Role of Glutathione in Chalcone Derivative Induced Apoptosis of Brugia malayi and its Possible Therapeutic Implication.

PURPOSE: Oxidative stress is an essential component of innate response against microbes. The oxidative impact has a very subtle connection with apoptosis. Our previous work indicated presumptive evidence of apoptosis by the chalcone derivatives against the human lymphatic filarial parasite. Evidence suggests the involvement of glutathione-S-transferase (GST) in the mechanism of action of chalcone drugs. In the present study, we explored the implications of redox status in apoptosis of the parasite by this drug. RESULTS: Treatment with the representative drug, 4t, significantly decreased GSH level and increased GST activity in the Brugia malayi microfilariae (Mf) in comparison to Mf without 4t treatment. Drug-induced loss of motility of the parasites was reversed by the treatment with GSH (41%) and NAC (19%). A significant fall in rGST activity was observed due to drug addition, which could be reversed by the addition of GSH co-substrate, but not with the re-addition of rGST, indicating a vital role of GSH. In silico study demonstrated a favorable drug-GST enzyme interaction. Oxidative stress was reflected by increased protein carbonylation and intracellular reactive oxygen species level, in the drug-treated parasite. Mitochondrial oxygen consumption was reduced by the drug, which was reversed on the addition of GSH. Mitochondrial dysfunction was confirmed by MTT and cytochrome c assay. Apoptosis was confirmed by the inhibition in PARP activity. CONCLUSION: We conclude that the depletion of GSH by chalcone with concomitant mitochondrial dysfunction revealed a novel rationale of apoptosis in the parasite. Such a mechanism might have wide therapeutic implications.

Cardiological Society of India: Document on acute MI care during COVID-19.

The unprecedented and rapidly spreading Coronavirus Disease-19 (COVID-19) pandemic has challenged public health care systems globally. Based on worldwide experience, India has initiated a nationwide lockdown to prevent the exponential surge of cases. During COVID-19, management of cardiovascular emergencies like acute Myocardial Infarction (MI) may be compromised. Cardiological Society of India (CSI) has ventured in this moment of crisis to evolve a consensus document for care of acute MI. However, this care should be individualized, based on local expertise and governmental advisories.

Prevalence of hypertension among Indian adults: Results from the great India blood pressure survey.

OBJECTIVE: Hypertension is the most important risk factor for cardiovascular morbidity and mortality. There is limited data on hypertension prevalence in India. This study was conducted to estimate the prevalence of hypertension among Indian adults. METHODS: A national level survey was conducted with fixed one-day blood pressure measurement camps across 24 states and union territories of India. Hypertension was defined as systolic blood pressure (BP) ≥140 mmHg or a diastolic BP ≥90 mmHg or on treatment for hypertension. The prevalence was age- and gender-standardized according to the 2011 census population of India. RESULTS: Blood pressure was recorded for 180,335 participants (33.2% women; mean age 40.6 ± 14.9 years). Among them, 8,898 (4.9%), 99,791 (55.3%), 35,694 (11.9%), 23,084 (12.8%), 9,989 (5.5%), and 2,878 (1.6%) participants were of the age group 18-19, 20-44, 45-54, 55-64, 65-74, and ≥ 75 years, respectively. Overall prevalence of hypertension was 30.7% (95% confidence interval [CI]: 30.5, 30.9) and the prevalence among women was 23.7% (95% CI: 23.3, 24). Prevalence adjusted for 2011 census population and the WHO reference population was 29.7% and 32.8%, respectively. CONCLUSION: There is a high prevalence of hypertension, with almost one in every three Indian adult affected.

Glioblastoma invasion and NMDA receptors: A novel prospect.

