BAR and Cancer —

This is an important paper indicating the molecular biology of cancer of the breast.

The amino (N) terminus of BRCA 1 has a RING domain that interacts with ubiquitin-conjugating enzymes and is required for its ubiquitin ligase activity. Ligase enzymes catalyse the joining together of molecules of two substances and with a breaking of a diphopsatebond in a nucleoside triphosphate. They used to be called synthetase.

Many disease-causing mutations are found within this region, and loss of the ligase activity is associated with suscepti bility to breast cancer. BRCAl dependent ubiquitin conjugates are generated at sites of DNA damage repair in human cells.

BRCAl recruitment to chromatin at sites of DNA damage occurs through a complex cascade of protein modifications and interac tions, and BRCAl is the third in a sequence of ubiquitin ligases recruited to such sites. Binding of the mediator of DNA damage checkpoint 1 (MDCl) protein to the phosphorylated tail of histone H2AX (‘)’-H2AX) at sites of DNA breakage recruits the ubiquitin ligase RNF8, which generates ubiquitin chains bound by RAP80:ABRAl, which in turn recruits BRCAl through its carboxy (C) terminus 14-20. The activity of the second ubiquitin ligase, RNF168, maintains the ubiquitin chain signal initiated by RNF8 and thus helps retain BRCAl at these sites.

Mutations in BRCAl are associated with a high risk of breast and ovarian cancer. BRCA1 participates in the DNA damage response and acts as a ubiquitin ligase…

In this paper Morris and colleagues report that BRCA1 is modified by small ubiquitin-like modifier (SUMO) in response to genotoxic stress, and co-localizes at sites of DNA damage with SUM01, SUM02/3 and the SUMO-conjugating enzyme Ubc9. PI AS SUMO E3 ligases eo-localize with and modulate SUMO modification of BRCA 1, and are required for BRCA 1 ubiquitin ligase activity in cells.

PIAS SUMO ligases are required for complete accumulation of double-stranded DNA (dsDNA) damage-repair proteins subsequent to RNF8 accrual, and for proficient double-strand break repair. These data demonstrate that the SUMOylation pathway plays a significant role in mammalian DNA damage response.

Morris JR et al 2009 The SUMO modification pathway is involved in the BRCA 1 response to genotoxic stress Nature vol 462 pp 886-890

Bowel Cancer —

Genes and the aetiology of colonic cancer.

Sansom O J et al 2007, Nature April 5th , vol 446, 676-679

The APC gene encodes the adenomatous polyposis coli tumour suppressor protein. Mutation of the germline characterizes familial adenomatous polyposis (FAP), an autosomal intestinal cancer syndrome. Inactivation of APC is also recognized as the key early event in the development of sporadic colorectal cancers1, and its loss results in constitutive activity of the β-catenin-Tcf4 transcription complex. The proto-oncogene c-MYC has been identified as a target of the Wnt pathway in colorectal cancer cells in vitro, in normal crypts in vivo’ and in intestinal epithelial cells acutely transformed on in vivo deletion of the APC gene; The role of Myc in the intestine after Ape loss has been studied, after deleting both Ape and Myc in the adult murine small intestine. Loss of Myc reversed the phenotypes of perturbed differentiation, migration, proliferation and apoptosis, which occur on deletion of Ape Myc is required for the majority of Wnt target gene activation following Ape loss. These data establish Myc as the critical mediator of the early stages of neoplasia following Ape loss.

This may appear obscure to Nutritionists.

If we are to break away from repeated mantras that certain food items are involved in the ain science will be seen as poking sticks down a rabbit hole and hoping for something to turn up.

Cancer Aetiology —

Theories for the causation of cancer litter the literature. There are so many and Nutrition is on of the prominent contributors, not to the debate but as dogmatic statements.

In one respect this is so naïve , and yet there are other examples of success with adding nutrients; folic acid in preventing neurological birth defects and zinc and vitamin A and outcome in infants.

On the other hand in my field I always felt uncomfortable with the suggestion that dietary fibre was an universal agent in the prevention of colonic disease. If similar claims were made for a drug there would be legal actions.

In Nature 2008 vol 451 p 781 there is a touching obituary of a great surgeon scientist M Judah Folkman who died comparatively young.

He noticed the vascular nature of tumours. He saw the undue concentration of blood vessels in tumours as an extension of a fundamental process in the normal physiology, embryonic development and disease including cancer.

He demonstrated the first angiogenesis factor basic fibroblast growth factor and inhibitiors angiostatin and endostatin. He felt that there is a place for angiogenesis inhibitors which acted in the same manner as statins in coronary heart disease.

A fine example of laboratory studies to fortify an observation rather than powerful recommendations based solely on epidemiological observations. The two marry together.

Cancer And Ageing —

The common biology of cancer and ageing

The biological processes involved in the development of cancer and the process of ageing have much in common.

Perhaps cancer is a process where the process is concentrated in one organ and ageing involves the whole or most of the body.

The ageing process involves a wide range of molecular stresses

loss of telomeres, which are the specialised structures at the ends of chromosomes. They protect the natural chromosome ends from fusion and therefore are essential for chromosome stability, rather like a ferule at the end of a walking stick.
the de-repression of the cyclin dependent kinase inhibitor 2a ( CDKN2a )
the accumulation of DNA damage and the subsequent activation of DNA damage response.
This process is reviewed in Nature

Finkel et al 2007 Nature, The common biology of cancer and ageing vol 448, 767-774

It is also interesting that a reduced dietary intake slows the ageing process and may prevent the development a of cancer.

cancer of the breast —

There is insufficient information about the combined effects on breast cancer incidence of low-penetrance genetic susceptibility polymorphisms and environmental factors (reproductive, behavioural, and anthropometric risk factors for breast cancer). This study looks for evidence of gene-environment interactions, and compared genotypic relative risks for breast cancer across the other risk factors in a large UK prospective study.

They tested gene-environment interactions in 7610 women who developed breast cancer and 10196 controls without the disease, studying the effects of12 polymorphisms FGFR2-rs2981582, TNRC9-rs3803662, 2q35-rs13387042, MAP3Kl-rs889312, 8q24-rs13281615, 2p-rs4666451, 5p12-rs981782, CASP8-rsl045485, LSP1-rs3817198, 5q-rs30099, TGFB1-rsI982073, and ATM-rs1800054 in relation to prospectively collected information about ten established environmental risk factors age at menarche, parity, age at first birth, breastfeeding, menopausal status, age at menopause, use of hormone replacement therapy, body-mass index, height, and alcohol consumption.

After allowance for multiple testing none of the 120 comparisons yielded significant evidence of a gene-environment interaction. By contrast with previous suggestions, there was little evidence that the genotypic relative risks were affected by use of hormone replacement therapy, either overall or for oestrogen-receptor-positive disease.

Only one of the 12 polymorphisms was correlated with any of the ten other risk factors: carriers of the high-risk C allele of MAP3Kl-rs889312 were significantly shorter than non-carriers .

Risks of breast cancer associated with low-penetrance susceptibility polymorphisms do not vary significantly with these ten established environmental risk factors.

Travis et al 2010 Lancet Gene-environment interactions in 7610 women with breast cancer: prospective evidence from the Million Women Study vol 375 2143-2151

Cancer and Feeding —

It is well established that dietary restriction, which involves limiting nutrient intake below normal levels but without reaching malnutri tion, extends lifespan, youthfulness, age-associated traits and diseases, includ ing cognitive deterioration and cancer in most, if not all, species – probably including humans, This might be due to the evolutionary advantage of keeping alive under suboptimal nutrient availability, and postponing reproduction until food is plentiful.

But dietary restriction does not affect all types of cancer similarly, raising questions about the generality of its effects and its mode of action in cancer. ‘Writing in Nature 9th April 2009, Kalaany and Sabatini and with a commentary by Brunet describe the behaviour of address these questions in both human tumour cells and animal models of human cancer.

