Adverse reaction

Some fascinating research coming out at the moment on the potential negative effects of exercise. Since this goes counter to what we are all told such studies warrant close examination but certainly should not be simply dismissed because they don't fit the dominant paradigm.

First up, from the Mayo Clinic Proceedings this month: Potential Adverse Cardiovascular Effects From Excessive Endurance Exercise
where they review some of the evidence that long-term excessive endurance exercise can induce pathologic structural remodeling of the heart and large arteries.


Physically active people are much healthier than their sedentary counterparts. Exercise is one of the most important things you need to do on a daily basis,” he explains. “But what this paper points out is that a lot of people do not understand that the lion’s share of health benefits accrue at a relatively modest level. Extreme exercise is not really conducive to great cardiovascular health. Beyond 30-60 minutes per day, you reach a point of diminishing returns.

Second, and of more general relevance to the general population, a paper in PLoS ONE this week : Adverse Metabolic Response to Regular Exercise: Is It a Rare or Common Occurrence?

The review of six previous studies on exercise found that working out worsened at least one measure of heart risk — blood pressure, insulin level or levels of HDL cholesterol or triglycerides — for about 10% of people. About 7% of people declined on at least two measures.
For a scientist this doesn't seem that surprising after some reflection - although, on average, exercise may lead to a favorable outcome there may be a range of responses from individuals that span a range from very favorable all the way down to an unfavorable change.

Unfortunately I think you can imagine the headlines:
For those looking for an excuse to avoid exercise, here's one 
Can Exercise Actually Be Bad For You?‎
Exercise could be, er, bad for your heart, study says‎

Oh, and tomorrow is National Running Day...

Coronary risk factors

If you watched the first part of the HBO series below then you learned about the Bogalusa Heart Study -  a 40 year study investigating the early natural history of coronary artery disease and essential hypertension. This type of long term cohort study was pioneered by the Framingham Heart Study which began in1948 and is now on its third generation of participants. Such studies have generated literally thousands of papers and have helped to unravel and quantify the contribution of various risk factors to heart disease.


In class Claudia mentioned BMI (online calculator here). Someone mentioned how broad the categories were (for my height even the normal category covers a 50lb range from 144 to 194lb). Which is a very good point - putting people into three categories: normal, overweight and obese is about the crudest measure we could use. However it is a simple measure that is easy to calculate.


There are other more complicated measures of health that use more information and express the outcome as risk rather than just 'good' and 'bad'. For example one of the classic outcomes of the Framingham heart study has been the development of the Framingham risk score - which expresses your 10-year risk of developing cardiovascular disease. This number can then be compared to the mean for people you age. Your values will all be very low because you are young. If I put my values in I get 2%, which is slightly alarming until you compare it to the average for men 40-49 which is 11%. Yikes.


Other risk score calculations are available at the Framingham Heart Study website.

Causes of obesity - part 2

Well if you did your homework and watched the HBO shows you heard quite a bit about fatty liver disease and saw some fatty. I haven't watched the last two shows yet but, so far, there's been no mention of an intriguing new hypothesis that obesity and fatty liver disease in particular may be infectious and therefore treatable with antibiotics. This is not a new suggestion but some of the best evidence to date, from studies of mice, was published in February in Nature:

Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity

"When healthy mice were co-housed with mice that had altered gut microbes, the healthy mice also developed a susceptibility for development of liver disease and obesity."

A number of newspapers and blogs picked up on this fairly dramatic result. Here's part of a blog posting by Suzanne O'Malley at the Huffington Post:

New findings suggest that obesity and liver disease can be caused by proteins that change microbe populations in the stomach, according to a study published in the February 2012 issue of the journal Nature. The Yale immunobiologists' discovery suggests that obesity and non-alcoholic fatty liver disease (NAFLD) may be infectious and treatable with targeted antibiotics. At least that was the case for mice. NAFLD is caused by metabolic syndrome -- diabetes, hypertension, and high blood cholesterol -- which are also risk factors for heart disease. Researchers expanded on an earlier study that showed microbial imbalances in the stomach, caused by the same family of proteins, heightened the risk of intestinal diseases such as colitis. The most extraordinary finding, according to senior author Richard A. Flavell, a Howard Hughes Medical Institute investigator and professor of immunobiology at Yale School of Medicine, was that the changed intestinal environment that led to obesity and liver disease was infectious among the community of mice studied.
 ...
The next step, Flavell says, is extending this research to humans and identifying more precisely the bacteria involved in the progression to liver disease.

