Identification of 5-(3-(methylsulfonyl)phenyl)-3-(4-(methylsulfonyl)phenyl)-3H-imidazo[4,5-b]pyridine as novel orally bioavailable and metabolically stable antimalarial compound for further exploration

Malaria continues to be a significant public health problem threatened by the emergence and spread of resistance to artemisinin-based combination therapies and marked half a million deaths in 2016. A new imidazopyridine chemotype has been envisaged through scaffold-hopping approach combined with docking studies for putative-binding interactions with Plasmodium falciparum phosphatidylinositol-4-kinase (PfPI4K) target. The docking results steered to the synthesis of compound 1 [5-(3-(methylsulfonyl)phenyl)-3-(4-(methylsulfonyl)phenyl)-3H-imidazo[4,5-b]pyridine] followed by the in vitro screening for antiplasmodial activity and ADME-PK studies. Combined with potent antimalarial activity of compound 1 (Pf3D7 IC₅₀ = 29 nM) with meager in vitro intrinsic clearance, moderate plasma-protein binding, and acceptable permeability, compound 1 displayed sustained exposure and high oral bioavailability in mice and can thus have the potential as next generation PI4K inhibitor for in vivo studies.     

Role of Intraoperative Esophagogastroenteroscopy in Minimizing Gastrojejunostomy-Related Morbidity: Experience with 2,311 Laparoscopic Gastric Bypasses with Linear Stapler Anastomosis

Background

Anastomotic leaks and strictures of the gastrojejunostomy are a cause of major morbidity following laparoscopic Roux-en-Y gastric bypass (LRYGB). Reported rates of leaks vary between 0 and 5.2 %. This has led bariatric surgeons to use a variety of intraoperative methods to detect incompetent suture lines. The aim of the study was to evaluate the role of intraoperative endoscopy in reducing the rate of postoperative anastomotic complications. The setting of this study is in a community teaching hospital.

Methods

Medical records of 2,311 patients who underwent a LRYGB from 2002 to 2011 were retrospectively reviewed utilizing the hospitals’ bariatric surgery database. Demographics, weight, body mass index, intraoperative endoscopy results, and postoperative outcomes within 90 days after surgery were analyzed.

Results

Endoscopy was attempted in 2,311 patients and completed in 2,308 (99.9 %). Intraoperative leak was detected in 80 (3.5 %) patients; suture line was reinforced in 46 patients (2 %), while in the other 34 patients the leak was transient at only high insufflation pressure. Postoperative clinical leaks were detected in four cases (0.2 %) two of which had initial leaks intraoperatively. In two cases, the anastomosis was too tight and required reconstruction. Twenty-five patients (1.1 %) developed early postoperative strictures requiring endoscopic dilatation within 90 days. Three patients (0.1 %) had iatrogenic injury at the time of intraoperative endoscopy, all three healed without delayed morbidity.

Conclusions

The routine use of intraoperative endoscopy in LRYGB with the linear stapler anastomosis technique is associated with a complication/failure rate of 0.3 % and low gastrojejunostomy-related morbidity after LRYGB within 90 days (leak rate of 0.2 % and stricture rate of 1.1 %).     

Declining incidence of osteoporotic hip fracture in Australia

Summary

Between 1997?C1998 and 2006?C2007 in Australia, the age-standardised incidence rates of hip fractures declined by 20 and 13?%, in females and males, respectively. Although this may be related to the rollout of public health campaigns and strategies addressing osteoporosis, absolute numbers of hip fractures continued to increase.

Background

Previous reports described an increasing trend in osteoporotic hip fracture incidence in Australia in the 1980s with a stabilisation over the 1990s.

Aim

The aim of this study was to describe national trends in the incidence of osteoporotic hip fracture in Australia between 1997?C1998 and 2006?C2007.

Methods

Data on low-trauma hip fractures in persons aged 50?years and over were obtained from the National Hospital Morbidity Database. Cases where the patient was transferred in from another hospital were excluded. Age-standardised incidence rates were calculated and a linear test for trend applied.

Results

Although the absolute number of hip fracture cases has continued to increase, from 14,769 in 1997?C1998 to 16,412 in 2006?C2007, these numbers are lower than previous predictions based on population ageing. Over the 10-year period, the age-standardised incidence rates in females declined by 20?%, from 370 to 295 per 100,000, while the age-standardised incidence rates in males declined by 13?%, from 200 to 174 per 100,000. Both declines were statistically significant. The sex difference in incidence rates narrowed between 1997?C1998 (females 85?% higher) and 2006?C2007 (females 70?% higher).

Conclusions

The age-standardised incidence of osteoporotic hip fracture in Australia is falling. This may be related to the uptake of bisphosphonates as well as the rollout of public health campaigns and strategies addressing osteoporosis.     

Gallstone abscess as a result of dropped gallstones during laparoscopic cholecystectomy

INTRODUCTIONWith the advent of laparoscopic cholecystectomy we have seen a “disease of medical progress” (DOMP). Herein we report a complication that developed 7 years after laparoscopic cholecystectomy.PRESENTATION OF CASEA 42 year old woman presented with worsening right-sided pain and tenderness. Seven years prior she underwent a laparoscopic cholecystectomy. Computed tomography demonstrated a subhepatic retroperitoneal inflammatory mass. On open exploration a 4 cm × 6 cm retroperitoneal mass was excised. The mass contained purulent material and gallstones.DISCUSSIONLaparoscopic cholecystectomy has become the “gold standard” for the treatment of symptomatic gallstones. Prior to laparoscopic cholecystectomy there was no body of literature about lost gallstones thus making this a DOMP. In contrast, it is reported that as many as 5.4–19% of laparoscopic cholecystectomies have stones spilled with variable rates of retrieval. Our case demonstrates an extreme example of a complication resulting seven years after a laparoscopic cholecystectomy with gallstones left behind.CONCLUSIONRecognizing that gallstones will be lost during some cases of laparoscopic cholecystectomy, we must remain vigilant and make a full attempt to retrieve all stones to prevent such rare but not insignificant potential complications.     

