Compliance With Higher Education-Related Tobacco Control Law Provisions by Institutions of National Importance in India.

Introduction India formulated an anti-tobacco and anti-smoking law in 2003 in response to its resolutions in the United Nations' bodies. This law has been detailed subsequently to make it focussed on educational institutions, which are supposed to perform on-ground action in a decentralized manner. The first step is to put up signboards prohibiting the sale of cigarettes and tobacco products within 100 yards, the second is prohibiting smoking within the campus, and the third is implementing the law related to collecting fines from the offenders as well as the presence of vendors within 100 yards. Additional information on awareness activities was also sought. The focus of this paper is on India's premier educational institutions called the "Institutions of National Importance" by the Indian legislature. These are India's premier public institutions which have the maximum focus of the Indian government by making them of high quality, and non-compliance with the tobacco control law in these institutions should be taken seriously. Methods The paper checked for compliance with the Indian Tobacco Control Law in 79 of these Institutions of National Importance. The requirement for information to be collected from institutions was first derived from the legal act and the rules. Then, the Right to Information Act of 2005, India's transparency law, was used to file applications for information, and certified information from the institutions was collected and reported. Results Only 39.2% of the institutions had the requisite boards prohibiting sales within 100 yards of the institutions. The requirement of having boards prohibiting smoking fared a little better at 73.4% of institutions complying but was not universal. A total of 43% of institutions denied the information pertaining to the collection of fines, either by not providing a requisite reply or stating that this was not part of the record. The information regarding the presence of vendors was not universally supplied with 65.8% of institutions stating the same to not in record or not within the purview. With respect to the awareness activities though, 72.2% of the institutions stated to have some awareness activity for tobacco control and cessation. Conclusion The results show an overall weak compliance with the law. India's health regulators and educational watchdogs must implement anti-smoking and anti-tobacco laws strictly in Indian educational institutions as this is where young people are found. Something as simple as the installation of signboards by educational institutions cannot be overlooked by them. The law must become stricter with deterrence. This must be most intense in the Institutions of National Importance which form the premier institutions in India and become the role model for other institutions in India.

Decentralisation of the Compliance of Anti-tobacco Law in India: The Case of Higher Educational Institutions in New Delhi, India.

Introduction This paper studies the decentralised compliance responsibility of India's tobacco control legislation, called the Cigarettes and Other Tobacco Products (Prohibition of Advertisement and Regulation of Trade and Commerce, Production, Supply and Distribution) Act of 2003, with its rules, which the government has outsourced to higher educational institutions, studied through an example of New Delhi. The study looks into the three most important parameters of decentralised compliance. Two of these require the installation of signboards by higher educational institutions, and the third involves imposing and collecting fines against persons found smoking within the educational institutions. Regarding the boards, the first board is about the warning prohibiting the sale within 100 yards of educational institutions, and the second one prohibits smoking in educational institutions. The study also checks with the educational institutions whether there is a presence of cigarette and tobacco product vendors within 100 yards of the institution, where the sale of such products has been banned by law. The study also found educational activities to create awareness in the institutions for tobacco control and cessation. Methods Thirty-six higher educational institutions, including universities, were randomly selected and studied through a unique methodology using India's transparency law, i.e., the Right to Information Act 2005. The portions of the law, which was direct compliance, or related compliance by the higher educational institution was included in the study. This justified the decentralised responsibility of these higher educational institutions. Applications for information under the transparency law were requested and supplied. Out of the 47 institutions, in which information requests were filed, 36 provided the information under the law. Credible information was provided by the higher educational institutions and this information was collated and interpreted to provide insights into the compliance by the higher educational institutions. Results Only 44.4% of the institutions had a board prohibiting the sale of cigarettes and other tobacco products. This was a non-universal compliance by the higher educational institutions. 88.9 per cent had boards prohibiting smoking in the higher educational institutions. Only one out of the 36 had an instance of smoking recorded and collection of fines. While 47.2% reported to not have any instance of smoking and fine collection. Fifty per cent of the institutions had no record of fine collection amounting to defiance of the law. 75 per cent of institutions did some kind of awareness activities which was not a direct statutory requirement, but a recommended guideline. Conclusion The results show that the intent to decentralise the compliance of the tobacco control law in New Delhi by the higher educational institutions has not been universally successful and requires much effort for its on-ground penetration. Such studies have a policy impact as they serve as an example for the generalisability of such statutes, which only work when there is implementation from the bottom-up and when the deterrent is also strong with incentivisation to the educational institutions to implement tobacco control with vigour.

