diet and prognosis after colon cancer surgery

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.

anaphylatic response to synthetic folic acid

Food fortification with folic acid is the vogue. As nutritionists we must wonder why long term watching of folic acid dietary intake is not enough
In the Lancet 2007, Smith et al report a case of a woman who had well documented anaphylactic responses to 5 mg of synthetic folic acid
This is rare and may be related to the synthetic folic acid acts as a hapten
This is very rare but worth watching for.

osteoporosis, calcium and vitamin D supplementation

Osteoporosis is a progressive disabling bone condition where the bones soften as a result of bone resorption exceeding bone formation. Tang et al in a careful review of the prescription of calcium and vitamin D concluded that calcium ( 1200 mg / day ) or calcium plus 800 iu of vitamin D in addition to the calcium significantly and beneficially decreased bone loss and decreased fractures.
Notes of caution.
Many people fail to last the course of treatment and it is essential to take this supplement for years
It is better to start aged between 50-70 than older.
Be careful of too much calcium , we are talking of grammes per day can lead to hypercalcaemia, the milk alkali syndrome. Rare but exists. ( Kaklamanos and Perros 2007 Milk alkali syndrome without the milk , BMJ vol 335 397-8
(Tang et al 2007 Use of calcium or calcium in combination with vitamin D supplementation to prevent fractures and bone loss in people aged 50 years and older: a meta analysis Lancet vol 370 pp 657-66 and comment Reginster J-Y 2007, Calcium and vitamin D for osteoporotic fracture risk Lancet vol 370, 632-3)

probiotics and diarrhoea in children

Probiotics are all the rage. But not all act in an effective manner. In a clinical trial of young children aged 3-36 months a variety of five probiotics drinks were compared over five days
The trial was to ask the children’s parents purchase a specific probiotic product: oral rehydration solution (control group); Lactobacillus rhamnosus strain GG;Saccharomyces boulardii; Bacillus clausii; mix of L delbrueckii var bulgaricus, Streptococcus thermophilus,L acidophilus, and Bifidobacterium bifidum; or Entemcoccus faecium SF68.
The outcome of success was judged by duration of diarrhoea and daily number and consistency of stools. Secondary outcomes were duration of vomiting and fever and rate of admission to hospital. Safety and tolerance were also recorded.
The median duration of diarrhoea was significantly shorter (P<0.001) in children who received L rhamnosus strain GG (78.5 hours) and the mix of four bacterial strains (70.0 hours) than in children who received oral rehydration solution alone (115.0 hours). One day after the first probiotic administration, the daily number of stools was significantly lower (P<0.001) in children who received L rhamnosus strain GG and in those who received the probiotic mix than in the other groups. The remaining preparations did not affect primary outcomes.
Not all commercially available probiotics preparations are effective in children with acute diarrhoea.
Canani et al 2007 Probiotics for treatment of acute diarrhoea in children: randomised clinical trail of five diffeent preparations. BMJ 335, 340-2

Huntington's disease and ubiquitin

Huntington’s disease or Huntington’s chorea is a terrible dominantly inherited neurodegenerative disease. The basis of this problem is an accumulation of fragments of polyglutamine expanded protein in affected neurons. There is also in Huntington’s disease and Alzheimers an abnormal enrichment of ubiquitin . . Ubiquitin metabolism may be in disarray. Ubiquitin is widely found in cells and nuclei and undergoes an ATP dependent reaction with proteins with condensation of its terminus with lysine amino groups. Cyclin degradation in the control of the cell cycle is triggered by ubiquitination .
Huntington’s disease is thought to be secondary to quite wide spread changes in ubiquitin metabolism.
Bennett et al 2007 Global changes to the ubiquitin system in Huntingdon’s disease.

population arsenic poisoning in Bangladesh

Many water wells in Bangladesh are contaminated with arsenic. More than 70 million people are affected. In the 1970s and 80s various International Agencies joined together to dig wells to allow the population access to clean water.10 million wells were dug , but the presence of arsenic was unsuspected and untested for.
The arsenic is a fluke , the result of leaching from the Himalayan mountains and carried down over thousands of years. The amount of arsenic is 5 to 10 times the upper limits of safety.
The result is a terrible poisoning with 27 million drinking water with over 50 ppb arsenic and 50 million 10 ppb, the safe concentration. The food produced from plants watered by contaminated water may also be poisonous.
The safe concentration may be 1.7 ppb.
The poisoning includes blackening of the hands and feet, nodular growths and gangrene and ulcers. Cancer can be a later development.
The Lancet describes the valiant attempts of Joseph Graziano and his colleagues from Columbia University USA to try and remedy this.
The work includes clinical care but perhaps central to the whole study is to dig new wells often close to the poisoned wells which produce clean water.
Loewenberg S 2007 Scientists tackle water contamination in Bangladesh Lancet vol 370, 471-2
Loewenberg S 2007, Profile Joseph Graziano : tackling arsenic poisoning in Bangladesh. Lancet. Vol 370 p 477

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.

