mitochonria and post trauma illness

These are such ingenious and clever two papers
Serious physical injury, or trauma, is a major cause of morbidity and mortality worldwide, Patients who survive the initial trauma, despite medical and surgical care, often remain critically ill. One cause of this extension of danger is the systemic inflammatory response syndrome with shock and compromised function of several organs. The clinical symptoms of post-traumatic syndromes, fever, increased heart rate and low blood pressure (shock) are similar to the signs and symptoms of the systemic inflammatory response to severe infection, i.e. sepsis. The molecular mechanism of these severe problems has been poorly understood.
In Nature 4th March 2010 Zhang et al. identify one of the pathways that triggers trauma associated syndromes and links it to pathways implicated in sepsis-associated syndromes.
It was previously proposed that traumatic stress syndrome was due to bacterial escaping from the bowel and infecting the patient. Zhang et al suggest that mitochondria are the link. Mitochondria are believed to be organelles that originated from bacteria that parasitized eukaryotic cells and retain many similarities with bacteria. So during trauma these mitochondria pour out of the damaged tissues and cause a form of sepsis.
Calfee and Matthay 2010 Culprits with evolutionary ties Nature vol 464 pp 41-42
Zhang 2010 Circulating mitochondrial DAMPs cause inflammatory responses to injury Nature vol 464 pp 104-107

Mosquitos and human odours

The malaria mosquito, Anopheles gambiae, is involved in the deaths of about one million humans every year. The female mosquitoes feed on human blood and whilst sucking their victim's blood the mosquitoes unwittingly transmit the malaria causing parasite that threatens half of the world's population. The number of people world wide who get malaria each year is greater than the population of the United States.
Human derived odorants have a key role in the mosquito tracing their human food sources. Female mosquitoes find the odour of patients with malaria particularly attractive.
Some of the mosquito’s odorant receptors are tuned into human derived compounds eg indole , an important component of human sweat. The receptors respond to phenol, methylphenols and other aromatic compounds and 3–methylindole , an odorant that induces females of another mosquito species to lay eggs.
Leal WS , 2010, The treacherous scent of a human. Nature vol 464 2010
Carey et al 2010 Odorant reception in the malarial mosquito Anopheles gambiae , Nature vol 464 , 66-71

Prognosis in nutrition

This review by Hemingway et al BMJ 20th Feb 2010 pp 410 ( Ten steps towards improving prognosis research)is to my mind of paramount importance for nutritionists. They strongly criticise the science of prognosis in clinical medicine.They describe low quality,low impact prognosis research in clinical medicine which is then inflated by the Media.
Are we in nutrition any better?
The authors define prognosis research as the study of the relationship between
occurrences of outcomes and predictors in defined populations of people with disease.
Observational research evaluating three broad questions.
1. Causes of disease progression
2. Prediction of risk in individuals
3. And individual response to treatment
They site instances where multiple papers have been written which have failed to answer quite simple prognostic questions.
They identify 10 areas where specific actions would make studies more reliable.
The goals should be
1. Identification of single biomarkers that independent association with outcome.
2. Development of multivariable risk prediction models that predict an individual’s outcome.
3. Identification of biomarkers that predict response to treatment
The translation of emerging putative prognostic biomarkers from the laboratory to the bedside(or table ).
This is a science that Nutrition could look at with advantage.
We have good logic for
1. 5 pieces of fruit and vegetable a day
2. Low salt intake
3. Plenty of fibre in the diet.
4. Being overweight
Have we evidence that changing our life styles to accommodate to these dietary challenges makes any difference to health or life expectation? Are these recommendations applicable to all age groups and physical states e.g. growth, pregnancy.
Good prognostic studies might be helpful.
Hemingway et al 2010 Ten steps towards improving prognosis research BMJ vol 340 pp 410-413