PURPOSE: Glioblastoma cells create glutamate-rich tumor microenvironment, which initiates activation of ion channels and modulates downstream intracellular signaling. N-methyl-D-aspartate receptors (NMDARs; a type of glutamate receptors) have a high affinity for glutamate. The role of NMDAR activation on invasion of glioblastoma cells and the crosstalk with α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) is yet to be explored. MAIN METHODS: LN18, U251MG, and patient-derived glioblastoma cells were stimulated with NMDA to activate NMDAR glutamate receptors. The role of NMDAR activation on invasion and migration and its crosstalk with AMPAR were evaluated. Invasion and migration of glioblastoma cells were investigated by in vitro trans-well Matrigel invasion and trans-well migration assays, respectively. Expression of NMDARs and AMPARs at transcript level was evaluated by quantitative real-time polymerase chain reaction. RESULTS: We determined that NMDA stimulation leads to enhanced invasion in LN18, U251MG, and patient-derived glioblastoma cells, whereas inhibition of NMDAR using MK-801, a non-competitive antagonist of the NMDAR, significantly decreased the invasive capacity. Concordant with these findings, migration was significantly augmented by NMDAR in both cell lines. Furthermore, NMDA stimulation upregulated the expression of GluN2 and GluA1 subunits at the transcript level. CONCLUSIONS: This study demonstrated the previously unexplored role of NMDAR in invasion of glioblastoma cells. Furthermore, the expression of the GluN2 subunit of NMDAR and the differential overexpression of the GluA1 subunit of AMPAR in both cell lines provide a plausible rationale of crosstalk between these calcium-permeable subunits in the glutamate-rich microenvironment of glioblastoma.

2019 John Insall Award: Fructosamine is a better glycaemic marker compared with glycated haemoglobin (HbA1C) in predicting adverse outcomes following total knee arthroplasty: a prospective multicentre study.

AIMS: The best marker for assessing glycaemic control prior to total knee arthroplasty (TKA) remains unknown. The purpose of this study was to assess the utility of fructosamine compared with glycated haemoglobin (HbA1c) in predicting early complications following TKA, and to determine the threshold above which the risk of complications increased markedly. PATIENTS AND METHODS: This prospective multi-institutional study evaluated primary TKA patients from four academic institutions. Patients (both diabetics and non-diabetics) were assessed using fructosamine and HbA1c levels within 30 days of surgery. Complications were assessed for 12 weeks from surgery and included prosthetic joint infection (PJI), wound complication, re-admission, re-operation, and death. The Youden's index was used to determine the cut-off for fructosamine and HbA1c associated with complications. Two additional cut-offs for HbA1c were examined: 7% and 7.5% and compared with fructosamine as a predictor for complications. RESULTS: Overall, 1119 patients (441 men, 678 women) were included in the study. Fructosamine level of 293 µmol/l was identified as the optimal cut-off associated with complications. Patients with high fructosamine (> 293 µmol/l) were 11.2 times more likely to develop PJI compared with patients with low fructosamine (p = 0.001). Re-admission and re-operation rates were 4.2 and 4.5 times higher in patients with fructosamine above the threshold (p = 0.005 and p = 0.019, respectively). One patient (1.7%) from the elevated fructosamine group died compared with one patient (0.1%) in the normal fructosamine group (p = 0.10). These complications remained statistically significant in multiple regression analysis. Unlike fructosamine, all three cut-offs for HbA1c failed to show a significant association with complications. CONCLUSION: Fructosamine is a valid and an excellent predictor of complications following TKA. It better reflects the glycaemic control, has greater predictive power for adverse events, and responds quicker to treatment compared with HbA1c. These findings support the screening of all patients undergoing TKA using fructosamine and in those with a level above 293 µmol/l, the risk of surgery should be carefully weighed against its benefit. Cite this article: Bone Joint J 2019;101-B(7 Supple C):3-9.

Clinical and angiographic profiles and six months outcomes of smokers with acute ST segment elevation myocardial infarction undergoing primary percutaneous coronary angioplasty.

BACKGROUND: Outcomes of primary percutaneous coronary intervention (PCI) for acute STEMI (ST-segment elevation myocardial infarction) in smokers are expected to be better than non-smokers as for patients of acute STEMI with or without fibrinolytic therapy. OBJECTIVES: This comparative study was designed to evaluate the outcomes of primary PCI in patients with acute STEMI in smokers and non-smokers. Clinical and angiographic profile of the two groups was also compared. METHODS: Over duration of two year, a total of 150 consecutive patients of acute STEMI eligible for primary PCI were enrolled and constituted the two groups [Smokers (n=90), Non-smokers (n=60)] of the study population. There was no difference in procedure in two groups. RESULTS: In the present study of acute STEMI, current smokers were about a decade younger than non-smokers (p value=0.0002), majority were male (98.9% vs 56.6%) were male with a higher prevalence of hypertension and diabetes mellitus (61.67% vs 32.28% and 46.67% vs 14.44%, p=0.001) respectively. Smokers tended to have higher thrombus burden (p=0.06) but less multi vessel disease (p=0.028). Thirty day and six month mortality was non-significantly higher in smokers 4.66% vs 1.33% (p=0.261) and 5.33% vs 2.66% (p=NS) respectively. Rate of quitting smoking among smokers was 80.90% at 6 months. CONCLUSION: The study documents that smokers with acute STEMI have similar outcomes as compared to non smokers with higher thrombus burden and lesser non culprit artery involvement. Smokers present at much younger age emphasizing the role of smoking cessation for prevention of myocardial infarction.

