p53 and cancer.

This important review discusses this key subject of p53 and cancer aetiology.

Whibley et al l2009 p53 polymorphisms: cancer implications Nature Reviews Cancer vol 9, 95-107

The normal functioning of p53 is a potent barrier to cancer. Tumour-associated mutations in TP53, typically single nucleotide substitutions in the coding sequence, are a hallmark of most human cancers and cause dramatic defects in p53 function. By contrast, only a small fraction, if any, of the >200 naturally occurring sequence variations (single nucleotide polymorphisms, SNPs) of TP53 in human populations are expected to cause measurable perturbation of p53 function. Polymorphisms in the TP53 locus that might have cancer-related phenotypical manifestations are the subject of this Review.
Polymorphic variants of other genes in the p53 pathway, such as MDM2, which might have biological consequences either individually or in combination with p53 variants are also discussed.

prions and Alzheimers disease

Alzheimer's disease yield is associated with an abnormal build-up of amyloid-β (Aβ) peptides( 40-42 amino acids length) in the brain. Small, soluble aggregates of A β-A β oligomers - impair memory by disrupting memory-related functions of synaptic junctions between neurons. Lauren et al in Nature show that the prion protein might mediate the pathogenic effects of A-β oligomers.
The prion protein (PrP) is anchored to the cell membrane and associates with membrane microdomains called lipid rafts. It occurs in at least two conformational states. The cellular form, PrPc, is involved in maintaining the brain's white matter, and in regulating this tissue's innate immune cells, responses to oxidative stress and neuron formation. The highly pathogenic form, PrPsc, is a misfolded version of PrPc, and is resistant to enzymatic degradation. PrPsc is the main cause of a group of fatal neurodegenerative disorders called transmissible spongiforrn encephalopathies that includes Creutzfeldt-Iakob disease and mad cow disease.
A β binds to and influences the function of many cellular proteins. Lauren et al in their study conclude or suggest that Prpc itself acts as a receptor to to mediate the deleterious effects of the Aβ-42 oligomer.
Lauren et al 2009 Cellular prion mediates impairment of synaptic plasticity by amyloid- β oligomers Nature vol 457, pp 1128-1132
Cisse and Mucke 2009 A prion protein connection. Nature vol 457, pp 1090-1

Prions that cause brain disease may infect and move across the brain cells by travelling in the nano tubules and also dendrtic cells which connect these cells.
Nature 2009 prion highjackers vol 457 p 1060

Plasma phospholipase A2

This a fascinating further insight into the complexities of the atherosclerotic process. How this relates to nutrition I do not know, but the interesting thought is what happens when the essential fatty acids are reduced in the diet. Which is a further aspect of this intriguing process.
Secretory phospholipase A, (sPLA,) enzymes hydrolyse the ester bond of phospholipid molecules at the sn-2 position to produce two potentially bioactive lipids that include non-esterified fatty acids (mainly arachidonic acid) and lysophospholipids. Of the ten-member family of sPLA, enzymes, groups IIA (sPLA,-IIA), V (sPLA,-V), and X (sPLA,-X) are highly expressed in human atherosclerotic lesions in which the various groups contribute differentially to atherogenesis.
Human A2 phospholipases (PLA2s) propagate inflammation by producing arachidonic acid precursors from membrane glycerophospholipid. Classes. Two of the five major PLA2 have been suggested to be involved in the atherosclerosis process and its complications: secretory type and lipoprotein-associated.
Population studies demonstrate the independent predictive value of increased circulating secretory PLA2 (sPLA2) and lipoprotein-associated PLA2 to predict the possibility of future cardiovascular disease events. PLAs are also aetiological risk factors for plaque progression, destabilisation, and rupture.
Three sPLA, subtypes are involved in the remodelling of lipoproteins, with adverse consequences for their function. sPLA,-X and sPLA,-V modify HDL, resulting in attenuation of its ability to affect reverse-cholesterol transport. sPLA,-lla and sPLA,-V remove phospholipids from LDL, making it more susceptible to retention through binding to matrix proteoglycans in the subintimal space. Consequently LDL is liable to increased oxidation, further increasing its affinity as a substrate for lipoprotein-associated PLA,. The products of lipoprotein-associated PLA, hydrolysis of oxidised LDL, Iysophosphatidylcholine and oxidised free fatty acids, have multiple proatherogenic actions, the most important being to increase apoptosis of macrophages in the necrotic core of vulnerable plaques, which predisposes the individual to rupture and coronary or cerebral thrombosis.
Corson 2009 Phospholipase A2, inhibitors in atherosclerosis: the race is on. Lancet , vol 373, pp 608-10
Rosenson et al 2009 Effects of 1-H-indole-3-glyoxamide (A-002) on concentrations of secretory phospholipase A2 ( plasma study ):a phase 11 doble bind, randomised, placebo-controlled trial . The Lancet vol 373 pp 649-58

