The capsid protein of infectious bursal disease virus contains a functional α4β1 integrin ligand motif

Infectious bursal disease virus (IBDV), a member of the dsRNA Birnaviridae family, is an important immunosuppressive avian pathogen. We have identified a strictly conserved amino acid triplet matching the consensus sequence used by fibronectin to bind the α4β1 integrin within the protruding domain of the IBDV capsid polypeptide. We show that a single point mutation on this triplet abolishes the cell-binding activity of IBDV-derived subviral particles (SVP), and abrogates the recovering of infectious IBDV by reverse genetics without affecting the overall SVP architecture. Additionally, we demonstrate that the presence of the α4β1 heterodimer is a critical determinant for the susceptibility of murine BALB/c 3T3 cells to IBDV binding and infectivity. Our data suggests that the IBDV might also use the α4β1 integrin as a specific binding receptor in avian cells.     

Is advanced esophageal adenocarcinoma a distinct entity from intestinal subtype gastric cancer? Data from the AGAMENON-SEOM Registry

Gastric Cancer - Advanced esophageal adenocarcinoma (EAC) is generally treated similarly to advanced gastroesophageal junction (GEJ-AC) and gastric (GAC) adenocarcinomas, although GAC clinical...     

High prevalence of chigger mite infection in a forest-specialist frog with evidence of parasite-related granulomatous myositis

Parasitology Research - Amphibians are hosts for a wide variety of micro- and macro-parasites. Chigger mites from the Hannemania genus are known to infect a wide variety of amphibian species across...     

Endothelial Dysfunction in Patients with Chronic Kidney Disease Results from Advanced Glycation End Products (AGE)-Mediated Inhibition of Endothelial Nitric Oxide Synthase through RAGE Activation

