bluuebunny/crossref_metadata_2025 huggingface dataset:
Nutritional modulation of immune function
Authors: Grimble R. F.
Published: September 2008

The inflammatory response to injury and infection, although an essential part of immune function, carries the risk of severe tissue depletion and immunosuppression. These outcomes increase morbidity and delay recovery. Evidence is accumulating that single-nucleotide polymorphisms in the genes controlling pro-inflammatory cytokine production adversely influence the response. Immunonutrition provides a means of modulating the inflammatory response to injury and infection, and thereby improves clinical outcome. n-3 Polyunsaturated fatty acids (n-3 PUFA), glutamine, arginine, S amino acids and nucleotides are important components of immunonutrient mixes. While animal model studies suggest that all these components may exert a beneficial effect in patients, the number of large randomized placebo-controlled trials utilizing immunonutrition is fairly limited and the observed effects are relatively small. Meta-analyses suggest that while immunonutrition may not reduce mortality rates, a reduction in hospital length of stay, decreased requirements for ventilation and lower infection rates are achieved by this mode of nutrition. The present paper discusses some underlying reasons for the difficulty in demonstrating the clinical efficacy of immunonutrition. Paramount among these reasons is the antioxidant status and genetic background of the patient. A number of studies suggest that there is an inverse relationship between inflammation and T-cell function. Immuno-enhancive effects have been shown in a number of studies in which n-3 PUFA, glutamine and N-acetyl cysteine have been employed. All these nutrients may exert their effects by suppressing inflammation; n-3 PUFA by direct suppression of the process and glutamine and N-acetyl cysteine by acting indirectly on antioxidant status. Glutamine and nucleotides exert a direct effect on lymphocyte proliferation. Preliminary data suggests that not all genotypes are equally sensitive to the effects of immunonutrition. When further studies have been conducted to discern the precise interaction between each individual's genotype of relevance to the response to injury and infection, and immunonutrients, the level of precision in the application of immunonutrition will undoubtedly improve.
Enteral and parenteral nutrition: evidence-based approach
Authors: Jeejeebhoy Khursheed N.
Published: September 2008

Nutrition support for patients in hospital has become an essential form of therapy. Total parenteral nutrition (TPN) was the preferred way of giving nutrition to hospital patients for many years but enteral nutrition (EN) is now the preferred route. EN is believed to promote gut function and prevent translocation of intestinal bacteria, thus reducing the incidence of sepsis in critically ill patients. In consequence, the use of TPN has been discouraged as a dangerous form of therapy. Critical review of the data suggests that in the human subject TPN does not cause mucosal atrophy or increase translocation of bacteria through the small intestine. However, overfeeding, which is easy with TPN, can explain the results of studies which have shown that TPN increases sepsis. Furthermore, the risks of TPN-induced complications have been exaggerated. When there is risk of malnutrition and EN is not tolerated, or there is gut failure, TPN is an equally effective and safe alternative.
Pro-inflammatory cytokines and adipose tissue
Authors: Coppack Simon W.
Published: September 2008

Cytokines appear to be major regulators of adipose tissue metabolism. Therapeutic modulation of cytokine systems offers the possibility of major changes in adipose tissue behaviour. Cytokines within adipose tissue originate from adipocyte, preadipocyte and other cell types. mRNA expression studies show that adipocytes can synthesise both tumour necrosis factor a (TNF-a) and several interleukins (IL), notably IL-1b and IL-6. Other adipocyte products with ‘immunological’ actions include complement system products and macrophage colony-stimulating factor. Cytokine secretion within adipocytes appears similar to that of other cells. There is general agreement that circulating TNF-a and IL-6 concentrations are mildly elevated in obesity. Most studies suggest increased TNF-a mRNA expression or secretionin vitroin adipose tissue from obese subjects. The factors regulating cytokine release within adipose tissue appear to include usual ‘inflammatory‘ stimuli such as lipopolysaccaride, but also the size of the fat cellsper seand catecholamines. There is conflicting data about whether insulin and cortisol regulate TNF-a. The effects of cytokines within adipose tissue include some actions that might be characterised as metabolic. TNF-a and IL-6 inhibit lipoprotein lipase, and TNF-a additionally stimulates hormone-sensitive lipase and induces uncoupling protein expression. TNF-a also down regulates insulin-stimulated glucose uptake via effects on glucose transporter 4, insulin receptor autophosphorylation and insulin receptor substrate-1. All these effects will tend to reduce lipid accumulation within adipose tissue. Other effects appear more ‘trophic’, and include the induction of apoptosis, regulation of cell size and induction of de-differentiation (the latter involving reduced peroxisome proliferator-activated receptor g). Cytokines are important stimulators and repressors of other cytokines. In addition, cytokines appear to modulate other regulatory systems. Examples of the latter include effects on leptin secretion (probably stimulation followed by inhibition) and reduction of b3-adrenoceptor expression. There seems to be no clear agreement as to which cytokines derived from adipose tissue act as remote regulators, i.e. hormones. Leptin, which is structurally a cytokine, is also a hormone. IL-6 appears to be released systemically by adipose tissue, but TNF-a is probably not. Both leptin and IL-6 appear to act on the hypothalamus, IL-6 acts on the liver, while leptin may have actions on the pancreas. The importance of the immune system in whole-body energy balance provides a rationale for the links between cytokines and adipose tissue. It seems clear that TNF-a is a powerful autocrine and paracrine regulator of adipose tissue. Other cytokines, notably leptin, and possibly IL-6, have lesser actions on adipose tissue. These cytokines act as hormones, reporting the state of adipose tissue stores throughout the body.
Fetal programming of cardiovascular function through exposure to maternal undernutrition
Authors: Langley-Evans Simon C.
Published: September 2008