When human-tumour cell lines are implanted into mice, some lines cannot expand if the animals’ caloric intake is reduced by 40% for a period of 3 weeks. The cell lines that were resistant to the antitumour benefits of this nutrient restric tion carried mutations that led to the constitutive (continuous) activation of the signalling pathway mediated by the hormone insulin. These cell lines had mutations that activated the enzyme PI3K, a key component of the insulin signalling pathway, or inactivated PTEN phosphatase, an enzyme that counter acts PI3K action. So it seems that, to exert its anticancer benefits, limited dietary intake must reduce insulin-mediated signalling.

In further experiments, only tumours with an active PI3K pathway were resistant to dietary restriction. What’s more, activating this pathway was both necessary and sufficient for tumour resistance to reduced food intake. Finally, the FOXO proteins, which are major down stream targets of the PI3K signalling and affect gene transcription , seems to execute the effects of dietary restriction as FOXO transcription factors were inactivated in the tumours resistant to reduced nutrient intake.

There was an increase in pro grammed cell death (apoptosis). Reduced food intake could affect other cellular processes that contribute to tumour size, cell proliferation; or trigger autophagy, a ‘self-eating’ cellular process that would help to recycle nutrients and ward off cancer by eliminating damaged proteins or organelles; or it might help to reduce the growth of new blood vessels in tumours – a process known as angiogenesis – thus affecting the tumour micro environment rather than the tumour cells.

Dietary restriction in moderation might reduce the chances of developing cancer along with not smoking.

Brunet 2009 When restriction is good . Nature vol 458 pp 713-4

Kalaany and Sabatini 2009 Tumours with P12K activation are resistant to dietary restriction. Nature vol 458 pp 725 – 731

Cancer Biology —

RAS is one of the most commonly mutated gene families in human cancers – one of its three members (KRAS, HRAS and NRAS) is mutated in about 20% of human tumours. Attempts to target mutant RAS proteins directly with small-molecule inhibitors have so far proved unsuccessful, so there has been considerable interest in finding signalling pathways that function downstream of RAS and whose blockade might be selectively toxic to tumour cells. Two papers in Nature 5th November 2009 pro vide evidence that targeting one such pathway, the NF- KB signalling pathway, may be an effec tive approach to treat RAS-mutant tumours such as lung cancers. Barbie et al.’ (page 108) identify a component of the NF-KB pathway as a potential target in RAS-mutant cancer cells, and Meylan et al’ (page 104) show that inhibition of NF-KB signalling impairs tumour formation in a mouse model ofRAS-induced lung cancer. The NF-KB transcriptional program control is a multitude of cell functions, most notably the regulation of cell death and inflammation

The use of the RNA-interference technique to selectively inhibit gene expression, together with knowledge of the full sequence of the human genome, has made possible large-scale functional genomic screens. In these, each gene in the genome (or at least a significant propor tion of genes) is silenced one by one, and the effect on cell function is assayed. This approach has recently been used to investigate which genes, when silenced, kill cells bearing mutant RAS but not cells that lack this mutation so-called synthetic lethal interactions. Barbie et al’ looked for synthetic lethal interactions in a panel of cell lines, some of which had activating mutations in KRAS. The authors inhibited genes thought to be important for the develop mentof cancer and identified several genes whose reduced activity seemed to selectively kill the RAS-mutant cells. After KRAS itself, silencing the gene TBK1, an upstream regu lator of the NF-KB pathway, was most effec tive for selectively killing RAS-mutant cells. TBK1 is thought to activate NF-KB by phosphorylating IKB, an F-KB inhibitor. It also activates other transcription factors involved in inflammatory responses, such as IRF3 and IRF7 (ref. 5).

Downward 2009 A tumour gene’s fatal flaws Nature vol 462 pp 44-45

Cancer Cells 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, 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 cell’s 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 elimination. 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 cells escape anoikis, or anoikis prevents cancer. Several ontogenesis hinder anoikis but the mechanism is obscure.

One oncogene ERBB” 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.

In an interesting twist, Schafer et al. note that anoikis can be prevented in normal, detached, glucose-starved.cells if they are given antioxiants 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.

Cancer Genome —

This is a fascinating review of the molecular biology of cancer by Straton et al in Nature. Cancer is responsible for one in eight deaths worldwide and includes more than 100 distinct diseases with diverse risk factors and epidemiology in most of the cell types and organs of the human body. The cancers are characterized by relatively unrestrained proliferation of cells that can invade beyond normal tissue boundaries and metastasize to distant organs.

There is a central role of the genome in cancer develop¬ment and bizarre chromosomal aberrations. Agents that damage DNA and generate mutations also cause cancer. Subsequently, increasingly refined analyses of cancer cell chromo¬somes showed that specific and recurrent genomic abnormalities, such as the translocation between chromosomes 9 and 22 in chronic mye¬loid leukaemia (known as the ‘Philadelphia’ translocation’:”), are associated with particular cancer types.

All cancers are thought to share a common pathogenesis. Each is the outcome of a process of cancer development is based on two constituent processes, the continuous acquisition of heritable genetic variation in individual cells by more-or-less random mutation and natural selection acting on the resultant phenotypic diversity. The selection may weed out cells that have acquired deleterious mutations or it may foster cells carrying alterations that confer the capability to proliferate and survive more effectively than their neighbours. Occasionally, however, a single cell acquires a set of sufficiently advantageous mutations that allows it to proliferate autonomously, invade tissues and metastasize.

The DNA sequence of a cancer cell genome, and indeed of most normal cell genomes, has acquired a set of differences from its original fertilized egg. These are called somatic mutations-to distinguish them from germline mutations that are inherited from parents and transmitted to offspring.

The somatic mutations in a cancer cell genome may encompass several distinct classes of DNA sequence change. These include sub¬stitutions of one base by another; insertions or deletions of small or large segments of DNA; re arrangements, in which DNA has been broken and then rejoined to a DNA segment from elsewhere in the genome; copy number increases from the two copies present in the normal diploid genome, sometimes to several hundred copies (known as gene amplification); and copy number reductions that may result in complete absence of a DNA sequence from the cancer genome

The cancer cell may have acquired, from exogenous sources, completely new DNA sequences, notably those of viruses such as human papilloma virus, Epstein Ban virus, hepatitis B virus, human T lymphotropic virus 1 and human herpes virus 8, each of which is known to contribute to the genesis of one or more type of cancer,

The cancer genome will also have acquired epigenetic changes which alter chromatin structure and gene expression, and which manifest at DNA sequence level by changes in the methylation status of some cytosine residues.

The thousands of mitochondria present in cells each carry a circular genome of approximately 17 kilobases. Somatic mutations in mitochondrial genomes have been reported in many human cancers, although their role in the development of the disease is not clear.

The mutations found in a cancer cell genome have accumulated over the lifetime of the cancer patient. It is likely that the mutation rates of each of the various structural classes of somatic mutation differ and that there are differences among cell types too. Mutation rates increase in the presence of substantial exogenous mutagenic exposures, for example tobacco smoke carcinogens, naturally occurring chemicals such as aflatoxins, which are produced by fungi, or various forms of radiation including ultraviolet light. These exposures are associated with increased rates of lung, liver and skin cancer, respectively,

The rest of the somatic mutations in a cancer cell genome have been acquired during the segment of the cell lineage in which predecessors of the cancer cell already show phenotypic evidence of neoplastic change. For example, colorectal and endometrial cancers with defective DNA mismatch repair due to abnormalities in genes such as MLHl and MSH2, show increased rates of acquisi¬tion of single nucleotide changes and small insertions/deletions at polynucleotide tracts.

