Effect of Lactate Export Inhibition on Anaplastic Thyroid Cancer Growth and Metabolism.

BACKGROUND: Anaplastic thyroid cancer (ATC) is an aggressive malignancy without effective treatments. ATC cells demonstrate upregulated glycolysis (Warburg effect), generating lactate that is subsequently exported by monocarboxylate transporter 4 (MCT4). This study aims to determine whether MCT4 inhibition can suppress ATC growth. STUDY DESIGN: ATC cell lines 8505C, JL30, and TCO1 were grown in low (3 mmol/L; LG) or high (25 mmol/L; HG) glucose medium containing the lactate shuttle inhibitors acriflavine (10-25 µmol/L; ACF), syrosingopine (100 µmol/L; SYR), or AZD3965 (20 µmol/L; AZD). Lactate level and cell proliferation were measured with standard assays. Seahorse analysis was performed to determine glycolytic response. RESULTS: Compared with HG, addition of ACF to LG decreased lactate secretion for both 8505C (p < 10-5) and JL30 (p < 10-4) cells, whereas proliferation was also reduced (p < 10-4 and 10-5, respectively). During Seahorse analysis, addition of oligomycin increased acidification by 84 mpH/min in HG vs 10 mpH/min in LG containing ACF (p < 10-5). Treatment with LG and SYR drastically diminished 8505C and TCO1 growth vs HG (p < 0.01 for both). LG and AZD treatment also led to reduced proliferation in tested cell lines (p ≤ 0.01 for all) that was further decreased by addition of ACF (p < 10-4 vs HG, p ≤ 0.01 vs LG and AZD). CONCLUSION: Inhibition of lactate shuttles significantly reduced proliferation and glycolytic capacity of ATC cells in a low-glucose environment. Targeting suppression of glycolytic and lactate processing pathways may represent an effective treatment strategy for ATC.

Glycolytic inhibition with 3-bromopyruvate suppresses tumor growth and improves survival in a murine model of anaplastic thyroid cancer.

BACKGROUND: Anaplastic thyroid cancer is a rare but devastating malignancy. Anaplastic thyroid cancer cells exhibit the Warburg effect by preferentially undergoing glycolysis even in aerobic conditions, leading to high glucose use. Here we assess if targeted inhibition of glycolysis can diminish anaplastic thyroid cancer growth and improve outcomes. METHODS: Human anaplastic thyroid cancer cell line 8505C was grown in medium containing high (25 mmol/L) or low (3 mmol/L) glucose concentration and hexokinase II inhibitor 3-bromopyruvate (200 µM). Cellular proliferation, migration, and invasion were measured. An orthotopic xenograft model of anaplastic thyroid cancer was generated in nude mice using 8505C cells. Animals were provided standard chow or a ketogenic diet and treated with 3-bromopyruvate (1.8 mg/kg). Overall survival time was monitored. Necropsies were performed to harvest tumors for analysis. RESULTS: Growth of 8505C in low-glucose medium with 3-bromopyruvate decreased cell proliferation by 89%, migration by 44%, and invasion by 73% (P < .001 for all) compared with high glucose. Animals concomitantly receiving a ketogenic diet and 3-bromopyruvate exhibited smaller tumor volumes (P = .03), slower tumor growth rates (P = .01), and improved overall survival (P = .006) compared with standard-diet control subjects. Monotherapy with a ketogenic diet or 3-bromopyruvate alone did not reduce tumor size or increase survival over the standard-diet control group. CONCLUSION: Glycolytic inhibition with 3-bromopyruvate inhibits tumor growth and extends survival in a murine model of anaplastic thyroid cancer when combined with the ketogenic diet. Thus, targeted glycolytic inhibition of anaplastic thyroid cancer exhibits context-specific utility and may only be effective during ketosis induced by dietary restriction of glycolytic inputs.

Efficiency analysis in the management of COVID-19 pandemic in India based on data envelopment analysis.