A substantial and robust body of epidemiological evidence indicates that prenatal dietary experience may be a factor determining cardiovascular disease risk. Retrospective cohort studies indicate that low birth weight and disproportion at birth are powerful predictors of later disease risk. This prenatal influence on non-communicable disease in later life has been termed programming. Maternal nutritional status has been proposed to be the major programming influence on the developing fetus. The evidence from epidemiological studies of nutrition, fetal development and birth outcome is, however, often weak and inconclusive. The validity of the nutritional programming concept is highly dependent on experimental studies in animals. The feeding of low-protein diets in rat pregnancy results in perturbations in fetal growth and dimensions at birth. The offspring of rats fed low-protein diets exhibit a number of metabolic and physiological disturbances, and are consistently found to have high blood pressure from early postnatal life. This experimental model has been used to explore potential mechanisms of programming through which maternal diet may programme the cardiovascular function of the fetus. Indications from this work are that fetal exposure to maternally-derived glucocorticoids plays a key role in the programming mechanism. Secondary to this activity, the fetal hypothalamic–pituitary–adrenal axis may stimulate renin–angiotensin system activity, resulting in increased vascular resistance and hypertension.
Regulation of mucosal immune responses in effector sites
Authors: Bailey M. , Plunkett F. J. , Rothkötter H.-J. , Vega-Lopez M. A. , Haverson K. , Stokes C. R.
Published: September 2008

In human disease and rodent models, immune responses in the intestinal mucosa can be damaging. Damage is characterised by villus atrophy, crypt hyperplasia and reduced ability to digest and absorb nutrients. In normal individuals active responses to harmless environmental antigens associated with food and commensal bacteria are controlled by the development of immunological tolerance. Similar pathological changes occur in piglets weaned early from their mothers. Active immune responses to food antigens are observed in these piglets, and we and others have hypothesised that the changes occur as a result of transient allergic immune responses to novel food or bacteria antigens. The normal mechanism for producing tolerance to food antigens may operate at induction (Peyer’s patches and mesenteric lymph nodes) or at the effector stage (intestinal lamina propria). In our piglet studies immunological tolerance occurs despite the initial active response. Together with evidence from rodents, this observation suggests that active responses are likely to be controlled at the effector stage, within the intestinal lamina propria. Support for this mechanism comes from the observation that human and pig intestinal T-cells are susceptible to apoptosis, and that this process is accelerated by antigen. We suggest that the role of the normal mature intestinal lamina propria is a balance between immunological effector and regulatory function. In neonatal animals this balance develops slowly and is dependant on contact with antigen. Immunological insults such as weaning may tip the balance of the developing mucosal immune system into excessive effector or regulatory function resulting in transient or chronic allergy or disease susceptibility.
Nutritional factors and immune functions of gut epithelium
Authors: Sanderson Ian R.
Published: September 2008

The intestinal epithelium acts as a barrier to the external environment contained within the lumen of the gut. It also transports solutes for nutrition and for immunological surveillance. The present review develops the hypothesis that changes in diet, through the composition of the lumen environment, alter the expression of genes in the epithelium. These genes include those that encode for proteins that signal to the mucosal immune system. Directly changing the expression of signalling molecules in the intestinal epithelium using transgenic techniques alters immune function. For example, up regulation of the chemokine macrophage inflammatory protein-2 increases neutrophil recruitment. Furthermore, lumen molecules such as short-chain fatty acids regulate chemokine expression by epithelial cells. By this means, the epithelium acts as a transducing monolayer signalling between the contents of the intestine and the mucosal immune system.
Dietary fatty acid modulation of mucosally-induced tolerogenic immune responses
Authors: Harbige Laurence S. , Fisher Benjamin A. C.
Published: September 2008

Immunological unresponsiveness or hyporesponsiveness (tolerance) can be induced by feeding protein antigens to naïve animals. Using a classical oral ovalbumin gut-induced tolerance protocol in BALB/c mice we investigated the effects of dietaryn-6 andn-3 polyunsaturated fatty acids (PUFA) on high-and low-dose oral tolerance (and in non-tolerised animals, i.e. effects of antigen challenge alone) in relation to lymphoproliferative, cytokine and antibody responses. Fish oil rich in long-chainn-3 fatty acids decreased both T-helper (Th) 1- and Th2-like responses. In contrast, borage (Borago officinalis) oil rich inn-6 PUFA, of which γ-linolenic acid is rapidly metabolised to longer-chainn-6 PUFA, increased Th1-like responses and decreased Th2-like responses, and possibly enhanced suppressor cell or Th3-like activity. These findings are in general agreement with other studies on the effects of long chainn-3 PUFA on immune system functions, and characterise important differences between long-chainn-3 andn-6 PUFA, defining more precisely and broadly the immunological regulatory mechanisms involved. They are also discussed in relation to autoimmune disease.
The athlete’s diet: nutritional goals and dietary strategies
Authors: Maughan Ron
Published: September 2008