Molecular characterization,isolation, pathology and pathotyping of peafowl (Pavo cristatus) origin Newcastle disease virus isolates recovered from disease outbreaks in three states of India

Disease outbreak investigations were carried out in three states of Northern India namely Haryana (Rewari), Uttar Pradesh (Noida) and Delhi, where a total of 110 Indian peafowls (Pavo cristatus) showed sudden onset of nervous signs and died within a period of two weeks during June, 2012. The F (fusion) gene-based RT-PCR detection of Newcastle disease virus (NDV) in affected tissues confirmed the presence of the virus. Three NDV isolates were selected (one from each area under investigation) and further characterized. They were found to be of virulent pathotype (velogenic NDV) based on both pathogenicity assays (MDT, ICPI and IVPI) and partial F gene sequence analysis. Additionally, the phylogenetic analysis revealed that the isolates belonged to the genotype VIIi and XIII of class II avian Paramyxovirus serotype1 (APMV-1) and related closely to new emerging sub-genotypes. This is the first report regarding the presence of the fifth panzootic vNDV genotype VIIi from India. In this scenario, extensive epidemiological studies are suggested for surveillance of NDV genotypes in wild birds and poultry flocks of the country along with adopting suitable prevention and control measures.     

Redox modulatory protective effects of ω-3 fatty acids rich fish oil against experimental colitis

Ulcerative colitis (UC), a form of inflammatory bowel disease (IBD), is an immune-modulated disorder characterized by chronic and recurring inflammatory episodes. Oxidative stress and COX pathway of prostaglandin (PG) biosynthesis are indispensable to pathogenesis of UC. Any imbalance between PGs can compromise the mucosal homeostasis, leading to mucosal damage and chronic inflammation. However, blocking these PGs using classical Cox inhibitors such as non-steroidal anti-inflammatory drugs (NSAIDs) can instead aggravate signs of IBD. Therefore, realizing the need for safer and well tolerable alterative treatment approaches, currently, we evaluated the efficacy of n-3 fatty acids rich fish oil (FO) in the resolution of UC. Using a dextran sodium sulfate (DSS) model of experimental colitis, we have demonstrated that supplementation of FO containing 180?mg EPA and 120?mg DHA for 1 month relieved the signs (diarrhea, bloody stools, weight loss) of colitis-associated inflammation. To understand the biophysical changes associated with FO mediated inflammatory regulation, impedance measurement and Fourier transform infrared spectroscopy (FTIR) were done. These changes were also correlated with oxidative stress through markers such as GST, glutathione peroxidase (GPx), LPO, catalase, protein carbonyl content, GR, etc. in colonic mucosa. The modulation of COX mediated pathways in UC-associated inflammation was observed by protein expressions of various pro-inflammatory cytokines such as TNF-α and enzymes of PG synthesis such as COX-2, PGES, TXAS, and anti-inflammatory PGDS. Refuting the earlier reports that suggested the contradictory effects of FO, in the current study, we evidently demonstrated that the protective effects of FO are mediated through molecular mechanisms involving the redox-regulation of metabolism of key lipid metabolites.     

Immunopathology and immunotherapeutic strategies in severe acute respiratory syndrome coronavirus 2 infection

The outbreak of coronavirus disease 2019 (COVID‐19) and pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), has become a major concern globally. As of 14 April 2020, more than 1.9 million COVID‐19 cases have been reported in 185 countries. Some patients with COVID‐19 develop severe clinical manifestations, while others show mild symptoms, suggesting that dysregulation of the host immune response contributes to disease progression and severity. In this review, we have summarized and discussed recent immunological studies focusing on the response of the host immune system and the immunopathology of SARS‐CoV‐2 infection as well as immunotherapeutic strategies for COVID‐19. Immune evasion by SARS‐CoV‐2, functional exhaustion of lymphocytes, and cytokine storm have been discussed as part of immunopathology mechanisms in SARS‐CoV‐2 infection. Some potential immunotherapeutic strategies to control the progression of COVID‐19, such as passive antibody therapy and use of interferon αβ and IL‐6 receptor (IL‐6R) inhibitor, have also been discussed. This may help us to understand the immune status of patients with COVID‐19, particularly those with severe clinical presentation, and form a basis for further immunotherapeutic investigations.     

Ultrasonographic estimation of fetal gestational age by fetal kidney length

Introduction: Fetal kidney length vs biparietal diameter (BPD) and femur length (FL) were comparatively evaluated and the role of fetal kidney length in estimating gestational age was determined in the second and third trimesters. Materials and methods: The study was carried out on 199 women with singleton uncomplicated pregnancies attending the outdoor patient department (OPD) for routine ultrasound fetal biometry. Fetal kidney length was measured biweekly, between 18 weeks and 38 weeks of gestation. Linear regression models for estimation of gestational age were derived from biometric indices (BPD and FL) and kidney length. Result: The earliest age at which fetal kidney could be seen sonographically was the 18th week of gestation with the mean kidney length of 12 ± 1.31 mm. The mean sonographic kidney length at the 38th week of gestation was 40.4 ± 1.71 mm, indicating that the mean fetal kidney length increases as pregnancy progresses from 18 weeks to 38 weeks of gestation. Conclusion: The best linear regression model for estimating fetal gestational age is femur length, kidney length, and biparietal diameter in that order, with standard error of ±3.85 days, ±8.04 days, and ±8.75 days, respectively.