The role of the CNS endothelium in the pathogenesis of multiple sclerosis.

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) causing neurological disability in young adults. The neuropathological features of MS include large perivascular inflammatory cell infiltrates, microglia activation, antigen presentation and reactive astrogliosis. The CNS is protected by highly regulated blood-brain barrier (BBB) that is breached in MS as detected by MRI. Formation and regulation of the BBB involves the interactions of the interendothelial tight junction-associated proteins, occludin, ZO-1 and claudin. The results from this study suggest that the BBB is disrupted at the molecular level with alterations in ZO-1 and occludin expression being observed in blood vessels from MS tissue compared with normal control white matter. Tight junction (TJ) disruption was observed predominantly within vessels from active MS lesion however disruption was also observed within the normal appearing white matter and chronic lesions. The results of this study suggest that TJ disruption plays a critical in disease progression as TJ abnormalities were observed in conjunction with serum protein leakage and large inflammatory infiltrates. BBB leakage as gauged by MRI is reported to cease after an attack however this study shows that a low level of persistent serum protein leakage occurs in chronic lesions.The recruitment of circulating leukocytes and resident glial cells to sites of CNS inflammation is dependant on the interaction of adhesion molecules, chemokines and their receptors and cytokines and their receptors. A disintegrin and metalloproteinase-17 (ADAM-17) is an enzyme that has been shown to mediate proteolytic cleavage of some of these inflammatory components. The results in this study have described the constitutive expression of ADAM-17 by the cerebral endothelial cells in human and rat CNS. ADAM-17 is also shown to be expressed by resident glia and inflammatory cells and is elevated in active MS lesions and in the spinal cords of rats during peak phase of experimental autoimmune encephalomyelitis suggesting a pathogenic role for ADAM-17 in these disease processes. In vitro studies confirmed the production of ADAM-17 by cerebral endothelial cells and astrocytes. ADAM-17 expression is increased under pro-inflammatory conditions whereas its natural inhibitor TIMP3 is decreased. Release of TNF from GP8 cell surface is induced following treatment with TNF and LPS

Repeatability of induced sputum measurements in moderate to severe asthma

SummaryBackgroundNovel therapies are being developed for patients with moderate to severe asthma. These patients may have neutrophilic airway inflammation. Induced sputum is commonly used as an endpoint in clinical trials of asthma therapies. We have performed repeated induced sputum sampling in moderate to severe asthma patients to understand the variability of cell counts, including neutrophils, and performed power calculations for studies in this group of patients.MethodsNineteen patients with moderate to severe asthma with evidence of airflow obstruction (FEV1 ≤ 80% predicted) and suboptimal control (ACQ ≥ 1) performed repeated induced sputum separated by 1 month.ResultsThe Ri of neutrophil percentage and absolute eosinophil count demonstrated good (0.61) and moderate (0.56) repeatability respectively, but there was a poor level of agreement for eosinophil percentage and absolute neutrophil counts. The within subject SD for sputum neutrophil percentage was 15.8. In cross over studies, sample sizes of n = 14 and n = 54 are required to detect changes in neutrophil percentages by 20 and 10 % respectively at 90% power.ConclusionsSputum neutrophil percentage has good reproducibility in patients with moderate to severe asthma

A comparison of collision cross section values obtained via travelling wave ion mobility-mass spectrometry and ultra high performance liquid chromatography-ion mobility-mass spectrometry : application to the characterisation of metabolites in rat urine