Indefinite Causal Order in a Quantum Switch.

Quantum mechanics allows events to happen with no definite causal order: this can be verified by measuring a causal witness, in the same way that an entanglement witness verifies entanglement. Here, we realize a photonic quantum switch, where two operations A[over ^] and B[over ^] act in a quantum superposition of their two possible orders. The operations are on the transverse spatial mode of the photons; polarization coherently controls their order. Our implementation ensures that the operations cannot be distinguished by spatial or temporal position-further it allows qudit encoding in the target. We confirm our quantum switch has no definite causal order by constructing a causal witness and measuring its value to be 18 standard deviations beyond the definite-order bound.

Increased postoperative glucose variability is associated with adverse outcomes following orthopaedic surgery.

Aims: The aim of this study was to examine the association between postoperative glycaemic variability and adverse outcomes following orthopaedic surgery. Patients and Methods: This retrospective study analyzed data on 12 978 patients (1361 with two operations) who underwent orthopaedic surgery at a single institution between 2001 and 2017. Patients with a minimum of either two postoperative measurements of blood glucose levels per day, or more than three measurements overall, were included in the study. Glycaemic variability was assessed using a coefficient of variation (CV). The length of stay (LOS), in-hospital complications, and 90-day readmission and mortality rates were examined. Data were analyzed with linear and generalized linear mixed models for linear and binary outcomes, adjusting for various covariates. Results: The cohort included 14 339 admissions, of which 3302 (23.0%) involved diabetic patients. Patients with CV values in the upper tertile were twice as likely to have an in-hospital complication compared with patients in the lowest tertile (19.4% versus 9.0%, p < 0.001), and almost five times more likely to die compared with those in the lowest tertile (2.8% versus 0.6%, p < 0.001). Results of the adjusted analyses indicated that the mean LOS was 1.28 days longer in the highest versus the lowest CV tertile (p < 0.001), and the odds of an in-hospital complication and 90-day mortality in the highest CV tertile were respectively 1.91 (p < 0.001) and 2.10 (p = 0.001) times larger than the odds of these events in the lowest CV tertile. These associations were significant even for non-diabetic patients. After adjusting for hypoglycaemia, the relationships remained significant, except that the CV tertile no longer predicted mortality in diabetics. Conclusion: These results indicate that higher glycaemic variability is associated with longer LOS and in-hospital complications. Glycaemic variability also predicted death, although that primarily held for non-diabetic patients in the highest CV tertile following orthopaedic surgery. Prospective studies should examine whether ensuring low postoperative glycaemic variability may reduce complication rates and mortality. Cite this article: Bone Joint J 2018;100-B:1125-32.

Can next generation sequencing play a role in detecting pathogens in synovial fluid?

AIMS: The diagnosis of periprosthetic joint infection can be difficult due to the high rate of culture-negative infections. The aim of this study was to assess the use of next-generation sequencing for detecting organisms in synovial fluid. MATERIALS AND METHODS: In this prospective, single-blinded study, 86 anonymized samples of synovial fluid were obtained from patients undergoing aspiration of the hip or knee as part of the investigation of a periprosthetic infection. A panel of synovial fluid tests, including levels of C-reactive protein, human neutrophil elastase, total neutrophil count, alpha-defensin, and culture were performed prior to next-generation sequencing. RESULTS: Of these 86 samples, 30 were alpha-defensin-positive and culture-positive (Group I), 24 were alpha-defensin-positive and culture-negative (Group II) and 32 were alpha-defensin-negative and culture-negative (Group III). Next-generation sequencing was concordant with 25 results for Group I. In four of these, it detected antibiotic resistant bacteria whereas culture did not. In another four samples with relatively low levels of inflammatory biomarkers, culture was positive but next-generation sequencing was negative. A total of ten samples had a positive next-generation sequencing result and a negative culture. In five of these, alpha-defensin was positive and the levels of inflammatory markers were high. In the other five, alpha-defensin was negative and the levels of inflammatory markers were low. While next-generation sequencing detected several organisms in each sample, in most samples with a higher probability of infection, there was a predominant organism present, while in those presumed not to be infected, many organisms were identified with no predominant organism. CONCLUSION: Pathogens causing periprosthetic infection in both culture-positive and culture-negative samples of synovial fluid could be identified by next-generation sequencing. Cite this article: Bone Joint J 2018;100-B:127-33.