Disparities in prostate cancer screening, diagnoses, management, and outcomes between Indigenous and non-Indigenous men in a universal health care system.

BACKGROUND: Indigenous Peoples have higher morbidity rates and lower life expectancies than non-Indigenous Canadians. Identification of disparities between Indigenous and non-Indigenous men regarding prostate cancer (PCa) screening, diagnoses, management, and outcomes was sought. METHODS: An observational cohort of men diagnosed with PCa between June 2014 and October 2022 was studied. Men were prospectively enrolled in the province-wide Alberta Prostate Cancer Research Initiative. The primary outcomes were tumor characteristics (stage, grade, and prostate-specific antigen [PSA]) at diagnosis. Secondary outcomes were PSA testing rates, time from diagnosis to treatment, treatment modality, and metastasis-free, cancer-specific, and overall survivals. RESULTS: Examination of 1,444,974 men for whom aggregate PSA testing data were available was performed. Men in Indigenous communities were less likely to have PSA testing performed than men outside of Indigenous communities (32 vs. 46 PSA tests per 100 men [aged 50-70 years] within 1 year; p < .001). Among 6049 men diagnosed with PCa, Indigenous men had higher risk disease characteristics: a higher proportion of Indigenous men had PSA ≥ 10 ng/mL (48% vs. 30%; p < .01), TNM stage ≥ T2 (65% vs. 47%; p < .01), and Gleason grade group ≥ 2 (79% vs. 64%; p < .01) compared to non-Indigenous men. With a median follow-up of 40 months (interquartile range, 25-65 months), Indigenous men were at higher risk of developing PCa metastases (hazard ratio, 2.3; 95% CI, 1.2-4.2; p < .01) than non-Indigenous men. CONCLUSIONS: Despite receiving care in a universal health care system, Indigenous men were less likely to receive PSA testing and more likely to be diagnosed with aggressive tumors and develop PCa metastases than non-Indigenous men.

Does the Presence of Asbestos-Containing Materials in Buildings Post-construction and Before Demolition Have an Impact on the Exposure to Occupants in Non-occupational Settings?

This narrative review aims to determine if asbestos-containing materials in buildings pose a hazard to building occupants in non-occupational settings. This paper is limited to the post-construction and pre-demolition stages of a building. The researchers selected 19 studies from the 126 studies screened, concerning exposure to asbestos fibers in non-occupational building settings, with a focus on post-construction and pre-demolition phases. The literature review found that certain conditions, such as the measurement techniques, standards, and previous data availability, prevent a conclusive answer to the research question. Some studies have pointed towards an effect of asbestos-containing materials on health of occupants in non-occupational settings. But, there are some that do not suggest a positive relationship between non-occupational exposure and the presence of asbestos-containing materials, and therefore these provide scope for further research, as these studies also do not rule out the relationship completely. The present study highlights the gaps in current knowledge and indicates areas for further research. Until conclusive evidence based on revised threshold standards and accurate measurement techniques is available, asbestos-containing materials may be considered unsafe for use in non-occupational settings, especially ones that young people and children occupy.

Synthesis and Biological Evaluation of Novel 1H-Benzo[d]imidazole Derivatives as Potential Anticancer Agents Targeting Human Topoisomerase I.

