Spherical Functions Associated With the Three Dimensional Sphere

In this paper, we determine all irreducible spherical functions \Phi of any K -type associated to the pair (G,K)=(\SO(4),\SO(3)). This is accomplished by associating to \Phi a vector valued function H=H(u) of a real variable u, which is analytic at u=0 and whose components are solutions of two coupled systems of ordinary differential equations. By an appropriate conjugation involving Hahn polynomials we uncouple one of the systems. Then this is taken to an uncoupled system of hypergeometric equations, leading to a vector valued solution P=P(u) whose entries are Gegenbauer's polynomials. Afterward, we identify those simultaneous solutions and use the representation theory of \SO(4) to characterize all irreducible spherical functions. The functions P=P(u) corresponding to the irreducible spherical functions of a fixed K-type \pi_\ell are appropriately packaged into a sequence of matrix valued polynomials (P_w)_{w\ge0} of size (\ell+1)\times(\ell+1). Finally we proved that \widetilde P_w={P_0}^{-1}P_w is a sequence of matrix orthogonal polynomials with respect to a weight matrix W. Moreover we showed that W admits a second order symmetric hypergeometric operator \widetilde D and a first order symmetric differential operator \widetilde E.Comment: 49 pages, 2 figure

Systematic Investigation of the Permeability of Androgen Receptor PROTACs.

Bifunctional molecules known as PROTACs simultaneously bind an E3 ligase and a protein of interest to direct ubiquitination and clearance of that protein, and they have emerged in the past decade as an exciting new paradigm in drug discovery. In order to investigate the permeability and properties of these large molecules, we synthesized two panels of PROTAC molecules, constructed from a range of protein-target ligands, linkers, and E3 ligase ligands. The androgen receptor, which is a well-studied protein in the PROTAC field was used as a model system. The physicochemical properties and permeability of PROTACs are discussed.This work was funded by Alzheimer’s Research UK (grant: ARUK-2015DDI-CAM), with support from the ALBORADA Trust. The ALBORADA Drug Discovery Institute is core funded by Alzheimer’s Research UK (registered charity No. 1077089 and SC042474)

Randomised trial of glutamine and selenium supplemented parenteral nutrition for critically ill patients

Background: Mortality rates in the Intensive Care Unit and subsequent hospital mortality rates in the UK remain high. Infections in Intensive Care are associated with a 2–3 times increased risk of death. It is thought that under conditions of severe metabolic stress glutamine becomes "conditionally essential". Selenium is an essential trace element that has antioxidant and anti-inflammatory properties. Approximately 23% of patients in Intensive Care require parenteral nutrition and glutamine and selenium are either absent or present in low amounts. Both glutamine and selenium have the potential to influence the immune system through independent biochemical pathways. Systematic reviews suggest that supplementing parenteral nutrition in critical illness with glutamine or selenium may reduce infections and mortality. Pilot data has shown that more than 50% of participants developed infections, typically resistant organisms. We are powered to show definitively whether supplementation of PN with either glutamine or selenium is effective at reducing new infections in critically ill patients. Methods/design: 2 × 2 factorial, pragmatic, multicentre, double-blind, randomised controlled trial. The trial has an enrolment target of 500 patients. Inclusion criteria include: expected to be in critical care for at least 48 hours, aged 16 years or over, patients who require parenteral nutrition and are expected to have at least half their daily nutritional requirements given by that route. Allocation is to one of four iso-caloric, iso-nitrogenous groups: glutamine, selenium, both glutamine & selenium or no additional glutamine or selenium. Trial supplementation is given for up to seven days on the Intensive Care Unit and subsequent wards if practicable. The primary outcomes are episodes of infection in the 14 days after starting trial nutrition and mortality. Secondary outcomes include antibiotic usage, length of hospital stay, quality of life and cost-effectiveness. Discussion: To date more than 285 patients have been recruited to the trial from 10 sites in Scotland. Recruitment is due to finish in August 2008 with a further six months follow up. We expect to report the results of the trial in summer 2009. Trial registration: This trial is registered with the International Standard Randomised Controlled Trial Number system. ISRCTN87144826Not peer reviewedPublisher PD

Why Can't Rodents Vomit? A Comparative Behavioral, Anatomical, and Physiological Study

