeated and largely destroyed. […] President Roosevelt was considered very bold when he proclaimed in September that the Russian front would hold and that Moscow could not be taken. […] Even in August 1942, after my visit to Moscow and the conferences there, General Brooke, who had accompanied me, adhered to the opinion that the Caucasus Mountains would be traversed and the basin of the Caspian dominated by German forces, and we prepared accordingly on the largest possible scale for a defensive campaign in Syria and Persia.”

“In the whole of the war ninety-one merchant ships were lost on the Arctic route, amounting to 7.8 per cent. of the loaded vessels outward bound and 3.8 per cent. of those returning. Only fifty-five of these were in escorted convoys. Of about four million tons of cargo dispatched from America and the United Kingdom, an eighth was lost. In this arduous work the Merchant Navy lost 829 lives, while the Royal Navy paid a still heavier price. Two cruisers and seventeen other war-ships were sunk and 1,840 officers and men died. The forty convoys to Russia carried the huge total of £428,000,000 worth of material, including 5,000 tanks and over 7,000 aircraft from Britain alone. […] The […] extreme difficulties of the Arctic route, together with future strategic possibilities, made [the] creation of a major supply route to Russia through the Persian gulf [a] prime objective. […] Starting in September 1941, this enterprise, begun and developed by the British Army, and presently to be adopted and expanded by the United States, enabled us to send to Russia, over a period of four and a half years, five million tons of supplies.”

“As we had flown [back to Britain, after the Arcadia Conference] for more than ten hours through mist and had had only one sight of a star in that time, we might well be slightly off our course. Wireless communication was of course limited by the normal war-time rules. It was evident from the discussions which were going on that we did not know where we were. Presently Portal, who had been studying the position, had a word with the captain, and then said to me, “We are going to turn north at once.” […] As I left the aircraft [after the landing] the [air] captain remarked, “I never felt so much relieved in my life as when I landed you safely in the harbour.” I did not appreciate the significance of his remark at the moment. Later on I learnt that if we had held on our course for another five or six minutes before turning northwards we should have been over the German batteries in Brest. We had slanted too much to the southward during the night. Moveover, the decisive correction which had been made brought us in, not from the south-west, but from just east of south – that is to say, from the enemy’s direction rather than from that from which we were expected. This had the result, as I was told some weeks later, that we were reported as a hostile bomber coming in from Brest, and six Hurricanes from Fighter Command were ordered out to shoot us down. However, they failed in their mission.”

“By the end of March [1942] the first phase of the Japanese war plan had achieved a success so complete that it surprised even its authors. Japan was master of Hong Kong, Siam, Malaya, and nearly the whole of the immense island region forming the Dutch East Indies. Japanese troops were plunging deeply into Burma. In the Philippines the Americans still fought on at the Corregidor, but without hope of relief. […] Whether it was wiser to organize their new perimeter thoroughly or by surging forward to gain greater depth for its defence seemed for [the Japanese leaders] a balanced strategic problem. After deliberations in Tokyo the more ambitious course was adopted. […] The Japanese High Command had shown the utmost skill and daring in making and executing their plans. They started however upon a foundation which did not measure world forces in true proportion. They never comprehended the latent might of the United States. […] they were drawn into a gamble, which even if it had won would only have lengthened their predominance by perhaps a year, and, as they lost, cut it down by an equal period. In the actual result they exchanged a fairly strong and gripped advantage for a wide and loose domain, which it was beyond their power to hold; and, being beaten in this outer area, they found themselves without the forces to make a coherent defence of their inner and vital zone. Nevertheless at this moment in the world struggle no one could be sure that Germany would not break Russia, or drive her beyond the Urals, and then be able to come back and invade Britain; or as an alternative spread through the Caucasus and Persia to join hands with the Japanese vanguards in India.”

Churchill included these interesting thoughts on the status of affairs roughly in the middle of the war: “I had now been twenty-eight months at the head of affairs, during which we had sustained an almost unbroken series of military defeats. […] The fact that we were no longer alone, but instead had the two most mighty nations in the world in alliance fighting desperately at our side, gave indeed assurances of ultimate victory. But this, by removing the sense of mortal peril, only made criticism more free. Was it strange that the whole character and system of the war direction, for which I was responsible, should have been brought into question and challenge? It is indeed remarkable that I was not […] dismissed from power, or confronted with demands for changes in my methods, which it was known I should never accept. I should then have vanished from the scene with a load of calamity on my shoulders, and the harvest, at last to be reaped, would have been ascribed to my belated disappearance.”

“In September [1942] 30 per cent. of Axis shipping supplying North Africa was sunk, largely by air action. In October the figure rose to 40 per cent. The loss of petrol was 66 per cent. […] There had been serious derangements in the enemy’s command. Rommel had gone to hospital in Germany at the end of September and his place was taken by General Stumme. Within twenty-four hours of the start of the battle [of El Alamein] Stumme died of a heart attack. [Talk about bad timing…] […] The Battle of El Alamein differed from all previous fighting in the Desert. The front was limited, heavily fortified, and held in strength. There was no flank to turn. A break-through must be made by whoever was the stronger and wished to take the offensive. In this way we are led back to the battles of the First World War on the Western Front. […] It may almost be said, “Before Alamein we never had a victory. After Alamein we never had a defeat.”

An important thing I learned from the book was the answer to the question why the (Western) Allied forces were mainly fighting in Africa during the first part of the war, but didn’t seemingly really do much else aside from trying to keep the Germans from bombing their cities and sinking their ships. A very important point is that landing craft was the binding constraint, and these were in desperately short supply, and it took a lot of time to build up the supply. It would have made no sense for the Allied to have tried to unload substantial numbers of soldiers in Europe during the first years; they would have been slaughtered, and valuable landing crafts would have been lost. What might have happened, had such a strategy been pursued, might have been repeated experiences like those of the Dieppe raid, where almost 60 % of the soldiers who made it ashore were killed, wounded or captured, and the rest had to be evacuated within hours. So instead the Allied leaders tried to seek out the enemy where they were actually capable of taking him on, and that way bind resources of his which could not be used on the Eastern front – which ended up meaning mainly military engagements in Africa and the Mediterranean. Operation Torch could be initiated successfully significantly sooner than any sort of successful cross-Channel operation could.

“[In May 1943] there were 185 German divisions on the Russian front. […] Brooke [during a strategy meeting at that time] set out our whole Mediterranean strength [available for operations in the near future]. Deducting seven divisions to be sent home for the cross-Channel operation and two to cover British commitments to Turkey, there would be twenty-seven Allied divisions available in the Mediterranean area. […] In the initial assault [of the invasion of Sicily] nearly 3,000 ships and landing-craft took part, carrying between them 160,000 men, 14,000 vehicles, 600 tanks, and 1,800 guns.” And still this was small potatoes compared to the forces engaged in conflict on the Eastern front – which makes you think…

“In 1940 and 1941 we lost four million tons of merchant shipping a year. In 1942, after the United States was our Ally, this figure nearly doubled, and the U-boats sank ships faster than the Allies could build them. During 1943, thanks to the immense shipbuilding programme of the United States, the new tonnage at last surpassed losses at sea from all causes, and the second quarter saw, for the first time, U-boat losses exceed their rate of replacement. […] In May alone forty U-boats perished in the ocean. […] The convoys came through intact, the supply line was safe, the decisive battle had been fought and won. […] The extirpation of Axis power in North Africa opened to our convoys the direct route to Egypt, India, and Australia […] The long haul round the Cape, which had cost us so dear in time, effort, and tonnage, would soon be ended. The saving of an average of forty-five days for each convoy to the Middle East increased magnificently at one stroke the fertility of our shipping.”

