Recent Approaches in Portal Hypertension Involving Risk Stratification and Medical Management.

Portal hypertension leads to the formation of portosystemic collaterals that divert portal blood to the systemic circulation and bypass the liver, resulting in multiple severe complications. Portal hypertension has classically been diagnosed using invasive methods to calculate the hepatic venous pressure gradient. There has been a recent evolution in portal hypertension pathology emphasizing dynamic changes and integrated pathophysiology, as well as concurrent changes in medical management. There is now a focus on using less-invasive approaches to diagnose portal hypertension and novel treatments that target the various components of evolving portal hypertension pathophysiology. This article details the latest techniques in diagnosing and treating portal hypertension that are becoming cornerstones of portal hypertension management.

Effect of immune activation on the kynurenine pathway and depression symptoms - A systematic review and meta-analysis.

Dysregulated kynurenine (KYN) pathway has been implicated in the pathophysiology of depression. In this systematic review, we examined the relationship between kynurenine pathway metabolites (KYN, kynurenic acid KYNA, tryptophan TRP, quinolinic acid QUIN, KYN/TRP ratio) and depression symptoms in the context of pro-inflammatory activation and immune response. Out of 5,082 articles, fifteen studies were suitable; ten studies (N = 315 medically ill patients treated with interferon-alpha IFN-α) reported baseline and post-intervention plasma KYN, TRP and KYN/TRP ratios which were included in quantitative meta-analysis. Data from five studies were summarized (IFN-α, interferon-beta IFN-ß, and lipopolysaccharide LPS). We found that IFN-α treatment in patients with chronic illnesses was associated with decreased TRP, increased levels of KYN and KYN/TRP ratio and depression scores from baseline to follow-up at both 4 and 24 weeks. Our findings suggest that increased risk of depression observed after immune-activating agents in patients with chronic medical illnesses is likely mediated by the kynurenine pathway. Further prospective studies are required to investigate the exact pathophysiology of the KYN pathway in depression.

Variability in postural control with and without balance-based torso- weighting in people with multiple sclerosis and healthy controls.

BACKGROUND: People with multiple sclerosis (MS) have diminished postural control, and center of pressure (COP) displacement varies more in this population than in healthy controls. Balance-based torso-weighting (BBTW) can improve clinical balance and mobility in people with MS, and exploration using both linear and nonlinear measures of COP may help determine whether BBTW optimizes movement variability. OBJECTIVE: The aim of this study was to investigate the effects of BBTW on people with MS and healthy controls during quiet standing. DESIGN: This was a quasi-experimental study comparing COP variability between groups, between eye closure conditions, and between weighting conditions in the anterior-posterior and medial-lateral directions. METHODS: Twenty participants with MS and 18 healthy controls stood on a forceplate in 4 conditions: eyes open and closed and with and without BBTW. Linear measures of COP displacement included range and root mean square (RMS). Nonlinear measures included approximate entropy (ApEn) and Lyapunov exponent (LyE). Three-way repeated-measures analyses of variance compared measures across groups and conditions. The association between weighting response and baseline nonlinear variables was examined. When significant associations were found, MS subgroups were created and compared. RESULTS: The MS and control groups had significantly different range, RMS, and ApEn values. The eyes-open and eyes-closed conditions had significantly different range and RMS values. Change with weighting correlated with LyE (r=-.70) and ApEn (r=-.59). Two MS subgroups, with low and high baseline LyE values, responded to BBTW in opposite directions, with a significant main effect for weighting condition for the LyE variable in the medial-lateral direction. LIMITATIONS: The small samples and no identification of impairments related to LyE at baseline were limitations of the study. CONCLUSIONS: The LyE may help differentiate subgroups who respond differently to BBTW. In both subgroups, LyE values moved toward the average of healthy controls, suggesting that BBTW may help optimize movement variability in people with MS.

GLRB is the third major gene of effect in hyperekplexia.

