Evolution web site

The Science Journal Nature as part of the celebrations of Darwin’s birth has set up a web site
www.nature.com/evolutiongems
an accessible facility for papers published over the last 10 years in Nature which explains and gives examples of the dynamics of evolution by natural selection.

happiness and health

Two linked studies, by Fowler and Christakis, and Cohen-Cole and Fletcher, discuss the transmission of health related factors through social networks.
That behaviours may spread over time from one person to another through their immediate and more distant social contacts. Social epidemiology has established the relevance of social connectedness for health, and social network transmission may be one mechanism through which both beneficial and adverse effects are mediated."
The article by Fowler and Christakis investigated the social transmission of happiness. Happiness is related to several aspects of well being, including better work performance, greater job satisfaction, good family relationships, and a more satisfying social life," but what has it got to do with health and nutrition?
Measures of happiness, cheerfulness, and related constructs were associated prospectively with reduced mortality, both in initially healthy people and in those with established illnesses. These effects were independent of initial health status, age, demographic factors, and risk factors, and not affected by anxiety and depression. These results indicate that happiness is beneficial over and above the absence of misery.
The pathways through which happiness might influence future health are not well established, Evidence relating happiness to health behaviours such as smoking, physical activity, and diet is mixed. More consistent findings have emerged from studies that look at biological outcomes. Happiness has been associated with lower cortisol output over the day, attenuated inflammatory responses, and patterns of heart rate variability indicative of healthy cardiac autonomic control. These associations are independent of socio-economic characteristics and negative affective states. One possibility is that frontal and limbic brain mechanisms that regulate neuroendocrine and autonomic function play a role. Happiness is also related to greater social connectedness and stronger ratings of social support.
Infectious disease epidemiologists have long studied how social networks affect the transmission of infectious agents.
Fowler and Christakis suggest that behaviours and psychological states relevant to health may also be transmitted from person to person.
Social bonds, especially friendship bonds, are often established between similar people sharing common personal attributes and the environments in which they live and work. These characteristics have been shown to be related to health outcomes and psychological states.
Fowler and Christakis use data from the Framingham Heart Study to investigate whether happiness in the "ego" (a key person in the study) is affected by the happiness of "alters" (people connected to the ego), Mutual friends may be more similar to one another than non-mutual friends or alter perceived friends (when the alter thinks of the ego as a friend but this is not reciprocated). Although the results seem to show slightly stronger associations for nearby friends than for nearby alter perceived friends, these two estimates may not really be all that different.
An intriguing finding is that the happiness of next door neighbours is more strongly associated with the happiness of the ego than it is for neighbours in the same block.
The important aspect of this for nutrition is that communal eating, a dying mode of food ingesition may be of great health importance.
Steptoe and Diez Roux 2009 Happiness, health and social networks BMJ vol 38 pp 1-2
Fowler and Christakis 2009 Dynamic spread of happiness in a large social network: longitudinal analysis of the Framingham Heart Study social network BMJ vol 338, pp 23-34
Cohen-Cole and Fletcher 2008 detecting implausible social network effects in acne, height and headaches. Longitudinal analysis BMJ vol 337

Vitamin B12 reviewed

Cobalamin or vitamin B12 deficiency is common in elderly patients but because of the varied manifestations of this condition may not be recognised. There is a very good review in the QJM by Dali-Yousef and Andres detailing the wide range of clinical, some subtle consequences of B12 deficiency.
There is the classical but uncommon pernicious anaemia, but more commonly food-cobalamin malabsorption, that is an inability to release cobalamin from food or its binding proteins. This is usually a consequence of atrophic gastritis, possibly related to helicobacter pylori infection and long term use of acid suppressors.
There are also mutations in the genes controlling the B12 receptors in the ileum responsible for B2 absorption.
The deficiency may be identified by serum B12 concentrations and maybe in addition serum homocysteine concentrations.
The clinical manifestations are wide but include
Fatigue, sensory neuropathy,
Combined sclerosis of the spinal cord
Haemolytic anemia
This deficiency must be looked for where there are neurological conditions.
Dali-Youcef and Andres 209 An update on cobalamin deficiency in adults QJM
vol 102, pp 17-28.

