Identification of potential inhibitors of Zika virus NS5 RNA-dependent RNA polymerase through virtual screening and molecular dynamic simulations

Zika virus (ZIKV) is one of the mosquito borne flavivirus with several outbreaks in past few years in tropical and subtropical regions. The non-structural proteins of flaviviruses are suitable active targets for inhibitory drugs due to their role in pathogenicity. In ZIKV, the non-structural protein 5 (NS5) RNA-Dependent RNA polymerase replicates its genome. Here we have performed virtual screening to identify suitable ligands that can potentially halt the ZIKV NS5 RNA dependent RNA polymerase (RdRp). During this process, we searched and screened a library of ligands against ZIKV NS5 RdRp. The selected ligands with significant binding energy and ligand-receptor interactions were further processed. Among the selected docked conformations, top five was further optimized at atomic level using molecular dynamic simulations followed by binding free energy calculations. The interactions of ligands with the target structure of ZIKV RdRp revealed that they form strong bonds within the active sites of the receptor molecule. The efficacy of these drugs against ZIKV can be further analyzed through in-vitro and in-vivo studies.     

Pentoxifylline Increases Antiadhesion Effect of Streptokinase on Postoperative Adhesion Formation: Involvement of Fibrinolytic Pathway

Pentoxifylline reduces peritoneal adhesions and increases peritoneal fibrinolysis in rodents. Furthermore, the activation of the fibrinolytic system by streptokinase leading to degradation of fibrin is effective in the prevention of adhesion formation. We have investigated the effects of pentoxifylline and streptokinase alone and/or coadministration on postoperative intra-abdominal adhesion formation in adult female NMRI mice. Drugs were administered from the day of surgery until 10 days after surgery. At relaparotomy 11 days after surgery, the abdomen was opened, and the adhesions were graded in a blinded fashion utilizing the classification system described. Oral gavage administration of lower doses of pentoxifylline (3.125, 6.25, and 12.5 mg/kg) had no significant effect on postsurgical adhesion formation, while the higher doses of pentoxifylline (25 and 50 mg/kg) significantly decreased postsurgical adhesion formation. Moreover, intraperitoneal injection of lower doses of streptokinase (9.375, 18.75, and 37.5 unit/kg, i.p.) had no significant effect on postsurgical adhesion formation, while the higher doses of streptokinase (75 and 150 unit/kg) significantly decreased postsurgical adhesion formation. In other series of experiments, coadministration of lower doses of pentoxifylline and streptokinase doses, which were ineffective when given alone, significantly decreased postsurgical intra-abdominal adhesion formation compared with streptokinase control group. The results suggest that pentoxifylline may interfere with streptokinase in the reduction of postoperative intra-abdominal adhesion formation by enhancing local fibrinolytic activity.     

Clinical outcome and bowel function after surgical treatment in Hirschsprung's disease

Background:

Bowel function has been reported to be adversely affected following surgery in cases of Hirschsprung. We retrospectively studied both the clinical outcome and bowel function status following surgery in patients diagnosed with Hirschprung''s disease (HD). 161 cases, who underwent pull-through operations for HD in Sheikh Pediatric Tertiary Centre, Mashhad, Iran. The specified time bracket spanned between 2006 and 2011.

Materials and Methods:

Data was extracted from Health Information System with the aim of investigating patients for both short and long-term gastrointestinal (GI) complications after surgery bases in addition to the concurrence of any associated anomalies. Three main procedures were analysed in this respect (Swenson, Duhamel and Soave).

Results:

In a study of 96 (59%) boys and 65 (40.3%) girls, mortality rate was reported to be 15.5% (15 males and 10 females). A considerable majority of almost three fourths were detected with both early and late GI complications after surgery. The latter mainly included constipation (30.8%), incontinence (19.8%), enterocolitis (8%), diarrhea (11%) in a declining order of incidence. Down syndrome and others HD-associated anomalies were detected in 3.7% and 24.3% of cases respectively.

