Mechanism of anorexia during acute illness.

It is good to read papers which look at mechanism rather than describe phenomena. This a good paper describing why anorexia is a feature of acute illness.
Anorexia is part of the body’s acute-phase response to illness. Microbial products such as lipopolysaccharides. which are also commonly used to model acute illness, trigger the acute-phase response and cause anorexia mainly through pro-inflammatory cytokine
Lipopolysaccharide stimulate cytokine production through the cell-surface structural molecule CD14 and toll-like receptor-4. Cytokines ultimately change neural activity in brain areas controlling food intake and energy balance. The blood-brain barrier endothelial cells (BBB EC) are an important site of cytokine action in this context. BBB EC and perivascular cells (microglia and macrophages) form a complex regulatory interface that modulates neuronal activity by the release of messengers (e.g. PG. NO) in response to peripheral challenges. Serotonergic neurons originating in the raphe nuclei and glucagon-like peptide-1-expressing neurons in the hindbrain may be among the targets of these messengers, because serotonin (5-HT). acting through the 5-HT2C receptor, and glucagon-like peptide-l have recently emerged as neurochemical mediators of lipopolysaccharides anorexia. The central melanocortin system, which is a downstream target of serotonergic neurons, also appears to be involved in mediation of lipopolysaccharide anorexia. Interestingly. Lipopolysaccharides also reduce orexin expression and the activity of orexin neurons in the lateral hypothalamic area of fasted mice. As the eating-stimulatory properties of orexin are apparently related to arousal, the inhibitory effect of lipopolysaccharides on orexin neurons might be involved in lipopolysaccharide-induced inactivity and anorexia.
In summary, the immune signalling pathways of lipopolysaccharides -induced. and presumably acute illness-induced, anorexia converge on central neural signalling systems that control food intake and energy balance in healthy individuals
Langhans 2007 Signals generating anorexia during acute illness Proceedings of the Nutrition Society vol 66 p 321-330
Lipopolysaccharid.es: food intake: Acute-phase response: Cytokines

Conjugated linoleic acid in breast milk

A study by Rist et al looked at whether the incorporation of organic dairy and meal products in the maternal diet affects the contents of the conjugated linoleic add isomers (CLA) and trans-vaccenic acid (TVA) in human breast milk.
The term conjugated linoleic acid describes a mixture of positional and geometric isomers of linoleic acid (C18:2n-6) which contain a conjugated double-bond system instead of the more common isolated double bonds
. Rumenic or cis-9.trans-11-octadecadienoic acid (cis 9 trans 11-C18:2) is the most common conjugated linoleic acid isomer and is often regarded as the biologically most relevant one. The various conjugated linoleic acids are produced in the rumen of ruminant animals mainly by the bacteria Butyrivibrio fibrisolvens through reactions of iso-merization and biohydrogenation. These reactions lead as well to the formation of a wide variety of trans- and cis-monoenic fatty acids (especially C18: 1 trans isomers). In addition, trans-vaccenic acid trans 11-C18: 1,) which originates, from linoleic and linolenic acid plays an important role as precursor of rumenic acid.
Conjugated linoleic acids are currently receiving much attention in nutritional research, since there is experimental evidence suggesting that these fatty acids might have anti-carcinogenic, anti-atherosclerotic, anti-diabetic and immune-modulating effects, as well as a favourable influence on body fat composition, i.e. on the proportion of fat tissue to muscle mass .
Milk samples from 312 breastfeeding mothers participating in the KOALA Birth Cohort Study have been analysed. The participants had documented varying lifestyles in relation to the use of conventional or organic products. Breast milk samples were collected 1 month postpartum and analysed for fatty acid composition. The content of rumenic acid (the main conjugated linoleic acid) increased in a statistically significant way from a conventional diet (no organic dairy/meat products. 0.25 weight % (wt%), to a moderately organic diet (50-90% organic dairy/meat,.0.29 wt%.) and to a strict organic diet (> 90% organic dairy/meat. 0.34 wt%,).
The levels of trans-vaccenic acid were increased among the participants with a moderate organic diet (0.54 wt %) and those with a strict organic diet (0.59 wt%,). in comparison with the conventional group (0.48 wt % ).
Eating organic dairy products changes the conjugated linoleic acid content of mother’s breast milk.