Each somatic mutation in a cancer cell genome, whatever its structural nature, may be classified according to its consequences for cancer development. Driver mutations confer growth advantage on the cells carrying them and have been positively selected during the evolution of the cancer. They reside, by definition, in the subset of genes known as ‘cancer genes’. The remainder of mutations are ‘passengers’ that do not confer growth advantage, but happened to be present in an ancestor of the cancer cell when it acquired one of its drivers.

A driver mutation is causally implicated in oncogenesis and gives growth advantage to the cancer cell and has been positively selected in the microenvironment of the tissue in which the cancer arises. A driver mutation need not be required for maintenance of the final cancer (although it often is) but it must have been selected at some point along the lineage of cancer development shown in Fig. 1.

A passenger mutation has not been selected, has not conferred clonal growth advantage and has therefore not contributed to cancer development.

The known cancer genes are wide in their tissue specificities and mutation prevalences. Some, for example TP53 and KRAS, are frequently mutated in diverse types of cancer whereas others are rare and/or restricted to one cancer type. In some cancer types, for example colorectal and pancreatic cancer, abnormalities in several known cancer genes are common. In contrast, in gastric cancer, relatively few mutations in known cancer genes have been reported.

Approximately 90% of the known somatically mutated cancer genes are dominantly acting, that is, mutation of just one allele is sufficient to contribute to cancer development.

For some cancers, classification and treatment protocols are now defined by the presence of abnormal cancer genes.eg acute myeloid leukaemia, for example, is subclassified on the basis of the presence of abnormalities involving specific cancer genes. Each subtype has a characteristic gene expression profile, cellular morphology, clinical syndrome, prognosis and opportunity for targeted therapy.

Stratton et al 2009 The cancer genome A review. Nature vol 458 pp 719-724

Cancer of the breast —

There is insufficient information about the combined effects on breast cancer incidence of low-penetrance genetic susceptibility polymorphisms and environmental factors (reproductive, behavioural, and anthropometric risk factors for breast cancer). This study looks for evidence of gene-environment interactions, and compared genotypic relative risks for breast cancer across the other risk factors in a large UK prospective study.

They tested gene-environment interactions in 7610 women who developed breast cancer and 10196 controls without the disease, studying the effects of12 polymorphisms

FGFR2-rs2981582, TNRC9-rs3803662, 2q35-rs13387042, MAP3Kl-rs889312, 8q24-rs13281615, 2p-rs4666451, 5p12-rs981782, CASP8-rsl045485, LSP1-rs3817198, 5q-rs30099, TGFB1-rsI982073, and ATM-rs1800054

in relation to prospectively collected information about ten established environmental risk factors

age at menarche, parity, age at first birth, breastfeeding, menopausal status, age t menopause, use of hormone replacement therapy, body-mass index, height, and alcohol consumption.

After allowance for multiple testing none of the 120 comparisons yielded significant evidence of a gene-environment interaction. By contrast with previous suggestions, there was little evidence that the genotypic relative risks were affected by use of hormone replacement therapy, either overall or for oestrogen-receptor-positive disease.

Only one of the 12 polymorphisms was correlated with any of the ten other risk factors: carriers of the high-risk C allele of MAP3Kl-rs889312 were significantly shorter than non-carriers.

Risks of breast cancer associated with low-penetrance susceptibility polymorphisms do not vary significantly with these ten established environmental risk factors.

Travis et al 2010 Lancet Gene-environment interactions in 7610 women with breast cancer: prospective evidence from the Million Women Study vol 375 2143-2151

Cardiovascular Risk —

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.

Nutrition in the Aetiology of Disease
Cardiovascular disease and fruit and vegetable consumption —

The consumption of fruit and vegetables is associated with a lower cardiovascular disease risk. Smoking may affect the strength of this association. The objective of this study was to compare the relationship between the frequency of fruit and vegetables intake and cardiovascular disease risk in male current, former and never smokers.

A prospective study in men (n=8060) aged 50–59 years who were recruited in France and Northern Ireland. The frequency of fruit and vegetables intake was assessed by using a food frequency questionnaire. The outcome criteria were incident cases of acute coronary syndrome (ACS) and total cardiovascular disease (coronary heart disease and stroke) over 10-year period.

A total of 367 acute coronary syndrome and 612 cardiovascular disease events occurred during the follow-up period. A multivariate analysis revealed a statistically significant interaction between smoking status and fruit and vegetables intake for acute coronary syndrome and for cardiovascular disease (both P’s<0.05).

In current smokers, the relative risks for acute coronary syndrome were 0.78 (0.54–1.13) and 0.49 (0.30–0.81) in the second and third tertiles of fruit and vegetables intake, respectively (P for trend<0.001); for cardiovascular disease, the values were 0.80 (0.59–1.08) and 0.64 (0.44–0.93) respectively (P for trend<0.001).

In contrast, no statistically significant associations were observed for never and former smokers. Similar statistical interactions for acute coronary syndrome were observed for fruit intake (P=0.07) and vegetable intake (P<0.05) taken separately.

These results suggest that high fruit and vegetable intake is associated with a lower risk of cardiovascular disease in male smokers.

Dauchet et al (2010 ) Association between the frequency of fruit and vegetable consumption and cardiovascular disease in male smokers and non-smokers European Journal of Clinical Nutrition 64, 578–586;

Clinical Trials —

There is a very thoughtful and important commentary in Nature 446, 8th March 2007 p 137 on Keeping Faith with Trial Volunteers by Piccart and Goldhirsch and colleagues. The article discusses the concept of clinical trails from the point of view of the volunteers. They give of themselves to very varying extent. From the giving of a sample of blood to full scale studies. It is only reasonable that they have the best of study design, data collection analysis and full publication of results. I suspect that the animals used in experiments should ask the same as they give everything of themselves and die.

The article talks of the large clinical trials which require huge financial resources, in excess of the moneys available to academic researchers. This means partnership with industrial sources of money. The article suggests that pharmaceutical companies may structure the trials to answer important questions for their own needs for their drugs. Which is very reasonable. Except that academics might and should want to use the trial to test hypotheses that would be important in developing new strategies. For example length of follow up.

They suggest that academic investigators negotiate with industry before committing themselves to trials in the following areas

data control. The important academic quest is to look at the data from every point of view. The funding company may not wish to do this and may withdraw financial support. That is the company is looking to control trial data.
the use of the companies statisticians to look at the data and not to give the raw material to the academics.
They suggest that the academics have first look at the data and then hand it on to the company which can then use the data for their own benefit.
All the time it is important to remember the trial subjects and their contribution. It is kind to contact the subjects after the trial is complete and to inform them of the outcome.

These big trials are less common in nutrition. They should happen and when they do, please define the rules of engagement with the funders.

Colon Cancer —

Diet may matter for prognosis of colon cancer

A diet rich in red and processed meats, fat, sweets, and refined grains (also called the Western dietary pattern) seems to increase the risk of recurrence of disease and death in people with colon cancer. A prospective observational study assessed dietary habits in more than 1000 people with stage III colon cancer who participated in a randomised trial of chemotherapy regimens after complete surgical resection of the primary tumour.

People in the highest fifth of Western dietary pattern were more than three times as likely to have a recurrence or die during a median follow-up of 5.3 years than people in the lowest fifth. The results remained significant after adjusting for sex, age, nodal stage, body mass index, physical activity, baseline performance status, and trial treatment group. However, the prudent dietary pattern wasn’t protective: a diet with higher intake of fish and poultry, fruits and vegetables, legumes and whole grains didn’t improve outcome. ( Journal American Medical Association 2007 , vol 298, 754-64 )

I am not sure what this tells us but clearly here is an instance for a range of collaborative trials. Patients long to know what to eat after cancer surgery. Someone might find out using proper clinical trial, not prejudiced guesses.