Small molecules that modulate biological functions are targets of modern-day drug discovery efforts. A new series of novel 1H-benzo[d]imidazoles (BBZs) were designed and synthesized with different functional groups at the phenyl ring and variable lengths of the alkyl chain at the piperazine end as anticancer agents. We identified human topoisomerase I (Hu Topo I) as a probable target of these molecules through a computational study and DNA relaxation assay, a functional assay of the Hu Topo I enzyme. UV absorption, fluorescence, and circular dichroism spectroscopy were used to study interactions between BBZ and DNA. Out of 16 compounds, 11a, 12a, and 12b showed strong binding affinity and thermal stabilization of AT sequence-specific DNA. BBZs were screened against a panel of 60 human cancer cell lines at National Cancer Institute, USA. Most potent molecules 11a, 12a, and 12b showed 50% growth inhibition (GI50) in a concentration range from 0.16 to 3.6 µM cancer cells. Moreover, 12b showed 50% inhibition of the relaxation of DNA by Hu Topo I at 16 µM. Furthermore, flow cytometry revealed that 11a, 12a, and 12b cause prominent G2M arrest of cancer cells. In view of the above, we propose that 12b deserves to be further evaluated for its therapeutic use as an anticancer agent.

Pyrazoline analogs as potential anticancer agents and their apoptosis, molecular docking, MD simulation, DNA binding and antioxidant studies.

N-formyl pyrazoline derivatives (3a-3l) were designed and synthesized via Michael addition reaction through cyclization of chalcones with hydrazine hydrate in presence of formic acid. The structural elucidation of N-formyl pyrazoline derivatives was carried out by various spectroscopic techniques such as 1H, 13C NMR, FT-IR, UV-visible spectroscopy, mass spectrometry and elemental analysis. Anticancer activity of the pyrazoline derivatives (3a-3l) was evaluated against human lung cancer (A549), fibrosarcoma cell lines (HT1080) and human primary normal lung cells (HFL-1) by MTT assay. The results of anticancer activity showed that potent analogs 3b and 3d exhibited promising activity against A549 (IC50 = 12.47 ± 1.08 and 14.46 ± 2.76 µM) and HT1080 (IC50 = 11.40 ± 0.66 and 23.74 ± 13.30 µM) but low toxic against the HFL-1 (IC50 = 116.47 ± 43.38 and 152.36 ± 22.18 µM). The anticancer activity of potent derivatives (3b and 3d) against A549 cancer cell line was further confirmed by flow cytometry based approach. DNA binding interactions of the pyrazoline derivatives 3b and 3d have been carried out with calf thymus DNA (Ct-DNA) using absorption, fluorescence and viscosity measurements, circular dichroism and cyclic voltammetry. Antioxidant potential of N-formyl pyrazoline derivatives (3a-3l) has been also estimated through DPPH (2,2-diphenyl-1-picrylhydrazyl) free radical and H2O2. Results revealed that all the compounds exhibited significant antioxidant activity. In silico molecular modelling and ADMET properties of pyrazoline derivatives were also studied using PyRx software against topoisomerase II receptor with PDB ID: 1ZXM to explore their best hits. MD simulation of 3b and 3d was also carried out with topoisomerase II for structure-function correlation in a protein. HuTopoII inhibitory activity of the analogs (3a-3l) was examined by relaxation assay at varying concentrations 100-1000 µM.

Novel pyrazolo[3,4-d]pyrimidine with 4-(1H-benzimidazol-2-yl)-phenylamine as broad spectrum anticancer agents: Synthesis, cell based assay, topoisomerase inhibition, DNA intercalation and bovine serum albumin studies.

A series of new pyrazolo[3,4-d]pyrimidine possessing 4-(1H-benzimidazol-2-yl)-phenylamine moiety at C4 position and primary as well as secondary amines at C6 position has been designed and synthesized. Their antitumor activities were evaluated against a panel of 60 human cancer cell lines at National Cancer Institute (NCI). Six compounds displayed potent and broad spectrum anticancer activities at 10 µM. Compounds 8, 12, 14 and 17 proved to be the most active and efficacious candidate in this series, with mean GI50 values of 1.30 µM, 1.43 µM, 2.38 µM and 2.18 µM, respectively against several cancer cell lines. Further biological evaluation of these compounds suggested that these compounds induce apoptosis and inhibit human topoisomerase (Topo) IIα as a possible intracellular target. UV-visible and fluorescence studies of these compounds revealed strong interaction with ct-DNA and bovine serum albumin (BSA).

Design, synthesis, cytotoxicity, HuTopoIIα inhibitory activity and molecular docking studies of pyrazole derivatives as potential anticancer agents.

