Polyamines Drive Myeloid Cell Survival by Buffering Intracellular pH to Promote Immunosuppression in Glioblastoma

Glioblastoma is characterized by the robust infiltration of immunosuppressive tumor-associated myeloid cells (TAMCs). It is not fully understood how TAMCs survive in the acidic tumor microenvironment to cause immunosuppression in glioblastoma. Metabolic and RNA-seq analysis of TAMCs revealed that the arginine-ornithine-polyamine axis is up-regulated in glioblastoma TAMCs but not in tumor-infiltrating CD8+ T cells. Active de novo synthesis of highly basic polyamines within TAMCs efficiently buffered low intracellular pH to support the survival of these immunosuppressive cells in the harsh acidic environment of solid tumors. Administration of difluoromethylornithine (DFMO), a clinically approved inhibitor of polyamine generation, enhanced animal survival in immunocompetent mice by causing a tumor-specific reduction of polyamines and decreased intracellular pH in TAMCs. DFMO combination with immunotherapy or radiotherapy further enhanced animal survival. These findings indicate that polyamines are used by glioblastoma TAMCs to maintain normal intracellular pH and cell survival and thus promote immunosuppression during tumor evolution

Mitochondrial electron transport chain is necessary for NLRP3 inflammasome activation

The NLRP3 inflammasome is linked to sterile and pathogen-dependent inflammation, and its dysregulation underlies many chronic diseases. Mitochondria have been implicated as regulators of the NLRP3 inflammasome through several mechanisms including generation of mitochondrial reactive oxygen species (ROS). Here, we report that mitochondrial electron transport chain (ETC) complex I, II, III and V inhibitors all prevent NLRP3 inflammasome activation. Ectopic expression of Saccharomyces cerevisiae NADH dehydrogenase (NDI1) or Ciona intestinalis alternative oxidase, which can complement the functional loss of mitochondrial complex I or III, respectively, without generation of ROS, rescued NLRP3 inflammasome activation in the absence of endogenous mitochondrial complex I or complex III function. Metabolomics revealed phosphocreatine (PCr), which can sustain ATP levels, as a common metabolite that is diminished by mitochondrial ETC inhibitors. PCr depletion decreased ATP levels and NLRP3 inflammasome activation. Thus, the mitochondrial ETC sustains NLRP3 inflammasome activation through PCr-dependent generation of ATP, but via a ROS-independent mechanism.publishedVersionPeer reviewe

Global variation in diabetes diagnosis and prevalence based on fasting glucose and hemoglobin A1c

Fasting plasma glucose (FPG) and hemoglobin A1c (HbA1c) are both used to diagnose diabetes, but these measurements can identify different people as having diabetes. We used data from 117 population-based studies and quantified, in different world regions, the prevalence of diagnosed diabetes, and whether those who were previously undiagnosed and detected as having diabetes in survey screening, had elevated FPG, HbA1c or both. We developed prediction equations for estimating the probability that a person without previously diagnosed diabetes, and at a specific level of FPG, had elevated HbA1c, and vice versa. The age-standardized proportion of diabetes that was previously undiagnosed and detected in survey screening ranged from 30% in the high-income western region to 66% in south Asia. Among those with screen-detected diabetes with either test, the age-standardized proportion who had elevated levels of both FPG and HbA1c was 29-39% across regions; the remainder had discordant elevation of FPG or HbA1c. In most low- and middle-income regions, isolated elevated HbA1c was more common than isolated elevated FPG. In these regions, the use of FPG alone may delay diabetes diagnosis and underestimate diabetes prevalence. Our prediction equations help allocate finite resources for measuring HbA1c to reduce the global shortfall in diabetes diagnosis and surveillance

Worldwide trends in underweight and obesity from 1990 to 2022: a pooled analysis of 3663 population-representative studies with 222 million children, adolescents, and adults

