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Pathological placental inflammation increases the risk for several adult disorders, but these mediators are also expressed under homeostatic conditions, where their contribution to adult health outcomes is unknown. Here we define an inflammation-related expression signature, primarily expressed in Hofbauer cells of the term placenta and use expression quantitative trait loci to create a polygenic score (PGS) predictive of its expression. Using this PGS in the UK Biobank we conduct a phenome-wide association study, followed by Mendelian randomization and identify protective, sex-dependent effects of the placental module on cardiovascular and depressive outcomes. Genes differentially regulated by intra-amniotic infection and preterm birth are over-represented within the module. We also identify aspirin as a putative modulator of this inflammation-related signature. Our data support a model where disruption of placental Hofbauer cell function, due to preterm birth or prenatal infection, contributes to the increased risk of depression and cardiovascular disease observed in these individuals. Placental inflammation is sometimes associated with health outcomes later in life. Here, the authors find that expression of genes associated with the homeostatic function of Hofbauer cells, a placenta-specific macrophage, are associated with protection from adult cardiovascular and depressive disorders [ABSTRACT FROM AUTHOR]

Background: Archaea of the order Thermoplasmatales are widely distributed in natural acidic areas and are amongst the most acidophilic prokaryotic organisms known so far. These organisms are difficult to culture, with currently only six genera validly published since the discovery of Thermoplasma acidophilum in 1970. Moreover, known great diversity of uncultured Thermoplasmatales represents microbial dark matter and underlines the necessity of efforts in cultivation and study of these archaea. Organisms from the order Thermoplasmatales affiliated with the so-called "alphabet-plasmas", and collectively dubbed "E-plasma", were the focus of this study. These archaea were found predominantly in the hyperacidic site PM4 of Parys Mountain, Wales, UK, making up to 58% of total metagenomic reads. However, these archaea escaped all cultivation attempts. Results: Their genome-based metabolism revealed its peptidolytic potential, in line with the physiology of the previously studied Thermoplasmatales isolates. Analyses of the genome and evolutionary history reconstruction have shown both the gain and loss of genes, that may have contributed to the success of the "E-plasma" in hyperacidic environment compared to their community neighbours. Notable genes among them are involved in the following molecular processes: signal transduction, stress response and glyoxylate shunt, as well as multiple copies of genes associated with various cellular functions; from energy production and conversion, replication, recombination, and repair, to cell wall/membrane/envelope biogenesis and archaella production. History events reconstruction shows that these genes, acquired by putative common ancestors, may determine the evolutionary and functional divergences of "E-plasma", which is much more developed than other representatives of the order Thermoplasmatales. In addition, the ancestral hereditary reconstruction strongly indicates the placement of Thermogymnomonas acidicola close to the root of the Thermoplasmatales. Conclusions: This study has analysed the metagenome-assembled genome of "E-plasma", which denotes the basis of their predominance in Parys Mountain environmental microbiome, their global ubiquity, and points into the right direction of further cultivation attempts. The results suggest distinct evolutionary trajectories of organisms comprising the order Thermoplasmatales, which is important for the understanding of their evolution and lifestyle. [ABSTRACT FROM AUTHOR]

First Person is a series of interviews with the first authors of a selection of papers published in Journal of Cell Science, helping researchers promote themselves alongside their papers. Anthony Dornan is first author on ‘Compromised junctional integrity phenocopies age)dependent renal dysfunction in Drosophila Snakeskin mutants’, published in JCS. Anthony conducted the research described in this article while at Prof. Julian Dow’s lab at School of Molecular Biosciences, University of Glasgow, UK, where he currently works as a Lab Manager/Research Technician. Anthony’s research focuses on applying molecular genetic techniques, predominantly using the model organism Drosophila and in particular the fly’s Malpighian (renal) tubules, to address fundamental questions in the physiology of cell signalling, transport and stress responses. [ABSTRACT FROM AUTHOR]

