Bax phosphorylation association with nucleus and oligomerization after neonatal Hypoxia–ischemia

Neonatal hypoxia–ischemia (HI) is a common occurrence in preterm and low‐birth‐weight infants, and the incidence of low‐birth‐weight and preterm births is increasing. Characterization of brain injury after HI is of critical importance in developing new treatments that more accurately target the injury. After severe HI, neuronal cells undergo necrosis and secondary apoptosis of the surrounding cells as a result of neuroinflammation. We sought to characterize the biochemical pathways associated with cell death after HI. Bax, a cell death signaling protein, is activated after HI and translocates to the nucleus, endoplasmic reticulum, and mitochondria. The translocation patterns of Bax affect the resultant cell death phenotype (necrotic or apoptotic) observed. Although Bax is known to oligomerize once it is activated, less is known about the factors that control its translocation and oligomerization. We hypothesize that Bax kinase‐specific phosphorylation determines its oligomerization and intracellular localization. Using well‐established in vivo and in vitro models of neonatal HI, we characterized Bax oligomerization and multiorganelle translocation. We found that HI‐dependent phosphorylation of Bax determines its oligomerization status and multiorganelle localization, and, ultimately, the cell death phenotype observed. Understanding the mechanisms of Bax translocation will aid in the rational design of therapeutic strategies that decrease the trauma resulting from HI‐associated inflammation. © 2013 Wiley Periodicals, Inc.     

Impact and persistence of cirrhotic cardiomyopathy after liver transplantation

Cirrhotic cardiomyopathy causes variable degree of systolic and diastolic dysfunction (DD) and conduction abnormalities. The primary aim of our study was to determine whether pre‐transplant DD and prolonged corrected QT (QTc) predict a composite of mortality, graft failure, and major cardiovascular events after liver transplantation. We also evaluated the reversibility of cirrhotic cardiomyopathy after transplantation. Adult patients who underwent liver transplantation at our institution from January 2007 to March 2009 were included. Data were obtained from institutional registry, medical record review, and evaluation of echocardiographic images. Among 243 patients, 113 (46.5%) had grade 1 DD, 16 (6.6%) had grade 2 DD, and none had grade 3 DD. The mean pre‐transplant QTc was 453 milliseconds. After a mean post‐transplant follow‐up of 5.2 years, 75 (31%) patients satisfied the primary composite outcome. Cox regression analysis did not show any significant association between DD and the composite outcome (P=.17). However, longer QTc was independently associated with the composite outcome (HR: 1.01, 95% confidence interval: 1.00–1.02, P=.05). DD (P<.001) and left ventricular mass index (P=.001) worsened after transplantation. In conclusion, QTc prolongation appears to be associated with worse outcomes. Although DD did not impact outcomes, it significantly worsened after transplantation.     

Finer gauge of cutting but not pencil-point needles correlate with lower incidence of post-dural puncture headache: a meta-regression analysis

Purpose

Post-dural puncture headache (PDPH) is a well-known neurological outcome caused by leakage of cerebrospinal fluid during neuraxial anesthesia. Studies aimed at assessing the efficacy of finer gauged spinal needles to reduce the incidence of PDPH have produced conflicting results. We have therefore examined the effect of the gauge of cutting needles and pencil-point needles, separately, on the incidence of PDPH.

Methods

The PubMed, EMBASE and Google Scholar databases were searched for randomized studies which compared PDPH incidence in a head-to-head analysis of individual needle gauges of similar needle designs (cutting and pencil-point). A meta-regression analysis was performed taking into account various covariates, such as needle gauge and design, mean age of patient population, surgery type, percentage of males and females in study population and year of publication.

Results

Of the 22 studies (n = 5631) included in the analysis, 12 (n = 3148) and ten (n = 2483) compared different gauges of cutting needles and pencil-point needles, respectively. After adjusting for covariates, meta-regression analysis was performed for all studies that randomly compared individual needle gauges of similar needle design. Whereas the incidence of PDPH inversely correlated with gauge in cutting needles (β = ?1.36 % per gauge, P = 0.037), no relationship was noted in pencil-point needles (β = ?0.32 % per gauge, P = 0.114). Female gender was the only covariate that reached a statistically significant correlation with the incidence of PDPH in both models.

Conclusions

A significant relationship between needle gauge and subsequent rate of PDPH was noted in cutting needles, but not pencil-point needles.

     

Polymorphisms of <Emphasis Type="Italic">ICAM-1</Emphasis> and <Emphasis Type="Italic">IL-6</Emphasis> genes related to endometriosis in a sample of Brazilian women

Purpose

This study investigated the possibility of K469E (rs5498) and G241R (rs1799969) polymorphisms, in ICAM-1 gene, and G634C (rs1800796), in IL-6 gene, being associated with the occurrence of endometriosis in a sample of Brazilian women.

Methods

We genotyped 200 women (100 in control group and 100 in endometriosis group) by PCR-RFLP technique for G634C, K469E, and G241R polymorphisms.

Results

No significant difference was observed in genotypic frequency between control and endometriosis groups for G634C and K469E polymorphisms (p?=?0.61 and p?=?0.22, respectively). In addition, no significant difference between stages I-II and III-IV of the disease was found for both SNPs (p?=?0.63 and p?=?0.24, respectively). All individuals were wild homozygotes for G241R polymorphism.

