Imidazo[2,1-b]thiazole based indoleamine-2,3-dioxygenase 1 (IDO1) inhibitor: Structure based design, synthesis, bio-evaluation and docking studies.

Indoleamine-2,3-dioxygenase 1 (IDO1) is an immunomodulatory enzyme known to catalyse the initial and rate limiting step of kynurenine pathway of l-tryptophan metabolism. IDO1 enzyme over expression plays a crucial role in progression of cancer, malaria, multiple sclerosis and other life-threatening diseases. Several efforts over the last two decades have been invested by the researchers for the discovery of different IDO1 inhibitors and the plasticity of the IDO1 enzyme ligand binding pocket provide ample opportunities to develop new heterocyclic scaffolds targeting this enzyme. In the present work, based on the X-ray crystal structure of human IDO1 coordinated with few ligands, we designed and synthesized new fused heterocyclic compounds and evaluated their potential human IDO1 inhibitory activity (compound 30 and 41 showed IC50 values of 23 and 13 µM, respectively). The identified HITs were observed to be non-toxic to HEK293 cells at 100 µM concentration. The observed activity of the synthesized compounds was correlated with the specific interactions of their structures at the enzyme pocket using docking studies. A detailed analysis of docking results of the synthesized analogues as well as selected known IDO1 inhibitors revealed that most of the inhibitors have some reasonable docking scores in at least two crystal structures and have similar orientation as that of co-crystal ligands.

Poly-(Lactic-co-Glycolic) Acid Nanoparticles for Synergistic Delivery of Epirubicin and Paclitaxel to Human Lung Cancer Cells.

Combination therapy using chemically distinct drugs has appeared as one of the promising strategies to improve anticancer treatment efficiency. In the present investigation, poly-(lactic-co-glycolic) acid (PLGA) nanoparticles electrostatically conjugated with polyethylenimine (PEI)-based co-delivery system for epirubicin and paclitaxel (PLGA-PEI-EPI-PTX NPs) has been developed. The PLGA-PEI-EPI-PTX NPs exhibited a monodispersed size distribution with an average size of 240.93 ± 12.70 nm as measured through DLS and 70.8-145 nm using AFM. The zeta potential of 41.95 ± 0.65 mV from -17.45 ± 2.15 mV further confirmed the colloidal stability and PEI modification on PLGA nanoparticles. Encapsulation and loading efficiency along with in vitro release of drug for nanoparticles were done spectrophotometrically. The FTIR analysis of PLGA-PEI-EPI-PTX NPs revealed the involvement of amide moiety between polymer PLGA and PEI. The effect of nanoparticles on the cell migration was also corroborated through wound healing assay. The MTT assay demonstrated that PLGA-PEI-EPI-PTX NPs exhibited considerable anticancer potential as compared to the naïve drugs. Further, p53 protein expression analysed through western blot showed enhanced expression. This study suggests that combination therapy using PLGA-PEI-EPI-PTX NPs represent a potential approach and could offer clinical benefits in the future for lung cancer patients.

Versatile biomedical potential of biosynthesized silver nanoparticles from Acacia nilotica bark.

The present study reports the development of potent silver nanoparticles (AgNPs) using bark extract of Acacia nilotica and evaluation of its wound healing, anti-biofilm, anti-cancer and anti-microbial activity. Stable, small sized nanoparticles with spherical morphology were obtained after significant optimization studies that was evaluated through UV-visible spectroscopy. Thereafter, physicochemical characterization of biosynthesized AgNPs was carried out through DLS and FESEM for evaluation of size. EDAX and FTIR were carried out for the evaluation of composition and possible functional groups involved in the reduction and capping of AgNPs. The antibacterial potential was investigated through disc diffusion assay against Escherichia coli (E. coli) and Pseudomonas aeruginosa (P. aeruginosa). Further, the Congo Red Assay (CRA) successfully revealed the anti-biofilm activity against Bacillus subtilis (B. subtilis), Staphylococcus aureus (S. aureus), Proteus vulgaris (P. vulgaris), Pseudomonas aeruginosa (P. aeruginosa). Alamar blue assay was conducted in A549 cells to reveal the remarkable anticancer activity of biosynthesized AgNPs that resulted in a very appreciable manner. Further, the wound healing activity of AgNPs can heal the excised wound of mice up-to 100% within 15 days. All these studies suggested that our biosynthesized AgNPs possess versatile biomedical application.

