Multi-Step Regulation of Interferon Induction by Hepatitis C Virus

Acute hepatitis C virus (HCV) infection evokes several distinct innate immune responses in host, but the virus usually propagates by circumventing these responses. Although a replication intermediate double-stranded RNA is produced in infected cells, type I interferon (IFN) induction and immediate cell death are largely blocked in infected cells. In vitro studies suggested that type I and III IFNs are mainly produced in HCV-infected hepatocytes if the MAVS pathway is functional, and dysfunction of this pathway may lead to cellular permissiveness to HCV replication and production. Cellular immunity, including natural killer cell activation and antigen-specific CD8 T-cell proliferation, occurs following innate immune activation in response to HCV, but is often ineffective for eradication of HCV. Constitutive dsRNA stimulation differs in output from type I IFN therapy, which has been an authentic therapy for patients with HCV. Host innate immune responses to HCV RNA/proteins may be associated with progressive hepatic fibrosis and carcinogenesis once persistent HCV infection is established in opposition to the IFN system. Hence, innate RNA sensing exerts pivotal functions against HCV genome replication and host pathogenesis through modulation of the IFN system. Molecules participating in the RIG-I and Toll-like receptor 3 pathways are the main targets for HCV, disabling the anti-viral functions of these IFN-inducing molecules. We discuss the mechanisms that abolish type I and type III IFN production in HCV-infected cells, which may contribute to understanding the mechanism of virus persistence and resistance to the IFN therapy.     

Cancer‐associated somatic DICER1 hotspot mutations cause defective miRNA processing and reverse‐strand expression bias to predominantly mature 3p strands through loss of 5p strand cleavage

Our group recently described recurrent somatic mutations of the miRNA processing gene DICER1 in non‐epithelial ovarian cancer. Mutations appeared to be clustered around each of four critical metal‐binding residues in the RNase IIIB domain of DICER1. This domain is responsible for cleavage of the 3′ end of the 5p miRNA strand of a pre‐mRNA hairpin. To investigate the effects of these cancer‐associated 'hotspot' mutations, we engineered mouse DICER1‐deficient ES cells to express wild‐type and an allelic series of the mutant DICER1 variants. Global miRNA and mRNA profiles from cells carrying the metal‐binding site mutations were compared to each other and to wild‐type DICER1. The miRNA and mRNA profiles generated through the expression of the hotspot mutations were virtually identical, and the DICER1 hotspot mutation‐carrying cells were distinct from both wild‐type and DICER1‐deficient cells. Further, miRNA profiles showed that mutant DICER1 results in a dramatic loss in processing of mature 5p miRNA strands but were still able to create 3p strand miRNAs. Messenger RNA (mRNA) profile changes were consistent with the loss of 5p strand miRNAs and showed enriched expression for predicted targets of the lost 5p‐derived miRNAs. We therefore conclude that cancer‐associated somatic hotspot mutations of DICER1, affecting any one of four metal‐binding residues in the RNase IIIB domain, are functionally equivalent with respect to miRNA processing and are hypomorphic alleles, yielding a global loss in processing of mature 5p strand miRNA. We further propose that this resulting 3p strand bias in mature miRNA expression likely underpins the oncogenic potential of these hotspot mutations. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Relationship of regular physical activity with neuroelectric indices of interference processing in young adults

The relationship of physical activity with interference processing was examined using behavioral and neuroelectrical measures in young adults divided into more active and less active groups. The participants completed Stroop (i.e., color-naming) and reverse Stroop (i.e., word-meaning) tasks that differed in the level of difficulty while event-related potentials were assessed. In the low interference Stroop task, participants were asked to respond to the ink color of the word, while the meaning was either congruent or incongruent with the color. In the high interference reverse Stroop task, participants had to indicate the meaning of colored words while ignoring the color of the font. The results indicated that young adults in the more active group exhibited a shorter response time (RT) and a lower intra-individual variability of RT than did those in the less active group. These behavioral differences were associated with larger P2 and P3 and smaller N450 amplitudes in the Stroop task and with larger P2 and N2 and smaller N450 amplitudes in the reverse Stroop task. No differences were observed in the contingent negative variation (CNV) between the groups. These findings suggest that, for young adults, regular physical activity is positively associated with a better neural efficiency in resource allocation for tasks that require the ability to inhibit cognitive interference and provide evidence for the potential neural mechanisms underlying the improved Stroop performance.     