Conclusion

This study suggests that polymorphisms K469E, G241R, and G634C are not associated with increased susceptibility to endometriosis in Brazilian women.

     

A common variant association study reveals novel susceptibility loci for low HDL‐cholesterol levels in ethnic Arabs

The genetic susceptibility to acquiring low high density lipoprotein‐cholesterol (LHDLC) levels is not completely elucidated yet. In this study, we performed a common variant association study for harboring this trait in ethnic Arabs. We employed the Affymetrix high‐density Axiom Genome‐Wide ASI Array (Asian population) providing a coverage of 598,000 single nucleotide variations (SNPs) to genotype 5495 individuals in a two‐phase study involving discovery and validation sets of experiments. The rs1800775 [1.31 (1.22–1.42); p = 3.41E‐12] in the CETP gene and rs359027 [1.26 (1.16–1.36); p = 2.55E‐08] in the LMCD1 gene were significantly associated with LHDLC levels. Furthermore, rs3104435 [1.26 (1.15–1.38); p = 1.19E‐06] at the MATN1 locus, rs9835344 [1.16 (1.08–1.26); p = 8.75E‐06] in the CNTN6 gene, rs1559997 [1.3 (1.14–1.47); p = 9.48E‐06] in the SDS gene and rs1670273 [1.2 (1.1–1.31); p = 4.81E‐06] in the DMN/SYNM gene exhibited suggestive association with the disorder. Seven other variants including rs1147169 in the PLCL1 gene, rs10248618 in the DNAH11, rs476155 in the GLIS3, rs7024300 in the ABCA1, intergenic rs10836699, rs11603691 in P2RX3 and rs750134 in CORO1C gene exhibited borderline protective properties. Validation and joint meta‐analysis resulted in rs1800775, rs3104435 and rs359027 retaining their predisposing properties, while rs10836699 and rs11603691 showed protective properties. Our data show several predisposing variants across the genome for LHDLC levels in ethnic Arabs.     

Maintaining the ties that bind: the role of an intermediate visual memory store in the persistence of awareness

Segregation and feature binding are essential to the perception and awareness of objects in a visual scene. When a fragmented line-drawing of an object moves relative to a background of randomly oriented lines, the previously hidden object is segregated from the background and consequently enters awareness. Interestingly, in such shape-from-motion displays, the percept of the object persists briefly when the motion stops, suggesting that the segregated and bound representation of the object is maintained in awareness. Here, we tested whether this persistence effect is mediated by capacity-limited working-memory processes, or by the amount of object-related information available. The experiments demonstrate that persistence is affected mainly by the proportion of object information available and is independent of working-memory limits. We suggest that this persistence effect can be seen as evidence for an intermediate, form-based memory store mediating between sensory and working memory.     

Neuronal firing rates and patterns in the globus pallidus internus of patients with cervical dystonia differ from those with Parkinson's disease

Cervical dystonia (CD) is a movement disorder that involves involuntary turning and twisting of the neck caused by abnormal muscle contraction. Deep brain stimulation (DBS) in the globus pallidus internus (GPi) is used to treat both CD and the motor symptoms of Parkinson's disease (PD). It has been suggested that the differing motor symptoms in CD and PD may arise from a decreased GPi output in CD and elevation of output in PD. To test this hypothesis, extracellular recordings of GPi neuronal activity were obtained during stereotactic surgery for the implantation of DBS electrodes in seven idiopathic CD and 14 PD patients. The mean GPi neuronal firing rate recorded from CD patients was lower than that in PD patients (P < 0.001; means +/- SE: 71.4 +/- 2.2 and 91.7 +/- 3.0 Hz, respectively). Furthermore, GPi neurons fired in a more irregular pattern consisting of more frequent and longer pauses in CD compared with PD patients. When comparisons were done based on locations of recordings, these differences in firing rates and patterns were limited to the ventral portion of the GPi. In contrast, no difference in firing rate or pattern was observed in the globus pallidus externus between the two groups. These findings suggest that alterations in both firing rate and firing pattern may underlie the differing motor symptoms associated with these two movement disorders.     

Glecaprevir + pibrentasvir for treatment of hepatitis C

Introduction: Glecaprevir/pibrentasvir is a fixed-dose combination regimen of a new generation NS3/4A inhibitor and an NS5A inhibitor with potent antiviral activity against all hepatitis C virus (HCV) genotypes. This regimen offers a shorter course of therapy (8 weeks) for selected patients regardless of genotype and has demonstrated high virological efficacy for retreatment of individuals who previously failed an NS5A containing regimen. Glecaprevir and pibrentasvir are minimally excreted by the kidneys; thus this regimen can safely be used in individuals with severe chronic kidney disease (CKD), including those undergoing hemodialysis.

Areas covered: This review covers the mechanism of action, pharmacokinetics, clinical applications, efficacy, and safety profile of glecaprevir/pibrentasvir. It also covers key phase 2 and 3 clinical trials that led to licensure of this regimen.

Expert opinion: Glecaprevir/pibrentasvir is the latest antiviral regimen licensed in the United States for treatment of HCV infection. Although several other direct-acting antiviral agents (DAAs) are currently available, glecaprevir/pibrentasvir has some unique characteristics that expand treatment options for HCV infection, including patients with comorbidities such as advanced stage CKD or prior treatment failure to antiviral regimens containing other DAAs.