Acanthamoeba castellanii induces host cell death via a phosphatidylinositol 3-kinase-dependent mechanism

Granulomatous amoebic encephalitis due to Acanthamoeba castellanii is a serious human infection with fatal consequences, but it is not clear how the circulating amoebae interact with the blood-brain barrier and transmigrate into the central nervous system. We studied the effects of an Acanthamoeba encephalitis isolate belonging to the T1 genotype on human brain microvascular endothelial cells, which constitute the blood-brain barrier. Using an apoptosis-specific enzyme-linked immunosorbent assay, we showed that Acanthamoeba induces programmed cell death in brain microvascular endothelial cells. Next, we observed that Acanthamoeba specifically activates phosphatidylinositol 3-kinase. Acanthamoeba-mediated brain endothelial cell death was abolished using LY294002, a phosphatidylinositol 3-kinase inhibitor. These results were further confirmed using brain microvascular endothelial cells expressing dominant negative forms of phosphatidylinositol 3-kinase. This is the first demonstration that Acanthamoeba-mediated brain microvascular endothelial cell death is dependent on phosphatidylinositol 3-kinase

Hydrological modelling improvements required in basins in the Hindukush-Karakoram-Himalayas region

Millions of people rely on river water originating from basins in the Hindukush-Karakoram-Himalayas (HKH), where snow- and ice-melt are significant flow components. One such basin is the Upper Indus Basin (UIB), where snow- and ice-melt can contribute more than 80% of total flow. Containing some of the world’s largest alpine glaciers, this basin may be highly susceptible to global warming and climate change, and reliable predictions of future water availability are vital for resource planning for downstream food and energy needs in a changing climate, but depend on significantly improved hydrological modelling. However, a critical assessment of available hydroclimatic data and hydrological modelling in the HKH region has identified five major failings in many published hydro-climatic studies, even those appearing in reputable international journals. The main weaknesses of these studies are: i) incorrect basin areas; ii) under-estimated precipitation; iii) incorrectly-defined glacier boundaries; iv) under-estimated snow-cover data; and v) use of biased melt factors for snow and ice during the summer months. This paper illustrates these limitations, which have either resulted in modelled flows being under-estimates of measured flows, leading to an implied severe water scarcity; or have led to the use of unrealistically high degree-day factors and over-estimates of glacier melt contributions, implying unrealistic melt rates. These effects vary amongst sub-basins. Forecasts obtained from these models cannot be used reliably in policy making or water resource development, and need revision. Detailed critical analysis and improvement of existing hydrological modelling may be equally necessary in other mountain regions across the world

Escherichia coli K1 RS218 Interacts with Human Brain Microvascular Endothelial Cells via Type 1 Fimbria Bacteria in the Fimbriated State

Escherichia coli K1 is a major gram-negative organism causing neonatal meningitis. E. coli K1 binding to and invasion of human brain microvascular endothelial cells (HBMEC) are a prerequisite for E. coli penetration into the central nervous system in vivo. In the present study, we showed using DNA microarray analysis that E. coli K1 associated with HBMEC expressed significantly higher levels of the fim genes compared to nonassociated bacteria. We also showed that E. coli K1 binding to and invasion of HBMEC were significantly decreased with its fimH deletion mutant and type 1 fimbria locked-off mutant, while they were significantly increased with its type 1 fimbria locked-on mutant. E. coli K1 strains associated with HBMEC were predominantly type 1 fimbria phase-on (i.e., fimbriated) bacteria. Taken together, we showed for the first time that type 1 fimbriae play an important role in E. coli K1 binding to and invasion of HBMEC and that type 1 fimbria phase-on E. coli is the major population interacting with HBMEC

C‐reactive protein level as a predictor of difficult emergency laparoscopic cholecystectomy

Background: Studies focused on C‐reactive protein (CRP) as a marker of difficult laparoscopic cholecystectomy are limited to small case series. The aim of this study was to evaluate the association between preoperative CRP concentration and difficulty of laparoscopic cholecystectomy in patients admitted with a biliary emergency presentation. Methods: Patients with an emergency admission for biliary disease treated between 2012 and 2017 with a documented preoperative CRP level were analysed. Elective patients and those with other concurrent causes of increased CRP concentration were excluded. The intraoperative difficulty grade was based on the Nassar scale. Statistical analysis was conducted to determine the association of preoperative CRP level with difficulty grading, adjusted for the interval to surgery. Results: A total of 804 emergency patients were included. The mean preoperative peak CRP level was 64·7 mg/l for operative difficulty grade I, 69·6 mg/l for grade II, 98·2 mg/l for grade III, 217·5 mg/l for grade IV and 193·1 mg/l for grade V, indicating a significant association between CRP concentration and Nassar grade (P < 0·001). Receiver operating characteristic (ROC) curve analysis showed an area under the curve of 0·78 (95 per cent c.i. 0·75 to 0·82), differentiating patients with grade I–III from those with grade IV–V operative difficulty. ROC curve analysis found a cut‐off CRP value of 90 mg/l, with 71·5 per cent sensitivity and 70·5 per cent specificity in predicting operative difficulty of grade IV or V. Logistic regression analysis found preoperative peak CRP level to be predictive of Nassar grade I–III versus grade IV–V operative difficulty, also when adjusted for timing of surgery (odds ratio 5·90, 95 per cent c.i. 2·80 to 12·50). Conclusion: Raised preoperative CRP levels are associated with greater operative difficulty based on Nassar scale grading