Is it a safe practice to administer oxygen during uncomplicated delivery: A randomized controlled trial?

Background

Newborns exposed to oxygen suffer from an oxidative stress with significant alterations in the concentrations of superoxide dismutase (SOD) and glutathione (GSSG).

Objective

To investigate the biological and clinical effects of oxygen administration to delivering mothers.

Methods

We conducted a randomized, double-blinded, controlled trial on a cohort of delivering women (n = 56) with an uncomplicated term pregnancy. Women were randomly assigned to one of two groups: Oxygen group or Room Air group. The Oxygen group received 100% oxygen (2 l/min) via nasal cannula for at least 30 min before delivery. Subjects in the Room Air group were connected to a nasal cannula while on room air. Concentrations of SOD (μg/g of Hb) and GSSG (μM/ml) were measured in maternal and umbilical cord blood. Bivariate and multivariate analyses were used to compare the two groups using the SAS system.

Results

Maternal SOD and GSSG did not differ between the two groups at baseline or after delivery. Concentrations of SOD and GSSG in umbilical cord blood did not differ between groups. More infants in Oxygen Group required delivery room resuscitation (20% vs. 0%, P = 0.03). This difference could not be explained by mode of delivery, infant sex, or other confounders.

Conclusions

Maternal exposure to oxygen during delivery is not associated with changes in umbilical cord SOD or GSSG. Further studies are needed to explore mechanisms responsible for the need of resuscitation in the oxygen group.     

Screening for coeliac disease among Egyptian children

Introduction

To screen for coeliac disease in Egyptian children with non-endocrinal short stature, refractory iron deficiency anaemia and type 1 diabetes. Also, to evaluate the sensitivity and specificity of different serological tests for diagnosis of coeliac disease (CD).

Material and methods

The study included 292 patients with clinical risk of CD. Testing for coeliac antibodies was performed, together with upper gastrointestinal endoscopy and small intestinal biopsy.

Results

Eleven patients (44%) among 25 patients with refractory iron deficiency anaemia, 23 patients (34.3%) among 67 patients with non-endocrinal short stature, and 6 patients (3%) among 200 patients with type I diabetes mellitus were diagnosed by jejunal biopsy as having coeliac disease. AGA (IgG) had the highest sensitivity for diagnosing CD (80.0%) followed by the TTG (72.7%) antibody, while ARA had the highest specificity (95.9%) followed by anti-EMA (94.7%).

Conclusions

Coeliac disease is more common in Egyptian children with refractory iron deficiency anaemia, non-endocrinal short stature and type 1 diabetes than was previously thought; therefore it is mandatory to screen such patients for CD. Serological tests showed fairly good sensitivity and specificity for the diagnosis; however, intestinal biopsy remains the cornerstone for definitive diagnosis of patients with immunological reaction to gluten.     

Acute fulminant myocarditis in children and adolescents: the role of mechanical circulatory assist

We report children and adolescents in fulminant myocarditis undergoing prolonged circulatory support with different assist devices. Between 1994 and 2004, seven children and adolescents (aged 7-18 years, mean age 13.5 years) were treated with VADs (5 Thoratec, 1 Medos, 1 Novacor) for circulatory support. Three patients underwent left ventricular support; biventricular support was necessary in four patients. Four patients (three left VADs, one bi-VAD) could be successfully bridged to heart transplantation after a mean support time of 163 days (56-258 days). One 7-year-old girl (Medos-BVAD) died after a support time of 11 days because of irreversible multiorgan failure. One 18-year-old patient was successfully weaned from Thoratec BVAD after 66 days with complete recovery of left ventricular function. As good markers, atrial and brain natriuretic peptides were found which reached normal values after recovery of myocardial function. A 15-year-old girl is still on the device. In children or adolescents with irreversible shock in fulminant myocarditis with an anticipated mortality of 100%, both successful bridging to heart transplantation and successful bridging to recovery are possible. Young patients with fulminant myocarditis should be rapidly transferred to a clinic with a mechanical circulatory support program to offer this life-saving option.     

