global warming, the medieval view.

Global warming and climate change arc established facts with thoughts arising on the fate of the planet in the next few decades. One approach is through the computer models used by the Intergovernmental Panel on Climate Change. Another is to consider how conditions changed in warmer historical periods, notably AD800-l300, the Medieval Warm Period. This book
THE GREAT WARMING: Climate Change and the Rise and Fall of Civilizations by Brian Fagan
Blooms bury
is a sequel to another volume The Little Ice Age which covered the global cooling from about 1430 to 1850.
In Europe in the 12th and 13th centuries, England exported wine to France, and wine was also produced in southern Norway. The Norse settlement of Greenland in the
AD 980s, enjoyed a flourishing economy for three centuries until it was abandoned to the ice around 1450.
The Medieval Warm Period was not however a discrete episode when climate was distinctly different from what came before.
The collapse of the Classic Maya civilisation in Central America in the ninth century was probably precipitated by successive droughts in a land where water supplies were always under stress.
The settlement of remote Easter Island (Rapanui) around 1200 AD by canoeists heading east from Polynesia with westerly winds may have been made feasible by the faltering of the usual northeasterly Pacific trade winds during El Nino events connected with warmer sea-surface temperatures.
Genghis Khan's Mongol invasion in the early 13th century could have been prompted partly by drought wreaking havoc on the pastures of the steppes. This possibility is supported by the withdrawal of his grandson Batu Khan and the Golden Horde in the 1240s at the height of their military success with the return of cooler, wetter conditions.
These suggestions are based on climatological studies of recent vintage, using ice-cores, deep-sea and lake cores, coral records and tree rings, and historical documents such as the reports of the flowering of cherry trees in Japan and Korea that date back a thousand years.
Five-hundred-year-old pines from the mountains of Mongolia have allowed experts to construct a climatic sequence back to AD 850. The prolonged warm period detected in the Mongolian tree rings coincides with Genghis Khan's conquests, Tree rings from multiple western locations agree that the four driest periods centred on AD935, 1034, 1150 and 1253. followed by an extended wetter period from 1300-1900. then a return to droughts.
. Also important is the variation in solar irradiance caused by small tilts in earth's orbit, sunspots and major volcanic eruptions the eruption of Mount Pinatubo in the Philippines in 1991, for example, counteracted current global warming for several years.
The medieval warming was generally good for Europe, but it produced prolonged droughts in many parts of the world, including the Sahara. Peru, India and northern China.
In a review of this book Robinson in the Financial Times Weekend Magazine March 15/16 2008 p 29 points out that the in the future the much larger human population, many living close to starvation, will be peculiarly susceptible to global warming.

metabolic syndrome , useful diagnosis or not?

The BMJ has interesting debates on contentious topics and in the 22 March 2008 the question of the value of the diagnosis of the metabolic syndrome is discussed.
The International Diabetes Federatioi definition of the metabolic syndrome is
Presence of central obesity—Waist circumference varies with ethnicity.
If body mass index is >30 central obesity can be assumed
Plus any two of the following: Triglyceride concentration >1.7 mmol/l or receiving specific treatment for this lipid abnormality High density lipoprotein cholesterol<1.03 mmol/l in men, <1.29 mmol/l in women, or receiving specific treatment for hypercholesterolaemia
Systolic blood pressure >130 mm Hg or diastolic >85 mmol/l, or treatment for hypertension
Fasting plasma glucose >5.6 mmol/l or previously diagnosed glucose type 2 diabetes. If >5.6 mmol/l, oral glucose tolerance test is strongly recommended but is not necessary to diagnose the syndrome
Two groups of experts are asked “Should we dump the metabolic syndrome ?
Professor Gale of Bristol argues whilst the diagnosis is a useful label but is too
imprecise fo clinical usage..
George Alberti and Dr Zimmet argue for its use and value in deciphering the multifactorial nature of the problem..
Gale, Alberti and Zimmet 2008, Should we dump the metabolic syndrome. BMJ vol 336
pp 640-641.