When talented, motivated and highly trained athletes meet for competition the margin between victory and defeat is usually small. When everything else is equal, nutrition can make the difference between winning and losing. Although the primary concern of many athletes is to supplement the diet with protein, vitamins and minerals, and a range of more exotic compounds, key dietary issues are often neglected. Athletes must establish their nutritional goals, and must also be able to translate them into dietary strategies that will meet these goals. Athletes are often concerned with dietary manipulations in the period around competition, but the main role of nutrition may be to support consistent intensive training which will lead to improved performance. Meeting energy demand and maintaining body mass and body fat at appropriate levels are key goals. An adequate intake of carbohydrate is crucial for maintaining muscle glycogen stores during hard training, but the types of food and the timing of intake are also important. Protein ingestion may stimulate muscle protein synthesis in the post-exercise period, promoting the process of adaptation in the muscles. Restoration of fluid and electrolyte balance after exercise is essential. If energy intake is high and a varied diet is consumed, supplementation of the diet with vitamins and minerals is not warranted, unless a specific deficiency is identified. Specific strategies before competition may be necessary, but this requirement depends on the demands of the sport. Generally, it is important to ensure high pre-competition glycogen stores and to maintain fluid balance. There is limited evidence to support the use of dietary supplements, but some, including perhaps creatine and caffeine, may be beneficial.
Fine and ultrafine particles of the diet: influence on the mucosal immune response and association with Crohn’s disease
Authors: Lomer Miranda C. E. , Thompson Richard P. H. , Powell Jonathan J.
Published: September 2008

Crohn’s disease is a modern Western disease characterised by transmural inflammation of the gastrointestinal tract. It is of unknown aetiology, but evidence suggests that it results from a combination of genetic predisposition and environmental factors. Bacterial-sized microparticles (0·1–1·0 µm) are potent adjuvants in model antigen-mediated immune responses and are increasingly associated with disease. Microparticles of TiO2and aluminosilicate accumulate in macrophages of human gut-associated lymphoid tissue where the earliest signs of lesions in Crohn’s disease are observed. Dietary microparticles are of endogenous or exogenous origin. Endogenous microparticles dominate and are calcium phosphate (most probably hydroxyapatite), which precipitates in the lumen of the mid-distal gastrointestinal tract due to secretion of Ca and phosphate in thesuccus entericus. Exogenous dietary microparticles are contaminants (soil and/or dust) and food additives. TiO2, for example, is a food colourant, and aluminosilicates are anti-caking agents, although some aluminosilicates occur as natural contaminants. Food additives alone account for ingestion of approximately 1012particles/person per d. Possible mechanisms for the role of exogenous and endogenous dietary microparticles in promoting toleragenic or immune responses of gastrointestinal mucosal phagocytosis are discussed. In a double-blind randomised pilot study we have shown that a diet low in Ca and exogenous microparticles appears to alleviate the symptoms of ileal Crohn’s disease, with a significant (P= 0·002) improvement in the Crohn’s disease activity index. A multi-centre trial and further mechanistic studies at the cellular level are underway.
Manipulating the sulfur amino acid content of the early diet and its implications for long-term health
Authors: Rees William D.
Published: September 2008

Epidemiological studies of human populations show that poor growthin uteropredisposes an individual to the later development of type 2 (non-insulin-dependent) diabetes mellitus and hypertension in adulthood. This phenomenon is not confined to man; feeding pregnant rats diets moderately deficient in protein has a similar effect, programming the adult blood pressure and glucose metabolism of the offspring. A restriction in the amino acid supply was thought to cause poor fetal growth. However, recent experiments have shown that this is not the case and instead have implicated the metabolism of the S-containing amino acids. Many semi-synthetic experimental diets contain an imbalance in S-containing amino acids, forcing the animal to synthesise a sizeable part of its cysteine requirement from methionine. Unfortunately, when the diet is low in protein, the oxidation of amino acids is reduced, perturbing methionine metabolism and increasing levels of homocysteine. It is this interaction between protein content and composition of the diet which influences neonatal viability and may also determine the long-term health of the offspring. An excess of homocysteine is known to affect levels of two of the main mediators of cellular methylation reactions, S-adenosyl methionine and methylene tetrahydrofolate. S-adenosyl methionine is the methyl donor for the methylation of newly-synthesised DNA, regulating chromatin assembly and gene expression. The balance between S-adenosyl methionine and the methylated derivatives of folic acid may be critical for the development of differentiating cells and the long-term regulation of gene expression.
Salivary antioxidants and periodontal disease status
Authors: Sculley Dean V. , Langley-Evans Simon C.
Published: September 2008