A comprehensive Collision Cross Section (CCS) library was obtained via Travelling Wave Ion Guide mobility measurements through direct infusion (DI). The library consists of CCS and Mass Spectral (MS) data in negative and positive ElectroSpray Ionisation (ESI) mode for 463 and 479 endogenous metabolites, respectively. For both ionisation modes combined, TWCCSN2 data were obtained for 542 non-redundant metabolites. These data were acquired on two different ion mobility enabled orthogonal acceleration QToF MS systems in two different laboratories, with the majority of the resulting TWCCSN2 values (from detected compounds) found to be within 1% of one another. Validation of these results against two independent, external TWCCSN2 data sources and predicted TWCCSN2 values indicated to be within 1-2% of these other values. The same metabolites were then analysed using a rapid reversed-phase ultra (high) performance liquid chromatographic (U(H)PLC) separation combined with IM and MS (IM-MS) thus providing retention time (tr), m/z and TWCCSN2 values (with the latter compared with the DI-IM-MS data). Analytes for which TWCCSN2 values were obtained by U(H)PLC-IM-MS showed good agreement with the results obtained from DI-IM-MS. The repeatability of the TWCCSN2 values obtained for these metabolites on the different ion mobility QToF systems, using either DI or LC, encouraged the further evaluation of the U(H)PLC-IM-MS approach via the analysis of samples of rat urine, from control and methotrexate-treated animals, in order to assess the potential of the approach for metabolite identification and profiling in metabolic phenotyping studies. Based on the database derived from the standards 63 metabolites were identified in rat urine, using positive ESI, based on the combination of tr, TWCCSN2 and MS data.</p

T lymphocyte insensitivity to corticosteroids in chronic obstructive pulmonary disease

<p>Abstract</p> <p>Background</p> <p>There are increased numbers of activated lymphocytes in the lungs of chronic obstructive pulmonary disease (COPD) patients. The clinical benefits of corticosteroids in COPD patients are limited. Our hypothesis is that lymphocytes play a role in this corticosteroid insensitivity.</p> <p>Objectives</p> <p>To investigate the effects of the corticosteroid dexamethasone on lung lymphocyte cytokine production from patients with COPD compared to controls.</p> <p>Methods</p> <p>Cultured airway lymphocytes obtained by bronchoscopy from healthy non-smokers (HNS), smokers (S) and COPD patients were stimulated with phytohaemagglutinin (PHA) & phorbol myristate acetate (PMA), +/- dexamethasone. Supernatants were assayed for interleukin (IL)-2 and interferon (IFN)γ. Immunofluoresence was used to analyse changes in CD8 glucocorticoid receptor (GRα and GRβ) expression.</p> <p>Results</p> <p>The inhibition of PHA/PMA stimulated IFNγ production by dexamethasone was reduced in COPD patients compared to HNS (<it>p </it>< 0.05 at concentrations from 0.1-1 μM). There was also a significant reduction (<it>p </it>< 0.05) in the mean inhibitory effect at 1 μM in COPD patients (54.1%) compared to smokers (72.1%), and in smokers compared to HNS (85.5%). There was a numerically reduced effect of dexamethasone on IL-2 production that did not reach statistical significance. There was no difference in GRα and GRβ expression in follicular CD8 cells between COPD patients (50.9% and 30.4% respectively) and smokers (52.9% and 29.7% respectively).</p> <p>Conclusions</p> <p>IFNγ production from COPD airway lymphocytes is corticosteroid insensitive. This phenomenon may be important in the poor clinical response often observed with corticosteroids.</p

Cost-effectiveness of dabigatran etexilate for the prevention of stroke and systemic embolism in UK patients with atrial fibrillation

Objective To assess the cost-effectiveness of dabigatran etexilate, a new oral anticoagulant, versus warfarin and other alternatives for the prevention of stroke and systemic embolism in UK patients with atrial fibrillation (AF). Methods A Markov model estimated the cost-effectiveness of dabigatran etexilate versus warfarin, aspirin or no therapy. Two patient cohorts with AF (starting age of <80 and ≥80 years) were considered separately, in line with the UK labelled indication. Modelled outcomes over a lifetime horizon included clinical events, quality-adjusted life years (QALYs), total costs and incremental cost-effectiveness ratios (ICERs). Results Patients treated with dabigatran etexilate experienced fewer ischaemic strokes (3.74 dabigatran etexilate vs 3.97 warfarin) and fewer combined intracranial haemorrhages and haemorrhagic strokes (0.43 dabigatran etexilate vs 0.99 warfarin) per 100 patient-years. Larger differences were observed comparing dabigatran etexilate with aspirin or no therapy. For patients initiating treatment at ages <80 and ≥80 years, the ICERs for dabigatran etexilate were £4831 and £7090/QALY gained versus warfarin with a probability of cost-effectiveness at £20 000/QALY gained of 98% and 63%, respectively. For the patient cohort starting treatment at ages <80 years, the ICER versus aspirin was £3457/QALY gained and dabigatran etexilate was dominant (ie, was less costly and more effective) compared with no therapy. These results were robust in sensitivity analyses. Conclusions This economic evaluation suggests that the use of dabigatran etexilate as a first-line treatment for the prevention of stroke and systemic embolism is likely to be cost-effective in eligible UK patients with AF