Purpose: This article measured the performance of 32 states and union territories (UTs) of India against COVID-19 disease using efficiency score which was calculated by data envelopment analysis (DEA) and compared the efficiency score with the different models which are used in many articles to evaluate the efficiency of healthcare system. Here the input parameters are taken as public health expenditure in a million, number of hospitals, number of hospital beds, percentage of health workers, population density, and number of infected, and output parameters divided into good and bad categories such as the number of recovered are taken as good output. The number of death is taken as bad outputs. The modified undesirable output model is used to calculate efficiency score and compared the efficiency score with Charnes, Cooper, and Rhodes (CCR) and Banker, Charnes, and Cooper (BCC) models. Finally, the states & UTs are completely ranked with the help of efficiency score and Maximal Balance Index, and evaluated benchmarking for each states & UTs. Data Source: Secondary data were collected from Census 2011 and the Ministry of health & family welfare, Government of India on 32 stats & UTs (NHAC, 2018; NHP, 2019; COVID19India, 2021). Results: According to Undesirable model results, 16 (50%) of 32 Indian states & UTs s were found to be efficient. Among the efficient DMUs, Chandigarh is the most efficient unit and Meghalaya is the most inefficient unit. Rajasthan was the most referenced state for inefficient states. Limitation: The efficiency score is affected by changing the number of inputs and outputs. The lack of more effective parameters are used to evaluate performance and enable qualitative variable comparison.

Ketogenic diet combined with antioxidant N-acetylcysteine inhibits tumor growth in a mouse model of anaplastic thyroid cancer.

BACKGROUND: Anaplastic thyroid cancer is an aggressive and fatal malignancy. Many advanced cancers are characterized by glucose dependency, leading to oxidative stress and cellular proliferation. Therefore, we sought to determine if a low glucose environment (in vitro) or a ketogenic diet (in vivo) could inhibit anaplastic thyroid cancer tumor growth when combined with the antioxidant N-acetylcysteine. METHODS: In vivo, nude mice were injected with the anaplastic thyroid cancer cell line 8505C (n = 6/group). Group 1 was fed a standard diet; Group 2 was fed a ketogenic diet; Group 3 was given standard diet with N-acetylcysteine (40 mM in the drinking water); and Group 4 was fed ketogenic diet with N-acetylcysteine. Tumor volumes, ketones, and glucose were measured. H&E stains and immunohistochemistry for Ki-67 and Caspase 3 were performed on the tumors. In vitro, 8505C cells were cultured in high glucose (25 mM), low glucose (3 mM), high glucose plus N-acetylcysteine (200 uM), or low glucose plus N-acetylcysteine for 96 hours. We performed CyQUANT proliferation (Thermo Fisher Scientific, Waltham, MA), Seahorse glycolytic stress (Agilent, Santa Clara, CA), and reactive oxidative stress assays. RESULTS: Ketogenic diet plus N-acetylcysteine decreased in vivo tumor volume compared to standard diet (22.5 ± 12.4 mm3 vs 147 ± 54.4 mm3, P < .05) and standard diet plus N-acetylcysteine (P < .05). Blood ketone levels were significantly higher for the mice in the ketogenic diet group compared to standard diet (1.74 mmol/L vs 0.38 mmol/L at week 5, P < .001). However, blood glucose levels were not significantly different between ketogenic diet and standard diet groups. Cells cultured in low glucose plus N-acetylcysteine had significantly reduced proliferation compared to high glucose (98.1 ± 5.0 relative fluorescence units vs 157.8 ± 2.1 relative fluorescence units, P < .001). Addition of N-acetylcysteine to low glucose lowered glycolysis function compared to high glucose (39.0 ± 2.2 mpH/min/cell vs 89.1 ± 13.2 mpH/min/cell, P < .001) and high glucose plus N-acetylcysteine (37.4 ± 2.5 mpH/min/cell vs 70.3 ± 3.3 mpH/min/cell, P < .001). Low glucose plus N-acetylcysteine decreased reactive oxidative stress compared to high glucose (119 ± 34.7 relative fluorescence units vs 277 ± 16.0 relative fluorescence units, P = .014). CONCLUSION: The combination of a ketogenic diet or glucose restriction with the antioxidant- N-acetylcysteine significantly reduced tumor growth in vivo and in vitro. Further studies are warranted to explore these metabolic therapies in anaplastic thyroid cancer.