I had a friend , a devoted naturalist and ate the ideal diet by her lights. She developed cancer of the ovary. She refused treatment except surgery. She took malt for her three years prognosis. As good an outcome as more radical treatment.

CVS Infarction —

Greece is a country where in the original 7 countries study the prevalence of myocardial infarction in rural Greece was only 0.3% in middle aged men. Now the prevalence is comparable to the USA and rising. This is in contrast to other countries where the prevalence is falling.

Importantly here is a country where the Mediterranean diet is the rule. Or is it any more. Diets are changing, Modes of life are changing, Smoking is increasing as is the prevalence of diabetes, smoking, high blood pressure hypercholesterolaemia.

Who knows if the amount and type of cigarette is important. But why are people abandoning their traditional food for a more unhealthy diet? Or is there another element to this story?

Gikas et al 2008 Prevalence trends for myocardial infarction and conventional risk factors among Greek adults ( 2002-06) QJM vol 101 705-712

Birtwhistle What ever happened to the Mediterranean diet 2008 vol 101 741-742

Dark chocolate lowers blood pressure —

One small square of dark chocolate a day could have a clinical effect on blood pressure, according to a preliminary trial from Germany. People aged ,56-74 who ate 6.3 g of dark chocolate for 18 weeks dropped their systolic blood pressure nearly 3 mm Hg more than those given a matching portion of white chocolate. The dark chocolate, which contained 30 m of polyphenols, reduced diastolic blood pressure by a mean of 1.9 mm Hg (1.1 to 2.7).

The researchers think that the flavanols family of polyphenols are probably responsible, mediated by the vasodilator S-nitrosoglutathione. At the end of the trial, serum concentrations of S-nitrosoglutathione were significantly higher in the group given dark chocolate.

The 44 participants had baseline blood pressures between 130/85 and 160/100. They were healthy, reasonably affluent non-smokers with normal body weight and a habitually low-intake of alcohol and chocolate.

JAMA 2007, vol 298, 49-60

Diabetes in Asian populations —

There is an epidemic of obesity and diabetes in the Asia Pacific region. The Pacific Island diet has shifted from one based on traditional root crops and sea food to one relying on energy dense and nutritionally poor imported food.

Obesity i.e. BMI greater than 30kg/m2 is found in 30-75 % of different populations in this area. Diabetes is found in 47 to 14% of these populations. The epidemic is found in Hong Kong and also China.

Diabetes is found in 7.7% of Hong Kong adults associated with an increasing obesity rate. Similar figures are found in China.

For every person in the World with Diabetes there are three in China with diabetes ( 93 million )

Presumably due to changing dietary patterns, availability of food and cultural changes in life styles.

Cheng 2010 Asia Pacific faces Diabetes challenge Lancet vol 375 pp 2207-2210

Diarrhoea —

Since Fleming discovered the anti bacterial activity of penicillin, a range of antibiotics have been discovered. An important source of antibiotics has been from soil micro organisms These have varied in their usefulness and toxic properties. Bearing in mind that their original role was to protect themselves in the soil environment which is a free for all. Some micro organisms produce herbicides as well as antibiotics.

Quinn JP2007, Unchartered route for antibiotics Nature 448, 415-416

When used in clinical care in man diarrhoea is a common side effect which can have a considerable impact on a person already enfeebled by an infection. Clostridia difficile is a common cause of the diarrhoea.

Normally there is a protective coat of micro organisms on the mucosa of the intestine and colon. When a really effective antibiotic arrives this protection is lost and Clostridia difficile takes over, along with a brisk diarrhoea. .

The method of preventing this complication would be to replace the depleted bacteria with sympathetic microorganisms using pro biotics which are a living beneficial bacteria or yeasts that are taken orally to restore the microbial balance. There are many pro biotic preparations on the market. They have a long history dating from the 19th century. The revival of yoghurt as a cure all dates from that time.

In a trial of various probiotics taken at the same time as the antibiotic, those who took the probiotics did not become colonised with Clostridia difficile whereas the placebo group were less fortunate ( 17% ). However the numbers were small and recruited over a long period of time.

Probiotics are poorly designated , but are a harmless addition to care and even nice to take.

McFarland LV 2007. Diarrhoea associated with antibiotic use. BMJ; 335: 54

Hickson M et al . Use of probiotic Lactobacillus preparation to prevent diarrhoea associated with antibiotics: randomised double blind placebo trial . BMJ , 335: 80-3

Diet And Cancer —

Amid substantial publicity the World Cancer Research Fund has published its report on cancer, physical activity and diet

www.wcrf-uk.org.

The overall recommendations are 10 in number, of which the first 7 are the general ones.

It would be interesting to know how these recommendations fit with the large pool of knowledge on the molecular biology of cancer which now exists and is being added to. Shades of Mr Casaubon in George Elliot’s novel Middlemarch.

1. Be as lean as possible without becoming underweight

Convincing evidence shows that weight gain and obesity increases the risk of a number of cancers, including bowel and breast cancer. Maintain a healthy weight through a balanced diet and regular physical activity to help keep your risk lower.

2. Be physically active for at least 30 minutes every day

There is strong evidence that physical activity protects against cancers including bowel and breast cancer. Being physically active is also key to maintaining a healthy weight. Any type of activity counts-the more you do the better! Try to build some into your everyday life.

3. Avoid sugary drinks. Limit consumption of energy-dense foods and drinks (particularly processed foods high in added sugar, or low in fibre, or high in fat. Try to eat lower energy-dense foods such as vegetables, fruits and wholegrains instead. Opt for water or unsweetened tea or coffee in place of sugary drinks.

4. Eat more of a variety of vegetables, fruits, wholegrains and pulses such as beans. . As well as eating your 5 A DAY, try to include wholegrains (e.g. brown rice, wholemeal bread and pasta) and/or pulses with every meal.

5. Limit consumption of red meats (such as beef, pork and lamb) and avoid processed meats

6. If consumed at all. limit alcoholic drinks to 2 for men and 1 for women a day

7. Limit consumption of salty foods and food processed with salt (sodium)

8. Don”t use supplements to protect against cancer

Research shows that high-dose nutrient supplements can affect our risk of cancer, so it’s best to opt for a balanced diet without supplements.

Dirty Food —

Food safety supervision in the USA is split across a number of Agencies.

According to the Centers for Disease Control and prevention in Georgia 76 million Americans contract food-borne illnesses each year and 5000 die.

Culprits include spinach and lettuce contaminated with E coli and salmonella bearing tomatoes.

These infections must relate in part to farm practices eg managing manure, irrigation and farm worker hygiene.

Nature vol 445, 15/2/2007 pages 683-4

GI Cancer —

In the Newsletter published by the American Gasttoenterology Association there is an interesting article by Kunnumakkara and Aggarwal ( AGA perspectives vol 3 issue 6 pp8-10 )

The write of the belief that sporadic cancers are preventable especially gastrointestinal cancers. To support this belief – gastrointestinal cancers are more common in developed countries than in developing countries. The incidence of colorectal cancer in India is less than a tenth that in the U.S.

Grilled meal and fried foods, environmental pollutants, and certain viruses and bacteria have been linked to tumoro-genesis of the GI tract in rodent models.

Dietary components derived from fruits and vegetables have been shown to suppress carcinogenesis in animals.

Epidemiological studies and limited clinical trials in humans suggest a role for fruits and vegetables in the prevention of GI cancers.

The foods and the active agents that have been so far linked with prevention of GI cancers include resveratrol from grapes, peanuts and berries; catechins from tea; genistein from soybean; caffeic acid from mustard seeds, olive oil from olives; curcumin from turmeric; quercetin from onions; ellagic acid from pomegranate; diallyl disulfide from garlic; sulforaphane from broccoli; lycopene from tomato; and indoIe-3-carbinol from cruciferous vegetables .

