Peripartum anaesthetic management of a patient with Brugada syndrome and myoadenylate deaminase deficiency.

Brugada syndrome is a rare electrophysiological cardiac disease which can result in serious arrhythmias and sudden cardiac death. Peripartum management is centred around avoiding arrhythmogenic drugs, including high doses of sodium channel blocking drugs such as bupivacaine. Myoadenylate deaminase deficiency, also known as adenosine monophosphate deaminase deficiency, is the commonest cause of myopathy in Caucasians. There is evidence that myoadenylate deaminase deficiency can predispose patients to developing malignant hyperthermia when exposed to specific anaesthetic agents. We present a case of a pregnant patient with both Brugada syndrome and myoadenylate deaminase deficiency, in which analgesic and general anaesthetic options for each condition presented potentially conflicting dilemmas for the delivery of intrapartum care.

Diagnosing peri-implant disease using the tongue as a 24/7 detector.

Our ability of screening broad communities for clinically asymptomatic diseases critically drives population health. Sensory chewing gums are presented targeting the tongue as 24/7 detector allowing diagnosis by "anyone, anywhere, anytime". The chewing gum contains peptide sensors consisting of a protease cleavable linker in between a bitter substance and a microparticle. Matrix metalloproteinases in the oral cavity, as upregulated in peri-implant disease, specifically target the protease cleavable linker while chewing the gum, thereby generating bitterness for detection by the tongue. The peptide sensors prove significant success in discriminating saliva collected from patients with peri-implant disease versus clinically asymptomatic volunteers. Superior outcome is demonstrated over commercially available protease-based tests in saliva. "Anyone, anywhere, anytime" diagnostics are within reach for oral inflammation. Expanding this platform technology to other diseases in the future features this diagnostic as a massive screening tool potentially maximizing impact on population health.Early detection of gum inflammation caused by dental implants helps prevent tissue damage. Here, the authors present a peptide sensor that generates a bitter taste when cleaved by proteases present in peri-implant disease, embed it in a chewing gum, and compare the probe to existing sensors using patient saliva.

Increased expression of miR-187 in human islets from individuals with type 2 diabetes is associated with reduced glucose-stimulated insulin secretion.

AIMS/HYPOTHESIS: Type 2 diabetes is characterised by progressive beta cell dysfunction, with changes in gene expression playing a crucial role in its development. MicroRNAs (miRNAs) are post-transcriptional regulators of gene expression and therefore alterations in miRNA levels may be involved in the deterioration of beta cell function. METHODS: Global TaqMan arrays and individual TaqMan assays were used to measure islet miRNA expression in discovery (n = 20) and replication (n = 20) cohorts from individuals with and without type 2 diabetes. The role of specific dysregulated miRNAs in regulating insulin secretion, content and apoptosis was subsequently investigated in primary rat islets and INS-1 cells. Identification of miRNA targets was assessed using luciferase assays and by measuring mRNA levels. RESULTS: In the discovery and replication cohorts miR-187 expression was found to be significantly increased in islets from individuals with type 2 diabetes compared with matched controls. An inverse correlation between miR-187 levels and glucose-stimulated insulin secretion (GSIS) was observed in islets from normoglycaemic donors. This correlation paralleled findings in primary rat islets and INS-1 cells where overexpression of miR-187 markedly decreased GSIS without affecting insulin content or apoptotic index. Finally, the gene encoding homeodomain-interacting protein kinase-3 (HIPK3), a known regulator of insulin secretion, was identified as a direct target of miR-187 and displayed reduced expression in islets from individuals with type 2 diabetes. CONCLUSIONS/INTERPRETATION: Our findings suggest a role for miR-187 in the blunting of insulin secretion, potentially involving regulation of HIPK3, which occurs during the pathogenesis of type 2 diabetes.

Impact of missing data on standardised mortality ratios for acute myocardial infarction: evidence from the Myocardial Ischaemia National Audit Project (MINAP) 2004-7.