Medieval Islamic Medicine

Medieval Islamic Medicine published by Georgetown University and Edinburgh University Press
by Peter Pormann and Emilie Savage-Smith
Reviewed by Yasmin Khan in Nature 2007 Medical History without Frontiers vol 448, 870

Islamic medicine has a long history especially in the medieval period of over thousand years and derives its past form vast geographical regions from Spain and North Africa in the west, to central Asia and India in the east. Its origins were the Islamic faith, but also collaboration of Muslims with non-Muslims, who used Arabic to publish heir ideas. .
The book describes the origins of Medieval Islamic medicine and the subsequent contacts with medicine in other cultures.
Muslims saw the body as well as the soul as precious, because it was derived from and accountable to God as the creator. The body therefore required constant and dutiful care. The body was to be maintained and preserved and protected from abuse. These concepts were drawn from ancient Greece and added to by the Islamic faith.
The book emphasizes the influence on early Muslim medical practitioners by Unani Tibb, an Islamic medical tradition dating from early Greek medicine. This involved balancing, through diet and medicinal herbs, the four humours air, earth, fire and water, which correspond to the four bodily fluids blood, phlegm, black bile and yellow bile and understanding that a good environment and spiritual peace are essential for good health. Today such a holistic approach to well-being, although experiencing a resurgence, is outside mainstream modern medicine.
There was a tradition of free specialized treatment which has its modern equivalence in the National Health Service.

RNA and gene control

The discovery of DNA and RNA was to describe the anatomy of the mechanism whereby heritable information was transferred from generation to generation.
Now the physiology and biochemistry of the mechanism is being described.
Ericka Check in Nature 2007, Hitting the on switch , 448, pp 855-868 discusses RNA interference. This is the process whereby small pieces of RNA regulates the expression of genes. RNA has been seen as the carrier pigeon of the system, that DNA is all. RNA however is important in controlling the transfer of information held by DNA.
Small strands of RNA stick together in pairs and can turn off specific genes. Short interfering RNAs ( siRNAs ) ( also known as short hair pin RNAs ( shRNAs). These act by using a protein (RISC) to cut up the longer messenger RNAs. The small RNAs are able to target messenger RNA through their sequence matches and destroy the messenger RNA. There are also more than 500 miRNA which are directly encoded by DNA.
Methylation has been seen as a prime silencer of gene activity.
It is also possible that the interference pathway may activate genes. if this is the case then a whole new approach to molecular Biology is waiting to be discovered.

surgery and obesity

In the June/July 2007 American Gastroenterology Perspectives there are two very interesting articles. One on the future of treatment of Crohns disease
The second is Technologies in the pipeline for obesity., by Susan Yanovski. P 9 and 15.
Obesity is a scourge of Western affluent society. The surgeons have inevitably something to offer.
The laparoscopic banding of the stomach.
Intragastric balloons
Implantable gastric electrical stimulators
Vagal pacemakers
Vagal blockers
Deep brain stimulation with electrode pacemakers

The food industry is looking at nice food with little calorie content ( fruit and vegetables ?)

Games industry
Video games which stimulate exercise..

surgery and obesity

In the June/July 2007 American Gastroenterology Perspectives there are two very interesting articles. One on the future of treatment of Crohns disease
The second is Technologies in the pipeline for obesity., by Susan Yanovski. P 9 and 15.
Obesity is a scourge of Western affluent society. The surgeons have inevitably something to offer.
The laparoscopic banding of the stomach.
Intragastric balloons
Implantable gastric electrical stimulators
Vagal pacemakers
Vagal blockers
Deep brain stimulation with electrode pacemakers

The food industry is looking at nice food with little calorie content ( fruit and vegetables ?)

Games industry
Video games which stimulate exercise..

Institutionalised starvation

One of the most common causes of population wide malnutrition is the indifference of governments or a deliberate plan by governments to use food as a political weapon.
One good example of this was the policy introduced by Stalin in the 1920s. The successful plan allowed starvation in the Ukraine in order to bring the protesting peasants into control through starving millions to death.
This State tyranny has been followed in the extermination camps of the Nazis and elsewhere.
In the report of the Solidarity Peace Trust reported in Medicine, Conflict and Survival 2007, vol 23, 153-171, similar tactics are being followed in Africa by the Zimbabwe. The use of food as a political weapon.
This method of subjugating populations still goes on.

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.
Hypertension remains a problematic disorder, even in developed countries with functioning health-care sys­tems, a large number of available effective treatments, and overwhelming research evidence in relevant popula­tions, for several reasons. Screening for hypertension is not done systematically and the diagnosis is often made at a late stage when target-organ damage has already happened. The optimum time to start treatment remains under discussion. As is the pressure at which treatment hould start.

genistein and bone mineral density

A reduction of bone mineral density of less than 0.795g/cm3 is called osteopenia and is associated with increased spontaneous bone facture. This is found more frequently in post menopausal women.
The phytoestrogen genistein has been shown to significantly increase bone density in a trial reported in the BMJ 2007, vol 335, p 299 from the original paper ( Marini et al Effects of the phytoestrogen genistein on bone metabolism in osteopenic postmenopausal women : a randomised trial Ann Intern Med 2007; 146: 839-47).
The women in the trial took 54 mg of genistein each day, 20% withdrew because of gastrointestinal effects ( constipation and dyspepsia ) .
Bone metabolism improved in the women who took the genistein and bone mineral density improved by at least 20%.
Another example of the role that plant secondary metabolites can have in humans. However it would be better to find a low dose primary nutritional source eaten over a life time than a larger dose with unknown as yet potential complications ( maybe , maybe not)