Development of a Teaching Program on The State of the Salt Ingestion Which Prevents Heatstroke and High Blood Pressure

In vitro enzymatic profiles for tofacitinib and PIK-294. (DOC 35 kb

Hallmarks of the Mott-Metal Crossover in the Hole-Doped Pseudospin-1/2 Mott Insulator Sr\u3csub\u3e2\u3c/sub\u3eIrO\u3csub\u3e4\u3c/sub\u3e

The physics of doped Mott insulators remains controversial after decades of active research, hindered by the interplay among competing orders and fluctuations. It is thus highly desired to distinguish the intrinsic characters of the Mott-metal crossover from those of other origins. Here we investigate the evolution of electronic structure and dynamics of the hole-doped pseudospin-1/2 Mott insulator Sr2IrO4. The effective hole doping is achieved by replacing Ir with Rh atoms, with the chemical potential immediately jumping to or near the top of the lower Hubbard band. The doped iridates exhibit multiple iconic low-energy features previously observed in doped cuprates—pseudogaps, Fermi arcs and marginal-Fermi-liquid-like electronic scattering rates. We suggest these signatures are most likely an integral part of the material’s proximity to the Mott state, rather than from many of the most claimed mechanisms, including preformed electron pairing, quantum criticality or density-wave formation

Lethal Injection for Execution: Chemical Asphyxiation?

Data from executions in the US suggest that current lethal injection protocols do not effect death through the mechanisms intended, and that potentially aware inmates could die through pancuronium-induced asphyxiation

Perioperative Quality Initiative (POQI) consensus statement on the physiology of blood pressure control as applied to perioperative medicine.

Background: A multi-disciplinary, international working subgroup of the Third Perioperative Quality Initiative (POQI) consensus meeting reviewed the (patho)physiology and measurement of arterial blood pressure (ABP), as applied to perioperative medicine. Methods: We addressed predefined questions by undertaking a modified Delphi analysis, in which primary clinical research and review articles were identified using MEDLINE. Strength of recommendations, where applicable, were graded by NICE guidelines. Results: Perioperative ABP management is a physiologically-complex challenge influenced by multiple factors: (i) ABP is the input pressure to organ blood flow, but is not the sole determinant of perfusion pressure; (ii) blood flow is often independent of changes in perfusion pressure, due to autoregulatory changes in vascular resistance; (iii) microvascular dysfunction uncouples microvascular blood flow from ABP (haemodynamic incoherence) From a practical clinical perspective, we identified that: (i) ambulatory measurement is the optimal method to establish baseline ABP; (ii) automated and invasive ABP measurements have inherent physiological and technical limitations; (iii) individualised ABP targets may change over time, especially during the perioperative period. There remains a need for research in non-invasive, continuous arterial pressure measurements, macro- and microcirculatory control, regional perfusion pressure measurement and the development of sensitive, specific and continuous measures of cellular function to evaluate blood pressure management in a physiologically coherent manner. Conclusion: The multivariable, complex physiology contributing to dynamic changes in perioperative ABP may be underappreciated clinically. The frequently unrecognised dissociation between ABP, organ blood flow, microvascular and cellular function requires further research that develops a more refined, contextualized clinical approach to this routine measurement