AKT1, mutation and cancer aetiology

John D. Carpten et al A transforming mutation in the pleckstrin homology domain of AKTl in cancer
Nature 2007, vol 448, 439-444
It is important for Nutritionists to appreciate the profound discoveries which are being made in Molecular Biology . There are so many naïve statements associating all manner of dietary excesses or deficiencies and cancer aetiology, based on epidemiological studies. To my mind these statements demean Nutrition in an increasingly sophisticated Scientific environment.
The enzyme AKTl (v-akt murine thymoma viral oncogene homologue 1) kinase is important in the most frequently proliferation and survival pathway in cancer, yet mutations of AKTl have not been reported. In the paper Carpten and his colleagues report the identification of a somatic mutation in human breast, colorectal and ovarian cancers that results in a glutamic acid to lysine substitution at amino acid 17 (E17K) in the lipid-binding pocket of AKTl. Lys17 alters the electrostatic interactions of the pocket and forms new hydrogen bonds with a phosphoinositide ligand. This mutation activates AKTl by means of pathological localization to the plasma membrane, stimulates downstream signalling, transforms cells and induces leukaemia in mice. This mechanism indicates a direct role of AKTl in human cancer, and adds to the known genetic alterations that promote oncogenesis through the phosphatidylinositol-3-OH kinase/AKT pathway.

obesity and inflammatory proceses.

In the May 21st 2007, Nature vol 447, pp 525-7 Kendall Powell gives a chatty account of fat metabolism
It is worth reading
One thing that did occur to me was a result of the reminder that adipose tissue produces TNFά, and cytokine interleukin both indicators of low grade inflammatory processes. In addition macrophages invade fat tissue, macrophages are associated with an inflammatory response.
In this article coherent arguments are made for the inflammatory response being part of the complications of obesity.
I worked as a Gastroenterologist. For most of my working life duodenal ulcers were seen to be a consequence of excess gastric acid secretion and that stress was the basis of this. Then it was shown that the causal agent was infection of the gastric and duodenal mucosa by Helicobacter pylorides. Everyone until then everyone assumed that no bacteria could survive in the hostile environs of the stomach. Since it was possible to eradicate the Helicobacter by antibiotics duodenal ulceration has ceased to be a problem.
What if obesity is the consequence of an infection . Not necessarily primarily in the adipose tissue . It is easy to dismay such a silly idea out of hand but remember the duodenal ulcer story and the inflammatory process was thought to be due to the acid.

neural tube defects and folic acid in flour

In an article in New Engl J of Med 2007, 357, 135-42 it was an article
Neural tube defects and fortification of flour with folic acid.
In 1998 the Canadian Government decreed that cereal products should be fortified with folic acid.
Following which there has been a 46% reduction in all neural tube defects , spina bifida reduced by 46%, and anencephaly by 38%.
Canadian Millers add 0.15 mg of folic acid to each 100 g flour and 0.25mg to pasta.
This gives an extra 150ųg per day.
The USA also fortified cereal and pasta flour in 1998 but the overall decrease is 28%

aetiology of childhood obesity

Childhood and adult obesity is a real problem. There are so many bottoms around which require two seats to fit their shape.
There is a brilliant review on the aetiology of childhood obesity in the Nutrition Research Review, 2007, 20, 29-45 by KL Procter..
Of the models suggested to account for this increase the one chosen is an ecological one which discusses individual, social and cultural and physical environment.
A genetic reason as a prime cause is dismissed out of hand. The environment must be the prime contributor regardless of the genetic predisposition.
The factors discussed are
Physical activity children exercise less and watch television more
Diet , this is not clear cut as more food is not necessarily being eaten
Eating patterns , snacking and missing main meals. Meals are less defined and grazing is the norm.
Diet composition again a complex topic.
Consumption of unhealthy foods fast foods and soft drinks.
Obesogenic environment
Foetal environment birth weight, maternal smoking, is associated with childhood obesity
Infant environment regarded by some as critical
Family structure
School environment
Neighbourhood environment
And others, the food industry, TV adverts and general attitudes and policies.

