Brain Mitochondria as a Therapeutic Target for Carnosic Acid.

Carnosic acid (CA), a diterpene obtained mainly from Rosmarinus officinalis and Salvia officinalis, exerts antioxidant, anti-inflammatory, and anti-apoptotic effects in mammalian cells. At least in part, those benefits are associated with the ability that CA modulates mitochondrial physiology. CA attenuated bioenergetics collapse and redox impairments in the mitochondria obtained from brain cells exposed to several toxicants in both in vitro and in vivo experimental models. CA is a potent inducer of the major modulator of the redox biology in animal cells, the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2), which controls the expression of a myriad of genes whose products are involved with cytoprotection in different contexts. Moreover, CA upregulates signaling pathways related to the degradation of damaged mitochondria (mitophagy) and with the synthesis of these organelles (mitochondrial biogenesis). Thus, CA may be considered an agent that induces mitochondrial renewal, depending on the circumstances. In this review, we discuss about the mechanisms of action by which CA promotes mitochondrial protection in brain cells.

Coenzyme Q10, Biochanin A and Phloretin Attenuate Cr(VI)-Induced Oxidative Stress and DNA Damage by Stimulating Nrf2/HO-1 Pathway in the Experimental Model.

Hexavalent chromium [Cr(VI)] has emerged as a prevailing environmental and occupational contaminant over the past few decades. However, the knowledge is sparse regarding Cr(VI)-induced neurological aberrations, and its remediation through natural bioactive compounds has not been fully explored. This study intended to probe the possible invigorative effects of nutraceuticals such as coenzyme Q10 (CoQ10), biochanin A (BCA), and phloretin (PHL) on Cr(VI) intoxicated Swiss albino mice with special emphasis on Nrf2/HO-1/NQO1 gene expressions. Mice received potassium dichromate (75 ppm) through drinking water and were simultaneously co-treated intraperitoneally with CoQ10 (10 mg/kg), BCA, and PHL (50 mg/kg) each for 30-day treatment period. The statistics highlight the elevated levels of lipid peroxidation (LPO) and protein carbonyl content (PCC) with a concomitant reduction in the superoxide dismutase (SOD), glutathione-S-transferase (GST), reduced glutathione (GSH), total thiols (TT), catalase (CAT), and cholinesterase activities in the Cr(VI)-exposed mice. The collateral assessment of DNA fragmentation, DNA breakages, and induced histological alterations was in conformity with the above findings in conjugation with the dysregulation in the Nrf2 and associated downstream HO-1 and NQO1 gene expressions. Co-treatment with the selected natural compounds reversed the above-altered parameters significantly, thereby bringing cellular homeostasis in alleviating the Cr(VI)-induced conciliated impairments. Our study demonstrated that the combination of different bioactive compounds shields the brain better against Cr(VI)-induced neurotoxicity by revoking the oxidative stress-associated manifestations. These compounds may represent a new potential combination therapy due to their ability to modulate the cellular antioxidant responses by upregulating the Nrf2/HO-1/NQO1 signaling pathway against Cr(VI)-exposed population. HIGHLIGHTS: Cr(VI)-associated heavy metal exposure poses a significant threat to the environment, especially to living organisms. Cr(VI) exposure for 30 days resulted in the free radical's generation that caused neurotoxicity in the Swiss albino mice. Natural compounds such as coenzyme Q10, biochanin A, and phloretin counteracted the neurotoxic effect due to Cr(VI) exposure in scavenging of free radicals by enhancing Nrf2/HO-1/NQO1 gene expressions in maintaining the cellular homeostasis.

Effectiveness of early awake self proning strategy in non-intubated patients with COVID-19 hypoxemia: an open-labelled randomized clinical trial from Jodhpur, India.

