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1.
Indian J Psychiatry ; 66(5): 449-456, 2024 May.
Article in English | MEDLINE | ID: mdl-38919578

ABSTRACT

Background: Digitalization in the form of increased Internet use through screen media has also shown its ramification like cyberbullying. They are aggressive acts with the intention or motivation to harm another person through technology. The aim is to study the prevalence of cyberbullying and its association with mental illness in the adolescent age group (15-19 years). Methods: This community-based cross-sectional study was rolled out among adolescents aged 15-19 years. A total of 387 were given a semistructured interviewer-administered questionnaire consisting of general details, cyberbullying victimization, and offending questions, PHQ-9 and GAD-7. Results: The mean (SD) age was 16.8 (1.3) years. More than half (53.2%) were males, and nearly three-fourths (74.4%) were school-going. Around 28.2% reported being cyberbullied at least once in their lifetime. About 7.0% of adolescents were cyberbullied more than once, and 0.8% more than five times in the past 30 days. The most common ways were posting a mean or hurtful picture (31.9%) and the concerned person's comments (24.2%) online. Multivariable logistic regression analysis found that adolescents attending colleges (AOR 1.9, 95% CI 1.1 to 3.4), using tobacco (AOR 2.5, 95% CI 1.4 to 4.5), and depressed (of any severity, AOR 2.0, 95% CI 1.1 to 4.3) were at significantly increased risk of being cyberbullied (P < 0.05). Conclusion: The prevalence of cyberbullying among adolescents aged 15-19 is notable, with significant associations found between cyberbullying and attending college, tobacco use, and depression. Understanding the correlates of cyberbullying can inform targeted interventions to support mental health and well-being among adolescents.

2.
Mycology ; 15(1): 70-84, 2024.
Article in English | MEDLINE | ID: mdl-38558844

ABSTRACT

In India, the incidence of mucormycosis reached high levels during 2021-2022, coinciding with the COVID-19 pandemic. In response to this, we established a multicentric ambispective cohort of patients hospitalised with mucormycosis across India. In this paper, we report their baseline profile, clinical characteristics and outcomes at discharge. Patients hospitalized for mucormycosis during March-July 2021 were included. Mucormycosis was diagnosed based on mycological confirmation on direct microscopy (KOH/Calcofluor white stain), culture, histopathology, or supportive evidence from endoscopy or imaging. After consent, trained data collectors used medical records and telephonic interviews to capture data in a pre-tested structured questionnaire. At baseline, we recruited 686 patients from 26 study hospitals, of whom 72.3% were males, 78% had a prior history of diabetes, 53.2% had a history of corticosteroid treatment, and 80% were associated with COVID-19. Pain, numbness or swelling of the face were the commonest symptoms (73.3%). Liposomal Amphotericin B was the commonest drug formulation used (67.1%), and endoscopic sinus surgery was the most common surgical procedure (73.6%). At discharge, the disease was stable in 43.3%, in regression for 29.9% but 9.6% died during hospitalization. Among survivors, commonly reported disabilities included facial disfigurement (18.4%) and difficulties in chewing/swallowing (17.8%). Though the risk of mortality was only 1 in 10, the disability due to the disease was very high. This cohort study could enhance our understanding of the disease's clinical progression and help frame standard treatment guidelines.

3.
J Clin Endocrinol Metab ; 109(2): e667-e674, 2024 Jan 18.
Article in English | MEDLINE | ID: mdl-37715962

ABSTRACT

CONTEXT: Treatment of hyperprolactinemia with ergoline dopamine agonists (DAs) can be complicated by intolerance and resistance. OBJECTIVE: This study examines the efficacy and tolerability of the nonergot DA ropinirole for the long-term treatment of hyperprolactinemia. METHODS: Twelve hyperprolactinemic women were treated with ropinirole in a 6-month, open-label, dose-escalation trial; 7 of the 12 continued treatment in an extension study for up to 17 months. Ropinirole doses were uptitrated to achieve normal prolactin (PRL) levels, restore menses, and eliminate galactorrhea. RESULTS: Two of the 12 participants were DA naive; 6 of 12 were ergot DA intolerant; and 1 of 12 had known ergot DA resistance. Baseline PRL levels were 126.2 ± 41.4 ng/mL (SEM). Ropinirole was uptitrated from 0.125 to 0.25 mg/h to a median total daily dose (TDD) of 2 mg/d (1-4 mg/d [interquartile range]). PRL normalization was achieved in 50% of the participants (5 with microadenomas and 1 with idiopathic hyperprolactinemia) at a median effective TDD of 1 mg/d. Of the patients achieving PRL normalization, 83% were ergot DA intolerant. A persistent partial biochemical response (PRL reduction >50% from baseline) was achieved in 17% of the participants. During treatment, menses resumed in 67% of amenorrheic patients; galactorrhea resolved in 67%. Mild adverse effects were reported in 92% of participants; however, ropinirole was not discontinued because of intolerance even among the 50% of individuals with a prior history of ergot DA intolerance and resultant medication discontinuation. CONCLUSION: These data demonstrate the efficacy and tolerability of ropinirole for the treatment of hyperprolactinemia in patients with microprolactinomas and idiopathic hyperprolactinemia and suggest ropinirole may represent a novel therapeutic alternative for treating hyperprolactinemic disorders in patients with ergot DA intolerance.