Food and water deprivation in animals before transport

James P. Hogan et al review The physiological and metabolic impacts on sheep and cattle of feed and water deprivation before and during transport in Nutrition Research Reviews (2007). 20. 17-28
In traditional livestock farming systems, animals were driven across land on foot, receiving food and water en route, but nowadays they are nearly always transported by road or rail. This is usually from a farm to a market, or abattoir, or from a farm specialised in breeding stock to one reserved for fattening. Such journeys can cover thousands of km and take several days. Food and water provision is nearly always suspended during transportation and it is also common practice to deny sheep and cattle access to feed and water for several hours before transport. The practice of feed and water deprivation before transport was first called a 'curfew by Wythes. This is distinct from undernutrition (a prolonged inadequate supply of nutrients to sustain good health and, in the case of immature or underweight animals, growth potential') and malnutrition ('a deficit, imbalance or excess of nutrients with consequential adverse effects on health and growth potential')".
The feed and water deprivation before transport has two main aims. The first is to reduce digesta load in the gastrointestinal tract in an attempt to reduce fouling of other animals, the trucks and roads over which they pass, and carcass contamination. The second, in situations where animals arc sold by weight, is to permit a more accurate prediction of carcass weight.
The short-term interruption to nutrient supply associated with feed and water deprivation will in particular affect functioning of the rumen and the rest of the digestive tract, tissue homeostasis and control of enteropathogenic bacteria by rumen microbes. Effects on metabolism in animal muscle will also influence meat quality. The process of gathering animals on a farm, holding them in yards, often with unfamiliar companions, loading them aboard unfamiliar vehicles and then transporting them, subjects the animals to multiple stressors. These are manifested by substantial increases in the circulating levels of corticosteroids, notably cortisol, and the release of catecholamines such as adrenaline
Animals need to recover quickly after feed and water deprivation in order to maintain the efficiency of production or ensure meat quality.
There is species and individual responses to feed and water deprivation . Sheep do better than cattle. Young animals, deer in winter and stock exposed to feed and water deprivation in the morning.

Bone Health, polyphenols and caffeine in tea

In Nutrition Research Review 2007 , 20, 89-105, T. P. Dew.et al write on Bone mineral density, polyphenols and caffeine: a reassessment
In an ageing society, the maintenance of good bone health with age is important. In osteoporosis, bone becomes increasingly porous, resulting in both greater chance and severity of bone fracture at the hip. spine, forearm and shoulder. Bone fractures result in reduced mobility, discomfort and a higher risk of early mortality. Osteoporosis can cost the UK over £1-7 billion for the treatment of hip fracture.
Elderly women are at risk from osteoporosis, because they can lose between 10 and 15 % of their bone every decade after the menopause. Women lend to have lower peak bone mass than men, and that levels of oestrogen (a hormone with a positive effect on bone health) are decreased during and after menopause and tend to live longer than men.
Bone tissue is in a constant state of flux. The skeleton has obvious mechanical roles and is also a Calcium depository for the rest of the body, with calcium being removed and replaced as required. The state of bone flux within an individual can be described in terms of bone mineral density. Bone metabolism is controlled by a variety of growth hormones, sex steroid hormones (such as oestrogens), thyroxine. corticosteroids and insulin. Three hormones play vital roles, 1.25-dihydroxycholecalciferol. parathyroid hormone and calcitonin. As well as affecting dietary calcium adsorption efficiencies, these hormones also influence the three cell types relevant to bone formation and metabolism osteoblasts (hone formation), osteocytes (bone maintenance) and osteoclasts (bone resorption). The balance between the formation and resorption of bone tissue is affected by genetic and environmental (for example, diet and lifestyle) factors.
Several studies have shown benefit from drinking tea and bone mineral density and fracture risk. This could be due to the fluoride and polyphenol components of tea. Caffeine consumption has been sen as a potential risk factor for low bone mass density and high fracture risk.
Fruit and vegetable intake which includes increased polyphenols intake may also contribute positively to bone health.
In this review the evidence surrounding the function(s) of poly phenol-rich foods in bone health is examined, along with more recent studies challenging the relevance of caffeine consumption to in vivo Ca balance. Plant foods rich in polyphenols such as tea. fruit and vegetables, as significant factors in a healthy diet and lifestyle, may have positive rules in bone health, and the negative role of caffeine may have been overestimated.

coronary heart disease predictor for UK, QRISK

It is useful to have a algorithm which enables a prediction of whether an individual is a t risk of coronary heart disease. The middle aged rotund plethoric faced cigarette smoking bloke is a cert for a coronary. But what about the others.
Hippisley-Cox and her colleagues in BMJ , 2007 Derivation: prospective open cohort study and validation of QRISK, a new cardiovascular disease score for he United Kingdom
Risk equations derive from the Framingham study in the USA. However this algorithm does not include social deprivation.
The QRISK score was based on 10 million patients in 529 general practices.
Risk factors wee
Age
Sex
Smoking status
Systolic blood pressure
Ratio of total serum cholesterol to high density lipoprotein
Body mass index
Family history of coronary heart disease in first degree relatives
Area measure of deprivation
Existing treatment with antihypertensive drugs.
Back to our middle aged rotund plethoric faced cigarette smoking bloke, the football terraces are full of these marvellous men.