Glycinergic neurotransmission is a major inhibitory influence in the CNS and its disruption triggers a paediatric and adult startle disorder, hyperekplexia. The postsynaptic α(1)-subunit (GLRA1) of the inhibitory glycine receptor (GlyR) and the cognate presynaptic glycine transporter (SLC6A5/GlyT2) are well-established genes of effect in hyperekplexia. Nevertheless, 52% of cases (117 from 232) remain gene negative and unexplained. Ligand-gated heteropentameric GlyRs form chloride ion channels that contain the α(1) and ß-subunits (GLRB) in a 2α(1):3ß configuration and they form the predominant population of GlyRs in the postnatal and adult human brain, brainstem and spinal cord. We screened GLRB through 117 GLRA1- and SLC6A5-negative hyperekplexia patients using a multiplex-polymerase chain reaction and Sanger sequencing approach. The screening identified recessive and dominant GLRB variants in 12 unrelated hyperekplexia probands. This primarily yielded homozygous null mutations, with nonsense (n = 3), small indel (n = 1), a large 95 kb deletion (n = 1), frameshifts (n = 1) and one recurrent splicing variant found in four cases. A further three cases were found with two homozygous and one dominant GLRB missense mutations. We provide strong evidence for the pathogenicity of GLRB mutations using splicing assays, deletion mapping, cell-surface biotinylation, expression studies and molecular modelling. This study describes the definitive assignment of GLRB as the third major gene for hyperekplexia and impacts on the genetic stratification and biological causation of this neonatal/paediatric disorder. Driven principally by consanguineous homozygosity of GLRB mutations, the study reveals long-term additive phenotypic outcomes for affected cases such as severe apnoea attacks, learning difficulties and developmental delay.

Student nurses' reasons behind the decision to receive or decline influenza vaccine: a cross-sectional survey.

This cross-sectional questionnaire survey examined influenza vaccination among 430 student nurses. Only 12.2% (95% CI 9.1-15.3%) of student nurses received the seasonal vaccine regularly with 27.6% (95% CI 23.3-31.8%) ever having received seasonal or pandemic H1N1 vaccine. Intention to be vaccinated was associated with having previously been vaccinated (p<0.001) but not whether the vaccine was perceived as beneficial (p=0.36). Previous influenza illness was associated with having the influenza vaccine (p<0.001). The most frequently reported reason for receiving the seasonal influenza vaccine was being deemed at risk (42.4%) and for H1N1 vaccine was because it was offered for free (32.6%). For both vaccines the most reported reason for not being vaccinated was a perception of it not being needed. Student nurses form a substantial and influential part of the future healthcare workforce but to translate the widely held acceptance that influenza vaccine is beneficial into actual uptake, a more targeted and persuasive message is needed.

A mutation in the mouse Amelx tri-tyrosyl domain results in impaired secretion of amelogenin and phenocopies human X-linked amelogenesis imperfecta.

Amelogenesis imperfecta (AI) describes a broad group of clinically and genetically heterogeneous inherited defects of dental enamel bio-mineralization. Despite identification of a number of genetic mutations underlying AI, the precise causal mechanisms have yet to be determined. Using a multi-disciplinary approach, we describe here a mis-sense mutation in the mouse Amelx gene resulting in a Y --> H substitution in the tri-tyrosyl domain of the enamel extracellular matrix protein amelogenin. The enamel in affected animals phenocopies human X-linked AI where similar mutations have been reported. Animals affected by the mutation have severe defects of enamel bio-mineralization associated with absence of full-length amelogenin protein in the developing enamel matrix, loss of ameloblast phenotype, increased ameloblast apoptosis and formation of multi-cellular masses. We present evidence to demonstrate that affected ameloblasts express but fail to secrete full-length amelogenin leading to engorgement of the endoplasmic reticulum/Golgi apparatus. Immunohistochemical analysis revealed accumulations of both amelogenin and ameloblastin in affected cells. Co-transfection of Ambn and mutant Amelx in a eukaryotic cell line also revealed intracellular abnormalities and increased cytotoxicity compared with cells singly transfected with wild-type Amelx, mutant Amelx or Ambn or co-transfected with both wild-type Amelx and Ambn. We hypothesize that intracellular protein-protein interactions mediated via the amelogenin tri-tyrosyl motif are a key mechanistic factor underpinning the molecular pathogenesis in this example of AI. This study therefore successfully links phenotype with underlying genetic lesion in a relevant murine model for human AI.