Circadian Rhythm and blood formation

Haematopoietic stem cells (HSCs) circulate in the blood, where they can home to sites throughout the body. The release of these cells into the blood stream has now been found to be regulated by circadian rhythms. In mice, Haematopoietic stem cells undergo pronounced fluctuations corresponding to circadian oscillations induced by continuous light or by a 12-hour time-shift or'jet lag'. Timing of the expression of the chemokine CXCL12 in the stem cell niche was also in step with the oscillations in response to adrenergic signals delivered locally by nerves in the bone marrow. The rhythmic release of stem cells into the blood during the animal's resting period suggests a possible role in regeneration.
Scadden 2008 Stem cells traffic in time Nature vol 452. pp 416-17
Mendez-Ferrers et al 2008 Haemopoietic stem cell relese is regulated by circadian oscillations Nature vol 452 pp 442-447

Obesity susceptibility and genetics, a complex

Complex human diseases result from the interplay of many genetic and environmental factors. To build up a picture of the factors contributing to one such disease, obesity, gene expression was evaluated as a quantitative trait in blood and adipose tissue samples from hundreds of Icelandic subjects aged 18 to 85. The results reveal a tendency to certain characteristic patterns of gene activation in the fatty tissues — though to a much lesser extent in the blood —of people with a higher body mass index. A transcriptional network constructed from the adipose tissue data has significant overlap with a network based on mouse adipose tissue data.
Experimental support for the idea that complex diseases are emergent properties of molecular networks influenced by genes and environment comes from a study in mice. Mice were examined for disturbances in genetic expression networks that correlate with metabolic traits associated with obesity, diabetes and atherosclerosis. Three genes — Lpl, Lactb andPpm1l— were identified as previously unknown obesity genes. This 'molecular network' approach raises the prospect that therapies might be directed at whole 'disease networks', rather than at one or two specific genes.
This is such interesting work. There must be a range of disease liabilities from the direct relationship of gene change and Haemophilia or Thalassaemia to the consequences of a complex web of interconnecting genes and an accumulated liability prompted by the environment being conducive to such developing obesity and atheroma.
Emilsson et al 2008, Genetics of gene expression and its effect on disease Nature vol 453 pp 423-428
Chen et al 2008, Variations in DNA elucidation molecular networks that cause disease. Nature vol 452 pp 429-435

Food additives and the European Food safety Authority

Rory Watson BMJ 29th March 2008, p 687
The European Food Safety Authority has rejected suggestions in a study by researchers at Southampton University last year of a link between hyper activity in children and two mixtures of food colours and the preservative sodium benzoate (Lancet 20O7; vol 370; pp 1560-7).The study, which was commissioned by the U K Food Standards Agency.
After a request from the European Commission, the Parma based authority asked its panel on food additives, flavourings, processing aids, and food contact materials to assess the study's findings that the colourings and preservative in the diet led to more hyperactivity in 3 year old and 8-9 year old children.
In its report, published on 14 March, the panel listed its many reservations about the study's findings. It pointed to the lack of consistency in the results with respect to the age and sex of the children and the type of observer (parent, teacher, or independent assessor); the unknown clinical relevance of the effects measured; and the lack of information on any dose-response relation.
The panel also maintained that the fact that mixtures were studied made it impossible to identify the effects of individual additives and noted the absence, of a plausible biological mechanism that might explain the possible link between behaviour and the consumption of colours. As a result, the authority, which advises the European Union on food safety, maintained that there is no basis for changing present recommendations on the acceptable daily intake of the food colours or sodium benzoate.

The report is at www.efsa.europa.eu.