A interesting coincidence , diet induced longevity and gastric cancer

In a blog published earlier today I wrote about PHA-4 and SKN-1 which extend survival after dietary restriction in these roundworms. These two proteins are transcription factors, which regulate the expression of many genes. They may also trigger hormones that coordinate physiological responses to dietary restriction.
The PHA-4 protein, was originally described for its role in the development of the pharynx in worm embryos, and is a member of the forkhead family of transcription factors, and is very similar to mammalian FOXA proteins. In mammals, FOXA proteins have developmental roles, and regulate glucose metabolism later in life. The requirement for PHA-4 is very specific.
In a paper by JiHun Kim et al they mention that increased phosphorylation of FOXO1A, a FOXO transcription factor, has been implicated in several human They show that in gastric carcinomas, the expression of pFOXO1A was observed in 84.6% of 272 cases examined, The expression of pFOXO1A is a frequent and early event in gastric tumorigenesis and that there is a significant correlation between pFOXO1A and better prognosis.
Diet induced longevity and gastric cancer, association or fluke?
Ji Hun Kim et al , 2007, Constitutive phosphorylation of the FOXO1A transcription factor as a prognostic variable in gastric cancer. Modern Pathology (2007) 20, 835–842;
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prions, structure, infectivity and amyloid formation.

There is a commentary and paper in the Nature of 31st of May 2007 on prion of great interest..
Prions are proteins which form insoluble amyloid structures associated with neurodegenerative disorders in mammals. The intriguing place of prions is that they are proteins whose conformation and ability for amyloid formation is self-seeding) and thereby infectious. The conformatiorially converted prion state can be transmitted from cell to cell within or, in some cases, between organisms. Prions, too, can be either deadly or beneficial.
The ability of proteins to form P-.sheet-rich amvloids is associated not only with disease, but also with diverse normal biological functions, including cell adhesion , skin pigmentation, adaptation to environmental stresses and perhaps even long-term neuronal memory.
The first identified prion protein identified was PrP, whose conversion to the prion conformcr (PrPsc) is associated with .several fatal neuro-degenerative diseases. More recently, several prions in yeast and other fungi have been identified that are unrelated to PrP or one another-; some of these may have beneficial effects. The most well-studied is Sup35 , a translation-termination factor whose conversion to the prion state reduces its activity. This increases the read-through of stop codons, revealing hidden genetic variation and creating complex new phenotypes in a single step.
Sup35 prions show two of the properties of prion biology that were initially identified for mammalian PrP. First, both Sup35 and PrP can adopt not just one prion conformation, but several related yet structurally distinct conformations (known as strain.or variants). Each conformation self-perpetuates and gives a distinct biological phenotype. Second, the transmission of the prion state between proteins of different species is limited by a species barrier that can occasionally be crossed. In both yeast and mammals the ability to establish and overcome species barriers is, in some unknown way, related to the ability of prions to form distinct Strains.
The carboxy-terminal domain of Sup35 encodes the translation-termination function Whether Sup35 exists in either a prion or a non-prion state is controlled by the interplay of two other domains11”. The middle region (M) has a strong solubilising activity and is very rich in charged residues. The amino (N) terminus is readily forms the amyloid conformation and is of unusually low sequen ce complexity, composed primarily of glutamine, asparagine, glycine and tyrosine residues .
In its non-prion state NM is compact, but plastic , rapidly fluctuating through diverse conformations. The structure of NM in its prion state is of interest. It may be that two discrete regions of the N domain are in self-contact within NM; the region between them is sequestered from intermolecular contacts, whereas elements proximal and distal to the contacts are not part of the amyloid core. Cross-linking NM molecules at one of the intermolecular contacts, but not elsewhere, accelerates nucleation. Other evidence suggests that most residues of the N domain are in jntermolecular contact, stacking in-register on themselves.
Single substitution mutations in certain regions of the N terminus can have profound effects on many aspects of prion biology: they can inhibit replication, bias prion conversion towards the production of distinct strains, and increase or decrease the ability of prions to cross species barriers. Which suggests that precise features of amino acid sequence have critical roles in Sup35 prion biology. Remarkably, however, scrambling the sequence of X docs not prevent prion formation. NM prion formation maybe mainly dependent on the amino acid composition and largely independent of primary sequence.
The authors of this remarkable paper show that only a small subset of ScNM peptides capture the ScNM protein from solution. And this is sufficient to convert soluble proteins to the prion state.
The same sequence elements are responsible for the species seeding activity and formation of distinct prion strains.
Surewicz W 2007 discriminating taste of prions Nature 447, pp 541-2
Tesier PM and Lindquist S 2007 Prion recognition elements govern nucleation, strain recognition and species barrier 447, 556-561