Subject(s)
Amenorrhea , Galactorrhea , Hyperprolactinemia , Indoles , Pituitary Neoplasms , Prolactinoma , Pregnancy , Humans , Female , Hyperprolactinemia/drug therapy , Hyperprolactinemia/etiology , Pituitary Neoplasms/complications , Pituitary Neoplasms/drug therapy , Prolactinoma/complications , Prolactinoma/drug therapy , Dopamine Agonists/adverse effects , Galactorrhea/chemically induced , Galactorrhea/drug therapy , Prolactin
4.
Cureus ; 15(10): e47413, 2023 Oct.
Article in English | MEDLINE | ID: mdl-38022138

ABSTRACT

Introduction While mentoring students during regular medical education has a long-standing tradition in many developed countries' medical schools, it has yet to become a standard practice in the majority of medical institutions, especially in the developing world, such as India. In institutions where mentoring programs are sparsely implemented, there is a lack of data regarding their assessment. Methodology This qualitative study involved two groups of students - nine undergraduate medical students (five male and four female) and 10 undergraduate medical students (six male and four female) who had at least three years of experience in the existing mentorship program at a tertiary care teaching hospital. We conducted two focused group discussions (FGDs) with these two groups of students using a guide, with FGDs lasting 45 and 50 minutes, respectively. We recorded the audio and it was transcripted to text. Thematic analysis of the transcripts from the 2 FGDs was conducted using Atlasti (Version 7.1.8) software to assess perceptions of the mentorship program. Results The content analysis of the discussions revealed two broad themes, namely "Current Functioning of the Programme" and "Suggestions for Improvement." These themes were further divided into multiple domains and subdomains, providing a comprehensive overview of the study's findings. Although there is a consensus among students that the mentorship program is essential, the current operational framework still has limited confidence due to biases, fears, and misinformation among the students. Conclusion The ongoing medical curriculum imparts a vast amount of scientific knowledge within a limited timeframe, with practical application occurring primarily in the last three years of the academic curriculum and minimal emphasis on ethical practice, professionalism, effective communication, handling urgent health situations, and interacting with family members, underscores the genuine need for a structured mentorship curriculum for undergraduate medical students. To enhance the program's effectiveness, the active involvement of undergraduate students must address their specific needs.

6.
J Educ Health Promot ; 12: 101, 2023.
Article in English | MEDLINE | ID: mdl-37288394

ABSTRACT

BACKGROUND: The chances of nonhealing foot ulcer among the diabetic is 10-20 times more than people without diabetes. Foot ulcer among diabetes population affects more than 40-60 million globally. There is a dearth of quality data on the factor among the diabetes patients, which hastens the progression of diabetic foot. The study aims to assess the risk factors associated with foot ulcer among the diabetics. MATERIALS AND METHODS: The study was a cross-sectional comparative study in tertiary care hospital in Maharashtra, India. The study population included 200 diabetic foot ulcer patients and 200 of their age and gender matched comparator were patients with diabetes without foot ulcers. The sampling method was stratified random sampling. RESULTS: The mean age of both the groups of patients was around 54 years. Alcohol consumption, physical activity outside home, low foot care practices, irregularity of diabetic medication, and family history of diabetes among mothers were found to be factors associated with diabetes foot ulcer. CONCLUSION: There is a need to stratify the diabetes patients in regular care as per risk categories depending on the presence of above risk factors. This will not only prioritization of diabetes care in terms of future risk but also reduce the progression of complications like diabetes foot and resulting amputation through an active preventive intervention.