This is either a comment on the original study, the Lancet for publishing the report or the UK FSA. Or
that the EU authority already had entrenched views on the topic and could not be convinced by any
argument. .

exercise and energy

There were an important series of papers on energy in Proceedings of the Nutrtion Society in 2003.
The first by Westerterp discussed the Impacts of vigorous and non-vigorous activity on daily energy expenditure 2003 Proceedings of the Nutrition Society vol 62, 651-661
Activity intensity is a potential determinant of activity-induced energy expenditure. Tri-axial accelerometery is the most objective measurement technique for the assessment of activity intensity, in combination with doubly-labelled water for the measurement of energy expenditure under free-living conditions. Data on the effects of subject characteristics, including body size and age, and exercise training on the relationship between activity intensity and daily energy-expenditure are reviewed. Average daily metabolic rate and non-basal energy expenditure are positively related to body size. The duration and intensity of physical activities do not need to be equivalent to the energy spent on activity. Obese subjects spend more energy on physical activity but can perform fewer activities, especially high-intensity (weight-bearing) activities, because of their higher body weight. Physical activity generally declines gradually from about 60 years of age onwards. Most subjects > 80 years have an activity level well below the level defined for sedentary middle-aged adults. Spending relatively more time on low-intensity activities has a negative effect on the mean physical activity level. To obtain a higher physical activity level does not necessarily imply high-intensity activities. In an average subject 25 % of the activity-induced energy expenditure may be attributed to high-intensity activities. Exercise training, as a form of high-intensity activity, affects the physical activity level more in younger subjects than in elderly subjects.
The second by Blundell et al discusses Cross talk between physical activity and appetite control: does physical activity stimulate appetite? 2003 Proceedings of the Nutrition Society, vol 62 pp 663-666
Physical activity has the potential to modulate appetite control by improving the sensitivity of the physiological satiety signalling system, by adjusting macronutrient preferences or food choices and by altering the hedonic response to food. There is evidence for all these actions. Concerning the impact of physical activity on energy balance, there exists a belief that physical activity drives up hunger and increases food intake, thereby rendering it futile as a method of weight control. There is. however, no evidence for such an immediate or automatic effect. Short (1-2 d)-term and medium (7-16d)-term studies demonstrate that men and women can tolerate substantial negative energy balances of <4MJ energy cost/d when performing physical activity programmes. Consequently, the immediate effect of taking up exercise is weight loss (although this outcome is sometimes difficult to assess due to changes in body composition or fluid compartmentalization). However, subsequently food intake begins to increase in order to provide compensation for about 30% of the energy expended in activity. This compensation (up to 16d) is partial and incomplete. Moreover, subjects separate into compensators and non-compensators. The exact nature of these differences in compensation and whether it is actually reflective of non-compliance with protocols is yet to be determined. Some subjects (men and women) performing activity with a cost of <4MJ/d for 14 d. show no change in daily energy intake. Conversely, it can be demonstrated that when active individuals are forced into a sedentary routine food intake does not decrease to a lower level to match the reduced energy expenditure. Consequently, this situation creates a substantial positive energy balance accompanied by weight gain. The next stage is to further characterize the compensators and non-compensators, and to identify the mechanisms (physiological or behavioural) that are responsible for the rate of compensation and its limit..

Control of gene regulation, ? a role for soya

Differential expression of the eukaryotic genome through cell differentiation or response to environmental changes requires specific modulation of its nuclear organization. These processes enable regulated genes to prevail against regulatory constraints of chromatin structure in which DNA is wrapped around core nucleosomes consisting of octamers of histones H2A. H2B, H3 and H4. Overcoming the structural restriction of chromatin upon gene expression is achieved in part through the modulation of particular marks that define active or inactive chromatin domains.
DNA methyl transferases establish and maintain the pattern of genomic DNA methylation on cytosines of CpG dinucleotides. This cpigenetic mark is linked to gene repression: hypomethylated DNA is associated with active genes, whereas hypermethylated genes are silent.
Although gene expression correlates with CpG demethy-lation, processes that either remove the 5-methyl group or that exchange methylated cytosines with cytosines are yet to be elucidated. .
Processes that regulate gene transcription are directly under the influence of the genome organization. The epigenome contains additional information that is not brought by DNA sequence, and generates spatial and functional constraints that complement genetic instructions.
Metivier et al in Nature 6th march 2008 present evidence of a dynamic role for DNA methylation in gene regulation in human cells. Periodic, strand-specific methylation/demethylation occurs during transcriptional cycling of the pS2/TFFl gene promoter on activation by oestrogens.
DNA methyltransferases exhibit dual actions during these cycles, being involved in CpG methylation and active demethylation of 5mCpGs through deamination. Inhibition of this process precludes demethylation of the pS2 gene promoter and its subsequent transcriptional activation. Cyclical changes in the methylation status of promoter CpGs may thus represent a critical event in transcriptional achievement.
The interesting point here for nutritionists is that if oestrogen act in this manner then soy products which have an mild oestrogenic activity might also
Metivier et al 2008 Cyclical DNA methylation of a transcriptionally active promoter Nature vol 452, pp 45-50