methylation and all that

Methylation and all that
Mammals use methylation for the heritable silencing of retrotransposons and imprinted genes and for the inactivation of the X chromosome in females.
The establishment of patterns of DNA methylation during gametogenesis depends upon DNMT3L, an enzymatically inactive regulatory factor that is related in sequence to the DNA methyltransferase DNMT3A and DNMT3B. DNMT3L interacts with the end of a histone H3 which in turn is inhibited by methylation of the histone H3.
Histone methylation is central for regulating chromatin structure, gene transcription and the epigenetic state of the cell.
This is not obscure yawn material but has significance in
1.this is how the heritable factors held in DNA are controlled, and the role of the proteins histones.
2. Methylation may well be dependent upon dietary elements , folic acid, vitamin B12 comes to mind. Clearly this is a guess but this is fascinating
Ooi et al DNMT3L ( 2007 ) connects unmethylated lysine 4 of histone H3 to de novo methylation of DNA. Nature vol 448, 714-717
Lan et al ( 2007 ) Recognition of unmethylated histone H3 lysine 4 links BHC80 to LSD1-medaited gene expression. Nature vol 448, 718-722

Jasmonates

Jasmonates are essential phytohormones for plant development and survival. They are the major lipid in the jasmine scent. However they are important in plant development processes, response to environmental stress, wounding , water deficit, and pathogen and pest attacks, root growth , fruit ripening, tendril coiling, reproductive development and senescence. .
They are synthesised from linolenic acid, and are structurally related to prostaglandins.
A paper in Nature
Chini et al 207 The Jaz family of repressors is the missing link in jasmonate signalling. Nature vol 448, 666-671 ,
This paper discusses the negative regulatory feed back loop that jasmonate is involved in the plant.

iron metabolism

There is a brilliant review of iron metabolism and the implications for deficiency in the Lancet
Zimmermann and Hurrell Nutritional iron deficiency 2007 Lancet 370, 511-20
Estimates of iron deficiency in developed countries are usually derived from specific indicators of iron status. These are expensive so in developing countries estimates are often based on haemoglobin alone which does not allow for other causes of anaemia , eg vitamin A deficiency), infectious disorders (particularly malaria, HIV disease, and tuberculosis), haemoglobinopathies, and ethnic differences in normal haemoglobin distributions.
WHO estimates that 39% of children younger than 5 years, 48% of children between 5 and 14 years, 42% of all women, and 52% of pregnant women in developing countries are anaemic, with half having iron deficiency anaemia. Iron deficiency is also common in women and young children in industrialised countries. In the UK, 21% of female teenagers between 11 and 18 years, and 18% of women between 16 and 64 years are iron deficient.. Other countries have similar figures.
Human beings are unable to excrete iron actively, so its concentration in the body must be regulated at the site of iron absorption in the proximal small intestine . Diets contain haem and non-haem (inorganic) iron; each form has specific transporters. There is an intestinal haem iron transporter which is upregulated by iron deficiency, which may also transport folate. Transport of non-haem iron from the intestinal lumen into the enterocytes is mediated by the divalent metal ion transporter 1 which transports only ferrous iron, but most dietary iron that enters the duodenum is in the ferric form. Therefore, ferric iron must be first reduced to ferrous iron, possibly by the brush border ferric reductase, duodenal cytochrome b or by other reducing agents, eg ascorbic acid. Inside the enterocyte, iron may be stored as ferritin or crosses the basolateral membrane into the blood, controlled by the transport protein ferroportin 1, and the iron oxidase, hephaestin.
When red cell are old they are broken down in the spleen and the freed iron binds to transferrin , which binds to transferrin receptors in the bone marrow and this iron is incorporated into new red cells.
Within cells, iron status upregulates or downregulates ferritin and transferring receptors important in iron homeostasis by binding at the post-transcription level iron regulatory proteins to specific non-coding sequences in their mRNAs, called iron-responsive elements. Various genes are modulated by iron status, many of these genes are not directly related to iron metabolism.
During gestation, the fetus stores about 250 mg of iron which is used during breastfeeding, as breastmilk supplies only about 0-15 mg of absorbed iron per day, whereas requirements for absorbed iron are about 0-55 mg per day. Low birth weight infants do not store sufficient iron and are at risk of developing iron deficiency while being breastfed. During growth in childhood, about 0-5 mg of iron per day is absorbed in excess of body losses; adequate amounts of iron during growth typically results in a 70-kg man accumulating about 4 g of body iron. About 2-3 g of body iron is within haemoglobin and about 1 g is stored as ferritin or haemosiderin, mainly in the liver. Men absorb and excrete about 0-8 mg of iron per day, and women, during childbearing years, should absorb almost twice as much (1 -4mg per day) to cover menstrual losses. The usual diet of a population strongly affects iron bioavailabiiity,so that recommended intakes for iron depend on diet characteristics.
Nutritional iron deficiency arises when physiological requirements cannot be met by iron absorption from diet. Dietary iron bioavailability is low in populations eating plant-based diets with little meat. In meat, 30-70% of iron is haem iron, 15-35% of which is absorbed.” However, in plant-based diets most dietary iron is non-haem iron, and its absorption is often less than 10%. The absorption of non-haem iron is increased by meat and ascorbic acid, but inhibited by phytates, polyphenols, and calcium.The needs for iron increase in infants and young children, adolescents, and in menstruating and pregnant women.
Increased blood loss from gastrointestinal parasites aggravates dietary deficiencies in many developing countries.
During the first two trimesters of pregnancy, iron deficiency anaemia increases the risk for preterm labour, low birthweight, infant mortality, and predicts iron deficiency in infants after 4 months of age. Data for the adverse effects of iron deficiency on cognitive and motor development in children are equivocal because environmental factors limit their interpretation
Strategies
There are three main strategies for correcting iron deficiency in populations, alone or in combination: education combined with dietary modification or diversification, or both, to improve iron intake and bioavailability; iron supplementation (provision of iron, usually in higher doses, without food); and iron fortification of foods. A new approach is biofortification through plant breeding or genetic engineering. Although dietary modification and diversification is the easiest , changing dietary practices and preferences is difficult, and foods that provide highly bioavailable iron (such as meat) are expensive.
For oral supplementation, ferrous iron salts (ferrous sulphate and ferrous gluconate) are preferred as they are cheap and have high bioavailability. Standard therapy for iron deficiency anaemia in adults is a 300-mg tablet of ferrous sulphate (60 mg of iron) three or four times per day.
Iron fortification is probably the most practical, sustainable, and cost-effective long-term solution to control iron deficiency at the national level. Fortification of foods with iron is more difficult than it is with other nutrients, such as iodine in salt and vitamin A in cooking oil. The most bioavailable iron compounds are soluble in water or diluted acid, but often react with other food components to cause flavour, and colour changes, fat oxidation, or both.Thus, less soluble forms of iron, although less well absorbed, are often chosen for fortification to avoid unwanted sensory changes.