These agents may have protective effects against GI cancers by targeting multiple molecular targets.

Curcumin gives curry powder (turmeric) its yellow colour, and is the dietary agent which the authors know most with respect to GI cancers. Its active ingredient is diferuloylmethane. Curcumin has been shown to protect animals from a wide variety of carcinogens that cause GI cancers .

A protective effects of curcumin have also been reported in patients with Crohn’s disease, ulcerative colitis, irritable bowel disease (IBS) and tropical pancreatitis).

The mechanisms mediating the inhibitory effects of curcumin have been extensively investigated. Their group showed that curcumin down-regulates the activation of NF-kB, leading to down-regulation of anti-apoptoric, cell proliferative, invasive and angiogenic gene products.

Curcumin also suppresses the activation of STAT3 HIF-1 and PPAR-y. Curcumin down-regulates the activity and expression of both COX2 and 5-LOX , down-regulates the expression of TNF,ILl.-l and IL-6; and inhibits EGF receptor signalling. In spite of interfering with all these targets, curcumin has been found to be pharmacologically safe at very high doses, with no dose-limiting toxicity.

I have always been sceptical of comparisons of disease incidence between developed and developing countries. Many diseases so studied occur in an age group older than generally experienced in the developing world. It would also be possible to say that intestinal parasites, malaria and under nutrition may also protect.

Having said that this is serious and interesting work and offers great interest. Remember aspirin and its wide therapeutic value.

GI Infection —

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

Grapes and Cognition —

Alzheimer’s disease is the cause of 60 to 80 % of cases of dementia Worldwide. There are some 25 million cases and this number is expected to rise. Mild cognitive impairment identifies individuals with elevated risk for dementia, and some 10% a year progress to Alzheimer’s disease.

Even age-associated memory impairment, formally called benign forgetfulness, may be associated with very early neurodegeneration. Older adult with subjective memory complaints with age-associated memory impairment show degradation in the medial temporal lobe. There is a trebling of risk of Alzheimer’s disease in these individuals. Memory complaints and associated manifestations in everyday functioning are indicators of neurodegeneration. Preventive interventions begun at an early stage cannot be other than good.

Specific constituents of grape juice e.g. polyphenols have neuroprotective effects.

Epidemiological studies indicate that consumption of fruits and vegetables is associated with lower risk of neurodegenerative disorders and better cognitive performance in the elderly.

Concord grape juice contains polyphenol compounds, which have antioxidant and anti-inflammatory properties and influence neuronal signalling. Concord grape juice supplementation has been shown to reduce inflammation, blood pressure and vascular pathology in individuals with Cardio vascular disease and consumption of such flavonoid containing foods is associated with a reduced risk for dementia. In this initial investigation of neurocognitive effects, Krikorian and colleagues Brit J Nutrition 2010 vol 103 pp 730-734 enrolled twelve older adults with memory decline but not dementia in a ran¬domised, placebo-controlled, double-blind trial with Concord grape juice supplementation for 12 weeks. Significant improvement was observed in verbal learning and non-Significant enhancement of verbal and spatial recall. There was no appreciable effect of the intervention on depressive symptoms and no effect on weight or waist circumference. A small increase in fasting insulin was observed for those consuming grape juice. These preliminary findings suggest that supplementation with Concord grape juice may enhance cognitive function for older adults with early memory decline and offers hope for future studies.

Krikorian et al 2010 Concord juice supplementation improves memory function in older adults with mild cognitive impairment, Brit J Nutrition vol 103 pp 730-734

Heart Disease Hunt —

In Science there are two recent reports of single-nucleotide polymorphism ( SNP) which give an enhanced risk of heart disease in white populations. These are found in the same tight area in chromosome 9 , in a non coding region close to two tumour suppressing genes. ( Science doi:10.1126/science 1142447 and doi : science 10.1142843 (2007).

Those individuals who carry one of these high risk clusters have a 30-40% increase in having heart disease and possessing both increases the risk to 64%.

Which is very interesting but does not say what happens if one ignores the usual prudent advise of not smoking, weight control, diet and exercise.

In the great Novel, “The confessions of a justified sinner” James Hogg , describes how a man belonging to a fundamental Christian Faith was told by his Minister that he was saved. So the hero went out and lived a raucous life as he was confident that he was eventually going to Heaven.

Does having a clean sheet in terms of predisposing genetic SNPs in ones DNA remove the need to be prudent?

Not worth the risk. The important pointers are surely there for us all.

Homocysteine —

Supplements to lower homocysteine concentration disappoint again

Epidemiological and genetic studies show a clear association between high serum concentrations of homocysteine and a higher risk of cardiovascular disease. So for more than a decade, researchers have been trying to reduce the risk of cardiovascular disease by giving people homocysteine lowering supplements of B vitamins and folic acid. Four large trials have already reported disappointing results. Now a fifth finds that B vitamins and folk acid don’t prevent cardiovascular disease, even in high risk patients with chronic, renal failure. Once again, the supplements brought down the participant’s homocysteine concentrations but not their risk of death, heart attack, stroke , or amputation .

No one can explain why the supplements don’t work in large trials, although one explanation is the attenuating effect of fortifying cereals with folic acid.

BMJ 22nd September 2007, supplements to lower homocysteine concentrations disappoint again vol 335, p587

Jamison et al JAMA 2007, Effect of homocysteine lowering on mortality and vascular disease in advanced chronic kidney disease and end-stage renal disease. Vol 298, 1163-1170.

Homocysteine is a non-protein-forming sulphur amino acid whose metabolism is at the intersection of two metabolic pathways: remethylation and transsulfuration. In remethylation, homocysteine acquires a methyl group from N-5-methyltetrahydrofolate or from betaine to form methionine. The reaction with N-5-methyltetrahydrofolate occurs in all tissues and is vitamin B]2 dependent, whereas the reaction with betaine is confined mainly to the liver and is vitamin B[2 independent. A considerable proportion of methionine is then activated by ATP to form S-adenosylmethionine (SAM). SAM serves primarily as a universal methyl donor to a variety of acceptors. 5-adenosyl homocysteine (SAH), the by-product of these methylation reactions, is subsequently hydrolysed, thus regenerating homocysteine, which then becomes available to start a new cycle of methyl-group transfer. This hydrolysis is a reversible reaction that favours the synthesis of SAH and that elevated cellular concentrations of this metabolite are likely to accompany all forms of hyperhomocysteinemia.

.In the transsulfuration pathway, homocysteine condenses will form cystathionine in an irreversible reaction catalyzed by the pyridoxal -5′- phosphate (PLP)-containing enzyme -cystathionine. β- synthase.is hydrolyzed by a second PLP-containing enzyme, γ -cystathionase, to cysteine and α -ketobutyrate. Excess cysteine is oxidized to taurine excreted in the urine.

Thus, in addition to the synthesis of cysteine, this transulfuration pathway effectively catabolises excess homocysteine which is not required for methyl transfer.

Selhub J 1999 Homocysteine vol 19, 217-8

Could it be that the emphasis is on the wrong system. What if the transsulfuration enzyme reaction system is lacking. There is synergy between the two pathways and this is nutritionally regulated. The addition of folic acid or other B vitamin may be of secondary rather than primary import.

Homocysteine Risk —

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

Hospital Food —

In the olden days ward sisters ruled over the in patient community. One of her treasured skills was the provision of treats to the ill, regardless of the time of day and night. Now we have Health and Safety, food bought long distances in lorries and strict and brief timetables for eating. No wonder that patients loose weight in Hospital

The penny takes some time to drop but now the National Patient Safety Agency is suggesting that all patients should have access to food and fluid 24 hours a day and that there is a food plan in place for each patient and nutritional screening.

Not before time.