Purpose: Pomegranate fruit, Punica granatum L. (Punicaceae), and its constituents have been shown to inhibit inflammation. In this study, we aimed to assess the effects of freeze-dried pomegranate (PWE) on PGE production in IL-1β-stimulated SK-N-SH cells. Methods: An enzyme immunoassay (EIA) was used to measure prostaglandin E (PGE) production from supernatants of IL-1β-stimulated SK-N-SH cells. Expression of COX-2, phospho-IκB, and phospho-IKK proteins was evaluated, while NF-κB reporter gene assay was carried out in TNFα-stimulated HEK293 cells to determine the effect of PWE on NF-κB transactivation. Levels of BACE-1 and Aβ in SK-N-SH cells stimulated with IL-1β were measured with an in cell ELISA. Results: PWE (25-200 μg/ml) dose dependently reduced COX-2-dependent PGE production in SK-N-SH cells stimulated with IL-1β. Phosphorylation of IκB and IKK was significantly ( p < 0.001) inhibited by PWE (50-200 μg/ml). Our studies also show that PWE (50-200 μg/ml) significantly ( p < 0.01) inhibited NF-κB transactivation in TNFα-stimulated HEK293 cells. Furthermore, PWE inhibited BACE-1 and Aβ expression in SK-N-SH cells treated with IL-1β. Conclusions: Taken together, our study demonstrates that pomegranate inhibits inflammation, as well as amyloidogenesis in IL-1β-stimulated SK-N-SH cells. We propose that pomegranate is a potential nutritional strategy in slowing the progression of neurodegenerative disorders such as Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Aim To evaluate the association with diabetic kidney disease of single nucleotide polymorphisms ( SNPs) that may contribute to mitochondrial dysfunction. Methods The mitochondrial genome and 1039 nuclear genes that are integral to mitochondrial function were investigated using a case (n = 823 individuals with diabetic kidney disease) vs. control (n = 903 individuals with diabetes and no renal disease) approach. All people included in the analysis were of white European origin and were diagnosed with Type 1 diabetes before the age of 31 years. Replication was conducted in 5093 people with similar phenotypes to those of the discovery collection. Association analyses were performed using the plink genetic analysis toolset, with adjustment for relevant covariates. Results A total of 25 SNPs were evaluated in the mitochondrial genome, but none were significantly associated with diabetic kidney disease or end-stage renal disease. A total of 38 SNPs in nuclear genes influencing mitochondrial function were nominally associated with diabetic kidney disease and 16 SNPS were associated with end-stage renal disease, secondary to diabetic kidney disease, with meta-analyses confirming the same direction of effect. Three independent signals (seven SNPs) were common to the replication data for both phenotypes with Type 1 diabetes and persistent proteinuria or end-stage renal disease. Conclusions Our results suggest that SNPs in nuclear genes that influence mitochondrial function are significantly associated with diabetic kidney disease in a white European population. [ABSTRACT FROM AUTHOR]

It has traditionally been believed that resistance training can only induce muscle growth when the exercise intensity is greater than 65 % of the 1-repetition maximum (RM). However, more recently, the use of low-intensity resistance exercise with blood-flow restriction (BFR) has challenged this theory and consistently shown that hypertrophic adaptations can be induced with much lower exercise intensities (<50 % 1-RM). Despite the potent hypertrophic effects of BFR resistance training being demonstrated by numerous studies, the underlying mechanisms responsible for such effects are not well defined. Metabolic stress has been suggested to be a primary factor responsible, and this is theorised to activate numerous other mechanisms, all of which are thought to induce muscle growth via autocrine and/or paracrine actions. However, it is noteworthy that some of these mechanisms do not appear to be mediated to any great extent by metabolic stress but rather by mechanical tension (another primary factor of muscle hypertrophy). Given that the level of mechanical tension is typically low with BFR resistance exercise (<50 % 1-RM), one may question the magnitude of involvement of these mechanisms aligned to the adaptations reported with BFR resistance training. However, despite the low level of mechanical tension, it is plausible that the effects induced by the primary factors (mechanical tension and metabolic stress) are, in fact, additive, which ultimately contributes to the adaptations seen with BFR resistance training. Exercise-induced mechanical tension and metabolic stress are theorised to signal a number of mechanisms for the induction of muscle growth, including increased fast-twitch fibre recruitment, mechanotransduction, muscle damage, systemic and localised hormone production, cell swelling, and the production of reactive oxygen species and its variants, including nitric oxide and heat shock proteins. However, the relative extent to which these specific mechanisms are induced by the primary factors with BFR resistance exercise, as well as their magnitude of involvement in BFR resistance training-induced muscle hypertrophy, requires further exploration. [ABSTRACT FROM AUTHOR]