In an attempt to find potential anticancer agents, a series of novel ethyl 4-(3-(aryl)-1-phenyl-1H-pyrazol-4-yl)-2-oxo-6-(pyridin-3-yl)cyclohex-3-enecarboxylates 5a-i and 5-(3-(4-fluorophenyl)-1-phenyl-1H-pyrazol-4-yl)-3-(pyridin-3-yl)-4,5-dihydropyrazole-1-carbothioamides 6a-i were designed, synthesized and evaluated for their topoisomerase IIα inhibitory activity and in vitro cytotoxicity against a panel of cancerous cell lines (MCF-7, NCI-H460, HeLa) and a normal cell line (HEK-293T). Molecular docking studies of all the synthesized compounds into the binding site of topoisomerase IIα protein (PDB ID: 1ZXM) were performed to gain a comprehensive understanding into plausible binding modes. These compounds were also screened for in silico drug-likeliness properties on the basis of the absorption, distribution, metabolism and excretion (ADME) prediction. Among all the synthesized compounds, analogue 5d showed superior cytotoxicity with an IC50 value of 7.01±0.60µM for HeLa, 8.55±0.35µM for NCI-H460 and 14.31±0.90 for MCF-7 cancer cell lines. Further, compound 5d showed 70.82% inhibition of topoisomerase IIα at a concentration of 100µM with maximum docking score of -8.24. Results of ADME prediction revealed that most of these compounds showed in silico drug-likeliness properties within the ideal range.

Screening of Psychological Distress in Cancer Patients During Chemotherapy: A Cross-sectional Study.

OBJECTIVE: The objective of this prospective, noninterventional, 8-months, observational study was to analyze and compare depression, anxiety, and stress (DAS) levels and their impacting factors in homogenous surviving cancer patients receiving chemotherapy as compared to normal control. MATERIALS AND METHODS: A prospective and descriptive study was carried out jointly by Pharmacology and Oncology departments of a tertiary care center in Malwa region of Punjab. The data was collected by administering the validated questionnaire/response (21-item Depression Anxiety and Stress Scale (DASS-21)) after taking ethical approval and informed consent. RESULTS: All eligible 300 subjects participated in the study and they were compared with 300 matched control. The mean age of the cases (cancer patients) and controls was 50.58 ± 13.64 and 46.1 ± 11.78 (mean (M) ± standard deviation (SD)) years. Statistical significant difference was observed in mean 'scoring of DAS' in cancer patients when compared with control groups. Anxiety mean scoring showed a statistical significant difference in groups (according to chemotherapy cycles given and duration of disease). Stress was more observed in breast cancer patients. CONCLUSION: Holistic approach in cancer management including psychological evaluation and its solution at appropriate time/stage signifies the need of time as the present study revealed that the percentage of DAS as per the DASS scale was 90, 56, and 28%, respectively. A judicious diagnosis with an apposite intercession including psychological consultation with social support at appropriate time may alleviate the extra burden of psychological disorder, rather enhance the quality of life of cancer-affected rural population.

Activation of proteolytic enzymes and depression of the sarcolemmal Na+/K+-ATPase in ischemia-reperfused heart may be mediated through oxidative stress.

We tested whether the activation of proteolytic enzymes, calpain, and matrix metalloproteinases (MMPs) during ischemia-reperfusion (I/R) is mediated through oxidative stress. For this purpose, isolated rat hearts were subjected to a 30 min global ischemia followed by a 30 min reperfusion. Cardiac function was monitored and the activities of Na(+)/K(+)-ATPase, Mg(2+)-ATPase, calpain, and MMP were measured. Depression of cardiac function and Na(+)/K(+)-ATPase activity in I/R hearts was associated with increased calpain and MMP activities. These alterations owing to I/R were similar to those observed in hearts perfused with hypoxic medium, H(2)O(2) and xanthine plus xanthine oxidase. The I/R-induced changes were attenuated by ischemic preconditioning as well as by perfusing the hearts with N-acetylcysteine or mercaptopropionylglycine. Inhibition of MMP activity in hearts treated with doxycycline depressed the I/R-induced changes in cardiac function and Na(+)/K(+)-ATPase activity without affecting the calpain activation. On the other hand, inhibition of calpain activity upon treatment with leupeptin or MDL 28170 significantly reduced the MMP activity in addition to attenuating the I/R-induced alterations in cardiac function and Na(+)/K(+)-ATPase activity. These results suggest that the I/R-induced depression in Na(+)/K(+)-ATPase and cardiac function may be a consequence of the increased activities of both calpain and MMP because of oxidative stress in the heart.