Social jetlag

Social Jetlag and Obesity
People who have different sleep patterns at the weekend than they do during the work week may get "social jet lag," according to new research. That shift in our natural sleep patterns is linked to obesity.
For every hour of social jet lag, the risk of being overweight or obese rises about 33%, says researcher Professor Till Roenneberg.

'Social jetlag' is measured as the average midpoint of a person's sleep on weekdays compared to weekends. The difference in those numbers gives the 'social jet lag'. So, a person who goes to bed at 1 am and gets up at 6 am during the working week, and goes to bed at 1 am but only gets up at 9am at weekends for example, would have 1.5 hours of social jet lag.

How do muscles contract?

I spent a bit too long on immunology and ran out of time to cover muscles. Check out section 48.1 and 48.2 in your textbook which cover this quite clearly.

Note though that this 'sliding filament' model of muscle contraction was only discovered in the 1950's. The key evidence used to construct the model was a series of electron micrographs like those to the right of the picture.

You textbook does a nice job of interpreting the micrographs (figs 48.1 and 48.2) in the context of the theory but it's interesting to consider if you only had the pictures do you think you would have come up with the correct model?

The sliding filament model was actually proposed by two groups working independently and their papers were published together in the same issue of Nature.

 Structural changes in muscle during contraction: interference microscopy of living muscle fibres

Changes in the cross-striations of muscle during contraction and stretch and their structural interpretation 
 
In 2004 Nature published a special focus to celebrate the papers and look at progress in the subsequent decades on 'one of the most intriguing of biological problems: that of the conversion of chemical energy to mechanical work'.

Suicide-bags

Suicide-bags would probably be a good name for a band. If this was the 1970's. Suicide-bags is also a name for the lysosomes found within cells because as well as pathogen destruction they are involved in the natural process of cell organelle recycling and even cell death. This degradation and recycling of ageing and dying cells, or autophagy, is attracting a lot of attention these days because of its links to disease and aging.

The science writter Carl Zimmer wrote an article for the New York Times on this topic, Self-Destructive Behavior in Cells May Hold Key to a Longer Life based on a paper in Trends in Cell Biology: The regulation of aging: does autophagy underlie longevity?
Recent evidence has revealed that autophagic activity is required for lifespan extension in various long-lived mutant organisms, and that numerous autophagy-related genes or proteins are directly regulated by longevity pathways. These findings support the emerging view that autophagy is a central regulatory mechanism for aging in diverse eukaryotic species.

Mile high club

Thanks to Wired magazine for that gratuitous headline.

Claudia mentioned some of the issues of altitude for respiration. For a long time athletes have explored the benefits of training at altitude. The key benefit is that prolonged exposure to low oxygen concentrations (it's actually a low pressure but the effect is the same) leads to increased red blood cell concentrations.

However the downside is that it is hard to work your muscles at appropriately high intensities at low oxygen concentrations. One solution that has been around for a while is to 'live high, train low'. This works because the advantages of living at altitude come about from simply being there even if you are just sleeping, eating, working, whatever. But you go to low altitude to train at appropriate intensities. However this is inconvenient to say the least. Hence the development of low oxygen sleeping chambers and even low oxygen offices. These don't mimic the low pressure of altitude but simply reduce the oxygen concentration to induce the same effect.

Looks like it's a pretty big business - Hypoxico are one of the main companies and have an intriguing range of products.

But as anyone who has spent any time at altitude will tell you, there's a downside. From the Wired article:  Mile-High Club: Do Oxygen Tents Boost Athletic Performance?

Crawford discounts anything beyond a placebo effect, claiming that the low-oxygen environment hampers recovery and robs the athlete of sleep, a primary component of any training program. “Why am I starving my athlete of oxygen that he needs to recover?” Crawford asks.