See www.npsa.nhs.uk

Nutrition in the Aetiology of Disease
Hypertension —

In a Seminar on essential hypertension, Franz Messerli and colleagues Lancet 2007 vol 370 pp 591 – 603 accompanied by an editorial Lancet 2007 vol 337, p 539 indicate that the risk of becoming hypertensive during lifetime exceeds 90% for a person in a developed country. The common triad of obesity, diabetes, hyperlipidaemia, and high blood pressure, if left untreated for too long, leads to cardiovascular disease, stroke, renal failure, dementia, and early death.

Worldwide, the estimated number of adults with hypertension was 972 million in 200of which 639 million live in developing countries. By 2025, the total number is expected to increase to 156 billion. Lifestyle factors, such as physical inactivity, a salt-rich diet with processed and fatty foods, and alcohol and tobacco use, are basic to this changing pattern of disease.. The problem is spreading to emerging economies, such as India and China. And even countries in Africa are noticing a sharp increase in patients with hypertension, at least in urban settings. For example, in 2006, hypertension was the second most reported medical condition in greater Accra, Ghana, up from fifth in 2005.

IBS —

Guidlines for the management of irritable bowel syndrome in the United Kingdom recommend that the diagnosis should be made on clinical grounds alone, without invasive investigations, unless alarm symptoms such as rectal bleeding are present. General practitioners therefore need efficacious treatments that do not require monitoring and are cheap, safe, and readily available. People with irritable bowel syndrome have been instructed to increase their intake of dietary fibre. When this failed, smooth muscle relaxants and antispasmodics were used. More recently, peppermint oil, shown to have antispasmodic – properties has been used to treat irritable bowel syndrome. Whether these agents are effective in treating irritable bowel syndrome is controversial. Results of randomised controlled trials are conflicting and systematic reviews have come to different conclusions.

Ford et al 2008 BMJ carried out a systematic review and meta-analysis to determine the effect of fibre, antispasmodics, and peppermint oil in the treatment of irritable bowel syndrome.

They concluded that fibre, antispasmodics and peppermint oil were all more effective than placebo in treating the symptoms of irritable bowel.

This is an important analysis of the treatment of a common and troublesome condition.

Ford et al 2008 Effect of fibre, antispasmodics and peppermint oil in the treatment of irritable bowel syndrome: systematic review and meta-analysis. BMJ vol 337 pp 1388-92

IBS —

An Evidence-Based Position Statement on the Management of Irritable Bowel Syndrome by an American College of Gastroenterology IBS Task Force

Irritable bowel syndrome (IBS) is a common disorder characterized by abdominal pain and altered bowel habit for at least 3 months. With this publication, an American College of Gastroenterology Task Force updates the 2002 Monograph on IBS in light of new data. A series of systematic reviews were performed to evaluate the diagnostic yield of investigations and the efficacy of treatments for IBS. The Task Force recommends that further investigations are unnecessary in young patients without alarm features with the exception of celiac sprue serology, which may be of benefit in some patients.

Further investigation such as colonoscopy is recommended in those over 50 years of age and in patients with alarm features. Trials suggest psyllium fiber, certain antispasmodics, and peppermint oil are effective in IBS patients although the quality of the evidence is poor. Evidence suggests that some probiotics may be effective in reducing overall IBS symptoms but more data are needed. Antidiarrheals reduce the frequency of stools but do not affect the overall symptoms of IBS. 5HT3 antagonists are efficacious in IBS patients with diarrhea and the quality of evidence is good. Patients need to be carefully selected, however, because of the risk of ischemic colitis. 5HT3 agonists are modestly effective in IBS patients with constipation and the quality of evidence is good although the possible risk of cardiovascular events associated with these agents may limit their utility.

Tricyclic antidepressants and selective serotonin reuptake inhibitors have been shown to be effective in IBS patients of all subtypes. The trials generally are of good quality but the limited number of patients included in trials implies that further evidence could change the confidence in the estimate of effect and therefore the quality of evidence was graded as moderate.

Nonabsorbable antibiotics are effective particularly in diarrhea-predominant IBS and selective C-2 chloride channel activators are efficacious in constipation-predominant IBS with a moderate quality of evidence.

Psychological therapies may also provide benefit to IBS patients although the quality of evidence is poor.

American College of Gastroenterology IBS Task Force 2009 An Evidence-Based Position Statement on the Management of Irritable Bowel Syndrome Am J Gastroenterology vol 104: S1 – S35;

Immuno Nutrition —

A supplement to the October 2007 British Journal of Nutrition; vol 98, supplement 1 is devoted to immuno nutrition in Health and disease. This is a tour de force. A brilliant example of modern scientific nutrition at its very best.

There are four introductory reviews including the recent history of the science.

The improvements in nutrition consequent upon the improved knowledge of what matters in nutrition is described by Scrimshaw and Solomon, who have achieved so much in this field.

The benefits of better nutrition and supplements of vitamins( vitamins A, D, E, C, B6, B12 ) and trace elements( iron, copper, selenium, zinc ) are major advances in Health and disease reduction

There are papers on the immune system and micronutrients, fatty acids and bioactive compounds ,and alcohol. The inflammatory process and obesity. Finally the important area of immuno nutrition and illness.

The President and vice President of the Work shop modestly call the publication excellent overview, an understatement.

Linoleic Acid and UC —

Wood 2009 IBD: High dietary intake of linoleic acid more than doubles the risk of ulcerative colitis, Nature Reviews Gastroenterology and Hepatology 7, 65

A high dietary intake of linoleic acid—an essential n-6 polyunsaturated fatty acid found in red meats, polyunsaturated margarines and various cooking oils—more than doubles the risk of developing incident ulcerative colitis, according to the results of a new multicenter European study. Linoleic acid is converted to arachidonic acid, which is incorporated into the colonocyte cell membrane; once released from the cell membrane, arachidonic acid is metabolized to proinflammatory eicosanoids (including prostaglandin E2, leukotriene B4 and thromboxane A2).

Wood 2009 IBD: High dietary intake of linoleic acid more than doubles the risk of ulcerative colitis, Nature Reviews Gastroenterology and Hepatology 7, 65

Liver and TPN —

David A. J. Lloyd and Simon M. Gabe 2007 Managing liver dysfunction in parenteral nutrition, Proceedings of the Nutrtion Society vol 66 530-538

Parenteral nutrition is such a help in the compromised patient. When I ran the TPN service in the Hospital where I worked live abnormalities were a constant problem. So I found this article very interesting.

Parenteral nutrition is life saving in patients with intestinal failure but liver dysfunction is a frequent problem, especially in neonates. Although abnormal liver function tests associated with short-term parenteral nutrition are usually benign and transient, liver dysfunction in both children and adults receiving long-term parenteral nutrition can progress to end-stage liver disease and liver failure. The aetiology of parenteral nutrition-associated liver disease is complex and multi factorial, with a range of patient, disease and nutrition-related factors implicated. Sepsis is of particular importance, as is the lack of enteral nutrition and overfeeding with intravenous glucose and/or lipid. Deficiencies of a number of amino acids including cholinc and taurine have also been implicated. Management of hepatic dysfunction in parenteral nutrition should initially focus on preventing its occurrence. Sepsis should be managed appropriately, enteral nutrition should be encouraged and maximised where possible and parenteral overfeeding should be avoided. Provision of parenteral lipid should be optimised to prevent the adverse effects of both deficiency and excess, and cyclical rather than continuous parenteral feeding should be administered. There is some evidence of benefit in neonates from oral antibiotics to prevent intestinal bacterial overgrowth and from oral ursodeoxycholic acid, but less to support their use in adults. Similarly, data to support widespread use of parenteral choline or taurine supplementation are lacking at present. Ultimately, severe parenteral nutrition-associated liver disease may necessitate referral for small intestine and/or liver transplantation.