Periodontal disease is a common chronic adult condition. The bacteriumPorphyromonas gingivalishas been implicated in the aetiology of this disease, which causes destruction of the connective tissue and bone around the root area of the tooth. It has been observed that invadingP. gingivalisbacteria trigger the release of cytokines such as interleukin 8 and tumour necrosis factor α, leading to elevated numbers and activity of polymorphonucleocytes (PMN). As a result of stimulation by bacterial antigens, PMN produce the reactive oxygen species (ROS) superoxide via the respiratory burst as part of the host response to infection. Patients with periodontal disease display increased PMN number and activity. It has been suggested that this proliferation results in a high degree of ROS release, culminating in heightened oxidative damage to gingival tissue, periodontal ligament and alveolar bone. Antioxidant constituents in plasma have been well-documented, being chiefly ascorbate, albumin and urate, and these are known to display sensitivity to dietary antioxidant intakes. The concentration of antioxidants in saliva does not appear to mirror those of plasma. The extent of dietary influence upon salivary antioxidant status is unclear. Urate is the predominant salivary antioxidant, with albumin and ascorbate providing minor contributions. Previous research has found reduced salivary antioxidant activity in patients suffering from periodontal disease. An improved understanding of the role antioxidants play in periodontitis, and the influence of nutrition on antioxidant status, may lead to a possible nutritional strategy for the treatment of periodontal disease.
The adipose organ: morphological perspectives of adipose tissues
Authors: Cinti Saverio
Published: September 2008

Anatomically, an organ is defined as a series of tissues which jointly perform one or more interconnected functions. The adipose organ qualifies for this definition as it is made up of two tissue types, the white and brown adipose tissues, which collaborate in partitioning the energy contained in lipids between thermogenesis and the other metabolic functions. In rats and mice the adipose organ consists of several subcutaneous and visceral depots. Some areas of these depots are brown and correspond to brown adipose tissue, while many are white and correspond to white adipose tissue. The number of brown adipocytes found in white areas varies with age, strain of animal and environmental conditions. Brown and white adipocyte precursors are morphologically dissimilar. Together with a rich vascular supply, brown areas receive abundant noradrenergic parenchymal innervation. The gross anatomy and histology of the organ vary considerably in different physiological (cold acclimation, warm acclimation, fasting) and pathological conditions such as obesity; many important genes, such as leptin and uncoupling protein-1, are also expressed very differently in the two cell types. These basic mechanisms should be taken into account when addressing the physiopathology of obesity and its treatment.
Adipose tissue and the insulin resistance syndrome
Authors: Frayn Keith N.
Published: September 2008

Obesity is associated with insulin resistance. Insulin resistance underlies a constellation of adverse metabolic and physiological changes (the insulin resistance syndrome) which is a strong risk factor for development of type 2 diabetes and CHD. The present article discusses how accumulation of triacylglycerol in adipocytes can lead to deterioration of the responsiveness of glucose metabolism in other tissues. Lipodystrophy, lack of adipose tissue, is also associated with insulin resistance. Any plausible explanation for the link between excess adipose tissue and insulin resistance needs to be able to account for this observation. Adipose tissue in obesity becomes refractory to suppression of fat mobilization by insulin, and also to the normal acute stimulatory effect of insulin on activation of lipoprotein lipase (involved in fat storage). The net effect is as though adipocytes are ‘full up’ and resisting further fat storage. Thus, in the postprandial period especially, there is an excess flux of circulating lipid metabolites that would normally have been ‘absorbed’ by adipose tissue. This situation leads to fat deposition in other tissues. Accumulation of triacylglycerol in skeletal muscles and in liver is associated with insulin resistance. In lipodystrophy there is insufficient adipose tissue to absorb the postprandial influx of fatty acids, so these fatty acids will again be directed to other tissues. This view of the link between adipose tissue and insulin resistance emphasises the important role of adipose tissue in ‘buffering’ the daily influx of dietary fat entering the circulation and preventing excessive exposure of other tissues to this influx.
A heliocentric view of leptin
Authors: Frühbeck Gema
Published: September 2008

Leptin is significantly broadening our understanding of the mechanisms underlying neuroendocrine function. Initially, based on a rather static view of the hormone, most investigations focused on the effects of leptin on food intake control and body-weight homeostasis, with attention primarily focused on the implications of leptin as a lipostatic factor and central satiety agent. However, the almost ubiquitous distribution of leptin receptors in peripheral tissues provided a fertile area for investigation and a more dynamic view of leptin started to unfold. This adipocyte-derived circulating peptidic hormone, with a tertiary structure resembling that of members of the long-chain helical cytokine family, has generated an enormous interest in the interaction as well as integration between brain targets and peripheral signals. Considerable evidence for systemic effects of leptin on specific tissues and metabolic pathways indicates that leptin operates both directly and indirectly to orchestrate complex pathophysiological processes. Disentangling the biochemical and molecular mechanisms in which leptin is involved represents one of the major challenges ahead.
The evidence for glutamine use in the critically-ill
Authors: Griffiths Richard D.
Published: September 2008

Research into the metabolic role of glutamine in trauma and sepsis brings evidence to suggest a conditional deficiency occurs because increased and altered tissue demands exceed endogenous production. Such a deficiency has functional implications, and the restorative provision of parenteral glutamine has been shown to offer improved clinical outcomes in a variety of conditions. In the critically-ill it is associated with improvements in immune function, and improved survival from infection leading to an overall improved outcome.
Plasminogen activator inhibitor-1 and haemostasis in obesity
Authors: Mutch Nicola J. , Wilson Heather M. , Booth Nuala A.
Published: September 2008