Clinical trials and strength of significance

There is a very relevant Editorial in the BMJ of 8th March 2008.
In February 2008, Kirsch and colleagues reported a meta-analysis of the efficacy of antidepressants using data from clinical trials submitted to the Food and Drug Administration. They provocatively concluded, "there seems little evidence to support the prescription of anti depressant medication to any but the most severely depressed patients."
In January this year. The authors of the Editorial Turner and Rosenthal published an article about the selective publication of antidepressant trials and its influence on apparent efficacy and also used FDA data. Our main finding was that antidepressant drugs are much less effective than is apparent from journal articles. From the Food and Drug Administration data we derived an overall effect size of 0.31. Kirsch and colleagues used FDA data from four of the 12 drugs we examined and calculated an overall effect size of 0.32.
Although these two sets of results were in excellent agreement, the authors interpreted the results quite differently. In contrast to Kirsch and colleagues' conclusion that antidepressants are ineffective, Turner and Rosenthal concluded that each drug was superior to placebo. The difference in our interpretations stems from Kirsch and colleagues' use of the criteria for clinical significance recommended by the UK's National Institute for Health and Clinical Excellence (NICE).
Clinical significance is an important concept because a clinical trial can show superiority of a drug to placebo in a way that is statistically, but not clinically, significant. Tests of statistical significance give a yes or no answer (for example, P<0.05 is deemed significant. P>0.05 non-significant) that tells us whether the true effect size is zero or not, but it tells us nothing about the size of the effect.: In contrast, effect size does, gives clinical significance. Values of 0.2, 0.5, and 0.8 were proposed to represent small, medium, and large effects, respectively.1
NICE chose the "'medium" value of 0.5 as a cut-off below which the benefit of a drug are not clini¬cally significant. This is problematic because there is no longer a continuous measure, but the answer is a yes or no measure. Suggesting that drug efficacy is either totally present or absent, even when comparing values as close together as 0.51 and 0.49. Kirsch and colleagues compared their effect size of 0.32 to the 0.50
cut-off and concluded that the benefits of antidepressant drugs were of no clinical significance.
But on what basis did NICE adopt the 0.5 value as a cut-off? When Cohen first proposed these landmark effect size values, he wrote, "The terms small", 'medium', and 'large' are relative ... to each other ... the definitions are arbitrary . . . these proposed conventions were set forth throughout with much diffidence, qualifications, and invitations riot to employ them if possible." He also said, "The values chosen had no more reliable a basis than my own intuition." Thus, it seems doubtful that he would have endorsed NICE's use of an effect size of 0.5 as an absolute test for drug efficacy.
They emphasise the importance of stating the clinical strength of recommendations.
This is in general not a common thought in nutrition. This is such a thought provoking paper
Turner and Rosenthal 2008 Efficacy of antidepressants BMJ vol 336, 516-7

