Abstract Introduction: Gestational diabetes mellitus (GDM) is defined as diabetes diagnosed in the second or third trimester of pregnancy that was not clearly overt diabetes before gestation. ...Unrecognized and untreated GDM confers significantly greater maternal and fetal risk, which is largely related to the degree of hyperglycemia. The specific risks of diabetes in pregnancy include but are not limited to, spontaneous abortion, pre-eclampsia, fetal anomalies, macrosomia, neonatal hypoglycemia, hyperbilirubinemia, and respiratory distress syndrome. Additionally, GDM is also implicated in long-term metabolic derangements in the offspring in the form of obesity/overweight, hypertension, dysglycemia, insulin resistance, and dyslipidemias later in life. To determine the prevalence of anthropometric and metabolic derangements in children between 1 and 5 years of age, born to women with GDM. Methods: This hospital-based cross-sectional study was conducted between November 2019 and November 2021 at our Pediatric Endocrine Clinic. Women were diagnosed as having GDM based on the American Diabetes Association Criteria (2019). History regarding the treatment of the GDM (diet only/diet and medical treatment) and detailed physical examination, including anthropometry and blood pressure, were recorded. Blood samples were collected from children for the estimation of their metabolic profile. Results: Overweight, obesity, and severe obesity were present in 18 (11.3%), 2 (1.3%), and 2 (1.3%) children, respectively. Hypertension was found in 21 (19.4%) children. Elevated LDL, triglyceride, and total cholesterol were seen in 3 (1.9%), 84 (52.5%), and 1 (0.6%) children, respectively. Impaired fasting glucose (IFG) was found in 6 (3.8%) children, while 27 (16.9%) subjects were found to be having impaired glucose tolerance after OGTT. Insulin resistance was found in 30 (18.8%) children. GDM mothers with a higher BMI tended to have children with a higher BMI (correlation coefficient, r = .414, P < .001). Higher serum triglyceride levels (r = −0.034, P = 0.672) were recorded in children, irrespective of the BMI of their mothers. There was no significant correlation of maternal BMI with blood pressure (r = −0.134, P = 0.091) or with HOMA-IR (r = 0.00, P = 0.996) in children. However, mothers with a higher BMI had children with statistically higher fasting blood glucose (r = +0.339, P = <0.001) as well as blood glucose 2 hours after OGTT (r = +0.297, P = <0.001). This positive correlation of maternal BMI with the glucose metabolism of their offspring was observed for both male and female genders. Conclusion: Children of women with GDM had a higher BMI, and the mode of treatment for GDM did not lead to differences in childhood BMI. The higher BMI of a GDM mother is associated with altered glucose metabolism in their offspring. Deranged levels of triglyceride across the gender were not found to be statistically significant. This has implications for future metabolic and cardiovascular risks in targeting this group for intervention studies to prevent obesity and disorders of glucose metabolism as one potential strategy to prevent adverse metabolic health outcomes.
Although immunotherapy has revolutionized cancer care, there is still an urgent need to enhance its efficacy and ensure its safety. A correct cancer theory and proper scientific method empower ...pertinent cancer research and enable effective and efficient drug versus therapy development for patient care. In this perspective, we revisit the concept of immune privilege in a cancer cell versus normal cell, as well as in a cancer stem cell versus normal stem cell. We re-examine whether effective immunotherapies are efficacious due to their anti-cancer and/or immune modulatory mechanisms. We reassess why checkpoint inhibitors (CPIs) are not equal. We reconsider whether one can attribute the utility of immunotherapy to specific cancer subtypes and its futility to certain tumor/immune compartments, components, and microenvironments. We propose ways and means to advance immunotherapy beyond CPIs by combining anti-PD1/L1 with various other treatment modalities according to an appropriate scientific theory, e.g., stem cell origin of cancer, and based on available clinical evidence, e.g., randomized clinical trials. We predict that a stem cell theory of cancer will facilitate the design of better and safer immunotherapy with improved selection of its use for the right patient with the right cancer type at the right time to optimize clinical benefits and minimize potential toxic effects and complications.
