Long-term health and human capital effects of in utero exposure to an industrial disaster: a spatial difference-in-differences analysis of the Bhopal gas tragedy.

OBJECTIVES: Globalisation and industrialisation can increase economic opportunity for low/middle-income nations, but these processes may also increase industrial accidents and harm workers. This paper examines the long-term, cohort-based health effects of the Bhopal gas disaster (BGD), one of the most serious industrial accidents in history. DESIGN: This retrospective analysis uses geolocated data on health and education from India's National Family Health Survey-4 (NFHS-4) and the 1999 Indian Socio-Economic Survey by the National Sample Survey Organization (NSSO-1999) to examine the health effects of exposure to the BGD among men and women aged 15-49 years living in Madhya Pradesh in 2015-2016 (women n=40 786; men n=7031 (NFHS-4) and n=13 369 (NSSO-1999)), as well as their children (n=1260). A spatial difference-in-differences strategy estimated the relative effect of being in utero near Bhopal relative to other cohorts and to those further from Bhopal separately for each dataset. RESULTS: We document long-term, intergenerational impacts of the BGD, showing that men who were in utero at the time were more likely to have a disability that affected their employment 15 years later, and had higher rates of cancer and lower educational attainment over 30 years later. Changes in the sex ratio among children born in 1985 suggest an effect of the BGD up to 100 km from the accident. CONCLUSIONS: These results indicate social costs stemming from the BGD that extend far beyond the mortality and morbidity experienced in the immediate aftermath. Quantifying these multigenerational impacts is important for policy consideration. Moreover, our results suggest that the BGD affected people across a substantially more widespread area than has previously been demonstrated.

The Association Between Alzheimer's Disease-Related Markers and Physical Activity in Cognitively Normal Older Adults.

Previous studies have indicated that physical activity may be beneficial in reducing the risk for Alzheimer's disease (AD), although the underlying mechanisms are not fully understood. The goal of this study was to evaluate the relationship between habitual physical activity levels and brain amyloid deposition and AD-related blood biomarkers (i.e., measured using a novel high-performance mass spectrometry-based assay), in apolipoprotein E (APOE) ε4 carriers and noncarriers. We evaluated 143 cognitively normal older adults, all of whom had brain amyloid deposition assessed using positron emission tomography and had their physical activity levels measured using the International Physical Activity Questionnaire (IPAQ). We observed an inverse correlation between brain amyloidosis and plasma beta-amyloid (Aß)1-42 but found no association between brain amyloid and plasma Aß1-40 and amyloid precursor protein (APP)669-711. Additionally, higher levels of physical activity were associated with lower plasma Aß1-40, Aß1-42, and APP669-711 levels in APOE ε4 noncarriers. The ratios of Aß1-40/Aß1-42 and APP669-711/Aß1-42, which have been associated with higher brain amyloidosis in previous studies, differed between APOE ε4 carriers and non-carriers. Taken together, these data indicate a complex relationship between physical activity and brain amyloid deposition and potential blood-based AD biomarkers in cognitively normal older adults. In addition, the role of APOE ε4 is still unclear, and more studies are necessary to bring further clarification.

Minimizing scattered radiation dose in cardiac catheterization laboratory during interventional procedures using lead free drape - MILD study.

OBJECTIVE: RADPAD is a lead-free sterile drape that reduces scattered radiation during fluoroscopic procedures. We aimed to study the effect of using RADPAD on primary operator (PO) and secondary operator (SO) during coronary angiography (CAG) as well as percutaneous coronary intervention (PCI). METHODS: 137 patients undergoing elective CAG and PCIwere randomized in a 1:1 pattern with or without the RADPAD. The ratio of PO received dose in mrem to total Air Kerma (AK) in mGy, Dose Area Product (DAP) in mGycm2 and Cine Adjusted Screening Time (CAST) in minute, at the end of the procedure with or without RADPAD were measured and designated as dose relative to AK, DAP and CAST. The exposure ratios were compared for both cohorts. RESULTS: There was no significant difference in CAST, DAP and AK between the two patient cohorts. PO radiation dose relative to CAST was 0.15 ± 0.18 mrem/min for RADPAD cohort and 0.43 ± 0.31 mrem/min for No RADPAD cohort (p < 0.00001). PO dose relative to DAP was 0.00042 ± 0.00049 mrem/mGycm2 for RADPAD cohort and 0.0011 ± 0.0013 mrem/mGycm2 for No RADPAD cohort (p = 0.000014). PO dose relative to AK was 0.0030 ± 0.0037 mrem/mGy for RADPAD cohort and 0.0071 ± 0.0049 mrem/mGy for No RADPAD cohort (p < 0.00001). All PO doses relative to CAST, DAP and AK were significantly reduced in the RADPAD cohort compared to the No RADPAD cohort. Similar findings were observed for the SO also. CONCLUSION: RADPAD significantly reduces radiation exposure to both PO and SO during CAG and PCI.

