SIRT6 in Regulation of Mitochondrial Damage and Associated Cardiac Dysfunctions: A Possible Therapeutic Target for CVDs.

Cardiovascular diseases (CVDs) can be described as a global health emergency imploring possible prevention strategies. Although the pathogenesis of CVDs has been extensively studied, the role of mitochondrial dysfunction in CVD development has yet to be investigated. Diabetic cardiomyopathy, ischemic-reperfusion injury, and heart failure are some of the CVDs resulting from mitochondrial dysfunction Recent evidence from the research states that any dysfunction of mitochondria has an impact on metabolic alteration, eventually causes the death of a healthy cell and therefore, progressively directing to the predisposition of disease. Cardiovascular research investigating the targets that both protect and treat mitochondrial damage will help reduce the risk and increase the quality of life of patients suffering from various CVDs. One such target, i.e., nuclear sirtuin SIRT6 is strongly associated with cardiac function. However, the link between mitochondrial dysfunction and SIRT6 concerning cardiovascular pathologies remains poorly understood. Although the Role of SIRT6 in skeletal muscles and cardiomyocytes through mitochondrial regulation has been well understood, its specific role in mitochondrial maintenance in cardiomyocytes is poorly determined. The review aims to explore the domain-specific function of SIRT6 in cardiomyocytes and is an effort to know how SIRT6, mitochondria, and CVDs are related.

Mechanisms Behind the Pharmacological Application of Biochanin-A: A review.

This review was aimed at summarizing the cellular and molecular mechanisms behind the various pharmacological actions of biochanin-A. Many studies have been reported claiming its application in cancers, metabolic disorders, airway hyperresponsiveness, cardiac disorders, neurological disorders, etc. With regard to hormone-dependent cancers like breast, prostate, and other malignancies like pancreatic, colon, lung, osteosarcoma, glioma that has limited treatment options, biochanin-A revealed agreeable results in arresting cancer development. Biochanin-A has also shown therapeutic benefits when administered for neurological disorders, diabetes, hyperlipidaemia, and other chronic diseases/disorders. Isoflavones are considered phenomenal due to their high efficiency in modifying the physiological functions of the human body. Biochanin-A is one among the prominent isoflavones found in soy (glycine max), red clover (Trifolium pratense), and alfalfa sprouts, etc., with proven potency in modulating vital cellular mechanisms in various diseases. It has been popular for ages among menopausal women in controlling symptoms. In view of the multi-targeted functions of biochanin-A, it is essential to summarize it's mechanism of action in various disorders. The safety and efficacy of biochanin-A needs to be established in clinical trials involving human subjects. Biochanin-A might be able to modify various systems of the human body like the cardiovascular system, CNS, respiratory system, etc. It has shown a remarkable effect on hormonal cancers and other cancers. Many types of research on biochanin-A, particularly in breast, lung, colon, prostate, and pancreatic cancers, have shown a positive impact. Through modulating oxidative stress, SIRT-1 expression, PPAR gamma receptors, and other multiple mechanisms biochanin-A produces anti-diabetic action. The diverse molecular mechanistic pathways involved in the pharmacological ability of biochanin-A indicate that it is a very promising molecule and can play a major impact in modifying several physiological functions.

Clinical Spectrum of Mercury Poisoning in India: Case-series from a Poison Control Center.