Background and objectives: Advanced glycation end products, known pro-inflammatory and pro-oxidative compounds that accumulate in patients with chronic kidney disease, may play a major role in their high prevalence of endothelial dysfunction and subsequent cardiovascular disease. This study examined the association of advanced glycation end product accumulation with cellular receptor for advanced glycation end product expression and endothelial dysfunction as well as the mechanisms of this association in chronic kidney disease.Design, setting, participants, & measurements: A cross-sectional study was conducted of ambulatory patients without diabetes and with different stages of chronic kidney disease (n = 51), compared with gender- and age-matched healthy subjects. Fasting blood was obtained for measurement of advanced glycation end products and mRNA receptor for advanced glycation end product expression in peripheral blood mononuclear cells. Endothelial reactivity was assessed by the microcirculatory response to local ischemia (postocclusive reactive hyperemia) and local hyperthermia (thermal hyperemia). Sera were pooled and passed through affinity columns to separate advanced glycation end product–rich fractions, which were incubated with human aortic endothelial cells, with or without blockade of receptor for advanced glycation end product, to measure their effect on endothelial nitric oxide synthase.Results: Glomerular filtration rate correlated with serum advanced glycation end product, mRNA receptor for advanced glycation end product levels, postocclusive reactive hyperemia, and thermal hyperemia. Serum advanced glycation end product correlated with receptor for advanced glycation end product and inversely with postocclusive reactive hyperemia. Advanced glycation end product–rich fractions from chronic kidney disease sera suppressed endothelial nitric oxide synthase expression of human aortic endothelial cells compared with sera from healthy subjects, an effect abrogated by receptor for advanced glycation end product blockade.Conclusions: This study demonstrates for the first time an association of excess advanced glycation end product burden with increased peripheral blood mononuclear cell mRNA receptor for advanced glycation end product and in vivo endothelial dysfunction in patients with chronic kidney disease. Endothelial dysfunction in chronic kidney disease may be partly mediated by advanced glycation end product–induced inhibition of endothelial nitric oxide synthase through receptor for advanced glycation end product activation.The epidemiologic association between chronic kidney disease (CKD) and cardiovascular disease (CVD) has been firmly established (1–3). Traditional CVD risk factors such as hypertension and hyperlipidemia do not fully explain the high prevalence of CVD in CKD (1). The recognition that inflammation, oxidative stress (OS), and endothelial dysfunction (ED) are common abnormalities in CVD has led to a detailed exploration of these pathways in search of new risk factors (4–8). Because renal failure is associated with increasing circulating levels of advanced glycation end products (AGE) (9) and these compounds are known to promote inflammation, OS, and ED, they are likely to play an important role in the pathogenesis of CVD in this population (10–12).Numerous in vitro and animal studies have implicated AGE in the pathogenesis of CVD (10–12) via several receptor-independent and receptor-dependent mechanisms. For instance, AGE have direct influence on the structural integrity of the vessel wall and the underlying basement membranes in part induced by cross-linking of subendothelial matrix molecules, such as collagen, or by disruption of matrix–matrix and matrix–cell interactions (13,14). Other actions of AGE include nitric oxide (NO) quenching (15) and endothelial NO synthase (eNOS) inhibition (16), thereby adversely affecting vascular endothelium and its protective functions, particularly vascular relaxation. The direct mechanistic links between AGE and their endothelial effects have not been clearly delineated but may include enhanced expression and activity of receptor for AGE (RAGE) (17). In fact, expression of RAGE on peripheral blood monocytes has been found to be upregulated in patients without diabetes and with CKD (18).The link among OS, inflammation, and ED as a new paradigm of atherosclerosis provides the rationale for a variety of studies, including flow-mediated vasodilation and reactive hyperemia of the microcirculation, gauging endothelial function as an index of the susceptibility of the vasculature to atherosclerosis (19–26). This noninvasive interrogation of the cutaneous microvasculature responses to both flow and thermal stimulations may offer a simple screening test for the presence of systemic ED (26). ED, defined by these noninvasive vascular tests, is a common finding in patients with CKD (22–25) and could reflect reduced NO generation (27) or impaired activity (16). Possible causes of NO deficiency are substrate (l-arginine) limitation as a result of perturbed renal biosynthesis of this amino acid or increased levels of circulating endogenous inhibitors of eNOS, such as asymmetric dimethylarginine, homocysteine, or AGE (26). Sera from patients with CKD as well as in vitro prepared AGE significantly suppress eNOS activity in cultured vascular endothelial cells (16,28), suggesting that the excess AGE in CKD may contribute to their ED.Notwithstanding all of the experimental data suggesting a major role for AGE in causing ED/CVD, the few human studies correlating serum AGE levels with cardiovascular outcome have given conflicting results. Two studies of hemodialysis patients who were followed for a variable period of time demonstrated that serum AGE levels were strong and independent predictors of mortality (29,30). Conversely, a study from Germany showed that high serum AGE levels at baseline were associated with better outcome in hemodialysis patients who were followed for 32 mo (31) and a group in Sweden showed that plasma pentosidine did not predict outcome of a group of patients who had ESRD and were identified close to the start of renal replacement therapy (32)Despite the long-term postulation that AGE excess could lead to ED in CKD, no study has specifically described the relationship between circulating AGE levels and in vivo tests of endothelial function in these patients; therefore, we performed a study to examine this relationship in a group of patients with CKD and measured two widely known circulating AGE (^ɛN-carboxymethyl-lysine [CML] and methyl-glyoxal [MG] derivatives) and the in vivo arteriolar vasodilatory response to both local ischemia and hyperthermia in a cohort of patients without diabetes and with CKD. Furthermore, we wanted to test whether the observed eNOS impairment in CKD could result from the excess of circulating AGE and whether this effect was mediated via RAGE. For this, we evaluated the effect of AGE from serum of patients with CKD on the eNOS expression of human aortic endothelial cells (HAEC) with or without blockade of RAGE expression. We also measured RAGE expression in peripheral mononuclear cells as a surrogate indicator of RAGE expression in endothelial cells. The findings suggest that CKD-related ED is due partly to excess accumulation of AGE, which activate RAGE to suppress eNOS in the vasculature.     