Lean body mass and creatinine excretion rate

The response to stress as happens in severe injury or illness is a
catabolic state. This results in loss of lean body mass and a worsening
physical state.
It is essential that there is adequate nutritional support with protein
and energy during this crisis.
Catabolism results in the release of amino acids which are metabolised
to end products including urea. There is also the release of intercellular
products including potassium, phosphate and magnesium. Arginine oxidation
is reflected in creatinine production.
Carlotti et al in QJMed have looked at whether there is an increased rate of creatinine urinary excretion with the catabolic state in children who had experienced severe trauma. They related this to balances of potassium, phosphate and magnesium to evaluate the benefit of nutritional therapy during this crisis.
They concluded that negative balances of intracellular components (potassium, phosphate and magnesium ) and an increase in rate of creatinine excretion heralded the onset of catabolism
Carlotti et al 2008 Indicators of lean body mass catabolism: emphasis
On the creatinine excretion rate QJ Med vol 101, 197-205

prostate cancer and phyto-oestrogens

Prostate cancer is an important and increasing public health problem. It is the second most common cancer in men after lung cancer, and accounts for 10% of all male cancer-related deaths. Within the last three decades. prostate cancer incidence in Scotland has more than doubled, with 2335 cases of Prostate cancer diagnosed in 2002 . The relatively low risk of prostate cancer in Asian populations compared with Western countries, suggests that dietary factors may influence the prevalence of and mortality from this disease . Of special interest is the group of plant-derived nutrients called phyto-oestrogens. in particular isoflavones (genistein, daidzein and equol) and lignans (enterolactone and enterodiol).
Isoflavones are found mainly in soybeans and soy products, foods that are consumed in far greater amounts by populations in Asia compared with those in Western countries . In Western countries, soy foods tend to be eaten most frequently by vegetarians and vegans . Isoflavone precursors are metabolised by the gut microflora to give rise to compounds such as daidzein, genistein and equol . Another group of phyto-oestrogens are the lignans; they are derived from the plant precursors matairesinol and secoisolariresinol which are present in a wide variety of plant foods, including linseed, legumes, cereals, fruits and vegetables. These plant precursors are metabolised by gut microflora into the lignans enterolactone and enterodiol.
The biological properties of phyto-oestrogens include antiviral, antiangiogenic and amioxidam properties Phyto-oestrogens possess weak oestrogenic activity, they compete with oestradiol in binding to the nuclear oestrogen receptor and also stimulate the synthesis of sex hormone-binding globulin, which in turn mediates the plasma levels of testosterone on which the growth, develop¬ment, maintenance and function of the prostate gland is dependent. In addition, phyto-oestrogens can inhibit steroid-metabolising enzymes, including 5α-reductase and aromatase. and also the cell signalling apparatus by the inhibition of tyrosine-specific protein kinases .
Several epidemiological studies support the role of phyto-oestrogens and soy foods in reducing cancer risk However, this evidence is limited, in particular for prostate cancer with only a few studies examining this association usually in populations with high isoflavone/soy food consumption.
This study by Heald et al describes a population-based case-control study of diet, inherited susceptibility and prostate cancer undertaken in the lowlands and central belt of Scotland to investigate the effect of phyto-oestrogen intake and serum concentrations on prostate cancer risk. A total of 433 cases and 483 controls aged 50-74 years were asked to complete a validated FFQ and provide a non-fasting blood sample. Multivariate logistic regression analysis found significant inverse associations with increased serum concentrations of enterolactone and with the consumption of soy foods. However, no significant associations were observed for isoflavone intake or serum genistein, daidzein and cquol.
This study supports the hypotheses that soy foods and enterolactone metabolised from dietary lignans protect against prostate cancer in older Scottish men.
Heald et al 2008 Phyto-oestrogens and risks of prostate cancer in Scottish men. British Journal of Nutrition vol 98, 388-396