diet and longevity

Dietary restriction, which means a reduction of food intake by 40-60% without causing malnutrition can benefit health and extend lifespan of yeast, worms, flies, rodents and perhaps even primates. In the May 31st copy of Nature two papers important insights are given for the mechanism.
After dietary restriction, the small roundworm Caenorhabditis elegans. livses 20-50% longer than their normally fed counterparts. The papers give a role for a pair of evolutionary conserved proteins PHA-4 and SKN-1 which extend survival after dietary restriction in these roundworms. These two proteins are transcription factors, which regulate the expression of many genes. They may also trigger hormones that coordinate physiological responses to dietary restriction.
The PHA-4 protein, was originally described for its role in the development of the pharynx in worm embryos, and is a member of the forkhead family of transcription factors, and is very similar to mammalian FOXA proteins. In mammals, FOXA proteins have developmental roles, and regulate glucose metabolism later in life. The requirement for PHA-4 is very specific.
Panowski and his colleagues also found that a conserved nuclear factor called SMK-1 is required for longevity In addition, dietary restriction triggered the expression of several genes encoding superoxide-dismutase enzymes, which protect animals from oxidative damage — a cause of ageing.
In adult worms, PHA-4 is found in the intestine, gonad and a handful of neurons. Nevertheless, it influences survival of the whole organism, probably by controlling the production of hormones in some of these tissues, which then signal throughout the body.
Mammalian FOXA regulates glucagons which is also released during fasting in higher organisms. Like PHA-4, SKN-1 also functions early in embryonic development, where it specifies the formation of the intestine and related tissues'. Later in life, it helps to protect animals from oxidative stress1". This transcription factor is related to NRF2 transcription factors, which perform similar functions in mammals' .SKN-1 is also involved in the food deprivation longevity interaction SKN-1 from neurons is required for the effect on longevity, not the similar form in the intestine.
Dietary restriction increases mitochondial activity, this may be promoted through SKN-1 activity.
This is such exciting news and merits carefully follow up.
Antebi A, 2007, When less is more Nature 447, 536-7

Panowski SH et al 2007, PHA-4/Foxa mediates diet restriction –induced longevity of C elegans . Nature, 447, 550-555

Bishop NA and Guarente L t al 2007 , Two neurons mediate diet restriction – induced
longevity in C-elegan, Nature 447, 545- 549

Exercise and well being

Exercised and health

Physical exercise is good for us, and is said to decrease the risk of coronary heart disease, type 2 diabetes and cancer of the colon. It is curious that in any list of reduced risk whatever the pre disposing element is , cancer of the colon is on the list.
Walking even at 3 miles / hour increases respiratory and cardiac measures and blood glucose concentrations. Most of all there is an enhanced feeling of well being.
Everyone who has had 3-4 year old children knows that it is essential to give them a run about to burn off some of the exuberance of being 3-4.
There is no reason to believe that this requirement becomes unnecessary as one grows older.
30 minutes of moderate exercise on most days of the week cannot be other than good.
Walking is such an exercise, gardening and cycling are also good as is swimming
Ogilvie D et al 2007, Interventions to promote walking : systemic review BMJ , 334, 1204-7
Andersen LB 2007 Physical activity and health BMJ 334, 1173.

Soluble fibres and cholesterol lowering

In the Brit Journal of Nutrition ( 2007, 97, 1049-1050 ) there is an interesting review by Poppitt on the cholesterol lowering properties of soluble oat fibre and β-glucans. The potential for a reduction in cardiovascular risk with a high intake of dietary fibre was originally suggested by Ancel Keys and colleagues in the Journal of Nutrition in 1960. An intake of whole; grains may decrease the incidence of fatal and nonfatal coronary heart disease, which may be affected through a hypocbolesterolaemic action effect of the viscous soluble fibre component of whole-grain foods such as oat and barley cereals rather than the insoluble fibre component of whole-grain foods such as wheat and rice. However, not all published studies of high soluble fibre oat and barley products show cholesterol-lowering effects.
Soluble fibre is found in many legumes (including peas, beans), some fruits (including apples, pears) and the plaintain seed husk psyllium (Plantago psyliutm). However it is the β-glucan soluble fibre of cereals, with linear unbranched polysaccharides of linked β(1→3)-(1→4)D glucopyranose units, which appears to be important in the cholesterol-lowering properties of viscous soluble fibre.
It is differences in factors such as solubility, viscosity and molecular weight of β-glucans which may be the reason for conflicting outcomes. The mechanisms by -which β-glucan may act includes increased intestinal viscosity and/or bile acid binding which in turn may (i) decrease reabsorption of bile acids and drive bile acid synthesis from hepatic cholesterol, hence depleting the body’s cholesterol pool and/or (ii) decrease absorption of intestinal cholesterol. Another mechanism could be that bile acids entering the colon are sequestrated by bacteria, of which there increased activity when the colon is exposed to fermentable fibre.
There have been mixed results form trials with of β glucans. The differences may be due to unfavourable structural changes during commercial purification, (depolymcrisation of the linear structure, decreasing molecular weight and viscosity ). Mild extraction conditions may not deactivate endogenous 6-glucanases and hence increase depolymerisation: cooking processes may decrease peak MW. and freezing and storage may reduce the extractability of β-glucan in the intestine.
In 1997 the US Food and Drug Administration (FDA) concluded that B-glucan soluble fibre (3g/d) from oat bran and rolled oats or from whole-grain barley and dry-milled barley products are efficacious in lowering total and LDL-cholesterol concentrations.
Poppitt S 2007 Soluble oat and barley β-glucan enriched products: can we predict cholesterol lowering effects
Gelissen and Eastwood 1995 Taurocholic acid adsorption during non-starch polysaccharide fermentation : an in vitro study 74, 221-228

