mitochondrial diseases

Mitochondria have important roles in cellular processes, for example, production of cellular energy in the form of ATP and pro¬grammed cell death (apoptosis). Each mitochondrion contains between two and ten copies of mtDNA,. Cells have numerous mitochondria, a cell may harbour several thousand mtDNA copies. Mutations in mtDNA occur at a tenfold or higher rate than in nuclear DNA, possibly due to a high concentration of free oxygen radicals, lack of histones and limited mtDNA repair mechan¬isms.
Diseases caused by mtDNA mutations are numerous, over 150 mutations (including 100 deletions and approximately 50 point mutations) have been identified that are associated with serious human disorders, including myopathies, neu¬rodegenerative diseases, diabetes, cancer and infertility. mtDNA mutations are increasingly implicated in Alzheimer's, Parkinson's and Huntington's diseases.
Typically, a cell contains only one type of mtDNA (homoplasmy). If an individual cell contains two or more types of mtDNA-that is, as a mixture of normal and mutant mtDNA, the phenomenon is known as heteroplasmy. Heteroplasmy allows lethal mutations to persist and most importantly to pass to the next generation. MtDNA is maternally inherited through the egg's cytoplasm, whereas sperm mitochondria constitute a minor fraction of the zygote's cohort and are rapidly eliminated after fertilization.
Possibly 1 in 3,500-6000 people has either mtDNA disease or is at risk for development of mtDNA-based disorders, most of which are incurable.

Tachibana et al (2009) Mitochondrial gene replacement in primate offspring and embryonic stem cells. .Nature vol 461 pp 367-372

Surgery for obesity

Bariatric surgery, or weight-loss surgery, are the various surgical procedures to treat obe¬sity by modification of the gastrointestinal tract to reduce nutrient intake and/or absorption. This review discusses how appetite and levels of gastrointestinal hormones are altered after bariatric surgery.

Surgical removal of.body fat such as liposuction or abdo¬minoplasty are not considered bariatric surgical proce¬dures.

Surgical pro¬cedures can be grouped in two main categories:

Restrictive procedures, e.g. gastric banding reducing the volume of the stomach and physically preventing excessive consumption of food

Or bypass proce¬dures, e.g. Roux-en- Y gastric bypass , a small stomach pouch is created with a stapler and bypasses the stomach remnant.

Gut hormones are an important element in appetite regulation as a result of the signals from the periphery to the brain. Such hormones include ghrelin, peptide YY, glucagon-like peptide-l and gastric inhibitory polypeptide, all of which are currently being investigated as potential obesity treat¬ments.

Bariatric surgery is currently the most effective therapy for substantial and sustained weight loss. Understanding how levels of gut hormones are modulated by such procedures has greatly contributed to the comprehension of the underlying mechanisms of appetite and obesity.
Bueter and le Roux 2009 Bariatric surgery as a model to study appetite control , Proceedings of the Nutrition Society vol 68 , 227-233

Obesity genes

Wells (2009 ) Thrift: a guide to thrifty genes, thrifty phenotypes and thrifty norms
International Journal of Obesity (2009) 33, 1331–1338.
There is a growing interest in evolutionary models of human adiposity, ‘thrifty genes’ or ‘thrifty phenotypes’, a variety of metabolic or behavioural traits which gives frugality in the expenditure or storage of energy.
At the broadest level, humans represent a thrifty species relative to other mammals, indicating that metabolic adaptations had a crucial role in the emergence of the Homo lineage, in particular in buffering reproduction from ecological stochasticity. Some variability in adiposity may be due to genotypes systematically favoured in certain ecological settings.
Genetic variability is also present within populations, and may be considered bet hedging (distributing risk across offspring to increase parental fitness). Bet hedging is an alternative to genetic drift to account for genetic variability in the absence of strong selective pressures. Contrasting with genetic variability emerging over the long-term, thrifty phenotypes represent a response to short-term ecological variability. Physiological plasticity allows the emergence of variability in response to ecological cues experienced directly or by very recent ancestors.
Cultural norms or individual preferences allow voluntary behavioural manipulation of thrift in individuals. Overall, there is a range of factors and processes both favouring and opposing thrifty genes, which may reflect moderate bet hedging rather than systematic adaptation. Plasticity protects the genome from selective pressures by tailoring the organism to ongoing ecological conditions. The fact that obesity can occur in different individuals through different genotypes, life histories and behaviours indicates that different treatments are also likely to be required.