The connection between obesity and disordered haemostasis is well established, but incompletely understood. There is a strong link between inhibition of fibrinolysis and obesity, and elevation of the plasma inhibitor, plasminogen activator inhibitor-1 (PAI-1), is regarded as a central factor. Here we explore the increased risk of atherothrombotic disorders in obese subjects, and the evidence for metabolic and genetic causes. There is a clear relationship between plasma PAI-1 and obesity, and adipose tissue synthesises PAI-1, as has been shown in mouse and rat models, and more recently in human material. This tissue also produces several effector molecules that can up regulate PAI-1. These molecules include transforming growth factor b, tumour necrosis factor a, angiotensin II and interleukin 6, all of which up regulate PAI-1 in various cell types. The issue of whether adipose tissue directly contributes to plasma PAI-1, or whether it primarily contributes indirectly, its products stimulating other cells to produce PAI-1 that feeds into the plasma pool, is not yet resolved. Finally, we briefly examine other proteins of haemostasis that are products of adipose tissue. Further studies are needed to define the regulation of these proteins, in adipose tissue itself and in other cells influenced by its products, in order to extend recent insights into the links between obesity and haemostasis.
Gating Pore Currents in DIIS4 Mutations of NaV1.4 Associated with Periodic Paralysis: Saturation of Ion Flux and Implications for Disease Pathogenesis
Authors: Struyk Arie F. , Markin Vladislav S. , Francis David , Cannon Stephen C.
Published: September 2008

S4 voltage–sensor mutations in CaV1.1 and NaV1.4 channels cause the human muscle disorder hypokalemic periodic paralysis (HypoPP). The mechanism whereby these mutations predispose affected sarcolemma to attacks of sustained depolarization and loss of excitability is poorly understood. Recently, three HypoPP mutations in the domain II S4 segment of NaV1.4 were shown to create accessory ionic permeation pathways, presumably extending through the aqueous gating pore in which the S4 segment resides. However, there are several disparities between reported gating pore currents from different investigators, including differences in ionic selectivity and estimates of current amplitude, which in turn have important implications for the pathological relevance of these aberrant currents. To clarify the features of gating pore currents arising from different DIIS4 mutants, we recorded gating pore currents created by HypoPP missense mutations at position R666 in the rat isoform of Nav1.4 (the second arginine from the outside, at R672 in human NaV1.4). Extensive measurements were made for the index mutation, R666G, which created a gating pore that was permeable to K+ and Na+. This current had a markedly shallow slope conductance at hyperpolarized voltages and robust inward rectification, even when the ionic gradient strongly favored outward ionic flow. These characteristics were accounted for by a barrier model incorporating a voltage-gated permeation pathway with a single cation binding site oriented near the external surface of the electrical field. The amplitude of the R666G gating pore current was similar to the amplitude of a previously described proton-selective current flowing through the gating pore in rNaV1.4-R663H mutant channels. Currents with similar amplitude and cation selectivity were also observed in R666S and R666C mutant channels, while a proton-selective current was observed in R666H mutant channels. These results add support to the notion that HypoPP mutations share a common biophysical profile comprised of a low-amplitude inward current at the resting potential that may contribute to the pathological depolarization during attacks of weakness.
Afrothismiagabonensis sp. nov. (Burmanniaceae) from Gabon
Authors: Dauby G. , Parmentier I. , Stévart T.
Published: September 2008

A new species Afrothismia gabonensis Dauby & Stévart (Burmanniaceae) is described from the Pongara National Park (Gabon). It is the second Afrothismia species recorded from this country and the twelfth of the genus. The new species mainly differs from Afrothismia winkleri by its dorsal tepals which are much longer. Information on the species’ ecology, phenology and distribution is provided.
Acacia fumosa sp. nov. (Fabaceae) from eastern Ethiopia
Authors: Thulin Mats
Published: September 2008

The new species Acacia fumosa is described and illustrated. It is confined to the Somali National Regional State (Ogaden) in eastern Ethiopia, where it is dominant and widespread on limestone hills in an area of at least 8 000 km2. Acacia fumosa is closely related to A. ochracea in south‐western Somalia, but differs, for example, in its ash grey, smooth and non‐flaking bark, densely pubescent leaves, and pink flowers.
Lectotypification of Actinidia
Authors: Li Xin‐Wei , Li Jian‐Qiang
Published: September 2008

A lectotype of the genus Actinidia Lindley and its type species Actinidia callosa Lindley is designated.
Relationship of low‐density lipoprotein (LDL) particle size to thyroid function status in Koreans
Authors: Kim Chul Sik , Kang Jun Goo , Lee Seong Jin , Ihm Sung Hee , Yoo Hyung Joon , Nam Ji Sun , Ahn Chul Woo , Kim Kyung Rae
Published: September 2008

Objective  Dyslipidaemia is a well‐known manifestation of thyroid dysfunction. Recently, small low‐density lipoprotein (LDL) particle size has been linked with development of cardiovascular disease. To better understand the effects of thyroid dysfunction on the development of cardiovascular disease, we examined LDL particle size and lipid profiles in subjects with different thyroid function.

Methods  Included were 46 patients with overt hypothyroidism, 57 patients with subclinical hypothyroidism, 46 patients with overt hyperthyroidism, 51 patients with subclinical hyperthyroidism, and 110 age‐ and sex‐matched healthy control subjects. We measured LDL particle size and lipid profiles in these subjects.