fetal growth

Fetal growth in the first trimester has far reaching implications
What happens to babies in the womb has implications way beyond birth. The first trimester seems particularly important, A link has been established between poor growth in the first trimester and adverse birth outcomes in 1631 pregnant women with reliable dates. They also recorded accelerated growth in infancy for these babies, who seemed to be "catching up" growth they had missed in the first trimester. Rapid growth in infancy is a well known risk factor for cardiovascular dis¬ease in adults. A poor intrauterine environment in early pregnancy may have lifelong implica-tions, say the researchers.
They used crown-rump length between the 10th and 13th week of pregnancy as a proxy for early fetal growth. Smoking and failing to take folic acid supplements were both inde¬pendently associated with shorter crown-rump length in the first trimester. So were increases in diastolic blood pressure and maternal hae¬matocrit. After multiple adjustments, babies with a crown-rump length in the bottom fifth had more than twice the odds of being born preterm, at low birth weight , or small for gestational age compared with other babies.
lAMA 2010;303:527-34

Vitamin D

Rickets still occurs in dark¬skinned infants who are exclusively fed on breast milk.
Cod-liver oil and sunshine exposure were recognised as the cures for rickets in the late 19th century.
There are two types of physiologically important vitamin D: cholecalci¬ferol (D3) and ergocalciferol (D2). D3 is synthesised in the skin from 7-dehydrocholesterol in cell membranes upon exposure to UVB (290-320 nrn), while D2 is plant and yeast derived and produced exogenously by UV irradiation of ergostero]
Vitamin D in the circulation is metabolised to 25-hydroxyvitamin D (25(OH)D) in the liver and further metabolised to the active metabolite, 1,25-dihydroxyvita¬min D (l,25(OH2D), in the kidney. The concentration of 1,25(OH2D is highly regulated by a variety of factors including serum parathyroid hormone and P.
The majority of circulating 25(OH)D and l,25(OH2D is bound to vitamin D binding protein and Albumin ( 10-20 %), and a small fraction is free.
The majority of circulating 25(OH)D and 1,25(OHhD is bound to vitamin D binding protein (DBP) (80-90 %) and albumin (10-20 %), while a small fraction of both 25(OH)D
Vitamin D-DBP complex is taken up by proximal tubules through the endocytic receptor megalin, after which DBP is proteolytically degraded, leaving the vitamin D metabolites for physiological action or metabolism,
The half-lives of vitamin D, 25(OH)D and 1,25(OH2D are approximately 24 h, 3 weeks and 4h respectively
Liver production of 25(OH)D is not significantly regulated and is primarily dependent on the availability of vitamin D.
Measuring the total levels of serum 25(OH)D is considered the best estimate of vitamin D nutritional status.
Vitamin D may reduces the risk of bone fracture, falls, autoimmune diseases, type 2 diabetes, CVD and cancer.
There is still epidemic vitamin D insufficiency especially among individuals living at high latitudes or with dark skin.
Serum levels of 25-hydroxyvitamin D' (25(OH)D) are considered the best biomarker of vitamin D nutritional status. 'Appropriate' sunshine exposure or oral supplementation is necessary to maintain sufficient vitamin D status, which is generally accepted as serum 25(OH)D > 75 nmol/l.


Wang 2009 Epidemiology of vitamin D in health and disease . Nutrition Research Reviews vol 22 ;188-203

Sulfur amino acids

The sulfur amino acids, methionine and cysteine, are implicated in numerous biological functions and diseases, aside from their role in protein synthesis
Methionine is an indispensable amino acid and is transmethylated intracellularly to homocysteine via S-adenosylmethionine, the principal biological methyl donor in mammalian cells and a precursor for polyamine synthesist. Reduced -adenosylmethionine concen¬trations, as a consequence of low methionine intake or folate deficiency, mainly lead to a deregulation in DNA methylation.

Homocysteine is a sulfur-containing amino acid present in the blood and tissues but not incorporated into protein. Homo¬cysteine can be converted into cy teine via cystathionine through the trans-sulfuration pathway, an irreversible process Homocysteine can also be methylated back to methionine via the remethylation pathway. The combination of transmethylation and remethylation pathways comprises the methionine cycle which occurs in most cells. However, the trans-sulfuration pathway has a limited tissue distribution and is restricted to the liver, kidney, intestine, pancreas and adrenals.