7.
J Clin Endocrinol Metab ; 108(9): 2262-2271, 2023 08 18.
Article in English | MEDLINE | ID: mdl-36897161

ABSTRACT

CONTEXT: Individual responses to weight loss (WL) medications vary widely and prediction of response remains elusive. OBJECTIVE: We investigated biomarkers associated with use of lorcaserin (LOR), a 5HT2cR agonist that targets proopiomelanocortin (POMC) neurons that regulate energy and glucose homeostasis, to identify predictors of clinical efficacy. METHODS: Thirty individuals with obesity were treated with 7 days of placebo and LOR in a randomized crossover study. Nineteen participants continued on LOR for 6 months. Cerebrospinal fluid (CSF) POMC peptide measurements were used to identify potential biomarkers that predict WL. Insulin, leptin, and food intake during a meal were also studied. RESULTS: LOR induced a significant decrease in CSF levels of the POMC prohormone and an increase in its processed peptide ß-endorphin after 7 days; ß-endorphin/POMC increased by 30% (P < .001). This was accompanied by a substantial decrease in insulin, glucose, and homeostasis model assessment of insulin resistance before WL. Changes in CSF POMC peptides persisted after WL (6.9%) at 6 months that were distinct from prior reports after diet alone. Changes in POMC, food intake, or other hormones did not predict WL. However, baseline CSF POMC correlated negatively with WL (P = .07) and a cutoff level of CSF POMC was identified that predicted more than 10% WL. CONCLUSION: Our results provide evidence that LOR affects the brain melanocortin system in humans and that effectiveness is increased in individuals with lower melanocortin activity. Furthermore, early changes in CSF POMC parallel WL-independent improvements in glycemic indexes. Thus, assessment of melanocortin activity could provide a way to personalize pharmacotherapy of obesity with 5HT2cR agonists.


Subject(s)
Pro-Opiomelanocortin , beta-Endorphin , Humans , Pro-Opiomelanocortin/cerebrospinal fluid , Cross-Over Studies , Obesity/drug therapy , Weight Loss , Melanocortins , Glucose , Insulin
8.
J Family Med Prim Care ; 11(5): 1943-1948, 2022 May.
Article in English | MEDLINE | ID: mdl-35800530

ABSTRACT

Introduction: Family planning is one of the essential health care services to promote and ensure reproductive health. Nearly 40.2 percent of men think it as a woman's responsibility as per the National Family Health Survey 4. Not much attention has been given to the male partners in the usage of contraceptives. So, this study was conducted to assess the male participation in family planning among married males in a rural area of Chhattisgarh. Methodology: A sample of 365 married males were interviewed through a semi-structured questionnaire at a primary health care center. Results: Only 48 (13.1%) participants were using condoms or male sterilization as a method of contraception at the time of the study. Good involvement of males in family planning was found to be (10.9%) in our study. Those who were above the poverty line and educated (graduation and above) had good involvement in family planning. The chief reason cited for not opting for male sterilization by participants was fear of physical weakness followed by family opposition. Conclusion: The socio-cultural barrier in itself demotivates men from getting involved in the family planning program. This study recommends increasing health literacy regarding family planning among men by including it in the school curriculum and through awareness activities and counseling that influences them positively and motivates them to accept contraceptive services and shared decision making. Sterilization facilities should be made accessible to them to further encourage them.

9.
J Family Med Prim Care ; 11(3): 847-851, 2022 Mar.
Article in English | MEDLINE | ID: mdl-35495829

ABSTRACT

Iodine deficiency is the most prevalent micronutrient deficiency in India and is one of the most important causes of preventable brain damage. Iodine deficiency disorders affect an individual's ability to work efficiently, which directly impacts the overall development and economic productivity of any nation. Global experiences have shown that salt fortification is the most effective way to control and reduce the burden of IDD in the community. Thirty-six years have passed since the declaration of universal salt iodization (USI) implementation in India by the Central Council of Health in 1983. However, iodine deficiency still remains a public health problem in the whole country.