Association of ITGAM, TNFSF4, TNFAIP3 and STAT4 gene polymorphisms with risk of systemic lupus erythematosus in a North Indian population.

Several susceptibility genes have been associated with systemic lupus erythematosus (SLE) across different populations worldwide. However, data on association between genetic polymorphisms and SLE from Indian population is scarce. We aimed to replicate the association of single nucleotide polymorphisms (SNPs) in ITGAM, TNFSF4, TNFAIP3 and STAT4 genes with susceptibility to SLE in a North Indian population. Three hundred and ninety-four SLE patients and 583 unrelated healthy controls of the same ethnic background were enrolled. All samples were genotyped for SNPs in ITGAM (rs1143679), TNFSF4 (rs2205960), TNFAIP3 (rs5029939) and STAT4 (rs7574865) using TaqMan genotyping assay. At allele level, significant association with susceptibility to SLE was detected with polymorphisms in ITGAM (A vs. G, odds ratio (OR) = 1.73, 95% confidence interval (CI) = 1.30-2.30, p < 0.001), TNFSF4 (T vs. G, OR = 1.33, 95% CI = 1.08-1.64, p < 0.01), TNFAIP3 (G vs. C, OR = 1.91, 95% CI = 1.27-2.85, p < 0.01) and STAT4 (T vs. G, OR = 1.38, 95% CI = 1.13-1.69, p < 0.01). All four SNPs were associated with SLE under a dominant model with an OR of 1.47 (95% CI = 1.07-2.04, p < 0.05) for ITGAM, 1.30 (95% CI = 1.01-1.69, p < 0.05) for TNFSF4, 1.90 (95% CI = 1.25-2.90, p < 0.01) for TNFAIP3 and 1.38 (95% CI = 1.06-1.78, p < 0.05) for STAT4. Under a recessive model, significant association was found with ITGAM (OR = 4.87, 95% CI = 2.17-10.91, p < 0.001), TNFSF4 (OR = 1.84, 95% CI = 1.13-3.00, p < 0.05) and STAT4 (OR = 1.82, 95% CI = 1.19-2.77, p < 0.01). In conclusion, single nucleotide polymorphisms in ITGAM, TNFSF4, TNFAIP3 and STAT4 genes are associated with susceptibility to SLE in a North Indian population.

Pattern of physical activity and associated sociodemographic factors: A community based study using Global Physical Activity questionnaire

Introduction: Non-communicable diseases (NCDs) account for nearly half of the overall global burden of disease. Physical inactivity has been reported to be a major independent "modifiable" risk factor for NCDs. Assessment of pattern of physical activity and associated factors would help in informing the participants and policy makers for appropriate interventions. Methodology: A community based cross sectional study in Doiwala block of Dehradun district, in a state of north India, was conducted among early middle-aged adults i.e., 30-50 years of age. Based on the prevalence of 26.1% recommended physical activity, the sample size was calculated to be 296. Standard Global Physical activity questionnaire (GPAQ) was used to assess physical activity pattern. Results: Mean age of the respondents was 39 years. The proportion of people engaged in vigorous activities, at work or for recreation was only 8.5%. Moderate activity at work (16.7% vs 9.5%) and walking/ bicycling while travel to and from places (63.9% vs 38.5%) was more common in rural areas as compared to urban areas. Moderate activity for recreation was however more common in urban areas (31.8% vs 14.6%). Sedentary habits of women in urban areas were unhealthier as compared to women in rural areas as well as men in urban areas. Conclusions: Integration of physical activity at work of people engaged in skilled and professional jobs by instituting minor modifications in the working environment is recommended.

Spatial Fuzzy C Means and Expectation Maximization Algorithms with Bias Correction for Segmentation of MR Brain Images.