Rist et al 2007 Influence of organic diet on the amount of conjugated linoleic acids in breast milk of lactating women in the Netherlands. British Journal Nutrition vol 97, 735-743

BMI and undernutrition in the older subjects.

In recent years there has been a proliferation of nutrition screening tools but under nutrition remains prevalent amongst older subjects.
Screening tools commonly include BM1 as the widely-accepted 'gold standard' indicator of malnutrition. Whilst BM1 may be an appropriate tool for population studies when it can be measured accurately in research conditions, the use of BMl in clinical practice may mask important weight changes and result in a failure to alert healthcare staff to a nutritional problem.
The inclusion of BMl has been identified as a barrier to completing the screening process at ward level. Also, feedback from dieticians working with older subjects indicates that 72 % of those using BMl express concerns that it is of limited use for practical reasons or that the reference range (20-25 kg/m2) is not appropriate to older subjects.
Further evidence questions whether or not BMl is applicable for inclusion in methods used to identify an older subject at risk of undcr nutrition in a variety of care settings. In view of these findings it is advocated that weight change over a period of time together with clinical judgement is a far superior prognostic indicator of under nutrition.
Despite screening, there is evidence that inpatients continue to lose weight before discharge. Further experiential evidence from both community and ward settings suggests that inadequacies in care planning, food provision and a lack of assistance with feeding are common. In order to improve the management of under nutrition in older subjects it is therefore recommended that the focus of attention should be on addressing these practical issues and on the effective monitoring of these processes.
Cook et al 2005 Use of BMI in the assessment of undernutrtion in older subjectdd: reflecting on practice. Proceedings of the Nutriton Society vol 64 313-317

Undernutrition: BMl: Older subjects

Exercise and bone mass

Bailey and Brook-Wavell have written an interesting review on exercise and bone mineral density in the Proceedings of the Nutrition Society.
Physical activity is a major physiological method for increasing and maintaining bone mineral density and geometry. With an important role in maintaining peak bone mass and strength, and reducing the risk of future osteoporotic fracture. However, not all exercise is effective, so a prescription in terms of optimal type, intensity, frequency and duration is required.
Studies using animal models suggest that loading that is high in magnitude, rapidly applied and novel is most effective, whilst duration is less important beyond a threshold number of cycles.
In human subjects cross-sectional studies comparing different athletic populations suggest that those who participate in high- or odd-impact sports have higher bone mineral density; whilst impact exercise, strength training and brief high-impact-jump training interventions increase bone mineral density in pre-menopausal women.. Brief hopping exercises were shown to be feasible for sedentary pre-menopausal women, producing ground-reaction forces as high as those from jumping. Regularly performing these hopping exercises over 6 months was found to increase femoral-neck bone mineral density of the trained leg relative to the control leg. women.
Bailey and Brook-Wavell 2008 Exercise for optimising peak bone mass in women Proceedings of the Nutrition Society vol 67, pp9-18