Results  No significant differences were found in LDL particle size between the groups with different thyroid function. Serum total cholesterol and LDL‐cholesterol levels were significantly higher in the cases of hypothyroidism than in the cases of hyperthyroidism and the healthy control subjects. Serum triglyceride levels were higher in subjects with overt hypothyroidism than in those with overt hyperthyroidism or healthy control subjects.

Conclusions  LDL particle size, the emerging risk factor for atherosclerosis, did not appear to be significantly affected by the degree of thyroid dysfunction. Increased risk of atherosclerosis in hypothyroidism does not appear to be associated with LDL particle size, the non‐traditional cardiovascular risk factor.
Intron polymorphism in the KIAA0350 gene is reproducibly associated with susceptibility to type 1 diabetes (T1D) in the Han Chinese population
Authors: Wu Xiaopan , Zhu Xilin , Wang Xin , Ma Juan , Zhu Shuying , Li Jingyun , Liu Ying
Published: September 2008

Objective  Three independent genome‐wide association studies in white populations have reported that single nucleotide polymorphisms (SNPs) in the KIAA0350 gene are associated with susceptibility to type 1 diabetes (T1D). The gene product of KIAA0350 is predicted to be a sugar binding C‐type lectin. In the present study, we investigated whether SNPs in this gene were associated with T1D in the Han Chinese population.

Design and methods  In this case‐controlled association study, a total of 205 T1D patients and 422 non‐diabetic subjects of the Han Chinese population were enrolled. Two SNPs, namely, rs17802927 and rs725613, in the KIAA0350 gene were genotyped using a polymerase chain reaction–restriction fragment length polymorphism (PCR–RFLP) protocol.

Results  The intron SNP rs725613 was strongly associated with T1D in the Han Chinese population [P = 0·00007, odds ratio (OR) = 0·527, 95% confidence interval (CI) = 0·383–0·726], and the frequencies of its genotypes in the T1D group significantly differed from those in the control group (P = 0·0001).

Conclusion  The intron polymorphism rs725613 in the KIAA0350 gene is associated with susceptibility to T1D, and this association is not race specific.
Foraging strategies and patch distributions: intraguild interactions between Dicyphus hesperus and Encarsia formosa
Authors: BENNETT J. A. , GILLESPIE D. R. , SHIPP J. L. , VANLAERHOVEN S. L.
Published: September 2008

Abstract 1. Competing foragers are affected by the distribution of resources, but can also affect resource distribution. Intraguild predators may affect the distribution of both the shared prey and the intraguild prey, which are also their competitors.

2. Variation in foraging strategies and their effects on resource distributions may influence the outcome of intraguild interactions between an intraguild predator and its intraguild prey. This was tested using whitefly Trialeurodes vaporariorum as the shared resource, the parasitoid Encarsia formosa as the intraguild prey, and Dicyphus hesperus, an omnivore, as the intraguild predator on tomato (Lycopersicon esculentum) and mullein (Verbascum thapsus) plants, within enclosures in a greenhouse. Treatments were established with and without the intraguild predator and at high and low intraguild prey densities.

3. The interaction between D. hesperus and E. formosa showed significant asymmetry, with D. hesperus populations being unaffected by E. formosa densities, although E. formosa populations were reduced by the inclusion of D. hesperus. However, the inclusion of D. hesperus diminished density‐dependent effects limiting E. formosa populations at high release densities.

4. Dicyphus hesperus reduced the average patch size and the proportion of patches occupied by whitefly. Increasing the release rate of E. formosa had no effect on any distributional measure. Based upon the foraging ecology of both species, the foraging activities of D. hesperus appear to have modified the patch distribution so that its foraging strategy becomes more successful than that of E. formosa. These properties may provide an important mechanism determining the outcome of species interactions.
Prevention of haemophilic arthropathy in haemophilic children with inhibitors
Authors: RODRIGUEZ‐MERCHAN E. C.
Published: September 2008

Summary.  Prophylaxis is the ideal manner to treat haemophilia patients without inhibitors. In fact, it can prevent the orthopaedic complications that commonly bedevil haemophilia patients without inhibitors in the absence of such prophylaxis or when they are only managed by on‐demand treatment. Currently, there are two agents that allow us to control haemostasis in patients with inhibitors, i.e. recombinant factor VIIa (rFVIIa) and activated prothrombin complex concentrate (APCC). Both agents can be used for arthropathy prevention, or for intensive on‐demand treatment in haemophilia patients with inhibitors. In this paper, we have tried to find an answer to the question of which bypassing agents (rFVIIa or APCC) could be used in children and adults.
Prevention of haemophilic arthropathy during childhood. May common orthopaedic management be extrapolated from patients without inhibitors to patients with inhibitors?
Authors: RODRIGUEZ‐MERCHAN E. C. , HEDNER U. , HEIJNEN L. , JIMENEZ‐YUSTE V. , LEE C. A. , MORFINI M. , QUEROL F. , ROOSENDAAL G. , SANTAGOSTINO E. , SOLIMENO L. P.
Published: September 2008