The ethics of the use of these devices by athletes has been discussed by the World Anti-Doping Agency (WADA), which claimed that it could be equivalent to blood doping and therefore they should be banned. Blood doping is the use of hormones such as erythropoietin (EPO) which boost red blood cell production. These were banned  for most sports in 1986. In 2006 the WADA announced that 'the overwhelming consensus of our health, medicine and research committees – was that, at this time, it is not appropriate to do so." Presumably because there would be no mechanism to enforce such a ban

Save your breath....and use it to generate electricity!

You may have thought that inhaling and exhaling held their own intrinsic values and that was plenty.  In with the good air, out with the bad air.... 

But seems there's much more you can do with the CO2 coming out of your nose.  Of course there is the music potential: Nose flutes,   Nose harps...

But now there's even more...  from Science Daily,  "Electricity from the Nose - Engineers Make Power from Human Respiration".  Who knew?  

Apnea, static and otherwise

Unfortunately (or perhaps fortunately) the static apnea video is no longer available but here's a picture which is very, very similar to the video. I'll paste my earlier description and the much more exciting video with freediving champion William Trubridge below.

Static apnea is floating face down in a swimming pool whilst holding your breath - quite possibly the most boring sport in the world to watch (it makes cricket look exciting) but physiologically quite interesting. For example divers now use glossopharyngeal insuffation - this is a method of pumping additional air into the lungs widely used by reptiles and amphibians (picture a frogs bulging neck) but not by humans. Until a few decades ago when free divers discovered that by using the tongue as a piston an additional liter or so of air can be forced into the lungs. Don't try this at home though, rupturing the lung is a real possibility unless you work up to it.

How long can you hold your breath? A minute? A minute and a half?

What do you think the world record is. Four minutes? Five minutes? Ten minutes? Think again. The static apnea record is ELEVEN AND A HALF MINUTES!

Curiously the techniques involved don't involve keeping the brain alive without oxygen, that's simply not possible, but getting oxygen to the brain even though you aren't breathing.

If you breath oxygen beforehand though the record is much longer - two people have now exceeded TWENTY MINUTES.

(Here's a challenge - using knowledge of physiology and physics could you predict that the record would be almost twice as long using pure oxygen compared to the ~20% oxygen in air?)

Free diving is much more challenging because you must perform physical exercise without breathing (and face the changing pressure at depth.) There are all sorts of categories including 'no limits' where divers use a weighted sled to pull them down and then air bags to ascend. You still have to hold your breath of course... The world record for this is an amazing 214m (over 700 feet). But the purest form of the sport is where the diver swims down and back under his own power without even the benefit of fins. Watch this amazing dive by William Trubridge, who has set further records since this video - currently his record is an amazing 101m. I love how calm and collected he is. Every movement seems perfectly choreographed and he is clearly maximizing efficiency and not speed.

Obesity epidemic

We haven't started our physiology section yet but with today's dramatic headlines from the CDC's 'Weight of the Nation' event I thought I'd post a little about obesity.

Obesity is not simply being overweight, it's usually defined as having a Body Mass Index over 30. To put this in perspective I weigh 160lb and have a BMI pretty much in the middle of the normal range. If I put on 70lbs of weight (which would be about two Otto's worth - Otto is the 30+lb cat in the picture who has since lost weight) I would still not be obese (although I would be overweight!) So obesity is not simply a medical term for being overweight - it is a precise medical term for being VERY overweight. We know that at this point obesity causes many serious health problems.

Now in today's headlines we see the shocking news that 36% of American's are now obese (up from 12% in 1990 and 22% in 2000) and by 2030 that is estimated to rise to 42% leading to somewhere around half a TRILLION dollars in extra healthcare costs between now and then (compared to if obesity rates stayed at 2010 levels). This is all based on a paper in the American Journal of Preventive Medicine - Obesity and Severe Obesity Forecasts Through 2030.
About the only good news is that the paper actually results in a lower estimate of future obesity than some previous analyses but that's cold comfort given the conclusions:

The study estimates a 33% increase in obesity prevalence and a 130% increase in severe obesity prevalence over the next 2 decades. If these forecasts prove accurate, this will further hinder efforts for healthcare cost containment.