Sarcopenia, leucine and protein

Ageing is associated with a gradual loss of skeletal muscle mass, known as sarcopaenia . These age-related changes in skeletal muscle mass are attributed to a disruption in the regulation of skeletal muscle protein synthesis and/or degradation
Protein turnover in skeletal muscle tissue is highly responsive to nutrient intake in healthy, young individ¬uals. In the elderly, the muscle protein synthetic response to food intake seems to be blunted, which is likely due to impaired anabolic signalling in skeletal muscle tissue and may be a key factor in the aetiology of sarcopaenia.
In addition to food intake, physical activity can effectively modulate muscle protein metabolism, stimulating both muscle protein synthesis and breakdown. However, post-exercise net protein balance will remain negative in the absence of food intake Recently, Koopman and colleagues have reported that co-ingestion of protein and leucine with carbohydrate following physical activity can increase muscle protein synthesis to the same extent in young and elderly lean men
The latter indicates that the combined ingestion of carbohydrate and protein with additional free leucine might indeed represent an effective strategy to further increase muscle protein synthesis and/or to inhibit protein degradation following physical activity. Follow-up studies have shown that leucine has the ability to function as a nutritional signalling molecule that stimulates muscle protein synthesis at the level of translation initiation through the activation of mTOR
In addition, leucine has also been shown to have the potential to affect muscle protein metabolism by decreasing the rate of protein degradation . most likely by stimulating insulin secretion.
In previous studies, Koopman et al have shown that the combined ingestion of carbohydrate, protein and leucine is more effective than the-ingestion of only carbohydrate in stimulating muscle protein synthesis in vivo in man. More recent data suggest that the intake of amino acid mixtures or proteins with additional leucine can further enhance muscle protein synthesis in the elderly. However, the proposed surplus value of leucine co-ingestion under normal living conditions, in which physical activity is followed by food intake, has not yet been assessed.
In a study reported in the British Journal of Nutrition , Koopman et al determined the potential surplus value of free leucine co-ingestion on post-exercise muscle protein synthesis in elderly men (about 75 years old) under conditions where large amounts of whey protein and carbohydrate are being ingested.
However the ingestion of leucine, carbohydrate and protein following physical exercise in the elderly does not increase muscle protein .
Koopman et al 2008 Co-ingestion of leucine with protein does not further augment post-exercise muscle protein synthesis rates in elderly men British Journal of Nutrition vol 99 57-580.

Intracellular copper

In a recent copy of Nature Chemical Biology Davis and Halloran discuss cellular copper ion chemistry. Transition metals such as zinc, copper and iron are necessary to reach intracellular concentration of tens to hundreds of micromolar. Few if any of these ions are thought to be 'free' or readily accessible in terms of their thermodynamic availability or reaction chemistry. The mechanisms by which cells control the metal occupancy of a given metal-binding site—that is, how metalloenzymes acquire the correct metal ion at the right time in cellular growth—are emerging through physiochemical characterization of a range of conserved metal trafficking pathways.
The regulation of metal ion availability requires the concerted activity of numerous metal receptors, including metal transporters, metallochaperones and metalloregulatory factors.
Mechanistic and structural insights into the chemistry of cellular copper-trafficking machinery have predominately focused on cysteine (that is, thiol)-rich CuCI) sites which are associated with inherited diseases of copper metabolism.
In a series of recent studies characterizing methionine-rich domains of copper trafficking proteins, some unexpected copper-thioether chemistry is emerging. As was the case for cysteine thiolate-rich sites, the CuCI) coordination chemistry of such proteins is quite distinct from that seen in copper enzymes.
Two fundamental differences are emerging between the two classes: they each function in chemically distinct subcellular compartments, and they use quite different electrostatic contributions to achieve Cu(I) binding selectivity and transfer.
Most of the cysteine-rich copper sites characterized to date are found in reducing intracellular compartments, whereas an abundance of methionine-rich copper sites are found in the oxidizing compartments and the extracellular milieu.
One important feature of the methionine-rich sites and motifs is their selectivity against the two most abundant intracellular transition metal ions: zinc and iron. Notably, the +2 ions of these metals are not favoured for binding in the methionine-rich sites, but hundreds of examples of zinc and iron ions bound to CXXC motifs in higher-coordinate or metal-cluster sites can be found in the metalloprotein literature (for example, in zinc finger proteins and iron-sulfur proteins).
As our understanding of the methionine-rich chemistry expands to include extracytosolic proteins, a broad picture is emerging of biological cuprous coordination and ligand-exchange chemistry. Different coordination motifs seem to be tailored to different pathways and cellular environments in order to preserve copper-specific recognition within a robust metal-binding site. A corollary to this idea, however, is the consideration that metal-trafficking sites may also be responsive to changing cellular environments, as oxidative bursts may release copper or zinc ions from cysteine-rich (or methionine-rich) metal-binding sites as the ligating groups are oxidized and the metal-binding sites are disrupted. The interplay between the intimate coordination chemistry of each family of sites and the changing metabolic needs of the cell may well prove to be a key to unlocking the roles of metal ions in intracellular signaling processes.
Davis and Halloran 2008 A place for thioether chemistry in cellular copper ion recognition and trafficking Nature Chemical Biology vol 4 148-151.