Cysteine is considered a semi-indispensable amino acid whose availability is dependent upon methionine intake. However, dietary cysteine can satisfy a proportion of the sulfur amino acid requirement, the so-called cysteine-sparing effect on dietary methionine requirernent. Cysteine is a constituent amino acid of the tripeptide glutathione (γ-Glu-Cys-Gly), the major cellular antioxidant in mammals, and serves also as a precursor for the synthesis of taurine, pyruvate, sulfate and hydrogen sulfide (H2S) .

The gastrointestinal tract is a metabolically significant site of sulfur amino acid metabolism in the body and metabolises about 20 % of the dietary methionine intake which is mainly transmethylated to homocysteine and trans-sulfurated to .cysteine. The gastrointestinal tract accounts for about 25 % of the whole-body transmethylation and trans-sulfurarion.
The gut also utilises 25 % of the dietary cysteine intake and the cysteine uptake by the gut represents about 65 % of the splanchnic first-pass uptake.

Sulfur amino acids deficiency significantly suppresses intestinal mucosal growth and reduces intestinal epithelial cell proliferation, and increases intestinal oxidant stress in piglets.

Suggesting that intestinal metabolism of dietary methionine and cysteine is nutritionally important for intestinal mucosal growth. Besides their role in protein synthesis, methionine and cysteine are precursors of important molecules. S-adenosylmethionine, a metabolite of methionine, is the principal biological methyl donor in mammalian cells and a precur or for polyamine synthesis. Cysteine is the rate-limiting amino acid for glutathione synthesis, the major cellular antioxidant in mammal .

Bauchart-Thevret et al 2009 Intestinal metabolism of sulphur amino acids Nutrition Research Review vol 22 pp 175-187

Diet and longevity

Dietary restriction - reduced food intake without malnutrition prolongs life span in yeast, worms, flies, rodents, monkeys and possibly humans.
But dietary restriction also often impairs fecundity, possibly because maintenance of the overall body mass (the non -germline parts of an organism), and thus long life, do not give space for reproductive activity.
Biologists have long thought that an organism's response to food shortage is an evolutionary device that allows individuals to survive a famine by diverting resources away from reproduction and reallocating them to essential functions for survival
Grandison et al in Nature 2009 report that this idea is almost certainly wrong. They find that dietary amino acids are respon¬sible for shortening lifespan and increasing reproduction in the fruitfly Drosophila mela¬nogaster, but that both longevity and fecun¬dity can be maximized when intake of these nutrients is finely tuned.

It has become clear that rich diets shorten life, not because of excess calories but rather because of dietary imbalance, with lifespan and fecundity being maximized at different nutritional optima, Specific nutrients are implicated in dietary restriction, especially amino acids, Reducing the intake of casein, a major amino-acid source, extends lifespan but decreases fecundity in Drosophila. Simi¬larly, methionine restriction promotes lon¬gevity in flies, rats and mice..
In a series of painstaking experiments, Grandison et al fed female flies a restricted diet that extends lifespan at the expense of fecundity, and then tried to restore the short¬life and high- fecundity characteristics of fully fed flies by adding back specific nutrients. Adding carbohydrates, lipids or vitamins made no difference. But adding amino acids short¬ened lifespan and increased egg production to the level observed under full feeding..
Grandison et al. found that adding all non-essential amino acids only marginally shortened lifespan and did not change fecundity, whereas adding all essential amino acids decreased lifespan and increased egg production as much as combin¬ing all amino acids or full feeding.
Methionine alone increased fecundity as much as full feeding but without reducing lifespan. Methionine together with one or several other essential amino acids is responsible for the life span-shortening effect of full feeding.
The benefits of methionine might be through the IIS-insulin /insulin-like growth factor (IGF) pathway .