worm infestation and anaemia

In poor countries , some 1.2 billion people are infected by roundworms, more than 700 million by hookworm or whipworm. This high prevalence has much to do with the disposal of faecal material.
The burden on physical and cognitive development in children is substantial. Anaemia is also a problem. 15-25% of anaemia in East Africa is a consequence of hookworm infection. The species of worm affects the risk of anaemia, depending on whether or not the worm induces inflammation in the intestinal mucosa.
Routine deworming programmes are important in increasing haemoglobin concentrations.
In addition to eradicating the infestation it is advisable to replenish the depleted iron stores.
.Awasthi S and Bundy D 2007, Intestinal nematode infection and anaemia in developing countries. BMJ, 334, 1065-6
Gulani A et al 2007 Effect of administration of intestinal anthelmintic drugs on haemoglobin: a systemic review of randomised controlled trials 334, 1095-7

Food fortification and micro nutrients

Food fortification
In the British Journal of Nutrition there is a commentary and an article on the benefits of this in Ireland.
Micronutrient malnutrition is a prime cause of ill health, iron , zinc and vitamin A and D , vitamin C and Vitamin B2 being prime examples.
Obviously a sufficient healthy diet is the answer which is not always seemingly possible. An alternative is food fortification. This ensures automatic delivery to the population. The poor are the most likely to benefit from this programme. It is sad to say often it is the less intellectually endowed who are the most at risk. This process has been applied for over 80 years.
The fortified food must be available to all parts of the population. , rich and poor
Where micro nutrient deficiency is extreme fortification is no substitute for the prime supplement in higher dosage
Supplements are less good when infection increases the need for the supplement.
The supplementation must be feasible in the local commonly eaten foods, e.g. flour, breakfast cereals and margarines
Supplementation may be given in foods eaten by particularly at risk populations e.g. children and the elderly.
Manufacturers might add supplements as part of the processing of the foods, within government regulatory limits.
Fortification is regarded as voluntary when the food industry freely chooses to supplement a micronutrient
It is important that the Government supervises the supplementation.
The range of foods which are allowed to be fortified may be quite narrow.
The stability of the micronutrient in that food during cooking is an important consideration
In Ireland of 3000 foods surveyed, 1.9% were fortified, mainly breakfast cereals. Fortification makes a significant contribution to the intakes of micronutrients for riboflavin, folate, vitamin D and iron. Calcium and vitamin D are worthy of consideration.
Rosenberg I 2007, Further evidence that food fortification improves micronutrient status Brit Journal of Nutrition 97, 1051-1052
Hannon EM et al 2007, The impact of voluntary fortification of foods on micronutrient intakes in Irish adults 97, 1177-1186

In the BMJ 2007 vol 334, pp 1252-3 the advisability of supplementing folic acid to foods is considered and whether this should be mandatory.
Wald NJ and Oakley GP argue for fortification. The less well off have the most to gain. The reduction in neural tube defects justifies the case. Supplementation must precede conception. There is a possible debatable reduction in cardiovascular disease and reducing the rate of cognitive decline with age. Maybe reduce the incidence of colon cancer . There is the threat of undiagnosed B12 deficiency and neurological consequences. This is unlikely at the dosages used. Synthetic folic acid is more biologically available than natural folic acid and is stable during cooking.
Hubner and his colleagues disagree. The metabolism and action of synthetic folic acid may not be similar to natural folic acid. They refute the protective effects of synthetic folic acid and suggest that the answer is natural folic acid.
They claim that there is an increased rather than a decreased risk of cancer with supplementation. The supplement promoting the growth of premalignant lesions and facilitating their conversion to a malignant process.
Which indicates that improving food intake is best and that governments should concentrate on nutrition

Forbes theory and body fat and fat free inter-relationship.

There is great attachment to biological modelling. When it works it is great but many have fallen by the way side
Hall in Brit J of Nutrition 2007, 97, 1059-63 ( Body fat and free fat mass inter-relationships :Forbes theory revisited.