BACKGROUND: Standardised mortality ratios (SMR) are often used to depict cardiovascular care. Data missingness, data quality, temporal variation and case-mix can, however, complicate the assessment of clinical performance. OBJECTIVES: To study Primary Care Trust (PCT) 30-day SMRs for STEMI and NSTEMI whilst considering the impact of missing data for age, sex and IMD score. DESIGN: Observational study using data from the Myocardial Ischaemia National Audit Project (MINAP) database to generate PCT SMR maps and funnel plots for England, 2004-2007. PATIENTS: 217,157 PATIENTS: 40.4% STEMI and 59.6% NSTEMI. RESULTS: 95% CI 30-day unadjusted mortality: STEMI 5.8% to 6.2%; NSTEMI 6.6% to 6.9%; relative risk, 95% CI 1.14, 1.10 to 1.19. Median (IQR) data missingess by PCT for composite of age, sex and IMD score was 1.4% (0.7% to 2.2%). For STEMI and NSTEMI statistically significant predictors of mortality were mean age (STEMI: P<0.001; NSTEMI: P<0.001), proportion of females (STEMI: P<0.001; NSTEMI: P<0.001) and proportion of missing ages (STEMI: P=0.02; NSTEMI: P<0.001). Proportion of missing sex also predicted 30-day mortality for NSTEMI (P=0.01). Maps of SMRs demonstrated substantial mortality variation, but no evidence of North / South divide. There were significant correlations between STEMI and NSTEMI observed (R² 0.72) and standardised mortality (R² 0.49) rates. PCT data aggregation gave an acceptable model fit in terms of deviance explained. For STEMI there were 33 (21.7%) regions below the 99.8% lower limit of the associated performance funnel plot, and 28 (18.4%) for NSTEMI; the inclusion of missing data did not affect the distribution of SMRs. CONCLUSIONS: The proportion of missing data was associated with 30-day mortality for STEMI and NSTEMI, however it did not influence the distribution of PCTs within the funnel plots. There was considerable variation in mortality not attributable to key patient-specific factors, supporting the notion of regional-dependent variation in STEMI and NSTEMI care.

Use of fluorescently labelled deoxyribonuclease I to spatially measure G-actin levels in migrating and non-migrating cells.

Lamellipodium protrusion is linked to actin filament disassembly in migrating fibroblasts [Cramer, 1999: Curr. Biol. 9:1095-1105]. To further study this relationship, we have identified a method to specifically and sensitively detect G-actin in distinct spatial locations in motile cells using deoxyribonuclease I (DNase I). Although DNase I can bind both G- and F-actin in vitro [Mannherz et al., 1980: Eur. J. Biochem. 95:377-385], when cells were fixed in formaldehyde and permeabilized in detergent, fluorescently-labelled DNase I specifically stained G-actin and not F-actin. 92-98% of actin molecules were stably retained in cells during fixation and permeabilization. Further, increasing or decreasing cellular G-actin concentration by treating live cells with latrunculin-A or jasplakinolide, respectively, caused a respective increase and decrease in DNase I cell-staining intensity as expected. These changes in DNase I fluorescence intensity accurately reflected increases and decreases in cellular G-actin concentration independently measured in lysates prepared from drug-treated live cells (regression coefficient = 0.98). This shows that DNase I cell-staining is very sensitive using this method. Applying this method, we found that the ratio of G-/F-actin is lower in both the lamellipodium and in a broad band immediately behind the lamellipodium in migrating compared to non-migrating fibroblasts. Thus, we predict that protrusion of the lamellipodium in migrating fibroblasts requires tight coupling to filament disassembly at least in part because G-actin is relatively limited within and behind the lamellipodium. This is the first report to directly demonstrate high sensitivity of cell-staining for any G-actin probe and this, together with the ready commercial accessibility of fluorescently-labelled DNase I, make it a simple, convenient, and sensitive tool for cell-staining of G-actin.