Visibility of Strings After Postplacental Intracesarean Insertion of CuT380A and Cu375 Intrauterine Contraceptive Device: A Randomized Comparative Study.

OBJECTIVES: To compare the incidence of visible strings after postplacental intracesarean insertion of Cu375 and CuT380A intrauterine contraceptive devices (IUD). METHODS: This was a prospective, randomized comparative study. A total of 100 women fulfilling the inclusion and exclusion criteria underwent postplacental intracesarean insertion of either Cu375 IUD or CuT380A IUD. Women were followed up at 1, 6 weeks and 3 months after IUD insertion and were questioned about IUD expulsion or removal at each visit. The cervix was inspected to visualize the IUD strings. Data were analyzed by Chi-square test. RESULTS: At 6-week follow-up, 97.9% women in group A versus 41.7% women in group B had strings visible at the cervical os and at 3 months 100% women in group A versus only 47.9% women in group B (p < 0.001) had visible strings of IUD. CONCLUSION: Both Cu375 and CuT380A IUD are safe postpartum method of contraception but Cu375 if used for intracesarean IUD insertion increases the incidence of visible IUD strings. Hence, it avoids radiological investigations and invasive procedures at follow-up visits required to locate the IUD when strings are not visible. CTRI No. CTRI/2015/09/006221.

National sample survey to assess the new case disease burden of leprosy in India.

A national sample survey of leprosy was undertaken in partnership with Indian Council of Medical Research (ICMR) institutions, National Leprosy Eradication Programme (NLEP), Panchayati Raj members, and treated leprosy patients to detect new cases of leprosy in India. The objectives of the survey were to estimate the new leprosy case load; record both Grade 1 and Grade 2 disabilities in the new cases; and to assess the magnitude of stigma and discrimination prevalent in the society. A cluster based, cross-sectional survey involving all States was used for the door-to-door survey using inverse sampling methodology. Rural and urban clusters were sampled separately. The population screened for detecting 28 new cases in rural and 30 in urban clusters was enumerated, recorded and analyzed. Data capture and analysis in different schedules were the main tools used. For quality control three tiers of experts were utilized for the confirmation of cases and disabilities. Self-stigma was assessed in more than half of the total new patients detected with disabilities by the approved questionnaire. A different questionnaire was used to assess the stigma in the community. A population of 14,725,525 (10,302,443 rural; 4,423,082 urban) was screened and 2161 new cases - 1300 paucibacillary (PB) and 861 multibacillary (MB) were detected. New case estimates for leprosy was 330,346 (95% Confidence limits, 287,445-380,851). Disabilities observed in these cases were 2.05/100,000 population and 13.9 per cent (302/2161) in new cases. Self-stigma in patients with disabilities was reduced, and the patients were well accepted by the spouse, neighbour, at workplace and in social functions.

Intergenerational Change in Anthropometric Indices and Their Predictors Among Children in New Delhi Birth Cohort.

OBJECTIVE: To evaluate intergenerational change in anthropometric indices of children and their predictors. DESIGN: Prospective cohort. PARTICIPANTS: New Delhi Birth Cohort participants (F1), born between 1969 and 1972, were followed-up for anthropometry at birth and 6-monthly intervals until 21 years. Their children (F2) below 10 years were evaluated anthropometrically. OUTCOME MEASURE: Intergenerational change (F2-F1) in height, weight and body mass index (BMI) of children in comparison to their parents at corresponding ages. RESULTS: 432 F2-F1 pairs were analyzed in age-groups of 0-5 (26.9%) and 5-10 (73.1%) years. Children were considerably taller (0-5 years 0.99 SD; 5-10 years 1.17 SD) and heavier (0-5 years 0.77 SD; 5-10 years 1.52 SD) while only those aged 5-10 years were broader (had a higher BMI; 1.03 SD), than their parents. These increases for 0-5 and 5-10 years, respectively corresponded to 3.9 and 6.4 cm for height, 1.3 and 5.4 kg for weight and 0.2 and 1.9 kg/m2 for BMI. Lower parents' anthropometric indices and poor water supply and sanitation facilities; higher age of parents at child birth and of children when measured (for height and weight); and more parental education (for weight and BMI), were associated with greater intergenerational gains in children. CONCLUSION: Over one generation in an urban middle-class population, whose general living conditions had improved, under-five children have become considerably taller and heavier, and 5-10 year old children have additionally become broader, than their parents at corresponding ages. Child populations probably 'grow up' before 'growing out'.