Twenty years ago Forbes suggested that body fat mass and fat free mass are in a sense companions and a change in one induces a change in the other and in the same direction. That there is an empirical, non-linear relationship between Free Fat Mass and body Fat Mass using cross-sectional body composition data and that longitudinal changes of body composition were described by movement along the cross-sectional curve
From this hypothesis Forbes expressed a mathematical expression for the Free Fat Mass proportion of body weight change as a function of the initial body Fat Mass.. Forbes's mathematical expression is strictly valid only for infinitesimal weight changes.
Hall has looked at this to account for macroscopic weight changes. The new equation predicts that the composition of weight change depends on both the direction and magnitude of the weight change in addition to the initial body fat mass.
The new equation was compared with experimental data from underfeeding and overfeeding in humans.
Hall also discusses the relationship between Forbes's theory and an alternative representation of body composition change that assumes the existence of an energy partitioning parameter, called the P-ratio The P-ratio defines the fraction of an energy imbalance accounted for by changes of the bodv's protein reserves. The P-ratio depends on the initial body composition s well as the direction and magnitude of weight change.

diet surveys, under reporting,dietary record and obesity

The popular use of epidemiology in nutrition requires that the tools used are accurate. If conclusions are drawn for associations between dietary intake and other variables the whole study is flawed when the results are incorrect.
Estimating under-reporting of energy intake in dietary surveys using an individualised method
Rennie et al British Journal of Nutrition , 2007, 97, 1169-76

This study compares a method of estimating under reporting using individualised estimates of energy requirements, against the Goldberg cut-off method in measuring under reporting of energy intake in the 2000 National Diet and Nutrition Survey and against doubly labelled water measures of Total Energy Expenditure in the National Diet and Nutrition Survey feasibility study.
Assessments of diet in epidemiological studies are usually based on self-report methods but the validity of these methods is dependent on the accuracy with which participants record their dietary intake. The Under-reporting of energy intake by self-reported dietary methods is well recognised. The methods used to estimate under reporting in population-based studies commonly assume a sedentary lifestyle.
This study in a population aged 19-64 years compares estimated under reporting using individualised estimates of energy requirements with a population cut-off based on minimum energy needs. Physical activity diaries and 7d weighed dietary records were completed concurrently. Mean daily energy intake was calculated from the dietary records.
Reported physical activity was used to define each subject's activity level, and then to calculate estimated energy requirements from published equations. The doubly-label led water) method provides an accurate measure of total energy expenditure
Most commonly, reported dietary intake is expressed as a multiple of BMR estimated from equations and a cut-off applied, below which subjects arc identified as low-energy reporters (Goldberg et al . This is usually applied to individuals, and the Goldberg cut-off technique was devised primarily to define under reporting under reporting in groups level. It is excellent for under reporting in sedentary subjects, but less useful in subjects with higher energy expenditures. This method introduces systematic bias in a mixed population
By the individual method under reporting was approximately 27 % of energy needs in men and 29% in women, with 75% of men and 77% of women classified as under-reporters. Using the population method 80 and 88% were classified as under-reporters respectively. When subjects who reported their eating being affected by dieting or illness during dietary recording were excluded, under reporting was 25 % of energy needs in both sexes. As one would expect under reporting was higher in overweight and obese men and women compared with their lean counterparts Under reporting of energy intake must be considered in dietary surveys.

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DNA replication and repairs

The role of some nutrients in metabolism is explained by their anti-oxidant influence on the molecular biological framework of the cell. This very useful series of reviews
In Nature 2007, vol 447, pp 923-958
give an insight into the systems which antioxidants might be protecting. A really good read.

Replication and protection of telomeres
R.E. Verdun SJ.Karlseder p 925-931
The ends of chromosomes need special protection against cellular processes that alter their genetic content It is essential to protect the chromosome ends to prevent triggering of the DNA-damage repair machinery and enzymatic attack.. These processes include digestion by enzymes, inappropriate repair by the DNA-damage repair machinery and the failure of DNA polymerases to replicate DNA strands completely. Protection is provided by telomeres. Telomeres are tightly regulated complexes consisting of repetitive G-rich DNA and specialized proteins Telomeres not only conceal linear chromosome ends from detection and inappropriate repair but also provide a buffer to counteract replication-associated shortening They are highly regulated and specialized and their structure and length contribute to chromosomes integrity .The review discusses how telomeres interact and cooperate with the DNA replication and DNA-damage repair machineries.