BACKGROUND: Mercury is a naturally occurring heavy metal that finds wide application in industrial and household settings. It exists in three chemical forms which include elemental (Hg0 ), inorganic mercurous (Hg+) or mercuric (Hg++) salts, and organic compounds. All forms are highly toxic, particularly to the nervous, gastrointestinal, and renal systems. Common circumstances of exposure include recreational substance use, suicide or homicide attempts, occupational hazards, traditional medicines, and endemic food ingestions as witnessed in the public health disasters in Minamata Bay, Japan and in Iraq. Poisoning can result in death or long-term disabilities. Clinical manifestations vary with chemical form, dose, rate, and route of exposure. AIMS AND OBJECTIVES: To summarize the incidence of mercury poisoning encountered at an Indian Poison Center and use three cases to highlight the marked variations observed in clinical manifestations and long-term outcomes among poisoned patients based on differences in chemical forms and routes of exposure to mercury. MATERIALS AND METHODS: A structured retrospective review of the enquiry-database of the Poison Information Center and medical records of patients admitted between August 2019 and August 2021 in a tertiary care referral center was performed. All patients with reported exposure to mercury were identified. We analyzed clinical data and laboratory investigations which included heavy metal (arsenic, mercury, and lead) estimation in whole blood and urine samples. Additionally, selected patients were screened for serum voltage-gated potassium ion channels (VGKC)- contactin-associated protein-like 2 (CASPR2) antibodies. Three cases with a classical presentation were selected for detailed case description. RESULTS: Twenty-two cases were identified between August 2019 and August 2021. Twenty (91%) were acute exposures while two (9%) were chronic. Of these, three representative cases have been discussed in detail. Case 1 is a 3.5-year-old girl who was ought to the emergency department with suspected elemental-mercury ingestion after biting a thermometer. Clinical examination was unremarkable. Chest and abdominal radiography revealed radiodense material in the stomach. Subsequent serial radiographs documented distal intestinal transit of the radiodense material. The child remained asymptomatic. This case exemplifies the largely nontoxic nature of elemental mercury ingestion as it is usually not absorbed from the gastrointestinal tract. Case 2 is a 27-year-old lady who presented with multiple linear nodules over both upper limbs after receiving a red intravenous injection for anemia. Imaging revealed metallic-density deposits in viscera and bones. Nodular biopsy was suggestive of mercury granulomas. A 24-hour urine mercury levels were elevated. She was advised chelation therapy with oral dimercaptosuccinic acid (DMSA). Case 3 is a 22-year-old lady who presented with acrodynia, neuromyotonia, tremulousness, postural giddiness, tachycardia, and hypertension for 2 months, associated with intractable, diffuse burning pain over the buttocks and both lower limbs, 1 month after completing a 3-week course of traditional medications for polycystic ovarian syndrome. A 24-hour urine normetanephrine levels and mercury levels were markedly elevated. Serum anti-VGKC antibodies were present. She was treated with glucocorticoids and oral DMSA with a favorable clinical response. CONCLUSIONS: The clinical manifestations of mercury toxicity are highly variable depending on the source, form, and route of mercury exposure and are related to its toxicokinetics.

Expediting Molecular Translational Approach of Mesenchymal Stem Cells in COVID-19 Treatment.

Coronavirus disease (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in late 2019 with severe respiratory failure and organ damage that later appeared as a pandemic disease. Worldwide, people's mental and physical health and socioeconomic have been affected. Currently, with no promising treatment for COVID-19, the existing anti-viral drugs and vaccines are the only hope to boost the host immune system to reduce morbidity and mortality rate. Unfortunately, several reports show that people who are partially or fully vaccinated are still susceptible to COVID-19 infection. Evidence suggests that COVID-19 immunopathology may include dysregulation of macrophages and monocytes, reduced type 1 interferons (IFN-1), and enhanced cytokine storm that results in hypersecretion of proinflammatory cytokines, capillary leak syndrome, intravascular coagulation, and acute respiratory distress syndrome (ARDS) ultimately leading to the worsening of patient's condition and death in most cases. The recent use of cell-based therapies such as mesenchymal stem cells (MSCs) for critically ill COVID-19 patients has been authorized by the Food and Drug Administration (FDA) to alleviate cytokine release syndrome. It protects the alveolar epithelial cells by promoting immunomodulatory action and secreting therapeutic exosomes to improve lung function and attenuate respiratory failure. As a result, multiple clinical trials have been registered using MSCs that aim to use various cell sources, and dosages to promote safety and efficacy against COVID-19 infection. In this review, the possibility of using MSCs in COVID-19 treatment and its associated challenges in their use have been briefly discussed.

Sirtuins as therapeutic targets for improving delayed wound healing in diabetes.