Maternal Age at Childbirth and Perinatal and Under five Mortality in a Prospective Birth Cohort from Delhi.

OBJECTIVE: To evaluate the relationship between maternal age at child birth, and perinatal and under-five mortality. DESIGN: Prospective birth cohort. SETTING: Urban community. PARTICIPANTS: 9169 pregnancies in the New Delhi Birth Cohort resulted in 8181 live births. These children were followed for survival status and anthropometric measurements at birth (+3 days), 3,6,9 and 12 months (7 days), and every 6 months thereafter until 21 years age. Information on maternal age at child birth and socio-demographic profile was also obtained. OUTCOME MEASURES: Offspring mortality from 28 weeks gestation till 5 years age. RESULTS: Offspring mortality (stillbirths - 5 years; n=328) had a U-shaped association with maternal age (P<0.001). Compared to the reference group (20-24 years), younger (≤19 years) and older (≥35 years) maternal ages were associated with a higher risk of offspring mortality (HR: 1.68; 95% CI 1.16, 2.43 and HR 1.48; 95% CI 1.01, 2.16, respectively). In young mothers, the increased risk persisted after adjustment for socio-economic confounders (maternal education, household income and wealth; HR 1.51; 95% CI 1.03, 2.20) and further for additional behavioral (place of delivery) and biological mediators (gestation and birthweight) (HR 2.14; 95% CI 1.25,3.64). Similar associations were documented for post-perinatal deaths but for perinatal mortality the higher risk was not statistically significant (P >0.05). In older mothers, the increased mortality risk was not statistically significant (P >0.05) after adjustment for socio-economic confounders. CONCLUSION: Young motherhood is associated with an increased risk of post-perinatal mortality and measures to prevent early childbearing should be strengthened.

Testing of Hypothesis in Equivalence and Non Inferiority Trials-A Concept.

Establishing the appropriate hypothesis is one of the important steps for carrying out the statistical tests/analysis. Its understanding is important for interpreting the results of statistical analysis. The current communication attempts to provide the concept of testing of hypothesis in non inferiority and equivalence trials, where the null hypothesis is just reverse of what is set up for conventional superiority trials. It is similarly looked for rejection for establishing the fact the researcher is intending to prove. It is important to mention that equivalence or non inferiority cannot be proved by accepting the null hypothesis of no difference. Hence, establishing the appropriate statistical hypothesis is extremely important to arrive at meaningful conclusion for the set objectives in research.

To evaluate the effect of perceived stress on menstrual function.

INTRODUCTION: Menstrual irregularities affect 2-5% of childbearing women, a number that is considerably higher among females under constant stress during a cycle. AIM: To study the effect of perceived stress on cycle length, regularity and dysmenorrhoea. MATERIALS AND METHODS: A cross-sectional study was conducted on 100 female undergraduate students of a medical college. A questionnaire along with the Perceived Stress Scale (PSS) and Pictorial Blood Assessment Chart (PBAC) was provided to the students. The menstrual pattern was then correlated with the PSS using the chi- square test and the Fisher's Exact test for statistical analysis. OBSERVATIONS AND RESULTS: Out of the 100 undergraduate medical students, 30 students had a PSS score >20 while 70 had a score ≤20. An association was established between high stress levels (PSS >20) and menstrual irregularity. No association was found in students with PSS >20 with hypomenorrhoea, menorrhagia, dysmenorrhoea, long cycle length and short cycle length. CONCLUSION: High stress levels (PSS >20) was associated with only menstrual irregularities and not with duration, amount of flow or dysmenorrhoea. Hence, other causes should be looked for in young women complaining of menstrual problems before stress is assumed to be the cause.