Awake self-proning is being used widely as respiratory support in COVID-19 hypoxemia, in resource-limited settings. We aimed to investigate the effectiveness of early awake self-proning in preventing mortality and the need for intubation in adults with moderate COVID-19 hypoxemia. In this randomized clinical trial with inten-tion-to-treat analysis, we enrolled eligible adults with COVID-19 hypoxemia (SpO2 <94%), requiring supplemental oxygen via nasal prongs or facemask from a tertiary-care setting in Jodhpur, India between June 15 to December 24, 2020. Awake proning comprised of 4-hour cycles with prone position maintained 2 h per cycle. The control group did not maintain any specific position. All participants received standard care. The primary outcomes were 30-day mortal-ity and requirement for mechanical ventilation. Of 502 participants included, mean (SD) age was 59.7 (12.7) years with 124 women (24.6%); 257 were randomized to awake-proning, 245 to control group and all 502 were included for follow-up mortality analysis. Mortality at follow-up was 16.3% in the awake-prone and 15.1% in the control group [OR:1.10 (0.68-1.78), p=0.703). The requirement of mechanical ventilation was 10% in both groups (p=0.974). Survival time (in days) was not significantly different between the groups [Log-rank test, HR: 1.08 (95% CI, 0.70-1.68), p=0.726]. Likewise, time to intubation was comparable (Log-rank test, HR: 0.93 (95% CI, 0.56-1.70), p=0.974). Hence, awake self-proning did not improve survival or requirement of mechanical-ventilation in non-intubated patients with mild to moderate COVID-19 hypox-emia. Trial Registration: Clinical trial registry of India, ID: CTRI/2020/06/025804.   The trial is accessible from WHO's International Clinical Trials Registry Platform (ICTRP) at https://trialsearch.who.int ***************************************************************   *Appendix Authors list  Deepak Kumar1, Gopal Krishna Bohra1, Nishant Kumar Chauhan2, Nikhil Kothari3, Vijaya Lakshmi Nag4 Sanjeev Misra5  1Department of Internal Medicine; 2Department of Pulmonary Medicine; 3Department of Anaesthesiology and Critical Care; 4Department of Microbiology; 5Department of Surgical Oncology, All India Institute of Medical Sciences, Jodhpur, India.

Therapeutic effects of CoenzymeQ10, Biochanin A and Phloretin against arsenic and chromium induced oxidative stress in mouse (Mus musculus) brain.

Arsenic and chromium are the most common environmental toxicants prevailing in nature. Hence, the present study endeavors to investigate the salutary effects of Coenzyme Q10 (CoQ10), Biochanin A (BCA), and Phloretin (PHL) on the combined neurotoxic impact of arsenic and chromium in the Swiss albino mice (Mus musculus). Sodium meta-arsenite (100 ppm) and potassium dichromate (75 ppm) were given orally in conjugation with CoQ10 (10 mg/kg), BCA & PHL (50 mg/kg each) in accordance with body weight per day for the 2 weeks experimental duration. Weight reduction was figured out in the exposed toxic group of arsenic and chromium in contrast with the comparison group (control), and with the selected anti-oxidants treatment, it rose significantly to the basal status (p < 0.05). The concentration of arsenic and chromium was reduced significantly (p < 0.001) amidst all the natural compounds co-medicated groups. Anti-oxidant indicators, viz. lipid peroxidation (LPO) and protein carbonyl content (PCC), were found elevated, with reduction observed in the levels of superoxide dismutase (SOD), reduced glutathione (GSH), glutathione s-transferase (GST), and total thiols (TT) in the arsenic and chromium, co-exposed mice. The alterations in redox homeostasis were well corroborated with the estimations of cholinesterase's enzymes (p < 0.05) along with DNA fragmentation assay and altered Nrf2 signaling. The administration of CoQ10, BCA, and PHL ameliorated the effects of arsenic and chromium induced oxidative stress in the exposed mice. Our research unfolds the remedial outcome of these natural compounds contrary to the combined arsenic and chromium associated-neurotoxicity in the experimental model.

Correlates of Metabolic Syndrome in Patients with Schizophrenia: An Exploratory Study.

Metabolic syndrome (MS) is commonly reported in patients with severe mental illness including schizophrenia, but data is sparse from north-western India. The study was aimed to assess the metabolic profile in patients with schizophrenia. Patients with schizophrenia and healthy controls (N = 55 in each group) were recruited from psychiatric outpatient clinic and evaluated for the presence of metabolic syndrome using the modified National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP-III) criteria. Prevalence of MS was significantly greater in patient group (34.5%), compared to healthy controls (14.5%). Other 31 patients (56.4%) had one or two metabolic abnormalities. Most common metabolic abnormality was higher waist circumference in both the groups. Nearly half of the patients (56%) were obese. Greater age, weight, body mass index, and obesity were significantly associated with MS and similar variables were significant predictors of MS. MS was not associated with duration and severity of schizophrenia (PANSS score), attitude towards psychotropics (DAI-10 score), functionality (GAF score) and demographic variables. Metabolic abnormalities were significantly greater in patients with schizophrenia. It calls for comprehensive evaluation of the patients with schizophrenia, with timely management and effective prevention of metabolic problems.

