Genetic variants related to insulin metabolism are associated with gestational diabetes mellitus.

The current study sought to investigate the associations of common genetic risk variants with gestational diabetes mellitus (GDM) risk in the north Indian population and to evaluate their utility in identifying GDM cases. A case-control study, including 300 pregnant women, was included, and clinical and pathological information was collected. The amplification-refractory mutation system (ARMS) was used for genotyping four single nucleotide polymorphisms (SNPs), namely FTO (rs9939609), PPARG2 (rs1801282), SLC30A8 (rs13266634), and TCF7L2 (rs12255372). The odds ratio and confidence interval were determined for each SNP in different genetic models. Further, attributable risk, population penetrance, and relative risk were also calculated. The risk allele A of FTO (rs9939609) poses a two times higher risk of GDM (p = 0.02, OR = 2.5). The CG and GG genotypes of PPARG2 (rs1801282) have half a lower risk of GDM. In SLC30A8 (rs13266634), the recessive model analysis showed a two times higher risk of having GDM, while the recessive model (TT vs. GG + GT) analysis in TCF7L2 (rs12255372) indicates a lower risk of GDM. Finally, the relative risk, population penetrance, and attributable risk for risk allele in all four variants was higher in GDM mothers. All four polymorphisms were found to be significantly associated with BMI, HbA1c, and insulin. Our study first time confirmed a significant association with GDM for four variants, FTO, PPARG2, SLC30A8, and TCF7L2, in the North Indian population.

Tongues Tied by Orofacial Myofunctional Therapy about Tongue Tie: A Narrative Review.

Aim and Background: The respective review articles aim is to provide an overview as well as describes and enlists different orofacial myofunctional therapy exercises as a modality for tongue tie secondary to surgery.Tongue tie is the basically a connection that joints base of tongue to the floor of mouth. This leads to difficulties various difficulties such as altered speech, oral habits, maligned teeth and many more. During formative years, most children successfully treated of tongue tie by releasing it, but problems start after its correction. That it may can reappear or may lead to same difficulties as prior. Parents and clinicians are only concerned about speech and aesthetics after release of tongue tie. But OMT plays important role ore and post-surgical procedure. OMT help in proper tongue posture along with reducing the probability of tissue reattachment after surgery by exercises. This therapy positively influenced functions by reducing deleterious habits. Methods: A review of relevant literature is predicated on articles found using free text terms, mesh terms, and some basic tongue tie as well as tongue tie release pamphlets that were published in English up until the year 2023 in the electronic databases PubMed, EBSCO, Scopus, Google Scholar, and Web of Science. With the aid of mesh keywords, the initial search yielded 38-40 articles; 20-35 were chosen depending on the requirements. Also we searched for orofacial myofunctional exercises or exercises recommended after tongue tie release. Results: Various exercises enlisted in our article that will guide a individual before and after tongue tie release which will give positive outcomes such as proper tongue posture, speech, swallow, regained aesthetics and self-esteem. Conclusion: Tongue plays an important role in development of perioral structures as well as in the swallow to good speech articulation and dental occlusion. So, as pediatric dentist its important know that after release of tongue tie what to do and how to maintain. This review article is focused on the various orofacial myofunctional therapy techniques employed for tongue tie but not a single one to describe them. Clinical significance: Our pertaining review act as a guide for clinicians as well as individuals to manage tongue tie after its release. How to cite this article: Shah SS, Agarwal PV, Rathi N, et al. Tongues Tied by Orofacial Myofunctional Therapy about Tongue Tie: A Narrative Review. Int J Clin Pediatr Dent 2024;17(1):109-113.

Urinary extracellular vesicles-encapsulated miRNA signatures: A new paradigm for urinary bladder cancer diagnosis and classification.