ethics commitees and our debt to Maurice Pappworth

Having written about human experimentation ethics committees and remembered Maurice Pappworth I looked at his book written in 1967 again. He was a very great and courageous man.
This was written some 12 years after eminent German physicians who had acted as wartime Nazi experimenters on Jewish captives.
The experiments he discusses on unwitting unknowing patients the young and babies, individuals with learning disabilities and prisoners can hardly be countenanced today. He carefully demolishes all logics for such experiments and this includes experiments on oneself.
Yet many everyday clinical techniques date from those times. Though in fairness the first experiments on ultrasound were conducted on a piece of butchers steak.
There can never be too much time spent in planning experiments, and explaining to the subjects if indeed they are involved .
Perhaps the question should always start, could these experiments be done on tissue isolates , preferably yeast.
I thought of having to explain to a family what went wrong which is a painful thought. Even more so for the individual and the family.
This book
Human Guinea Pigs, experimentation on man MH Pappworth Routledge and Kegan Paul 1967
is a salutary read, at times very painful and brings back memories of experiments in a nearby Professorial Medical Unit when I was a junior doctor.
So when one goes through the tedious pernickety process of an Ethics Committee be thankful.

ethics committees

Ethics committees are central to all research. As the pressures increase on individuals to promote research then it is inevitable that short cuts may be taken.
Also a few Ethics committees can be ponderous, pompous and very long winded.
In an article in nature 9 Ledford H 2007 Trial and error Nature 2007 448, pp531-3
there is an interesting article on the problems confronting ethics committees in a litigious society.
I was for many years the chairman of an ethics committee and the problems were real.
I remember once someone complaining to a friend and colleague that his project had been refused, the response was surely no one would ever do that to another human being. End of complaint.
The history of ethics committees is of brave knowledgeable people complaining that the famous and influential in the profession could do what they wanted to patients.
As with many well-intentioned efforts in the field of health care the legitimate concerns about protecting the rights and welfare of human subjects participating medical research have now assumed a life of their own.
Until the mid-part of the 20th century there were few concerns regarding medical ethics. This changed in 1946 when 20 high-ranking Nazi physicians were placed on trial in Nuremberg, Germany and charged with war crimes against humanity for performing experimental procedures on human beings without their consent.
In 1966, Henry Beecher, a physician from Harvard University and, in 1967, Maurice Pappworth, physician from London published evidence that there were significant abuses in the conduct of research involving human subjects at many of the leading medical research institutions in America and Britain. From this point many people gathered behind the need to have ethics committees.
Maurice Pappworth(1910-1994 ) suffered grievously at the hands of the Medical Establishment for his publications and out spoken approach. He is not mentioned in the paper. He wrote a very damning account of what was happening in Human Guinea Pigs, published in 1967. Many of the great in medicine mentioned in that book never forgave him.
At the "grass roots" level came to the creation of Human Subject Research Review Committees at medical facilities throughout the Britain and the United States. These Committees were originally organized for the expressed purpose of protecting the rights and welfare of patient participants in medical research projects and to make research and patient and volunteers safe.