Conclusions:

Constipation and foecal incontinence were the most prevalent postoperative complications, which were reported almost as frequent in other studies. Yet, Enterocolitis, was reported slightly less in prevalence. Also mortality rates were considerably higher, compared to developed nations.Key words: Bowel function, constipation, foecal incontinence, Hirschsprung''s disease     

Occurrence of a mosquito vector in bird houses: Developmental consequences and potential epidemiological implications

Even with continuous vector control, dengue is still a growing threat to public health in Southeast Asia. Main causes comprise difficulties in identifying productive breeding sites and inappropriate targeted chemical interventions. In this region, rural families keep live birds in backyards and dengue mosquitoes have been reported in containers in the cages. To focus on this particular breeding site, we examined the capacity of bird fecal matter (BFM) from the spotted dove, to support Aedes albopictus larval growth. The impact of BFM larval uptake on some adult fitness traits influencing vectorial capacity was also investigated. In serial bioassays involving a high and low larval density (HD and LD), BFM and larval standard food (LSF) affected differently larval development. At HD, development was longer in the BFM environment. There were no appreciable mortality differences between the two treatments, which resulted in similar pupation and adult emergence successes. BFM treatment produced a better gender balance. There were comparable levels of blood uptake and egg production in BFM and LSF females at LD; that was not the case for the HD one, which resulted in bigger adults. BFM and LSF females displayed equivalent lifespans; in males, this parameter was shorter in those derived from the BFM/LD treatment. Taken together these results suggest that bird defecations successfully support the development of Ae. albopictus. Due to their cryptic aspects, containers used to supply water to encaged birds may not have been targeted by chemical interventions.     

Genetic Characterization of Echinococcus granulosus from a Large Number of Formalin-Fixed,Paraffin-Embedded Tissue Samples of Human Isolates in Iran

Cystic echinococcosis (CE), caused by the larval stage of Echinococcus granulosus, presents an important medical and veterinary problem globally, including that in Iran. Different genotypes of E. granulosus have been reported from human isolates worldwide. This study identifies the genotype of the parasite responsible for human hydatidosis in three provinces of Iran using formalin-fixed paraffin-embedded tissue samples. In this study, 200 formalin-fixed paraffin-embedded tissue samples from human CE cases were collected from Alborz, Tehran, and Kerman provinces. Polymerase chain reaction amplification and sequencing of the partial mitochondrial cytochrome c oxidase subunit 1 gene were performed for genetic characterization of the samples. Phylogenetic analysis of the isolates from this study and reference sequences of different genotypes was done using a maximum likelihood method. In total, 54.4%, 0.8%, 1%, and 40.8% of the samples were identified as the G1, G2, G3, and G6 genotypes, respectively. The findings of the current study confirm the G1 genotype (sheep strain) to be the most prevalent genotype involved in human CE cases in Iran and indicates the high prevalence of the G6 genotype with a high infectivity for humans. Furthermore, this study illustrates the first documented human CE case in Iran infected with the G2 genotype.     

The 11-item Medication Adherence Reasons Scale: reliability and factorial validity among patients with hypertension in Malaysian primary healthcare settings

INTRODUCTION

The aim of this study was to assess the reliability and validity of a modified Malaysian version of the Medication Adherence Reasons Scale (MAR-Scale).

METHODS

In this cross-sectional study, the 15-item MAR-Scale was administered to 665 patients with hypertension who attended one of the four government primary healthcare clinics in the Hulu Langat and Klang districts of Selangor, Malaysia, between early December 2012 and end-March 2013. The construct validity was examined in two phases. Phase I consisted of translation of the MAR-Scale from English to Malay, a content validity check by an expert panel, a face validity check via a small preliminary test among patients with hypertension, and exploratory factor analysis (EFA). Phase II involved internal consistency reliability calculations and confirmatory factor analysis (CFA).

RESULTS

EFA verified five existing factors that were previously identified (i.e. issues with medication management, multiple medications, belief in medication, medication availability, and the patient’s forgetfulness and convenience), while CFA extracted four factors (medication availability issues were not extracted). The final modified MAR-Scale model, which had 11 items and a four-factor structure, provided good evidence of convergent and discriminant validities. Cronbach’s alpha coefficient was > 0.7, indicating good internal consistency of the items in the construct. The results suggest that the modified MAR-Scale has good internal consistencies and construct validity.

