Circulating Antigens Levels in Different Clinical Forms of the Schistosoma mansoni Infection

With the aim to evaluate the circulating cathodic antigen (CCA) levels in relation to the different clinical phases of Schistosoma sp. infection a sandwich ELISA using monoclonal antibody 5H11 was performed. The sera of three groups of 25 Brazilian patients with acute, intestinal and hepatosplenic forms of S. mansoni infection were tested and compared to a non-infected control group. Patients and control groups were matched for age and sex and the number of eggs per gram of feces was equally distributed among the three patient groups. Sensitivity of 100%, 72%, 52% of the assay was observed for the intestinal, hepatosplenic and acute toxemic groups respectively. The specificity was 100%. Intestinal and hepatosplenic groups presented CCA levels significantly higher in comparison to those observed for acute patients (F-ratio = 2,524; p = 0.000 and F-ratio = 6,314; p = 0.015 respectively). There was no significant difference of CCA serum levels between hepatosplenic and intestinal groups (F-ratio = 1,026; p = 0.316).

Effect of immunisation against angiotensin II with CYT006-AngQb on ambulatory blood pressure: a double-blind, randomised, placebo-controlled phase IIa study.

BACKGROUND: Hypertension can be controlled adequately with existing drugs such as angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers. Nevertheless, treatment success is often restricted by patients not adhering to treatment. Immunisation against angiotensin II could solve this problem. We investigated the safety and efficacy of CYT006-AngQb-a vaccine based on a virus-like particle-that targets angiotensin II to reduce ambulatory blood pressure. METHODS: In this multicentre, double-blind, randomised, placebo-controlled phase IIa trial, 72 patients with mild-to-moderate hypertension were randomly assigned with a computer-generated randomisation list to receive subcutaneous injections of either 100 mug CYT006-AngQb (n=24), 300 mug CYT006-AngQb (24), or placebo (24), at weeks 0, 4, and 12. 24-h ambulatory blood pressure was measured before treatment and at week 14. The primary outcomes were safety and tolerability. Analyses were done by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00500786. FINDINGS: Two patients in the 100 mug group, three in the 300 mug group, and none in the placebo group discontinued study treatment. All patients were included in safety analyses; efficacy analyses did not include the five dropouts, for whom no data were available at week 14. Five serious adverse events were reported (two in the 100 mug group, two in the 300 mug group, and one in the placebo group); none were deemed to be treatment related. Most side-effects were mild, transient reactions at the injection site. Mild, transient influenza-like symptoms were seen in three patients in the 100 mug group, seven in the 300 mug group, and none in the placebo group. In the 300 mug group, there was a reduction from baseline in mean ambulatory daytime blood pressure at week 14 by -9.0/-4.0 mm Hg compared with placebo (p=0.015 for systolic and 0.064 for diastolic). The 300 mug dose reduced the early morning blood-pressure surge compared with placebo (change at 0800 h -25/-13 mm Hg; p<0.0001 for systolic, p=0.0035 for diastolic). INTERPRETATION: Immunisation with CYT006-AngQb was associated with no serious adverse events; most observed adverse events were consistent with local or systemic responses similar to those seen with other vaccines. The 300 mug dose reduced blood pressure in patients with mild-to-moderate hypertension during the daytime, especially in the early morning. FUNDING: Cytos Biotechnology AG.

Novel loci for adiponectin levels and their influence on type 2 diabetes and metabolic traits: a multi-ethnic meta-analysis of 45,891 individuals.

Circulating levels of adiponectin, a hormone produced predominantly by adipocytes, are highly heritable and are inversely associated with type 2 diabetes mellitus (T2D) and other metabolic traits. We conducted a meta-analysis of genome-wide association studies in 39,883 individuals of European ancestry to identify genes associated with metabolic disease. We identified 8 novel loci associated with adiponectin levels and confirmed 2 previously reported loci (P = 4.5×10(-8)-1.2×10(-43)). Using a novel method to combine data across ethnicities (N = 4,232 African Americans, N = 1,776 Asians, and N = 29,347 Europeans), we identified two additional novel loci. Expression analyses of 436 human adipocyte samples revealed that mRNA levels of 18 genes at candidate regions were associated with adiponectin concentrations after accounting for multiple testing (p<3×10(-4)). We next developed a multi-SNP genotypic risk score to test the association of adiponectin decreasing risk alleles on metabolic traits and diseases using consortia-level meta-analytic data. This risk score was associated with increased risk of T2D (p = 4.3×10(-3), n = 22,044), increased triglycerides (p = 2.6×10(-14), n = 93,440), increased waist-to-hip ratio (p = 1.8×10(-5), n = 77,167), increased glucose two hours post oral glucose tolerance testing (p = 4.4×10(-3), n = 15,234), increased fasting insulin (p = 0.015, n = 48,238), but with lower in HDL-cholesterol concentrations (p = 4.5×10(-13), n = 96,748) and decreased BMI (p = 1.4×10(-4), n = 121,335). These findings identify novel genetic determinants of adiponectin levels, which, taken together, influence risk of T2D and markers of insulin resistance.