10.
J Educ Health Promot ; 11: 84, 2022.
Article in English | MEDLINE | ID: mdl-35573633

ABSTRACT

BACKGROUND: The ongoing coronavirus disease 2019 (COVID-19) pandemic induced the governments around the world to impose harsher preventive measures like stay at home order, lock down etc., to contain the spread of infection. This measure increased the stress of the general population through isolation of masses, loss of employment, and loss of recreation. There is a dearth of quality data showing anxiety levels among the population and association of novel nonpharmaceutical measures such as online meditation with it. MATERIALS AND METHODS: The study is a cross-sectional comparative study based on an online survey. The study population included 74 adult participants, out of which 30, included in the study group were attending structured online meditation sessions and 44 of the participants as a comparison group after matching age, gender, location of residence, and socioeconomic status. The data was collected using self-administered questionnaire. Multiple logistic regression was applied to ascertain factors contributing to the anxiety levels of the participants. RESULTS: Both the groups of participants were comparable in terms of their demographic characteristics. The mean generalized anxiety disorder (GAD 7) score among the participants of online meditation program was significantly lower as compared to those not attending any online meditation. 6.7% of the participants of online meditation had GAD 7 score more than 10 as compared to 13.6% among the comparison group (P value 0.7). CONCLUSION: "At home" mental health promotion measures such as structured online meditation can serve an important role in mitigating the mental health impact of COVID-19 pandemic on the community. Further researches are needed to assess the feasibility and effectiveness of such measures.

11.
J Med Chem ; 65(5): 4350-4366, 2022 03 10.
Article in English | MEDLINE | ID: mdl-35195996

ABSTRACT

Mutations in MEK1/2 have been described as a resistance mechanism to BRAF/MEK inhibitor treatment. We report the discovery of a novel ATP-competitive MEK1/2 inhibitor with efficacy in wildtype (WT) and mutant MEK12 models. Starting from a HTS hit, we obtained selective, cellularly active compounds that showed equipotent inhibition of WT MEK1/2 and a panel of MEK1/2 mutant cell lines. Using a structure-based approach, the optimization addressed the liabilities by systematic analysis of molecular matched pairs (MMPs) and ligand conformation. Addition of only three heavy atoms to early tool compound 6 removed Cyp3A4 liabilities and increased the cellular potency by 100-fold, while reducing log P by 5 units. Profiling of MAP855, compound 30, in pharmacokinetic-pharmacodynamic and efficacy studies in BRAF-mutant models showed comparable efficacy to clinical MEK1/2 inhibitors. Compound 30 is a novel highly potent and selective MEK1/2 kinase inhibitor with equipotent inhibition of WT and mutant MEK1/2, whose drug-like properties allow further investigation in the mutant MEK setting upon BRAF/MEK therapy.


Subject(s)
Protein Kinase Inhibitors , Proto-Oncogene Proteins B-raf , Adenosine Triphosphate/metabolism , Cell Line, Tumor , MAP Kinase Kinase 1 , Mitogen-Activated Protein Kinase Kinases/metabolism , Mutation , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Proto-Oncogene Proteins B-raf/genetics
12.
J Family Med Prim Care ; 11(10): 6499-6505, 2022 Oct.
Article in English | MEDLINE | ID: mdl-36618226

ABSTRACT

Introduction: The mortality from coronavirus disease 2019 (COVID-19) infection and the severity of it vary among populations. There is a dearth of research on epidemiology and clinical outcomes in central Indian populations with COVID-19. Our aim was to provide an analysis of all hospitalized mortality among patients with COVID-19 infection in a tertiary care hospital of Chhattisgarh in central India. This analysis helped us to know the severity predictors for mortality and in future will help the authorities to formulate a plan to decrease the mortality in the epidemic or uncertain ongoing pandemic. Methodology: This was a retrospective observational study using the hospital-based record of multi-disciplinary teaching hospital in Chhattisgarh, India. All COVID-19 reverse-transcriptase polymerase chain reaction-positive patients who were declared dead or died during the course of treatment from April 1, 2020 to March 31, 2021 were included in the study. In-hospital mortality was the primary outcome of interest. In secondary analysis, age and gender distribution, co-morbidity, length of stay, and the cause of death were also investigated. Results: A total of 7495 patients with a confirmed diagnosis of COVID-19 were enrolled in the study, of whom 762 (10.16%) died in the hospital with COVID-19 as the primary cause of death. The majority of the patients were more than 60 years of age (45.7%). A total of 416 (54.4%) of the deceased patients were having co-morbidity with diabetes (13.4%), hypertension (16.4%), or both (24.4%). The majority of the patients who succumbed had a hospital stay of less than a week (≤7) (68.5%). More than half of the patients (58.3%) who expired had referred and reported to the hospital in the second or third week of illness. The respiratory system involvement was the dominant contributor of death with pneumonia (78.8%) being the most common cause, followed by acute respiratory distress syndrome (62.2%). 13.6% of expired patients had multiple system involvement, and 11.2% had sepsis as well. Conclusion: Mortality in COVID-19 patients was associated with advanced age, co-morbidities such as diabetes and hypertension, and delay in hospitalization. These are high-risk groups and should be vaccinated against COVID-19 on priority.