malnutrition and prognosis in hospital patients

In a study looking at malnutrition as an independent predictor of 1-year mortality following acute illness, Gariballa and Forster studied four hundred and forty-live randomly selected hospitalised patient. Their nutritional status was assessed from anthropometric, haematological and biochemical data. Nutritional status was compared between survivors and non-survivors at baseline, 6 weeks and 6 months. Using Cox’s proportional hazard analysis, they measured the association between nutritional assessment variables and 1 -year mortality after adjusting for disability, chronic illness, medications, smoking and tissue inflammation. Nutritional status was significantly worse amongst non-survivors compared with survivors, and non -survivors showed marked and significant deterioration in all measures of nutritional status compared with survivors. After adjusting for poor prognostic indicators the hazard ratios of death in the fourth, third and second quarters of both baseline serum albumin and mid-upper arm circumference distributions relative to the first were 0-68, 0-77 and 0-58 and 0-61. 1-0 and 0-87 respectively. Intervention studies are needed to determine whether the relationship between malnutrition and the poor outcome highlighted by the present study is causal or a mere association.
Gariballa and Forster 2007 Malnutrition is an independent predictor of 1-year mortality following acute illness Proceedings of the Nutrition Society vol 98, 332-336.

malnutrition and prognosis in hospital patients

In a study looking at malnutrition as an independent predictor of 1-year mortality following acute illness, Gariballa and Forster studied four hundred and forty-live randomly selected hospitalised patient. Their nutritional status was assessed from anthropometric, haematological and biochemical data. Nutritional status was compared between survivors and non-survivors at baseline, 6 weeks and 6 months. Using Cox’s proportional hazard analysis, they measured the association between nutritional assessment variables and 1 -year mortality after adjusting for disability, chronic illness, medications, smoking and tissue inflammation. Nutritional status was significantly worse amongst non-survivors compared with survivors, and non -survivors showed marked and significant deterioration in all measures of nutritional status compared with survivors. After adjusting for poor prognostic indicators the hazard ratios of death in the fourth, third and second quarters of both baseline serum albumin and mid-upper arm circumference distributions relative to the first were 0-68, 0-77 and 0-58 and 0-61. 1-0 and 0-87 respectively. Intervention studies are needed to determine whether the relationship between malnutrition and the poor outcome highlighted by the present study is causal or a mere association.
Gariballa and Forster 2007 Malnutrition is an independent predictor of 1-year mortality following acute illness Proceedings of the Nutrition Society vol 98, 332-336.

Childhood obesity prevention and exercise

This is a somewhat older review but still very relevant published by Reilly and McDowell in the Proceedings of the Nutrition Society in 2003.
The emergence of the childhood obesity epidemic, was not apparent in the UK until 1999.
Interventions for prevention and treatment of childhood obesity typically target increases in physical activity and. more recently, reductions in physical inactivity (sedentary behaviour such as television viewing). However, the evidence base for such strategies is extremely limited. Randomised controlled trials that targeted activity or inactivity, that followed up children or adolescents for at least 1 year and that included an objective weight-related outcome measure were included.
The evidence base has increased markedly since the completion of earlier reviews, although high-quality evidence is still lacking. This position reflects a combination of factors; limitations in trial design before the advent of the Cochrane and CONSORT processes; the major difficulties (methodological, financial, practical, ethical) presented by carrying out long-term research in this area.
The evidence on childhood obesity prevention is not encouraging, although promising targets for prevention are now clear, notably reduction in sedentary behaviour.
There is stronger evidence that targeting activity and/or inactivity might be effective in paediatric obesity treatment, but doubts as to interventions, and the clinical relevance of the interventions is unclear..
A number of previous studies have noted the possibility that the large-scale changes in society that have driven the obesity epidemic may be beyond the reach of interventions aimed only at the family or school environment
Large-scale policy or strategic initiatives, employing macroenvironmental or "ecological' approaches, may be essential if the public health impact of the childhood obesity epidemic is to be addressed However, any such initiatives should also be evidence based and should be evaluated rigorously
Reilly and McDowell 2003 Physical activity interventions in the prevention and treatment of paediatric obesity: systematic review and critical appraisal Proceedings of the Nutrition Society vol 62 pp 611-619