May 20, 2016 Posted by | books, history | Leave a comment

Quotes

i. “It is both more difficult and more complicated to die than people think.” (Halldór Laxness)

ii. “There’s a cruel lot of sorrow in most people’s lives.” (W. B. Maxwell, The Devil’s Garden)

iii. “the best causes sometimes need the best advocates.” (-ll-)

iv. “Mavis, taking a present of tea and sugar to one of the Cross Roads cottages, had found her digging in the garden, and, struck by her pitiful aspect, had questioned her and elicited her history. It was a common enough one in those parts. Not being wanted at home, she had been “lent” to Mrs. Neath, the cottage woman, in exchange for her keep, and was mercilessly used by the borrower. She rose at dawn, worked as the regular household drudge till within an hour of school-time, then walked into Rodchurch for the day’s schooling with a piece of dry bread in her pocket as dinner; and on her return from school worked again till late at night. She admitted that she felt always hungry, always tired, always miserable; that she suffered from cold at night in her wretched little bed; and that Mrs. Neath often beat her.” (-ll-)

v. “Despair itself if it goes on long enough, can become a kind of sanctuary in which one settles down and feels at ease.” (Charles Augustin Sainte-Beuve) (Le désespoir lui-même, pour peu qu’il se prolonge, devient une sorte d’asile dans lequel on peut s’asseoir et reposer)

vi. “Most often we are judging not others, but rather our own faculties in others.” (-ll-) (Le plus souvent nous ne jugeons pas les autres, mais nous jugeons nos propres facultés dans les autres)

vii. “It is comfortable to live in the belief that you are great, though your greatness is latent.” (Italo Svevo) (È un modo comodo di vivere quello di credersi grande di una grandezza latente.)

viii. “There are some people who can receive a truth by no other way than to have their understanding shocked and insulted.” (Carl Sandburg)

ix. “More people are flattered into virtue than bullied out of vice.” (Robert Smith Surtees)

x. “Among other things Jonestown was an example of a definition well known to sociologists of religion: a cult is a religion with no political power.” (Tom Wolfe)

xi. “Life resembles a novel more often than novels resemble life.” (George Sand) (La vie ressemble plus souvent à un roman qu’un roman ne ressemble à la vie)

xii. “Life is a long ache which rarely sleeps and can never be cured.” (George Sand)

xiii. “What egotism, what stupid vanity, to suppose that a thing could not happen because you could not conceive it!” (Philip Wylie)

xiv. “All creeds and opinions are nothing but the mere result of chance and temperament.” (Joseph Henry Shorthouse)

xv. “I have no particular political views but I was and am struck by the idea that the left and the right are always entirely similar when they become extreme – they click together like two edges of a magnet.” (Alan Williams)

xvi. “We see things not as they are, but as we are ourselves.” (H. M. Tomlinson)

xvii. “Strange as it may seem, no amount of learning can cure stupidity, and formal education positively fortifies it.” (Stephen Vizinczey)

xviii. “A life postponed too long might never be lived.” (Joan Slonczewski)

xix. “Hell is being alive, and being alive is all there is.” (Michael Marshall Smith)

xx. “It is fortunate that each generation does not comprehend its own ignorance. We are thus enabled to call our ancestors barbarous.” (Charles Dudley Warner)

 

May 16, 2016 Posted by | quotes | Leave a comment

Random stuff

I find it difficult to find the motivation to finish the half-finished drafts I have lying around, so this will have to do. Some random stuff below.

i.

(15.000 views… In some sense that seems really ‘unfair’ to me, but on the other hand I doubt neither Beethoven nor Gilels care; they’re both long dead, after all…)

ii. New/newish words I’ve encountered in books, on vocabulary.com or elsewhere:

Agleyperipeteia, disseverhalidom, replevinsocage, organdie, pouffe, dyarchy, tauricide, temerarious, acharnement, cadger, gravamen, aspersion, marronage, adumbrate, succotash, deuteragonist, declivity, marquetry, machicolation, recusal.

iii. A lecture:

It’s been a long time since I watched it so I don’t have anything intelligent to say about it now, but I figured it might be of interest to one or two of the people who still subscribe to the blog despite the infrequent updates.

iv. A few wikipedia articles (I won’t comment much on the contents or quote extensively from the articles the way I’ve done in previous wikipedia posts – the links shall have to suffice for now):

Duverger’s law.

Far side of the moon.

Preference falsification.

Russian political jokes. Some of those made me laugh (e.g. this one: “A judge walks out of his chambers laughing his head off. A colleague approaches him and asks why he is laughing. “I just heard the funniest joke in the world!” “Well, go ahead, tell me!” says the other judge. “I can’t – I just gave someone ten years for it!”).

Political mutilation in Byzantine culture.

v. World War 2, if you think of it as a movie, has a highly unrealistic and implausible plot, according to this amusing post by Scott Alexander. Having recently read a rather long book about these topics, one aspect I’d have added had I written the piece myself would be that an additional factor making the setting seem even more implausible is how so many presumably quite smart people were so – what at least in retrospect seems – unbelievably stupid when it came to Hitler’s ideas and intentions before the war. Going back to Churchill’s own life I’d also add that if you were to make a movie about Churchill’s life during the war, which you could probably relatively easily do if you were to just base it upon his own copious and widely shared notes, then it could probably be made into a quite decent movie. His own comments, remarks, and observations certainly made for a great book.

May 15, 2016 Posted by | astronomy, Computer science, history, language, Lectures, mathematics, music, random stuff, Russia, wikipedia | Leave a comment

The Second World War (II)

Here’s my first post about Churchill’s book(s). In this post I’ll add some further observations and data; I’m roughly two-thirds through the book(s) at this point.

“a significant proportion of our whole war effort had to be devoted to combating the mine. A vast output of material and money was diverted from other tasks, and many thousands of men risked their lives night and day in the minesweepers alone. The peak figure was reached in June 1944, when nearly sixty thousand were thus employed.”

“On January 10, 1940, anxieties about the Western Front received confirmation. A German staff major of the 7th Air Division had been ordered to take some documents to headquarters in Cologne. He missed his train and decided to fly. His machine overshot the mark and made a forced landing in Belgium, where Belgian troops arrested him and impounded his papers, which he tried desperately to destroy. These contained the entire and actual scheme for the invasion of Belgium, Holland, and France on which Hitler had resolved. […] I was told about all this at the time […] It was argued in all three countries concerned that probably it was a plant. But this could not be true. There could be no sense in the Germans trying to make the Belgians believe that they were going to attack them in the near future. This might make them do the very last thing the Germans wanted, namely, make a plan with the French and British Armies […] I therefore believed in the impending attack. We appealed to Belgium, but the Belgian King and his Army staff merely waited, hoping that all would turn out well. […] no further action of any kind was taken by the Allies or the threatened States. […] Hitler, […] ordered, after venting his anger, new variants [of the invasion plans] to be prepared.”

“until July 1944 Britain and her Empire had a substantially larger number of divisions in contact with the enemy than the United States. This general figure includes not only the European and African spheres but also all the war in Asia against Japan. […] Out of 781 German and 85 Italian U-boats destroyed in the European theatre, the Atlantic and Indian Oceans, 594 were accounted for by British sea and air forces […] of shipping losses by enemy action suffered by all nations throughout the war […] 80 per cent. were suffered in the Atlantic Ocean, including British coastal waters and the North Sea. Only 5 per cent. were lost in the Pacific. […] Up till the end of 1943 the British discharge of bombs upon Germany had in the aggregate exceeded by eight tons to one those cast from American machines”

“My relations with the President [Roosevelt – US] gradually became so close that the chief business between our two countries was virtually conducted by […] personal interchanges between him and me. […] In all I sent him nine hundred and fifty messages, and received about eight hundred in reply.”

“Altogether there came to the rescue of the Army under the ceaseless air bombardment of the enemy about eight hundred and sixty vessels […] at 2.23 p.m. on June 4 the Admiralty, in agreement with the French, announced that Operation “Dynamo” was now completed. More than 338,000 British and Allied troops had been landed in England. […] On June 17 it was announced that the Pétain Government had asked for an armistice, ordering all French forces to cease fighting, without even communicating this information to our troops. General Brooke was consequently told to come away with all men he could embark and any equipment he could save. We repeated now on a considerable scale, though with larger vessels, the Dunkirk evacuation. Over twenty thousand Polish troops who refused to capitulate cut their way to the sea and were carried by our ships to Britain. […] In all there were evacuated from all French harbours 136,000 British troops and 310 guns; a total, with the Poles, of 156,000 men.”