waist measurements review

J Stevens1,2, E G Kat and Huxley (2010) Associations between gender, age and waist circumference European Journal of Clinical Nutrition 64, 6–15;
S A Lear et al (2010) Appropriateness of waist circumference and waist-to-hip ratio cutoffs for different ethnic groups European Journal of Clinical Nutrition 64, 42–61;

vitamin D

Peterlik and Cross ( 2009 ) Vitamin D and calcium insufficiency-related chronic diseases: molecular and cellular pathophysiology European Journal of Clinical Nutrition vol 63, 1377–1386
A compromised vitamin D status, characterized by low 25-hydroxyvitamin D (25-(OH)D) serum levels, and a nutritional calcium deficit are widely encountered in European and North American countries, independent of age or gender. Both conditions are linked to the pathogenesis of many degenerative, malignant, inflammatory and metabolic diseases. Studies on tissue-specific expression and activity of vitamin D metabolizing enzymes, 25-(OH)D-1α-hydroxylase and 25-(OH)D-24-hydroxylase, and of the extracellular calcium-sensing receptor (CaR) have led to the understanding of how, in non-renal tissues and cellular systems, locally produced 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3) and extracellular Ca2+ act jointly as key regulators of cellular proliferation, differentiation and function. Impairment of cooperative signalling from the 1,25-(OH)2D3-activated vitamin D receptor (VDR) and from the CaR in vitamin D and calcium insufficiency causes cellular dysfunction in many organs and biological systems, and, therefore, increases the risk of diseases, particularly of osteoporosis, colorectal and breast cancer, inflammatory bowel disease, insulin-dependent diabetes mellitus type I, metabolic syndrome, diabetes mellitus type II, hypertension and cardiovascular disease. Understanding the underlying molecular and cellular processes provides a rationale for advocating adequate intake of vitamin D and calcium in all populations, thereby preventing many chronic diseases worldwide.

Causes of Obesity

Obesity is a very busy topic.
This review in Critical Reviews in Food science and Nutrition makes a thorough evaluation of the 10 putative contributors to the obesity epidemic. The review is comprehensive and well worth reading
The obesity epidemic is a global issue and shows no signs of abating, while the cause of this epidemic remains unclear.
The eating energy-dense foods and reduced physical activity are the alleged causes of the epidemic, despite a lack of solid evidence to demonstrate their causal role.
The writers accept that these may contribute to obesity, but propose several alternative putative contributors that would benefit from equal consideration and attention.
Evidence for microorganisms, epigenetics, increasing maternal age, greater fecundity among people with higher adiposity, assortative mating, sleep debt, endocrine disruptors, pharmaceutical iatrogenesis, reduction in variability of ambient temperatures, and intrauterine and intergenerational effects as contributing factors to the obesity epidemic are reviewed herein.
Their questioning of the big two stems from two points. First, the evidence supporting various elements of the big two as contributors to individual or population levels of obesity is often quite weak. Second, even though some elements of the big two do very likely play some role in influencing obe¬sity levels, we believe that an unquestioned assumption of their pre-eminence has led to the possibly ill-advised expenditure of public effort and funds on programs aimed at reducing popu¬lation levels of obesity that has also reduced the exploration of other potential causes and the alternative obesity reduction programs that might stem from their identification.
The big two seem to they have an appeal based, in part, on their simplicity and the fact that they require little specialized knowledge to comprehend and deal with easily observable as-pects of life with which all of us are familiar.
What are some of the specific facts that enhance our scepticism of the big two as near-omnipotent causes of the obesity epidemic?
1. Papers on Restaurant Dining, Physical education , urban life, high fructose corn syrup consumption and vending machines do not support these attractive ideas.
2. Infections and obesity. A number of bacterial infections have been shown in animal experiments to increase weight in the infected host. Fat cells and macrophages have many similar functions and affecting macrophages by infection may influence adipocyte response
3. Epigenetics and obesity There may be environmental influences on our genetic make up.
4. Maternal age older mums, fatter offspring
5. Fat people or rather individuals with a genetic predisposition have more children than those with a lover level of adiposity.
6. Human adiposity levels have a genetic component.
7. Decreased Sleep may influence the mediators of appetite and energy homeostasis
8. Endocrine disrupters and obesity, including plasticizers ( bisphenyl ether and bisphenol A ) which are stable in the environment.
9. Pharmaceutical drugs
10. Ambient temperature

McAllister et al 2009 Ten putative contributors to the obesity epidemic . Critical Reviews in Food science and Nutrition vol 49, 868-913