The Fuzzy C Means (FCM) and Expectation Maximization (EM) algorithms are the most prevalent methods for automatic segmentation of MR brain images into three classes Gray Matter (GM), White Matter (WM) and Cerebrospinal Fluid (CSF). The major difficulties associated with these conventional methods for MR brain image segmentation are the Intensity Non-uniformity (INU) and noise. In this paper, EM and FCM with spatial information and bias correction are proposed to overcome these effects. The spatial information is incorporated by convolving the posterior probability during E-Step of the EM algorithm with mean filter. Also, a method of pixel re-labeling is included to improve the segmentation accuracy. The proposed method is validated by extensive experiments on both simulated and real brain images from standard database. Quantitative and qualitative results depict that the method is superior to the conventional methods by around 25% and over the state-of-the art method by 8%.

Anti-inflammatory effect of dikaempferol rhamnopyranoside, a diflavonoid from Eugenia jambolana Lam. Leaves.

Traditionally, the Indian Blackberry or locally called Jamun, Eugenia jambolana Lam. (Syn.: Syzygium cumini), is well known for its pharmacological potential, particularly anti-inflammatory. Here, we studied kaempferol-7-O-α-L-rhamnopyranoside]-4'-O-4'- [kaempferol-7-O-α-L-rhamnopyranoside (EJ-01) isolated from the E. jambolana leaves for possible anti-inflammatory activity. EJ-01 (3, 10 and 30 mg/kg, p.o.) was assessed for anti-inflammatory activity using carrageenan-induced paw edema model in mice by determining edema volume, myeloperoxidase (MPO), nitrite plus nitrate (NOx) and cytokine levels in paw edema tissue. EJ-01 significantly attenuated the edema, MPO levels, tumor necrosis factor-alpha (TNF-α) and interleukin-1beta (IL-1ß) levels in the edema of paw at the 5th hour after carrageenan injection at all doses. EJ-01 (30 mg/kg) decreased the nitric oxide (NO) levels of the edema of paw at the 5th hour after carrageenan injection. The anti-inflammatory mechanisms of EJ-01 might be related to the decrease in the level of edema paw by reduced activities of NO and MPO. It probably exerts anti-inflammatory effects through the suppression of TNF-α and IL-1ß. Therefore, we conclude that EJ-01 could be positively exploited for itspotential benefits against inflammatory diseases and support the pharmacological basis of E. jambolana as traditional herbal medicine for the treatment of inflammatory diseases.

Sofosbuvir and simeprevir combination therapy in the setting of liver transplantation and hemodialysis.

We report safety, tolerability, and 12-week sustained virologic response with half-standard dose sofosbuvir and standard-dose simeprevir combination therapy in a hepatitis C virus genotype 1a-infected liver transplant recipient on hemodialysis - uncharted territory for sofosbuvir-based therapy. The patient was a non-responder to prior treatment with pegylated interferon plus ribavirin. Sofosbuvir efficacy was maintained despite pill-splitting and administration of half-standard dose, 200 mg per day. No drug-drug interactions were noted with tacrolimus-based immunosuppression. Laboratory tests remained stable or improved during therapy. Our observation, if reproduced in a larger study, may lead to significant improvement in clinical outcomes and cost savings in this patient population.

Efficacy and tolerance of papain gel with conventional drilling method: a clinico-microbiological study.

BACKGROUND: Conventional methods of caries removal are commonly associated with pain, fear and discomfort. Chemomechanical methods were introduced to instill a positive dental attitude. Agents like GK-101, Caridex, Carisolv did not prove effective alternatives owing to their high cost, need of special instruments and taste of chlorine. A new chemomechanical agent, Papacarie®, has been introduced to overcome these deficiencies. OBJECTIVE: This study was aimed to compare the effectiveness and tolerance of Papacárie® with the conventional method. METHOD: 25 children with at least two primary teeth with broad cavitated occlusal or cervical lesion were selected. One carious tooth from each patient was randomly treated with each of Papacarie® and conventional drilling method, one after the other. Time taken for caries excavation, child's pain perception, change in anxiety levels, microbial flora and child's preference of treatment were recorded separately for both the methods. RESULT: Although the mean time taken for caries removal by the Papacarie® method was slightly longer (P≯0.05) but it led to reduction in pain and anxiety (p<0.05). The viable bacterial counts were significantly reduced by either of the two methods (P <0�0001). More patients preferred Papacarie® over conventional method of treatment (P<0.05). CONCLUSION: Papacárie® method seems to be a better alternative to conventional method of caries removal.