Dietary Fibre definition

John Cummings and others explain a new definition of dietary fibre in the Lancet published January 31st 2009.
On November 20th the 30th session of Codex Committee on Nutrition and Foods for Special Dietary Uses met in South Africa and agreed a definition for dietary fibre.
Dietary fibre means carbohydrate polymers with ten or more monomeric units, which are not hydrolysed by endogenous enzymes in small intestine of human beings and belong to following categories:
Edible carbohydrate polymers naturally occurring in food as consumed
Carbohydrate polymers, which have been obtained from raw material in food by physical, enzymatic, or chemical means and which have been shown to have physiological effect of benefit to health by generally accepted scientific evidence to competent authorities
Synthetic carbohydrate polymers, which have been shown to have physiological effect of benefit to health by generally accepted scientific evidence to competent authorities
Methods of analysis for dietary fibre to be agreed.

Cummings et al 2009 Dietary Fibre : an agreed definition. Lancet vol 373 365-6

obesity, genes and exercise

Mustelin et al 2009 Physical activity reduces the influence of genetic effects on BMI and waist circumference: a study in young adult twins. International Journal of Obesity 33, 29–36;

Obesity and exercise are influenced by genetic and environmental factors. However, whether obesity and physical inactivity share the same genetic versus environmental etiology has not been studied. Mustelin et al analyzed these relationships, and also examined whether physical activity modifies the degree of genetic influence on body mass index (BMI) and waist circumference (WC). The FinnTwin16 Study is a population-based, longitudinal study of five consecutive birth cohorts (1975–1979) of Finnish twins. Data on height, weight, WC and physical activity of 4343 subjects at the average age of 25 (range, 22–27 years) years were obtained by a questionnaire and self-measurement of WC. The overall heritability estimates were 79% in males and 78% in females for BMI, 56 and 71% for WC and 55 and 54% for physical activity, respectively. There was an inverse relationship between physical activity and WC in males and females, and between physical activity and BMI in females. Physical activity significantly modified the heritability of BMI and WC, with a high level of physical activity decreasing the additive genetic component in BMI and WC. Physically active subjects were leaner than sedentary ones, and physical activity reduced the influence of genetic factors to develop high BMI and WC. This suggests that the individuals at greatest genetic risk for obesity would benefit the most from physical activity.
This is a fascinating study as it is not usual to see an environmental or behavioural activty over ride the genetic make up. Furthermore exercise appears to be important in the retention of a normal weight.

obesity and low grade inflammation

Hotamisligil has reviewed obesity and its related low grade inflammatory changes. Obesity is associated with chronic low-grade inflammation. Inflammatory signals interfere with insulin action and disrupt metabolic homeostasis. The c-Jun N-terminal kinase (JNK) has been identified as a central mediator of insulin resistance. Recent studies showed that in obesity compromising endoplasmic reticulum (ER) function results in insulin resistance and type 2 diabetes that are dependent on JNK activation. In contrast, enhancing ER function in transgenic mice or by the use of chemical chaperones protects against diet-induced insulin resistance. Hence, ER stress and the related signaling networks present a critical mechanism underlying obesity-induced JNK activity, inflammatory response and insulin resistance.
Hotamisligil (2008) Inflammation and endoplasmic reticulum stress in obesity and diabetes International Journal of Obesity 32, S52–S54;

leptin upate

Villanueva and M G Myers Jr review the knowledge of Leptin receptor signaling and the regulation of mammalian physiology
The adipocyte-derived hormone, leptin, signals the status of body energy stores to the central nervous system to regulate appetite and energy expenditure. A specific long-form leptin receptor (LepRb), a type I cytokine receptor, mediates leptin action on LepRb-expressing neurons in the brain. Leptin binding to LepRb activates the associated Janus kinase-2 (Jak2) tyrosine kinase to promote the phosphorylation of Jak2 and three residues on LepRb; each of these sites mediates a distinct aspect of downstream LepRb signaling, with differing physiologic functions. Tyr1138 STAT3 signaling suppresses feeding, but is not required for a number of other leptin actions. Tyr985 binds SH2-containing tyrosine phosphatase-2 and suppressor of cytokine signaling-3 and primarily mediates the attenuation of LepRb signaling in vivo. The role for Tyr1077, the major regulator of signal transducer and activator of transcription-5 (STAT5) during leptin signaling, in the physiologic response to leptin remains unclear, although the obese phenotype of animals deleted for STAT5 in the brain suggests the potential importance of this signaling pathway. Leptin also modulates a number of other signaling pathways in the brain, including PI 3-kinase, mammalian target of rapamycin and AMP-dependent protein kinase; the pathways by which leptin controls these signals remain unclear, however, and may involve some indirect mechanisms. Important issues regarding leptin action and LepRb signaling in the future include not only the more thorough analysis of intracellular signaling pathways, but the neural substrate by which leptin acts, as most major populations of LepRb neurons remain poorly studied.
E C Villanueva and M G Myers Jr 2008 Leptin receptor signaling and the regulation of mammalian physiology Int J Obes 2008 32: S8-S12