Acute Lung Injury with Amphotericin Infusion in a Patient with Invasive Mucormycosis.

BACKGROUND: Amphotericin B is a pivotal drug for the management of invasive fungal infections. However, it has a significant toxicity profile with acute infusion reactions like fever, chills, vomiting, anaphylaxis, and nephrotoxicity in patients with long-term use. Pulmonary reactions mimicking acute pulmonary edema are unusual with amphotericin. CASE DESCRIPTION: We report a case of a 51-year-old male diagnosed with rhinomaxillary mucormycosis, who developed acute onset breathlessness, bilateral diffuse pulmonary infiltrates after amphotericin infusion. The patient recovered spontaneously within a few hours after the cessation of amphotericin, which was parallel with the normalization of Chest X-ray. Furthermore, the Naranjo adverse reaction probability score was 9, which established a definite causal relation between drug use and adverse event. CONCLUSION: Clinicians should be aware of acute lung injury in patients treated with amphotericin infusion. In cases with no alternative available, a slow infusion of amphotericin with close monitoring is required to prevent life-threatening pulmonary reactions.

Acute Myocardial Infarction in Hemophilia A with HIV and Hyperhomocysteinemia- a rare case report.

BACKGROUND: Patients with hemophilia have a hypocoagulable state and less chances of thrombus formation. Therefore, expected to have a lower cardiovascular mortality than the general population. The lower cardiovascular mortality can be explained by less chances of thrombus formation due to hypocoagulability. CASE PRESENTATION: Here we present a case of a 42-year-old male patient presented with severe chest pain radiating to back for 4 days. ECG was suggestive of recent acute anteroseptal myocardial infarction. There was a history of receiving intravenous recombinant factor VIII, 1 hour prior to the onset of chest pain for knee joint swelling. The occurrence of acute coronary syndromes in patients with hemophilia A is uncommon and rarely reported. CONCLUSION: Here we report a patient of severe hemophilia A who developed acute myocardial infarction after administration of recombinant factor VIII.

Evaluation of Liver Histopathological Findings of Coronavirus Disease 2019 by Minimally Invasive Autopsies.

AIM: The severe acute respiratory syndrome coronavirus 2 outbreak resulted in severe health impact with the loss of many lives across the world. Pulmonary parenchyma suffers the most from the brunt of the infection. However, evidence suggested a systemic involvement during the course of illness. Information on morphological changes of the liver is sparse in the literature. We aimed to evaluate the pathological findings in the liver by minimally invasive autopsies. METHODS: Postmortem core biopsies of the liver obtained from patients who succumbed to coronavirus disease 2019 disease were studied. Demographic findings, comorbidities, and relevant laboratory tests were collected. Detailed histopathological changes were assessed. RESULTS: Liver function tests were available in 40 cases, and it was deranged in 80% cases. A spectrum of histological changes was observed. Macrovesicular steatosis and nonspecific portal inflammation of mild degree were the common morphological changes. Features suggestive of vascular alteration were noted in more than half of the cases. These included increased portal vein branches, irregular luminal dilation, and herniation of portal veins into the periportal hepatocytes. In addition, we observed morphological changes attributed to terminal shock-related changes. CONCLUSION: The present study results highlight that liver parenchyma changes may be related to multiple pathogenic mechanisms. The presence of vascular alteration in portal tracts suggests derangement of hepatic vasculature related to systemic hypercoagulable state induced by the viral infection. It remains to be established if the histological changes are related to direct viral insult or to the systemic response caused by the viral attack.

Evaluation of Bone Marrow Findings of COVID-19 by Minimally Invasive Autopsies: A Single Tertiary Care Centre Experience from India.