Metabolic effects of parenteral nutrition enriched with n-3 polyunsaturated fatty acids in critically ill patients

BACKGROUND & AIMS: n-3 fatty acids are expected to downregulate the inflammatory responses, and hence may decrease insulin resistance. On the other hand, n-3 fatty acid supplementation has been reported to increase glycemia in type 2 diabetes. We therefore assessed the effect of n-3 fatty acids delivered with parenteral nutrition on glucose metabolism in surgical intensive care patients. METHODS: Twenty-four surgical intensive care patients were randomized to receive parenteral nutrition providing 1.25 times their fasting energy expenditure, with 0.25 g of either an n-3 fatty acid enriched-or a soy bean-lipid emulsion. Energy metabolism, glucose production, gluconeogenesis and hepatic de novo lipogenesis were evaluated after 4 days. RESULTS: Total energy expenditure was significantly lower in patients receiving n-3 fatty acids (0.015+/-0.001 vs. 0.019+/-0.001 kcal/kg/min with soy bean lipids (P<0.05)). Glucose oxidation, lipid oxidation, glucose production, gluconeogenesis, hepatic de novo lipogenesis, plasma glucose, insulin and glucagon concentrations did not differ (all P>0.05) in the 2 groups. CONCLUSIONS: n-3 fatty acids were well tolerated in this group of severely ill patients. They decreased total energy expenditure without adverse metabolic effects.

EORTC Radiation Oncology Group quality assurance platform: establishment of a digital central review facility.

OBJECTIVE: Quality assurance (QA) in clinical trials is essential to ensure treatment is safely and effectively delivered. As QA requirements have increased in complexity in parallel with evolution of radiation therapy (RT) delivery, a need to facilitate digital data exchange emerged. Our objective is to present the platform developed for the integration and standardization of QART activities across all EORTC trials involving RT. METHODS: The following essential requirements were identified: secure and easy access without on-site software installation; integration within the existing EORTC clinical remote data capture system; and the ability to both customize the platform to specific studies and adapt to future needs. After retrospective testing within several clinical trials, the platform was introduced in phases to participating sites and QART study reviewers. RESULTS: The resulting QA platform, integrating RT analysis software installed at EORTC Headquarters, permits timely, secure, and fully digital central DICOM-RT based data review. Participating sites submit data through a standard secure upload webpage. Supplemental information is submitted in parallel through web-based forms. An internal quality check by the QART office verifies data consistency, formatting, and anonymization. QART reviewers have remote access through a terminal server. Reviewers evaluate submissions for protocol compliance through an online evaluation matrix. Comments are collected by the coordinating centre and institutions are informed of the results. CONCLUSIONS: This web-based central review platform facilitates rapid, extensive, and prospective QART review. This reduces the risk that trial outcomes are compromised through inadequate radiotherapy and facilitates correlation of results with clinical outcomes.

Recuento de células progenitoras endoteliales en pacientes con ictus tratados previamente con estatinas

Estudio prospectivo de pacientes con ictus isquémico agudo cuyo objetivo es estudiar la influencia del tratamiento con estatinas sobre el recuento plasmático de Células Progenitoras Endoteliales (CPEs) determinadas por citometría de flujo. Se incluyeron 131 pacientes, el 32.1% pre-tratados con estatinas. El recuento de CPEs fue superior en los pacientes pre-tratados en el momento basal (p=0.015) y a los 7 días (p=0.029), pero equivalente a los 3 meses (p=0.49). El pre-tratamiento con estatinas se asocia a mayor recuento de CPEs en fase aguda y subaguda del infarto, sugiriendo un posible efecto reparador endotelial de las estatinas en la isquemia cerebral.