Bladder cancer (BCa) stands as prevalent malignancy of the urinary system globally, especially among men. The clinical classification of BCa into non-muscle invasive bladder cancer (NMIBC) and muscle-invasive bladder cancer (MIBC) is crucial for prognosis and treatment decisions. However, challenges persist in current diagnostic methods like Urine cytopathology that shows poor sensitivity therefore compromising on accurately diagnosing and monitoring BCa. In recent years, research has emphasized the importance of identifying urine and blood-based specific biomarkers for BCa that can enable early and precise diagnosis, effective tumor classification, and monitoring. The convenient proximity of urine with the urinary bladder epithelium makes urine a good source of noninvasive biomarkers, in particular urinary EVs because of the packaged existence of tumor-associated molecules. Therefore, the review assesses the potential of urinary extracellular vesicles (uEVs) as noninvasive biomarkers for BCa. We have elaborately reviewed and discussed the research that delves into the role of urinary EVs in the context of BCa diagnosis and classification. Extensive research has been dedicated to investigating differential microRNA (miRNA) expressions, with the goal of establishing distinct, noninvasive biomarkers for BCa. The identification of such biomarkers has the potential to revolutionize early detection, risk stratification, therapeutic interventions, and ultimately, the long-term prognosis of BCa patients. Despite notable advancements, inconsistencies persist in the biomarkers identified, methodologies employed, and study populations. This review meticulously compiles reported miRNA biomarkers, critically assessing the variability and discrepancies observed in existing research. By synthesizing these findings, the article aims to direct future studies toward a more cohesive and dependable approach in BCa biomarker identification, fostering progress in patient care and management.

Elevated glycosylation of CD36 in platelets is a risk factor for oxLDL-mediated platelet activation in type 2 diabetes.

Platelet activation and related cardiovascular complications are the hallmarks of type 2 diabetes (T2D). We investigated the mechanism of platelet activation in T2D using MS-based identification of differentially expressed platelet proteins with a focus on glycosylated forms. Glycosylation is considered one of the common post-translational modifications in T2D, and N/O-linked glycosylation of glycoproteins (GPs)/integrins is known to play crucial roles in platelet activation. Our platelet proteome data revealed elevated levels of GPs GPIbα, GPIIbIIIa, GPIV (CD36), GPV and integrins in T2D patients. T2D platelets had elevated N-linked glycosylation of CD36 at asparagine (Asn)408,417 . Enrichment analysis revealed a close association of glycosylated CD36 with thrombospondin-1, fibrinogen and SERPINA1 in T2D platelets. The glycosylation of CD36 has previously been reported to increase cellular uptake of long-chain fatty acids. Our in silico molecular docking data also showed a favorable binding of cholesterol with glycosylated Asn417 CD36 compared to the non-glycosylated form. We further investigated the CD36:LDL cholesterol axis in T2D. Elevated levels of oxidized-low density lipoprotein (oxLDL) were found to cause significant platelet activation via CD36-mediated stimulation of Lyn-JNK signaling. Sulfo-N-succinimidyl oleate, an inhibitor of CD36, effectively inhibited oxLDL-mediated platelet activation and adhesion in vitro. Our study suggests increased glycosylation of CD36 in T2D platelets as a potential route for oxLDL-mediated platelet activation. The oxLDL:CD36 axis may thus be exploited as a prospective target to develop therapeutics against thrombosis in T2D.

Alpha-ketoglutarate supplementation reduces inflammation and thrombosis in type 2 diabetes by suppressing leukocyte and platelet activation.

The interplay between platelets and leukocytes contributes to the pathogenesis of inflammation, thrombosis, and cardiovascular diseases (CVDs) in type 2 diabetes (T2D). Our recent studies described alpha-ketoglutarate (αKG), a Krebs cycle intermediate metabolite as an inhibitor to platelets and leukocytes activation by suppressing phosphorylated-Akt (pAkt) through augmentation of prolyl hydroxylase-2 (PHD2). Dietary supplementation with a pharmacological concentration of αKG significantly inhibited lung inflammation in mice with either SARS-CoV-2 infection or exposed to hypoxia treatment. We therefore investigated if αKG supplementation could suppress hyperactivation of these blood cells and reduce thromboinflammatory complications in T2D. Our study describes that dietary supplementation with αKG (8 mg/100 g body wt. daily) for 7 days significantly reduced the activation of platelets and leukocytes (neutrophils and monocytes), and accumulation of IL1ß, TNFα, and IL6 in peripheral blood of T2D mice. αKG also reduced the infiltration of platelets and leukocytes, and accumulation of inflammatory cytokines in lungs by suppressing pAkt and pP65 signaling. In a cross-sectional investigation, our study also described the elevated platelet-leukocyte aggregates and pro-inflammatory cytokines in circulation of T2D patients. T2D platelets and leukocytes showed an increased aggregation and thrombus formation in vitro. Interestingly, a pre-incubation of T2D blood samples with octyl αKG significantly suppressed the activation of these blood cells and ameliorated aggregate/thrombus formation in vitro. Thus, suggesting a potential therapeutic role of αKG against inflammation, thrombosis, and CVDs in T2D.