Discriminating transcriptional changes that drive disease pathogenesis from nonpathogenic and compensatory responses is a daunting challenge. This is particularly true for neurodegenerative diseases, ...which affect the expression of thousands of genes in different brain regions at different disease stages. Here we integrate functional testing and network approaches to analyze previously reported transcriptional alterations in the brains of Huntington disease (HD) patients. We selected 312 genes whose expression is dysregulated both in HD patients and in HD mice and then replicated and/or antagonized each alteration in a Drosophila HD model. High-throughput behavioral testing in this model and controls revealed that transcriptional changes in synaptic biology and calcium signaling are compensatory, whereas alterations involving the actin cytoskeleton and inflammation drive disease. Knockdown of disease-driving genes in HD patient-derived cells lowered mutant Huntingtin levels and activated macroautophagy, suggesting a mechanism for mitigating pathogenesis. Our multilayered approach can thus untangle the wealth of information generated by transcriptomics and identify early therapeutic intervention points.
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•Neurons implement changes at the transcriptional level to counteract excitotoxicity•Elevated NFKB/actin cytoskeletal signaling increases mHTT levels, driving disease•Downregulating inflammatory pathways reduces mHTT protein levels and neurotoxicity•Antagonizing HD-related expression changes in NFKB/RAC genes enhances autophagy
Various “omic” methodologies produce voluminous amounts of data, but distinguishing the changes that drive a disease from those that represent compensatory mechanisms or secondary responses is exceedingly difficult, time-consuming, and costly. A combination of functional and network approaches can tackle the challenge on a large scale, as shown here using Huntington disease transcriptomics as a test case.
Generally, a language changes according to its speakers' speech community and their family and living locality. On the basis of its usages, region and environment, every native speaker differs in the ...process of language change, vocabulary, style, context, situations, topics, etc. The language change process regularly happens in all the languages of the world. As Aitchison (1991) suggested that, "Language like everything else, gradually transforms itself over the centuries". The current study is an attempt to analyse the phonological changes in Urdu as spoken in Rampur. Mostly the speakers of Rampuri Urdu break the consonant clusters using monosyllabic words. For instance, they use the words /xphrase omittedrphrase omittedc/, and /dphrase omittedrphrase omittedd/in place of /xphrase omittedrc/ 'expenditure' and /dphrase omittedrd/ 'pain' and change the CVCC structure into the CVCVC structure. This study is purely based on the spoken data collected from native speakers of Urdu in the Rampur district of Uttar Pradesh. Keywords: Rampuri Urdu, Phonology, language change, monosyllabic structure, consonant clusters.
In this case report, we present two rare cases of acute post-streptococcal glomerulonephritis with unusual manifestations in the form of myocardial dysfunction and thrombocytopenia. APSGN typically ...follows Streptococcal infections and is characterized by inflammation of glomeruli. These cases, however, exhibited additional complexities. The first case involved a 12-year-old male with fever, shortness of breath, and cough. He presented with pedal edema, pallor, and hypertension. Laboratory findings revealed thrombocytopenia, anemia, and decreased C3 levels, while echocardiography indicated grade-3 diastolic dysfunction. The second case featured a 5-year-old female with icterus, fever, and body swelling. She had a palpable liver, pleural effusion, and thrombocytopenia. Both cases were diagnosed with APSGN, congestive heart failure, and thrombocytopenia. Thrombocytopenia is a rare finding in APSGN, and its etiology remains debated. Treatment included decongestive therapy and antihypertensive medication. Notably, thrombocytopenia in both cases improved without specific intervention, challenging the necessity of steroids or IVIg therapy. This report illuminates on the atypical presentation of APSGN, highlighting the potential coexistence of glomerulonephritis and thrombocytopenia. It underscores the need for further research to better understand this association and determine appropriate treatment protocols. These cases emphasize the importance of considering diverse clinical manifestations in the context of APSGN, calling for a broader understanding of this condition.
Generally, it can be seen that most of the Urdu speakers from the western Uttar Pradesh frequently use address terms in formal as well as colloquial use for everyday conversation. Such usage is ...considered as an integral feature of socio-cultural aspects in terms of language and society. Such types of usage may be useful for sociolinguistic information especially pertaining to interlocutors, about their relationships and circumstances. In the past few decades such terms are studied in different languages of the world in which scholars have been focussing on identifying different types of 'addresses', for instance, personal names, general and occupation titles, kinship related terms, religion- oriented expressions, honorificity in terms of intimacy, personal pronouns, descriptive phrases, etymologies, etc. This work is an attempt to inquire accurate and proper use of the vast range of choices for addressing individuals of different age groups having various contexts being used by western Uttar Pradesh Urdu speakers. Furthermore, this study also shows a number of culture specific address terms which may not have English or Hindi equivalent. Keywords: Address Terms, Urdu of Western Uttar Pradesh (specially spoken in Rampur and adjoining districts), Interlocutors, Impact of Khadiboli on Urdu.