Genome diversity in the Gulf of Oman

There is a great game being played in the molecular biology world genome analysis . It is possible to trace the migration of peoples across he world and long standing theories for the migrations are being tested. It is quite a thought that mankind evolved in Africa and then was able o slowly move to Australia and down the Americas to geographical isolation thereafter.
In addition here are the great Trade route, eg the Silk Road wherein traders brought goods to and from China to the coast of the Mediterranean Sea.
Arabia has served as a strategic crossroads for human dissemination , providing natural connection between the distant populations: of China and India in the east to the western civilizations along the Mediterranean.
In the paper the authors explore this region’s critical role in the migratory episodes leaving Africa to Eurasia and back, using high resolution Y chromosome analysis of males from the United Arab Emirates. Qatar and Yemen .
With the exception of Yemen, southern Arabi, South Iran and South Pakistan show high diversity in their Y-haptogroup substructure possibly as a result of gene flow along the coastal crescent shaped corridor of the Gulf of Oman facilitating human dispersals. Increased rates of marriages between close relatives may have an impact in Yemen and Qatar, which experience significant heterozygote deficiencies at various hypervariable autosomal STR loci.
What interest is this to an nutritionist. Wel, any theory which purports to attribute environmental change eg diet to a particular health problem must bear in mind the diversity of the human population or lack of diversity in a particular population.
Cadenas et al 2008 Y-chromosome diversity characterizes the Gulf of Oman , European Journal of Human Genetics. Vol 16, 374-386

Nutrition 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

Body-mass index and cancer risk

Excess bodyweight, expressed as increased body-mass index {BMI), is associated with the risk of some common adult cancers. Renehan and his colleagues report in the Lancet February 16 2008 a systematic review and meta-analysis to assess the strength of associations between BMI and different sites of cancer and also to look at differences in these associations between sex and ethnic groups.
They did electronic searches to identify prospective studies of incident cases of 20 cancer type and also to study- the risk of cancer associated with a 5 kg/m1 increase in BMI.
141 articles), including 282137 incident cases were recorded. . In men. a 5 kg/m2 increase in BMI was strongly associated with oesophageal adenocarcinoma (BR 1-52,),thyroid (1-33,), colon ( 1-24,), and renal {1-24,) cancers. In women, there was strong associations between a 5 kg/mi increase in BMI and endometrial (1-59,), gallbladder (1-59, ), oesophageal adenocarcinoma (1- 51,), and renal (1-34,) cancers.
Associations were stronger in men than in women for colon (p<0-0001) cancer.
Associations were generally similar in studies from North America, Europe and Australia, and the Asia-Pacific region, but we recorded stronger associations in Asia-Pacific populations between increased BMI and premenopausal (p=0 - 009) and postmenopausal (p=006) breast cancers.
Increased BMI is associated with increased risk of common and less common malignancies. For some cancer types, associations differ between sexes and populations of different ethnic origins.
Renehan et al 2008 Body –mass index and incidence of cancer: a systematic review and meta-analysis of prospective and observational studies. Lancet vol 371 pp 569-578.