Fisetin attenuates doxorubicin-induced cardiotoxicity by inhibiting the insulin-like growth factor II receptor apoptotic pathway through estrogen receptor-α/-ß activation.

Doxorubicin (DOX), an effective chemotherapeutic drug, has been used to treat various cancers; however, its cardiotoxic side effects restrict its therapeutic efficacy. Fisetin, a flavonoid phytoestrogen derived from a range of fruits and vegetables, has been reported to exert cardioprotective effects against DOX-induced cardiotoxicity; however, the underlying mechanisms remain unclear. This study investigated fisetin's cardioprotective role and mechanism against DOX-induced cardiotoxicity in H9c2 cardiomyoblasts and ovariectomized (OVX) rat models. MTT assay revealed that fisetin treatment noticeably rescued DOX-induced cell death in a dose-dependent manner. Moreover, western blotting and TUNEL-DAPI staining showed that fisetin significantly attenuated DOX-induced cardiotoxicity in vitro and in vivo by inhibiting the insulin-like growth factor II receptor (IGF-IIR) apoptotic pathway through estrogen receptor (ER)-α/-ß activation. The echocardiography, biochemical assay, and H&E staining results demonstrated that fisetin reduced DOX-induced cardiotoxicity by alleviating cardiac dysfunction, myocardial injury, oxidative stress, and histopathological damage. These findings imply that fisetin has a significant therapeutic potential against DOX-induced cardiotoxicity.

Navigating a Path to Rifampicin Resistance in Tuberculosis.

For model bacteria, genetic drug resistance usually arises from antibiotic-tolerant subpopulations, but whether this is true for the globally important pathogen Mycobacterium tuberculosis-the cause of tuberculosis-is not known. Here, we discuss a recent article by Sebastian et al. (J. Sebastian, A. Thomas, C. Levine, R. Shrestha, et al., mBio 14:e0279522, 2023, 10.1128/mbio.02795-22) which leverages a robotic transwell microtiter experimental system coupled with deep sequencing of a barcoded library of M. tuberculosis to answer this question for rifampicin resistance. The authors investigate two distinct forms of antibiotic-tolerant subpopulations-classical tolerance, characterized by prolonged minimum duration of killing, and "differentially detectable" (DD) bacilli that are viable but can be recovered only in liquid medium as opposed to plating. They demonstrate that, indeed, resistance arises preferentially from both rifampicin-tolerant subpopulations, though earlier in the DD population. Use of barcoded libraries and parallel culture systems shows promise in investigating phenotypes mediated by minority subpopulations of bacteria such as development of antibiotic resistance.

Antepartum hemorrhage and its maternal and perinatal outcome: An experience at a hospital in North India.

Introduction and Aim: Antepartum hemorrhage (APH) is one of the deadliest complications in obstetrics. It can complicate about 2-5% of pregnancies. It contributes significantly to maternal and perinatal mortality and morbidity during pregnancy and childbearing worldwide. The aim of this study was to determine maternal and fetal outcomes in patients presenting with APH. Materials and Methods: This was a retrospective study. Pregnant women with >28 weeks gestation reporting to the Department of Obstetrics and Gynecology from May 2021 to April 2022 were included in the study. Ethical approval from the institutional ethical committee was taken. Result: This study included 76 patients of APH. Most patients in the analysis were found to be second gravida (30%). Anemia was the most common associated morbidity (51.31%). 58% of these patients were of placenta previa, 14% were of abruption, and 10% were of accreta. Among all patients, 94.74% recovered well. 2.63% of cases could not be saved and resulted in maternal mortality. The proportions of babies alive, intra-uterine death (IUD), and intubated were 86.84%, 11.84%, and 1.32%, respectively. 17.1% of patients required a lifesaving cesarean hysterectomy. Conclusion: APH is an obstetrical emergency that requires timely diagnosis and early intervention. Swift management is required to improve maternal and fetal outcomes.

Journal of family medicine and primary care- A five year bibliometric analysis from 2016 to 2020.