mapping chromatin and understanding epigenetics

A very interesting problem is that of why do cells differ in their formation and in structures. Bone cells in bone being different to say liver cells in liver.
Yet they have identical genome structure. Even more complicated are multicellular structures.
The basis of this different form lies in the chromatin state. Chromatin is the combination of histones and other proteins in a package with the DNA. In an explanatory article Baylin and Schuebel ( The epigenomic era opens 2007 Nature 448, 548-9 )describe chromatin as the software for the readout of the DNA hard drive.
If there is a change in the hard drive ie in the primary sequence of the DNA then a genetic alteration or mutation occurs
If the change is due to a change in the chromatin then there is an epigenetic change which is an alteration in the heritable states of DNA function. This is the expression and interaction of genes especially during the development process. There is no change in gene structure. Epigenetic change is the mechanism whereby there is flexibility in gene expression and the same genome package produces different cellular structures in the same organism.,
The central unit of chromatin is the nucleosome, which is constructed from short regions of DNA wound around an octet of histone proteins. This unit can modulate the readout from DNA in at least three ways.
1. nucleosomes can be physically rearranged on DNA by complexes known as chromatin-remodelling proteins, the greater the distance between nucleosomes, and hence the ‘openness’ of chromatin, the higher the likelihood that such regions of DNA will be transcribed into RNA.
2. many nucleosomes can be compacted into higher-order aggregates to form closed chromatin, or heterochromatin, thereby preventing transcription. The balance between the open and closed parts of the genome facilitates proper gene-expression patterns in given cell types, and also prevents unwanted gene transcription.
3. there is a complex interplay between enzymes that can modify particular amino acids in the histone component of the nucleosomes, and those that reverse the modifications. The modifications, or histone ‘marks’ interact with proteins that bind to and interpret them. The marks were initially seen as a histone code’, the idea being that a restricted number of them would specify the ‘on’ or off state of RNA production from DNA .
4. the constituents of chromatin, and nucleosome structure, position .and modification, are highly complex. It is a balance between these factors that marks an individual gene, or groups of genes, for various levels and states of expression”.
. Mikkelsen T S, et al in a paper entitled
Genome-wide maps of chromatin state in pluripotent and lineage-committed cells 2007 Nature 448 553-9 report the application of single-molecule-based sequencing technology for profiling histone modifications in mammalian cells. They found that lysine 4 and lysine 27 trimethylation effectively discriminates genes that are expressed, poised for expression, or stably repressed, and therefore reflect cell state and lineage potential. Lysine 36 trimethylation marks primary coding and non-coding transcripts, facilitating gene annotation.
Trimethylation of lysine 9 and lysine 20 is detected at satellite, telomeric and active long-terminal repeats, and can spread into proximal unique sequences. Lysine 4 and lysine 9 trimethylation marks imprinting control regions.This study provides a framework for the application of comprehensive chromatin profiling towards characterization of diverse mammalian cell populations.

cancer and ALK tyrosine kinase

Lung cancer is the major and most preventable cause of cancer world wide. 80% of these tumours are non-small cell lung cancers. An article and a summarising article in Nature
Meyerson M Broken genes in solid tumours Nature 2007, 448, 545-6
Soda M Identification of the transforming EML4-ALK fusion gene in non small cell lung cancer. Nature 2007, 448,561-566
Shows that a position change of a gene associated with this form of cancer on chromosome 2 activates the gene ALK which encodes ALK tyrosine kinase. Tyrosine kinase regulate the activity of other proteins by adding phosphate to their tyrosine groups. The inhibition of such a gene expression has great potential in cancer therapy. And for a nutritionist these findings indicate that these transfer reactions may be amenable to some dietary change . Who know?.

the use of probiotics to prevent antibiotic complications

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

Oats, bile acids, cholesterol revisited.

Nearly 40 years ago I began to study fibre and bile acids turnover. I showed the binding of bile acids to fibre and in particular the lignin element. Dave Kritchevsky and Jon Story later and independently showed the same phenomenon. Experiments with feeding wheat bran failed to show any effect of wheat bran
Now at regular intervals repeat experiments appear, fresh as a daisy showing the association between fibre and bile acids
It is nice to see the work reconfirmed
Elleglad L and Andersson H 2007, Oat bran rapidly increases bile acid excretion and bile acid synthesis: an ileostomy study. European Journal of Clinical Nutrition 61, 938-945
The real puzzle in working out what is the mechanism of the hypo- cholesterolaemic effect of fibre and in particular rolled oats is what is happening in the colon. There is undoubtedly an increased flow of bile acids through the ileum into the colon. There is bacterial fermentation of bile acids and the oats in the colon. This is the big variable influencing how much bile acid is lost in the faeces. Is there a quantitative as well as a qualitative element. Does the chemistry of the bile acids returning to the live from the colon have a different effect of HMG reductase to the conjugated bile acids returning form the ileum
This question has not been resolved yet.