Tractament amb EPOCH a dosi ajustada i Rituximab en pacients no tractats amb LNH-B de cèl.lula gran de mal pronòstic

Aquest estudi multicèntric, fase IV analitza l’eficàcia i la seguretat del tractament amb dosi ajustada d’EPOCH amb Rituximab en infusió continua, en pacients no tractats prèviament amb mal pronòstic diagnosticats de limfomes B de cèl.lula gran. Material i mètodes. S’inclogueren 81 pacients, 68 d’aquests diagnosticats de Limfoma B difús de cèl.lula gran, 7 de Limfoma fol.licular grau III i 6 de Limfoma B primari de mediastí. Eren pacients de mal pronòstic segons IPI≥2 o IPIae≥1, ECOG/PS 0-4, estadi II-IV (estadi I si malaltia voluminosa al diagnòstic). Resultats. La edat mitjana era de 52 anys (rang, 21-77 anys), 92,5% d’alt risc segons l’IPIae. Es va obtenir resposta completa (RC i RCi) en el 79% dels pacients, la supervivència global i la supervivència lliure d’esdeveniment, a la mediana del temps de seguiment (34,3 mesos) va ser de 68% i 63,2%, respectivament. La supervivència lliure de malaltia als 5 anys va ser de 72,2% pels pacients que van assolir RC/RCi. Cap dels factors de risc de l’IPI o IPIae, ni els índexs per ells mateixos van resultar amb associació estadísticament significativa a la OS o PFS. Només es va obtenir associació entre els nivells de ß2 microglobulina (&3,5mg/l) i la PFS i OS (p=0,075 i p=0,015, respectivament). Es van reportar 54 episodis de neutropènia febril (11,5% dels cicles); i es van morir 27 pacients, 15 (55,5%) degut a progressió de la malaltia i 9 (33,3%) degut a sepsi o infecció grau 4. Conclusions. Els resultats aconseguits amb la combinació de Rituximab i DA-EPOCH mostren uns resultats prometedors i amb nivells de toxicitat molt acceptables en els pacients d’alt risc diagnosticats de Limfomes B de cèl.lula gran no tractats prèviament.

Role of the sub-cellular localization of RasGAP fragment N2 for its ability to sensitize cancer cells to genotoxin-induced apoptosis.

The specific sensitization of tumor cells to the apoptotic response induced by genotoxins is a promising way of increasing the efficacy of chemotherapies. The RasGAP-derived fragment N2, while not regulating apoptosis in normal cells, potently sensitizes tumor cells to cisplatin- and other genotoxin-induced cell death. Here we show that fragment N2 in living cells is mainly located in the cytoplasm and only minimally associated with specific organelles. The cytoplasmic localization of fragment N2 was required for its cisplatin-sensitization property because targeting it to the mitochondria or the ER abrogated its ability to increase the death of tumor cells in response to cisplatin. These results indicate that fragment N2 requires a spatially constrained cellular location to exert its anti-cancer activity.

Environmental effects of Deccan volcanism across the Cretaceous-Tertiary transition in Meghalaya, India

The Urn Sohryngkew section of Meghalaya, NE India, located 800-1000 km from the Deccan volcanic province, is one of the most complete Cretaceous-Tertiary boundary (KTB) transitions worldwide with all defining and supporting criteria present: mass extinction of planktic foraminifera, first appearance of Danian species, delta(13)C shift, Ir anomaly (12 ppb) and KTB red layer. The geochemical signature of the KTB layer indicates not only an extraterrestrial signal (Ni and all Platinum Group Elements (PGEs)) of a second impact that postdates Chicxulub, but also a significant component resulting from condensed sedimentation (P), redox fluctuations (As, Co, Fe, Pb, Zn, and to a lesser extent Ni and Cu) and volcanism. From the late Maastrichtian C29r into the early Danian, a humid climate prevailed (kaolinite: 40-60%, detrital minerals: 50-80%). During the latest Maastrichtian, periodic acid rains (carbonate dissolution; CIA index: 70-80) associated with pulsed Deccan eruptions and strong continental weathering resulted in mesotrophic waters. The resulting super-stressed environmental conditions led to the demise of nearly all planktic foraminiferal species and blooms (>95%) of the disaster opportunist Guembelitria cretacea. These data reveal that detrimental marine conditions prevailed surrounding the Deccan volcanic province during the main phase of eruptions in C29r below the KTB. Ultimately these environmental conditions led to regionally early extinctions followed by global extinctions at the KTB. (C) 2011 Elsevier B.V. All rights reserved.

Small Bowel Bacterial Overgrowth is found in 71% of IBS patients and associated symptoms respond wel to Rifaximin in a phase IV trial