Tackling global food insecurity

The Lancer has run a most important series of 5 review articles on malnutrition finishing with the February 6th edition of the Journal.
The final editorial reads
Later this month, the first batch of seeds will be stored in the Svalbard Global Seed Vault to ensure that should a major catastrophe ever hit the planet, survivors should at least have access to a seed bank and so may be able to grow food. Eventually, over 200 000 crop varieties will be hidden in this Arctic ice sanctuary deep in a mountain near the village of Longyearbyen, built by the Norwegian Government for the benefit of mankind. And last week, the Bill & Melinda Gates Foundation announced a S20 million grant to develop hardy rice crops to help poor farmers cope with the effects of climate change. While these visionary philanthropic works are admirable, what about doing something to help the millions of people throughout the world who are starving right now?
The World Food Programme continues to raise awareness of current food insecurity emergencies. Last week’s target was Tajikistan, where the coldest winter in five decades and rising world food prices have resulted in a disastrous situation. If past experience is anything to go by, the Programme’s pleas for emergency funding will fall on
deaf donor ears, and many people in Tajikistan will starve. So why can’t the same attention, energy, innovation, and financial and technical resources, reserved to mitigate the effects of potential future disasters, be channelled into tackling current hunger crises? Although not immediately relievable by a scientific quick-fix, it should not be beyond the bounds of possibility to redistribute the abundance of global food resources and tackle wider socioeconomic factors often involved in food security issues.
The final article in our under nutrition Series clearly outlines what needs to be done. The global architecture of the international nutrition system needs to be radically reformed and become more accountable and inclusive. And everyone from major donors to the editors of academic journals all have their part to play. It is absurd and profoundly unjust that, as many countries are putting their resources into tackling the obesity epidemic, many people throughout the world are continuing to starve to death. We must all act now and turn the Series’ realistic recommendations into robust action. ■
The core problems were identified as
Lack of high level interest
Inadequate human sources
Unpredictable and inflexible funding
Inadequate strategies
Limited sticking power of policies
Structures that impede collaboration
Weak coordination
Weak linkages with countries


Their recommendations were
The international nutrition system—made up of international and donor organisations, academia, civil society, and the private sector—is fragmented and dysfunctional. Reform is needed so that it can perform key stewardship functions, mobilise resources, provide services in emergencies, and strengthen capacity in low-income and middle-income countries
Current processes for producing normative guidance are laborious and duplicative, and fail to produce guidance that is prioritised, succinct, and evidence-based.
Programme evaluation is weak, and insufficient resources are devoted to analysing and responding io major global challenges (including the evolving epidemiology of nutrition)
The funding provided by international donors to combat under nutrition is grossly insufficient and poorly targeted, and is inappropriately dominated by food aid and supply-led technical assistance. Much more investment is needed in human and institutional capacity for nutrition in low-income and middle-income countries
The problems of the international nutrition system are long-standing and deeply embedded in organisational structures and norms. The international community needs to identify and establish a new global governance structure that can provide greater accountability and participation for civil society and the private sector
Linkages with national-level processes need to be significantly enhanced, so that priorities that are felt at country level are better reflected in international normative guidance, donor funding, research, and advanced training
Morris et al 2008 Effective international action against under nutrition : why has it proven so difficult and what can be done to accelerate the progress. Lancet vol 371 pp 608-621
Leader Lancet 2008 Tackling global food insecurity Lancet vol 371 p 532

Cancer theories revisited

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.

genome wide association study

Genome susceptibility to diseases.
The Welcome Trust Case Control Consortium has made a large case control comparison of the gene structure of 14000 cases of seven common diseases with 2000 controls.
One wonders if the control group size is sufficiently large.
Nevertheless
They have identified 24 independent control association signals
1 for coronary artery disease
9 for Crohns disease
3 for rheumatoid arthritis
7 for type 1 diabetes
3 in type 2 diabetes
They are also have association studies for tuberculosis , breast cancer, multiple sclerosis ankylosing spondylitis and autoimmune thyroid disease.
All of these conditions have other aetiological theories grouped around them, including diet.
The old Chinese curse, to live in a time of change
The Welcome Trust Case Control Consortium 2007, Genome-wide association study of 14,000 cases of seven common diseases and 3000 shared controls. Nature vol 447, 661-678.