“Hitler and Stalin had much in common as totalitarians, and their systems of government were akin. […] On June 14, the day Paris fell, Moscow sent an ultimatum to Lithuania accusing her and the other Baltic States of military conspiracy against the U.S.S.R. and demanding radical changes of government and military concessions. On June 15 Red Army troops invaded the country. Latvia and Estonia were exposed to the same treatment. […] A Russian ultimatum to Roumania was delivered to the Roumanian Minister in Moscow at 10 p.m. on June 26. The cession of Bessarabia and the norther part of the province of Bukovina was demanded […] On June 27 Roumanian troops were withdrawn from the two provinces concerned, and the territories passed into Russian hands. […] On August 3-6 the pretence of pro-Soviet friendly and democratic Governments [in the Baltic] was swept away, and the Kremlin annexed the Baltic States to the Soviet Union.”

“From September 7 to November 3 an average of two hundred German bombers attacked London every night. […] The night raids were accompanied by more or less continuous daylight attacks by small groups or even single enemy planes, and the sirens often sounded at brief intervals throughout the whole twenty-four hours. To this curious existence the seven million inhabitants of London accustomed themselves. […] We did not know how long it would last. We had no reason to suppose that it would not go on getting worse. […] In the twelve months from June 1940 to June 1941 our civilian casualties were 43,381 killed and 40,856 seriously injured, a total of 94,237.”

“The only thing that ever really frightened me during the war was the U-boat peril. […] we poised and pondered together on this problem. It did not take the form of flaring battles and glittering achievements. It manifested itself through statistics, diagrams, and curves unknown to the nation, incomprehensible to the public. […] At the outset the Admiralty naturally thought first of bringing the ships safely to port, and judged their success by a minimum of sinkings. But now this was no longer the test. We all realised that the life and war effort of the country depended equally upon the weight of imports safely landed. In the week ending June 8, during the height of the battle in France, we had brought into the country about a million and a quarter tons of cargo, exclusive of oil. From this peak figure imports had declined at the end of July to less than 750,000 tons a week. […] I became increasingly concerned about this ominous fall in imports. “I see,” I minuted to the First Lord in the middle of February, 1941, “that entrances of ships with cargo in January were less than half of what they were last January.” The very magnitude and refinement of our protective measures – convoy, diversion, degaussing [a method employed to counteract magnetic mines – US], mine-clearance, the avoidance of the Mediterranean – the lengthening of most voyages in time and distance and the delays at the ports through bombing and the black-out, all reduced the operative fertility of our shipping to an extent even more serious than the actual losses. […] To the U-boat scourge was soon added air attack far out on the ocean by long-range aircraft. […] Powerful German cruisers were active. […] formidable vessels compelled the employment on convoy duty of nearly every available British capital ship. At one period the Commander-in-Chief of the Home Fleet had only one battleship in hand.”

“In the three months ending with May [1941] U-boats alone sank 142 ships, of 818,000 tons, of which 99 were British. […] in the same three months of March, April, and May 179 ships, of 545,000 tons, were sunk by air attack, mainly in the coastal regions. […] In the Atlantic [1942] proved the toughest [year] of the whole war. […] By the end of January [1942] thirty-one ships, of nearly 200,000 tons, had been sunk off the coast off the United States and Canadian coast. […] In February they destroyed seventy-one ships, of 384,000 tons, in the Atlantic, of which all but two were sunk in the American zone. […] The American Army Air Force, which controlled almost all military shore-based aircraft, had no training in anti-submarine warfare, whereas the Navy, equipped with float-planes and amphibians, had no means to carry it out, and in these crucial months an effective American defence system was only achieved with painful, halting steps. […] It was not until the end of the year that a complete interlocking convoy system covering all [the] immense areas [involved] became fully effective. […] In seven months the Allied losses in the Atlantic from U-boats alone amounted to over three million tons, which included 181 British ships of 1,130,000 tons. Less than one-tenth occurred in convoys. All this cost the enemy up to July no more than fourteen U-boats sunk throughout the Atlantic and Arctic Oceans, and of these kills only six were in North American waters. […] during [August] U-boats sank 108 vessels […] Between January and October 1942 the number of U-boats had more than doubled. 196 were operational […] All our escorts had to be cut to the bone for the sake of our main operations in Africa, and in November our losses at sea were the heaviest of the whole war, including 117 ships, of over 700,000 tons, by U-boats alone, another 100,000 from other causes.”

April 19, 2016 Posted by | books, history | Leave a comment

Einstein quotes

“Einstein emerges from this collection of quotes, drawn from many different sources, as a complete and fully rounded human being […] Knowledge of the darker side of Einstein’s life makes his achievement in science and in public affairs even more miraculous. This book shows him as he was – not a superhuman genius but a human genius, and all the greater for being human.”

I’ve recently read The Ultimate Quotable Einstein, from the foreword of which the above quote is taken, which contains roughly 1600 quotes by or about Albert Einstein; most of the quotes are by Einstein himself, but the book also includes more than 50 pages towards the end of the book containing quotes by others about him. I was probably not in the main target group, but I do like good quote collections and I figured there might be enough good quotes in the book for it to make sense for me to give it a try. On the other hand after having read the foreword by Freeman Dyson I knew there would probably be a lot of quotes in the book which I probably wouldn’t find too interesting; I’m not really sure why I should give a crap if/why a guy who died more than 60 years ago and whom I have never met and never will was having an affair during the early 1920s, or why I should care what Einstein thought about his mother or his ex-wife, but if that kind of stuff interests you the book has stuff about those kinds of things as well. My own interest in Einstein, such as it is, is mainly in ‘Einstein the scientist’ (and perhaps also in this particular context ‘Einstein the aphorist’), not ‘Einstein the father’ or ‘Einstein the husband’. I also don’t find the political views which he held to be very interesting, but again if you want to know what Einstein thought about things like Zionism, pacifism, and world government the book includes quotes about such topics as well.

Overall I should say that I was a little underwhelmed by the book and the quotes it includes, but I would also note that people who are interested in knowing more about Einstein will likely find a lot of valuable source material here, and that I did give the book 3 stars on goodreads. I did learn a lot of new things about Einstein by reading the book, but this is not surprising given how little I knew about him before I started reading the book; for example I had no idea that he was offered the presidency of Israel a few years before his death. I noticed only two quotes which were included more than once (a quote on pages 187-188 was repeated on page 453, and a quote on page 295 was repeated on page 455), and although I cannot guarantee that there aren’t any other repeats almost all quotes included in the book are unique, in the sense that they’re only included once in the coverage. However it should also be mentioned in this context that there are a few quotes on specific themes which are very similar to other quotes included elsewhere in the coverage. I do consider this unavoidable considering the number of quotes included, though.

I have included some sample quotes from the book below – I have tried to include quotes on a wide variety of topics. All quotes without a source below are sourced quotes by Einstein (the book also contains a small collection of quotes ‘attributed to Einstein’, many of which are either not sourced or sourced in such a manner that Calaprice did not feel convinced that the quote was actually by Einstein – none of the quotes from that part of the book’s coverage are included below).

“When a blind beetle crawls over the surface of a curved branch, it doesn’t notice that the track it has covered is indeed curved. I was lucky enough to notice what the beetle didn’t notice.” (“in answer to his son Eduard’s question about why he is so famous, 1922.”)

“The most valuable thing a teacher can impart to children is not knowledge and understanding per se but a longing for knowledge and understanding” (see on a related note also Susan Engel’s book – US)

“Teaching should be such that what is offered is perceived as a valuable gift and not as a hard duty.”

“I am not prepared to accept all his conclusions, but I consider his work an immensely valuable contribution to the science of human behavior.” (Einstein said this about Sigmund Freud during an interview. Yeah…)

“I consider him the best of the living writers.” (on Bertrand Russell. Russell incidentally also admired Einstein immensely – the last part of the book, including quotes by others about Einstein, includes this one by him: “Of all the public figures that I have known, Einstein was the one who commanded my most wholehearted admiration.”)

