An Improved Synthesis of BrettPhos- and RockPhos-Type Biarylphosphine Ligands

Improved processes for the preparation of biphenyl-based phosphine ligands t-BuBrettPhos, RockPhos, and BrettPhos are presented. The new methods, featuring the use of Grignard reagents and catalytic amounts of copper, are superior to the previous methods, which require the use of tert-butyllithium and stoichiometric amounts of copper. Specifically, the use of less dangerous reagents provides a safer process, while the use of catalytic amounts of copper allows for the isolation of pure products in high yield. These improvements are particularly significant for the large-scale preparation of these ligands.National Institutes of Health (U.S.) (GM46059)Astellas USA Foundatio

Intra-Arterial Thrombolysis after Full-Dose Intravenous tPA via the "Drip and Ship" Approach in Patients with Acute Ischemic Stroke: Preliminary Report

According to the "drip and ship" concept, patients who are not responsive to intravenous tissue plasminogen activator (IV-tPA) at a community hospital may be candidates for subsequent intra-arterial (IA) thrombolysis at a comprehensive stroke center. We elucidated the efficacy and safety of combined IV/IA thrombolysis via the drip and ship approach. We retrospectively reviewed patients with acute ischemic stroke who underwent combined IV/IA thrombolysis between March 2006 and June 2009. The patients were divided into two groups (inside hospital IV-tPA vs. outside hospital IV-tPA). We compared the short- and long-term clinical outcome, recanalization rate, intracranial hemorrhage after the procedure, and onset to treatment time between the two groups. A total of 23 patients with inside hospital IV-tPA and 10 patients with outside hospital IV-tPA were included. The mean pre-treatment National Institutes of Health Stroke Scale (NIHSS) scores were 15.8 and 17.5, respectively. Baseline characteristics were not significantly different between the two groups. The NIHSS score at 1 week and favorable outcome rate (modified Rankin Scale ≤2) 3 months after the procedure were not significantly different (p=0.730 and p=0.141, respectively). The rate of recanalization and intracranial hemorrhage were not significantly different (p=0.560 and p=0.730, respectively). The onset to IA thrombolysis time was also not significantly different (222.7 vs. 239.3 minutes, p=0.455). Our results suggest that initiation of IV-tPA in a community hospital with rapid transfer to a comprehensive stroke center for subsequent IA thrombolysis can be a safe and feasible therapeutic option in acute stroke management

Treatment of gram-positive deep sternal wound infections in cardiac surgery -experiences with daptomycin-

The reported incidence of deep sternal wound infection (DSWI) after cardiac surgery is 0.4-5% with Staphylococcus aureus being the most common pathogen isolated from infected wound sternotomies and bacteraemic blood cultures. This infection is associated with a higher morbidity and mortality than other known aetiologies. Little is reported about the optimal antibiotic management. The aim of the study is to quantify the application of daptomycin treatment of DSWI due to gram-positive organisms post cardiac surgery

Regulation of Intestinal Immune Response by Selective Removal of the Anterior, Posterior, or Entire Pituitary Gland in Trichinella spiralis Infected Golden Hamsters

The influence of anterior pituitary hormones on the gastrointestinal tract of humans and animals has been previously reported. Hypophysectomy (HYPOX) in the rat causes atrophy of the intestinal mucosa, and reduction of gastric secretion and intestinal absorption, as well as increased susceptibility to bacterial and viral infections. However, to our knowledge, no findings have been published concerning the immune response following HYPOX during worm infection, particularly that which is caused by the nematode Trichinella spiralis. The aim of this work was to analyze the effects of total or partial HYPOX on colonization of T. spiralis in the intestinal lumen, together with duodenal and splenic cytokine expression. Our results indicate that 5 days post infection, only neurointermediate pituitary lobectomy (NIL) reduces the number of intestinally recovered T. spiralis larvae. Using semiquantitative inmunofluorescent laser confocal microscopy, we observed that the mean intensity of all tested Th1 cytokines was markedly diminished, even in the duodenum of infected controls. In contrast, a high level of expression of these cytokines was noted in the NIL infected hamsters. Likewise, a significant decrease in the fluorescence intensity of Th2 cytokines (with the exception of IL-4) was apparent in the duodenum of control and sham infected hamsters, compared to animals with NIL surgeries, which showed an increase in the expression of IL-5 and IL-13. Histology of duodenal mucosa from NIL hamsters showed an exacerbated inflammatory infiltrate located along the lamina propria, which was related to the presence of the parasite. We conclude that hormones from each pituitary lobe affect the gastrointestinal immune responses to T. spiralis through various mechanisms

Neurobiology of rodent self-grooming and its value for translational neuroscience

Self-grooming is a complex innate behaviour with an evolutionarily conserved sequencing pattern and is one of the most frequently performed behavioural activities in rodents. In this Review, we discuss the neurobiology of rodent self-grooming, and we highlight studies of rodent models of neuropsychiatric disorders-including models of autism spectrum disorder and obsessive compulsive disorder-that have assessed self-grooming phenotypes. We suggest that rodent self-grooming may be a useful measure of repetitive behaviour in such models, and therefore of value to translational psychiatry. Assessment of rodent self-grooming may also be useful for understanding the neural circuits that are involved in complex sequential patterns of action.National Institutes of Health (U.S.) (Grant NS025529)National Institutes of Health (U.S.) (Grant HD028341)National Institutes of Health (U.S.) (Grant MH060379

The glial growth factors deficiency and synaptic destabilization hypothesis of schizophrenia