13.
Cell Signal ; 86: 110091, 2021 10.
Article in English | MEDLINE | ID: mdl-34298089

ABSTRACT

Metastatic progression is the key feature of prostate cancer primarily responsible for mortality caused by this disease. RAD9 is an oncogene for prostate cancer, and the encoded protein enhances metastasis-related phenotypes. RAD9 is a transcription factor with a limited set of regulated target genes, but the complete list of downstream genes critical for prostate carcinogenesis is unknown. We used microarray gene expression profiling and chromatin immunoprecipitation in parallel to identify genes transcriptionally controlled by RAD9 that contribute to this cancer. We found expression of 44 genes altered in human prostate cancer DU145 cells when RAD9 is knocked down by siRNA, and all of them bind RAD9 at their genomic location. FOXP1 and NDRG1 were down regulated when RAD9 expression was reduced, and we evaluated them further. We demonstrate that reduced RAD9, FOXP1 or NDGR1 expression decreases cell proliferation, rapid migration, anchorage-independent growth, anoikis resistance, and aerobic glycolysis. Ectopic expression of FOXP1 or NDRG1 partially restored aerobic glycolysis to prostate cancer cells with reduced RAD9 abundance, but only FOXP1 significantly complemented the other deficiencies. We thus show, for the first time, that RAD9 regulates FOXP1 and NDRG1 expression, and they function differently as downstream effectors for RAD9-mediated prostate cancer cell activities.


Subject(s)
Cell Cycle Proteins/metabolism , Gene Expression Regulation, Neoplastic , Intracellular Signaling Peptides and Proteins/metabolism , Prostatic Neoplasms , Cell Line, Tumor , Cell Proliferation , Forkhead Transcription Factors/genetics , Forkhead Transcription Factors/metabolism , Humans , Male , Prostatic Neoplasms/pathology , Repressor Proteins/metabolism , Transcription Factors/metabolism
14.
J Clin Endocrinol Metab ; 106(12): e5156-e5164, 2021 11 19.
Article in English | MEDLINE | ID: mdl-34255061

ABSTRACT

INTRODUCTION: Pregnancy is characterized by increased appetitive drive beginning early in gestation, yet the central mechanisms underlying this adaptation are poorly understood in humans. To elucidate central mechanisms underlying appetite regulation in early pregnancy, we examine plasma and cerebrospinal fluid (CSF) leptin and Agouti-related peptide (AgRP) as well as CSF proopiomelanocortin (POMC) as surrogates for brain melanocortin activity. METHODS: Plasma leptin, soluble leptin receptor, AgRP, and CSF leptin, POMC, and AgRP were collected from pregnant women before cerclage placement (16.6 ±â€…1.1 weeks; N = 24), scheduled cesarean section (39.2 ±â€…0.2 weeks; N = 24), and from nonpregnant controls (N = 24), matched for age and body mass index. RESULTS: Plasma leptin was 1.5 times higher in pregnancy vs controls (P = 0.01), but CSF leptin did not differ. CSF/plasma leptin percentage was lower in early pregnancy vs controls (0.8 ±â€…0.1 vs 1.7 ±â€…0.2; P < 0.0001) and remained unchanged at term (0.9 ±â€…0.1), supporting a decrease in leptin transport into CSF in pregnancy. Plasma AgRP, a peripheral biomarker of the orexigenic hypothalamic neuropeptide, was higher in early pregnancy vs controls (95.0 ±â€…7.8 vs 67.5 ±â€…5.3; P = 0.005). In early gestation, CSF AgRP did not differ from controls, but CSF POMC was 25% lower (P = 0.006). In contrast, at term, CSF AgRP was 42% higher vs controls (P = 0.0001), but CSF POMC no longer differed. Overall, the CSF AgRP/POMC ratio was 1.5-fold higher in early pregnancy vs controls, reflecting a decrease in melanocortin tone favoring appetitive drive. CONCLUSIONS: Pregnancy-specific adaptions in the central regulation of energy balance occur early in human gestation and are consistent with decreased leptin transport into brain and resistance to the effects of leptin on target melanocortin neuropeptides.