“I cannot understand the passive response of the whole civilized world to this modern barbarism. Doesn’t the world see that Hitler is aiming for war?” (1933. Related link.)

“Children don’t heed the life experience of their parents, and nations ignore history. Bad lessons always have to be learned anew.”

“Few people are capable of expressing with equanimity opinions that differ from the prejudices of their social environment. Most people are even incapable of forming such opinions.”

“Sometimes one pays most for things one gets for nothing.”

“Thanks to my fortunate idea of introducing the relativity principle into physics, you (and others) now enormously overrate my scientific abilities, to the point where this makes me quite uncomfortable.” (To Arnold Sommerfeld, 1908)

“No fairer destiny could be allotted to any physical theory than that it should of itself point out the way to the introduction of a more comprehensive theory, in which it lives on as a limiting case.”

“Mother nature, or more precisely an experiment, is a resolute and seldom friendly referee […]. She never says “yes” to a theory; but only “maybe” under the best of circumstances, and in most cases simply “no”.”

“The aim of science is, on the one hand, a comprehension, as complete as possible, of the connection between the sense experiences in their totality, and, on the other hand, the accomplishment of this aim by the use of a minimum of primary concepts and relations.” A related quote from the book: “Although it is true that it is the goal of science to discover rules which permit the association and foretelling of facts, this is not its only aim. It also seeks to reduce the connections discovered to the smallest possible number of mutually independent conceptual elements. It is in this striving after the rational unification of the manifold that it encounters its greatest successes.”

“According to general relativity, the concept of space detached from any physical content does not exist. The physical reality of space is represented by a field whose components are continuous functions of four independent variables – the coordinates of space and time.”

“One thing I have learned in a long life: that all our science, measured against reality, is primitive and childlike – and yet it is the most precious thing we have.”

“”Why should I? Everybody knows me there” (upon being told by his wife to dress properly when going to the office). “Why should I? No one knows me there” (upon being told to dress properly for his first big conference).”

“Marriage is but slavery made to appear civilized.”

“Nothing is more destructive of respect for the government and the law of the land than passing laws that cannot be enforced.”

“Einstein would be one of the greatest theoretical physicists of all time even if he had not written a single line on relativity.” (Max Born)

“Einstein’s [violin] playing is excellent, but he does not deserve his world fame; there are many others just as good.” (“A music critic on an early 1920s performance, unaware that Einstein’s fame derived from physics, not music. Quoted in Reiser, Albert Einstein, 202-203″)

April 12, 2016 Posted by | books, history, Physics, quotes, science | Leave a comment

Quotes

i. “Only half of writing is saying what you mean. The other half is preventing people from reading what they expected you to mean.” (James Richardson)

ii. “How often feelings are circular. How embarrassing to be embarrassed. How annoying to be annoyed.” (-ll-)

iii. “I worked so hard to understand it that it must be true.” (-ll-)

iv. “Always tell the Truth: where it is not loved, it is respected and feared.” (Thomas Fuller)

v. “the wise Man that holds his Tongue, says more than the Fool who speaks.” (-ll-)

vi. “‘Tis better for thee to be wise and not seem so, than to seem wise and not be so: Yet Men, for the most Part, desire and endeavor the contrary.” (-ll-)

vii. “If any one giveth thee excessive Praises more than can handsomely belong to thee, thou art to think of him, that he taketh thee for vain and credulous, and easy to be deceived, and effectually a Fool.” (-ll-)

viii. “When thou shewest Respect to any one, see that thy Submissions be proportionable to the Homage thou owest him. There is Stupidity and Pride in doing too little; but in over acting of it, there is Abjection and Hypocrisy.” (-ll-)

ix. “The Way to think we have enough, is not to desire to have too much.” (-ll-)

x. “A Friend to all, is a Friend to none.” (-ll-)

xi. “One needs time to free oneself of wrong convictions. If it happens too suddenly, they go on festering.” (Elias Canetti)

xii. “Duty largely consists of pretending that the trivial is critical.” (John Fowles)

xiii. “You have not converted a man, because you have silenced him.” (John Morley)

xiv. “It is a test of true theories not only to account for but to predict phenomena.” (William Whewell)

xv. “Personally, I find the concept of a “final theory,” or a “theory of everything,” rather limiting. The fun of discovery will most likely last as long as the human race continues.” (F. J. Duarte)

xvi. “There is no meaning to space that is independent of the relationships among real things of the world. …Space is nothing apart from the things that exist. …If we take out all the words we are not left with an empty sentence, we are left with nothing.” (Lee Smolin)

xvii. “One should never forget, that society would rather be amused than instructed.” (Adolph Freiherr Knigge)

xviii. “Clearly, a civilization that feels guilty for everything it is and does will lack the energy and conviction to defend itself.” (Jean-François Revel; quoted by Jeane Kirkpatrick during a speech she gave in 1984).

xix. “Democratic civilization is the first in history to blame itself because another power is working to destroy it.” (Jean-François Revel, 1983)

xx. “The only excuse for God is that He does not exist.” (Stendhal)

 

 

April 9, 2016 Posted by | quotes | Leave a comment

Human Drug Metabolism (I)

“It has been said that if a drug has no side effects, then it is unlikely to work. Drug therapy labours under the fundamental problem that usually every single cell in the body has to be treated just to exert a beneficial effect on a small group of cells, perhaps in one tissue. Although drug-targeting technology is improving rapidly, most of us who take an oral dose are still faced with the problem that the vast majority of our cells are being unnecessarily exposed to an agent that at best will have no effect, but at worst will exert many unwanted effects. Essentially, all drug treatment is really a compromise between positive and negative effects in the patient. […] This book is intended to provide a basic grounding in human drug metabolism, although it is useful if the reader has some knowledge of biochemistry, physiology and pharmacology from other sources. In addition, a qualitative understanding of chemistry can illuminate many facets of drug metabolism and toxicity. Although chemistry can be intimidating, I have tried to make the chemical aspects of drug metabolism as user-friendly as possible.”

I’m currently reading this book. To say that it is ‘useful if the reader has some knowledge’ of the topics mentioned is putting it mildly; I’d say it’s mandatory – my advice would be to stay far away from this book if you know nothing of pharmacology, biochem, and physiology. I know enough to follow most of the coverage, at least in terms of the big picture stuff, but some of the biochemistry details I frankly have been unable to follow; I think I could probably understand all of it if I were willing to look up all the words and concepts with which I’m unfamiliar, but I’m not willing to spend the time to do that. In this context it should also be mentioned that the book is very well written, in the sense that it is perfectly possible to read the book and follow the basic outline of what’s going on without necessarily understanding all details, so I don’t feel that the coverage in any way discourages me from reading the book the way I am – the significance of that hydrogen bond in the diagram will probably become apparent to you later, and even if it doesn’t you’ll probably manage.

In terms of general remarks about the book, a key point to be mentioned early on is also that the book is very dense and has a lot of interesting stuff. I find it hard at the moment to justify devoting time to blogging, but if that were not the case I’d probably feel tempted to cover this book in a lot of detail, with multiple posts delving into specific fascinating aspects of the coverage. Despite this being a book where I don’t really understand everything that’s going on all the time, I’m definitely at a five star rating at the moment, and I’ve read close to two-thirds of it at this point.

A few quotes:

“The process of drug development weeds out agents [or at least tries to weed out agents… – US] that have seriously negative actions and usually releases onto the market drugs that may have a profile of side effects, but these are relatively minor within a set concentration range where the drug’s pharmacological action is most effective. This range, or ‘therapeutic window’ is rather variable, but it will give some indication of the most ‘efficient’ drug concentration. This effectively means the most beneficial pharmacodynamic effects for the minimum side effects.”

If the dose is too low, you have a case of drug failure, where the drug doesn’t work. If the dose is too high, you experience toxicity. Both outcomes are problematic, but they manifest in different ways. Drug failure is usually a gradual process (days – “Therapeutic drug failure is usually a gradual process, where the time frame may be days before the problem is detected”), whereas toxicity may be of very rapid onset (hours).