Recommended nutritional Intakes for Children

Energy and reference values for European Children ( Prentice A et al Brit J Nutrition 2004, 92, S83-S146
National reference values for children aged 2 to 18 years across Europe are very varied.
The formulation of dietary reference values and nutritional recommendations require an understanding of the physiological requirements of a healthy individual.
The best definition of a physiological requirement should be
1.the amount and chemical form of a nutrient to maintain normal health and development without disturbance of the metabolism of any nutrient. An intake sufficient to meet physiological requirement which will differ between individuals
2. the amount of the nutrient or energy that will meet needs, in the environment in which the community lives using local foods.
The purpose of .nutritional reference values is to maintain and promote health and quality of life, and the vital metabolic and psychical and psychic functions in nearly all of the healthy individuals population. It is desirable to allow for the establishment of suitable body stores. Also to prevent nutrient-specific deficiency diseases .and deficiency symptoms.. but not in excess.
Central to the dietary reference values and recommendations is an understanding of the bioavailability of dietary nutrients; that is how much actually gets into the body and is available for metabolic and physiological functions. Bioavailability means the whole of absorption, distribution, metabolism and excretion. Bioavailability is affected by the composition of the diet, the chemical form of the nutrient and the nutritional status of the individual regarding that nutrient.
Bioavailability varies with age, with physiological state (e.g. puberty, pregnancy, lactation) and with nutritional status. For example, the absorption of many minerals increases during puberty and pregnancy, and excretion decreases. Metabolic adaptation in individuals with small body stores can lead to increased absorption efficiency in some situations but can also lead to smaller physiological requirements in others. Physiological requirements differ between different organ and tissues of the body.. A good example of this is the active transport of nutrients across the placenta in pregnancy.
The term Recommended Dietary Allowance for a nutrient was first used in 1941 to enable food rationing to be a safe policy for the population. The definition is the average amount of a nutrient which should be provided per head of a group of people if the needs of practically all of the population are to be met. Recommended has now been replaced by ‘reference value”.
Different countries have defined nutritional requirements, recommendations and reference values, and nutritional guidelines for their own populations. The guiding principle being that physiological requirements differ between individuals and that the handling of nutrients by the body may be substantially affected by environmental and individual factors.
The Scientific Committee on Food of the EU defined three reference values to describe the distribution of required dietary intakes within age- and gender-specific subgroups of the population:
1. The mean intake to meet the average physiological requirement, the Average Requirement (AR);
2. The 97.5th centile (mean + 2SD>, the Population Reference Intake being “theintake that will meet the needs of nearly all healthy people in the population or group”
3. The 2.5th centile (mean-2SD), the Lowest Threshold Intake , the intakebelow which nearly all individuals in the population or group will be unable to maintain metabolic integrity according to the criterion chosen”.
The UK used different terminology for the three Dietary Reference Values (DRV):
1. Estimated Average Requirement (EAR);
2. Reference Nutrient Intake (RNI = EAR +2SD)
3. Lower Reference Nutrient Intake (LRN1 = EAR —2SD).
All the definitions assume that the distribution is normal so that the standard deviation can be used to describe upper and lower values.
The USA/Canada, the Standing Committee on the Scientific Evaluation of Dietary Reference Intakes (Food and Nutrition Board. 1997) adopted a similar framework for the derivation of Dietary Reference Intakes
1. Estimated Average Requirement (EAR) as ‘the average daily nutrient intake level estimated to meet the nutrient requirement of half the healthy individuals in a particular life stage and gender group”;
2. Recommended Dietary Allowance (RDA) as “the average daily nutrient intake level estimated to meet the nutrient requirement of nearly all (97 to 98 per cent) healthy individuals in a particular life stage and gender group’.
When there is insufficient data to confidently give a recommendation the US/Canadian committee defined Adequate Intake (AI). , the “recommended average daily nutrient intake level’, to be used ‘when an RDA cannot be determined’
In recent years, the concept of an upper limit has been introduced, to define nutrient intakes which might be excessive and detrimental to health,. In the EU . an Upper Tolerable Nutrient Intake Level and the USA/Canada (Food and Nutrition Board. a Tolerable Upper Level

Nutrition needs in European Children

The British Journal of Nutrition devoted a supplement to the topic of Nutritional needs of children. This is a must read for nutritionists. ( BJN Vol 92, Supplement 2 October 2004 pp S 67-232)
This report based on two expert committees and gives an overview of the analysis of children’s nutritional needs in Europe. The data currently is diverse, based on a wide range of national criteria and often extends only to age 2years.
The nutrient needs of children include high and specific needs for nutrition particularly at times of rapid growth, infancy , pre school period and pre-pubertal period. Children have needs based on gender, metabolic needs including turnover, growth development and differentiation, physical activity and eating patterns and changing body composition with age.
The child is not a small adult but a future adult.
They have high metabolic demands but little body storage capacity, very much a just on time provision. As the modern child has quite an long expectation of life the laying down of healthy tissues is important.
Values for children are often extrapolated from adult values on a data per body weight or body surface area. The problems are compounded by the sometimes poor data that the calculations are based on.
Terminology is also a problem, Population Reference Values, Reference Values for Nutrient Intake , Dietary Reference Intake are used in different parts of Europe. . The use of these reference values vary.
Reference values are used for labelling of nutrient content of foods. Or recommending food intakes for populations.
It is also important to know what should be and what is actually eaten in the face of over eating and the current high prevalence of Obesity.
The eating patterns of children are changing across Europe. More time is spent watching television ands snacking. The orderly pattern of breakfast, lunch and evening meal consisting of home made foods may no longer be the pattern for many. The portion size of prepared foods is increasing. Overweight is not necessarily due to eating too much food and the problem is clearly complex.
The review gives detailed data for all nutrient requirements, country to country.
Food and eating habits are changing across Europe especially with a more global view and also better economic status. . Water intake and how the water is drunk is important, and need to be calculated along with metabolic water. . Sugary soft drinks, tea or plain water will have a different impact on the person. Also the ambient temperature and physical activity will influence water needs
The diet may influence cognition and behaviour in children. Whether or not the child eats breakfast is important.