annatto, yellow food colouring

The orange colour used to colour foods comes from the soft flesh of seeds of the annatto tree which grows in tropical America.

food waste

The UK has plans to build more than 1,000 anaerobic digesters to turn unwanted food and farm waste into energy and fertiliser. Anaerobic digesters break down organic waste naturally into a solid that can be used as fertiliser and a gas that can be burnt to generate heat and electricity.
Jane Kennedy, the UK Environment Minister, will declare anaerobic digesters the solution to organic waste. She will also launch a task group with instructions to identify how many should be installed by other sectors, such as the water industry, to make anaerobic digestion "a major source of renewable energy".
Other countries, notably Germany, have made widespread use of anaerobic digesters, and ministers are anxious to increase the number in Britain to reduce pressure on landfill sites and to cut greenhouse gas emissions. Farms produce 90 million tonnes of waste, including manure and slurry, while a further 12 to 20 million tonnes of wasted food and food scraps go into landfill after being thrown away by households, businesses, restaurants and hotels.
The Government plan to have 1000 anaerobic digesters by 2020; currently there are 20 such fixtures. . These would make the Farm self sufficient in electricity. Any excess would pass into the national grid.
The water industry deals with 1.73 million tonnes of sewage sludge each year, which could be used in digesters.
The hope would be to provide electricity and heat for 2 million homes.
Lewls Smith Environment Reporter Times February 17th p 14.

nutrition and eye health

The role of nutritional supplementation in prevention of onset or progression of ocular disease is of interest A review by Bartlett and Eperiesi looks at those antioxidants most appropriate for inclusion in an ideal ocular nutritional supplement, suitable for those with a family history of glaucoma, cataract, or age-related macular disease, or lifestyle factors predisposing onset of these conditions, such as smoking, poor nutritional status, or high levels of sunlight exposure. It would also be suitable for those with early stages of age-related ocular disease. Those highlighted for possible inclusion were vitamins A, B, C and E, carotenoids beta-carotene, lutein, and zeaxanthin, minerals selenium and zinc, and the herb, Ginkgo biloba. Conflicting evidence is presented for vitamins A and E in prevention of ocular disease; these vitamins have roles in the production of rhodopsin and prevention of lipid peroxidation respectively. B vitamins have been linked with a reduced risk of cataract and studies have provided evidence supporting a protective role of vitamin C in cataract prevention. Beta-carotene is active in the prevention of free radical formation, but has been linked with an increased risk of lung cancer in smokers. Improvements in visual function in patients with age-related macular disease have been noted with lutein and zeaxanthin supplementation. Selenium has been linked with a reduced risk of cataract and activates the antioxidant enzyme glutathione peroxidase, protecting cell membranes from oxidative damage while zinc, although an essential component of antioxidant enzymes, has been highlighted for risk of adverse effects. As well as reducing platelet aggregation and increasing vasodilation, Gingko biloba has been linked with improvements in pre-existing field damage in some patients with normal tension glaucoma. They suggest that vitamins C and E, and lutein/zeaxanthin should be included in our theoretically ideal ocular nutritional supplement.
Bartlett H, Eperjesi F 2004, An ideal ocular nutritional supplement? Ophthalmic Physiol Opt. 2004 (4):339-49

rats

Rats are a potent concern to mankind. In Bangladesh which is a very poor country, there is a national campaign to kill rats. It is estimated that rats may eat 10 % of crops and during plagues of rats this increases. Rat reproduction increases 3-4 times when they eat bamboo blossom.(Times Friday 6 2009 p 47)
Rat catchers may each kill 30-40,000 a year, a total of some 25 million a year. .
In Britain it is estimated that there are 80 million rats.
We are asked to compost out vegetable waste, care has to be taken that rats do not gather around this source of food.