GenotypePhenotype associations

One of the rewards of the avalanche of genome information are the findings that there are associations between diseases, behaviour patterns and genotype, the genotype- phenotype association. The genotype-genotype association .
However one should take such findings with a pinch of salt until
1. The report has been repeated and hence more likely to be true, ie replication
2. that vigorous statistical analyses have been performed
3. The study information is sufficient to make a judgement on the work
4. The data presented is sufficient to make independent statistical analysis.
5. The methodologies used are proper.
6. The control population is truly a control population and sufficiently large to make a significant comparison.
An expert working party has reported in Nature with criteria for accepting studies of genotype-phenotype associations assessed by genome-wide or candidate-gene approaches.
• Statistical analyses demonstrating the level of statistical significance of a finding should be published or at least available so that others can attempt to reproduce the reported results
• Explicit information should be provided about the study’s power to detect a range of effects
■The study should be epidemiologically sound, with careful accounting for potential biases in selection of subjects, characterization of phenotypes, comparability of environmental exposures’ (when possible) and underlying population structure in cases and controls
■ Phenotypes should be assessed according to standard definitions provided in the report
• Associations should be consistent (within the range of expected statistical fluctuation) and reported for the same phenotypes across study subgroups or across similar phenotypes in the entire study group
• Significance should not depend on altering the quality control methods beyond standard approaches that could change inclusion or exclusion of large numbers of samples or loci
■ Measures to assess the quality of genotype data should include results of known study sample duplicates or publicly available samples
• The results for concordance between duplicate samples (if applicable) as well as completion and call rates per SNP and per subject should be disclosed, along with ratesof missing data
• A subset of notable SNPs should be evaluated with a second technology that verifies thesame result with excellent concordance, because no technology is error-free
■ Associations with nearby SNPs in strong linkage disequilibrium with the putatively associated SNP should be reported (and should be similar)
The results of replication studies of previous findings should be reported even if the results are not significant.
■ Testing for differences in underlying population structure in case and controlgroups should be performed and reported
■ Appropriate correction for multiple comparisons across all statistical testsexamined should be reported.
■ Comparison to genome-wide thresholds should be described. Similarly, for bayesian approaches, the choice of prior probabilities should be described
Not easy stuff, but do not accept any of these widely publicised associations without thinking, is this sensible.
NGI-NHGRI working Group on Replication in Association studies (2007 Replicating genotype –phenotype associations Nature vol 447, 655-660

Epigentics review

I know this review is almost a year old but is very important.
The science of Epigenetics was in part developed by Waddington and his influence flows through these articles.
This is an important area for nutrition and is a rich source of ideas and research projects.
Epigenetics is the study of heritable changes in gene expression that are not due to changes in DNA sequence. Epigenetic changes allow for the differentiation of various cell types in an organism and cellular processes. X-chromosome inactivation in the female mammal is an example. This control may be upset by the aging process, neoplastic transformation, chronic inflammation and exposure to noxious influences and even by nutrition though this an unexplored area.
Epigenetic change may be de to chemical changes in the DNA or histones and also there is a role for RNA in this mechanism.
There are two well known epigenetic systems the Polycomb and Trithorax and DNA methylation.
The Polycomb and Trithorax are a group of proteins which maintain repressed or active transcription states of developmentally important genes. This system has a memory which can be transmitted to the next generations.
DNA methylation is associated with stable gene silencing eg the inactivation of the second X chromosome in the female mammal.
There are additional complex changes in protein complexes which regulate transcription. Changes in chromatin packing and histone modification the protein that packs around the DNA modify transcription.
A further modifying influence on gene activity is its position in the three dimensional structure of the chromosome, that is the manner in which the chromosome is shaped and the position of the chromosome in the nuclear structure and whether the gene is available for biochemical activity or hidden. This may vary from cell to cell and the activity of that cell and determine the cell’s function.
During development, cells are in a genetic state, from which they can differentiate into many cell types, and progressively become differentiated. . Their gene-expression programmes become more defined, restricted and fixed. . Pluripotent stem cells express genes that encode a set of core transcription factors, while genes that are required later in development are repressed by histone marks, with short-term, and flexible, epigenetic silencing. The methylation of DN A gives long-term epigenetic silencing of particular sequences — transposons, imprinted genes and pluripotency-associated genes in somatic cells. Long-term silencing can be reprogrammed by demethylation of DN A, and this process might involve DNA repair.
When there is change in these processes then disease may occur. The interesting situation is in repair and response to injury and inflammation and possibly malnutrition.
Nature Insight editor Campbell,2007 Epigenetics Nature vol 447, pp395-440