bioavailability or nutrient handling

•
• The British Journal of Nutrition has a very good Supplement on The Nutritional Needs of Children
• BJN 2007, vol 92, pp S 67-S 232 Editors Koletko B, et al
•
• In deciding how much should of a nutrient be recommended it is important to define Nutrient Handling.
• This is an interesting concept and identifies the different variables when food and its constituents are eaten.
•
• 1. Dietary intake (of foods or nutrient mixtures); impact of processing and preparation.
• 2. Milieu within the gastrointestinal tract (matrix effects, intraluminal nutrient interactions, gut transit time).
• 3. Mucosal binding.
• 4. Mucosal cell uptake.
• 5. Mucosal export (portal circulation or mesenteric lymphatic transport).
■ 6. Hepatic uptake.
• 7. Organ (including liver) clearance.
• 8. Biliary clearance and excretion.
• 9. Systemic circulation and peripheral distribution.
• 10. Renal clearance and excretion.
• 11. Peripheral tissue utilisation (e.g. metabolic/catabolic use. structural roles) and deposition.
Each nutrient can then be individually assigned one or more of these key steps as being rate-limiting for its utilisation.
Another variable will be age as these variable will be different at different ages of development.
However I was very interest ed to note that a very important variable the speed and length of time spent eating was not mentioned. This is an enormous variable and very neglected, by all but the traditional French eaters.

Thoughts on the aetiology of obesity

In a previous blogg I pondered on the aetiology of obesity and wondered
if there was an infective element.
Interesting there is a paper in New Engl J Med 2007, 357, 370-9 which describes the social nature of obesity. Close contacts tend to be obese together. Obesity gathers in clusters. Siblings, husbands and wives but not to neighbours. Might fit with an infection.
Another thought is that obesity and snacking go together. To snack usually means to eat crisps, biscuits and other high energy foods. It is of course possible that the E number compounds in these foods may have a deleterious effect on the eaters and have an influence on intake , metabolism and storage of fat.

English Channel and climate

Until 12000 years ago the south of England and the north of France were drained by a substantial river which passed through a vast shallow valley. Rivers which drained into this giant river included Rhine, Meuse, Thames and Schelde,
For most of the previous 50 million years the English Channel was a marine embayment but then the most recent glacier period changed the topography.
The level of the sea has varied considerably and was at some point 20000 years ago the sea was 100 meters below the present levels.
It is now suggested that the level of water in the English Channel is dependent upon the global climate and glacial periods when there is land contact between Britain and Europe.. The existence of the channel depends upon the general temperature and the presence of an ice age or not.
The development of the Channel has had profound effects on migration into Britain. It has also cut Europe adrift from Britain and they have been denied the glories of Cricket, wearing socks with sandals and fish and chips
Gibbard Europe cut adrift Nature 2007, vol 448, 259-60
Gupta S Catastrophic flooding origin of shelf valley systems in the English channel Nature 2007 vol 448 , 342-345
Another interesting paper discusses the origins of modern humans.
Manica et al The effect of ancient population bottle necks on human phenotypic variation , Nature 2007, vol 448, 346-8
This study using human skull measurements supports the hypothesis that modern humans originate from a single location in central or southern Africa. There is a smooth loss of genetic diversity with increasing distance from Africa. Extending as far as the most distant migration across Northern Europe into the Northern and then Southern Americas.

pregnacy, weight and maternal and foetal health

Weight and pregnancy
Pregnancy makes great demand on a woman’s body, though this is accompanied with the joy of the development of a new person.
Apparently half of pregnancies are unplanned.
World wide over 1 billion adults are overweight and 300 million clinically obese. In the USA the prevalence of obese women in the age group 20-39 years has risen from 9 % in 1960-62 to 28% in 1999—2000.
A large Swedish study of more than 200,000 pregnant women studied changes in body mass index from the beginning of the first pregnancy to the second pregnancy and maternal and perinatal outcomes.
Only, modest increases in weight of 1 to 2 units resulted in increased ill health, pre-eclampsia, diabetes, pregnancy induced hypertension and large for gestational age babies. . An increase of 3 units and the more dire consequences developed, including still births.
The message is that women who are fertile and wanting babies a body mass index of 30 is an upper limit.
The association between low body mass index and infertility, prematurity and low infant birth weight is well established.
It is important that women are of normal healthy weight before and during their pregnancies.
Walsh and Murphy, Weight and pregnancy; BMJ 2007; vol 335, 169