If the present results' in the fly are gener¬ally applicable, even mammals might be able to enjoy a long life without loss of fecundity by virtue of a suitably balanced diet.

Flat 2009 Diet and longevity in the balance Nature vol 462 pp 989-990

Grandison et al 2009 Amino acid imbalance explains extension of life span by dietary restriction in Drosophila.Nature vol 462 pp 1061-1064

genetics and obesity

Genetic link to obesity
Obesity is a highly heritable disorder but the genetic associations reported to date account for only a small percentage of the inherited variation in body mass index,
In Nature 2010 volume 463 two groups have reported deletions on chromosome16p11.2 that may explain part of the 'missing heritability' in terms of , high-penetrance mutations that are rare but when present are often associated with severe obesity.
This contrasts to more common gene defects less closely associated with clinical symptoms. Bochukova (2010 ) Large rare chromosomal deletions associated with severe early onset obesity vol 463 pp 666-670 . identified copy number variants in 300 patients with severe early-onset obesity, caused by deletions involving genes including SH2Bl, known to be involved in leptin and insulin signalling. Many of the patients also suffered neurodevelopmental disorders.
Walters et al.( 2010 A new highly penetrant form of obesity due to deletions on chromosome 16p11.2 Nature vol 463 671-675 identified deletions of at least 593 kilobases in 31 patients with a previously unrecognized type of extreme obesity.

cancer cell metabolism

This is an article which has very important long term interest for Nutrition.
Good cells perform their physiological activities at the right time and place. When removed from their natural surroundings they self-destruct,called anoikis . Cancer cells: however they survive, invade other tissues and continue to grow in unfamiliar territories. Schafer et al in Nature 2009 vol 461 pp 109-113 show that cancer-inducing oncogenes may protect cells from anoikis by maintaining the cells glucose consumption. Death of normal cells remote from their normal site is caused by starvation, and strongly connects cellular metabolism to cancer.
Anoikis occurs when cells detach from the basement membrane or the extracellular matrix, both of which provide them with survival signals Originally, anoikis was thought to be .executed by apoptosis - a programmed cell death set off by several different cues, which results in cell fragmentation and elimi¬nation. But blocking apoptosis does not prevent anoikis because detached cells die anyway. Moreover, another process, autophagy - in which the cell digests some of its own components is observed in anoikic cells. If autophagy runs its full course, cells kill themselves by self-consumption but, initially autophagy may help cells to survive starvation.
Cancer cells have an unbridled capacity for proliferation and invasion. Thus cancer cels escape anoikis , or anoikis prevents cancer. Several oncogenes hinder anoikis but the mechanism is obscure.
One oncogene ERBB2 encodes the epidermal growth factor receptor , a cell surface protein that is activated in 25% of breast cancers. Schafer et al. show that ERBB2 expression rescues detached cells from energy depletion by maintaining their glucose uptake, specifically by activating the cancer-inducing P13K/AKT pathway.
Once in the cell, glucose may be metabolized through several pathways, including glycolysis, in which it is broken down to pyruvate to generate ATP, the cell's energy currency, and NADH, a mediator of ATP production. Pyruvate is routed to the mitochondria where, in the presence of oxygen, it is metabolized to produce large amounts of ATP . Although oxygen is essential for generating the maximum yield of energy from glucose breakdown, it can also fatally damage the cell by contributing to various forms of oxidative stress. Glucose helps to prevent this oxidative stress by bypassing the initial steps of glycolysis and enters the pentose phosphate pathway. This produces less ATP but generates NADPH, a powerful mediator of antioxidative reactions that protect cells from oxidative damage.
Schafer et al. note that anoikis can be prevented in normal, detached, glucose-starved.cells if they are given antioxidants' showing that it is increased oxidative stress rather than decreased glycolysis that induces rapid anoikis.

Gotttlieb et al 2009 The fat and furious Nature vol 461 p 44-5

Schafer et al 2009Antioxidant and oncogene rescue of metabolic defects caused by loss of matrix attachment Nature vol 461 109-113.