Background Underweight and obesity are associated with adverse health outcomes throughout the life course. We estimated the individual and combined prevalence of underweight or thinness and obesity, and their changes, from 1990 to 2022 for adults and school-aged children and adolescents in 200 countries and territories. Methods We used data from 3663 population-based studies with 222 million participants that measured height and weight in representative samples of the general population. We used a Bayesian hierarchical model to estimate trends in the prevalence of different BMI categories, separately for adults (age ≥20 years) and school-aged children and adolescents (age 5–19 years), from 1990 to 2022 for 200 countries and territories. For adults, we report the individual and combined prevalence of underweight (BMI <18·5 kg/m2) and obesity (BMI ≥30 kg/m2). For schoolaged children and adolescents, we report thinness (BMI <2 SD below the median of the WHO growth reference) and obesity (BMI >2 SD above the median). Findings From 1990 to 2022, the combined prevalence of underweight and obesity in adults decreased in 11 countries (6%) for women and 17 (9%) for men with a posterior probability of at least 0·80 that the observed changes were true decreases. The combined prevalence increased in 162 countries (81%) for women and 140 countries (70%) for men with a posterior probability of at least 0·80. In 2022, the combined prevalence of underweight and obesity was highest in island nations in the Caribbean and Polynesia and Micronesia, and countries in the Middle East and north Africa. Obesity prevalence was higher than underweight with posterior probability of at least 0·80 in 177 countries (89%) for women and 145 (73%) for men in 2022, whereas the converse was true in 16 countries (8%) for women, and 39 (20%) for men. From 1990 to 2022, the combined prevalence of thinness and obesity decreased among girls in five countries (3%) and among boys in 15 countries (8%) with a posterior probability of at least 0·80, and increased among girls in 140 countries (70%) and boys in 137 countries (69%) with a posterior probability of at least 0·80. The countries with highest combined prevalence of thinness and obesity in school-aged children and adolescents in 2022 were in Polynesia and Micronesia and the Caribbean for both sexes, and Chile and Qatar for boys. Combined prevalence was also high in some countries in south Asia, such as India and Pakistan, where thinness remained prevalent despite having declined. In 2022, obesity in school-aged children and adolescents was more prevalent than thinness with a posterior probability of at least 0·80 among girls in 133 countries (67%) and boys in 125 countries (63%), whereas the converse was true in 35 countries (18%) and 42 countries (21%), respectively. In almost all countries for both adults and school-aged children and adolescents, the increases in double burden were driven by increases in obesity, and decreases in double burden by declining underweight or thinness. Interpretation The combined burden of underweight and obesity has increased in most countries, driven by an increase in obesity, while underweight and thinness remain prevalent in south Asia and parts of Africa. A healthy nutrition transition that enhances access to nutritious foods is needed to address the remaining burden of underweight while curbing and reversing the increase in obesit

Global variations in diabetes mellitus based on fasting glucose and haemogloblin A1c

Fasting plasma glucose (FPG) and haemoglobin A1c (HbA1c) are both used to diagnose diabetes, but may identify different people as having diabetes. We used data from 117 population-based studies and quantified, in different world regions, the prevalence of diagnosed diabetes, and whether those who were previously undiagnosed and detected as having diabetes in survey screening had elevated FPG, HbA1c, or both. We developed prediction equations for estimating the probability that a person without previously diagnosed diabetes, and at a specific level of FPG, had elevated HbA1c, and vice versa. The age-standardised proportion of diabetes that was previously undiagnosed, and detected in survey screening, ranged from 30% in the high-income western region to 66% in south Asia. Among those with screen-detected diabetes with either test, the agestandardised proportion who had elevated levels of both FPG and HbA1c was 29-39% across regions; the remainder had discordant elevation of FPG or HbA1c. In most low- and middle-income regions, isolated elevated HbA1c more common than isolated elevated FPG. In these regions, the use of FPG alone may delay diabetes diagnosis and underestimate diabetes prevalence. Our prediction equations help allocate finite resources for measuring HbA1c to reduce the global gap in diabetes diagnosis and surveillance.peer-reviewe

Using modified early warning score to predict need of lifesaving intervention in adult non-trauma patients in a tertiary state hospital