The vomiting (emetic) reflex is documented in numerous mammalian species, including primates and carnivores, yet laboratory rats and mice appear to lack this response. It is unclear whether these rodents do not vomit because of anatomical constraints (e.g., a relatively long abdominal esophagus) or lack of key neural circuits. Moreover, it is unknown whether laboratory rodents are representative of Rodentia with regards to this reflex. Here we conducted behavioral testing of members of all three major groups of Rodentia; mouse-related (rat, mouse, vole, beaver), Ctenohystrica (guinea pig, nutria), and squirrel-related (mountain beaver) species. Prototypical emetic agents, apomorphine (sc), veratrine (sc), and copper sulfate (ig), failed to produce either retching or vomiting in these species (although other behavioral effects, e.g., locomotion, were noted). These rodents also had anatomical constraints, which could limit the efficiency of vomiting should it be attempted, including reduced muscularity of the diaphragm and stomach geometry that is not well structured for moving contents towards the esophagus compared to species that can vomit (cat, ferret, and musk shrew). Lastly, an in situ brainstem preparation was used to make sensitive measures of mouth, esophagus, and shoulder muscular movements, and phrenic nerve activity-key features of emetic episodes. Laboratory mice and rats failed to display any of the common coordinated actions of these indices after typical emetic stimulation (resiniferatoxin and vagal afferent stimulation) compared to musk shrews. Overall the results suggest that the inability to vomit is a general property of Rodentia and that an absent brainstem neurological component is the most likely cause. The implications of these findings for the utility of rodents as models in the area of emesis research are discussed. © 2013 Horn et al

Cisplatin-induced emesis: systematic review and meta-analysis of the ferret model and the effects of 5-HT3 receptor antagonists

PURPOSE: The ferret cisplatin emesis model has been used for ~30 years and enabled identification of clinically used anti-emetics. We provide an objective assessment of this model including efficacy of 5-HT(3) receptor antagonists to assess its translational validity. METHODS: A systematic review identified available evidence and was used to perform meta-analyses. RESULTS: Of 182 potentially relevant publications, 115 reported cisplatin-induced emesis in ferrets and 68 were included in the analysis. The majority (n = 53) used a 10 mg kg(−1) dose to induce acute emesis, which peaked after 2 h. More recent studies (n = 11) also used 5 mg kg(−1), which induced a biphasic response peaking at 12 h and 48 h. Overall, 5-HT(3) receptor antagonists reduced cisplatin (5 mg kg(−1)) emesis by 68% (45–91%) during the acute phase (day 1) and by 67% (48–86%) and 53% (38–68%, all P < 0.001), during the delayed phase (days 2, 3). In an analysis focused on the acute phase, the efficacy of ondansetron was dependent on the dosage and observation period but not on the dose of cisplatin. CONCLUSION: Our analysis enabled novel findings to be extracted from the literature including factors which may impact on the applicability of preclinical results to humans. It reveals that the efficacy of ondansetron is similar against low and high doses of cisplatin. Additionally, we showed that 5-HT(3) receptor antagonists have a similar efficacy during acute and delayed emesis, which provides a novel insight into the pharmacology of delayed emesis in the ferret

New approaches to measuring anthelminthic drug efficacy: parasitological responses of childhood schistosome infections to treatment with praziquantel

By 2020, the global health community aims to control and eliminate human helminthiases, including schistosomiasis in selected African countries, principally by preventive chemotherapy (PCT) through mass drug administration (MDA) of anthelminthics. Quantitative monitoring of anthelminthic responses is crucial for promptly detecting changes in efficacy, potentially indicative of emerging drug resistance. Statistical models offer a powerful means to delineate and compare efficacy among individuals, among groups of individuals and among populations.; We illustrate a variety of statistical frameworks that offer different levels of inference by analysing data from nine previous studies on egg counts collected from African children before and after administration of praziquantel.; We quantify responses to praziquantel as egg reduction rates (ERRs), using different frameworks to estimate ERRs among population strata, as average responses, and within strata, as individual responses. We compare our model-based average ERRs to corresponding model-free estimates, using as reference the World Health Organization (WHO) 90 % threshold of optimal efficacy. We estimate distributions of individual responses and summarize the variation among these responses as the fraction of ERRs falling below the WHO threshold.; Generic models for evaluating responses to anthelminthics deepen our understanding of variation among populations, sub-populations and individuals. We discuss the future application of statistical modelling approaches for monitoring and evaluation of PCT programmes targeting human helminthiases in the context of the WHO 2020 control and elimination goals

Potential pitfalls in MitoChip detected tumor-specific somatic mutations: a call for caution when interpreting patient data

<p>Abstract</p> <p>Background</p> <p>Several investigators have employed high throughput mitochondrial sequencing array (MitoChip) in clinical studies to search mtDNA for markers linked to cancers. In consequence, a host of somatic mtDNA mutations have been identified as linked to different types of cancers. However, closer examination of these data show that there are a number of potential pitfalls in the detection tumor-specific somatic mutations in clinical case studies, thus urging caution in the interpretation of mtDNA data to the patients. This study examined mitochondrial sequence variants demonstrated in cancer patients, and assessed the reliability of using detected patterns of polymorphisms in the early diagnosis of cancer.</p> <p>Methods</p> <p>Published entire mitochondrial genomes from head and neck, adenoid cystic carcinoma, sessile serrated adenoma, and lung primary tumor from clinical patients were examined in a phylogenetic context and compared with known, naturally occurring mutations which characterize different populations.</p> <p>Results</p> <p>The phylogenetic linkage analysis of whole arrays of mtDNA mutations from patient cancerous and non-cancerous tissue confirmed that artificial recombination events occurred in studies of head and neck, adenoid cystic carcinoma, sessile serrated adenoma, and lung primary tumor. Our phylogenetic analysis of these tumor and control leukocyte mtDNA haplotype sequences shows clear cut evidence of mixed ancestries found in single individuals.</p> <p>Conclusions</p> <p>Our study makes two prescriptions: both in the clinical situation and in research 1. more care should be taken in maintaining sample identity and 2. analysis should always be undertaken with respect to all the data available and within an evolutionary framework to eliminate artifacts and mix-ups.</p