metabolic clock and control mechanisms

The activities of our bodies follow cycles of repeated oscillations, examples are the sleep-wake cycle, the feeding rhythm and variations in body temperature and hormonal levels. The anatomical centre of the mammalian circadian clock lies within the suprachiasmatic nucleus region of the brain in the anterior hypothalamus.
Many of these cyclic oscillations are circadian (of around 24-hour periodicity), and are controlled by an interplay of numerous molecular factors which ensure the accuracy of the 'body clock'. The body clock is , organized in complex feedback loops that involve gene transcription and the events that follow it.
The peripheral tissues of many creatures contain independent pacemakers involved in a 'synchronization web' that coordinates timing in all the tissues. The transcription of at least 10% of all cellular genes oscillates in a circadian manner indicates how the circadian transcriptional mechanisms influence a wide array of cellular functions.
PGC-1α is a transcriptional coactivator with an essential role in the maintenance of glucose, lipid and energy homeostasis.. It is highly responsive to a variety of environmental cues, temperature, nutritional status and physical activity. Liu and colleagues have shown that the transcriptional regulator PGC-1α is a key factor in the molecular pathways in the circadian control of energy metabolism,.
Several genes contribute to the regulation of the circadian rhythm, including Clock, Bmall, Per. Cry and Rev-erba. The findings of Liu et al showed in Nature that PGC-l α, has a central role in connecting the expression and function of these circadian clock genes in the regulation of energy metabolism, including gluconeogenesis (the synthesis of glucose from non-.sugar substrates), oxidative phosphorylation, oxidation of fatty acids and the biosynthesis of haem.
This function of PGC-l α seems to be mediated by nuclear receptors, such as ROR α, and other, unidentified, transcription factors.
Grimaldi and Sassone-Corsi (2007) Metabolic clockwork Nature vol 447 pp 386-7
Liu et al (2007 ) Transcriptional coactivator PGC-1a integrates the mammalian clock and energy metabolism ( 2007) Nature vol 447 pp 477-81

Genetics by numbers

Genetic association studies with coronary artery diseases are showing that single nucleotide polymorphisms ( SNPs ) found close together on chromosome 9 are associated with an increase prevalence of common diseases.
Individuals with two copies of them have an increased risk of coronary heart disease but less in its impact than diabetes or heavy smoking but is equivalent to smoking 10 cigarettes a day.
One wrong SNP increases the risk by 40%, two doubles the risk.
These are not necessarily the causative mutation but indictors in the long genomic region on chromosome 9 ( 9p21.3.)
There have been many false dawns in these studies, with more to come but this is all very interesting. Family history is still very important in defining risk. And makes one look harder at the claims for correlations between nutrition intake and disease. . The answer will be a balance between environmental factors and genomic patterns.
Finding a gene or SNP abnormality is not the same as describing the biology.
Risk SNPs
RS10811661 associated with diabetes found on chromosome 9
RS2241880 associated with Crohn’s disease on the long arm of chromosome 8
8Q24 associated with cancer of the breast, colorectal and prostate cancer on the long arm of chromosome 8
Baker 2008 Genetics by numbers Nature vol 451 pp516-7

Hunger: a modern history by James Vernon

Starvation is one of the terrible scourges of our world. In the words of the old song, it’s the rich that get the gravy and the poor……. Humiliating, deadly and unnecessary
Malnutrition is such a complex problem and has so many answers to the insoluble.
James Vernon has written a masterly book Hunger a modern History published by Harvard University Press which has an equally masterly review in Nature
Michael Sargent 2008 Starvation crime and punishment. Nature vol 451 pp 524-5
Amongst past theories are
Povery is a criminal act
Malthus‘s a God given discipline for the profligate
Charles Trevelyan on the Irish potato famine , a sharp and effectual remedy
A political weapon
Poor economic management and distribution

Malnutrition results from the availability of nutrients to individuals being insufficient.. Often but not always too many people for too little food.