BRA I and breast cancer

This is an important paper indicating the molecular biology of cancer of the breast.
The amino (N) terminus of BRCA 1 has a RING domain that interacts with ubiquitin-conjugating enzymes and is required for its ubiquitin ligase activity. Ligase enzymes catalyse the joining together ofmolecules of two substances and with a breaking of a diphopsatebond in a nucleoside triphosphate. They used to be called synthetase.
Many disease-causing mutations are found within this region, and loss of the ligase activity is associated with suscepti¬bility to breast cancer. BRCAl¬ dependent ubiquitin conjugates are generated at sites of DNA damage repair in human cells..
BRCAl recruitment to chromatin at sites of DNA damage occurs through a complex cascade of protein modifications and interac¬tions, and BRCAl is the third in a sequence of ubiquitin ligases recruited to such sites. Binding of the mediator of DNA damage checkpoint 1 (MDCl) protein to the phosphorylated tail of histone H2AX (')'-H2AX) at sites of DNA breakage recruits the ubiquitin ligase RNF8, which generates ubiquitin chains bound by RAP80:ABRAl, which in turn recruits BRCAl through its carboxy (C) terminus 14-20. The activity of the second ubiquitin ligase, RNF168, maintains the ubiquitin chain signal initiated by RNF8 and thus helps retain BRCAl at these sites.
Mutations in BRCAl are associated with a high risk of breast and ovarian cancer. BRCA1 participates in the DNA damage response and acts as a ubiquitin ligase..
In this paper Morris and colleagues report that BRCA1 is modified by small ubiquitin-like modifier (SUMO) in response to genotoxic stress, and co-localizes at sites of DNA damage with SUM01, SUM02/3 and the SUMO-conjugating enzyme Ubc9. PI AS SUMO E3 ligases eo-localize with and modulate SUMO modification of BRCA 1, and are required for BRCA 1 ubiquitin ligase activity in cells.
PIAS SUMO ligases are required for complete accumulation of double-stranded DNA (dsDNA) damage-repair proteins subsequent to RNF8 accrual, and for proficient double-strand break repair. These data demonstrate that the SUMOylation pathway plays a significant role in mammalian DNA damage response.

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

vitamin D, calcium and fractures

The role of vitamin D, either alone or in combination with calcium, in reducing fractures in reducing fractures is a contentious issue.. Some studies have shown a reduction in the risk of fractures, others have shown no effect, and one recent study found an increased risk of hip fracture.
In the linked study, the DIPART (vitamin D Individual Patient Analysis of Randomized Trials) group reports an individual patient data analysis aimed at identifying factors that influence the efficacy of vitamin D or vitamin D plus calcium in reducing fractures. The study also assessed the influence of dosing regimens and the co-administration of calcium.
Trials using vita¬min D (low or high dose) combined with calcium reduced the overall risk of fracture (hazard ratio 0.92, 9S% confi¬dence interval 0.86 to 0.99), but that only low dose (10 ug) vitamin D combined with calcium reduced the risk of hip fracture (0.74, 0.60 to 0.91). They found no association between fracture history and treatment response, or any association with age, sex, or hormone replacement therapy. Vitamin D alone, irrespective of dose, had no effect on fracture risk.
Whether vitamin D2 (ergocalciferol) and vitamin D3 (cholecalciferol) are equi-potent is not yet established. Recent consensus has suggested that serum concentrations of 70•80 nmol/l are needed for normal health.
Vitamin D has direct effects on muscle strength modulated by specific vitamin D receptors in human muscle tissue. Supplementation may increase muscle strength, thereby reducing the risk of falls and subsequent non-verte¬bral fractures. In combination with calcium, vitamin D reduced first falls by 27% at 12 months and 39% at 20 months, with a decrease in body sway.
So vitamin D ( 10-20 µg / day ) and calcium ( 1000 mg calcium / day ) supplementation appears to have merit.

Sahota 2009 Reducing the risk of fractures with calcium and vitamin D BMJ vol 340 p 109-110

The DIPART group 2009 Patient level pooled analyses of 68500 patients from seven major vitamin D fracture trials in US and Europe. BMJ vol 340, pp 139-140

A review on the nutritional value of the potato

CAMIRE, KUBOW, DONNELLY (2009) Potatoes and Human Health Critical Reviews in Food Sciences and Nutrition vol 49 823-840

The potato (Solanum tuberosum L.) tuber follows only rice and wheat in world importance as a food crop for human consumption. Cultivated potatoes have spread from the Andes of South America where they originated to 160 countries around the world. Consumption of fresh potatoes has declined whilst processed products have increased in popularity. As the potato becomes a staple in the diets of an increasing number of humans, small differences in potato nutritional composition will have major impacts on population health. The potato is a carbohydrate-rich. energy-providing food with little fat. Potato protein content is fairly low but has an excellent biological value of 90-100. Potatoes are particularly high in vitamin C and are a good source of several B vitamins and potassium. The skins provide substantial dietary fibre. Many compounds in potatoes contribute to antioxidant activity and interest in cultivars with pigmented flesh is growing. This review will examine the nutrient and bioactive compounds in potatoes and their impact on human health.