Mutators and long-term molecular evolution of pathogenic Escherichia coli O157:H7.

It has been proposed that an increased mutation rate (indicated by the frequency of hypermutable isolates) has facilitated the emergence of Escherichia coli O157:H7. Analysis of the divergence of 12 genes shows no evidence that the pathogen has undergone an unusually high rate of mutation and molecular evolution

Bootstrap calibration of TRANSMIT for informative missingness of parental genotype data

Informative missingness of parental genotype data occurs when the genotype of a parent influences the probability of the parent's genotype data being observed. Informative missingness can occur in a number of plausible ways and can affect both the validity and power of procedures that assume the data are missing at random (MAR). We propose a bootstrap calibration of MAR procedures to account for informative missingness and apply our methodology to refine the approach implemented in the TRANSMIT program. We illustrate this approach by applying it to data on hypertensive probands and their parents who participated in the Framingham Heart Study

Rhodium(II)-catalyzed stereocontrolled synthesis of dihydrofuran-3-imines from 1-Tosyl-1,2,3-triazoles

Rhodium(II) acetate catalyzes the denitrogenative transformation of 5-substituted and 4,5-disubstituted 1-sulfonyl-1,2,3-triazoles with pendent allyl and propargyl ether motifs to oxonium ylides that undergo [2,3]-sigmatropic rearrangement to give substituted dihydrofuran-3-imines in high yield and diastereoselectivity

Absent Toll-like receptor-9 expression predicts poor prognosis in renal cell carcinoma

<p>Abstract</p> <p>Background</p> <p>Toll-like receptor 9 (TLR9) is a cellular DNA-receptor whose activation with cognate ligands triggers an immune reaction, with increased production of inflammatory cytokines. The aim of this study was to examine the expression of TLR9 in renal cell carcinoma (RCC), which is generally renowned of its immunogenic nature. We also evaluated the prognostic value of TLR9 in RCC.</p> <p>Methods</p> <p>TLR9 expression in RCC was characterized with immunohistochemistry in a retrospective study population of 152 RCC patients who underwent renal surgery. The TLR9 staining intensity was compared with clinical parameters.</p> <p>Results</p> <p>Of the studied tumours, 112 (81%) exhibited cytoplasmic TLR9 immunostaining. No association was detected between cytoplasmic TLR9 immunoexpression intensity and stage, nuclear grade, histological subtype or tumour necrosis. Cytoplasmic TLR9 immunoexpression was, however, a marker of favourable RCC specific survival both in univariate analysis and in multivariate regression model.</p> <p>Conclusions</p> <p>We conclude that TLR9 expression is an independent prognostic marker of RCC and the absence of TLR9 expression is related to poorer prognosis in RCC.</p

Maternal Transmission of Resistance to Development of Allergic Airway Disease

Parental phenotype is known to influence the inheritance of atopic diseases, such as allergic asthma, with a maternal history being a more significant risk factor for progeny than paternal history. We hypothesized that recall Th1- or Th2-type immune responses during pregnancy would result in transfer of maternal factors that would differentially impact development of immune responsiveness in offspring. Following weaning, susceptibility and severity of allergic airway disease (a murine model of human asthma) was evaluated in progeny, disease being elicited by immunization with OVA-Al(OH)3 and challenge with aerosolized OVA. We found that progeny of mothers with Th1-biased immunity to OVA subjected to recall aerosol challenge during pregnancy had reduced levels of Ag-specific IgE and airway eosinophilia compared with progeny of mothers with Th2-biased immunity to OVA or naive mothers. Interestingly, progeny of mothers with Th1-type immunity to a heterologous albumin, BSA, were not protected from developing OVA-induced allergic airway disease. These findings demonstrated that maternal transfer of protection from development of allergic airway disease to offspring in this model of maternal Th1-type immunity was Ag specific