The lack of nutrients may be total or in certain nutrients.

Availability may be a result of
1. geography, being located remote from the food supply.
2. transport
3. war and strife
4. economics ability to pay for the food
5. poor farming techniques and wrong crops
6. destruction of crops by disease or weather
7. political connivance and corruption
8. poor education
9. pathology e.g. celiac disease.

Nutrients are
the total macro nutrient need
1. calories,
2. energy ( carbohydrates and fat )
3. proteins
4. maybe fibre, maybe not.

the micro nutrient needs

1. vitamins
2. trace metals

Insufficient for

1. pregnancy
2. growth of body and brain
3. energy
4. resistance to infections

population means those who are requiring food. This may be the usual areas, Africa and Asia. But any population may be drawn into this problem by war, global change or any other lack of food.

There is a small group who because of some disease or bodily malfunction are unable to absorb or utilise nutrients e.g. coeliac disease.

Obesity is the converse.
The availability of nutrients being more than sufficient for the population at risk.. Too much food for too few people.

cholera treatment and zinc supplements

Cholera is epidemic throughout the countries where the water supply is suspect. More than 3 million cases occur each year world wide of whom 100,000 die. The individuals who contact this problem are often malnourished and marginally zinc deficient before they develop this further mishap.
The mild cases are treated with oral dehydration with rice water being the commonest reliable treatment.
Severe case are treated in addition with anti-biotics.
A trial in Bangladesh shows tht30 mg a day of zinc supplementation reduces the period of diarrhoea and stool output.
Roy et al 2008, Zinc supplementation in children with cholera in Bangladesh: randomised controlled trial. BMJ vol 336, 266-268
Comment Lazzerini 2008 Zinc supplements for severe cholera are simple, well tolerated and could save money as well as lives. BMJ vol 336, 227-228.

soy isoflavone and bone metabolism

Ma and colleagues looked at studies of the effects of isoflavone intake on bone resorption and bone formation with a meta-analysis, of randomized controlled trials using urinary deoxypyridinoline, a bone resorption marker) and serum bone-specific alkaline phosphatase, a bone formation marker)
Nine studies with a total of 432 subjects were selected for meta-analysis. The urinary deoxypyridinoline concentration in subjects who consumed isoflavones decreased significantly. in comparison with that in subjects who did not consume isoflavones.
They concluded that soy soflavone intervention significantly inhibits bone resorption and stimulates bone formation in menopausal women:. These favorable effects occur even if less than 90mg/day of isoflavones are consumed or the intervention lasts less than 12 weeks.
Ma et al ( 2008)Soy isoflavone intake inhibits bone resorption and stimulates bone formation in menopausal women: meta-analysis of randomized controlled trials. European Journal of Clinical Nutrition 62, 155–161;

Smells

Smells are almost everywhere. They colour our lives and make for pleasure and repulsion and can influence our appetite and pleasure in eating.
The smell of a baby even its faeces and vomit have a soft smell which lacks offensiveness. The smell of a baby’s skin is so lovely.
As the child develops, smell depends on whether the child is male or female. Boys love nasty smells. Refuse to change socks, sometimes to wash only under duress and have a glory in farts and other malodorous smells. If a group of little boys are standing in a group chortling the odds are it is farts which is the subject under discussion. In general little girls at this stage are beginning to develop the civilising characteristics of the woman and already are attracted to pleasant smells whether this is in flowers, nature as a whole or artificial scents.
The growing male then adds in stale clothes, stale beer and wine and cigarettes to his malodour.
The halitosis appears and we have the odour picture. And a smelly dog.
In the kitchen we have the accumulation of the damp smells of old kitchens , overcooked cabbage, garlic , fish and other smells.
Old people's bedrooms smell of old people.
In nutrition if one comes into a house that smells one is put off eating. Some cafes have a damp horrid heavy old fish smell.
Air fresheners smell just as horrid.
So the answer is anosmia or to open the windows when ever possible.