Subject(s)
Adaptation, Physiological , Biomarkers/blood , Biomarkers/cerebrospinal fluid , Energy Metabolism , Melanocortins/analysis , Neuropeptides/analysis , Adult , Agouti-Related Protein/blood , Agouti-Related Protein/cerebrospinal fluid , Case-Control Studies , Female , Follow-Up Studies , Humans , Leptin/blood , Leptin/cerebrospinal fluid , Melanocortins/blood , Melanocortins/cerebrospinal fluid , Neuropeptides/blood , Neuropeptides/cerebrospinal fluid , Pregnancy , Pro-Opiomelanocortin/blood , Pro-Opiomelanocortin/cerebrospinal fluid , Prognosis , Receptors, Leptin/blood
15.
J Clin Invest ; 131(8)2021 04 15.
Article in English | MEDLINE | ID: mdl-33630762

ABSTRACT

Bardet-Biedl syndrome (BBS) is a rare autosomal recessive disorder caused by mutations in genes encoding components of the primary cilium and is characterized by hyperphagic obesity. To investigate the molecular basis of obesity in human BBS, we developed a cellular model of BBS using induced pluripotent stem cell-derived (iPSC-derived) hypothalamic arcuate-like neurons. BBS mutations BBS1M390R and BBS10C91fsX95 did not affect neuronal differentiation efficiency but caused morphological defects, including impaired neurite outgrowth and longer primary cilia. Single-cell RNA sequencing of BBS1M390R hypothalamic neurons identified several downregulated pathways, including insulin and cAMP signaling and axon guidance. Additional studies demonstrated that BBS1M390R and BBS10C91fsX95 mutations impaired insulin signaling in both human fibroblasts and iPSC-derived neurons. Overexpression of intact BBS10 fully restored insulin signaling by restoring insulin receptor tyrosine phosphorylation in BBS10C91fsX95 neurons. Moreover, mutations in BBS1 and BBS10 impaired leptin-mediated p-STAT3 activation in iPSC-derived hypothalamic neurons. Correction of the BBS mutation by CRISPR rescued leptin signaling. POMC expression and neuropeptide production were decreased in BBS1M390R and BBS10C91fsX95 iPSC-derived hypothalamic neurons. In the aggregate, these data provide insights into the anatomic and functional mechanisms by which components of the BBSome in CNS primary cilia mediate effects on energy homeostasis.


Subject(s)
Bardet-Biedl Syndrome/metabolism , Chaperonins/metabolism , Hypothalamus/metabolism , Induced Pluripotent Stem Cells/metabolism , Microtubule-Associated Proteins/metabolism , Mutation, Missense , Neurons/metabolism , Second Messenger Systems , Amino Acid Substitution , Animals , Bardet-Biedl Syndrome/genetics , Chaperonins/genetics , Cyclic AMP/genetics , Cyclic AMP/metabolism , Female , HEK293 Cells , Humans , Male , Mice , Mice, Transgenic , Microtubule-Associated Proteins/genetics
16.
Mol Cancer Ther ; 19(12): 2502-2515, 2020 12.
Article in English | MEDLINE | ID: mdl-33082276

ABSTRACT

Agents targeting metabolic pathways form the backbone of standard oncology treatments, though a better understanding of differential metabolic dependencies could instruct more rationale-based therapeutic approaches. We performed a chemical biology screen that revealed a strong enrichment in sensitivity to a novel dihydroorotate dehydrogenase (DHODH) inhibitor, AG-636, in cancer cell lines of hematologic versus solid tumor origin. Differential AG-636 activity translated to the in vivo setting, with complete tumor regression observed in a lymphoma model. Dissection of the relationship between uridine availability and response to AG-636 revealed a divergent ability of lymphoma and solid tumor cell lines to survive and grow in the setting of depleted extracellular uridine and DHODH inhibition. Metabolic characterization paired with unbiased functional genomic and proteomic screens pointed to adaptive mechanisms to cope with nucleotide stress as contributing to response to AG-636. These findings support targeting of DHODH in lymphoma and other hematologic malignancies and suggest combination strategies aimed at interfering with DNA-damage response pathways.


