L-ornithine L-aspartate for people with cirrhosis and hepatic encephalopathy

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: To assess the beneficial and harmful effects of L-ornithine L-aspartate versus placebo, no intervention, or other active interventions for people with cirrhosis and hepatic encephalopathy

Flumazenil versus placebo or no intervention for people with cirrhosis and hepatic encephalopathy

BACKGROUND: Hepatic encephalopathy is a common complication of cirrhosis which results in poor brain functioning. The spectrum of changes associated with hepatic encephalopathy ranges from the clinically 'indiscernible' or minimal hepatic encephalopathy to the clinically 'obvious' or overt hepatic encephalopathy. Flumazenil is a synthetic benzodiazepine antagonist with high affinity for the central benzodiazepine recognition site. Flumazenil may benefit people with hepatic encephalopathy through an indirect negative allosteric modulatory effect on gamma-aminobutyric acid receptor function. The previous version of this review, which included 13 randomised clinical trials, found no effect of flumazenil on all-cause mortality, based on an analysis of 10 randomised clinical trials, but found a beneficial effect on hepatic encephalopathy, based on an analysis of eight randomised clinical trials. OBJECTIVES: To evaluate the beneficial and harmful effects of flumazenil versus placebo or no intervention for people with cirrhosis and hepatic encephalopathy. SEARCH METHODS: We searched The Cochrane Hepato-Biliary Group Controlled Trials Register, CENTRAL, MEDLINE, Embase, Science Citation Index Expanded, and LILACS; meeting and conference proceedings; and bibliographies in May 2017. SELECTION CRITERIA: We included randomised clinical trials regardless of publication status, blinding, or language in the analyses of benefits and harms, and observational studies in the assessment of harms. DATA COLLECTION AND ANALYSIS: Two review authors extracted data independently. We undertook meta-analyses and presented results using risk ratios (RR) with 95% confidence intervals (CI) and I(2) values as a marker of heterogeneity. We assessed bias control using the Cochrane Hepato-Biliary Group domains; determined the quality of the evidence using GRADE; evaluated the risk of small-study effects in regression analyses; and conducted trial sequential, subgroup, and sensitivity analyses. MAIN RESULTS: We identified 14 eligible randomised clinical trials with 867 participants, the majority of whom had an acute episode of overt hepatic encephalopathy. In addition, we identified one ongoing randomised clinical trial. We were unable to gather outcome data from two randomised clinical trials with 25 participants. Thus, our analyses include 842 participants from 12 randomised clinical trials comparing flumazenil versus placebo. We classified one randomised clinical trial at low risk of bias in the overall assessment and the remaining randomised clinical trials at high risk of bias. The duration of follow-up ranged from a few minutes to two weeks, but it was less than one day in the majority of the trials.In total, 32/433 (7.4%) participants allocated to flumazenil versus 38/409 (9.3%) participants allocated to placebo died (RR 0.75, 95% CI 0.48 to 1.16; 11 randomised clinical trials; low quality evidence). The Trial Sequential Analysis and the one randomised clinical trial assessed as low risk of bias (RR 0.76, 95% CI 0.37 to 1.53) found no beneficial or harmful effects of flumazenil on all-cause mortality. The methods used to evaluate hepatic encephalopathy included several different clinical scales, electrophysiological variables, and psychometric tests. Flumazenil was associated with a beneficial effect on hepatic encephalopathy when including all randomised clinical trials (RR 0.75, 95% CI 0.71 to 0.80; 824 participants; nine randomised clinical trials; low quality evidence), or just the trial at low risk of bias (RR 0.78, 95% CI 0.72 to 0.84; 527 participants). The Trial Sequential Analysis supported a beneficial effect of flumazenil on hepatic encephalopathy. The randomised clinical trials included little information about causes of death and little information on non-fatal serious adverse events. AUTHORS' CONCLUSIONS: We found low quality evidence suggesting a short-term beneficial effect of flumazenil on hepatic encephalopathy in people with cirrhosis, but no evidence of an effect on all-cause mortality. Additional evidence from large, high quality randomised clinical trials is needed to evaluate the potential benefits and harms of flumazenil in people with cirrhosis and hepatic encephalopathy