BACKGROUND: A systems approach to understanding the etiology of schizophrenia requires a theory which is able to integrate genetic as well as neurodevelopmental factors. PRESENTATION OF THE HYPOTHESIS: Based on a co-localization of loci approach and a large amount of circumstantial evidence, we here propose that a functional deficiency of glial growth factors and of growth factors produced by glial cells are among the distal causes in the genotype-to-phenotype chain leading to the development of schizophrenia. These factors include neuregulin, insulin-like growth factor I, insulin, epidermal growth factor, neurotrophic growth factors, erbB receptors, phosphatidylinositol-3 kinase, growth arrest specific genes, neuritin, tumor necrosis factor alpha, glutamate, NMDA and cholinergic receptors. A genetically and epigenetically determined low baseline of glial growth factor signaling and synaptic strength is expected to increase the vulnerability for additional reductions (e.g., by viruses such as HHV-6 and JC virus infecting glial cells). This should lead to a weakening of the positive feedback loop between the presynaptic neuron and its targets, and below a certain threshold to synaptic destabilization and schizophrenia. TESTING THE HYPOTHESIS: Supported by informed conjectures and empirical facts, the hypothesis makes an attractive case for a large number of further investigations. IMPLICATIONS OF THE HYPOTHESIS: The hypothesis suggests glial cells as the locus of the genes-environment interactions in schizophrenia, with glial asthenia as an important factor for the genetic liability to the disorder, and an increase of prolactin and/or insulin as possible working mechanisms of traditional and atypical neuroleptic treatments

The Hunt for New Physics in the Flavour Sector with up vector-like quarks

We analyse the possible presence of New Physics (NP) in the Flavour Sector and evaluate its potential for solving the tension between the experimental values of \AJPKs and \BTNu with respect to the Standard Model (SM) expectations. Updated model independent analyses, where NP contributions are allowed in Bd - anti-Bd and Bs - anti-Bs transitions, suggest the need of New Physics in the $bd$ sector. A detailed analysis of recent Flavour data is then presented in the framework of a simple extension of the SM, where a $Q=2/3$ vector-like isosinglet quark is added to the spectrum of the SM. Special emphasis is given to the implications of this model for correlations among various measurable quantities. We include constraints from all the relevant quark flavour sectors and give precise predictions for selected rare processes. We find important deviations from the SM in observables in the $bd$ sector like the semileptonic asymmetry \asld, $B_{d}^{0}\to \mu ^{+}\mu ^{-}$ and $A^s_{SL}-A^d_{SL}$. Other potential places where NP can show up include $A_{J/\Psi\Phi}$, $\gamma$, $K_{L}^{0}\to \pi^{0}\nu \bar{\nu}$, $t\to Zq$ and $D^{0}\to \mu ^{+}\mu ^{-}$ among others. The experimental data favours in this model the existence of an up vector-like quark with a mass below $600(1000)$ GeV at $1(2)$ $\sigma$.Comment: 36 pages, 41 figures; minor changes and references added, matches version accepted for publicatio

A systematic review of the reporting of Data Monitoring Committees' roles, interim analysis and early termination in pediatric clinical trials

<p>Abstract</p> <p>Background</p> <p>Decisions about interim analysis and early stopping of clinical trials, as based on recommendations of Data Monitoring Committees (DMCs), have far reaching consequences for the scientific validity and clinical impact of a trial. Our aim was to evaluate the frequency and quality of the reporting on DMC composition and roles, interim analysis and early termination in pediatric trials.</p> <p>Methods</p> <p>We conducted a systematic review of randomized controlled clinical trials published from 2005 to 2007 in a sample of four general and four pediatric journals. We used full-text databases to identify trials which reported on DMCs, interim analysis or early termination, and included children or adolescents. Information was extracted on general trial characteristics, risk of bias, and a set of parameters regarding DMC composition and roles, interim analysis and early termination.</p> <p>Results</p> <p>110 of the 648 pediatric trials in this sample (17%) reported on DMC or interim analysis or early stopping, and were included; 68 from general and 42 from pediatric journals. The presence of DMCs was reported in 89 of the 110 included trials (81%); 62 papers, including 46 of the 89 that reported on DMCs (52%), also presented information about interim analysis. No paper adequately reported all DMC parameters, and nine (15%) reported all interim analysis details. Of 32 trials which terminated early, 22 (69%) did not report predefined stopping guidelines and 15 (47%) did not provide information on statistical monitoring methods.</p> <p>Conclusions</p> <p>Reporting on DMC composition and roles, on interim analysis results and on early termination of pediatric trials is incomplete and heterogeneous. We propose a minimal set of reporting parameters that will allow the reader to assess the validity of trial results.</p

Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition)

In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. For example, a key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process versus those that measure fl ux through the autophagy pathway (i.e., the complete process including the amount and rate of cargo sequestered and degraded). In particular, a block in macroautophagy that results in autophagosome accumulation must be differentiated from stimuli that increase autophagic activity, defi ned as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (inmost higher eukaryotes and some protists such as Dictyostelium ) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the fi eld understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. It is worth emphasizing here that lysosomal digestion is a stage of autophagy and evaluating its competence is a crucial part of the evaluation of autophagic flux, or complete autophagy. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. Along these lines, because of the potential for pleiotropic effects due to blocking autophagy through genetic manipulation it is imperative to delete or knock down more than one autophagy-related gene. In addition, some individual Atg proteins, or groups of proteins, are involved in other cellular pathways so not all Atg proteins can be used as a specific marker for an autophagic process. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field