FDG uptake by prosthetic arterial grafts in large vessel vasculitis Is not specific for active disease

OBJECTIVES: This study investigated the incidence and clinical significance of arterial graft-associated uptake of fluorodeoxyglucose in large-vessel vasculitis (LVV). BACKGROUND: The role of (18)F-labeled fluorodeoxyglucose-positron emission tomography/computed tomography ([(18)F]FDG-PET/CT) in the management of LVV remains to be defined. Although [(18)F]FDG uptake at arterial graft sites raises concerns regarding active arteritis or infection, its clinical significance in LVV has never been formally studied. METHODS: An observational prospective study sought to identify patients with Takayasu arteritis (TA) undergoing [(18)F]FDG-PET/CT more than 6 months after graft surgery from a large cohort of patients from 2 tertiary referral centers. [(18)F]FDG uptake by the graft and native arteries was scored on a scale of 0 to 3 relative to hepatic uptake, and periprosthetic maximum standardized uptake value (SUVmax) was calculated. Periprosthetic [(18)F]FDG uptake in active disease was compared with that in inactive disease, and arterial progression was assessed by prospective magnetic resonance angiography (MRA). RESULTS: Twenty-six subjects with TA were enrolled. All were afebrile with negative blood culture. Periprosthetic uptake was significant in 23 of 26 patients, and the mean SUVmax was 4.21 ± 1.46. Median periprosthetic [(18)F]FDG uptake score (3; interquartile range [IQR]: 3 to 3) was higher than in native aorta (1; IQR: 0 to 1; p < 0.001). Graft-specific [(18)F]FDG uptake was unrelated to disease activity. Despite the high frequency of graft-associated [(18)F]FDG uptake, sequential MRAs did not reveal arterial progression in 25 of 26 patients; the 1 remaining case showed minor progression limited to native arteries. Nine patients underwent repeated PET/CT scanning without showing changes in graft-specific uptake, despite increased treatment. CONCLUSIONS: Significant [(18)F]FDG uptake that is confined to arterial graft sites in patients with LVV does not reflect clinically relevant disease activity or progression. To minimize exposure to immunosuppression and in the face of negative blood culture, clinically quiescent arteritis, normal or stably raised C-reactive protein levels, we elected not to escalate treatment and monitor progression with MRA

Ethics takes time, but not that long

© 2007 Hansson et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution Licens

Elevated polygenic burden for autism is associated with differential DNA methylation at birth

This is the final version of the article. Available from BioMed Central via the DOI in this record.Autism spectrum disorder (ASD) is a severe neurodevelopmental disorder characterized by deficits in social communication and restricted, repetitive behaviors, interests, or activities. The etiology of ASD involves both inherited and environmental risk factors, with epigenetic processes hypothesized as one mechanism by which both genetic and non-genetic variation influence gene regulation and pathogenesis. The aim of this study was to identify DNA methylation biomarkers of ASD detectable at birth.This study was supported by grant HD073978 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institute of Environmental Health Sciences, and National Institute of Neurological Disorders and Stroke; and by the Beatrice and Samuel A. Seaver Foundation. We acknowledge iPSYCH and The Lundbeck Foundation for providing samples and funding. The iPSYCH (The Lundbeck Foundation Initiative for Integrative Psychiatric Research) team acknowledges funding from The Lundbeck Foundation (grant numbers R102-A9118 and R155–2014-1724), the Stanley Medical Research Institute, the European Research Council (project number 294838), the Novo Nordisk Foundation for supporting the Danish National Biobank resource, and grants from Aarhus and Copenhagen Universities and University Hospitals, including support to the iSEQ Center, the GenomeDK HPC facility, and the CIRRAU Center. This research has been conducted using the Danish National Biobank resource, supported by the Novo Nordisk Foundation. JM is supported by funding from the UK Medical Research Council (MR/K013807/1) and a Distinguished Investigator Award from the Brain & Behavior Research Foundation. The SEED study was supported by Centers for Disease Control and Prevention (CDC) Cooperative Agreements announced under the RFAs 01086, 02199, DD11–002, DD06–003, DD04–001, and DD09–002 and the SEED DNA methylation measurements were supported by Autism Speaks Award #7659 to MDF. SA was supported by the Burroughs-Wellcome Trust training grant: Maryland, Genetics, Epidemiology and Medicine (MD-GEM). The SSC was supported by Simons Foundation (SFARI) award and NIH grant MH089606, both awarded to STW