Hierarchy measure for complex networks

Nature, technology and society are full of complexity arising from the intricate web of the interactions among the units of the related systems (e.g., proteins, computers, people). Consequently, one of the most successful recent approaches to capturing the fundamental features of the structure and dynamics of complex systems has been the investigation of the networks associated with the above units (nodes) together with their relations (edges). Most complex systems have an inherently hierarchical organization and, correspondingly, the networks behind them also exhibit hierarchical features. Indeed, several papers have been devoted to describing this essential aspect of networks, however, without resulting in a widely accepted, converging concept concerning the quantitative characterization of the level of their hierarchy. Here we develop an approach and propose a quantity (measure) which is simple enough to be widely applicable, reveals a number of universal features of the organization of real-world networks and, as we demonstrate, is capable of capturing the essential features of the structure and the degree of hierarchy in a complex network. The measure we introduce is based on a generalization of the m-reach centrality, which we first extend to directed/partially directed graphs. Then, we define the global reaching centrality (GRC), which is the difference between the maximum and the average value of the generalized reach centralities over the network. We investigate the behavior of the GRC considering both a synthetic model with an adjustable level of hierarchy and real networks. Results for real networks show that our hierarchy measure is related to the controllability of the given system. We also propose a visualization procedure for large complex networks that can be used to obtain an overall qualitative picture about the nature of their hierarchical structure.Comment: 29 pages, 9 figures, 4 table

Modelling Students’ Thematically Associated Knowledge : Networked Knowledge from Affinity Statistics

Peer reviewe

Serum Levels of Advanced Glycation Endproducts and Other Markers of Protein Damage in Early Diabetic Nephropathy in Type 1 Diabetes

Objective To determine the role of markers of plasma protein damage by glycation, oxidation and nitration in microalbuminuria onset or subsequent decline of glomerular filtration rate (termed “early GFR decline”) in patients with type 1 diabetes. Methods From the 1st Joslin Kidney Study, we selected 30 patients with longstanding normoalbuminuria and 55 patients with new onset microalbuminuria. Patients with microalbuminuria had 8–12 years follow-up during which 33 had stable GFR and 22 early GFR decline. Mean baseline GFRCYSTATIN C was similar between the three groups. Glycation, oxidation and nitration markers were measured in protein and ultrafiltrate at baseline by liquid chromatography-tandem mass spectrometry using the most reliable methods currently available. Results Though none were significantly different between patients with microalbuminuria with stable or early GFR decline, levels of 6 protein damage adduct residues of plasma protein and 4 related free adducts of plasma ultrafiltrate were significantly different in patients with microalbuminuria compared to normoalbuminuria controls. Three protein damage adduct residues were decreased and 3 increased in microalbuminuria while 3 free adducts were decreased and one increased in microalbuminuria. The most profound differences were of N-formylkynurenine (NFK) protein adduct residue and Nω-carboxymethylarginine (CMA) free adduct in which levels were markedly lower in microalbuminuria (P<0.001 for both). Conclusions Complex processes influence levels of plasma protein damage and related proteolysis product free adducts in type 1 diabetes and microalbuminuria. The effects observed point to the possibility that patients who have efficient mechanisms of disposal of damaged proteins might be at an increased risk of developing microalbuminuria but not early renal function decline. The findings support the concept that the mechanisms responsible for microalbuminuria may differ from the mechanisms involved in the initiation of early renal function decline

Host Cell Transcriptome Profile during Wild-Type and Attenuated Dengue Virus Infection

10.1371/journal.pntd.0002107PLoS Neglected Tropical Diseases73

A common variant near TGFBR3 is associated with primary open angle glaucoma

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited.Primary open angle glaucoma (POAG), a major cause of blindness worldwide, is a complex disease with a significant genetic contribution.We performed Exome Array (Illumina) analysis on 3504 POAG cases and 9746 controls with replication of the most significant findings in 9173 POAG cases and 26 780 controls across 18 collections of Asian, African and European descent. Apart from confirming strong evidence of association at CDKN2B-AS1 (rs2157719 [G], odds ratio [OR] = 0.71, P = 2.81 × 10−33), we observed one SNP showing significant association to POAG (CDC7–TGFBR3 rs1192415, ORG-allele = 1.13, Pmeta = 1.60 × 10−8). This particular SNP has previously been shown to be strongly associated with optic disc area and vertical cup-to-disc ratio, which are regarded as glaucoma-related quantitative traits. Our study now extends this by directly implicating it in POAG disease pathogenesis