Novel mutations in typical and atypical genetic loci through exome sequencing in autosomal recessive cerebellar ataxia families.

Nearly a thousand mutations mapping to 60 different loci have been identified in cerebellar ataxias. However, almost 50% of the cases remain genetically uncharacterized and there is a difference in prevalence as well as in the phenotypic spectrum of ataxia among various geographical regions. This poses a challenge for setting up a genetic panel for screening ataxia. In our ataxic cohort of 1014 families, 61% are genetically uncharacterized (UC). We investigated the potential of whole exome sequencing in conjunction with homozygosity mapping (HM) to delineate the genetic defects in three uncharacterized families with recessive inheritance each manifesting some unusual phenotype: (i) infantile onset ataxia with hearing loss (IOAH), (ii) Juvenile onset cerebellar ataxia with seizures (JCS) and (iii) Friedreich ataxia-like (FA-like). We identified a novel missense mutation in c10orf2 in the family with IOAH, compound heterozygous mutations in CLN6 in the family with JCS and a homozygous frame-shift mutation in SACS in the FA-like patient. Phenotypes observed in our families were concordant with reported phenotypes of known mutations in the same genes thus obviating the need for functional validation. Our study revealed novel variations in three genes, c10orf2, CLN6, and SACS, that have so far not been reported in India. This study also demonstrates the utility of whole exome screening in clinics for early diagnosis.

Multi-instance learning attention model for amyloid quantification of brain sub regions in longitudinal cognitive decline.

Amyloid PET scans help in identifying the beta-amyloid deposition in different brain regions. The purpose of this study is to develop a deep learning model that can automate the task of finding amyloid deposition in different regions of the brain only by using PET scan and without the corresponding MRI scan. 2647 18F-Florbetapir PET scans are collected from Alzheimer's Disease Neuroimaging Initiative (ADNI) from multiple centres taken over a period. A deep learning model based on multi-instance learning and attention is proposed which is trained and validated using 80% of the scans and the remaining 20% of the scans are used for testing the model. The performance of the model is validated using Mean Absolute Error (MAE) and Root Mean Squared Error (RMSE). The proposed model is further tested upon an external dataset consisting of 1413 18F-Florbetapir PET scans from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's (A4) study. The proposed model achieves MAE of 0.0243 and RMSE of 0.0320 for summary Standardized Uptake Value Ratio (SUVR) based on composite reference region for ADNI test set. When tested on the A4-study dataset, the proposed model achieves MAE of 0.038 and RMSE of 0.0495 for summary SUVR based on the composite region. The results show that the proposed model provides less MAE and RMSE when compared with existing models. A graphical user interface is developed based on the proposed model where the predictions are made by selecting the files of 18F-Florbetapir PET scans.

Surgical Outcome in Patients with Traumatic and Atraumatic Optic Neuropathy Following Endoscopic Optic Nerve Decompression.

Endoscopic optic nerve decompression is a highly effective and reliable approach for patients with select cases of optic neuropathy. It reduces the hydrostatic pressure and helps in relieving the compressive forces within the intracanalicular portion of the optic nerve consequently preserving and arresting the deterioration of vision. The advantages of the endoscopic approach over other procedures include preservation of olfaction, quick recovery, lack of external scars and less morbidity. The objective of the study is to assess the surgical outcome of endoscopic optic nerve decompression in patients with traumatic and atraumatic optic neuropathy. The case records of consequent patients attending ENT department with defective vision due to traumatic and atraumatic causes were reviewed. The outcome was measured in terms of improvement in visual acuity by log MAR scale. Among the 14 patients studied, 57% were females and the median age of presentation was 33 years. As compared to preoperative baseline visual acuity, the overall improvement was achieved in 11 patients, with an effective rate of 78.5% postoperatively. Patients presenting with no light perception and residual vision had significant improvement in visual acuity after surgery. Trans-nasal endoscopic surgery helps in decompressing the optic nerve with proper exposure of the orbital apex and optic canal without any intracranial or intra-orbital complications. Further, being a minimally invasive procedure has great advantage in cases of optic neuropathy.