Maths and Cancer —

An old question is not why do we go to sleep but why do we wake up again ?

Similarly multicellular creatures are made of an array of different cellular structures all of which are dividing and developing until death for whatever reason.

One cause of death which is feared is cancer. To some extent the puzzle is not that cancer develops but that normal physiological growth, tissue formation and preservation is the norm. For cancer to develop a sequence of events must occur and a series of defence or constraining processes overcome.

The mathematician is a brave person who through formulae, assumptions and no constraints of laboratory data can tackle the problems of biological processes. These modelling arguments are very important if not sometimes difficult to follow. The popular problem to tackle is the cancer process.

Weinberg reviews a new book on the dynamics of cancer by Steven Frank which grapples with this interesting approach to as yet an unresolved problem.

Weinberg (2007 ) Using maths to tackle cancer Nature vol 449, 978-81

Frank Dynamics of Cancer : Incidence, inheritance and evolution . Princeton University Press .

Nutritional Support —

This article reviews the basics of surgical nutrition.

Malnutrition remains a common problem in surgical patients and is associated with significant morbidity and mortality. All surgical patients must undergo nutritional screening on admission to highlight malnourished or at risk patients and implement a nutritional plan. There is a strong association between malnutrition and poor clinical outcome

An interplay exists between nutritional status and illness that makes nutritional assessment and management difficult and interpretation of studies confusing.

Recent guidelines from the National Institute for Clinical Excellence (NICE), the British Association for Enteral and Parenteral Nutrition (BAPEN) and NHS Quality Improvement Scotland (NHS QlS) concerning nutritional support provide an excellent overview of malnutrition, screening tools and monitoring of nutritional support.

Nutritional requirements in health

A healthy adult requires approximately 20-25 kcal per kilogram body weight per day. The principal components of a normal diet are energy (carbohydrate and lipid), nitrogen, trace elements, minerals and vitamins. Metabolic stress associated with sepsis, trauma or surgery increases energy requirements to 35-40 kcal per kg per day and vitamins, minerals and trace elements are required for metabolic processes and normal cellular function and must be provided for patients requiring artificial nutritional support. Such support is best given by a multidisciplinary approach with a dedicated dietician and nutrition support team.

Nutritional assessment tools

BAPEN has produced a screening tool. Malnutrition Universal Screening Tool (MUST) which is uncomplicated, reliable and reproducible. Severe malnutrition can be assessed clinically as marked wasting of proximal limb muscles and pressure sores. Milder degrees of malnutrition may be unrecognised and more detailed assessments of nutritional status are requited

There is currently no single, simple and reliable technique for assessing nutritional status. There are a variety of techniques available which are briefly summarised.

Anthropometnc measurements include Body mass index (BMI), ie as body weight in kilograms divided by height in metres squared. A BMI of less than 18.5 implies nutritional impairment and a BMI below 15 is associated with significant mortality. Unplanned weight loss of more than 10% body weight over a six month oeriod is a prognostic indicator of poor clinical outcome..

Clinical techniques

Clinical history, in particular recent weight loss, a change in oral intake, gastrointestinal symptoms and functional capacity, combined with physical signs (muscle wasting, loss of subcutaneous fat and oedema) form the basis of the Subjective Global Assessment tool.

Biochemical markers

The plasma concentrations of proteins (albumin, pre-albumin.

transferrin and retinol-binding protein) have been used to assess nutritional status but none are particularly sensitive or specific.

The Nutrition Risk Index (NRI) is an equation using weight loss and serum albumin concentration. This equation is expressed as (1.519 x albumin g/L) + 0.417 x [present weight/ usual weight x 100). If the score is > 100 the patient is well nourished, 97.5-100 demonstrated mild malnutrition, 83.5-97 5 moderate malnutrition and

Delivery of nutritional support

The NICE guidelines recommend that nutritional support should be given to patients who have eaten little or nothing for more than 5 days, have poor absorptive capacity, high nutrient losses or have increased requirements due to catabolic processes. After patients are identified as malnourished, the route and type oi nutritional support must be decided. The usual approach to estimating a patient’s nutritional requirement is to estimate the energy requirements using the basal metabolic rate (BMR). Nutrition can be delivered by oral supplements, enteral or parenteral feeding, the route depending on an individual’s requirements and surgical condition. Enteral feeding has largely been regarded as superior to parenteral feeding, as it is cheaper, safer and “more physiological” but studies show this is not always the case. Both methods require quality care and positioning of the feeding tube TPN is life saving where there is intestinal failure. TPN requires a skilled support team

There are many unanswered questions about support nutrition. The general belief that this is an important support therapy.

Moyes and McKee 2008 A review of surgical nutrition . Scottish Medical Journal vol 53 pp 38-41

Open chromatin and diabetes —

A new study has identified a large number of open chromatin regions harboring active regulatory elements in human pancreatic islets. A type 2 diabetes–associated SNP in TCF7L2 was found to be located in a region of allele-specific open chromatin and shows allele-specific enhancer activity, suggesting a potential mechanism for this disease association. The prevalence of type 2 diabetes (T2D) has increased rapidly worldwide over the past several decades, a phenomenon that has been ascribed to the collision between an inherited predisposition and a westernized environment. Although the disease is characterized by impairments in both the secretion and the action of insulin, an inability of pancreatic beta-cells to increase insulin secretion so as to compensate for a decrease in insulin action precedes disease onset

DNA in eukaryotes is packed into chromatin. The basic component of chromatin is the nucleosome consisting of DNA wrapped around a histone octamer. Inside the cell nucleus, chromatin is folded into higher-order structures through various mechanisms, including repositioning of nucleosomes along the DNA, packing of nucleosomes into more condensed 3-dimensional configurations, looping of chromatin fibres, and tethering of chromosomal regions to nuclear structures. In such a particular context, the transition from a repressed compacted chromatin to a rather extended fibre is necessary for transcription. The chromatin opening includes three events, the initial factor getting access to nucleosome DNA, local chromatin opening mediated by activator/coactivator, and transcription associated with extensive chromatin opening. Chromatin dynamics, which is DNA sequence dependent, and also occurs in condensed fibre, provides the opportunity for activators binding to DNA. Coactivators recruited by the activator open the chromatin locally. However, it appears that genes adopt distinct chromatin opening mechanisms according to whether the gene is induced expression, developmental and tissue-specific expression, or constitutive expression. In contrast to transcription initiation-related local chromatin opening, large scale of chromatin opening is associated with a functional enhancer as well as high transcription rate.

The role of chromatin in the pathogenesis of diseases has attracted broad interests from the clinicians. Cis-elements of chromatin DNA helps defining the functional segments within the genome, which provide indispensable evidences to bio-informatics, and to the linkage between genomics and proteomics. The assembly of chromatin from multiple bio-active molecules displays new functions on gene activity.

Groop (2010 Open chromatin and diabetes risk,) Nature Genetics 42, 190 – 192 (2010)

P53 and Stress —

This is such an intriguing paper. Many lay people believe that there is a relationship between stress and the development of cancer. The tumour suppressor p53 is activated following stress and initiates a heterogeneous response in a cell-, tissue- and stress-dependent manner. This heterogeneity is reflected in the different physiological outcomes that follow p53 activation. One mechanism that may contribute to this variability is the promoter selectivity of p53 target genes. p53 is at the hub of numerous signalling pathways that are triggered in response to particular stresses, all of which can leave their mark on p53 by way of post-translational modifications and interactions with cofactors. The precise combination of these marks, much like the bars in a barcode, dictates the behavior of p53 in any given situation.

I am not sure what this tells us but there is the beginning of a revelation here.

Murray-Zmijewski et al 2008 A complex barcode underlies the heterogeneous response of p53 to stress

Nature Reviews Molecular Cell Biology 9, 702-712

Phytosterols —

Phytosterol-stanol enriched margarines are an attractive method to reduce the blood lipids.