Aim: To conduct a five-year bibliometric analysis of the Journal of Family Medicine and Primary Care (J Family Med Prim Care) between 2016 and 2020. Setting and Design: This retrospective secondary data analysis was conducted in the Department of Conservative, Endodontics and Aesthetic Dentistry, Dental Institute, Rajendra Institute of Medical Sciences, Ranchi, Jharkhand and Rohilkhand Medical College and Hospital, Bareilly, UP. Material and Methods: The data of publications including research articles, review and case reports excluding editorials and letters to the editor, commentaries and invited articles published in the J Family Med Prim Care between 2016 and 2020 were downloaded from the journal website and analysed in terms of the bibliometric parameters. Results: The results revealed that the journal gave equal weightage to all types of articles. The total number of articles published between 2016 and 2020 was 2,426 out of which 1,666 articles were published from India and the remaining from other parts of the world. In India, the state of Delhi had the maximum publications while speciality Preventive and Social Medicine (22.42%) and General Medicine (23.12%) had the maximum articles. Moreover, between 2016 and 2020, J Family Med Prim Care had 2,132 citations of published articles and had 65 publications in 2020 about the Corona Virus Disease (COVID-19) pandemic. Conclusion: The issue numbers per year for J Family Med Prim Care has gradually increased over time. The publication is open for all fields of medical, dental sciences and allied sciences.

Exopolyphosphatases PPX1 and PPX2 from Mycobacterium tuberculosis regulate dormancy response and pathogenesis.

Stress adaptation and virulence of various bacterial pathogens require stringent response pathways involving guanosine pentaphosphate and inorganic polyphosphate (PolyP). In M. tuberculosis, intracellular PolyP levels are maintained by the activities of polyphosphate kinase (PPK-1, PPK-2) and exopolyphosphatases (PPX-1, PPX-2). We demonstrate that these exopolyphosphatases cumulatively contribute to biofilm formation and survival of M. tuberculosis in nutrient limiting, low oxygen growth conditions and in macrophages. Characterization of single (Δppx2) and double knock out strain (dkppx) of M. tuberculosis demonstrated that these exopolyphosphatases are essential for establishing infection in guinea pigs and mice. Transcriptional profiling revealed that relative to the parental strain the expression of genes belonging to DosR regulon were significantly reduced in mid-log phase cultures of dkppx strain. We also show that PolyP inhibited the autophosphorylation activities associated with DosT and DosS sensor kinases. Host RNA-seq analysis revealed that transcripts involved in various antimicrobial pathways such as apoptosis, autophagy, macrophage activation, calcium signalling, innate and T-cell response were differentially expressed in lung tissues of dkppx strain infected mice. Taken together, we demonstrate that enzymes involved in PolyP homeostasis play a critical role in physiology and virulence of M. tuberculosis. These enzymes are attractive targets for developing novel interventions that might be active against drug-sensitive and drug-resistant M. tuberculosis.

Improvement in Oxygen Evolution Performance of NiFe Layered Double Hydroxide Grown in the Presence of 1T-Rich MoS2.

NiFe layered double hydroxide (NiFe LDH) grown in the presence of MoS2 (rich in 1T phase) shows exceptional performance metrics for alkaline oxygen evolution reaction (OER) in this class of composites. The as-prepared NiFe LDH/MoS2 composite (abbreviated as MNF) exhibits a low overpotential (η10) of 190 mV; a low Tafel slope of 31 mV dec-1; and more importantly, a high stability in its performance manifested by the delivery of current output for 45 h. It is important to note that this could be achieved with an exceedingly low loading of 0.14 mg cm-2. The mass activity of this composite (97 A g-1) is about 14 times greater than that of the conventional RuO2 (7 A g-1) at η = 200 mV. When normalized with respect to the total metal content, a mass activity of 1000 A g-1 (η = 300 mV) was achieved. Impedance analysis further reveals that the significant reduction in charge-transfer resistance and hence high current density (5 times greater as compared to NiFe LDH at η = 300 mV) observed for MNF is associated with interfacial adsorption kinetics of intermediates (R1). Significant enhancement in the intrinsic activity of MNF over LDH has been observed through normalization of current with the electrochemically active surface area. Computational studies suggest that the Ni centers in the composite act as the active sites for OER, which is well-corroborated with the observed postreaction appearance of Ni3+ species.