Endocrine disrupting chemicals: gestational diabetes and beyond.

Gestational Diabetes Mellitus (GDM) has been on the rise for the last two decades along with the growing incidence of obesity. The ubiquitous use of Endocrine-Disrupting Chemicals (EDCs) worldwide has been associated with this increase in GDM incidence. Epigenetic modifications such as DNA methylation, histone acetylation, and methylation have been associated with prenatal exposure to EDCs. EDC exposure can also drive a sustained disruption of the hypothalamus-pituitary-thyroid axis and various other signaling pathways such as thyroid signaling, PPARγ signaling, PI3K-AKT signaling. This disruption leads to impaired glucose metabolism, insulin resistance as well as ß-cell dysfunction, which culminate into GDM. Persistent EDC exposure in pregnant women also increases adipogenesis, which results in gestational weight gain. Importantly, pregnant mothers transfer these EDCs to the fetus via the placenta, thus leading to other pregnancy-associated complications such as intrauterine growth restriction (IUGR), and large for gestational age neonates. Furthermore, this early EDC exposure of the fetus increases the susceptibility of the infant to metabolic diseases in early life. The transgenerational impact of EDCs is also associated with higher vascular tone, cognitive aberrations, and enhanced susceptibility to lifestyle disorders including reproductive health anomalies. The review focuses on the impact of environmental toxins in inducing epigenetic alterations and increasing the susceptibility to metabolic diseases during pregnancy needs to be extensively studied such that interventions can be developed to break this vicious cycle. Furthermore, the use of EDC-associated ExomiRs from the serum of patients can help in the early diagnosis of GDM, thereby leading to triaging of patients based on increasing risk factor of the clinicopathological condition.

Renal angioplasty for atherosclerotic renal artery stenosis: Cardiologist's perspective.

Atherosclerotic renal artery stenosis (ARAS) is frequently associated with concomitant coronary and peripheral arterial disease with a significant impact on cardiovascular morbidity and mortality. Renal angioplasty of ARAS is more challenging because of increased incidence of technical failures, complications, and restenosis; while there is barely perceptible control of hypertension and only marginal improvement in renal function. This is because most of the patient population in recent randomized trials had unmanifested or clinically silent renovascular disease. Manifestations of RAS should be looked for and incorporated in the management plan particularly before deciding for revascularization. In the absence of clinical manifestation like renovascular hypertension, ischemic nephropathy, left ventricular failure, or unstable coronary syndromes; mere presence of RAS is analogous to presence of concomitant peripheral arterial disease which increases risk of adverse coronary events. Dormant-RAS in the absence of any manifestations can be managed with masterly inactivity. Chronological sequence of events and clinical condition of the patient help in decision making by identifying progressive renovascular disease. Selecting patients for renal artery stenting who actually will benefit from revascularization shall also decrease the unnecessary complications inherent with any interventional procedure. The present review is an attempt to analyze the current view on the diagnostic and management issues more specifically about the need and rationale behind angioplasty.

Concept of lipid droplet biogenesis.

Lipid droplets (LD) are functionally conserved fat storage organelles found in all cell types. LDs have a unique structure comprising of a hydrophobic core of neutral lipids (fat), triacylglycerol (TAG) and cholesterol esters (CE) surrounded by a phospholipid monolayer. LD surface is decorated by a multitude of proteins and enzymes rendering this compartment functional. Accumulating evidence suggests that LDs originate from discrete ER-subdomains, demarcated by the lipodystrophy protein seipin, however, the mechanisms of which are not well understood. LD biogenesis factors together with biophysical properties of the ER membrane orchestrate spatiotemporal regulation of LD nucleation and growth at specific ER subdomains in response to metabolic cues. Defects in LD formation manifests in several human pathologies, including obesity, lipodystrophy, ectopic fat accumulation, and insulin resistance. Here, we review recent advances in understanding the molecular events during initial stages of eukaryotic LD assembly and discuss the critical role of factors that ensure fidelity of this process.