Whilst the heritable nature of Type 2 diabetes has been recognized for many years, only in the past two decades have linkage analyses in families and genome-wide association studies in large populations begun to reveal the genetic landscape of the disease in detail. Whilst the former have provided a powerful means of identifying the genes responsible for monogenic forms of the disease, the latter highlight relatively large genomic regions. These often harbour multiple genes, whose relative contribution to exaggerated disease risk is uncertain. In the present study, the approaches that have been used to dissect the role of just a few ( TCF7L2, SLC30A8, ADCY5, MTNR1B and CDKAL1) of the ~ 500 genes identified at dozens of implicated loci are described. These are usually selected based on the strength of their effect on disease risk, and predictions as to their likely biological role. Direct determination of the effects of identified polymorphisms on gene expression in disease-relevant tissues, notably the pancreatic islet, are then performed to identify genes whose expression is affected by a particular polymorphism. Subsequent functional analyses then involve perturbing gene expression in vitro in β-cell lines or isolated islets and in vivo in animal models. Although the majority of polymorphisms affect insulin production rather than action, and mainly affect the β cell, effects via other tissues may also contribute, requiring careful consideration in the design and interpretation of experiments in model systems. These considerations illustrate the scale of the task needed to exploit genome-wide association study data for the development of new therapeutic strategies. [ABSTRACT FROM AUTHOR]

Aims To investigate the relationship βetween adiposity and plasma free fatty acid levels and the influence of total plasma free fatty acid level on insulin sensitivity and β-cell function. Methods An insulin sensitivity index, acute insulin response to glucose and a disposition index, derived from i.v. glucose tolerance minimal model analysis and total fasting plasma free fatty acid levels were available for 533 participants in the Reading, Imperial, Surrey, Cambridge, Kings study. Bivariate correlations were made Between insulin sensitivity index, acute insulin response to glucose and disposition index and Both adiposity measures (BMI, waist circumference and Body fat mass) and total plasma free fatty acid levels. Multivariate linear regression analysis was performed, controlling for age, sex, ethnicity and adiposity. Results After adjustment, all adiposity measures were inversely associated with insulin sensitivity index (BMI: β = -0.357; waist circumference: β = -0.380; βody fat mass: β = -0.375) and disposition index (BMI: β = -0.215; waist circumference: β = -0.248; βody fat mass: β = -0.221) and positively associated with acute insulin response to glucose [BMI: β = 0.200; waist circumference: β = 0.195; Body fat mass β = 0.209 (P values <0.001)]. Adiposity explained 13, 4 and 5% of the variation in insulin sensitivity index, acute insulin response to glucose and disposition index, respectively. After adjustment, no adiposity measure was associated with free fatty acid level, But total plasma free fatty acid level was inversely associated with insulin sensitivity index (β = -0.133), acute insulin response to glucose (β = -0.148) and disposition index [β = -0.218 (P values <0.01)]. Plasma free fatty acid concentration accounted for 1.5, 2 and 4% of the variation in insulin sensitivity index, acute insulin response to glucose and disposition index, respectively. Conclusions Plasma free fatty acid levels have a modest negative association with insulin sensitivity, β-cell secretion and disposition index But no association with adiposity measures. It is unlikely that plasma free fatty acids are the primary mediators of obesity-related insulin resistance or β-cell dysfunction. [ABSTRACT FROM AUTHOR]

Since the first pancreas transplants in the early 1960s, whole-organ pancreas transplantation, either alone or combined with kidney transplantation, has become commonplace in many countries around the world. Whole-organ pancreas transplantation is available in the UK, with ~200 transplants currently carried out per year. Patient survival and pancreas graft outcome rates are now similar to other solid organ transplant programmes, with high rates of long-term insulin independence. In the present review, we will discuss whole-pancreas transplantation as a treatment for diabetes, focusing on indications for transplantation, the nature of the procedure performed, graft survival rates and the consequences of pancreas transplantation on metabolic variables and the progression of diabetes-related complications. [ABSTRACT FROM AUTHOR]

The aim of the present work was to evaluate the effects of a grape seed procyanidin extract (GSPE) on proliferation and apoptosis in the pancreatic adenocarcinoma cell line MIA PaCa-2 and identify the components of the extract with higher activity. The effects of the extract were analyzed on the proliferation and apoptosis processes in MIA PaCa-2 cells, as well as in the levels of the apoptosis markers Bcl-2 and Bax, the mitochondrial membrane potential, and reactive oxygen species levels. Finally, the components of the extract with higher effects were elucidated using enriched fractions of the extract and pure compounds. The results showed that GSPE inhibits cell proliferation and increases apoptosis in MIA PaCa-2 cells, which is primarily mediated by the downregulation of the antiapoptotic protein Bcl-2 and the depolarization of the mitochondrial membrane. GSPE also reduced the formation of reactive oxygen species. The component of the extract that possesses the highest antiproliferative and proapoptotic activity was gallic acid. In conclusion, GSPE acts as anticarcinogenic in MIA PaCa-2 cells, with gallic acid as the major single active constituent of the extract. [ABSTRACT FROM AUTHOR]