Photosynthesis and Horst Witt

During the second half of the twentieth century, great strides were made in revealing the molecular details of oxygen-generating photosynthesis, the basis of almost all life on Earth. Horst Witt was one of the prime movers behind this revolution in understanding. His obituary appears in Nature 2007, vol 448, p425
Witt was born in 1922 in Bremen, Germany.
Witt chose oxygenic photosynthesis as his lifelong research topic. Inspired by the methods pioneered by George Porter and Ronald Norrish, he embarked on work with the technique of flash spectrophotometry. Using algae, in 1955 he discovered reactions of chlorophylls, carotenoids and cytochromes that occurred in microseconds. By 1961,he along with Lou Duysens and of Bessel Kok, demonstrated a scheme with two photochemical reaction centres in series
At photosystem II, electrons are removed from water, generating a strong oxidant, oxygen. At photosystem I, the electrons are used to produce a strong reductant, NADPH (and thence sugars). The energy difference between the strong oxidant and the strong reductant powers all oxygen-based life.
During the ensuing years,his team of investigators marked off milestones in photosynthesis research. They found that excess light energy is disposed of harmlessly as heat through protective carotenoids. They discovered that the reactive pigment of photosystem II is chlorophyll a: its cationic form extracts electrons from the active site of water oxidation, with kinetics that depends on the electrostatics of charge accumulation. And they identified plastoquinone as an electron acceptor in photosystem II, where it functions as a one-to-two electron gate and as a mobile carrier between the two photosystems.
A further success was to demonstrate reactions with associated proton uptake and release at opposite sides of the membrane, as shown earlier by Peter Mitchell, which generated the proton-motive force required for the synthesis of ATP.
Rut it was the mechanism of water oxidation that remained Witt’s career-long preoccupation. The manganese cluster In photosystem 11 is charged up with four oxidizing equivalents before it reacts with two water molecules, releasing dioxygen. Witt and his co-workers contributed valuable information on many aspects of the mechanism, including the valence changes of manganese, associated electrostatic changes and effects of extrinsic reductants. Despite these and other contributions from many laboratories around the world, understanding the detailed mechanism has remained a major challenge.
Witt’s early attempts to crystallize photosystem II were fruitless, and it seemed that the game would be lost to others. However, crystals of photosystem I were eventually obtained, a trimeric structure with multiple subunits, diverse electron co-factors, about 100 chlorophyll molecules and many carotenoids. Later photosystem 11 was crystallised.
Insights into a system central to life.
Junge and Rutherford 2007, Nature p425

multigene association with disease

Multigene susceptibility to disease.

As the molecular biologists discover more genes which predispose on to diseases the more evident it becomes that some common conditions are associated with more than one gene. What cannot be over emphasised is that these are susceptibilities which not always directly causal. No matter how many predisposing genes one has for obesity , food must be available in luxious amounts to generate fatty tissue.
There are at least seven genetic variants associated with symptomatic coronary heart disease. Three important ones are found on chromosomes 2, 6 and 9 and apparently these account for 38% of coronary heart disease in that population. The paper describing this is from Germany it is possibly different in other populations.
( Rosenzweig A in New Engl J Med 2007, vol 357, August 2nd ; Scanning the Genome for Coronary risk
And Samani N et al New Engl J Med vol 357 August 2nd Genomewide association analysis of coronary artery disease
Another condition or group of conditions with a genetic basis is inflammatory bowel disease. The genes which have been associated with Crohns disease are involved in barrier function and innate and adaptive immunity. There have been 7 and maybe more genes described with a role in this susceptibility or vulnerability.
The current aetiological concepts in the aetiology include the balance between commensal microbes and the immune response of the person. The nature of the host defences is all important. The mucosal barrier is all important.
So we have nice indicators that susceptibility and disease engendering circumstances interplay.
Xavier RJ and Podolsky DK 2007, Unravelling the pathogenesis of inflammatory bowel disease Nature 2007, vol 448, 427-434

body mass index defined for thinness

Body Mass Index cut offs to define thinness in children and adolescents.( Cameron N BMJ2007, vol 335, 166-7).
Central to any science is measurement. Body Mass Index ( weight/height2 )is a measure of overweight and it is suggested that there is continuous monitoring from childhood through to the elderly. The strength and weakness of these measurements and identification of the limits or cut off points is that the tables are based on developed countries.
The validity of these is less good in impoverished countries.
Cole and his colleagues (Body Mass Index cut offs to define thinness in children and adolescents. BMJ 2007, vol 335 , 194-7 ) have looked at this in nearly 200,000 males and females between birth to 25 years living in Great Britain, The Netherlands, Singapore and the United States.
WHO defines grade 2 thinness as having a BMI of under 17.
Cole and his colleagues define body mass index at age 18 as 18.5 kg/m2 for WHO grade 1, 17 kg/m2 and 16kg/m2 for WHO grade 3. thinness.
As childhood mortality is related to malnutrition these are very important sets of information.

Dark chocolate lowers blood pressure

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

obesity treatment and counselling

Dietary counselling is a short term solution to obesity
Dietary counselling is the mainstay of many weight loss programmes. To measure how well this works in practice a meta-analysis of 16 randomised controlled trials was made in the USA (Ann Intern Med 2007; vol 147 pp :41-50. Forty two of the trials included exercise as part of the programme. When compared with what they described as usual care, dietary counselling helped overweight and obese people lose just under two units of body mass index, or 6% of their initial body weight in one year. But weight increased once counselling finished. They regained about half their initial weight loss in three years. Weight gain accelerated towards the end of follow up, starting with 0.02 to 0.03 units of body mass index a month between 12 and 18 months and increasing to 0.04 units a month between 24 and 30 months.
Whether these small benefits make a lasting difference to people's risk of cardiovascular events or death is unclear. The researchers found no trials of dietary counselling with clinically useful end points.
The trials were generally of average or poor quality and tested a mixed bag of interventions. So there's likely to be some uncertainty around the final combined result.