Comparative efficacy of Micropore™ surgical dressing, Tegaderm™ and Lockit plus® for lumbar epidural catheter fixation in children: a prospective parallel group randomized controlled trial.

BACKGROUND: Proper fixation of an epidural catheter is necessary for desired drug effect and to prevent catheter displacement. Different techniques have been used for epidural catheter fixation. The aim of the study was to compare the relative efficacy of Micropore™ surgical dressing, Tegaderm™, and Lockit plus® in preventing lumbar epidural catheter migration in children. METHODS: We studied 167 patients aged 5-16 years, for up to 48 h. After the elective abdominal or lower limb surgery. Patients were randomly assigned to one of three groups: (1) Micropore™ surgical dressing (group M), (2) Tegaderm™ (group T), or (3) Lockit plus® (group L). Incidence and extent of epidural catheter migration in centimetres (cm); was compared at 24 and 48 h post epidural fixation. Correlation between epidural catheter migration and patient characteristics, and relative incidence of complications in three groups was also analysed. RESULTS: Incidence of catheter migration was 9.6% at 24 h (group M: 7.1%, group T: 21.1% and group L: 0%) and 45.5% at 48 h (group M: 66.1%, group T: 45.6% and group L: 24.1%). After 48 h, absolute migration (mean migration rounded off to the nearest 0.5 cm) was least in patients in group L: 0.34 cm (1.39) compared to group M 1.22 cm (SD: 1.85) group T: 0.94 cm (1.94) (p = <0.001). CONCLUSION: Up to 48 h after surgery, the Lockit plus® device demonstrated the less epidural catheter migration when compared to micropore surgical dressing or tegaderm in children undergoing elective abdominal or lower limb surgery.

Development of multi-epitope based subunit vaccine against Mycobacterium Tuberculosis using immunoinformatics approach.

The etiological agent of tuberculosis (TB), Mycobacterium tuberculosis, is a deadly pathogen that adapts to thrive within the host. Since 2020, the COVID-19 pandemic has had colossal health, societal, and economic consequences, which have affected the reporting of new incidences and mortality cases of TB. As per the WHO 2022 report, 10.6 million people were diagnosed with TB, and 1.6 million died worldwide. The increase in resistant strains of tuberculosis is making it more burdensome to reach the End TB strategy. A reliable and efficient TB vaccine that may avert both primary infection and recurrence of latent TB in adults and adolescents is of the utmost importance. In this study, we used computational techniques to predict the ability of HLA molecules to display epitopes for six TB proteins (PPE68, PE_PGRS17, EspC, LDT4, RpfD, and RpfC) to design the multi-epitope subunit vaccine. From the aimed proteins, the potential B-cell, helper T lymphocyte (HTL), and cytotoxic T lymphocyte (CTL) epitopes were predicted and linked together with LPA adjuvant, and the vaccine was designed. The vaccine's physicochemical analysis demonstrates that it is non-allergic, non-toxic, and antigenic. Then, the vaccine structure was predicted, improved, and verified to yield the optimal structure. The developed vaccine's binding mechanism with distinct immunogenic receptors (Tlr2 and MHC-II) was assessed utilizing molecular docking. The molecular dynamic simulation and MMPBSA analysis were performed to comprehend the complexes' dynamics and stability. The immune simulation was utilized to anticipate the vaccine's immunogenic attributes. In silico cloning was employed to demonstrate the efficient expression of the designed vaccine in E. coli as a host. Moreover, in vitro and in vivo animal testing is required to determine the efficacy of the in silico developed vaccine.Communicated by Ramaswamy H. Sarma.