Gravitational Collapse: Expanding and Collapsing Regions

We investigate the expanding and collapsing regions by taking two well-known spherically symmetric spacetimes. For this purpose, the general formalism is developed by using Israel junction conditions for arbitrary spacetimes. This has been used to obtain the surface energy density and the tangential pressure. The minimal pressure provides the gateway to explore the expanding and collapsing regions. We take Minkowski and Kantowski-Sachs spacetimes and use the general formulation to investigate the expanding and collapsing regions of the shell.Comment: 12 pages, 4 figures, accepted for publication in Gen. Relativ. Gra

Angiotensin converting enzyme inhibitors do not increase the risk of poor outcomes in COVID-19 disease. A multi-centre observational study

Background and aims Hypertension is associated with an increased risk of severe outcomes with COVID-19 disease. Angiotensin Converting Enzyme (ACE) inhibitors are widely used as a first line medication for the treatment of hypertension in the UK, although their use was suggested in early reports to increase the risk associated with SARS-CoV-2 infection. Methods A prospective cohort study of hospitalised patients with laboratory confirmed COVID-19 was conducted across three hospital sites with patients identified on the 9th April 2020. Demographic and other baseline data were extracted from electronic case records, and patients grouped depending on ACE inhibitor usage or not. The 60-day all-cause mortality and need for intubation compared. Results Of the 173 patients identified, 88 (50.8%) had hypertension. Of these 27 (30.7%) used ACE inhibitors. We did not find significant differences in 60-day all-cause mortality, the requirement for invasive ventilation or length of stay between our patient cohorts after adjusting for covariates. Conclusion This study contributes to the growing evidence supporting the continued use of ACE inhibitors in COVID-19 disease, although adequately powered randomised controlled trials will be needed to confirm effects

Systematic Review of Peer Support for Breastfeeding Continuation: Metaregression Analysis of the Effect of Setting, Intensity, and Timing

Objective To examine the effect of setting, intensity, and timing of peer support on breast feeding. Design Systematic review and metaregression analysis of randomised controlled trials. Data sources Cochrane Library, Medline, CINAHL, the National Research Register, and British Nursing Index were searched from inception or from 1980 to 2011. Review methods Study selection, data abstraction, and quality assessment were carried out independently and in duplicate. Risk ratios and 95% confidence intervals were calculated for individual studies and pooled. Effects were estimated for studies grouped according to setting (high income countries, low or middle income countries, and the United Kingdom), intensity (<5 and ≥5 planned contacts), and timing of peer support (postnatal period with or without antenatal care), and analysed using metaregression for any and exclusive breast feeding at last study follow-up. Results Peer support interventions had a significantly greater effect on any breast feeding in low or middle income countries (P<0.001), reducing the risk of not breast feeding at all by 30% (relative risk 0.70, 95% confidence interval 0.60 to 0.82) compared with a reduction of 7% (0.93, 0.87 to 1.00) in high income countries. Similarly, the risk of non-exclusive breast feeding decreased significantly more in low or middle income countries than in high income countries: 37% (0.63, 0.52 to 0.78) compared with 10% (0.90, 0.85 to 0.97); P=0.01. No significant effect on breast feeding was observed in UK based studies. Peer support had a greater effect on any breastfeeding rates when given at higher intensity (P=0.02) and only delivered in the postnatal period (P<0.001), although no differences were observed of its effect on exclusive breastfeeding rates by intensity or timing. Conclusion Although peer support interventions increase breastfeeding continuation in low or middle income countries, especially exclusive breast feeding, this does not seem to apply in high income countries, particularly the United Kingdom, where breastfeeding support is part of routine postnatal healthcare. Peer support of low intensity does not seem to be effective. Policy relating to provision of peer support should be based on more specific evidence on setting and any new peer services in high income countries need to undergo concurrent evaluation

Computational Experience On Four Algorithms For The Hard Clustering Problem

In this paper, we consider the problem of clustering m objects in c clusters. The objects are represented by points in n-dimensional Euclidean space, and the objective is to classify these m points into c clusters such that the distance between points within a cluster and its center is minimized. The problem is a difficult optimization problem due to the fact that: it posseses many local minima. Several algorithms have been developed to solve this problem which include the k-means algorithm, the simulated annealing algorithm, the tabu search algorithm, and the genetic algorithm. In this paper, we study the four algorithms and compare their computational performance for the clustering problem. We test these algorithms on several clustering problems from the literature as well as several random problems and we report on our computational experience