Ischemia-reperfusion-induced changes in sarcolemmal Na+/K+-ATPase are due to the activation of calpain in the heart.

Depression in cardiac performance due to ischemia-reperfusion (I/R) injury is associated with the development of oxidative stress and decreased sarcolemmal (SL) Na+/K+-ATPase activity. Since both I/R and oxidative stress have been reported to promote the occurrence of intracellular Ca2+ overload and activate proteases such as calpain, this study was undertaken to investigate whether the activation of calpain in I/R hearts is associated with alterations in the SL Na+/K+-ATPase activity and its isoform content. For this purpose, isolated rat hearts treated with and without 2 different calpain inhibitors (leupeptin and MDL28170) were subjected to 30 min ischemia followed by 60 min of reperfusion, and the cardiac function, SL Na+/K+-ATPase activity, Na+/K+-ATPase isoform protein content, and calpain activity were measured. The I/R-induced depressions in cardiac function, Na+/K+-ATPase activity, and protein content of Na+/K+-ATPase isoforms were associated with an increase in calpain activity , but were prevented by treatment of hearts with leupeptin. Incubation of SL membranes with calpain decreased the Na+/K+-ATPase activity and protein content of its isoforms; these changes were also attenuated by leupeptin. The I/R-induced alterations in cardiac function and the activity of SL Na+/K+-ATPase and calpain were Ca2+-dependent and were prevented by MDL28170, a specific inhibitor of calpain. The I/R-induced translocation of calpain isoforms (I and II) from the cytosol to SL and the changes in distribution of calpastatin were also attenuated by treatment with calpain inhibitors. These results suggest that the depression in cardiac function and SL Na+/K+-ATPase activity in I/R hearts may be due to changes in the activity and translocation of calpain.

Differences in ischemia-reperfusion-induced endothelial changes in hearts perfused at constant flow and constant pressure.

Isolated hearts subjected to ischemia-reperfusion (I/R) exhibit depressed cardiac performance and alterations in subcellular function. Since hearts perfused at constant flow (CF) and constant pressure (CP) show differences in their contractile response to I/R, this study was undertaken to examine mechanisms responsible for these I/R-induced alterations in CF-perfused and CP-perfused hearts. Rat hearts, perfused at CF (10 ml/min) or CP (80 mmHg), were subjected to I/R (30 min global ischemia followed by 60 min reperfusion), and changes in cardiac function as well as sarcolemmal (SL) Na(+)-K(+)-ATPase activity, sarcoplasmic reticulum (SR) Ca(2+) uptake, and endothelial function were monitored. The I/R-induced depressions in cardiac function, SL Na(+)-K(+)-ATPase, and SR Ca(2+)-uptake activities were greater in hearts perfused at CF than in hearts perfused at CP. In hearts perfused at CF, I/R-induced increase in calpain activity and decrease in nitric oxide (NO) synthase (endothelial NO synthase) protein content in the heart as well as decrease in NO concentration of the perfusate were greater than in hearts perfused at CP. These changes in contractile activity and biochemical parameters due to I/R in hearts perfused at CF were attenuated by treatment with l-arginine, a substrate for NO synthase, while those in hearts perfused at CP were augmented by treatment with N(G)-nitro-l-arginine methyl ester, an inhibitor of NO synthase. The results indicate that the I/R-induced differences in contractile responses and alterations in subcellular organelles between hearts perfused at CF and CP may partly be attributed to greater endothelial dysfunction in CF-perfused hearts than that in CP-perfused hearts.

L-arginine administration recovers sarcoplasmic reticulum function in ischemic reperfused hearts by preventing calpain activation.