Sirtuins are a vast family of histone deacetylases, which are NAD+ dependent enzymes, consisting of seven members, namely SIRT 1, SIRT 6 and SIRT 7 located within the nucleus, SIRT 2 in the cytoplasm and SIRT 3, SIRT 4 and SIRT 5 in the mitochondria. They have vital roles in regulating various biological functions such as age-related metabolic disorders, inflammation, stress response, cardiovascular and neuronal functions. Delayed wound healing is one of the complication of diabetes, which can lead to lower limb amputation if not treated timely. SIRT 1, 3 and 6 are potent targets for diabetic wound healing. SIRT 1 deficiency reduces recruitment of fibroblasts, macrophages, mast cells, neutrophils to wound site and delays wound healing; negatively expressing MMP-9. The SIRT 1 mediated signalling pathway in diabetic wound healing is the SIRT 1-FOXO-c-Myc pathway. On the contrary, SIRT 3 deficiency impairs proliferation and migration of fibroblasts and SIRT 6 deficiency impairs wound closure rate and interrupts the vascular remodelling. This review focuses on the role of sirtuins in improving delayed wound healing in diabetes and its natural modulators with their specific functions towards healing diabetic wounds.

Impact of prior vaccination with CovishieldTM and Covaxin® on mortality among symptomatic COVID-19 patients during the second wave of the pandemic in South India during April and May 2021: a cohort study.

BACKGROUND: COVID-19 vaccines were authorised for emergency use to mitigate the impact of the pandemic. This study evaluated the effect of prior vaccination with either Oxford Astra Zeneca's Covishield™ or Bharath Biotech's Covaxin® on mortality among symptomatic COVID-19 patients during the second wave of the pandemic in India. METHODOLOGY: In this cohort study comprising of RT-PCR confirmed symptomatic COVID-19 patients presenting during April and May 2021, the effect of prior vaccination on mortality (primary outcome), need for hospitalization, oxygen therapy, non-invasive ventilation (NIV) and intensive care unit (ICU) admission were assessed and expressed as risk ratio (RR) with 95% confidence intervals (CI). RESULTS: The mean (SD) age of the cohort (n = 4183) was 46.3 (15.5) years; 17.9% (748/4183) had received at least one dose of Covishield™ and 4.8% (201/4183) had received Covaxin®. Mortality was 0.2% (95% CI: 0.2% - 0.7%), 3.5% (1.9-5.2%), 6.2% (0.3-12%) and 12.9% (11.8-14.1%) among fully vaccinated (>2 weeks after two doses), partially vaccinated (>2 weeks after one dose or <2 weeks after two doses), indeterminate (<2 weeks after one dose) and unvaccinated patients respectively. The difference in mortality among unvaccinated vs. fully vaccinated was 12.7% (95% CI: 11.4-13.9%), unvaccinated vs. partially vaccinated was 9.4% (7.4-11.4%) and unvaccinated vs. indeterminate vaccinated was 6.8% (0.8-12.7%). On adjusted analysis, as compared to unvaccinated patients, at least one dose of vaccine reduced the need for hospitalization (RR: 0.40; 95% CI: 0.35-0.47), oxygen (0.33; 0.27-0.40), NIV (0.23; 0.17-0.32), ICU admission (0.18; 0.12-0.27) and mortality (0.18; 0.11-0.29). CONCLUSION: Among symptomatic COVID-19 patients, prior vaccination with Covishield ™ or Covaxin® impacted the severity of illness and reduced mortality during a period of widespread delta variant circulation. Full vaccination conferred greater protection than partial vaccination.

The impact of demonetisation on the utilisation of hospital services, patient outcomes and finances: a multicentre observational study from India.