Toxoplasma gondii, HCV, and HBV seroprevalence and co-infection among HIV-positive and -negative pregnant women in Burkina Faso

Toxoplasma gondii (T. gondii) infections can cause serious complications in HIV-infected pregnant women, leading to miscarriage, stillbirth, birth defects (e.g., mental retardation, blindness, epilepsy etc.) and could favor or enhance the mother-to-child transmission of HCV, HBV, and HIV vertical transmission. From May 20, 2004 to August 3, 2005, 336 18-45 years aged pregnant women, were enrolled for an investigation of the prevalence of serum antibodies against T. gondii, HCV, HBV, and HIV using ELISA. The prevalence of T. gondii, HCV, and HBV in pregnant women was 25.3%, 5.4%, and 9.8%, respectively and the HIV serostatus (61.6%) seems to be associated with greater prevalence rates of both T. gondii (28.5% vs. 20.2%) and HBV (11.6% vs. 7.0%). Without taking into account HIV, only 65.5% (220 of 336) of the women were not infected with these agents. The co-infection rate between HIV-infected and -negative women was different statistically: T. gondii/HBV 0.048 versus 0.015, T. gondii/HCV 0.014 versus 0.008, and HCV/HBV 0.005 versus 0.008, respectively. The elevated co-infection rate in HIV-positive women demonstrated that they are exposed to T. gondii, HCV, and HBV infections prevalently by sexual contact.     

Percutaneous fluoroscopic removal of a knotted Swan–Ganz catheter in a patient with a persistent left‐sided superior vena cava

Knotting of intravascular catheters is an uncommon but a well‐recognized occurrence. The Swan–Ganz catheter (SGC) is the one that knots most commonly. A case of a knotted SGC is described in a patient with a persistent left‐sided superior vena cava, and we propose that the presence of a left‐sided superior vena cava is a risk factor for knot formation not previously reported. We review the published work on the risk factors for knot formation and on the techniques used to remove knotted SGC. We describe a technique using a gooseneck snare and Omni Flush catheter (Angiodynamics, Queensbury, NY, USA) to loosen and untie a knotted SGC.     

Four-week administration of nimesulide, a cyclooxygenase-2 inhibitor, improves endothelial dysfunction in the hindlimb vasculature of streptozotocin-induced diabetic rats

The aim of this study was to examine the effect of chronic administration of nimesulide, a cyclooxygenase-2 inhibitor, on endothelial dysfunction in streptozotocin-induced diabetic rats. Three groups of Sprague-Dawley rats (300–350 g, n = 6) were used. The first group served as normoglycemic control and the second and third groups were rendered diabetic by an intraperitoneal injection of streptozotocin (60 mg/kg). The third group received the selective COX-2 inhibitor, nimesulide (20 mg/kg/day), orally by gavage for 4 weeks while the second group received only drinking water and served as diabetic control. At the end of the treatment period, the rats were anesthetized with urethane (1.2 g/kg) and mean arterial pressure, heart rate and hindlimb blood flow were monitored. This was followed by the injection of acetylcholine (endothelium-dependent vasodilator, 0.1–0.8 μg/kg) and sodium nitroprusside (endothelium-independent vasodilator 1–4 μg/kg). Mean arterial pressure was significantly reduced and hindlimb vascular conductance was not significantly affected in the control diabetic group when compared to the normoglycemic control group. Nimesulide treatment did not cause any significant change in any of the measured hemodynamic parameters. Acetylcholine and sodium nitroprusside induced dose-dependent increases in hindlimb vascular conductance in control normoglycemic rats which were attenuated in diabetic control rats. Nimesulide reversed the attenuation of acetylcholine-induced increase in hindlimb vascular conductance. In conclusion, chronic administration of the selective COX-2 inhibitor, nimesulide improved endothelial dysfunction in the hindlimb vasculature of streptozotocin induced diabetic rats. This suggests that COX-2 products might be involved in the pathogenesis of endothelial dysfunction in streptozotocin-induced diabetic rats.