car travel decline

This is not strictly nutrition, but of peripheral relevance. Road traffic has fallen for the first time in 30 years ( Times Friday 6th January p 6). Largely due to increased fuel costs and the recession.
The 34 million vehicles in Britain travelled 3.1 billion fewer miles last year, that is 90 mile less per motorist, costing the Tax Exchequer £165 million reduced income.
Road deaths fell more than 400 to 2610/annum, but more cyclists were killed , possibly inexperienced cyclists giving up the car.

purple urine

Coloured urine can be a dilemma to diagnose. Beeturia, red urine after eating beetroot is well known and the dark urine of dehydration also.
Purple urine has been reported after patient catheterisation. It is commoner in women, alkaline urine , constipation, plastic urinary catheterisation and certain bacteria e.g. E Coli , P mirabilis.
This phenomenon can also occur in alkaline urine as a result of the degradation of indican , a metabolite of dietary tryptophan into blue indigo and red indirubin by bacteria.
The urine returns to normal colour after eradicating the bacterial growth and acidification of the urine
Mumoli and Cei 2009 a case of purple urine.QJM 102 p 147.

Childhood Obesity

The Proceedings of the Nutrition Societ, August 2008 has a very informative series of papers on Behavioural nutrition and energy balance in the young.
Obesity is increasing, 17 % of US children and adolescents exceed the 95th percentile for BMI(1), and other developed countries are facing similar problems.
Childhood obesity has multiple causes, most of them capable of explaining only one part of the problem. Population-wide sedentary lifestyles and availability of energy-dense food is an important factor, but substantial individual differences in body weight exist suggest individual responses to the 'obesogenic' environment.
One mechanism for this variation is the early expression of appetitive traits, including low responsiveness to internal satiety signals, high responsiveness to external food cues, high subjective reward experienced when eating liked foods and preferences for energy-dense foods.
Case-control studies support the existence of such among obese children compared with normal-weight children. The origins of appetitive traits are as yet uncharted, but will include both genetic and environmental influences. Parental feeding style may affect the development of appetite.
Carnell and Wardle 2008 Appetitive traits and child obesity: measurements, origins and implications for intervention. Proc. Nutrition Society vol 67 , pp 343-355
Obesity in children is difficult to treat, but it seems to be easier to treat than adult obesity. The first step in treatment is to identify effective advice relating to nutrition and physical activity. In most treatment studies the macronutrient composition of the diet is not of major importance for treatment outcome. In relation to physical activity fat-utilisation strategies have been described.
The second step includes appropriate approaches to lifestyle change. Family therapy may be an effective approach in preventing severe obesity from developing during puberty. The family, not the therapist, assumes responsibility for the changes achieved.
Flodmark and Ohlsson 2008 Childhood obesity : from nutrition to behaviour. Proc. Nutrition Society vol 67 , pp 356-362