Objective Impaired fasting glucose (IFG) is a predictor of future diabetes and is increasingly common in children, but the extent to which it results from excess insulin demand or failure of supply is unclear. Our aim was to compare the behaviour of insulin sensitivity and beta-cell function in children who developed IFG with those whose glucose levels remained within the normal range. Methods We examined trends in fasting glucose, insulin sensitivity ( HOMA-S) and beta-cell function ( HOMA-B) in 327 healthy children annually from 5 to 15 yr, and the parents at baseline. Results Fifty-five children showed IFG, mostly after age 11 yr. Fasting glucose rose progressively and was higher throughout in those who developed IFG compared with those who did not (p < 0.001). Beta-cell function was lower from the age of 5 yr in those who developed IFG (p = 0.006), but there was no difference in BMI (p = 0.71). A difference in insulin sensitivity was revealed on adjustment for covariates (p = 0.03). Glucose was higher (p < 0.001), beta-cell function lower (p = 0.01), and insulin sensitivity the same (p = 0.86) in the mothers of children who showed IFG, compared with those who did not. Conclusions IFG is common in contemporary children, and appears to be related to a defect in beta-cell function already present at 5 yr. Similar findings in the mothers of IFG children suggest that the beta-cell defect may be transmissible. [ABSTRACT FROM AUTHOR]

Aims To replicate the association of genetic variants with estimated glomerular filtration rate ( GFR) and albuminuria, which has been found in recent genome-wide studies in patients with Type 2 diabetes. Methods We evaluated 16 candidate single nucleotide polymorphisms for estimated GFR in 3028 patients with Type 2 diabetes sampled from clinics across Tayside, Scotland, UK, who were included in the Genetics of Diabetes Audit and Research Tayside (Go DARTs) study. These single nucleotide polymorphisms were tested for their association with estimated GFR at entry to the study, with albuminuria, and with time to stage 3B chronic kidney disease (estimated GFR<45 ml/min/1.73 m2). We also stratified the effects on estimated GFR in patients with ( n = 2096) and without albuminuria ( n = 613). Results rs1260326 in GCKR (β=1.30, P = 3.23E-03), rs17319721 in SHROOM3 (β = −1.28, P-value = 3.18E-03) and rs12917707 in UMOD (β = 2.0, P-value = 8.84E-04) were significantly associated with baseline estimated GFR. Analysis of effects on estimated GFR, stratified by albuminuria status, showed that in those without albuminuria (normoalbuminura; n = 613), UMOD had a significantly stronger effect on estimated GFR (βnormo = 4.03 ± 1.23 vs βalbuminuria = 1.72 ± 0.76, P = 0.002) compared with those with albuminuria, while GCKR (βnormo = 0.45 ± 0.89 vs βalbuminuria = 1.12 ± 0.55, P = 0.08) and SHROOM3 (βnormo = −0.07 ± 0.89 vs βalbuminuria = −1.43 ± 0.53, P = 0.003) had a stronger effect on estimated GFR in those with albuminuria. UMOD was also associated with a lower rate of transition to stage 3B chronic kidney disease (hazard ratio = 0.83[0.70, 0.99], P = 0.03). Conclusion The genetic variants that regulate estimated GFR in the general population tend to have similar effects in patients with Type 2 diabetes and in this latter population, it is important to adjust for albuminuria status while investigating the genetic determinants of renal function. [ABSTRACT FROM AUTHOR]

