Neem leaf glycoprotein overcomes indoleamine 2,3 dioxygenase mediated tolerance in dendritic cells by attenuating hyperactive regulatory T cells in cervical cancer stage IIIB patients

Tolerogenic dendritic cells (DCs) are a subset of DCs characterized by abundant indoleamine 2,3 dioxygenase (IDO) expressions. IDO may be co-operatively induced in DCs by regulatory T (Tregs) cells and various DC maturation agents. Tregs are markedly amplified in the physiological system of cancer patients, inducing over tolerance in DCs that leads to the hyper accumulation of immunosuppressive IDO in tumor microenvironment, thereby, hampering anti-tumor immunity. Consequently, a major focus of current immunotherapeutic strategies in cancer is to minimize IDO, which is possible by reducing Tregs and using various IDO inhibitors. Neem leaf glycoprotein (NLGP), a natural and nontoxic immunomodulator, demonstrated several unique immunoregulatory activities. Noteworthy activities of NLGP are to mature DCs and to inhibit Tregs. As Tregs are inducer of IDO in DCs and hyperactive Tregs is a hallmark of cancer, we anticipated that NLGP might abrogate IDO induction in DCs by inhibiting Tregs. Evidences are presented here that in a co-culture of DCs and Tregs isolated from cervical cancer stage IIIB (CaCx-IIIB) patients, NLGP does inhibit IDO induction in DCs by curtailing the over expression of Cytotoxic T-Lymphocyte Antigen 4 (CTLA4) on Tregs and concomitantly induces optimal DC maturation. In contrast, in the presence of LPS as maturation agent the DCs displays a tolerogenic profile. This finding suggests the reduction of tolerogenecity of DCs in CaCx-IIIB patients by reducing the IDO pool using NLGP. Accordingly, this study sheds more light on the diverse immunomodulatory repertoire of NLGP.     

A 21st century approach to tackling dengue: Crowdsourced surveillance,predictive mapping and tailored communication

This paper describes a social media system to prevent dengue in Sri Lanka and potentially in the rest of the South and Southeast Asia regions. The system integrates three concepts of public health prevention that have thus far been implemented only in silos. First, the predictive surveillance component uses a computer simulation to forewarn health authorities and the general public about impending disease outbreaks. The civic engagement component allows the general public to use social media tools to interact and engage with health authorities by aiding them in surveillance efforts by reporting symptoms, mosquito bites and breeding sites using smartphone technologies. The health communication component utilizes citizen data gathered from the first two components to disseminate customized health awareness messages to enhance knowledge and increase preventive behaviors among citizens. The system, known as “Mo-Buzz,” will be made available on a host of digital platforms like simple mobile phones, smart phones and a website. We present challenges and lessons learnt including content validation, stakeholder collaborations and applied trans-disciplinary research.     

Amelioratory effect of Andrographis paniculata Nees on liver, kidney, heart, lung and spleen during nicotine induced oxidative stress

The ameliorative properties of bioactive compound andrographolide (ANDRO), aqueous extract of Andrographis paniculata (AE-AP) and vitamin E (vit.E) were tested against nicotine induced liver, kidney, heart, lung and spleen toxicity. A group of male Wistar rats were intraperitoneally administered vehicle, nicotine (1 mg/kg body weight/day), nicotine + ANDRO (250 mg/kg body weight/day), nicotine + AE-AP (250 mg/kg body weight/day) and nicotine + vit.E (50 mg/kg body weight/day) for the period of 7 days. The significantly increased levels of lipid peroxidation, protein oxidation and the decreased antioxidant enzyme status were noted in nicotine treated group as compared to vehicle treated group. ANDRO, AE-AP and vit.E significantly reduced the lipid peroxidation, protein oxidation and increased the antioxidant enzyme status. This indicates A. paniculata and vit.E may act as putative protective agent against nicotine induced tissue injury and may pave a new path to develop suitable drug therapy.     