Stress response

Stress in the sense of a disruption to the normal environs of a cell or organ or organism is a real problem. Knowledge of how the body reacts is mostly confined to hormone reaction, the flight and fight hormones etc.
There are a fascinating series of papers in Nature 5th Feb 2009 on the cellular response to stress, this will include nutrient deprivation.
In cells, protein homeostasis, which is a delicate balance between maintaining protein conformations, refolding misfolded proteins and degrading damaged proteins, is normally maintained by regulatory networks that control protein synthesis and degradation.
Molecular chaperones are key players in protein homeostasis, helping proteins to fold and preventing aggregation of misfolded proteins, which could have substantial, disease-related consequences. When environmental stress such as nutrient deprivation or oxygen shortage disrupts protein homeostasis, the cell responds. Nowhere is this process more controlled than in the endoplasmic reticulum, an extensive organelle consisting of inter connecting tubules that serves as the synthesis site for secretory and membrane proteins. Nicchitta, Korennykh et al. and Aragon et al demonstrate how that stress elicits the assembly at the endoplasmic reticulum of signalling centres that sense the accumulation of unfolded proteins.
They have looked at the emergency response at the endoplasmic reticulum.
In the unstressed cell, protein folding within the endoplasmic reticulum occurs efficiently; the unfolded protein sensor and signalling protein Irelp is inactive, and the HACl messenger RNA remains untranslated in the cytoplasm.
Under stress, protein folding is disrupted and unfolded proteins accumulate in the endoplasmic reticulum. It emerges that the binding of unfolded proteins to Irelp promotes clustering of this protein and activation of the endonuclease activity of its cytosolic domain. HAC1 mRNAs, themselves attached to multiple ribosomes, are then recruited to the activated Irelp clusters, and are processed there, allowing translation of the essential stress-response factor Hac1 p protein.
Nicchitta 2009 How to combat stress Nature vol 457 pp668-9
Korennykh et al 2009 The unfolded protein response signals through the high order assembly of Ire1 Nature vol 457, 687-693
Aragon et al 2009 Messenger RNA targeting to endoplasmic reticulum stress signalling sites Nature vol 457 pp 736-740

plasma carotenoids and health

A substantial fruit and vegetable intake have been associated with a decreased risk of various chronic medical conditions. The antioxidant properties of carotenoids, commonly found in fruits and vegetables, could be one explanation for this finding. Increased dietary carotenoid consumption and levels of individual plasma carotenoids may be associated with the decreased risk of cancer and cardio vascular disease. Levels of individual plasma carotenoids have been associated with specific risk factors for chronic medical conditions such a diet, exercise and cholesterol. Some authors suggest that total plasma carotenoids could be a marker of a diet high in fruits and vegetable. Farwell et al have examined the association between various traditional and more novel health risk factors with total plasma carotenoids in a cross-sectional sample of middle-aged and older men.

Total plasma carotenoid levels were primarily influenced by smoking, alcohol ingestion, lipid parameters and a-tocopherol. Current smoking was associated with lower levels of total plasma carotenoids, while daily alcohol ingestion, increasing plasma levels of LDL-C, HDL-C and a-tocopherol were each significantly associated with increasing levels of total plasma carotenoids.

Farwell et al 2008 The relationship between total plasma carotenoids and risk factors for chronic disease among middle aged men and older men Brit J Nutrition vol 100 , 883-889.

Body composition analysers

Childhood and adult obesity is an epidemic in the USA. It is important to have valid and reliable tools to assess growth and body composition. It is essential that we develop safe and accurate tools to assess body composition as well as readily affordable. Devices that accurately depict body fat percentage (%BF) can be used as a tool to evaluate an individual’s weight loss or gain over a period of time. Body composition analysis is important for understanding prortional changes in fat and lean mass for healthy individuals well as individuals with various health conditions. A number of devices are available on the market.
and ales of economical body composition analysers (i.e. bioe_~ trical impedance devices).
Traditionally, assessing body composition relied upon the principle of underwater weighing, which is the gold standard. Technology has improved and various new methods are available measure body composition. Dual-energy X-ray absorptiometry (DEXA) has become the preferred method for measuring body composition.
Jensky-Squires and colleagues tested the validity and reliability of the BioSpace InBody 320, Omron and Bod-eComm body composition devices in men and women ( 21-80 years) and boys and girls ( 10-17 years). They analysed percentage body fat (%BF) and compared the results with dual-energy X-ray absorptiometry (DEXA) in adults and compared the results of the InBody with underwater weighing (UW) in children. All body composition devices were correlated to DEXA except the Bod-eComm in women aged 71-80 years . In girls, the lnBody %BF was correlated with UW (r 0·79; P:S;0·010); however, a more moderate correlation
(r 0·69; P:s;O·01O) existed in boys. Bland-Altman plots indicated that all body composition devices underestimated %BF in adults (1·0-4·8 %) and overestimated %BF in children (0·3-2·3 %).
Independent t tests showed that the mean %BF assessed by the Bod-eComm in women (aged 51 -60 and 71-80 years) and in the Omron (age 18-35 years) were significantly different compared with DEXA. In men, the Omron (aged 18-35 years), and the lnBody (aged 36-50 years) were significantly different compared with DEXA (P=0·025; P=0·040 res pectively). In addition, independent t tests indicated that the InBody mean %BF in girls aged 10-17 years was significantly different from UW. Pearsori’s correlation analyses demonstrated that the Bod-eComm (men and women) and Omron (women) had significant mean differences compared with the reference criterion.
Therefore, the %BF output from these two devices should be interpreted with caution.
The interesting point that might be explored is are they all measuring the same thing?