Ketamine, a mild hallucinogenic class C drug, is the fastest growing ‘party drug’ used by 16–24 year olds in the UK. As the recreational use of Ketamine increases we are beginning to see the signs of major renal and bladder complications. To date however, we know nothing of a role for Ketamine in modulating both structure and function of the human renal proximal tubule. In the current study we have used an established model cell line for human epithelial cells of the proximal tubule (HK2) to demonstrate that Ketamine evokes early changes in expression of proteins central to the adherens junction complex. Furthermore we use AFM single-cell force spectroscopy to assess if these changes functionally uncouple cells of the proximal tubule ahead of any overt loss in epithelial cell function. Our data suggests that Ketamine (24–48 hrs) produces gross changes in cell morphology and cytoskeletal architecture towards a fibrotic phenotype. These physical changes matched the concentration-dependent (0.1–1 mg/mL) cytotoxic effect of Ketamine and reflect a loss in expression of the key adherens junction proteins epithelial (E)- and neural (N)-cadherin and β-catenin. Down-regulation of protein expression does not involve the pro-fibrotic cytokine TGFβ, nor is it regulated by the usual increase in expression of Slug or Snail, the transcriptional regulators for E-cadherin. However, the loss in E-cadherin can be partially rescued pharmacologically by blocking p38 MAPK using SB203580. These data provide compelling evidence that Ketamine alters epithelial cell-to-cell adhesion and cell-coupling in the proximal kidney via a non-classical pro-fibrotic mechanism and the data provides the first indication that this illicit substance can have major implications on renal function. Understanding Ketamine-induced renal pathology may identify targets for future therapeutic intervention. [ABSTRACT FROM AUTHOR]

Objectives. Activation of TLR7 and TLR9 and high serum levels of BAFF have been implicated in the pathogenesis of SLE. However, little is known about the effects of TLR9 activation on BAFF expression by human B cells. We investigated the effect of the TLR9 agonist, CpG-ODN 2006, on the expression of BAFF and its receptors BAFF-R, TACI and BCMA, in isolated B cells from healthy donors.Methods. We used RT-PCR, flow cytometry and ELISA to investigate the expression of BAFF, and flow cytometry for BAFF-R, TACI and BCMA. Functional assays assessed the responses of resting and CpG-ODN-activated B cells to exogenous soluble and membrane-bound BAFF.Results. CpG-ODN did not induce BAFF secretion, but increased expression of membrane-bound BAFF on B cells. CpG-ODN also induced the expression of TACI and BCMA, but did not up-regulate BAFF-R expression. In functional studies, CpG-ODN sensitized human B cells to proliferate in response to exogenous BAFF. This effect was inhibited by a blocking antibody against BAFF-R, but was not inhibited by anti-TACI or anti-BCMA antibodies. Membrane-bound BAFF, induced by CpG-ODN, co-stimulated the proliferation of B cells stimulated with anti-IgM in a manner that was dependent on the expression of surface BAFF on the CpG-ODN-treated B cells.Conclusion. TLR9 activation induces expression of membrane-bound BAFF on human B cells and leads to increased proliferation in response to both soluble and membrane-bound BAFF. These data extend our understanding of the role of TLR9 activation on human B cells and provide insights into the mechanisms by which TLR9 may participate in the pathogenesis of SLE. [ABSTRACT FROM PUBLISHER]

It has become widely accepted that Type 2 diabetes is inevitably life-long, with irreversible and progressive beta cell damage. However, the restoration of normal glucose metabolism within days after bariatric surgery in the majority of people with Type 2 diabetes disproves this concept. There is now no doubt that this reversal of diabetes depends upon the sudden and profound decrease in food intake, and does not relate to any direct surgical effect. The Counterpoint study demonstrated that normal glucose levels and normal beta cell function could be restored by a very low calorie diet alone. Novel magnetic resonance methods were applied to measure intra-organ fat. The results showed two different time courses: a) resolution of hepatic insulin sensitivity within days along with a rapid fall in liver fat and normalisation of fasting glucose levels; and b) return of normal beta cell insulin secretion over weeks in step with a fall in pancreas fat. Now that it has been possible to observe the pathophysiological events during reversal of Type 2 diabetes, the reverse time course of events which determine the onset of the condition can be identified. The twin cycle hypothesis postulates that chronic calorie excess leads to accumulation of liver fat with eventual spill over into the pancreas. These self-reinforcing cycles between liver and pancreas eventually cause metabolic inhibition of insulin secretion after meals and onset of hyperglycaemia. It is now clear that Type 2 diabetes is a reversible condition of intra-organ fat excess to which some people are more susceptible than others. [ABSTRACT FROM AUTHOR]