“To some extent, every patient has a unique therapeutic window for each drug they take, as there is such huge variation in our pharmacodynamic drug sensitivities. This book is concerned with what systems influence how long a drug stays in our bodies. […] [The therapeutic index] has been defined as the ratio between the lethal or toxic dose and the effective dose that shows the normal range of pharmacological effect. In practice, a drug […] is listed as having a narrow TI if there is less than a twofold difference between the lethal and effective doses, or a twofold difference in the minimum toxic and minimum effective concentrations. Back in the 1960s, many drugs in common use had narrow TIs […] that could be toxic at relatively low levels. Over the last 30 years, the drug industry has aimed to replace this type of drug with agents with much higher TIs. […] However, there are many drugs […] which remain in use that have narrow or relatively narrow TIs”.

“metabolites are usually removed from the cell faster than the parent drug”

“The kidneys are mostly responsible for […] removal, known as elimination. The kidneys cannot filter large chemical entities like proteins, but they can remove the majority of smaller chemicals, depending on size, charge and water solubility. […] the kidney is a lipophilic (oil-loving) organ […] So the kidney is not efficient at eliminating lipophilic chemicals. One of the major roles of the liver is to use biotransforming enzymes to ensure that lipophilic agents are made water soluble enough to be cleared by the kidney. So the liver has an essential but indirect role in clearance, in that it must extract the drug from the circulation, biotransform (metabolize) it, then return the water-soluble product to the blood for the kidney to remove. The liver can also actively clear or physically remove its metabolic products from the circulation by excreting them in bile, where they travel through the gut to be eliminated in faeces.”

“Cell structures eventually settled around the format we see now, a largely aqueous cytoplasm bounded by a predominantly lipophilic protective membrane. Although the membrane does prevent entry and exit of many potential toxins, it is no barrier to other lipophilic molecules. If these molecules are highly lipophilic, they will passively diffuse into and become trapped in the membrane. If they are slightly less lipophilic, they will pass through it into the organism. So aside from ‘ housekeeping ’ enzyme systems, some enzymatic protection would have been needed against invading molecules from the immediate environment. […] the majority of living organisms including ourselves now possess some form of effective biotransformational enzyme capability which can detoxify and eliminate most hydrocarbons and related molecules. This capability has been effectively ‘stolen’ from bacteria over millions of years. The main biotransformational protection against aromatic hydrocarbons is a series of enzymes so named as they absorb UV light at 450 nm when reduced and bound to carbon monoxide. These specialized enzymes were termed cytochrome P450 monooxygenases or sometimes oxido-reductases. They are often referred to as ‘CYPs’ or ‘P450s’. […] All the CYPs accomplish their functions using the same basic mechanism, but each enzyme is adapted to dismantle particular groups of chemical structures. It is a testament to millions of years of ‘ research and development ’ in the evolution of CYPs, that perhaps 50,000 or more man-made chemical entities enter the environment for the first time every year and the vast majority can be oxidized by at least one form of CYP. […] To date, nearly 60 human CYPs have been identified […] It is likely that hundreds more CYP-mediated endogenous functions remain to be discovered. […] CYPs belong to a group of enzymes which all have similar core structures and modes of operation. […] Their importance to us is underlined by their key role in more than 75 per cent of all drug biotransformations.”

I would add a note here that a very large proportion of this book is, perhaps unsurprisingly in view of the above, about those CYPs; how they work, what exactly it is that they do, which different kinds there are and what roles they play in the metabolism of specific drugs and chemical compounds, variation in gene expression across individuals and across populations in the context of specific CYPs and how such variation may relate to differences in drug metabolism, etc.

“Drugs often parallel endogenous molecules in their oil solubility, although many are considerably more lipophilic than these molecules. Generally, drugs, and xenobiotic compounds, have to be fairly oil soluble or they would not be absorbed from the GI tract. Once absorbed these molecules could change both the structure and function of living systems and their oil solubility makes these molecules rather ‘elusive’, in the sense that they can enter and leave cells according to their concentration and are temporarily beyond the control of the living system. This problem is compounded by the difficulty encountered by living systems in the removal of lipophilic molecules. […] even after the kidney removes them from blood by filtering them, the lipophilicity of drugs, toxins and endogenous steroids means that as soon as they enter the collecting tubules, they can immediately return to the tissue of the tubules, as this is more oil-rich than the aqueous urine. So the majority of lipophilic molecules can be filtered dozens of times and only low levels are actually excreted. In addition, very high lipophilicity molecules like some insecticides and fire retardants might never leave adipose tissue at all […] This means that for lipophilic agents:
*the more lipophilic they are, the more these agents are trapped in membranes, affecting fluidity and causing disruption at high levels;
* if they are hormones, they can exert an irreversible effect on tissues that is outside normal physiological control;
*if they are toxic, they can potentially damage endogenous structures;
* if they are drugs, they are also free to cause any pharmacological effect for a considerable period of time.”

“A sculptor was once asked how he would go about sculpting an elephant from a block of stone. His response was ‘knock off all the bits that did not look like an elephant’. Similarly, drug-metabolizing CYPs have one main imperative, to make molecules more water-soluble. Every aspect of their structure and function, their position in the liver, their initial selection of substrate, binding, substrate orientation and catalytic cycling, is intended to accomplish this deceptively simple aim.”

“The use of therapeutic drugs is a constant battle to pharmacologically influence a system that is actively undermining the drugs’ effects by removing them as fast as possible. The processes of oxidative and conjugative metabolism, in concert with efflux pump systems, act to clear a variety of chemicals from the body into the urine or faeces, in the most rapid and efficient manner. The systems that manage these processes also sense and detect increases in certain lipophilic substances and this boosts the metabolic capability to respond to the increased load.”

“The aim of drug therapy is to provide a stable, predictable pharmacological effect that can be adjusted to the needs of the individual patient for as long is deemed clinically necessary. The physician may start drug therapy at a dosage that is decided on the basis of previous clinical experience and standard recommendations. At some point, the dosage might be increased if the desired effects were not forthcoming, or reduced if side effects are intolerable to the patient. This adjustment of dosage can be much easier in drugs that have a directly measurable response, such as a change in clotting time. However, in some drugs, this adjustment process can take longer to achieve than others, as the pharmacological effect, once attained, is gradually lost over a period of days. The dosage must be escalated to regain the original effect, sometimes several times, until the patient is stable on the dosage. In some cases, after some weeks of taking the drug, the initial pharmacological effect seen in the first few days now requires up to eight times the initial dosage to reproduce. It thus takes a significant period of time to create a stable pharmacological effect on a constant dose. In the same patients, if another drug is added to the regimen, it may not have any effect at all. In other patients, sudden withdrawal of perhaps only one drug in a regimen might lead to a gradual but serious intensification of the other drug’s side effects.”

“acceleration of drug metabolism as a response to the presence of certain drugs is known as ‘enzyme induction’ and drugs which cause it are often referred to as ‘inducers’ of drug metabolism. The process can be defined as: ‘An adaptive increase in the metabolizing capacity of a tissue’; this means that a drug or chemical is capable of inducing an increase in the transcription and translation of specific CYP isoforms, which are often (although not always) the most efficient metabolizers of that chemical. […] A new drug is generally regarded as an inducer if it produces a change in drug clearance which is equal to or greater than 40 per cent of an established potent inducer, usually taken as rifampicin. […] inducers are usually (but not always) lipophilic, contain aromatic groups and consequently, if they were not oxidized, they would be very persistent in living systems. CYP enzymes have evolved to oxidize this very type of agent; indeed, an elaborate and very effective system has also evolved to modulate the degree of CYP oxidation of these agents, so it is clear that living systems regard inducers as a particular threat among lipophilic agents in general. The process of induction is dynamic and closely controlled. The adaptive increase is constantly matched to the level of exposure to the drug, from very minor almost undetectable increases in CYP protein synthesis, all the way to a maximum enzyme synthesis that leads to the clearance of grammes of a chemical per day. Once exposure to the drug or toxin ceases, the adaptive increase in metabolizing capacity will subside gradually to the previous low level, usually within a time period of a few days. This varies according to the individual and the drug. […] it is clear there is almost limitless capacity for variation in terms of the basic pre-set responsiveness of the system as well as its susceptibility to different inducers and groups of inducers. Indeed, induction in different patients has been observed to differ by more than 20-fold.”