The influence of preoperative dialysis on survival after continuous-flow left ventricular assist device implantation

 Open in a separate windowOBJECTIVESDialysis is considered a contraindication to continuous-flow left ventricular assist device (CF-LVAD) implantation. We evaluated clinical outcomes and survival in carefully selected, low-risk patients with renal failure who required dialysis before CF-LVAD implantation.METHODSWe extracted medical record data of patients who underwent CF-LVAD placement at our centre between 1 January 2006 and 31 August 2017, with 2 clinical scenarios: those who required long-term (>14 days) dialysis and those who required short-term (≤14 days) dialysis immediately before implantation. Demographic, clinical and intraoperative characteristics and survival outcomes were assessed.RESULTSOf 621 patients who underwent CF-LVAD implantation during the study period, 31 underwent dialysis beforehand. Of these, 17 required long-term dialysis (13 haemodialysis, 4 peritoneal dialysis), and 14 underwent short-term haemodialysis. Compared with the long-term dialysis patients, the short-term dialysis patients were more likely to be Interagency Registry for Mechanically Assisted Circulatory Support profile 1–2 (92.9% vs 70.6%; P < 0.001), to have needed preoperative mechanical circulatory support (78.6% vs 70.6%; P < 0.01) and to have higher in-hospital mortality (85.7% vs 29.4%; P = 0.01). Patients stable on long-term dialysis had acceptable overall survival and markedly better 6-month and 1-year survival than those with short-term dialysis before implantation (64.7% vs 14.3% and 58.8% vs 7.1%, respectively; P < 0.001).CONCLUSIONSCarefully selected patients who are stable on long-term dialysis have acceptable survival rates after CF-LVAD implantation. Patients with acute renal failure had much poorer outcomes than those with chronic end-stage renal disease.     

Defective signal transduction in B lymphocytes lacking presenilin proteins

The mammalian presenilin (PS) proteins mediate the posttranslational cleavage of several protein substrates, including amyloid precursor protein, Notch family members, and CD44, but they have also been suggested to function in diverse cellular processes, including calcium-dependent signaling and apoptosis. We carried out an integrative computational study of multiple genomic datasets, including RNA expression, protein interaction, and pathway analyses, which implicated PS proteins in Toll-like receptor signaling. To test these computational predictions, we analyzed mice carrying a conditional allele of PS1 and a germ line-inactivating allele of PS2, together with Cre site-specific recombinase expression under the influence of CD19 control sequences. Notably, B cells deficient in both PS1 and PS2 function have an unexpected and substantial deficit in both lipopolysaccharide and B cell antigen receptor-induced proliferation and signal transduction events, including a defect in anti-IgM-mediated calcium flux. Taken together, these results demonstrate a fundamental and unanticipated role for PS proteins in B cell function and emphasize the potency of (systems level) integrative analysis of whole-genome datasets in identifying novel biologic signal transduction relationships. Our findings also suggest that pharmacologic inhibition of PS for the treatment of conditions such as Alzheimer's disease may have potential consequences for immune system function.     

Metachronous Occurrence of Multifocal Phaeochromocytoma

The authors report an 8-yr-old boy who presented with hypertension, psychosis, and visual disturbances due to a left adrenal phaeochromocytoma which was excised. After 4 years, the child developed multifocal phaeochromocytomas in the left suprarenal area, right adrenal gland, and left para-aortic region. The tumors were excised along with re-implantation of normal adrenal tissue from the right adrenal into the omentum. The course of the disease and the family history were suggestive of von Hippel-Lindau (VHL) disease.     

In vitro-in vivo correlation and bioavailability studies of captopril from novel controlled release donut shaped tablet

A controlled release formulation of captopril which was coated and fabricated into a donut shaped tablet formulation, was investigated in rabbit for pharmacokinetic and in vitro-in vivo correlation studies. Coated donut shaped tablets were prepared and in vitro release was studied in simulated gastric fluid at three different RPMs. New Zealand albino male rabbits have been used as animal model for in vivo study. A sensitive and simple HPLC method was developed for the determination of captopril content in rabbit plasma. In vitro release studies showed that release patterns followed zero order for around 4 h. Single oral administration of coated donut shaped tablets in rabbit illustrated retained availability of captopril to the injected drug. Captopril content could pursue the same release pattern over the same time course in in vivo study. The in vivo-in vitro correlation coefficients obtained from point-to-point analysis were greater than 99% between concentrations at certain time points obtained from release study in simulated gastric fluid at different RPMs and HPLC analysis of rabbit's plasma. From the in vitro-in vivo correlation prediction it was evident that the coated donut shaped tablet is a good device for controlled delivery of captopril.