Oral Diseases (2012) 18, 169-177 Objectives: To isolate the CD133+CD44+ cells from human tongue squamous cell carcinoma (TSCC) Tca8113 cell line and investigate biological characteristics of them. Materials and methods: Immunomagnetic microbeads were applied to sort the CD133+CD44+ cells. Flow cytometry was used to detect isolation purity. The proliferation, clone-formation efficiencies, invasion and migration, gene expressions, and tumor-formation abilities were analyzed among CD133+CD44+, CD133−CD44−, and total population of cells. Results: The average purities of CD133+ and CD44+ cells reached 97.3% and 98.7%, respectively. The proliferation of CD133+CD44+ cells was significantly higher than the other two groups. The clone-forming efficiency of three groups was 70%, 8%, and 14%, respectively. The average invaded and migrated cell numbers of CD133+CD44+ and total population cells were 132 and 36.2, 311.6, and 156.2, respectively. The expressions of Bcl-2 and Sox2 in CD133+CD44+ cells were significantly higher than those in total population cells. A total of 104 CD133+CD44+ cells could form secondary tumors in nude mice, while the total population group needed 106 cells. Conclusions: The CD133+CD44+ subpopulation cells possess stem-like characteristics. They appear to be the potential targets for future biology therapy of human TSCC. [ABSTRACT FROM AUTHOR]

Studies suggest that pomegranates contain bioactive chemicals with potential for treatment and prevention of cancer. Pomegranate juice extracts (PJE) have been shown to inhibit cellular proliferation and tumor growth and induce cell death via apoptosis in a number of cancer cell lines. However, to date, few studies have investigated the potential of PJE in the treatment of leukemia. We investigated the potential effect of PJE on induction of apoptosis and inhibition of cellular proliferation in 8 leukemia cell lines (4 lymphoid and 4 myeloid) and nontumor hematopoietic stem cells (control cells). Apoptosis was assessed by 2 methods: Annexin V-FITC/propidium iodide staining with flow cytometric analysis and 4′-6-diamidino-2-phenylindole (DAPI) morphological assessment. Cell cycle stage was investigated using propidum iodide staining of DNA content and flow cytometric analysis. Live cell counts were also performed using a trypan exclusion assay. PJE significantly induced apoptosis in all cell lines, including nontumor control cells, although lymphoid cells and 2 of the myeloid cell lines were more sensitive. Furthermore, PJE induced cell cycle arrest. These results were confirmed by DAPI analysis and viable cell counts using trypan blue exclusion assay. Our results provide evidence that PJE contain bioactive compounds that could be used in the treatment of leukemia. [ABSTRACT FROM PUBLISHER]

Diabet. Med. 28, 1463-1475 (2011) Abstract Sir Harold Himsworth's prescient observations 75 years ago have recently been expanded to include a clear relationship between insulin resistance and central nervous system function. Insulin is a master regulator of corporeal ageing in all known species, determining the rate and expression of ageing in multiple body systems. Thus, it is not surprising that insulin also plays an important role in brain ageing and cognitive decline that is associated with pathological brain ageing. Brain ageing is accompanied by reduced insulin effectiveness, either by an inadequate cellular response to insulin or by insulin deficiency attributable to reduced insulin transport across the blood-brain barrier. Age-associated brain insulin abnormalities may contribute to cognitive decline in ageing, as have been documented in older adults with Type 2 diabetes mellitus and hypertension. With more extreme pathology, brain insulin resistance may be associated with neurogenerative diseases such as Alzheimer's disease, and the condition which precedes Alzheimer's disease, known as amnestic mild cognitive impairment. In the following review, we discuss the mechanisms through which insulin resistance may induce or potentiate pathological brain ageing and thereby create a neurobiological environment that promotes neurodegeneration and associated cognitive decline. This topic is timely, given that insulin resistance-associated conditions such as diabetes and obesity have reached epidemic proportions. The prevalence of such chronic conditions, in combination with a rapidly ageing population, may result in a corresponding increase in the prevalence of Alzheimer's disease and other cognitive disorders. Fortunately, insulin resistance-associated conditions are amenable to both pharmacologic and lifestyle interventions that may reduce the deleterious impact of insulin resistance on the ageing brain. [ABSTRACT FROM AUTHOR]