This one I added mostly because I didn’t know this and I thought it was worth including it here because it would make it easier for me to remember later (i.e., not because I figured other people might find this interesting):

CYP2E1 is very sensitive to diet, even becoming induced by high fat/low carbohydrate intakes. Surprisingly, starvation and diabetes also promote CYP2E1 functionality. Insulin levels fall during diet restriction, starvation and in diabetes and the formation of functional 2E1 is suppressed by insulin, so these conditions promote the increase of 2E1 metabolic capability. One of the consequences of diabetes and starvation is the major shift from glucose to fatty acid/tryglyceride oxidation, of which some of the by-products are small, hydrophilic and potentially toxic ‘ketone bodies’. These agents can cause a CNS intoxicating effect which is seen in diabetics who are very hypoglycaemic, they may appear ‘drunk’ and their breath will smell as if they had been drinking.”

A more general related point which may be of more interest to other people reading along here is that this is far from the only CYP which is sensitive to diet, and that diet-mediated effects may be very significant. I may go into this in more detail in a later post. Note that grapefruit is a major potentially problematic dietary component in many drug contexts:

“Although patients have been heroically consuming grapefruit juice for their health for decades, it took until the late 1980s before its effects on drug clearance were noted and several more years before it was realized that there could be a major problem with drug interactions […] The most noteworthy feature of the effect of grapefruit juice is its potency from a single ‘dose’ which coincides with a typical single breakfast intake of the juice, say around 200–300 ml. Studies with CYP3A substrates such as midazolam have shown that it can take up to three days before the effects wear off, which is consistent with the synthesis of new enzyme. […] there are a number of drugs that are subject to a very high gut wall component to their ‘first-pass’ metabolism […]; these include midazolam, terfenadine, lovastatin, simvastatin and astemizole. Their gut CYP clearance is so high that if the juice inhibits it, the concentration reaching the liver can increase six- or sevenfold. If the liver normally only extracts a relatively minor proportion of the parent agent, then plasma levels of such drugs increase dramatically towards toxicity […] the inhibitor effects of grapefruit juice in high first – pass drugs is particularly clinically relevant as it can occur after one exposure of the juice.”

It may sound funny, but there are two pages in this book about the effects of grapefruit juice, including a list of ‘Drugs that should not be taken with grapefruit juice’. Grapefruit is a well-known so-called mechanism-based inhibitor, and it may impact the metabolism of a lot of different drugs. It is far from the only known dietary component which may cause problems in a drug metabolism context – for example “cranberry juice has been known for some time as an inhibitor of warfarin metabolism”. On a general note the author remarks that: “There are hundreds of fruit preparations available that have been specifically marketed for their […] antioxidant capacities, such as purple grape, pomegranate, blueberry and acai juices. […] As they all contain large numbers of diverse phenolics and are pharmacologically active, they should be consumed with some caution during drug therapy.”

April 7, 2016 Posted by | biology, books, medicine, Pharmacology | Leave a comment

The Second World War (I?)

“I am perhaps the only man who has passed through both the two supreme cataclysms of recorded history in high executive office. Whereas […] in the First World War I filled responsible but subordinate posts, I was in this second struggle with Germany for more than five years the head of His Majesty’s Government. I write therefore from a different standpoint and with more authority than was possible in my earlier books. I do not describe it as history, for that belongs to another generation. But I claim with confidence that it is a contribution to history which will be of service to the future.”

“Let no one look down on those honourable, well-meaning men whose actions are chronicled in these pages without searching his own heart, reviewing his own discharge of public duty, and applying the lessons of the past to his future conduct.”

I am currently reading this book, which is really an abridgement of 6 different volumes written by Churchill. All of the stuff included is Churchill’s own stuff; the only thing that has been done is that some stuff has been left out, and some of the remaining stuff has been rearranged. Which means that you in this book get four books/subsections, rather than six. The titles of these are: Milestones to disaster (1919-May 10, 1940), Alone (May 10, 1940-June 22, 1941), The Grand Alliance (Sunday, December 7, 1941 and onwards), and Triumph and Tragedy (1943-1945). I have by now finished Book 1 (the Milestones to Disaster part), and I’ve read close to 100 pages of Book 2. It’s great stuff, and very detailed. In this post I have included quotes from roughly the first 150 pages of the book’s coverage, all of which belong to the ‘Milestones to disaster’ part.

“When Marshall Foch heard of the signing of the Peace Treaty of Versailles he observed with singular accuracy: “This is not peace. It is an Armistice for twenty years.””

[In the context of the reparations:] “whereas about £1,000 millions of German assets were appropriated by the victorious Powers, more than £1,500 millions were lent a few years later to Germany, principally by the United States and Great Britain […] until 1931 the victors, and particularly the United States, concentrated their efforts upon extorting by vexatious foreign controls their annual reparations from Germany. The fact that these payments were made only from far larger American loans reduced the whole process to the absurd. Nothing was reaped except ill-will. […] History will characterize all these transactions as insane. […] All this is a sad story of complicated idiocy”

“Deliberate extermination of whole populations was contemplated and pursued by both Germany and Russia in the Eastern war.”

“”We are apparently finished and done with economic cycles as we have known them,” said the President of the New York Stock Exchange in September.” [That would be September, 1929. Talk about bad timing… – US]

“The opinions of the Press and public were in no way founded upon reality […] delight in smooth-sounding platitudes, refusal to face unpleasant facts, desire for popularity and electoral success irrespective of the vital interests of the State, genuine love of peace and pathetic belief that love can be its sole foundation, obvious lack of intellectual vigour […] marked ignorance […] the utter devotion […] to sentiment apart from reality […]: all these constituted a picture of British fatuity and fecklessness which, though devoid of guile, was not devoid of guilt, and, though free from wickedness or evil design, played a definite part in the unleashing upon the world of horrors and miseries which, even so far as they have unfolded, are already beyond comparison in human experience. […] It is difficult to find a parallel to the unwisdom of the British and weakness of the French Governments, who none the less reflected the opinion of their Parliaments in this disastrous period” [the period in question being the early thirties – US].

“Several visitors of consequence came to me from Germany and poured their hearts out in their bitter distress. Most of these were executed by Hitler during the war.”

“It would be wrong in judging the policy of the British Government not to remember the passionate desire for peace which animated the uninformed, misinformed majority of the British people, and seemed to threaten with political extinction any party or politician who dared to take any other line. This, of course, is no excuse for political leaders who fall short of their duty. It is much better for parties or politicians to be turned out of office than to imperil the life of the nation. […] To be so entirely convinced and vindicated in a matter of life and death to one’s country, and not to be able to make Parliament and the nation heed the warning, or bow to the proof by taking action, was an experience most painful.”

“the number of Germans under regular military training in 1936 was 1,511,000 men. The effective strength of the French Army, apart from reserves, in the same year was 623,000 men, of whom only 407,000 were in France.”