Umami taste

There are five basic tastes- bitter, sweet, umami, sour and salty. Umami is the savoury flavour.
The molecular biology of this taste is being revealed by Li and colleagues.
The umami taste is due to the amino acid glutamate and enhanced by the ribonucleotides IMP and GMP. Appreciating this taste depends on G-protein coupled receptors of class ( C-GPCRs) similar to the sweet taste.
The umami taste ( T1R1-T1R3) and the sweet taste (T1R2-T1R3) share the same transmembrane subunit, T1R3, a unique subunit dictates the perception of that taste. Four amino acid residues deep in the VFT domain are critical to the distinction.
In creased savoury taste perception by the ribonucleotides IMP and GMP is affected by four amino acids located at the opening of the taste VFT domain.
Shadam 2009 A taste of umami Nature vol 457, p 161
F Zhang et al Proc Natl Acad Science USA 2008

drinking water and drugs

Snyder and colleagues ( Environmental Sci Technol 2008 ) have looked for and measured chemicals with biological properties in drinking water from treatment stations across the USA.
Of the 51 compounds looked for 34 were detected in at least one sample although not at significant concentrations. The herbicide atrazine and the drugs meprobamate( used in pain relief ) and phenytoin ( used for epilepsy control) were present in half of the samples.

chromosome telomeres and ageing

Mayor has written a fascinating review of the role of telomeres in ageing in the BMJ of 17th January 2009.
Chromosome in the body carries a marker that counts down from the day of birth to death, rather like a cellular sand clock. These biological timers are telomeres-repeat sequences of DNA that, together with associated proteins, cap the ends of chromosomes and protect them from degradation.
Telomeres shorten with each cell division. This shortening is accelerated in diseases associated with ageing-particularly cardiovascular disease and cancers-and in the presence of risk factors for these diseases such as obesity and high blood pressure. Shorter telomeres have also been found in women under chronic, severe stress More than 30 years ago, Olovnikov proposed that this shortening could provide a mechanism for a biological clock that determines cell behaviour. (Olovnikov's clock )-The measurements of telomere length could be used to detect early disease, allowing preventive measures to be put in place, and eventually that methods will be found to slow or even reverse the shortening.
Telomeres are made up of a large number of tandem repeats of the sequence TTAGGG. DNA polymerase cannot fully replicate the 3' end of linear DNA, so telomeres shorten progressively with each repeated cell division. Laboratory studies have shown that the telomere length of replicating cells is inversely correlated with age.
Telomere length is essentially a measure of biological age. This may partly explain why women live longer than men in most societies, as a: they generally have longer telorneres. .
Telomeres isolated from leucocytes from blood samples collected during major epidemiological and clinical trials are proving a rich hunting ground for information on telomeres and disease risk.
The average telomere length is shorter in people who have had a myocardial infarction before the age of 50 years than in controls matched for age and sex. Telomeres are also shorter in patients with severe triple vessel coronary artery disease than in people with angiographically normal coronary arteries.
But telomere length is not simply a consequence of the disease, but a risk factor.
The presumed biological mechanisms underlying telomere shortening are our old friends, oxidative stress and inflammation.
Physical activity reduces telomere length shortening, one study showed that 16 minutes of physical activity a week resulted in 200 nucleotide extra shortening in the telomere than in individuals active for three hours a week. These active individuals had telomere lengths equivalent to people 10 years younger.
So telomerase is the enzyme to watch and its control and the effect of nutrition and exercise. . Or is this cause or effect?
Mayor 2009 Unravelling the secrets of ageing BMJ vol 338 136-38