Background: Ruptured tendons heal very slowly and complete recovery from injury is uncertain. Platelet-rich plasma (PRP), a rich source of growth factors, is currently being widely tested as a soft tissue healing agent and may accelerate tendon repair. The authors assessed the ability of PRP to prevent in vitro adverse effects of 2 drugs commonly linked to tendon rupture and tendinopathy, glucocorticoids and fluoroquinolone antibiotics.Hypothesis: The pro-healing response induced by PRP protects human tenocytes against the cytotoxic effects of dexamethasone and ciprofloxacin.Study Design: Controlled laboratory study.Methods: Human primary hamstring tenocytes were exposed to different doses of ciprofloxacin and dexamethasone with and without PRP. AlamarBlue, β-galactosidase assay, and live/dead stain were used to measure, respectively, viability, senescence, and death in tenocyte culture.Results: The viability of cells exposed to high doses of ciprofloxacin was significantly decreased compared with controls, with no induced senescence but increased cell death. Dexamethasone reduced viable cell number without inducing overt cell death, but the number of senescent cells increased considerably. After co-treatment with 10% PRP, viable cell number increased significantly in both conditions and the number of dead cells decreased in ciprofloxacin-treated cultures. Moreover, dexamethasone-induced senescence was markedly reduced by co-treatment with 10% PRP.Conclusion: This study demonstrates that ciprofloxacin and dexamethasone have differing adverse effects on human tenocytes, with ciprofloxacin inducing cell death while dexamethasone primarily induces senescence. The authors showed that PRP can protect cultured human tenocytes against cell death or senescence induced by these drugs.Clinical Relevance: Both ciprofloxacin and dexamethasone are highly effective in treatment of inflammatory and infectious conditions, therefore new strategies to minimize their adverse effects are of strong interest. These findings suggest the potential for local administration of PRP to enhance tendon healing in patients undergoing glucocorticoid or fluoroquinolone treatment. [ABSTRACT FROM AUTHOR]

Background: Sterile surgical marker pens are commonly used in cartilage repair surgery to aid in the placement of periosteal patches or collagen membranes in autologous chondrocyte implantation.Purpose: To investigate the effects that methylene blue and crystal violet marker pen ink have on human chondrocytes when cultured on collagen membranes in vitro.Study Design: Controlled laboratory study.Methods: Human chondrocytes were applied to Chondro-Gide collagen membranes at a volume of 12 million cells. In the first experiment, 2 sterile marker pens, one containing methylene blue and the other crystal violet inks, were used to mark membranes immediately before the addition of cells. In the second experiment, the same marker pens marked the membranes after 7 days of cell culture. In each experiment, 3 groups of membrane were tested for each pen. Group A consisted of no ink mark, group B had only the uppermost “smooth” layer marked, and group C had the lower “porous” layer marked. All membranes were then cultured in standard growth media for 24 hours. Cell viability was assessed at 24 hours on all membranes using a live/dead-cell viability assay. Cell viability was quantified with florescent microscopy with mean percentage of live cells in each marker pen group compared with control membranes using the Student t test (P < .05).Results: Control membranes (group A) with no ink showed cell viability approaching 100%. A statistically significant reduction in cell viability with both methylene blue (23.1%; P < .0001) and crystal violet (18.9%; P < .0001) was found adjacent to the ink mark on the smooth side (group B) and on the porous side remote from the ink (group C) in both experiments (<30%; P < .0001). Areduction in cell viability was noted on the smooth side remote from the ink mark but did not reach statistical significance. Marked cell death was seen with both dyes (<15%; P < .0001) adjacent to the ink on the porous side.Conclusion: Chondrocyte viability is significantly reduced when cells are cultured in vitro on collagen membranes marked with methylene blue and crystal violet pen ink.Clinical Relevance: Surgeons should be aware of the potential negative effect of marker pens in cell-based therapies. [ABSTRACT FROM AUTHOR]

The article reports on the study conducted by the United Kingdom Prospective Diabetes Study, at the time of diagnosis of type 2 diabetes, which shows that approximately 50% of pancreatic beta-cell function typically has been lost. It is stated that evidence suggests that the loss may be as high as 80%. The progressive decline in insulin secretion and the worsening of peripheral insulin resistance make it increasingly difficult to maintain long-term glycemic control with oral antidiabetics drugs.