renal ammonia excretion

Acids generated from the metabolism of excess dietary protein are excreted largely as urinary ammonium (NH4 +) produced by cells in the proximal tubule of the kidney. NH4 + is transported into the urine from collecting-duct cells through parallel movement of hydrogen ions (H+) and ammonia (NH4). Biver et al now report that not all ammonia moves by free diffusion - as thought previously - and that most of it crosses through the Rhcg protein, which functions as an ammonia channel. The
V-ATPase pump mediates H+ transport into the urine, where it recombines with NH3 to form NH4+, As for the initial NH4 + entry into these cells, an ion pump Na+ -K+ -ATPase, which can carry NH4, + place of potassium.
Rhcg is related to the rhesus (Rh) antigen protein of red blood cells.
Probably one third of ammonia crosses the membrane channel by diffusion and the other two thirds using the Rhcg mechanism.
Knepper 2008 Courier service for ammonia. Nature vol 456 p 336-7.
Biver et al 2008 A role for Rhesus factor Rhcg in renal ammonium excretion and male fertility Nature vol 456 pp 3339-343

malnutrition in Britain

A review by McKinlay discusses this very important topic of disease related malnutrition. The cost is enormous both in hospital and long term care facilities. There is aslo much malnutrition in the population at large especially the elderly.
Recognising this is a real clinical requirement both generally and specifically for each new patient.
The body mass index BMI ( weight in kg divided by Height squared in meters squared ) is a good measure. Less than 18 is associated with severe muscle and function impairment.

The British Association of Parenteral and Enteral Nutrition ( BAPA ) suggest the Malnutrition Universal Screening Test

1. The measurement of height and weight and calculation of the BMI. This will identify patients with a BMI below 20 as well as those who are obese. It is surprising that doctors have traditionally accepted the importance of measuring weight but not of correlating it against height. BMI is simply the logical extension of the most basic clinical parameter and arguably should' be a routine part of good clinical practice. The Malnutrition Universal Screening Tool also supplies a range of surrogate measures for height, although surrogate measures for weight are more problematic, particularly in the acutely ill where oedema and injuries may make any measurement difficult.
2. The patient is then asked about unintentional weight loss of 5 or 10% over the preceding three to six months.
3. Finally, patients are asked whether they have eaten anything over the past five days.
A score greater than two indicates a significant risk of malnutrition.

McKinlay. 2008. Malnutrition : the spectre at the feast. J R. College Physicians Edinburgh vol 38 317-21

Seafood toxins

Marine toxins are of interest to investigators as a consequence of the associated health risk to human populations and the accompanying socioeconomic impact Seafood poisoning in humans is associated with bacteria and viruses but also various toxins produced by micro algae, especially dinoflagellates, and transferred to humans by marine bivalve molluscs. The ensuing food poisoning can be severe and even life threatening Amongst these are toxins such as the tetrodotoxins, saxitoxins, ciguatera toxins and brevetoxins. Also the chlorosulpholipids which are structurally and stereochemically complex and which bear stereochemicaly complex , polychlorinated acyclic carbon chains and one or two O-sulphate esters.. The mechanism of their biological activity is unknown. Chlorosulpholipids are associated with membranes in the organisms from which they are isolated, but little is understood about their role within biological membranes. Nilewski et al report the synthesis of a chlorosulpholipid cytotoxin, leading to confirmation of the proposed structure and the discovery of unanticipated reactivity of polychlorinated hydrocarbons. The concise synthetic approach should enable the preparation of material in sufficient quantities to facilitate biological studies.
Nilewski et al 2009 Total synthesis of a chlorosulpholipid cytotoxin associated with sea food poisoning. Nature vol 457, 573-576

carbon sequestration in oceans and iron.