Management of work-relevant upper limb disorders: a review

Background Upper limb disorders (ULDs) are clinically challenging and responsible for considerable work loss. There is a need to determine effective approaches for their management. Aim To determine evidence-based management strategies for work-relevant ULDs and explore whether a biopsychosocial approach is appropriate. Methods Literature review using a best evidence synthesis. Data from articles identified through systematic searching of electronic databases and citation tracking were extracted into evidence tables. The information was synthesized into high-level evidence statements, which were ordered into themes covering classification/diagnosis, epidemiology, associations/risks and management/treatment, focusing on return to work or work retention and taking account of distinctions between non-specific complaints and specific diagnoses. Results Neither biomedical treatment nor ergonomic workplace interventions alone offer an optimal solution; rather, multimodal interventions show considerable promise, particularly for occupational outcomes. Early return to work, or work retention, is an important goal for most cases and may be facilitated, where necessary, by transitional work arrangements. The emergent evidence indicates that successful management strategies require all the players to be onside and acting in a coordinated fashion; this requires engaging employers and workers to participate. Conclusions The biopsychosocial model applies: biological considerations should not be ignored, but psychosocial factors are more influential for occupational outcomes. Implementation of interventions that address the full range of psychosocial issues will require a cultural shift in the way the relationship between upper limb complaints and work is conceived and handled. Dissemination of evidence-based messages can contribute to the needed cultural shift

Noninterventional follow-up vs fluid bolus in RESPONSE to oliguria-The RESPONSE trial protocol and statistical analysis plan

Background Oliguria is a frequent trigger for administering a fluid bolus, but the effect of fluid bolus in improving urine output is inadequately demonstrated. Here, we summarize the protocol and detailed statistical analysis plan of the randomized, controlled RESPONSE trial comparing follow-up as the experimental group and a 500 mL crystalloid fluid bolus as the control group for oliguria in critically ill oliguric patients. Methods Our trial is an investigator-initiated, randomized, controlled, pilot trial conducted in three ICUs in two centers. We aim to randomize 1:1 altogether 130 hemodynamically stable oliguric patients either to a 2-hour follow-up without interventions or to receive a crystalloid bolus of 500 mL over 30 minutes. The primary outcome is the change in individual urine output during the 2-hour period compared to 2 hours preceding randomization. Doubling of the urine output is considered clinically significant. Additionally, we record the duration of oliguria, physiological and biochemical variables, adverse events, and the incidences of acute kidney injury and renal replacement therapy. Conclusions Oliguria is a frequent trigger for potentially harmful fluid loading. Therefore, the RESPONSE trial will give information of the potential effect of fluid bolus on oliguria in critically ill patients. Trial registration clinical.trials.gov, NCT02860572.Peer reviewe

CD73 regulates zoledronate-induced lymphocyte infiltration in triple-negative breast cancer tumors and lung metastases

IntroductionBisphosphonates (BPs) are bone-protecting osteoclast inhibitors, typically used in the treatment of osteoporosis and skeletal complications of malignancies. When given in the adjuvant setting, these drugs may also prevent relapses and prolong overall survival in early breast cancer (EBC), specifically among postmenopausal patients. Because of these findings, adjuvant nitrogen-containing BPs (N-BPs), such as zoledronate (ZOL), are now the standard of care for high-risk EBC patients, but there are no benefit-associated biomarkers, and the efficacy remains low. BPs have been demonstrated to possess anti-tumor activities, but the mechanisms by which they provide the beneficial effects in EBC are not known. MethodsWe used stably transfected 4T1 breast cancer cells together with suppression of CD73 (sh-CD73) or control cells (sh-NT). We compared ZOL effects on tumor growth and infiltrating lymphocytes (TILs) into tumors and lung metastases using two mouse models. B cell depletion was performed using anti-CD20 antibody.ResultsSh-CD73 4T1 cells were significantly more sensitive to the growth inhibitory effects of n-BPs in vitro. However, while ZOL-induced growth inhibition was similar between the tumor groups in vivo, ZOL enhanced B and T lymphocyte infiltration into the orthotopic tumors with down-regulated CD73. A similar trend was detected in lung metastases. ZOL-induced tumor growth inhibition was found to be augmented with B cell depletion in sh-NT tumors, but not in sh-CD73 tumors. As an internal control, ZOL effects on bone were similar in mice bearing both tumor groups.DiscussionTaken together, these results indicate that ZOL modifies TILs in breast cancer, both in primary tumors and metastases. Our results further demonstrate that B cells may counteract the growth inhibitory effects of ZOL. However, all ZOL-induced TIL effects may be influenced by immunomodulatory characteristics of the tumor