Protective facemask impact on human thermoregulation: an overview

The use of protective facemasks (PFMs) negatively impacts respiratory and dermal mechanisms of human thermoregulation through impairment of convection, evaporation, and radiation processes. The relatively minor reported increases in core temperature directly attributable to the wearing of PFMs suggest that associated perceptions of increased body temperature may have a significant psychological component or that regional or global brain temperature changes are involved. Modifications in PFM structure, components, and materials might allow for improved heat dissipation and enhanced compliance with use.     

Cirugía de las metástasis en la glándula suprarrenal: resultados de una serie de 35 pacientes

IntroductionThe objectives of this study are to present the results of adrenalectomies due to metastasis, and to analyse the prognostic factors that may help to predict long-term survival in this patient group.Patients and methodsA retrospective study was conducted on 35 patients who underwent adrenalectomy for metastases in the Hospital de Cruces from 1996 to January 2010. The survival analysis was performed using the Kaplan and Meier method.ResultsNon-small cell lung cancer (NSCLC) was the most frequent primary tumour, with 18 cases. In 15 patients the diagnosis of adrenal metastasis was synchronous with the primary tumour, and in 20 cases it was metachronous. Only 7 patients survived without disease for 12, 22, 26, 58, 60, 65 and 120 months after the adrenalectomy. The disease free survival at 5 years was 16% in the whole series, and 27% in the NSCLC sub-group. None of the prognostic factors evaluated (size greater than 4.5 cm, cell type, differentiation grade, chemotherapy, surgical technique, disease free interval) was statistically significant in the overall survival, either in the general series or in the sub-group of patients with NSCLC. However, in the general series with tumour recurrence, the difference in survival between metachronous and synchronous metastasis was statistically significant (P=.05), in favour of the former.ConclusionsAdrenalectomy improves the expected survival particularly in patients with NSCLC. Patients with metachronous metastases do not have a higher rate of disease free survival at 5 years than those with synchronous metastases, although they do have a longer survival with the disease. When there is tumour recurrence, it is usually early.     

Effects of Spray and Stretch on Postneedling Soreness and Sensitivity After Dry Needling of a Latent Myofascial Trigger Point

Objectives

To investigate (1) the effect of spray and stretch versus control on reducing postneedling soreness of 1 latent myofascial trigger point (MTrP) and (2) whether higher levels of psychological distress are associated with increased postneedling pain intensity.

Design

A 72-hour follow-up, single-blind randomized controlled trial.

Setting

University community.

Participants

Healthy volunteers (N=70; 40 men, 30 women) aged 18 to 36 years (mean age, 21±4y) with latent MTrP in 1 upper trapezius muscle.

Intervention

All subjects received a dry needling application over the upper trapezius muscle. Then, participants were randomly divided into 2 groups: an intervention group, which received spray and stretch over the needled trapezius muscle, and a control group, which did not receive any intervention.

Main Outcome Measures

Visual analog scale (at postneedling, posttreatment, and 6, 12, 24, 48, and 72h after needling), pressure pain threshold (at preneedling, postneedling, and 24 and 48h after needling). Psychological distress was evaluated by using the Symptom Checklist-90-Revised.

Results

Repeated-measures analysis of variance demonstrated a significant interaction between group and time (F_3,204.8=3.19; P<.05; η_p²=.04) for changes in postneedling soreness. Between-group differences were significant only immediately after intervention (P=.002), and there were no differences found between groups after 6 hours of the intervention (P>.05). Repeated measures of covariance showed that none of the psychological covariates affected these results. Somatization, anxiety, interpersonal sensitivity, and hostility were significantly correlated (P<.05) with postneedling pain intensity. Repeated-measures analysis of variance did not show a significant effect of spray and stretch on mechanical hyperalgesia (F_2.6,175=1.9; P=.131; η_p²=.02).