Novel Amylin Analogues Reduce Amyloid-ß Cross-Seeding Aggregation and Neurotoxicity.

BACKGROUND: Type 2 diabetes related human islet amyloid polypeptide (hIAPP) plays a dual role in Alzheimer's disease (AD). hIAPP has neuroprotective effects in AD mouse models whereas, high hIAPP concentrations can promote co-aggregation with amyloid-ß (Aß) to promote neurodegeneration. In fact, both low and high plasma hIAPP concentration has been associated with AD. Therefore, non-aggregating hIAPP analogues have garnered interest as a treatment for AD. The aromatic amino acids F23 and I26 in hIAPP have been identified as the key residues involved in self-aggregation and Aß cross-seeding. OBJECTIVE: Three novel IAPP analogues with single and double alanine mutations (A1 = F23, A2 = I26, and A3 = F23 + I26) were assessed for their ability to aggregate, modulate Aß oligomer formation, and alter neurotoxicity. METHODS: A range of biophysical methods including Thioflavin-T, gel electrophoresis, photo-crosslinking, circular dichroism combined with cell viability assays were utilized to assess protein aggregation and toxicity. RESULTS: All IAPP analogues showed significantly less self-aggregation than hIAPP. Co-aggregated Aß42-A2 and A3 also showed reduced aggregation compared to Aß42-hIAPP mixtures. Self- and co-oligomerized A1, A2, and A3 exhibited random coil conformations with reduced beta sheet content compared to hIAPP and Aß42-hIAPP aggregates. A1 was toxic at high concentrations compared to A2 and A3. However, co-aggregated Aß42-A1, A2, or A3 showed reduced neurotoxicity compared to Aß42, hIAPP, and Aß42-hIAPP aggregates. CONCLUSION: These findings confirm that hIAPP analogues with non-aromatic residues at positions 23 and 26 have reduced self-aggregation and the ability to neutralize Aß42 toxicity. This warrants further characterization of their protective effects in pre-clinical AD models.

Structure-based virtual screening, molecular dynamics and binding affinity calculations of some potential phytocompounds against SARS-CoV-2.

COVID-19 caused by a positive-sense single stranded RNA virus named as severe acute respiratory syndrome-Coronavirus-2 (SARS-CoV-2) triggered the global pandemic. This virus has infected about 10.37 Crores and taken lives of 2.24 Crores people of 213 countries to date. To cope-up this emergency clinical trials are undergoing with some existing drugs like remdesivir, flavipiravir, lopinavir-ritonavir, nafamostat, doxycycline, hydroxy-chloroquine, dexamethasone, etc., despite their severe toxicity and health hazards among diabetics, hypertensive, cardiac patients or normal individuals. The lack of safe and approved treatment for COVID-19 has forced the scientific community to find novel and safe compounds with potential efficacy. This study evaluates a few selective herbal compounds like glucoraphanin, vitexin, niazinin, etc., as a potential inhibitor of the spike protein and 3-chymotrypsin-like protease (3CLpro) or main protease (Mpro) of SARS-COV-2 through in-silico virtual studies such as molecular docking, target analysis, toxicity prediction and ADME prediction and supported by a Molecular-Dynamic simulation. Selective phytocompounds were docked successfully in the binding site of spike glycoprotein and 3CLpro (Mpro) of SARS-CoV-2. In-silico approaches also predict this molecule to have good solubility, pharmacodynamic property and target accuracy through MD simulation and ADME studies. These hit molecules niazinin, vitexin, glucoraphanin also obey Lipinski's rule along with their stable binding towards target protein of the virus, which makes them suitable for further biochemical and cell-based assays followed by clinical investigations to highlight their potential use in COVID-19 treatment.Communicated by Ramaswamy H. Sarma.

Amylin and beta amyloid proteins interact to form amorphous heterocomplexes with enhanced toxicity in neuronal cells.