Supplementation of vitamin D in pregnancy and its correlation with feto-maternal outcome.

CONTEXT: Vitamin D deficiency is widely prevalent throughout the world. Pregnant women, neonates and infants form most vulnerable groups for vitamin D deficiency. OBJECTIVE: (1) To find prevalence of vitamin D deficiency in pregnant women. (2) To evaluate the effect of supplementation with cholecalciferol in improving vitamin D levels in pregnant women and evaluate its correlation with feto-maternal outcome. DESIGN: Randomized control trial from years 2010 to 2012. SETTING: Tertiary care centre, Delhi, India. PARTICIPANTS: One-hundred and eighty pregnant women. Study population divided randomly into two groups: group A: nonintervention (60 women) and group B: intervention (120 women). INTERVENTION: The intervention group received supplementation of vitamin D in dosages depending upon 25(OH)-D levels. MAIN OUTCOME MEASURES: Risk of maternal complications such as preterm labour, pre-eclampsia and gestational diabetes associated with vitamin D deficiency and risk of low birthweight and poor Apgar score in infants of mothers with vitamin D deficiency. RESULTS: Adjusted serum 25(OH)-D concentration was lower in group A as compared to group B (mean 46·11 ± 74·21 nmol/l vs 80 ± 51·53 nmol/l). Forty-four percent patients in group A and 20·3% patients in group B developed preterm labour/pre-eclampsia/gestational diabetes. Newborns of mothers in group A had lower cord blood levels of 25(OH)-D levels as compared to group B (mean 43·11 ± 81·32 nmol/l vs 56·8 ± 47·52 nmol/l). They also had lower birthweight of mean 2·4 ± 0·38 kg as compared to group B 2·6 ± 0·33 kg. CONCLUSIONS: Vitamin D supplementation reduces risk of maternal comorbidities and helps improve neonatal outcomes.

Randomized Comparison of Isosorbide Mononitrate and PGE2 Gel for Cervical Ripening at Term including High Risk Pregnancy.

Aims. Prostaglandin E2 is the most commonly used drug for cervical ripening prior to labour induction. However, there are concerns regarding uterine tachysystole and nonreassuring fetal heart (N-RFH). Isosorbide mononitrate (IMN) has been used successfully for cervical ripening. The present study was conducted to compare the two drugs for cervical ripening at term in hospital. Methods. Two hundred women with term pregnancies referred for induction of labour with Bishop score less than 6 were randomly allocated to receive either 40 mg IMN tablet vaginally (n = 100) or 0.5 mg PGE2 gel intracervically (n = 100). Adverse effects, progress, and outcomes of labour were assessed. Results. PGE2 group had significantly higher postripening mean Bishop score, shorter time from start of medication to vaginal delivery (13.37 ± 10.67 hours versus 30.78 ± 17.29 hours), and shorter labour-delivery interval compared to IMN group (4.53 ± 3.97 hours versus 7.34 ± 5.51 hours). However, PGE2 group also had significantly higher incidence of uterine tachysystole (15%) and N-RFH (11%) compared to none in IMN group, as well as higher caesarean section rate (27% versus 17%). Conclusions. Cervical ripening with IMN was less effective than PGE2 but resulted in fewer adverse effects and was safer especially in high risk pregnancies.

Risk assessment for psychological disorders in postmenopausal women.

INTRODUCTION: Psychological symptoms are common & bothersome in post menopausal women. Hence, screening these women for risk factors for psychological disorders is an important measure to improve their health. OBJECTIVE: To study the risk assessment for psychological disorders in postmenopausal women Material & Methods: This was a prospective and observational study conducted in the Department of Obstetrics and Gynecology of a North Indian tertiary care hospital. It included a cross-section of 200 postmenopausal women attending gynecology OPD and menopausal clinic. RESULT: Psychological symptoms were present in 32% postmenopausal women while sleep disturbance and decreased concentration were reported by nearly 34%. Irritability, nervousness and depression were the presenting complaints in 31.5%, 28.5% and 23.5% women respectively. Mild depression was present in 41.5%, whereas 3% women suffered from clinical (moderate to severe) depression. Depression was significantly associated with vasomotor symptoms (p=0.000), past history of depression (p=0.048) and psychosocial stressors (p=0.000). CONCLUSION: Women during postmenopausal years are at increased risk of psychological disorders; hence assessment of mental health and address of related issues should be an integral part of comprehensive evaluation of these women.