Subject(s)
Antineoplastic Agents/pharmacology , Enzyme Inhibitors/pharmacology , Hematologic Neoplasms/metabolism , Oxidoreductases Acting on CH-CH Group Donors/antagonists & inhibitors , Pyrimidines/metabolism , Cell Line, Tumor , Cell Survival/drug effects , DNA Damage/drug effects , Dihydroorotate Dehydrogenase , Genomics/methods , Hematologic Neoplasms/drug therapy , Hematologic Neoplasms/etiology , Hematologic Neoplasms/pathology , Humans , Neoplasm Staging , Proteomics/methods
17.
Indian J Med Ethics ; -(-): 1-6, 2020 Jun 08.
Article in English | MEDLINE | ID: mdl-32546458

ABSTRACT

The ongoing pandemic of Covid-19 caused by the SARS-CoV-2 virus has infected more than 6 million all over the world and has caused more than 3.8 lakh fatalities till date(1) Health workers are the frontline responders and are exposed to a plethora of health hazards. Recently, an advisory by the Indian Council of Medical Research for the use of hydroxychloroquine as post-exposure prophylaxis was hailed as an outstanding initiative for the protection of healthcare workers and high risk contacts of patients. But the evidence of effectiveness available is only from in vitro studies and non-randomised control trials of insufficient sample size. Several ongoing large scale clinical trials are focused on the same research questions, the preliminary results of which are still awaited. The present study discusses the ethics of the introduction of therapeutic or preventive interventions based on limited available evidence during the ongoing pandemic of Covid-19.

.

19.
J Family Med Prim Care ; 9(2): 619-625, 2020 Feb.
Article in English | MEDLINE | ID: mdl-32318392

ABSTRACT

BACKGROUND AND AIMS: Breast and cervical cancers are two of the most common cancer diagnosed and are leading cause of death among females. Mortality and complication rates are higher in countries with lower awareness regarding breast and cervical cancer. The aim of this study is to assess the community inquisitive insight regarding breast and cervical carcinoma after sensitising them with health education. SETTING AND DESIGN: This is a qualitative research done on adolescent school going girls. The analysis is done using the verbal and written queries during group interaction sessions after the health education regarding breast and cervical cancer was imparted. RESULTS AND CONCLUSION: A community specific health education material regarding breast and cervical cancers should include information regarding normal physiological process like menstruation, available preventive, and screening and management modalities of common cancers, the explanations for myths and redressal of stigma prevailing in the specific community.

20.
J Alzheimers Dis ; 75(2): 471-482, 2020.
Article in English | MEDLINE | ID: mdl-32250301

ABSTRACT

BACKGROUND: Concentrations of soluble amyloid-ß (Aß) oscillate with the sleep-wake cycle in the interstitial fluid of mice and cerebrospinal fluid (CSF) of humans. Further, the concentration of Aß in CSF increases during sleep deprivation. Stress and disruption of the circadian clock are additional mechanisms hypothesized to increase CSF Aß levels. Cortisol is a marker for stress and has an endogenous circadian rhythm. Other factors such as glucose and lactate have been associated with changes in sleep-wake activity and/or Aß. OBJECTIVE: In this exploratory study, we used samples collected in a previous study to examine how sleep deprivation affects Aß, cortisol, lactate, and glucose in plasma and CSF from healthy middle-aged adults (N = 11). METHODS: Eleven cognitively normal participants without evidence of sleep disturbance were randomized to sleep deprivation or normal sleep control. All participants were invited to repeat the study. Cortisol, lactate, glucose, and Aß were measured in 2-h intervals over a 36-h period in both plasma and CSF. All concentrations were normalized to the mean prior to calculating mesor, amplitude, acrophase, and other parameters. RESULTS: One night of sleep deprivation increases the overnight concentration of Aß in CSF approximately 10%, but does not significantly affect cortisol, lactate, or glucose concentrations in plasma or CSF between the sleep-deprived and control conditions. CONCLUSION: These data suggest that sleep deprivation-related changes in CSF Aß are not mediated by stress or circadian disruption as measured by cortisol.


Subject(s)
Amyloid beta-Peptides/cerebrospinal fluid , Circadian Rhythm/physiology , Sleep Deprivation/cerebrospinal fluid , Sleep/physiology , Stress, Physiological/physiology , Stress, Psychological/cerebrospinal fluid , Adult , Cognition/physiology , Female , Glucose/cerebrospinal fluid , Humans , Hydrocortisone/cerebrospinal fluid , Lactic Acid/cerebrospinal fluid , Male , Middle Aged
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