Human pancreatic islet amyloid polypeptide (hIAPP) and beta amyloid (Aß) can accumulate in Type 2 diabetes (T2D) and Alzheimer's disease (AD) brains and evidence suggests that interaction between the two amyloidogenic proteins can lead to the formation of heterocomplex aggregates. However, the structure and consequences of the formation of these complexes remains to be determined. The main objective of this study was to characterise the different types and morphology of Aß-hIAPP heterocomplexes and determine if formation of such complexes exacerbate neurotoxicity. We demonstrate that hIAPP promotes Aß oligomerization and formation of small oligomer and large aggregate heterocomplexes. Co-oligomerized Aß42-hIAPP mixtures displayed distinct amorphous structures and a 3-fold increase in neuronal cell death as compared to Aß and hIAPP alone. However, in contrast to hIAPP, non-amyloidogenic rat amylin (rIAPP) reduced oligomer Aß-mediated neuronal cell death. rIAPP exhibited reductions in Aß induced neuronal cell death that was independent of its ability to interact with Aß and form heterocomplexes; suggesting mediation by other pathways. Our findings reveal distinct effects of IAPP peptides in modulating Aß aggregation and toxicity and provide new insight into the potential pathogenic effects of Aß-IAPP hetero-oligomerization and development of IAPP based therapies for AD and T2D.

Characterisation of the Structure and Oligomerisation of Islet Amyloid Polypeptides (IAPP): A Review of Molecular Dynamics Simulation Studies.

Human islet amyloid polypeptide (hIAPP) is a naturally occurring, intrinsically disordered protein whose abnormal aggregation into amyloid fibrils is a pathological feature in type 2 diabetes, and its cross-aggregation with amyloid beta has been linked to an increased risk of Alzheimer's disease. The soluble, oligomeric forms of hIAPP are the most toxic to ß-cells in the pancreas. However, the structure of these oligomeric forms is difficult to characterise because of their intrinsic disorder and their tendency to rapidly aggregate into insoluble fibrils. Experimental studies of hIAPP have generally used non-physiological conditions to prevent aggregation, and they have been unable to describe its soluble monomeric and oligomeric structure at physiological conditions. Molecular dynamics (MD) simulations offer an alternative for the detailed characterisation of the monomeric structure of hIAPP and its aggregation in aqueous solution. This paper reviews the knowledge that has been gained by the use of MD simulations, and its relationship to experimental data for both hIAPP and rat IAPP. In particular, the influence of the choice of force field and water models, the choice of initial structure, and the configurational sampling method used, are discussed in detail. Characterisation of the solution structure of hIAPP and its mechanism of oligomerisation is important to understanding its cellular toxicity and its role in disease states, and may ultimately offer new opportunities for therapeutic interventions.

The Link between Type 2 Diabetes and Neurodegeneration: Roles for Amyloid-ß, Amylin, and Tau Proteins.

A wealth of evidence indicates a strong link between type 2 diabetes (T2D) and neurodegenerative diseases such as Alzheimer's disease (AD). Although the precise mechanism remains unclear, T2D can exacerbate neurodegenerative processes. Brain atrophy, reduced cerebral glucose metabolism, and central nervous system insulin resistance are features of both AD and T2D. The T2D phenotype (glucose dyshomeostasis, insulin resistance, impaired insulin signaling) also promotes AD pathology, namely accumulation of amyloid-ß (Aß) and hyperphosphorylated tau and can induce other aspects of neuronal degeneration including inflammatory and oxidative processes. Aß and hyperphosphorylated tau may also have roles in pancreatic ß-cell dysfunction and in reducing insulin sensitivity and glucose uptake by peripheral tissues such as liver, skeletal muscle, and adipose tissue. This suggests a role for these AD-related proteins in promoting T2D. The accumulation of the islet amyloid polypeptide (IAPP, or amylin) within islet ß-cells is a major pathological feature of the pancreas in patients with chronic T2D. Co-secreted with insulin, amylin accumulates over time and contributes to ß-cell toxicity, ultimately leading to reduced insulin secretion and onset of overt (insulin dependent) diabetes. Recent evidence also suggests that this protein accumulates in the brain of AD patients and may interact with Aß to exacerbate the neurodegenerative process. In this review, we highlight evidence indicating T2D in promoting Aß and tau mediated neurodegeneration and the potential contributions of Aß and tau in promoting a diabetic phenotype that could further exacerbate neurodegeneration. We also discuss underlying mechanisms by which amylin can contribute to the neurodegenerative processes.

The Effects of Latrepirdine on Amyloid-ß Aggregation and Toxicity.