Abyssinia [see also this] was a member of the League of Nations. By a curious inversion it was Italy who had in 1923 pressed for her inclusion, and Britain who had opposed it. The British view was that the character of the Ethiopian Government and the conditions prevailing in that wild land of tyranny, slavery, and tribal war were not consonant with membership of the League. But the Italians had had their way” [incidentally if you want an update on how things are going in that part of the world, apropos all those migrants coming to Europe from that region these days, here’s some updated information: “Eritrea is a one-party state in which national legislative elections have been repeatedly postponed.[111] According to Human Rights Watch, the government’s human rights record is considered among the worst in the world. […] In June 2015, a 500-page United Nations Human Rights Council report accused Eritrea’s government of extrajudicial executions, torture, indefinitely prolonged national service and forced labour, and indicated that sexual harassment, rape and sexual servitude by state officials are also widespread.” (wikipedia)]

“One day in 1937 I had a meeting with Herr von Ribbentrop, German ambassador to Britain. […] he had asked Hitler to let him come over to London in order to make the full case for an Anglo-German entente or even alliance. […] What was required was that Britain should give Germany a free hand in the East of Europe. She must have her Lebensraum […] All that was asked of the British Commonwealth and Empire was not to interfere. There was a large map on the wall, and the Ambassador several times led me to it to illustrate his projects. After hearing all this I said at once that I was sure the British Government would not agree to give Germany a free hand in Eastern Europe. […] Ribbentrop turned abruptly away. He then said, “In that case, war is inevitable. There is no way out. The Fuehrer is resolved. Nothing will stop him and nothing will stop us.” We then returned to our chairs.” [At this time Churchill was just an MP, so Ribbentrop was not asking Churchill himself to consent to the proposed scheme and ‘make a deal’; he was trying to figure out if there was any deal to be made. The year after, on July 26, 1938, Lord Halifax, the British Foreign Minister, incidentally stated in Parliament that: “I do not believe that those responsible for the Government of any country in Europe to-day want war.” – US]

“On the day of the march of the German armies into Austria we heard that Goering had given a solemn assurance to the Czech Minister in Berlin that Germany had “no evil intentions towards Czechoslovakia” […] On the evening of the 26th [of September, 1938 – US] Hitler spoke in Berlin. […] He said categorically that the Czechs must clear out of the Sudetenland, but once this was settled he had no more interest in what happened to Czechoslovakia. “This is the last territorial claim I have to make in Europe.” […] Chamberlain returned to England [after signing the agreement – US]. […] from the windows of Downing Street he waved his piece of paper again and used these words, “This is the second time in our history that there has come back from Germany to Downing Street peace with honour. I believe it is peace for our time.”

“In 1938-39 British military expenditure of all kinds reached £304 millions,* and German was at least £1,500 millions. It is probable that in the last year before the outbreak Germany manufactured at least double, and possibly treble, the munitions of Britain and France put together […] in the single year 1938 Hitler had annexed to the Reich and brought under his absolute rule […] a total of over ten millions of subjects, toilers, and soldiers. […] The German armies were not capable of defeating the French in 1938 or 1939. The vast tank production with which they broke the French front did not come into existence till 1940”

“if you will not fight for the right when you can easily win without bloodshed, if you will not fight when your victory will be sure and not too costly, you may come to the moment when you will have to fight with all the odds against you and only a precarious chance of survival. There may even be a worse case. You may have to fight when there is no hope of victory, because it is better to perish than live as slaves.”

“At the Kremlin in August 1942 Stalin, in the early hours of the morning, gave me one aspect of the Soviet position. “We formed the impression,” said Stalin, “that the British and French governments were not resolved to go to war if Poland were attacked, but that they hoped the diplomatic line-up of Britain, France, and Russia would deter Hitler. We were sure it would not.””

“There were known to be twenty thousand organised German Nazis in England at this time [at the end of August, 1939US], and it would only have been in accord with their procedure in other friendly countries that the outbreak of war should be preceded by a sharp prelude of sabotage and murder. I had at that time no official protection, and I did not wish to ask for any; but I thought myself sufficiently prominent to take precautions. I had enough information to convince me that Hitler recognised me as a foe. My former Scotland Yard detective, Inspector Thompson, was in retirement. I told him to come along and bring his pistol with him. I got out my own weapons, which were good. While one slept the other watched.”

 

April 6, 2016 Posted by | books, history | Leave a comment

Quotes

i. “I prefer to be true to myself, even at the hazard of incurring the ridicule of others, rather than to be false, and incur my own abhorrence.” (Frederick Douglass)

ii. “To make a contented slave it is necessary to make a thoughtless one. It is necessary to darken the moral and mental vision and, as far as possible, to annihilate the power of reason.” (-ll-)

iii. “The part of life we really live is small. For all the rest of existence is not life, but merely time. […] In guarding their fortune men are often closefisted, yet, when it comes to the matter of wasting time, in the case of the one thing in which it is right to be miserly, they show themselves most prodigal.” (Seneca the Younger, On the shortness of life)

iv. “It takes the whole of life to learn how to live, and — what will perhaps make you wonder more — it takes the whole of life to learn how to die.” (-ll-)

v. “those who forget the past, neglect the present, and fear for the future have a life that is very brief and troubled […] They lose the day in expectation of the night, and the night in fear of the dawn.” (-ll-)

vi. “The best way to know your faults is to notice which ones you accuse others of.” (James Richardson)

vii. “To condemn your sin in another is hypocrisy. Not to condemn is to reserve your right to sin.” (-ll-)

viii. “Let me have my dreams but not what I dream of.” (-ll-)

ix. “The man who sticks to his plan will become what he used to want to be.” (-ll-)

x. “The new gets old much faster than the old gets older.” (-ll-)

xi. “Embarrassment is the greatest teacher, but since its lessons are exactly those we have tried hardest to conceal from ourselves, it may teach us, also, to perfect our self-deception.” (-ll-)

xii. “Bitterness is a greater failure than failure.” (-ll-)

xiii. “The surest sign that a man has a genuine taste of his own is that he is uncertain of it.” (W. H. Auden)

xiv. “All the things that happen and seem so important at the time, and yet you forget them, one after another.” (Thomas M. Disch)

xv. “Inspiration usually comes during work, rather than before it.” (Madeleine L’Engle)

xvi. “A man who knows how little he knows is well, a man who knows how much he knows is sick.” (Witter Bynner)

xvii. “What is well done is done soon enough.” (Guillaume de Salluste Du Bartas)

xviii. “Be advised that all flatterers live at the expense of those who listen to them.” (John de La Fontaine)

xix. “We are what we think. To change how people act, we must change what they believe.” (Mark Riebling)

xx. “Sometimes, only one person is missing, and the whole world seems depopulated.” (Alphonse de Lamartine)

March 23, 2016 Posted by | quotes | Leave a comment

Quotes

i. When you counsel someone, you should appear to be reminding him of something he had forgotten, not of the light he was unable to see. (Baltasar Gracián)

ii. “If you cannot make knowledge your servant, make it your friend.” (-ll-)

iii. “Knowing how to keep a friend is more important than gaining a new one.” (-ll-)

iv. “There are persons who, when they cease to shock us, cease to interest us.” (F. H. Bradley)

v. “Never curse an illness; better ask for health.” (Andrzej Majewski)

vi. “He who makes a paradise of his bread makes a hell of his hunger.” (Antonio Porchia)

vii. “The less you think you are, the more you bear. And if you think you are nothing, you bear everything.” (-ll-)

viii. “In its last moment, the whole of my life will last only a moment.” (-ll-)

ix. “I know what I have given you, I do not know what you have received.” (-ll-)

x. “The condemnation of an error is another error.” (-ll-)

xi. “If you are good to this one and that one, this one and that one will say you are good. If you are good to everyone, no one will say that you are good.” (-ll-)

xii. “All that can’t be is almost always a reproach against what can be.” (-ll-)

xiii. “Value yourself according to the burdens you carry, and you will find everything a burden.” (James Richardson)

xiv. “The single sin is less of a problem than the good reasons for it.” (-ll-)

xv. “The first abuse of power is not realizing that you have it.” (-ll-)

xvi. “Only the dead have discovered what they cannot live without.” (-ll-)

xvii. “Success is whatever humiliation everyone has agreed to compete for.” (-ll-)

xviii. “What did you do today? Nothing say our little children, and so do I. What we most are is what we keep mistaking for nothing.” (-ll-)

xix. “A day is only a day. But a life is only a life.” (-ll-)

xx. “Beware of knowing your virtues; you may lose them. Beware of knowing your vices; you may forgive them.” (-ll-)

March 12, 2016 Posted by | quotes | Leave a comment

Books 2016

I have been reading way too much fiction this year and not enough non-fiction and I have been feeling guilty about that, but I hope that I can make up for the shortfall of non-fiction (‘serious’) reading later in the year. We’ll see how it goes.

Regarding the ‘technical aspects’ of the list below, as usual the letters ‘f’ and ‘nf.’ in the parentheses correspond to ‘fiction’ and ‘non-fiction’, respectively, whereas the ‘m’ category covers ‘miscellaneous’ books. The numbers in the parentheses correspond to the goodreads ratings I thought the books deserved.