Summary.  We recommend prophylaxis in haemophilic children with an inhibitor as a way of preventing the musculoskeletal impairment that is likely to affect them. This approach has been used for children without inhibitors with excellent results. If prophylaxis is not feasible, we suggest that intensive on‐demand treatment should be given. Two agents, recombinant activated FVII (rFVIIa) and activated prothrombin complex concentrates (aPCC), are currently used to control haemostasis either for prophylaxis or intensive on‐demand treatment. As it is recombinant, rFVIIa would seem more appropriate to be employed in children. aPCC could be used in adults, or in the event of an unsatisfactory response to rFVIIa. We recommend prophylaxis or, at least, intensive on‐demand treatment in haemophilia children with inhibitors. Both rFVIIa and aPCC are being used for this purpose. It would seem that rFVIIa might be more appropriate for children as it is a recombinant product. Nevertheless, after skeletal maturity (in adults), both agents could be used indistinctively (taking into consideration that FEIBA is a plasma‐derived product). We still need more well‐designed comparative studies in order to be able to assert that our consensus‐based conclusion is evidence based. In orthopaedic surgery, both aPCC and rFVIIa have been reported to be effective in controlling perioperative haemostasis, although in practice most centres have so far used rFVIIa for their orthopaedic procedures. We recommend rehabilitation programmes for all patients with inhibitors in order to mitigate the disabling and handicapping impact of their condition and thereby enable them to achieve social integration. Programmes for haemophilic children without inhibitors can be applied to children with inhibitors but should be individually tailored.
The gustatory receptor family in the silkworm moth Bombyx mori is characterized by a large expansion of a single lineage of putative bitter receptors
Authors: Wanner K. W. , Robertson H. M.
Published: September 2008

The gustatory receptor (Gr) family of insect chemoreceptors includes receptors for sugars and bitter compounds, as well as cuticular hydrocarbons and odorants such as carbon dioxide. We have annotated a total of 65 Gr genes from the silkworm Bombyx mori genome. The Gr family in the silkworm moth includes putative carbon dioxide receptors and sugar receptors, as well as duplicated orthologues of the orphan DmGr43a receptor. Most prominent in this 65‐gene family, however, is a single large expansion of 55 Grs that we propose are predominantly ‘bitter’ receptors involved in perception of the large variety of secondary plant chemicals that caterpillars and moths encounter. These Grs might therefore mediate food choice and avoidance as well as oviposition site preference.
Immune recognition of the surface associated antigen, Tc‐SAA‐1, from infective larvae of Teladorsagia circumcincta
Authors: NISBET A. J. , KNOX D. P. , McNAIR C. M. , MEIKLE L. I. , SMITH S. K. , WILDBLOOD L. A. , MATTHEWS J. B.
Published: September 2008

A cDNA encoding a surface‐associated antigen was amplified by reverse transcriptase polymerase chain reaction (PCR) from RNA extracted from Teladorsagia circumcincta exsheathed third stage larvae (xL3). The protein encoded by this cDNA, Tc‐SAA‐1, displays 77% identity over 162 amino acid residues to a surface associated antigen from Ancylostoma caninum (Ac‐SAA‐1). Antiserum raised against a bacterially‐expressed recombinant form of Tc‐SAA‐1 reacted with a native protein in somatic and surface extracts of xL3 but not with L4 or adult parasites. Limited binding of anti‐Tc‐SAA‐1 antibody was observed on the cuticular surface of xL3 s, however, regions of localization underlying the cuticle were observed. Incubation of xL3 T. circumcincta with anti‐SAA rabbit serum failed to significantly inhibit penetration of the abomasal mucosa in vitro. IgA in abomasal mucus derived from sheep that had received a trickle infection of T. circumcincta bound recombinant Tc‐SAA‐1.
SUPPRESSING NADPH OXIDASE‐DEPENDENT OXIDATIVE STRESS IN THE VASCULATURE WITH NITRIC OXIDE DONORS
Authors: Selemidis Stavros
Published: September 2008

Reactive oxygen species produced in the vasculature, including superoxide anion, contribute to the pathogenesis of cardiovascular disease states, such as atherosclerosis. A critical source of superoxide is vascular NADPH oxidase and upregulation of this enzyme brings about the oxidative stress underlying atherosclerosis. Excessive superoxide in arteries directly inactivates endothelium‐derived nitric oxide (NO), compromising its vasoprotective effects.

Given that a reduction in NO bioavailability is key in the pathophysiology of atherosclerosis, replacement of NO by exogenously administered NO donors may restore the deficit in NO during disease. Although the organic nitrate family of NO donors is often the first choice for the acute management of symptoms of atherosclerosis and angina pectoris, most of the compounds in this class are unsuitable for long‐term therapy because they cause oxidative stress by activation and upregulation of vascular NADPH oxidase and induce tolerance to subsequent nitrate treatment and endogenous NO. These problems of nitrates have not only limited their therapeutic exploitation, but have also stifled interest in newer‐generation NO donors.

Recent evidence indicates that, in stark contrast with the organic nitrates, the newer‐age diazeniumdiolate NONOate class of NO donors suppress vascular NADPH oxidase‐dependent superoxide production and are less likely to induce tolerance, making them more suitable for suppression of oxidative stress in atherosclerosis.