Latrepirdine (Dimebon) has been demonstrated to be a neuroprotective and cognition improving agent in neurodegenerative diseases that feature protein aggregation and deposition, such as Alzheimer's disease (AD). The accumulation of amyloid-ß (Aß) protein aggregates is a key event in the neurodegenerative process in AD. This study explores if latrepirdine modulation of protein aggregation contributes to its neuroprotective mechanism of action. Assessment of neuronal cell death showed that there was a significant reduction in lactate dehydrogenase release at an equimolar ratio of Aß:latrepirdine and with lower concentrations of latrepirdine. The ability of latrepirdine to alter the formation of Aß42 aggregates was assessed by thioflavin-T fluorescence, western immunoblotting and atomic force microscopy (AFM). Despite showing a reduction in thioflavin-T fluorescence with latrepirdine treatment, indicating a decrease in aggregation, immunoblotting and AFM showed a modest increase in both the formation and size of Aß aggregates. The discrepancies between thioflavin-T and the other assays are consistent with previous evidence that cyclic molecules can interfere with thioflavin-T binding of amyloid protein preparations. The ability of latrepirdine to modulate Aß aggregation appears to be independent of its neuroprotective effects, and is unlikely to be a mechanism by which latrepirdine offers protection. This study investigates the effect of latrepirdine on Aß aggregation, and presents evidence suggesting that caution should be applied in the use of thioflavin-T fluorescence based assays as a method for screening compounds for protein aggregation altering properties.

Efficacy of stem cell in improvement of left ventricular function in acute myocardial infarction--MI3 Trial.

BACKGROUND & OBJECTIVES: Acute myocardial infarction (AMI) is characterized by irreparable and irreversible loss of cardiac myocytes. Despite major advances in the management of AMI, a large number of patients are left with reduced left ventricular ejection fraction (LVEF), which is a major determinant of short and long term morbidity and mortality. A review of 33 randomized control trials has shown varying improvement in left ventricular (LV) function in patients receiving stem cells compared to standard medical therapy. Most trials had small sample size and were underpowered. This phase III prospective, open labelled, randomized multicenteric trial was undertaken to evaluate the efficacy in improving the LVEF over a period of six months, after injecting a predefined dose of 5-10 × 10 [8] autologous mononuclear cells (MNC) by intra-coronary route, in patients, one to three weeks post ST elevation AMI, in addition to the standard medical therapy. METHODS: In this phase III prospective, multicentric trial 250 patients with AMI were included and randomized into stem cell therapy (SCT) and non SCT groups. All patients were followed up for six months. Patients with AMI having left ventricular ejection fraction (LVEF) of 20-50 per cent were included and were randomized to receive intracoronary stem cell infusion after successfully completing percutaneous coronary intervention (PCI). RESULTS: On intention-to-treat analysis the infusion of MNCs had no positive impact on LVEF improvement of ≥ 5 per cent. The improvement in LVEF after six months was 5.17 ± 8.90 per cent in non SCT group and 4.82 ± 10.32 per cent in SCT group. The adverse effects were comparable in both the groups. On post hoc analysis it was noted that the cell dose had a positive impact when infused in the dose of ≥ 5 X 10 [8] (n=71). This benefit was noted upto three weeks post AMI. There were 38 trial deviates in the SCT group which was a limitation of the study. INTERPRETATION & CONCLUSIONS: Infusion of stem cells was found to have no benefit in ST elevation AMI. However, the procedure was safe. A possible benefit was seen when the predefined cell dose was administered which was noted upto three weeks post AMI, but this was not significant and needs confirmation by larger trials.

Modulation of amyloid-ß 1-42 structure and toxicity by proline-rich whey peptides.

A proline-rich peptide product prepared from bovine whey protein that was enriched in several hydrophobic amino acids including proline (whey proline-rich peptide, wPRP) was shown to modulate the folding pathway of human amyloid beta peptide 1-42 (Aß42) into oligomers. Concentration-dependent changes in ThT-binding to Ab42 by wPRP indicated suppression of oligomerisation, that was supported by Transmission Electron Microscopy. Suppression of ß-sheet and specifically, anti-parallel ß-sheet structures by wPRP was demonstrated by ATR-FTIR spectroscopy, where evidence for capacity of wPRP to dissociate pre-existing ß-sheet structures in Aß42 was also apparent. Suppression of anti-parallel ß-sheets of oligomeric Aß42 was associated with rescue of yeast and SH-SY5Y neuronal cells providing important evidence for the association between anti-parallel ß-sheet structure and oligomer toxicity. It was proposed that the interaction of wPRP with Aß42 interfered with the anti-parallel folding pathway of oligomeric Aß42 and ultimately produced 'off-pathway' structures of lowered total ß-sheet content, with attenuated cellular toxicity.