Background: The prevalence of small intestinal bowel bacterial overgrowth (SIBO) in patients with irritable bowel syndrome (IBS) ranges from 43% to 78% as determined by the lactulose hydrogen breath (LHBT) test. Although rifaximine, a non-absorbable antibiotic, has been able to decrease global IBS symptoms as well as bloating in placebo-controlled randomized trials, these results were not repeated in phase IV studies in daily clinical practice. Aim: To assess the prevalence of SIBO in an IBS cohort and to evaluate the treatment response in the IBS cohort affected by SIBO. Methods: Enrolled patients were diagnosed with IBS using the following criteria: fulfillment of the Rome III criteria, absence of alarm symptoms (anemia, weight loss, nocturnal symptoms etc), normal fecal calproectin, normal endoscopic workup including histology. Celiac disease was excluded by serology and/or duodenal biopsy. All patients underwent lactulose hydrogen breath testing (LHBT) for SIBO diagnosis. Patients with SIBO were treated with rifaximine tablets (400mg twice daily for 14 days). Both before and at week 6 after rifaximin treatment, patients completed a questionnaire, where the following criteria were assessed individually using 11-point Likert scales: the bloating, flatulence, abdominal pain, diarrhea, and overall well-being. Results: Hundred-fifty IBS patients were enrolled (76% female, mean age 44 ± 16 years), of whom 106 (71%) were diagnosed with SIBO and consequently treated with rifaximine. Rifaximine treatment significantly reduced the following symptoms as assessed by the symptom questionnaire: bloating (5.5 ± 2.6 before vs. 3.6 ± 2.7 after treatment, p <0.001), flatulence (5 ± 2.7 vs. 4 ± 2.7, p = 0.015), diarrhea (2.9 ± 2.4 vs. 2 ± 2.4, p = 0.005), abdominal pain (4.8 ± 2.7 vs. 3.3 ± 2.5, p <0.001) and resulted in improved overall well-being (3.9 ± 2.4 vs. 2.7 ± 2.3, p <0.001). Thirteen of the 106 treated patients were lost to follow-up (12%). The LHBT was repeated 2-4 weeks after rifaximine treatment in 65/93 (70%) patients. Eradication of SIBO was documented in 85% of all patients (55/65), whereas 15% of patients (10/65) tested positive for SIBO as determined by the LHBT testing. Conclusions: The results of our phase IV trial indicate that a high proportion of IBS patients tested positive for SIBO. IBS symptoms (bloating, flatulence, diarrhea, pain, overall well-being) were significantly diminished following a 2-week treatment with rifaximine. These results support the previous findings of randomized controlled trials that the presence of SIBO is associated with symptom generation in IBS patients and that reduction and/or elimination of SIBO may help to alleviate IBSassociated symptoms.

Low relatedness among cooperatively breeding workers of the greenhead ant Rhytidoponera metallica

The greenhead ant Rhytidoponera metallica has long been recognized as posing a potential challenge to kin selection theory because it has large queenless colonies where apparently many of the morphological workers are mated and reproducing. However this species has never been studied genetically and important elements of its breeding system and kin structure remain uncertain. We used microsatellite markers to measure the relatedness among nestmates unravel the fine-scale population genetic structure and infer the breeding system of R. metallica. The genetic relatedness among worker nestmates is very low but significantly greater than zero (r = 0.082 +/- 0.015) which demonstrates that nests contain many distantly related breeders. The inbreeding coefficient is very close to and not significantly different from zero indicating random mating and lack of microgeographic genetic differentiation. On average. closely located nests are not more similar genetically than distant nests which is surprising as new colonies form by budding and female dispersal is restricted. Lack of inbreeding and absence of population viscosity indicates high gene flow mediated by males. Overall the genetic pattern detected in R. metallica suggests that a high number of moderately related workers mate with unrelated males from distant nests. This breeding system results in the lowest relatedness among nestmates reported for social insect species where breeders and helpers are not morphologically differentiated. [References: 69]

The effect of patient, provider and financing regulations on the intensity of ambulatory physical therapy episodes : a multilevel analysis based on routinely available data

Background: Many studies have found considerable variations in the resource intensity of physical therapy episodes. Although they have identified several patient-and provider-related factors, few studies have examined their relative explanatory power. We sought to quantify the contribution of patients and providers to these differences and examine how effective Swiss regulations are (nine-session ceiling per prescription and bonus for first treatments). Methods: Our sample consisted of 87,866 first physical therapy episodes performed by 3,365 physiotherapists based on referrals by 6,131 physicians. We modeled the number of visits per episode using a multilevel log linear regression with crossed random effects for physiotherapists and physicians and with fixed effects for cantons. The three-level explanatory variables were patient, physiotherapist and physician characteristics. Results: The median number of sessions was nine (interquartile range 6-13). Physical therapy use increased with age, women, higher health care costs, lower deductibles, surgery and specific conditions. Use rose with the share of nine-session episodes among physiotherapists or physicians, but fell with the share of new treatments. Geographical area had no influence. Most of the variance was explained at the patient level, but the available factors explained only 4% thereof. Physiotherapists and physicians explained only 6% and 5% respectively of the variance, although the available factors explained most of this variance. Regulations were the most powerful factors. Conclusion: Against the backdrop of abundant physical therapy supply, Swiss financial regulations did not restrict utilization. Given that patient-related factors explained most of the variance, this group should be subject to closer scrutiny. Moreover, further research is needed on the determinants of patient demand.