In an extensive study in Holland groups of individuals using either cholesterol lowering drugs or phytosterol-stanol enriched margarines, or both cholesterol lowering drugs and phytosterol-stanol enriched margarines and a control group were looked at over a 5 year period.

The reduction in lipid concentrations on average was

Cholesterol lowering drugs – -17%

Phytosterol stanol enriched margarine – -4%

cholesterol lowering drugs, plus phytosterol-stanol enriched margarines -29%

control 0%

The conclusion was that on their own the phytosterol-stanol enriched margarines were of modest value but with cholesterol reducing drugs had an enhancing effect.

Jong et al 2007 Exposure and effectiveness of phytosterol/stanol-enriched margarines

Nutrition in the Aetiology of Disease
Prostate – Soya

Prostate cancer is an important and increasing public health problem. It is the second most common cancer in men after lung cancer, and accounts for 10% of all male cancer-related deaths. Within the last three decades. prostate cancer incidence in Scotland has more than doubled, with 2335 cases of Prostate cancer diagnosed in 2002. The relatively low risk of prostate cancer in Asian populations compared with Western countries, suggests that dietary factors may influence the prevalence of and mortality from this disease. Of special interest is the group of plant-derived nutrients called phyto-oestrogens. in particular isoflavones (genistein, daidzein and equol) and lignans (enterolactone and enterodiol).

Isoflavones are found mainly in soybeans and soy products, foods that are consumed in far greater amounts by populations in Asia compared with those in Western countries. In Western countries, soy foods tend to be eaten most frequently by vegetarians and vegans. Isoflavone precursors are metabolised by the gut microflora to give rise to compounds such as daidzein, genistein and equol. Another group of phyto-oestrogens are the lignans; they are derived from the plant precursors matairesinol and secoisolariresinol which are present in a wide variety of plant foods, including linseed, legumes, cereals, fruits and vegetables. These plant precursors are metabolised by gut microflora into the lignans enterolactone and enterodiol.

The biological properties of phyto-oestrogens include antiviral, antiangiogenic and amioxidam properties Phyto-oestrogens possess weak oestrogenic activity, they compete with oestradiol in binding to the nuclear oestrogen receptor and also stimulate the synthesis of sex hormone-binding globulin, which in turn mediates the plasma levels of testosterone on which the growth, development, maintenance and function of the prostate gland is dependent. In addition, phyto-oestrogens can inhibit steroid-metabolising enzymes, including 5 α -reductase and aromatase. and also the cell signalling apparatus by the inhibition of tyrosine-specific protein kinases .

Several epidemiological studies support the role of phyto-oestrogens and soy foods in reducing cancer risk. However, this evidence is limited, in particular for prostate cancer with only a few studies examining this association usually in populations with high isoflavone/soy food consumption.

This study by Heald et al describes a population-based case-control study of diet, inherited susceptibility and prostate cancer undertaken in the lowlands and central belt of Scotland to investigate the effect of phyto-oestrogen intake and serum concentrations on prostate cancer risk. A total of 433 cases and 483 controls aged 50-74 years were asked to complete a validated FFQ and provide a non-fasting blood sample. Multivariate logistic regression analysis found significant inverse associations with increased serum concentrations of enterolactone and with the consumption of soy foods. However, no significant associations were observed for isoflavone intake or serum genistein, daidzein and cquol.

This study supports the hypotheses that soy foods and enterolactone metabolised from dietary lignans protect against prostate cancer in older Scottish men.

Heald et al 2008 Phyto-oestrogens and risks of prostate cancer in Scottish men. British Journal of Nutrition vol 98, 388-396

Prostate cancer: Phjto-oestrogens: Isoflaxones: Lignans: Sot foods

Nutrition in the Aetiology of Disease
QRISK —

The QRISK cardiovascular risk prediction was first published in 2007. The questionnaire predicts the chance of a cardiovascular event during the next 10 years. The questionnaire is available on the web and easily accessible through Google.

The questionnaire includes

Age, sex, systolic blood pressure, smoking status, serum cholesterol, : high density lipoprotein ratio, body mass index, family history of cardiovascular disease and social deprivation, and anti- hypertensive treatment. This questionnaire has been further validated in BMJ of 18th July 2009

Colins and Altman 2009 An independent external validation and evaluation of QRISK cardiovascular risk prediction: a prospective open cohort study. BMJ vol 339 pp 144-147.

Salt & Blood Pressure —

Blood pressure is the most important factor in the development of strokes and other cardiovascular diseases. The dietary intake of salt(sodium chloride) has a role in determining blood pressure and hypertension. This is well shown in clinical trials. This finding applies regardless of age, gender, ethnic origin, base line blood pressure and body mass.

Salt intake is a good predictor of the incidence of cardiovascular events.

There have been few studies on the benefits of reduced salt intake on clinical outcome as opposed to reducing blood pressure.

Cook and colleagues (BMJ 2007, vol 334, 885-8), now show the long term benefits of reduced dietary sodium on cardiovascular disease in people participating in controlled randomised trials of hypertension prevention and follow-up studies. More than 3000 participants without hypertension were randomised to a reduced sodium intake for 18 months or to a control arm. The reductions in sodium intake were 44 mmol/day and 33 mmol/day ( 2.6 and 2.0 g of salt), respectively. The results show that people originally allocated to either sodium reduction group had a 30% lower incidence of cardiovascular events in the next 10-1.5 years, irrespective of sex, ethnic origin, age, body mass, and blood pressure.

In 1985, the World Health Organization recommended that the average salt intake should be reduced to 5g per day or less. However, few countries- have policies for targeted reduction in salt intake.

In Westernised countries, people derive salt mostly from bread and processed food and only a small proportion comes from added salt. Any reduction therefore needs the involvement of the food industry.

In many developing countries, like those of sub-Saharan Africa, where the main source of salt is still added salt, there should be a place for education

Cook et al BMJ 2007, vol 334, 885-8

Cappuccio BMJ 2007, vol 335, pp 859-60

Sleep —

Sleep is an essential part of life . We spend a third of our life asleep. It is believed that growth takes place during sleep. As a thought do the developing adult obese grown fat during sleep.

Much is known about sleep intensity and levels of sleep eg REM ( Rapid eye movement ) Phase.

According to the Oxford University neuroscientist, Professor Russell Foster, adolescents have different sleep patterns to adults, and may need to lie around in bed all morning. In fact he believes that youngsters would achieve more if they were allowed to get up and start school later in the day. In the US and Germany, some schools have tried switching to later start times and have seen better exam results, as well as lower rates of truancy and depression.

Researchers in Germany, he added, have found that our sleep patterns change with age.We know teens want to go to bed two hours later than 40- to 50-ycar-olds and in 10% of them there’s a four-hour delay. It is interesting to know that the sleep patterns alter with age. Certainly the older one becomes, then the sleep pattern changes, for the worse.

The Week January 27th p 17

Smoking —

There is an exhibition at the Museum of London showing a history of smoking in London

Smoking cigarettes kills a Londoner every hour.

Cigarette butts account for 40% of the litter on London’s Streets.

Two million Londoners still regularly light up and smoke cigarettes.

Stomach 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.

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;

Strength-Mortality —

In a report coming from three counties , Sweden, Spain and the USA the association between muscular strength and mortality in men was examined

The cohort was 8762 men. After adjusting for age, physical activity , smoking, alcohol intake they found that an independent factor was muscular strength.

This is a strong protection against cardiovascular and respiratory disease and cancer.

They recommend regular resisting exercise involving the major muscle groups two or three times a week

Ruiz et al 2008, Association between muscular strength and mortality in men: prospective cohort study BMJ vol 337 92-96