OBJECTIVE: Earlier studies have shown that impaired cardiac contractility in ischemia reperfusion (IR) is associated with alterations in sarcoplasmic reticulum (SR) function. Impaired release of nitric oxide (NO) has been reported during IR, while administration of NO donors, such as L-arginine (LA), has been shown to improve cardiac performance in IR hearts. We therefore investigated the mechanisms underlying the recovery of contractile function in IR hearts treated with LA. METHODS: Isolated rat hearts subjected to 30 min of global ischemia were reperfused for 60 min. The effects of LA on cardiac performance, SR function and its regulation were examined. RESULTS: IR-induced impairment in cardiac performance was associated with a reduction in SR function and its regulation. IR caused an increase in calpain activity and a decrease in the sarcolemmal and SR nitric oxide synthase (NOS) isoform protein content as well as cytosolic NO levels. Administration of LA prevented contractile dysfunction in IR hearts, which was associated with a recovery of SR function and SR regulation by protein phosphorylation. This was consistent with a recovery in protein levels of major SR Ca2+-cycling and Ca2+-regulatory proteins. LA treatment attenuated an increase in calpain activity, possibly by nitrosylation of calpain, and increased cytosolic NO levels and SR NOS protein content in IR hearts. DISCUSSION: These results suggest that LA administration improved cardiac contractility by preventing alterations in SR Ca2+ handling and calpain activation in IR hearts.

The sarcoplasmic reticulum proteins are targets for calpain action in the ischemic-reperfused heart.

Ca(2+) overload and free-radical injury are two mutually non-exclusive phenomena suggested to cause myocardial ischemia-reperfusion (IR)-induced contractile dysfunction; however, the mechanisms underlying their effects are not clear. One possible mechanism is the proteolytic modification of proteins by Ca(2+)-dependent proteases, such as calpains, which are activated during Ca(2+) overload that occurs in IR. The sarcoplasmic reticulum (SR) plays a central role in mediating cardiac contractility and therefore any impairment in SR function will induce cardiac contractile dysfunction. We therefore investigated the possibility whether SR proteins were the target for calpain action in IR. Langendorff-perfused rat hearts were subjected to IR in the presence and absence of leupeptin, a calpain inhibitor and the effects of calpain inhibition was examined on cardiac performance, SR function, and its regulation by protein phosphorylation as well as expression of SR Ca(2+)-cycling and -regulatory proteins. Our results show a depression in cardiac contractile function and activation of calpain during IR. Treatment with leupeptin recovered cardiac contractile function and attenuated calpain activity in IR hearts. The cardioprotection observed upon leupeptin treatment was associated with improved SR function and regulation. The recovery in SR function and regulation was consistent with prevention of IR-induced decrease in the expression of key SR Ca(2+)-handling and -regulatory proteins. Our results suggest that a downregulation of SR proteins by calpain may be a mechanism by which Ca(2+) overload causes cardiac contractile dysfunction during IR.

Pathogenesis of atherosclerosis: A multifactorial process.

Atherosclerosis is a leading cause of mortality and morbidity in the western world. It has been recognized for over a century, and the understanding of its pathogenesis has undergone many changes. Pathophysiological studies have unravelled the interactions of molecular and cellular elements involved in atherogenesis. The focus has shifted to the novel risk factors as well as characteristics and stability of atherosclerotic plaque; the genetic predisposition has further broadened the pathogenetic mechanisms. This review focuses on the molecular mechanisms involved in the evolution of the atherosclerotic plaque that may pave the way for selecting optimal therapies and preventing plaque complications. Atherosclerosis is no longer a disease attributed mainly to the high lipid content of the body. New insight into the disease pathology has shown it to be a disease of much greater ramifications. Endothelial damage and reactive oxygen species (and other free radicals) have predominantly emerged as factors in virtually all pathways leading to the development of atherosclerosis due to hyperlipidemia, diabetes, hypertension or smoking. Novel risk factors such as hyperhomocysteinemia, infections and systemic lupus erythematosus have emerged. Atherosclerosis has come to be regarded as a chronic inflammatory disease with an autoimmune component. The genetic basis of the disease assumes significance as candidate genes are identified and gene therapy becomes a promising new addition to the existing, less substantial conventional therapies.