Human filarial proteins attenuate chronic colitis in an experimental mouse model.

Encouraged by our earlier results of promising therapeutic effect of filarial recombinant proteins BmALT2, BmCys and WbL2 individually in the mouse model of acute ulcerative colitis, in this study, these proteins have been explored individually and in different combinations for their therapeutic potential in dextran sulphate sodium (DSS)-induced chronic colitis mice. These mice, treated with filarial proteins, showed reduced disease parameters including body weight loss, disease activity index, macroscopic and histopathological scores of colon and myeloperoxidase activity in colonic mucosa. Among various treatment schemes, rBmALT2 + rBmCys which showed most pronounced therapeutic implication was found to downregulate the mRNA expressions of IFN-γ and TNF-α and upregulate IL-10 and TGF-ß expression in the splenocytes. Also, increase in level of IgG1 and IgG2a isotypes in the sera of rBmALT2 + rBmCys-treated colitis mice was noted. Activated NF-κB level was found to be reduced in the colon of treated colitis mice compared to untreated one. In conclusion, filarial proteins in combination have been shown to improve the clinicopathologic status of chronic colitis through suppression of pro-inflammatory immune response most possibly in NF-κB-dependent manner. We propose this therapeutic strategy to be tested further to be considered as an effective option in chronic colitis.

Status of Serum Calcium, Vitamin D and Parathyroid Hormone and Hematological Indices Among Lead Exposed Jewelry Workers in Dhaka, Bangladesh.

Jewelry utilizes lead either directly or as a base metal. Costume jewelry requires lead before molding and plating the product with valuable metals. Therefore, such ornaments have a great potential to release heavy metals having health hazards. Also, jewelry makers engaged in preparing German silver, an alloy, apply lead in smelting, alloying, rolling and milling silver wires and pieces. The metal is taken up by blood, soft tissues and bone. The biological effects of lead are dependent upon the level and duration of exposure. Lead inhibits three enzymes of heme biosynthesis- δ-amino-levulinic-acid dehydratase (ALAD), coproporphyrin oxidase, and ferrochelatase, impairing heme synthesis and depressing serum level of erythropoietin resulting in decreased hemoglobin synthesis. Lead exposure also affects calcium metabolism and impair the synthesis of Calcitriol. In the present study, jewelry makers from Dhaka, Bangladesh, were shown to have significantly high levels of lead, protein, albumin, and parathormone in their blood, and significantly high amount of zinc-protoporphyrin and δ-amino-levulinic-acid in their urine. The control group, on the other hand showed significantly higher amounts of calcium (both total and ionized form) Vitamin D3 and non-activated erythrocyte ALAD in their blood, along with hemoglobin. It might be due to inhibition of 1-α-hydroxylase enzyme in renal tubules. Lead causes nephro-toxicity and inhibits 1-α- hydroxylase enzyme leading to decreased calcitriol synthesis resulting in impaired calcium absorption across gastro-intestinal tract and renal tubules. Low Vitamin D3 and significantly increased Parathyroid hormone (PTH) in study group has been found.

Therapeutic potential of the immunomodulatory proteins Wuchereria bancrofti L2 and Brugia malayi abundant larval transcript 2 against streptozotocin-induced type 1 diabetes in mice.

Epidemiological and experimental evidence has supported the concept of using helminths as alternative bio-therapeutic agents in the treatment of type 1 diabetes (T1D). In the current study, two filarial proteins, recombinant Wuchereria bancrofti L2 (rWbL2) and Brugia malayi abundant larval transcript 2 (rBmALT-2) have been investigated, individually and in combination, for their therapeutic potential in streptozotocin (STZ)-induced T1D. The rWbL2 and rBmALT-2 proteins, when administered individually or in combination, have resulted in lowering of the blood glucose levels and reducing the incidence of T1D in mice. In addition, these proteins have led to reduced lymphocytic infiltration and decreased islet damage and inflammation. The curative effect was found to be associated with the suppression of release of tumour necrosis factor-α (TNF-α) and interferon-γ (IFN-γ), and increased production of interleukin (IL)-4, IL-5 and IL-10 cytokines by the splenocytes of the diabetic mice. Insulin-specific IgG1 and antigen-specific IgE antibodies were found to be elevated in the sera of mice treated with rWbL2 and rBmALT-2 proteins. From the findings in this study, it can be envisaged that both of these filarial immunomodulatory proteins have the potential to ameliorate T1D by altering the regulatory immune responses.