This post is ‘a work in progress’ and it’ll remain so for the rest of the year – I’ll update the post regularly throughout the year, so that new books, blogposts and reviews will be continuously added to the list/post as time goes by. You can see my 2016 goodreads reading challenge here – that overview includes cover views of the books.

1. 4.50 from Paddington (4, f). Agatha Christie.

2. Explaining Behavior: Reasons in a World of Causes (1, nf. Bradford Book). Goodreads review here.

3. Hickory Dickory Dock (3, f). Agatha Christie.

4. Death Comes As the End (3, f). Agatha Christie. Short goodreads review here.

5. At Bertram’s Hotel (3, f). Agatha Christie. Very short goodreads review here.

6. A Caribbean Mystery (3, f). Agatha Christie.

7. A Rulebook for Arguments (Hackett Student Handbooks) (1, nf. Hackett Publishing). Very short goodreads review here.

8. The Clocks (2, f). Agatha Christie.

9. Third Girl (2, f). Agatha Christie. Very short goodreads review here.

10. The Misanthrope (2, f). Molière. Very short goodreads review here.

11. The Secret Adversary (2, f). Agatha Christie. Short goodreads review here.

12. The Social Psychology of Nonverbal Communication (2, nf. Palgrave Macmillan). Goodreads review here. Blog coverage here.

13. N or M? (2, f). Agatha Christie. Goodreads review – with spoilers – here.

14. The Emergence of Norms (4, nf. Oxford University Press). Goodreads review here. Blog coverage here.

15. By the Pricking of My Thumbs (2, f). Agatha Christie.

16. The Godfather (4, f). Mario Puzo.

17. Partners in Crime (1, f). Agatha Christie. Short goodreads review here.

18. Elephants can Remember (1, f). Agatha Christie. Short goodreads review here.

19. Hallowe’en Party (1, f). Agatha Christie. Short goodreads review here.

20. French Leave (4, f). P. G. Wodehouse. Short goodreads review here.

21. A Few Quick Ones (3, f). P. G. Wodehouse.

22. Ice in the Bedroom (4, f). P. G. Wodehouse.

23. Over Seventy (4, f). P. G. Wodehouse. Short goodreads review here.

24. The Secret of Chimneys (2, f). Agatha Christie.

25. World Regions in Global Context (1, nf. Prentice Hall). Very long (600+ pages of content). Goodreads review here.

26. Something Fishy (3, f). P. G. Wodehouse.

27. Do Butlers Burgle Banks? (3,f). P.G. Wodehouse.

28. The Mirror Crack’d from Side to Side (1, f). Agatha Christie. Boring story, almost didn’t finish it.

29. Frozen Assets (4, f). P. G. Wodehouse.

30. A Cooperative Species: Human Reciprocity and Its Evolution (5, nf. Princeton University Press). Goodreads review here.

31. If I Were You (4, f). P. G. Wodehouse.

32. On the Shortness of Life (nf.). Seneca the Younger.

33. Barmy in Wonderland (3, f). P. G. Wodehouse.

34. A Gentleman of Leisure (3, f). P. G. Wodehouse. Very short goodreads review here.

35. Pearls, Girls and Monty Bodkin (5, f). P. G. Wodehouse. Short goodreads review here.

36. The Ultimate Quotable Einstein (3, nf. Princeton University Press). Blog coverage here.

37. The Luck Stone (2, f). P. G. Wodehouse. Goodreads review here.

38. Company for Henry (4, f). P. G. Wodehouse.

39. Bachelors Anonymous (5, f). P. G. Wodehouse. A short book, but very funny.

40. The Second World War (5, nf.) Winston Churchill. Very long, the book is a thousand pages long abridgement of 6 different volumes written by Churchill. Blog coverage here, here, here, and here. I added this book to my list of favourite books on goodreads.

41. The Old Reliable (3, f). P. G. Wodehouse.

42. Performing Flea (4, m). P. G. Wodehouse, William Townend.

43. Decline and Fall (3, f). Evelyn Waugh. Goodreads review here.

44. The Devil’s Garden (2, f). W. B. Maxwell. Goodreads review here.

45. The Road to Little Dribbling: Adventures of an American in Britain (3, m). Bill Bryson.

46. Bryson’s Dictionary of Troublesome Words: A Writer’s Guide to Getting It Right (3, nf.). Bill Bryson. Goodreads review here.

47. The Life and Times of the Thunderbolt Kid (3, m). Goodreads review here.

48. Shakespeare: The World as Stage (2, m). Bill Bryson.

49. One Summer: America, 1927 (2, m). Bill Bryson. Goodreads review here.

50. The Sicilian (3, f). Mario Puzo.

51. Fools Die (3, f). Mario Puzo. Short goodreads review here.

52. Not George Washington (2, f). P. G. Wodehouse. Short goodreads review here.

53. Pre-Industrial Societies: Anatomy of the Pre-Modern World (5, nf. Oneworld Publications). Goodreads review here. I added this book to my list of favourite books on goodreads.

54. The Last Don (4, f). Mario Puzo. Goodreads review here.

55. Fear and Loathing in Las Vegas (f). Hunter S. Thompson. Goodreads review here.

56. Aunts Aren’t Gentlemen (3, f). P. G. Wodehouse.

57. What If?: Serious Scientific Answers to Absurd Hypothetical Questions (2, m. Randall Munroe). Short goodreads review here.

58. Wilt (5, f). Tom Sharpe. Goodreads review here.

59. The Wilt Alternative (4, f). Tom Sharpe. Very short goodreads review here.

60. Wilt On High (4, f). Tom Sharpe. Short goodreads review here.

61. Wilt In Nowhere (3, f). Tom Sharpe.

62. The Wilt Inheritance (3, f). Tom Sharpe. Goodreads review here.

63. Monstrous Regiment (3, f). Terry Pratchett.

64. Porterhouse Blue (3, f). Tom Sharpe. Goodreads review here.

65. The Midden (4, f). Tom Sharpe. Goodreads review here.

66. Human Drug Metabolism: An Introduction (5, nf. Wiley). Goodreads review here. Blog coverage here and here.

67. Vintage Stuff (2, f). Tom Sharpe.

68. Blackadder: The Whole Damn Dynasty, 1485-1917 (5, f). Richard Curtis, Ben Elton, Rowan Atkinson & Jon Lloyd. Goodreads review here.

69. How the Endocrine System Works (2, nf. Wiley-Blackwell). Goodreads review here.

70. Suicide Prevention and New Technologies: Evidence Based Practice (1, nf. Palgrave Macmillan). Long(-ish) goodreads review here.

71. Blott on the Landscape (3, f). Tom Sharpe. Short goodreads review here.

72. Diabetes and the Metabolic Syndrome in Mental Health (2, nf. Lippincott Williams & Wilkins). Goodreads review here.

73. Palliative Care and End-of-Life Decisions (1, nf. Palgrave Pivot). Goodreads review here.

74. Ancestral Vices (4, f). Tom Sharpe. Goodreads review here.

75. Respirology (2, nf. Springer). Goodreads review here. Blog coverage here.

76. The Throwback (4, f). Tom Sharpe. Goodreads review here.

77. The Great Pursuit (3, f). Tom Sharpe.

78. Riotous Assembly (4, f). Tom Sharpe.

79. Indecent Exposure (3, f). Tom Sharpe.

80. Grantchester Grind (3, f). Tom Sharpe. Goodreads review here.

81. Time’s Arrow (4, f). Martin Amis. Short goodreads review here.

82. One Day in the Life of Ivan Denisovich (4, f). Aleksandr Solzhenitsyn. Short goodreads review here.

83. The Gropes (3, f). Tom Sharpe. Short goodreads review here.

84. The Old Devils (3, f). Kingsley Amis. Goodreads review here.

85. Me Talk Pretty One Day (5, m). David Sedaris. Goodreads review here.

Books I did not finish:

The Adventures of Huckleberry Finn (1, f). Mark Twain. Goodreads review here.

March 10, 2016 Posted by | books | Leave a comment

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