The 2019 novel coronavirus (2019-nCoV) originated in Wuhan City of China. In India, first confirmed case of coronavirus disease (COVID-19) was reported on January 30, 2020 and India is presently hit by second wave of COVID-19. The aim of the present study was to evaluate bone marrow findings of COVID-19 by minimally invasive autopsies to aid in understanding pathophysiology of the disease. This prospective study was conducted at tertiary care centre of Western Rajasthan. After obtaining approval from Institute's ethics committee and consent from next of kins, minimally invasive autopsies were conducted in 37 COVID-19 deceased patients within an hour after the death. The tissue specimens were processed with standard biosafety measures. Electronic medical records were reviewed retrospectively and patients' clinical details and results of laboratory investigations were noted. In this prospective study, bone marrow biopsies were collected from 37 COVID-19 minimally invasive autopsies. Mean age of these cases was 61.8 years and male: female ratio was 2.36. Comorbidities were observed in 25 (67.5%) of all cases. Histopathological analysis revealed hypercellular, normocellular and hypocellular marrow in 5, 25 and 5 cases respectively (two biopsies were inadequate). There was marked interstitial prominence of histiocytes in 24 (68.5%) cases. Out of these, evidence of haemophagocytosis was observed in 14 (40%) cases, marked increase of haemosiderin laden macrophages in 20 (57.1%) cases. There was prominence of plasma cells in 28 (80%) cases. The present study attempted to fill the gap of dearth of literature from our country in COVID-19 autopsy studies by highlighting bone marrow findings. The data support the evidence of development of secondary haemophagocytic lymphocytosis in COVID-19 cases.

Pathways of care and attitudes toward psychotropics in patients with depressive disorders and psychotic disorders.

Objectives: Delay in institution of appropriate mental healthcare is closely linked with attitudes, stigma, and availability of services, which further directs the help seeking pathways. This study was aimed to assess the pathway of care and attitudes toward psychotropic medications among patients with depressive disorder and psychotic disorders. Materials and Methods: Eighty outpatients with depressive disorder and 40 patients with psychotic disorder were assessed in a tertiary care center for pathways to care and attitude toward psychotropics through Attitude toward Psychotropic Medications Questionnaire and Drug attitude inventory-10. Results: The psychiatrist remained the most common first treatment contact (46% in depression and 62% in psychosis). Greater number of patients in psychotic disorder group had first treatment contact with faith healers or exorcist (17.5%), compared to depressive disorder (6.2%). Patients in depressive group had more favorable attitude toward psychotropics compared to psychosis group. Majority of patients had favorable attitude toward psychotropic medications, but they also had substantial misconceptions about side effects, utility, and need of taking lesser than prescribed doses. Conclusions: Although majority of patients had favorable attitude, they also had substantial misconceptions about medications. These issues need to be addressed for better delivery of comprehensive mental healthcare.

Evaluation of Pathological Findings of COVID-19 by Minimally Invasive Autopsies: A Single Tertiary Care Center Experience from India.

Objectives The 2019 novel coronavirus (2019-nCoV) has spread across the globe with more than 6 lakh deaths. Clinical autopsies are important to understand the pathobiology of the disease. Materials and Methods Autopsy techniques have been modified to be minimally invasive autopsies in all COVID-19 positive cases, and tissue biopsies were sampled from lungs, liver, and bone marrow within an hour after death. Detailed histological analysis was performed in the sampled tissues, along with immunohistochemistry. Patients' clinical records were collected. Statistical Analysis Descriptive statistics were used to summarize data. Results Of the 21 cases studied, 76.2% patients were ≥ 60 years of age, 80.9% were males, and 85.7% had co-morbidities. Histopathological analysis revealed diffuse alveolar damage (including exudative and organizing phase) in 88.9% cases. Microthrombi were seen in 44.4% cases. Additional findings include viral cytopathic changes, metaplastic change in the epithelium, intra-alveolar hemorrhage, and pulmonary edema. Liver showed centrizonal congestion with hepatocytic loss, lobular inflammation, steatosis, Kupffer cell hypertrophy, and sinusoidal neutrophilic infiltration, while significant portal infiltrate and cholestasis were absent to minimal. Bone marrow revealed hemophagocytosis in 60% cases. Conclusion Incorporation of minimally invasive autopsies provides an effective method to study the pathological findings in COVID-19 deaths in resource-constrained settings. Presence of pulmonary microthrombi in a significant number of cases supports the vascular events, apart from the characteristic diffuse alveolar damage, as an important pathogenic mechanism for lung injury in COVID-19 infections. Histopathological findings in the liver and bone marrow suggest indirect insult to these organs, related to circulatory and/or hyperinflammatory response to viral infections.

Empyema necessitans with osteomyelitis of fifth rib due to Nocardia farcinica: a case report.