CONCLUSION

The validated modified MAR-Scale (Malaysian version) was found to be suitable for use among patients with hypertension receiving treatment in primary healthcare settings. However, the comprehensive measurement of other factors that can also lead to non-adherence requires further exploration.     

Correlation between expression of MMP-9 and MMP-3 in Helicobacter pylori infected patients with different gastroduodenal diseases

Background and study aims

Helicobacter pylori (H. pylori) has been implicated in the pathogenesis of most important gastro-duodenal diseases, such as gastritis, peptic ulcer disease (PUD) and gastric cancer. H. pylori upregulates the expression and activity of several matrix metalloproteinases (MMPs) in the gastric mucosa, but the role of MMP-3 and MMP-9 in infected patients with H. pylori have not been clearly defined yet. We examined mucosal MMP-3 and MMP-9 mRNA levels in gastric mucosa of H. pylori infected patients and evaluated the effects of virulence factors cagA and vacA allelic variants on these levels. We also determined correlation between mucosal MMP-3 and MMP-9 mRNA levels and types of disease.

Hb Dhonburi (Neapolis) [beta126(H4)Val-->Gly] identified in a family from northern Iran

Thalassemias are the most common hereditary diseases in Iran, resulting from synthesis defects in one or more hemoglobin (Hb) subunits. The majority of patients suffer from beta-thalassemia (thal), but cases with microcytic hypochromic anemia and normal electrophoretic patterns are suspected to have alpha- or silent beta-thal. A family from the northern part of Iran, an area highly prevalent for thalassemias, was referred to us for prenatal diagnosis. The hematological data of the father indicated a pattern of beta-thal minor. Reverse hybridization analysis for the most common beta-globin mutations identified IVS-II-1 (G-->A) in the heterozygous state. The maternal laboratory data indicated a case more compatible with alpha-thal. Iron deficient anemia was ruled out, and common alpha-thal point mutations and deletions were investigated. As no mutation was detected, chain synthesis was performed and showed an alpha/beta chain ratio of 2.1, that was in the range of beta-thal minor. DNA sequencing of the entire beta-globin gene identified a heterozygous GTG-->GGG (Val-->Gly) mutation at codon 126, also known as Hb Dhonburi (Neapolis). Prenatal diagnosis of the fetal DNA showed the absence of the IVS-II-1 and codon 126 anomalies. This result demonstrates the importance of screening of individuals with mild microcytic hypochromic anemia for both alpha- and silent beta-thal mutations.     

Optimal β-blocker for prevention of atrial fibrillation after on-pump coronary artery bypass graft surgery: Carvedilol versus metoprolol

BACKGROUND: Atrial fibrillation (AF) is the most common arrhythmia after coronary artery bypass graft (CABG) surgery. It has been shown that prophylactic oral beta-blocker administration reduces the incidence of post-CABG AF. However, the optimal beta-blocker has not been identified. OBJECTIVE: This study sought to determine whether oral carvedilol (with its unique anti-inflammatory and antioxidant properties) is more effective than oral metoprolol for prevention of AF after CABG surgery. METHODS: Between April 2006 and December 2006, 120 patients (63 men, mean age 61 +/- 9.4 years) who were scheduled to undergo their first on-pump CABG were enrolled in this study. The patients were randomized in a prospective 1:1 manner to receive either oral carvedilol (n = 60) or oral metoprolol (n = 60). The end point of the study was the occurrence of the new-onset AF during the first 5 days after CABG. RESULTS: AF occurred in 29 of 120 patients (24.0%). The incidence of postoperative AF was 15.0% (9 of 60) in the carvedilol group and 33% (20 of 60) in the metoprolol group (P = .022). The carvedilol group was treated with mean daily dose of 46 +/- 9 mg and metoprolol group with mean daily dose of 93 +/- 11 mg. There were no differences between the study groups regarding any known preoperative, perioperative, or postoperative characteristics (all values were P >.05). No significant adverse effect was observed in either group. CONCLUSION: This prospective study suggested that oral carvedilol is more effective than oral metoprolol in the prevention of AF after on-pump CABG. It is well tolerated when started before and continued after the surgery. However, further prospective studies are needed to clarify this issue.