BackgroundMultiple transfusion therapy in Thalassemia Major has led to increased life expectancy but complications like endocrine dysfunction can occur due to secondary iron deposition especially in ...the endocrine organs despite chelation therapy.ObjectivesThe objective of this study was to determine the prevalence of endocrine dysfunctions in Transfusion dependent Thalassemic patients and correlation between serum ferritin levels and specific endocrine dysfunction.MethodsThe study included Transfusion dependent Thalassemic patients between the age group 5 to 18 years receiving at least a year of chelation therapy with deferasirox in a tertiary care centre. After proper consent/assent and clearance from the ethical committee, patients’ characteristics and investigations were recorded on a predesigned proforma. Patients were analysed for endocrine dysfunctions like Growth hormone deficiency, Hypothyroidism, Parathyroid dysfunction, dysglycemia and delayed puberty. Assessment for parathyroid dysfunction, dysglycemia and puberty was done in patients more than 10 years of age only.Data was expressed as Mean± S.D. with 95% confidence Intervals. Correlation between endocrine dysfunctions and serum ferritin levels was investigated using Pearson’s correlation and p value of <0.05 was considered significant.ResultsA total of 50 patients completed the study, out of which 16 patients were more than 10 years of age. The mean age of the study participants was 8.3±2.70 years with a male to female ratio of 2.8:1. The mean age of diagnosis was 16.87±14.03months and mean duration of chelation was 38.40±26.71 months. Endocrine dysfunction was observed in 28 patients (56%). Evaluation for parathyroid dysfunction, dysglycemia and pubertal disorders was done in patients more than 10 years of age only while short stature and thyroid dysfunction was evaluated in all 50 patients completing the study. Maximum prevalence was of parathyroid dysfunction, observed in 10 patients (62.5%) followed by short stature in 17 patients (34%), Impaired Fasting Glucose/Impaired Glucose Tolerance in 4 patients (25%) and subclinical hypothyroidism in 7 patients (14%). Pubertal delay and overt diabetes were not detected in any of the patients. Growth hormone deficiency on provocative stimulation test was observed in 8 patients out of 17 patients (47.05%) with short stature. The serum ferritin levels did not show a significant correlation with any of the endocrine dysfunctions.ConclusionsThis study showed that 56% of the Transfusion dependent Thalassemics had at least one endocrinopathy. A statistically insignificant correlation of endocrinopathy with serum ferritin levels was observed in the study. Irrespective of chelation therapy, patients with transfusion dependent thalassemia can have a considerably high prevalence of endocrine complications. Serum levels of ferritin cannot be utilised as a predictor of endocrine dysfunctions. Therefore, all patients with Thalassemia requiring frequent transfusions should undergo regular monitoring for endocrinopathies.
The recent discovery of intracellular complement activation, specifically anaphylatoxin generation and downstream autocrine receptor engagement in conventional α/β CD4+ T cells has provided new ...insights into mechanisms of T cell activation, polarisation, and homeostatic survival. Anaphylatoxin generation by antigen-presenting cells (APCs) which leads to paracrine signalling via anaphylatoxin receptors on T cells has also been observed but is less extensively described. It is speculated that cell-derived complement may also influence the activity of non-conventional α/β T cells, specifically invariant Natural Killer T (iNKT) cells. The modulation of iNKT cell effector function by cell-derived complement may manifest in two ways, either through autocrine signalling events or via paracrine signalling by neighbouring APCs. Through a combination of molecular biology approaches, a thorough appraisal of iNKT complement expression profiles was performed. Specifically, iNKT cells were shown to up-regulate C3 and the anaphylatoxin receptors C3aR and C5aR1 on their cell surface upon activation with the canonical ligand α-GalCer. Moreover, iNKT cells may 'recycle' C3 from the extracellular space, to potentially regulate complement in their local microenvironment. As iNKT cells mature dendritic cells (DC) in a CD40L-dependent manner, subsequent work showed that engagement of the CD40-CD40L axis also influenced DC complement expression profiles. Specifically, the alternative pathway (AP) complement protein Factor B (FB) along with C3 were positively modulated by CD40 ligation. Moreover, pharmacological inhibition of FB by proprietary GSK inhibitors, specifically cell-permeable small molecules was shown to suppress DC effector function. Subsequent work which assessed cell-derived anaphylatoxin generation was undertaken to validate the specificity of pharmacological inhibition. In conclusion, potential crosstalk mechanisms between the CD40- CD40L axis and FB may underscore DC activation profiles. Modulation of DC effector function may in turn influence iNKT activation at the iNKT-APC interface.
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