Evaluation of isosorbide mononitrate for cervical ripening prior to induction of labor for postdated pregnancy in an outpatient setting.

OBJECTIVE: To determine the safety and effectiveness of self-administered treatment with isosorbide mononitrate (IMN) for cervical ripening in Indian women with postdated pregnancies. METHODS: A randomized, placebo-controlled study was conducted with 200 women with postdated pregnancies and unfavorable cervices who self-administered vaginally either 2 40-mg tablets of IMN or 2 40-mg tablets of pyridoxine as placebo prior to admission for induction of labor. The main outcome variables were change in Bishop score, time from admission to delivery, and presence or absence of fetal and maternal morbidity. RESULTS: The Bishop score was significantly improved 24 hours after initiation of the outpatient IMN treatment (P<0.001) and the needs for further cervical ripening and oxytocin infusion were less in the study than in the control group (P<0.001 and P=0.008). The time from admission to delivery was also less (P<0.001). Moreover, the IMN treatment had no major adverse maternal or fetal effects. The vast majority of women in both groups were either satisfied or very satisfied with the outpatient treatment. CONCLUSION: The self-administration, at home, of isosorbide mononitrate leads to a safe and effective cervical ripening prior to labor induction in women with postdated pregnancies. CTRI Registration No.:CTRI/2011/091/000121.

Inverse sampling to study disease burden of leprosy.

BACKGROUND & OBJECTIVES: Estimation of disease burden due to leprosy by conventional sampling procedure is difficult due to large sample size requirement. In such situation, inverse sampling procedure could be a choice. A pilot study was undertaken to study the feasibility of adopting inverse sampling procedure over conventional sampling in an endemic area of Uttar Pradesh, India. METHODS: Two community development blocks one with high endemic, namely, Fatehganj, and other low endemic, Ramnagar, in Bareilly district of Uttar Pradesh, India, were selected. The Inverse sampling was adopted in Fatehganj and conventional cluster sampling was used in Ramnagar. As per the design of inverse sampling, 25 new cases of leprosy were to be detected from a population that could provide the cases. Under conventional sampling, a sample of 44,000 subjects (population) was targeted for the survey. RESULTS: In Fatehganj, 25 new cases of leprosy were detected from a sample of 14734 individuals. In Ramnagar, a total of 63 new cases of leprosy were found after covering a sample of 44686 individuals. Both the techniques provided similar estimates. The precision obtained under inverse sampling was though less than that under conventional sampling but found to be more feasible and suitable for estimation of leprosy due to less population to be covered, time and cost. INTERPRETATION & CONCLUSION: Our findings showed reveals that inverse sampling was advantageous over conventional sampling and could be adopted for the large scale survey at national level.

Curcuminoids modulates oxidative damage and mitochondrial dysfunction in diabetic rat brain.

Diabetes exacerbates neuronal injury induced by hyperglycemia mediated oxidative damage and mitochondrial dysfunction. The aim of the present study is to investigate the effects of curcuminoids, polyphenols of Curcuma longa (L.) on oxidative stress and mitochondrial impairment in the brain of streptozotocin (STZ)-induced diabetic rats. A marked increase in lipid peroxidation and nitrite levels with simultaneous decrease in endogenous antioxidant marker enzymes was observed in the diabetic rat brain, which was restored to normal levels on curcuminoids treatment. Down-regulation of mitochondrial complex I and IV activity caused by STZ induction was also up-regulated on oral administration of curcuminoids. Moreover, curcuminoids administration profoundly elevated the ATP level, which was earlier reduced in the diabetic brain. These results suggest that curcuminoids exhibit a protective effect by accelerating antioxidant defense mechanisms and attenuating mitochondrial dysfunction in the brain of diabetic rats. Curcuminoids thus may be used as a promising therapeutic agent in preventing and/or delaying the progression of diabetic complications in the brain.