Brugia malayi soluble and excretory-secretory proteins attenuate development of streptozotocin-induced type 1 diabetes in mice.

Understanding the modulation of the host-immune system by pathogens-like filarial parasites offers an alternate approach to prevent autoimmune diseases. In this study, we have shown that treatment with filarial proteins prior to or after the clinical onset of streptozotocin-induced type-1 diabetes (T1D) can ameliorate the severity of disease in BALB/c mice. Pre-treatment with Brugia malayi adult soluble (Bm A S) or microfilarial excretory-secretory (Bm mf ES) or microfilarial soluble (Bm mf S) antigens followed by induction of diabetes led to lowering of fasting blood glucose levels with as many as 57.5-62.5% of mice remaining nondiabetic. These proteins were more effective when they were used to treat the mice with established T1D as 62.5-71.5% of the mice turned to be nondiabetic. Histopathological examination of pancreas of treated mice showed minor inflammatory changes in pancreatic islet cell architecture. The therapeutic effect was found to be associated with the decreased production of cytokines TNF-α & IFN-γ and increased production of IL-10 in the culture supernatants of splenocytes of treated mice. A switch in the production of anti-insulin antibodies from IgG2a to IgG1 isotype was also seen. Together these results provide a proof towards utilizing the filarial derived proteins as novel anti-diabetic therapeutics.

In vitro and in vivo evaluation of 2-chloroethylnitrosourea derivatives as antitumor agents.

AIM: To evaluate potential of Naphthal-NU, Napro-NU and 5-Nitro-naphthal-NU, 2-chloroethylnitrosourea compounds with substituted naphthalimide in the pre-clinical studies. MATERIALS AND METHODS: In vitro cytotoxicity of three nitrosoureas was determined in human and mouse tumor cell lines by MTT assays. In vivo anti-tumor potential was evaluated in Sarcoma-180 (S-180) and Ehrlich's carcinoma (EC) solid tumors. Apoptosis in S-180 cells was analyzed by using Annexin V-Propidium Iodide (PI). Histological analysis of liver and kidney was performed at optimum dose (50 mg/kg). Expression status of CD4(+), CD8(+) and CD25(+) cells in treated mouse were also examined. RESULTS: Significant tumor growth retardation by the compounds was noted in early and advanced disease groups, as the life span of drug treated mice increased considerably. Drug induced killing was observed by induction of apoptosis. Naphthal-NU and 5-Nitro-naphthal-NU were effective to normalize the tumor induced structural abnormalities of liver and kidney. The compounds have no immunotoxic effect on CD4(+) and CD8(+) T cells and down regulate CD4(+)CD25(+) regulatory T cells. CONCLUSION: Overall data holds promise for the antitumor activity with lower toxicity of the compounds that can be utilized for the treatment of human malignant tumors.

Influence of alcohol on condom use pattern during non-spousal sexual encounter in male migrant workers in north India.

CONTEXT: Migrant workers constitute an important risk group for Human Immunodeficiency Virus/Acquired Immuno-Deficiency Syndrome transmission in India. Alcohol consumption before sexual intercourse has been postulated to influence condom use practices. This study aimed to assess this association with regard to non-spousal sexual encounters among male migrant workers in northern India. MATERIALS AND METHODS: A cross-sectional facility-based survey was conducted in 2011. Male migrant workers aged ≥18 years, who were born outside Haryana, who had moved to the current location after 15 years of age,had worked in the current factory for at least 1 year, who were willing to participate and were able to give written, informed consent were included in the study. A consecutive sampling was performed. Descriptive, bivariate and multiple logistic regression analyses were carried out. RESULTS: A total of 162 participants reported having experienced non-spousal sexual encounters in the last 1 year. The proportion of men who reported not having used a condom at their last non-spousal sexual encounter was 59.3%, and 78.4% of the men reported having consumed alcohol in the last 1 year. About 48.1% of men reported having consumed alcohol before their last non-spousal sexual encounter. Men who consumed alcohol were three times more likely to not use a condom at their last non-spousal sexual encounter (OR = 3.1, 95% CI: 1.5-6.4). This association persisted even after adjusting for relevant confounders. CONCLUSION: Alcohol consumption had a negative influence on condom use during non-spousal sexual encounter among male migrant workers. An integrated approach to promote condom use and reduce alcohol consumption among migrant men needs to be undertaken through targeted intervention strategies.