Expandable DNA repeats and human disease
S. M Mirkin p 932-940
Nearly 30 hereditary disorders in humans result from an increase in the number of copies of simple repeats in genomic DNA. These DNA repeats seem to be predisposed to such expansion because they have unusual structural features, which disrupt the cellular replication, repair and recombination machineries which affects gene coding or expression and leads to disease. The underlying disruption is that repeat-containing regions can form hairpins and other unusual structures when the DNA duplex separates. Repeat-associated diseases develop not only in response to the structural characteristics of repetitive DNA but also to those of the corresponding RNA. Many of these debilitating diseases result from repeat expansions in the non-coding regions of their resident genes.
Base-excision repair of oxidative DNA damage
S. S. David. V L. O’Shea & S. Kundu p 941-950
The specific pairing of DNA bases is crucial for the maintenance of genetic integrity. Bases are susceptible to oxidation by environmental agents and endogenous products, which modify the chemical structure and therefore the base-pairing properties of DNA
Base-excision repair has an important role in preventing mutations associated with a common product of oxidative damage to DNA, 8-oxoguani’ne. Recent structural studies have shown that 8-oxoguanine DNA glycosylases use an intricate series of steps to locate and excise 8-oxoguanine lesions efficiently against a high background of undamaged bases. The importance of preventing mutations associated with 8-oxoguanine is shown by a direct association between defects in the DNA glycosylase MUTYH and colorectal cancer. The properties of other guanine oxidation products and the associated DNA glycosylases that remove them are now also being revealed.

Chromatin dynamics and the preservation of genetic information
J A. Downs, M C. Nussenzweig and A Nussenzweig p 951-958
The genome is frequently damaged by double-strand breaks in the DNA. Changes in the cellular response to double-strand breaks are an important cause of cancer and other age-related pathologies. It is important to understand the enzymatic mechanisms involved in recognizing, signalling and repairing double-strand breaks. Chromatin has an important role in initiating, propagating and terminating this cellular response to DNA damage.
Genetic material in cells is organized into chromatin, which consists of DNA in association with histone proteins . This packaging makes damaged sites in the DNA relatively inaccessible to the repair machinery. The density of chromatin is reduced in the region of double-strand breaks, enabling access of DNA-damage sensor proteins to the lesion and initiation of repair. Much is known about how chromatin is ‘remodelled’ during gene transcription, and it is becoming evident that some of the same machinery is involved in the response to DNA damage.

homocysteine, folic acid supplements and stroke prevention

The role of raised total plasma homocysteine concentrations and cardiovascular disease is not proving to be as clear cut as originally hoped. Whilst raised total plasma homocysteine concentrations are associated with cardiovascular disease in observational studies, clinical trials have not realised these expectations, raising the possibility that raised total plasma homocysteine concentrations are innocent bystanders.
Several large trials using folic acid to lower raised total plasma homocysteine concentrations have failed to improve cardiovascular disease and when folic acid is added to vitamin B supplements may even accelerate risks.
The Lancet ( June 2nd 2007 volume 369, )reports a meta analysis study and a comment on the role of raised total plasma homocysteine concentrations, folic acid supplementation and stroke incidence. Wang and colleagues have undertaken a meta analysis of the various trials and found a modest benefit from the use of folic acid supplements. The comment is somewhat less enthusiastic pointing out the complexity of such studies which can be complicated by the addition of folic acid to food.
Whatever the final decision for the use of folic acid and the reduction of raised total plasma homocysteine concentrations and benefits for cardio vascular disease it may not prove to be as great a benefit as originally hoped for.
Carlsson 2007, Lowering homocysteine for stroke prevention Lancet vol 369, pp1841-2
Wang et al 2007 Efficacy of folic acid supplementation in stroke prevention: a meta analysis Lancet vol 369, pp 1876-82

