Chronic Granulomatous Disease; fundamental stages in our understanding of CGD

It has been 50 years since chronic granulomatous disease was first reported as a disease which fatally affected the ability of children to survive infections. Various milestone discoveries from the insufficient ability of patients' leucocytes to destroy microbial particles to the underlying genetic predispositions through which the disease is inherited have had important consequences. Longterm antibiotic prophylaxis has helped to fight infections associated with chronic granulomatous disease while the steady progress in bone marrow transplantation and the prospect of gene therapy are hailed as long awaited permanent treatment options. This review unearths the important findings by scientists that have led to our current understanding of the disease

Challenges and opportunities for conducting a vaccine trial during the COVID-19 pandemic in the United Kingdom

The COVID-19 pandemic has resulted in unprecedented challenges for healthcare systems worldwide. It has also stimulated research in a wide range of areas including rapid diagnostics, novel therapeutics, use of technology to track patients and vaccine development. Here, we describe our experience of rapidly setting up and delivering a novel COVID-19 vaccine trial, using clinical and research staff and facilities in three National Health Service Trusts in Cambridgeshire, United Kingdom. We encountered and overcame a number of challenges including differences in organisational structures, research facilities available, staff experience and skills, information technology and communications infrastructure, and research training and assessment procedures. We overcame these by setting up a project team that included key members from all three organisations that met at least daily by teleconference. This group together worked to identify the best practices and procedures and to harmonise and cascade these to the wider trial team. This enabled us to set up the trial within 25 days and to recruit and vaccinate the participants within a further 23 days. The lessons learned from our experiences could be used to inform the conduct of clinical trials during a future infectious disease pandemic or public health emergency

Regulation of α1-adrenoceptor linked phosphoinositide breakdown in cultured glia: role of protein phosphatases

This study attempts to identify the protein phosphatases and kinases involved in regulating receptor-mediated phosphoinositide metabolism in astrocytes derived from newborn rat cerebral cortex and maintained in culture. Noradrenaline produced a dose and time dependent accumulation of [3H] inositol phosphates which was mimicked by A61603 and blocked by RS17053 indicating the involvement of α1A-adrenoceptors in this response. Okadaic acid inhibited noradrenaline- evoked [3H] inositol phosphate accumulation in a time (t½, 5 min) and concentration (IC 50, 0.3μM) dependent manner; an effect which was reversed by the non-selective protein kinase inhibitor staurosporine. This suggests that protein phosphatase inhibition in these cells allows a kinase-mediated down regulation of receptor activity. A myristoylated protein kinase C inhibitor, at 10μM, reversed the effect of okadaic acid by some 60% whilst the cAMP-dependent protein kinase inhibitor, at the same concentration was without an effect. The involvement of protein kinase C in this response was further continued with the use of a protein kinase C activator, phorbol 12-myristate 13-acetate which inhibited noradrenaline-stimulated [3H] inositol phosphate accumulation (IC50 3nM) but was not additive with okadaic acid. The inhibitory effect of okadaic acid on noradrenaline-evoked [3H] inositol phosphate accumulation was overcome by long termphorbol ester treatment, thereby down regulating protein kinase activity in these cells. Pre-treatment of cultures with okadaic acid produced a loss of phosphatase activity and an increase in protein kinase C activity in these cultures. The effect of noradrenaline was found to be largely dependent upon extracellular Ca 2+. Ca2+ uptake into glial cells stimulated by α1-adrenoceptor activation was blocked in cultures pre-treated with a phosphatase inhibitor (okadaic acid) or kinase activator suggesting that receptor-coupled Ca 2+ influx is regulated by phosphorylation. Ca2+ release was also stimulated by α1-adrenoceptor activation but potentiated in cultures pre-treated with okadaic acid. Results thus point towards a role for a protein kinase in the mechanism by which receptors are coupled to and regulate phosphoinositide metabolism in glial cultures. The identity of particular protein phosphatases and protein kinases involved in this aspect of glial cell function are hereby a subject for investigation

Regulation of #alpha#_1-adrenoceptor-linked phosphoinositide breakdown in cultured glia Role of protein phosphates

SIGLEAvailable from British Library Document Supply Centre- DSC:DXN061836 / BLDSC - British Library Document Supply CentreGBUnited Kingdo

Challenges and opportunities for conducting a vaccine trial during the COVID-19 pandemic in the United Kingdom.

The COVID-19 pandemic has resulted in unprecedented challenges for healthcare systems worldwide. It has also stimulated research in a wide range of areas including rapid diagnostics, novel therapeutics, use of technology to track patients and vaccine development. Here, we describe our experience of rapidly setting up and delivering a novel COVID-19 vaccine trial, using clinical and research staff and facilities in three National Health Service Trusts in Cambridgeshire, United Kingdom. We encountered and overcame a number of challenges including differences in organisational structures, research facilities available, staff experience and skills, information technology and communications infrastructure, and research training and assessment procedures. We overcame these by setting up a project team that included key members from all three organisations that met at least daily by teleconference. This group together worked to identify the best practices and procedures and to harmonise and cascade these to the wider trial team. This enabled us to set up the trial within 25 days and to recruit and vaccinate the participants within a further 23 days. The lessons learned from our experiences could be used to inform the conduct of clinical trials during a future infectious disease pandemic or public health emergency