The paper also provides some estimates for 'severe obesity' (BMI>40 - for me that would be just about doubling my weight to 310lb). These estimates are actually worse than current estimates. By 2030 they predict that 10% of the US population will be severely obese.

Inbreeding Effects on Fertility in Humans

This is a bit late, my apologies, but the most interesting topic I've had so far is on inbeeding and fertility in humans. The main research paper source I used is here. There have been studies on problems with inbred children, but this is one of the few on inbred adults that I've seen.

The researchers focused on Hutterites, specifically the S-leut (Schmiedeleut) Hutterites of South Dakota.  These Hutterites are a reproductively isolated population and have high birth rates, making them ideal for this kind of study, but more importantly, socioeconomic standing is fairly equal throughout the population because they practice a communal lifestyle.

All present married adults (396) who participated were required to fill out a detailed reproductive history questionnaire, detailing family births, deaths, and marriages. Married women participants who were of reproductive age were provided with journals so they can note their menstrual cycles and with pregnancy tests that they were instructed to use if their menses was late.

In order to determine fertility, three tests were used. First, interbirth intervals in the married women were examined under the assumption that longer intervals meant a harder time conceiving or a problem with fetal loss. Second, they examined the time between a woman's first menses after a pregnancy and the menses before the next pregnancy. Women using birth control were excluded from this part of the study. Last, they examined family size and in all the S-leut women born after 1900, including families throughout the United States and Canada.

The main conclusion drawn was that the more inbred a woman is, the more reduced her fecundity. The scientists hypothesize that this reduction could result from "recessive alleles that could influence pathways involved in gametogenesis, hormonal cycling, sperm transport, ovulation,
fertilization, or implantation". Duh.

Multivitamins and pill wranglers take 2

I don't post too many repeats here but I think some of you may be interested in the two posts below. One the one hand there is very little evidence that multivitamins have a beneficial health effect. But on the other hand, why not take them if they might have a beneficial effect?

The first post,  Magic pill, is from 2009

(T)he study was so large and looked at so many aspects of health that it had a lot of statistical power to detect even a small effect. The study involved more than 160,000 women roughly split between those that took regular multivitamins and those that didn't. Eight years later they looked at a variety of disease incidences, including cancer (almost 10,000 cases) and cruder measures such as total mortality (again almost 10,000 deaths). Not even a hint of a difference.

This confirmed earlier studies by the NIH in 2006:"Most of the studies we examined do not provide strong evidence for beneficial health-related effects of supplements taken singly, in pairs, or in combinations of three or more." And by the United Kingdom's Food Standards Agency in 2007: "Vitamin and mineral supplements are not a replacement for good eating habits and supplements are unnecessary for healthy adults who eat a balanced diet."

For an interesting counterpoint consider this posting, Where's my pill wrangler?, from 2008.

'Kurzweil does not believe in half measures. He takes 180 to 210 vitamin and mineral supplements a day, so many that he doesn't have time to organize them all himself. So he's hired a pill wrangler, who takes them out of their bottles and sorts them into daily doses, which he carries everywhere in plastic bags.'

Kurzweil believes that radical technological advances will be made throughout the 21st century, and that many of those advances will benefit the field of medicine. Kurzweil has thus focused himself towards following a maximally healthy lifestyle to heighten his odds of living to see the day when science can make him immortal. His opinion on vitamin and health supplements is to take virtually anything that MIGHT have a positive effect even if the evidence is weak PROVIDED that the evidence is strong that it does no harm.

Obese is the new normal

Next week Claudia will talk about diet and nutrition, so here is a rather shocking survey I saw today to get you in the mood. Now surveys have all sorts of biases but if you use the same methodology year after year then you can track changes with a degree of accuracy.

According to a survey by the International Food Information Council Foundation, which has been conducted since 2006:

• Only 8% of Americans consider themselves to be obese even though 35% actually are.
• The percentage of people who say they don't exercise has risen from 37% to 43% just over the last year.