Relationship between Antibody Susceptibility and Lipopolysaccharide O-Antigen Characteristics of Invasive and Gastrointestinal Nontyphoidal Salmonellae Isolates from Kenya

Background: Nontyphoidal Salmonellae (NTS) cause a large burden of invasive and gastrointestinal disease among young children in sub-Saharan Africa. No vaccine is currently available. Previous reports indicate the importance of the O-antigen of Salmonella lipopolysaccharide for virulence and resistance to antibody-mediated killing. We hypothesised that isolates with more O-antigen have increased resistance to antibody-mediated killing and are more likely to be invasive than gastrointestinal. Methodology/Principal findings: We studied 192 NTS isolates (114 Typhimurium, 78 Enteritidis) from blood and stools, mostly from paediatric admissions in Kenya 2000-2011. Isolates were tested for susceptibility to antibody-mediated killing, using whole adult serum. O-antigen structural characteristics, including O-acetylation and glucosylation, were investigated. Overall, isolates were susceptible to antibody-mediated killing, but S. Enteritidis were less susceptible and expressed more O-antigen than Typhimurium (p\u3c0.0001 for both comparisons). For S. Typhimurium, but not Enteritidis, O-antigen expression correlated with reduced sensitivity to killing (r = 0.29, 95% CI = 0.10-0.45, p = 0.002). Both serovars expressed O-antigen populations ranging 21-33 kDa average molecular weight. O-antigen from most Typhimurium were O-acetylated on rhamnose and abequose residues, while Enteritidis O-antigen had low or no O-acetylation. Both Typhimurium and Enteritidis O-antigen were approximately 20%-50% glucosylated. Amount of S. Typhimurium O-antigen and O-antigen glucosylation level were inversely related. There was no clear association between clinical presentation and antibody susceptibility, O-antigen level or other O-antigen features. Conclusion/Significance: Kenyan S. Typhimurium and Enteritidis clinical isolates are susceptible to antibody-mediated killing, with degree of susceptibility varying with level of O-antigen for S. Typhimurium. This supports the development of an antibody-inducing vaccine against NTS for Africa. No clear differences were found in the phenotype of isolates from blood and stool, suggesting that the same isolates can cause invasive disease and gastroenteritis. Genome studies are required to understand whether invasive and gastrointestinal isolates differ at the genotypic level

Gradient Descent Optimization in Gene Regulatory Pathways

BACKGROUND: Gene Regulatory Networks (GRNs) have become a major focus of interest in recent years. Elucidating the architecture and dynamics of large scale gene regulatory networks is an important goal in systems biology. The knowledge of the gene regulatory networks further gives insights about gene regulatory pathways. This information leads to many potential applications in medicine and molecular biology, examples of which are identification of metabolic pathways, complex genetic diseases, drug discovery and toxicology analysis. High-throughput technologies allow studying various aspects of gene regulatory networks on a genome-wide scale and we will discuss recent advances as well as limitations and future challenges for gene network modeling. Novel approaches are needed to both infer the causal genes and generate hypothesis on the underlying regulatory mechanisms. METHODOLOGY: In the present article, we introduce a new method for identifying a set of optimal gene regulatory pathways by using structural equations as a tool for modeling gene regulatory networks. The method, first of all, generates data on reaction flows in a pathway. A set of constraints is formulated incorporating weighting coefficients. Finally the gene regulatory pathways are obtained through optimization of an objective function with respect to these weighting coefficients. The effectiveness of the present method is successfully tested on ten gene regulatory networks existing in the literature. A comparative study with the existing extreme pathway analysis also forms a part of this investigation. The results compare favorably with earlier experimental results. The validated pathways point to a combination of previously documented and novel findings. CONCLUSIONS: We show that our method can correctly identify the causal genes and effectively output experimentally verified pathways. The present method has been successful in deriving the optimal regulatory pathways for all the regulatory networks considered. The biological significance and applicability of the optimal pathways has also been discussed. Finally the usefulness of the present method on genetic engineering is depicted with an example