bisphosphonates and postmenopausal osteoporosis

This is strictly not nutrition but the concepts are very relevant to nutrition and important slowly evolving disease conditions.
Black et al looked at the use of Once yearly infusions of zoledronic acid for the treatment of postmenopansal osteoporosis. N Engl Med. 2007:356:1809-22
Oral bisphosphonates help prevent fractures in postmenopausal women, but they can be inconvenient to take and many women stop their treatment. These authors wanted to test whether a more convenient yearly infusion of intravenous zoledronic acid would also reduce the risk of fractures.
7765 postmenopausal women with osteoporosis took part in a randomised, double blind trial, sponsored by the manufacturers of zoledronic acid. Participants were given three infusions of zoledronic acid (5 mg) or a placebo at yearly intervals. They were followed up for 12 months after their last infusion. The authors looked for vertebral fractures in yearly spinal radiographs. Other fractures, including hip, were reported by participants and confirmed by radiographs. The authors monitored participants bone mineral density using dual energy x ray absorptiometry and used serum markers to monitor bone turnover.
Zoledronic acid is a third-generation bisphosphonate. .Analogues of pyrophosphate. the bisphosphonates bind to calcium hvdroxyapatite in the skeleton blocking calcium release. They inhibit osteoclast formation and osteoblast proliferation and induce osteoclast apoptosis. These agents also block skeletal calcium release induced by various factors released by tumours Both zoledronic acid and pamidronatc have been shown to have direct anti tumour effects in vitro, Zoledronic acid induces cell apoptosis and inhibits proliferation in human breast, prostate. and myeloma cell lines. ( Dunham D Journal of Pharmacy Society of Wisconsin Jan/Feb 2003, - 9-13)
3.3% (92/2822) of the women given zoledronic acid had a vertebral fracture, a reduction of 70% compared with the 10.9% (310/2853) of those given placebo Zoledronic acid also significantly reduced the risk of hip fracture (1.4% v 2.5%, ), all non-vertebral fractures, all clinical fractures, and clinical vertebral fractures. It also significantly increased women’s bone mineral density at the hip, lumbar spine, and femoral neck compared with placebo (by 6%, 6.7%, and 5.1%) and reduced bone turnover.
The down side is that an infusion of zoledronic acid was associated with a higher incidence of fever, myalgia, flu-like symptoms, headache, and arthralgia. It was also associated with a higher risk of serious atrial fibrillation (5% v 1.3%,), but no long term renal toxicity. One woman in each group developed osteonecrosis of the jaw, a rare side effect of intravenous bisphosphonates given in high doses to patients with cancer.
A single yearly infusion of 5 mg zoledronic acid helped prevent important osteoporotic fractures in this vulnerable population of postmenopausal women. The excess of atrial fibrillation is a worry and needs further investigation. Some women might find a yearly infusion easier and more convenient than regular oral drugs, and it’s possible the two routes are equally effective.
Reported in the BMJ 7th July 2007 p 36
It seems extraordinary that an annual infusion at a dose of 5 mg can have such a sustained effect.

lipid profile, obesity and bone mineral density

Osteoporosis is a major public health problem through its association with age-related fractures. Bone mineral density (BMD) is an important determinant of fracture risk, with an approximate doubling of fracture risk for every 1 SD reduction in BMD. Low bone mineral density is also associated with an increased risk of cardiovascular mortality in postmenopausal women, and several drugs, the statins, hormone replacement therapy and bisphosphonates alter bone density and lipid synthesis.
Furthermore osteoblasts and adipocytes share a common progenitor from stromal cells in bone marrow. This has led investigators to study the relationship between cholesterol concentration and bone mass, and to suggest a relationship between hyperlipidaemia and BMD as a link between atherosclerosis and osteoporosis.
E.M. Dennison et al in their paper Lipid profile, obesity and bone mineral density: the Hertfordshire Cohort Study, Q.J.Med 2007, 100, 297-303 have looked at this possible association in a population of 1000 men and women living in Hertfordshire. This population has already provided a wealth of information thanks to detailed information at birth allowing studies on birth weight and health events in later life.
The new study showed was that people with high triglyceride concentrations had better bones, and at least part of the explanation for this was that people with higher triglyceride concentrations tended to be 'fatter', which is apparently good for bones for many reasons. By contrast, people with high concentrations of HDL cholesterol, tended to have thinner bones. The reason for this is not clear, but it would appear that in in this group, people with high concentrations of HDL cholesterol tended to be slimmer, so this may be important.

Serum cholesterol and stanols

Stanol containing margarines and yogurt drinks are an attractive method to reduce the serum cholesterol. Apparently physiological. A Canadian concern is whether or not one is replacing one sterol for another in the blood and hence atheromatous plaques
M Kratz, et al in the European Journal of Clinical Nutrition (2007) 61, 896–905; found similar serum plant sterol responses of human subjects heterozygous for a mutation causing sitosterolemia and controls to diets enriched in plant sterols or stanols
They investigated the serum phytosterol responses of heterozygous relatives of sitosterolemia patients to diets enriched in phytosterols or stanols in a randomized double-blind crossover design.Eight heterozygous and 13 control subjects were recruited. One heterozygote and three controls dropped out.Seven heterozygotes and 10 controls received daily portions of margarine containing 2 g of plant sterols, 2 g of stanols or a control margarine for 6 weeks each in a randomized order. These phases were intercepted by wash-out periods of 6 weeks each.
Compared to the control period, serum phytosterol concentrations increased overall by more than 20% when subjects consumed the plant sterol margarine , with no significant difference between heterozygotes and controls , but decreased when subjects consumed the stanol-enriched margarine , again to a similar extent in heterozygotes and controls . The lowest total serum concentrations of cholesterol and phytosterols were seen after the diet enriched in stanols. Serum stanol concentrations increased on this diet, but on a very low level and never exceeded 0.05% of serum cholesterol levels in any subject.
They concluded that serum phytosterol concentrations increased only moderately in heterozygotes consuming a diet enriched in phytosterols, indicating that they retained considerable capacity to excrete phytosterols even at higher intakes.
Which is good news for stanols.
All I know practically is that my wife and I have increased serum cholesterol concentrations and took stanol containing yogurt for 6 months and no change was recordable.
Maybe a one off but very specific to us.