That finding is interesting for a couple of reasons, Smith Edge says. First, it represents an overall drop in the number of people who think of themselves as being overweight, and second, it shows that many people underestimate how bad their weight problem really is.

Only 57% of participants say they are concerned about their weight this year, down from 70% in 2010 and an all-time low for the survey.

Those who say they are trying to lose or maintain weight is also down, 69% in 2011 compared to 77% in 2010.

“This is a somewhat ominous trend,” says David L. Katz, MD, MPH, founding director of the Yale University Prevention Research Center in New Haven, Conn.
Katz thinks the survey may be picking up signs of a “normalization” of larger body sizes. As friends and families also grow in girth, people feel OK by comparison.
“We might like to be OK at any size, but the simple fact of the matter is that we’re not,” he says. “We are getting diabetes, we are getting heart disease, we are getting preventable cancers, many of them having to do with our size, and that’s not OK. These things are happening in our children, and that’s not OK.”

You can calculate your BMI here if you are curious. 'Obese' is a medical term for those people with a BMI over 30 and is not a value judgement. Changing your weight is not rocket science, it's pretty simple biology. Unfortunately most people are looking for quick fixes and the quick fix is unlikely to last.

Non-static apnea

Okay maybe floating face down in a swimming pool isn't for everyone. How about free-diving? The problem with this is that there are all sorts of categories including 'no limits' where divers use a weighted sled to pull them down and then air bags to ascend. You still have to hold your breath of course... The world record for this is an amazing 214m (over 700 feet). But the purest form of the sport is where the diver swims down and back under his own power without even the benefit of fins. Watch this amazing dive by William Trubridge, who has set further records since this video. I love how calm and collected he is. Every movement seems perfectly choreographed and he is clearly maximizing efficiency and not speed.

Static apnea

On Tuesday we will start our physiology section and Claudia will be talking about respiration. To get you pumped up (pun intended) I thought I'd post this video of what I only just discovered was a sport - static apnea. Basically this is floating face down in a swimming pool whilst holding your breath - quite possibly the most boring sport in the world to watch (it makes cricket look exciting) but physiologically quite interesting. For example if you watch the video you'll notice a demonstration of what I think is glossopharyngeal insuffation - this is a method of pumping additional air into the lungs widely used by reptiles and amphibians (picture a frogs bulging neck) but not by humans. Until a few decades ago when free divers discovered that by using the tongue as a piston an additional liter or so of air can be forced into the lungs. Don't try this at home though, rupturing the lung is a real possibility unless you work up to it.

How long can you hold your breath? A minute? A minute and a half?

What do you think the world record is. Four minutes? Five minutes? TEN minutes? Think again.

Curiously the techniques involved don't involve keeping the brain alive without oxygen, that's simply not possible, but getting oxygen to the brain even though you aren't breathing

Speaking of ecosystems...

By combining 22 newly sequenced faecal metagenomes of individuals from four countries with previously published data sets, here we identify three robust clusters (referred to as enterotypes hereafter) that are not nation or continent specific.

"We found that the combination of microbes in the human intestine isn't random," says Peer Bork, who led the study at EMBL: "our gut flora can settle into three different types of community -- three different ecosystems, if you like."

Report at ScienceDaily and the paper, Enterotypes of the human gut microbiome, is published in nature this week.

Human records

I don't know if anyone watched the London Marathon today. The BBC kindly made it available on the web on demand so you could watch the whole thing at your leisure. The stellar field this year led to a resurgence of interest about whether a sub-2 hour marathon will ever be run. Personally I think people underestimate the significance of the 4 minutes improvement it will take. However watching Emmanuel Mutai storm the second half of the course today led me to believe that maybe I'll see it in my lifetime. He ran the last 12km at a 2:02 pace (and promptly threw up the moment he crossed the line). To run a sub-2 hour marathon would require over 26 consecutive 4:35 miles. That's under 69 seconds for each quarter mile - approximately a lap of a track. Try it. For 69 seconds. Now imagine two hours of it. Humans are, or can be, extraordinarily good distance runners. Why?

Anyway, when we talk about human physiology, which we will shortly, it is always interesting to consider the human superlatives, Haile Gebrselassie or Usain Bolt.