Alzheimer's updates

Researchers have identified nine genes that might make people more likely to develop Alzheimer's disease. They confirmed earlier reports that a variation in the vitamin D3 receptor gene, on chromosome 12, might also increase risk for Alzheimer's. Low levels of vitamin D have been found in people with Alzheimer's and other dementias, leading researchers to suspect a link.In their study, the researchers compared 550,000 genetic variations in about 500 people with Alzheimer's and 500 people without the disease
Their findings are published in the January issue of The American Journal of Human Genetics,
New study supports statin's anti-dementia effects
NEW YORK (Reuters Health January 8, 2009) - In the largest cohort study to date, treatment with a cholesterol-lowering statin drug was found to reduce new cases of Alzheimer's disease, regardless of the specific type of statin used or a person's genetic risk for the disease. Numerous studies have looked at the relationship between statin use and the development of Alzheimer's disease, with conflicting results. One explanation for the inconsistencies is that only the fat soluble or "lipophilic" statins, which could get into the brain more easily than water soluble or "hydrophilic" statins, were included in the studies. Dr. M. M. B. Breteler and colleagues at the Erasmus Medical Centre in Rotterdam, the Netherlands, analyzed data from the prospective, population-based Rotterdam Study. The analysis included 6992 subjects, 55 years old or older, who were free of dementia when examined between 1990 and 1993.
During follow-up until 2005 (an average of 9.2 years), 582 subjects were diagnosed with Alzheimer's. After controlling for social, demographic and clinical factors that might raise a person's risk of getting the disease, statin users had a significant 43 percent reduced risk of Alzheimer's disease compared with those who never used statins. The protective effect was similar for fat soluble and water soluble statins.
The protective effect of statin use against Alzheimer's disease was also similar for persons with and without the major gene mutation associated with Alzheimer,s disease ( the apolipoprotein E-epsilon-4 allele)
Journal of Neurology, Neurosurgery and Psychiatry, January 2009.

SRF (serum response factor) and myocardin -- lessen blood flow in the brain and reduce the rate at which the brain is able to remove amyloid beta, the protein that accumulates in damaging quantities in the brains of Alzheimer's patients. Two processes are believed to play a role in Alzheimer's: a reduction in blood flow and a buildup of amyloid beta. These two proteins known for their role in the cardiovascular system were major factors in the development of Alzheimer's disease. The study was published online Dec. 21 in the journal Nature Cell Biology.

Fish oil and cardiovascular disease

The National Institute for Health and Clinical Excellence (NICE) recommends that after a myocardial infarction patients should eat two to four portions of oily fish a week or omega 3 acid ethyl esters. The aim is a daily intake of 1 g of long chain polyunsaturated fish oil and thereby to reduce the risk of death or further non-fatal cardiovascular events.
What is interesting and rather startling is the meagre evidence upon which this far reaching decision is based.
The evidence is a large trial in Italy 10 years ago (GISSI) who found substantial reduction in fatal but not non-fatal heart attacks. These trials are massive enterprises requiring management skills of the highest. Asking simple questions with impeccable statistics and number of willing participants.
Questions remain, are the results reproducible, is fish oil equi-potent to eicosapentanenoic acid, docosahexaenoic acid, or the combination of both. Is surgical treatment better?
The chosen population is important, high or low incidence of myocardial heart disease.
Such research is needed not only because of the millions of people with heart disease worldwide, but also because the world’s marine fauna is being pushed towards extinction largely for commercial gain.
Since GISSI only one large trial has been published. The Japan Eicosapentanenoic Acid Lipid Intervention Study(UELIS) found that the addition of eicosapentanenoic acid reduced major coronary events by around a fifth. The trial demonstrated the benefit of eicosapentanenoic acid without docosahexaenoic acid and eicosapentanenoic acid in addition to effective lipid lowering treatment. The findings are striking because fish consumption in Japan is high.
In a systematic review Leon and colleagues assess the effects of fish oil on the secondary prevention of mortality and arrhythmias arrhythmias. No conclusive answer is available as no new evidence is available. It is amazing that one of the tenets of
believe is so fragile. Or is it?

Brunner and Iso 2009 Fish oil and secondary prevention of cardiovascular disease .BMJ vol 338 ppp 118-9

GSSI-Prevention Investigation 1999 Lancet vol 354, 447-55

Leon et al 2009 Effect of fish oil on arrhythmias and mortality: systematic review. BMJ . vol 337 pp 149-152

biological rhythms

Periodic oscillations are the basis of time keeping. So begins an article in Nature .
Gore and van Oudenaarden 2009 The yin and yan of nature. Nature vol 457 pp271-2.
They describe how Gallileo’s observation on the pendulum altered time keeping. There are similar oscillatory networks in nature. Simplistically negative feed back with delay in between. Three genes may sequentially suppress each other. The three repressive interactions lead to net negative feed back with a delay in the biochemical processes involved. The delay must be a precise number of seconds. When conditions change then the system must retune. The key element of these oscillators is that they must be robust not transient.
The circadian pacemakers are based on a central pacemaker in the suprachiasmatic nucleus of the brain with subsidiary oscillators in cells. The gene circuitry are a set of transcriptional repressors ( CRY and PER) and activators ( BMAL1 and CLOCK).
Tigges et al describe such a system in mammalian cells. Negative feedback is provided by post-transcriptional repression of the gene encoding tTA by antisense RNA, and positive feedback because tTA enhances its own transcription.
The cell population must oscillate in a co-ordinated manner. Circadian oscillation is affected by sunlight and cell-cycle oscillations pause when there is a shortage of nutrients.
Tigges et al 2009 A tunable synthetic mammalian oscillator. Nature vol 457 pp 309-312.