Conclusions

The spray and stretch had a short-term (<6h) effect in reducing postneedling soreness of a latent MTrP. Pressure pain threshold did not significantly change after spray and stretch. Psychological factors are related to postneedling pain.     

Formulation in tablets of a cholera whole cells inactivated vaccine candidate

Licensed as well as candidate cholera vaccines available at the present requires the dose preparation (included buffer) at the moment of application. The aim of this work was to evaluate the presentation in oral tablets of an inactivated cholera vaccine to avoid that inconveniences during application. We have therefore compared inactivated cultures of Vibrio cholerae with tablets formulation vaccine. We obtained that antigenic activity (ELISA) and immunogenicity in animal model (ELISA and vibriocidal tests) of V. cholerae inactivated cell remained unaltered in the final tablet formulation. The results suggest that the oral tablet formulation could be a useful pharmaceutical form in order to produce a new and affordable cholera vaccine.     

Prevention and reversal of diabetic nephropathy in db/db mice treated with alagebrium (ALT-711)

BACKGROUND: Alagebrium (ALT-711) has been shown to improve renal dysfunction in animal models of diabetes. METHODS: To test its effects in diabetic nephropathy (DN), ALT-711 was administered (1 mg/kg daily i.p.) to 9-week-old female db/db mice (n = 15, group A1) for 3 weeks and to 3-month-old (n = 15, group A2), 7-month-old (n = 7, group A3), and 12-month-old (n = 5, group A4) female db/db mice for 12 weeks, while a similar number of diabetic and nondiabetic mice were used as controls. The epsilonN-carboxymethyllysine (CML) levels in serum, urine, skin, and kidney tissue were measured by enzyme-linked immunosorbent assay. The renal morphometric parameters were assessed by electron and light microscopy. RESULTS: By the 3rd week of treatment, the serum CML level decreased by 41%, and the urinary CML concentration increased by 138% from baseline, while the urinary albumin/creatinine ratio was lower (p < 0.05) in diabetic and nondiabetic group A1 mice. After 3 months of treatment, serum, skin, and kidney CML levels and urinary albumin/creatinine ratio were lower (p < 0.05) and the urinary CML levels higher (p < 0.05) in treated group A2, A3, and A4 animals compared with groups which received phosphate-buffered saline, with a similar pattern observed in nondiabetic mice. The renal morphological parameters characteristic of DN decreased in treated compared with untreated mice. CONCLUSION: Alagebrium may prevent, delay, and/or reverse established DN in db/db mice by reducing the systemic advanced glycation end product pools and facilitating the urinary excretion of advanced glycation end products.     

MicroRNA9 regulates neural stem cell differentiation by controlling Hes1 expression dynamics in the developing brain

Earlier studies show that Hes1 expression is oscillatory in neural stem cells but sustained and high in the roof plate and the floor plate, and that such different dynamics of Hes1 expression (oscillatory versus sustained) regulate different proliferation and differentiation characteristics of these cells (active in neural stem cells but rather dormant in roof/floor plate cells). The mechanism of how different dynamics of Hes1 expression is controlled remains to be determined. Here, we found that the seed sequence of microRNA‐9 (miR‐9) is complementary to the 3′‐UTR sequence of Hes1 mRNA. MiR‐9 is highly expressed in the ventricular zone of the developing brain, which contains neural stem cells, but it is not expressed in the roof plate or the floor plate. Over‐expression of miR‐9 negatively regulates the Hes1 protein expression by interacting with the 3′‐UTR of Hes1 mRNA, thereby inducing cell cycle exit and neuronal differentiation. Conversely, knockdown of miR‐9 inhibits neuronal differentiation. Furthermore, knockdown of miR‐9 inhibits the oscillatory expression of Hes1 mRNA in neural stem cells. These results indicate that miR‐9 regulates the proliferation and differentiation of neural stem cells by controlling the dynamics of Hes1 expression in the developing brain.