Here, it is hypothesized that NONOates provide a novel means of suppressing NADPH oxidase‐dependent oxidative stress to restore vascular NO levels to prevent, and even reverse, atherosclerosis.
POSSIBLE PARTICIPATION OF CHLORIDE ION CHANNELS IN ATP RELEASE FROM CANCER CELLS IN SUSPENSION
Authors: Nejime Namie , Kagota Satomi , Tada Yukari , Nakamura Kazuki , Hashimoto Michio , Kunitomo Masaru , Shinozuka Kazumasa
Published: September 2008

Cancer cells must detach from the primary focus to initiate the process of metastasis. Previously, we demonstrated that intracellular Ca2+ levels are increased in endothelial cells in the presence of cancer cells and that ATP derived from these cells causes this increase. The present study clarifies the mechanism of ATP release from cancer cells by investigating the effects of Cl− channel inhibitors and other drugs on ATP release from human fibrosarcoma cells (HT‐1080 cells).

Levels of extracellular ATP and its metabolites were measured using high‐performance liquid chromatography (HPLC) with fluorescent detection.

Significantly more extracellular ATP was released by suspended than by adherent HT‐1080 cells. The Cl− channel inhibitors 5‐nitro‐2‐(3‐phenylpropylamino) benzoic acid (100 µmol/L), gadolinium (100 µmol/L) and niflumic acid (100 µmol/L) all significantly inhibited ATP release from HT‐1080 cells (1 × 103 /mL) to 39.7 ± 6.5, 28.5 ± 2.5 and 82.5 ± 4.1% of control, respectively.

Neither of the p‐glycoprotein inhibitors (i.e. 50 µmol/L quinidine and 90 µmol/L verapamil) had any effect on ATP release from HT‐1080 cells. The gap junction hemichannel inhibitor Gap26 (300 µmol/L) slightly, but significantly, decreased ATP release by approximately 20%. The gap junction inhibitor 18‐α‐glycyrrhetinic acid (10 µmol/L) tended to inhibit ATP release from HT‐1080 cells, but the difference did not reach statistical significance.

These findings indicate that Cl− channels play the most important role in ATP release from detached cancer cells and that gap junction hemichannels are also associated with ATP release.
Changing trends in the proportion of adenocarcinoma of the esophagogastric junction in a large tertiary referral center in Japan
Authors: Kusano Chika , Gotoda Takuji , Khor Christopher J , Katai Hitoshi , Kato Hoichi , Taniguchi Hirokazu , Shimoda Tadakazu
Published: September 2008

Introduction:  A dramatic increase in incidence of adenocarcinoma of the esophagogastric junction (EGJ) over the past two decades has been reported in the West. However, epidemiological data from Asian countries have not shown a similar trend. The aim of this study was to determine the incidence of adenocarcinoma of the EGJ in a cohort of consecutive patients operated on for gastric adenocarcinoma at a major cancer referral center in Japan.

Method:  We reviewed pathological reports of all patients who underwent surgery for advanced gastric adenocarcinoma between 1962 and 2005 at the National Cancer Centre Hospital in Tokyo. Adenocarcinoma of the EGJ was defined from images recorded for each patient, in accordance with the classification of Siewert and Stein. The proportion of adenocarcinoma at the EGJ among operated gastric adenocarcinoma patients was compiled at five‐year intervals and serial comparison made.

Results:  A total of 6953 patients with advanced gastric adenocarcinoma were operated on; adenocarcinoma of EGJ was found in 520 patients. The overall proportion of adenocarcinoma of the EGJ increased from 2.3% (1962–1965) to 10.0% (2001–2005). The proportion of Siewert Type II rose from 28.5% (1962–1965) to 57.3% (2001–2005), while that of Type I remained at around 1%.

Conclusion:  An increasing trend of adenocarcinoma of EGJ is observed in this study of patients operated on for gastric adenocarcinoma from 1962 to 2005 in a large tertiary referral center in Japan.
Associations of interleukin‐6, C‐reactive protein and serum amyloid A with mortality in haemodialysis patients
Authors: WETMORE JAMES B , LOVETT DAVID H , HUNG ADRIANA M , COOK‐WIENS GALEN , MAHNKEN JONATHAN D , SEN SAUNAK , JOHANSEN KIRSTEN L
Published: September 2008

Background:  Individuals with end‐stage renal disease (ESRD) manifest a chronic inflammatory state. Serum albumin, C‐reactive protein (CRP), interleukin‐6 (IL‐6) and serum amyloid A (SAA) have been associated with mortality in ESRD, although reports vary as to whether they are true independent markers of mortality. We undertook a prospective study to determine whether these markers could predict mortality in ESRD.

Methods:  A cohort of individuals on haemodialysis was followed prospectively for a mean of 2.1 years. Albumin, CRP, IL‐6 and SAA were drawn at enrolment. Association between mortality and serum markers was assessed using Cox proportional hazards regression. A trend analysis was undertaken to establish the functional form of the association between serum markers and outcome.

Results:  After multivariable adjustment, IL‐6 was most strongly associated with mortality, followed closely by albumin (P = 0.0002 and P = 0.0005, respectively). CRP was marginally associated with mortality (P = 0.046), and SAA was not independently associated with mortality. In the final model adjusting for the effects of both IL‐6 and albumin simultaneously, both markers remained associated with mortality (P = 0.003 and P = 0.011).

Conclusion:  IL‐6 had the strongest independent association with mortality, followed closely by albumin. CRP and SAA were not associated with mortality when measured at single time points. Increasing levels of IL‐6 and decreasing levels of albumin were associated with increased mortality. IL‐6 and albumin may be capturing different aspects of the inflammatory burden observed in haemodialysis patients.