Background: Modified early warning score has been validated in many uses in the emergency department. We propose that the modified early warning score performs well in predicting the need of lifesaving interventions in the emergency department, as a predictor of patients who are critically ill. Objective: The study aims to evaluate the use of modified early warning score in sorting out critically ill patients in the emergency department. Methods: The patients’ demographic data and first vital signs (blood pressure, heart rate, temperature, respiratory rate, and level of consciousness) were collected prospectively. Individual modified early warning score was calculated. The outcome was a patient received one or more lifesaving interventions toward the end of stay in emergency department. Multivariate logistic regression analysis was utilized to assess the association between modified early warning score and other potential predictors with outcome. Results: There are a total of 259 patients enrolled into the study. The optimal modified early warning score in predicting lifesaving intervention was ≥4 with a sensitivity of 95% and specificity of 81%. Modified early warning score ≥4 (odds ratio = 96.97, 95% confidence interval = 11.82-795.23, p < 0.001) was found to significantly increase the risk of receiving lifesaving intervention in the emergency department. Conclusion: Modified early warning score is found to be a good predictor for patients in need of lifesaving intervention in the emergency department

Bioethical issues of tissue engineering and regenerative medicine: a preliminary review from Islamic perspective

Modern advances in biochemistry, cell and molecular biology, genetics, biomedical engineering and material sciences, have contributed to the development of tissue engineering and regenerative medicine (TERM). Although TERM is still in its initial phases, significant breakthrough in this cross- disciplinary area has clearly marked the way for the establishment of a promising new biomedicine technology which actively seeks to reconstruct tissues/organs or spare parts for the human body to repair, restore or replace damaged tissues. However, these breakthroughs have raised number of moral and legal questions, including among others, is it moral to genetically modify the human genes? What are the moral and legal implications of regenerative medicine? Does organ reconstruction or tissue replacement activity violate basic religious beliefs or legal status of the person? Through textual and analytical methods, this paper aims to explore relevant concerns from t he Islamic perspective. Besides the texts of the Qur’an and the Prophetic narrations (hadith), both Muslim jurists (fuqaha) and ethicists’ opinion on these matters would be unveiled

Bioethical issues of tissue engineering and regenerative medicine from Islamic perspective

Modern advances in biochemistry, cell and molecular biology, genetics, biomedical engineering and material sciences, have contributed to the development of tissue engineering and regenerative medicine (TERM). Although TERM is still in its initial phases, significant breakthrough in this crossdisciplinary area has clearly marked the way for the establishment of a promising new biomedicine technology which actively seeks to reconstruct tissues/organs or spare parts for the human body to repair, restore or replace damaged tissues. However, these breakthroughs have raised number of moral and legal questions, including among others, is it moral to genetically modify the human genes? What are the moral and legal implications of regenerative medicine? Does organ reconstruction or tissue replacement activity violate basic religious beliefs or legal status of the person? What is the scope and limitation of these practices? Through textual and analytical methods, this paper aims to answer these questions and other relevant concerns from Islamic perspective. Besides the texts of the Qur‟an and the Prophetic narrations (hadith), both Muslim jurists (fuqaha) and ethicists‟ opinion on these matters would be unveiled

Mothers’ perceptions and experiences on tongue-tie and frenotomy: a qualitative study

Introduction: Tongue-tie is a congenital condition of a thickened, tightened or shortened frenulum. This condition may cause breastfeeding difficulties to both mother and infant, such as ineffective suckling and painful nipple. In older children, it can cause speech difficulties. Although many studies have investigated the problems associated with tongue-tie and its treatments, there are limited studies on the mother’s experiences of tongue-tie and post frenotomy. This study aimed to explore the mother’s experiences of tongue-tie associated problems, frenotomy and the outcome. Methods: In-depth interviews were conducted in a one-on-one setting with fifteen mothers whose infant and children underwent frenotomy. Data were collected, transcripted, translated and analysed according to themes. Results: The analysis revealed a common story of stressful challenges and difficulties of breastfeeding. The mothers described that tongue-tie caused poor latching, nipple pain and bleeding, prolong feeding and lack of sleep. Their infant had poor weight gain, sleeping problems, insufficient milk transfer, fatigue and constant crying. For the older children, mothers complained of restricted tongue movement, difficulty in licking ice cream and speech problems. All of them agreed that the frenotomy procedure was easy, simple and less invasive and the outcome was positive. Furthermore, mothers continued breastfeeding without any difficulties and complications. Conclusion: Mothers in this study had difficulties with breastfeeding. However, all of the reported symptoms improved after frenotomy. They considered frenotomy was a simple and safe procedure that was highly recommended for symptomatic tongue-tie

Anti-GITR therapy promotes immunity against malignant glioma in a murine model

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