BACKGROUND: Empyema necessitans is a rare pulmonary condition described as the presence of pus in the pleural cavity with insidious extension into the surrounding soft tissue. The common microbial aetiology of empyema necessitans is tuberculosis. Nocardiosis a cause of empyema necessitans is rarely described in the literature. We herein present a case of an 80-year-old male with empyema necessitans with osteomyelitis of rib caused by Nocardia farcinica. CASE PRESENTATION: An 80-year-old male presented with complaints of soft swelling on the left lower posterior chest wall associated with dry cough and breathlessness on exertion. Computed Tomography (CT) thorax demonstrated empyema necessitans with features of left fifth rib osteomyelitis. Radiological guided aspiration of the chest wall collection revealed Nocardia species and surgical drainage of abscess was performed. Matrix-assisted laser desorption/ionization time-of-flight-mass spectrometry (MALDI-TOF-MS) identified the isolate as Nocardia farcinica. He was treated with three-drug regimen: Trimethoprim-sulfamethoxazole, amikacin and ceftriaxone for 2 weeks. After showing improvement patient was discharged and advised to take oral Trimethoprim-sulfamethoxazole for the next 6 months with periodic follow-up. CONCLUSIONS: As our case demonstrates, the possibility of invasive Nocardiosis should not be overlooked even in immunocompetent patients. Clinicians should aware of this rare entity while treating patients with empyema necessitans.

Thyrotoxic Periodic Paralysis with Thyroid Storm as the First Presentation of Graves' disease; a Case Report.

Thyrotoxic periodic paralysis is a rare endocrine emergency that manifests as acute onset muscle weakness and hypokalaemia secondary to thyrotoxicosis. It mainly occurs due to rapid and dramatic intracellular shift of potassium resulting in hypokalaemia and acute flaccid paralysis. This condition predominantly affects males of Asian descent, and presentation can range from mild generalized weakness to complete quadriplegia, as seen in our case. We herein report a case of a 40-year-old female, who presented to us with acute onset flaccid quadriplegia and thyroid storm, which is the first ever manifestation of previously undiagnosed Grave's disease. Liver abscess was found to be the underlying trigger for thyrotoxic paralysis and thyroid storm.

Clinical profile and outcome of patients with Crimean Congo haemorrhagic fever: a hospital based observational study from Rajasthan, India.

BACKGROUND: Crimean Congo haemorrhagic fever (CCHF) is an emerging zoonotic infection with high mortality. Nosocomial spread is described secondary to body fluid contact. METHODS: Patients meeting the case definition for viral haemorrhagic fever (VHF) from August to November 2019 were tested for CCHF after ruling out dengue, malaria, scrub typhus and leptospirosis in a tertiary teaching hospital in western Rajasthan, India. Diagnosis was confirmed using both quantitative reverse transcription polymerase chain reaction and immunoglobulin M/immunoglobulin G enzyme-linked immunosorbent assay for all patients. All hospital contacts were line listed and tested and symptomatic high-risk contacts received ribavirin post-exposure prophylaxis. Cohorting, personal protective equipment use and hand washing were employed to prevent nosocomial spread. RESULTS: Four patients tested positive for CCHF. We encountered uncommon initial presentations involving motor weakness and supraventricular tachycardia. Elevated serum lactate dehydrogenase and creatinine kinase were useful in clinical diagnosis. Only one patient survived despite ribavirin therapy. There was zero nosocomial transmission. A partial segment of nucleocapsid of amplified CCHF virus was 99.62% identical to the Afghanistan and Oman strains. CONCLUSIONS: The distribution of CCHF appears to be expanding, with CCHF emerging as endemic in Rajasthan, India. In this setting of high mortality, hand washing and PPE use prevented nosocomial transmission.

Hypercalcemic Encephalopathy as an Initial Presentation of Multiple Myeloma.

We report the case of an 84-year-old female presented to us with acute onset altered sensorium. On investigation, neurological and infectious causes were ruled out. On further evaluation, her serum calcium was found elevated (15.07 gm/dl). The diagnosis of hypercalcemic encephalopathy was made with the possibility of multiple myeloma due to raised total protein and globulin levels. Serum electrophoresis, immunofixation, and bone marrow examination confirmed the diagnosis of multiple myeloma. The patient was treated with bortezomib, dexamethasone, and lenalidomide. After 1 week, she improved with normalization of serum calcium. Herein, we highlight hypercalcemia as an important cause of encephalopathy. As our report suggests, metabolic encephalopathy can be the first presentation in multiple myeloma.