BACKGROUND: This study assessed trends in healthcare utilisation in relation to the implementation of an economic policy in India wherein 500 and 1000 rupee notes were demonetised. METHODS: In this ambidirectional observational study of private not-for-profit hospitals, data on hospital outpatient and inpatient numbers, surgeries, emergency department (ED) visits, obstetric admissions and mortality were obtained for pre-demonetisation (September/October 2016), early (November/December 2016) and late demonetisation (January/February 2017), and post-demonetisation periods (March/April 2017) and compared with the control period (2015-2016) from 11 centres (three tertiary hospitals; eight secondary). A Bayesian regression analysis was performed to adjust for seasonal (winter) effect. Monthly financial data, including the proportion of cash versus non-cash transactions, were collected. FINDINGS: Overall, at the pooled all-hospital level, Bayesian analysis showed non-significant increase in outpatients (535.4, 95% CI -7097 to 8116) and decrease in deaths (-6.3 per 1000 inpatients, 95% CI -15.45 to 2.75) and a significant decrease in inpatients (-145.6, 95% CI -286.4 to -10.63) during demonetisation. Analysis at the level of secondary and tertiary hospitals showed a variable effect. For individual hospitals, after adjusting for the seasonal effect, some hospitals observed a significant reduction in outpatient (n=2) and inpatient (n=3) numbers, ED visits (n=4) and mortality (n=2) during demonetisation, while others reported significantly increased outpatient numbers (n=3) and ED visits (n=2). Deliveries remained unchanged during demonetisation in the hospitals that provided the service. There was no significant reduction in hospital incomes during demonetisation. In tertiary hospitals, there was a significant increase in non-cash component of transactions from 35% to 60% (p=0.02) that persisted beyond the demonetisation period. CONCLUSIONS: The effect of demonetisation on healthcare utilisation was variable. Some hospitals witnessed a significant reduction in utilisation in some areas, while others reported increased utilisation. There was an increase in non-cash transactions that persisted beyond the period of demonetisation.

Secondary hospital rotation of postgraduate trainees: A pilot study.

Background: Postgraduate (PG) training in general medicine requires reorientation to meet the healthcare needs of India. In this pilot study, we designed a secondary hospital (SH) posting for medicine PGs to sensitize them to the practice of medicine and challenges in a rural SH setting. Methods: PG trainees in general medicine were sent for a 2-week rotation to select SHs. A faculty coordinator from the teaching hospital facilitated the programme. The SH faculty used qualitative tools to assess the performance of the trainees. The trainees also evaluated the programme using open- and close-ended questionnaires. Results: Eighteen PG trainees in general medicine were posted to six rural SHs. Data analysis showed that the training exposure provided sensitization to the challenges of medical practice in such settings and the need to be multicompetent. Seventeen (94%) trainees felt that they gained insight into the issues that are specific for practice at an SH and >80% expressed confidence about the knowledge and skills gained during that exposure to enhance medical practice in a resource-limited setting. They were also sensitized to various issues of secondary care including skills of multi-competence, the ability to handle a wide variety of cases with limited investigations, a cost-effective approach, decision-making on referrals, procedural competence and flexibility to adapt to new situations. Conclusion: A short SH posting can positively sensitize PGs to the practice of medicine and challenges in secondary care settings.

Acoustic and Aerodynamic Characteristics of Choral Singers.

OBJECTIVES: The study aimed to investigate and compare the acoustic and aerodynamic characteristics of choral singers and nonsingers. METHOD: Twenty choral singers and 20 nonsingers in the age range of 20-30 years with no vocal pathology participated in the study. For acoustic analysis, the voice sample was recorded and analyzed using Praat software (Phonetic Sciences, University of Amsterdam, Amsterdam, Netherlands) version 6.0.33 and for aerodynamic evaluation, Helios 401 PC based spirometer (Recorders & Medicare System Pvt. Ltd., Panchkula, Haryana, India) was used. RESULTS: The results from acoustic analysis of female groups revealed higher F0 in singers than nonsingers; higher jitter, shimmer, and noise-to-harmonics ratio (NHR) values were obtained for nonsingers compared to singers. Results from acoustic analysis of male groups revealed significantly higher F0 in singers than nonsingers and significantly higher shimmer and NHR values for nonsingers compared to singers. Results from aerodynamic analysis for both male and female groups revealed higher vital capacity, forced vital capacity, and slow vital capacity in singers than nonsingers. CONCLUSION: The results revealed better control over phonatory and respiratory subsystems among singers compared to nonsingers, although the singers were untrained. This could be possible due to the fact that long-term singing practices involving vocal modulation and changes in the breathing pattern, better respiratory control during the expiratory phase among singers. However, as the participants of the singing group are untrained, further studies are required to compare the acoustic and the aerodynamic characteristics with trained singers.