BACKGROUND: In the UK Prospective Diabetes Study (UKPDS), many subjects maintained glycemic goal (HbA1c < 7.0%) at 9 years, showing that ß-cell function was preserved and that the initial decline in ß-cell function recovered with sulphonylureas. Moreover, obese subjects using high daily doses of insulin for several years rarely require insulin or oral hypoglycemic agents to maintain their glycemic goal following weight loss achieved by gastric bypass surgery. Thus, declining ß-cell function during the course of type 2 diabetes mellitus (T2DM) is neither universal nor permanent. OBJECTIVE: To assess ß-cell function in morbidly obese subjects before insulin withdrawal and on attaining the glycemic goal with weight loss and oral agents. MATERIALS AND METHODS: Serum C-peptide (CPEP) and glucose (G) concentrations were determined up to 180 min during an oral glucose tolerance test (OGTT) with 75 glucose in 10 obese men with T2DM, before insulin withdrawal, and on achieving the glycemic goal with metformin, glimepiride, and weight loss. Ten age-matched healthy men participated as controls. Cumulative responses (CR) of CPEP and G were calculated by adding differences between the level at each time-period during OGTT and fasting (F) concentration. ß-Cell function was expressed as the FCPEP as well as the insulinogenic index (CRCPEP/CRG). Insulin sensitivity was determined as FCEP x FG. RESULTS: FCPEP was decreased, though still present, prior to insulin withdrawal. Moreover, on attaining the glycemic goal over 6-9 months, FCPEP, CRPEP/CRG, and FCPEP x FG improved markedly (P < 0.001). CONCLUSION: Decline in ß-cell function in morbidly obese T2DM may not be progressive and is reversible on improving insulin sensitivity and on eliminating the inhibition by exogenous insulin. [ABSTRACT FROM AUTHOR]

This article is based on a symposium held at the Wound Essentials annual summer conference in Birmingham, UK, on 2nd July 2015. The symposium was an interactive session exploring the importance of patient experience within dressing evaluations, presenting results and findings from a 150-patient case series and gauging the delegates' views via voting buttons. [ABSTRACT FROM AUTHOR]

Introduction: Receptor tyrosine kinase inhibitors (RTKIs) improve cancer survival but have cardiotoxic side effects, the mechanisms for which warrant further investigation. Endogenous cardiac stem cells (CSCs) support cardiac function and recovery from injury through paracrine action and tissue formation. Hypothesis: RTKI effects on CSCs directly impact on their ability to aid cardiac recovery from RTKI toxicity. Methods: We applied RTKIs (imatinib, sunitinib or sorafenib) to human CSCs in vitro , assessing: cell viability (fluorescein diacetate), proliferation (cell cycle flow cytometry), differentiation (quantified immunostaining) and growth factor generation (real-time qPCR). To determine in vivo impacts of the most CSC-toxic RTKI, adult male Wistar rats were injected with sunitinib (40mg.kg-1 (i.p.), 9 days), before 7 days' sunitinib withdrawal, with echocardiographic assessment throughout and end-point histology (in vivo work compliant with UK regulations). Statistics: ANOVA plus Tukey's test, significance: p <0.05; data are mean±SEM. Results: All 3 RTKIs reduced CSC survival (imatinib 91.5±0.9%; sunitinib 83.9±1.8%; sorafenib 75.0±1.6%, vs. 100% viability in control, n=4) and proliferation by cell cycling (imatinib: 29.3±4.3% cells in S/G2/M-phases, vs. 50.3±5.1% in control, n=3). RTKIs also reduced CSC regenerative potential: expression of genes linked to secretome (HGF, PDGF-A), or endothelial (PECAM1) and cardiomyocyte (Nkx2.5, Wnt2) differentiation were respectively decreased 3, 2, 2, 3 and 6-fold (n=3). Sunitinib also repressed CSC ability to form endothelial (32.3±3.2% vs. 44.3±3.5%, n=4) or smooth muscle (39.9±3.1% vs. 63.1±2.3%, n=4) cells. In vivo , sunitinib reduced cardiac ejection fraction to 67.9±1.9% (82.9±1.9% in control, n=12). CSC numbers in situ were reduced in hearts which failed to recover functionally after sunitinib withdrawal: 221.8±92.1 per 106 myocytes (non-recovery) vs. 427.0±56.4 (recovery) (n=6). Conclusions: We have found RTKIs reduce both CSC population maintenance and pro-regenerative abilities, and that CSC loss in vivo corresponds to cardiac inability to recover from RTKI-induced cardiotoxicity. This identifies an important mechanism for detecting long-term heart failure risk. [ABSTRACT FROM AUTHOR]

The article reports on the prevalence of epilepsy in people with mitochondrial disease, with topics including epilepsy patients, seizure management, and epilepsy treatment.

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