But what is equally interesting is the revolution that is taking place further back in the pack. Virtually unreported in the media was the new world record by Canadian Ed Whitlock in the Rotterdam marathon last week. Whitlock ran 3:25:43. A very nice but utterly unremarkable time you might think. But Ed Whitlock is 80. He beat the old 80-84 world record by almost 15 minutes and Whitlock is not unique. The gains made at older age groups are really amazing. This, of course, is actually much more relevant to most of us - gains made in medical understanding affect both our longevity and also the quality of our life.

For an equally inspiring female example check out this New York Times article on the amazing 91 year old Olga Kotelko: The Incredible Flying Nonagenarian.

When the efforts of medical science converge to simply prolong existence, you envision Updike’s golfer Farrell, poking his way “down the sloping dogleg of decrepitude.” But scientists like Taivassalo and Hepple have a different goal, and exercise — elixir not so much of extended life as extended youthfulness — may be the key to reaching it. James Fries, an emeritus professor at Stanford School of Medicine, coined the working buzz phrase: “compression of morbidity.” You simply erase chronic illness and infirmity from the first, say, 95 percent of your life. “So you’re healthy, healthy, healthy, and then at some point you kick the bucket,” Tarnopolsky says. “It’s like the Neil Young song: better to burn out than to rust.” You get a normal life span, but in Olga years. Who wouldn’t take it? 

Nicotine mode of action

By binding to nicotinic acetylcholine receptors, nicotine increases the levels of several neurotransmitters - acting as a sort of "volume control". It is thought that increased levels of dopamine in the reward circuits of the brain are responsible for the euphoria and relaxation and eventual addiction caused by nicotine consumption.

Smells like Teen Spirit, or maybe lilac....

Did you know that the 2004 Nobel Prize was awarded to Richard Axel and Linda B. Buck for their discoveries of "odorant receptors and the organization of the olfactory system"?

There's a nice summary of their research on the Nobel website (this is the summary of the summary - check the link for the full version):

The sense of smell long remained the most enigmatic of our senses. The basic principles for recognizing and remembering about 10,000 different odours were not understood. This year's Nobel Laureates in Physiology or Medicine have solved this problem and in a series of pioneering studies clarified how our olfactory system works. They discovered a large gene family, comprised of some 1,000 different genes (three per cent of our genes) that give rise to an equivalent number of olfactory receptor types. These receptors are located on the olfactory receptor cells, which occupy a small area in the upper part of the nasal epithelium and detect the inhaled odorant molecules.

Each olfactory receptor cell possesses only one type of odorant receptor, and each receptor can detect a limited number of odorant substances. Our olfactory receptor cells are therefore highly specialized for a few odours. The cells send thin nerve processes directly to distinct micro domains, glomeruli, in the olfactory bulb, the primary olfactory area of the brain. Receptor cells carrying the same type of receptor send their nerve processes to the same glomerulus. From these micro domains in the olfactory bulb the information is relayed further to other parts of the brain, where the information from several olfactory receptors is combined, forming a pattern. Therefore, we can consciously experience the smell of a lilac flower in the spring and recall this olfactory memory at other times.

Golden Years Truly Are Golden

As I mentioned in class the AAAS website reported on a PNAS paper out online yesterday: A snapshot of the age distribution of psychological well-being in the United States

In contrast to other, similar, studies this one used a large sample with fewer questions. In fact the sample size was over a third of a million people!

Stone's team found that global well-being declines from the 20s to age 50, then increases steadily. Happiness and enjoyment also increase after age 50. Although sadness is fairly flat throughout the age groups, most negative feelings decline with age. Worry stays level until about 50, then drops. Anger falls steadily from the 20s; stress peaks in the 20s, starts a decline, then plummets after age 50. The patterns are almost identical for men and women, although women have more stress, worry more, and are sadder at all ages, despite reporting better global well-being than men at most ages. The findings make sense to anyone who has gotten out of their 20s, says Stone. "If you were to do a survey and say, 'How many of you would like to be 25 again?' you don't get a lot of takers," he says.

Hopefully this news is not too depressing to those of you looking at 25 from the other side!