The Oceans are a possible answer to the accumulating carbon dioxide consequent upon excess burning of fossil fuels. If the algal growth could be increased then carbon dioxide take would increase. The main Ocean where this might take place is the Southern Ocean. Adding iron to the oceanic waters, both naturally as iron rich dust blown off the Crozet Islands or added artificially as is happening with the Indo-German vessel which adding 20 tonnes of iron to the water.
However as study reported in Nature suggests that the effect or benefit of such iron is less than anticipated.
Crozet rich dust may add some 270 tonnes of iron and a two to three fold increase in biological activity over an area equivalent to the area occupied by Ireland. But the deeper water are not affected to any extent. The export of carbon to the deeper levels is less than anticipated.
Maybe the type of iron used could be important.
Nature Ocean fertilization: dead in the water. vol 457, 520-1

Mechanism of gene mutation

This is a fascinating article in Nature by Hurst on genes and evolution, which during a time when Darwin’s work is being honoured is coming up with interesting results
What makes us humans unique, this must be in unique genes, where Darwinian positive selection has occurred. Genes thought to be hotspots for positive selection can be discovered by genome scans that pinpoint especially fast evolutionary change in DNA sequences. Work by Berglund et al. and Galtier et al, however, undermines the assumed connection between fast evolution and positive selection. Instead, it seems that hotspots have probably accelerated evolution by means of a biased DNA repair process, not because the changes were good for us. Indeed, many changes are probably detrimental.
We assume that mutations become common either through conferring an advantage on the organism (positive selection) or through chance (drift).

Berglund et al. report that their methods pinpoint different candidates for positive selection. Any position in a gene is occupied by one of four nucleotides, A, T, C or G, combinations of which code for amino acids - the building blocks of proteins. Curiously, the top candidates for positive selection show a great excess of nucleotide changes that were ancestrally either A or T but became G or C. Galtier et aI. find the same effect, and also show that it applies to hotspots in nonhuman primates.
If positive selection depended upon the choice of amino acids should not so consistently prefer a change of AT to Gc. Moreover, the bias, although highly localized within genes, is not unique to the protein coding parts of the gene, but is seen in the intervening non coding parts as well. Both groups conclude that the hotspot genes are not under positive selection at the protein level.
Some force is driving the transformation of AT to GC. What might the biasing force be? Changing nucleotides at synonymous sites modulates expression of a gene. But why then would the changes be highly localized within genes, and why is the bias also in non coding sequence? A simpler explanation than positive selection on either proteins or expression rate, and one that anticipated the new results, suggests a biased DNA repair process.
During the manufacture of sex cells, a cell with two copies of each of our 23 chromosomes divides to produce cells with just one set of each. During this process, chromosomes can swap DNA (recombination); this involves a break in one chromosome that exposes a single strand of the normally double-stranded DNA. The single strand then finds a complementary strand in its partner chromosome. The two strands pair up to make a new double stranded bit of DNA. The sequence of the two strands may not, however, be perfectly complementary and might break the rules of DNA pairing (G should pair with C, and A with T). Mismatch repair enzymes then correct rule violations. Imagine a C mismatched with an A. There are two choices for repair: replace C with T or replace A with G. The system is biased and more commonly replaces A with G. More generally, it favours Gs and Cs over As or Ts. The repair bias may be an evolved property to cope with a high mutation rate of C toT.
Biased gene conversion” (BGC), as the process is termed, explains a general trend towards higher rates of evolution in chromosome domains that commonly undergo recombination, and correctly predicts the high rates of recombination in the superfast hotspots. Many such sites lie towards the ends of chromosomes, where recombination is common.
Importantly, BGC can drive mutations that are deleterious. Given that BGC can force deleterious mutations to spread through a population, part of the high rate of evolution in the hotspots could be because of the subsequent spread of compensatory mutations.
Hurst 2009 A positive becomes a negative Nature vol 457 pp 54304