Internationl Health comparisons

This paper (Backman et al ) is a mine of information from many countries and their Health standards.
60 years ago, the Universal Declaration of Human Rights laid the foundations for the right to the highest attainable standard of health. This right is central to the creation of equitable health systems. We identify some of the right-to-health features of health systems, such as a comprehensive national health plan, and propose 72 indicators that reflect some of these features. We collect globally processed data on these indicators for 194 countries and national data for Ecuador, Mozambique, Peru, Romania, and Sweden. Globally processed data were not available for 18 indicators for any country, suggesting that organisations that obtain such data give insufficient attention to the right-to-health features of health systems. Where they are available, the indicators show where health systems need to be improved to better realise the right to health. We provide recommendations for governments, international bodies, civil-society organisations, and other institutions and suggest that these indicators and data, although not perfect, provide a basis for the monitoring of health systems and the progressive realisation of the right to health. Right-to-health features are not just good management, justice, or humanitarianism, they are obligations under human-rights law.
Backman et al 2008 Health systems and the right to health: an assessment of 194 countries Lancet vol 372 pp 2047-2083

Irritable Bowel Syndrome treatment

Guidelines for the management of irritable bowel syndrome in the United Kingdom recommend that the diagnosis should be made on clinical grounds alone, without invasive investigations, unless alarm symptoms such as rectal bleeding are present. General practitioners therefore need efficacious treatments that do not require monitoring and are cheap, safe, and readily available. People with irritable bowel syndrome have been instructed to increase their intake of dietary fibre. When this failed, smooth muscle relaxants and antispasmodics were used. More recently, peppermint oil, shown to have antispasmodic - properties has been used to treat irritable bowel syndrome. Whether these agents are effective in treating
irritable bowel syndrome is controversial. Results of randomised controlled trials are conflicting and systematic reviews have come to different conclusions.
Ford et al 2008 BMJ carried out a systematic review and meta-analysis to determine the effect of fibre, antispasmodics, and peppermint oil in the treatment of
irritable bowel syndrome.
They concluded that fibre, antispasmodics and peppermint oil were all more effective than placebo in treating the symptoms of irritable bowel.
This is an important analysis of the treatment of a common and troublesome condition.
Ford et al 2008 Effect of fibre, antispasmodics and peppermint oil in the treatment of irritable bowel syndrome: systematic review and meta-analysis. BMJ vol 337 pp 1388-92

Inequalities in healthy life years in Europe

How enjoyable old age is depends on many factors. In old age we reap the benefits and disadvantages of what has gone before. Diet, smoking, alcohol intake, exercise, family life, financial prudence and all the other boring things for young people.
Jagger et al in the Lancet discuss this aspect of life.
Life expectation is slowly increasing throughout the European Union (EU), both at birth and at 65 years. a greater number of elderly people are living longer. There is a significant gap between Eastern and Western EU countries.
Increasing life expectation does not necessarily mean a healthier population. Health expectation is a concept developed to bring a quality of life measure of life expectation (Healthy life years (HLY). People should have a healthy active old age. Not an extension of morbidity.
In 2005, an average 50-year-old man in the 25 EU countries could expect to live until 67 years free of activity limitation, and a woman to 68 years. HLYs at 50 years for both men and women varied more between countries than did life expectancy (HLY range for men: from 9-1 years in Estonia to 23-6 years in Denmark; for women: from 10 years in Estonia to 24 years in Denmark). Gross domestic product and expenditure on elderly care were both positively associated with HLYs at 50 years in men and women); however, in men alone, long-term unemployment was negatively associated and life-long learning positively associated with HLYs at 50 years of age.
The authors concluded that substantial inequalities in HLYs at 50 years exist within EU countries. That, without major improvements in population health, the target of increasing participation of older people into the labour force will be difficult to meet in all 25 EU countries-
Jagger et al 2008 Inequalities in healthy life years in the 25 countries of the European Union in 2005: a cross-national meta-regression analysis Lancet 2124-2131