Electroreduction of CO2 with Tunable Selectivity on Au-Pd Bimetallic Catalyst: A First Principle Study.

The electroreduction of CO2 exhibits great promise in mitigating CO2 from the atmosphere. However, it is quite challenging to produce C1 products selectively on metal surfaces due to inefficient binding of CO with a metal surface. Here, using density functional theory, we studied an experimentally viable system of gold alloyed with a high CO-binding metal palladium. It is observed that the selectivity toward formic acid and methane can be tuned on Au-Pd bimetallic catalysts. Pd-rich alloy surfaces such as Pd deposited on the (211) surface of Au (Pd@Au) are found to be highly selective toward formic acid with an ultralow limiting potential of -0.23 V vs SHE. Interestingly, as the surface of the alloy become Au-rich, the selectivity toward methane increases. Among all the Au-Pd bimetallic systems, the Au-rich (211) surface of Au3Pd alloy has a very low limiting potential of -0.9 V vs SHE for CO2 electroreduction to methane. The selectivity toward methane on this surface is enhanced due to its optimum CO* binding and the ease of CO* protonation to CHO*. The higher feasibility of CO* protonation is a result of the stabilization of adsorbed CHO*. This stabilization is attributed to the interaction of both C and O of the CHO* molecule with the surface Au and Pd. It is found that the selectivity of a catalyst depends upon the stability of various intermediates, which can be regulated by modifying the composition of Au and Pd in the alloy. The results presented here demonstrate broad opportunities to tune the selectivity of the catalyst with varying alloy compositions, which will help to develop novel catalysts for CO2 electroreduction.

Tuning Catalytic Activity in Ultrathin Bimetallic Nanowires via Surface Segregation: Some Insights.

The efficiency of heterogeneous catalysts critically depends on the nature of the surface. We present results on controlling the composition in ultrathin bimetallic AuPd. AuPd wires were grown using Au nanowire templates; the surface composition could be tuned by increasing the amount of Pd. Further, segregation of Pd to the surface could be induced in alloyed nanowires by annealing under a controlled CO atmosphere. Electrocatalytic activity of these bimetallic systems is assessed for the methanol oxidation reaction (MOR). While the MOR potential shows a monotonic increase with Pd content, the specific activity displays a typical volcano-type behavior. The CO-annealed nanowires show a lowering of potential owing to a higher Pd content on the surface while still maintaining the specific activity. These findings provide clear strategies to independently control the reaction potential and the activities of nanocatalysts. The experimental findings are well supported by the theoretical investigations using density functional theory (DFT) calculations.

α-Ketoglutarate Inhibits Thrombosis and Inflammation by Prolyl Hydroxylase-2 Mediated Inactivation of Phospho-Akt.

BACKGROUND: Phospho-Akt1 (pAkt1) undergoes prolyl hydroxylation at Pro125 and Pro313 by the prolyl hydroxylase-2 (PHD2) in a reaction decarboxylating α-ketoglutarate (αKG). We investigated whether the αKG supplementation could inhibit Akt-mediated activation of platelets and monocytes, in vitro as well as in vivo, by augmenting PHD2 activity. METHODS: We treated platelets or monocytes isolated from healthy individuals with αKG in presence of agonists in vitro and assessed the signalling molecules including pAkt1. We supplemented mice with dietary αKG and estimated the functional responses of platelets and monocytes ex vivo. Further, we investigated the impact of dietary αKG on inflammation and thrombosis in lungs of mice either treated with thrombosis-inducing agent carrageenan or infected with SARS-CoV-2. FINDINGS: Octyl αKG supplementation to platelets promoted PHD2 activity through elevated intracellular αKG to succinate ratio, and reduced aggregation in vitro by suppressing pAkt1(Thr308). Augmented PHD2 activity was confirmed by increased hydroxylated-proline and enhanced binding of PHD2 to pAkt in αKG-treated platelets. Contrastingly, inhibitors of PHD2 significantly increased pAkt1 in platelets. Octyl-αKG followed similar mechanism in monocytes to inhibit cytokine secretion in vitro. Our data also describe a suppressed pAkt1 and reduced activation of platelets and leukocytes ex vivo from mice supplemented with dietary αKG, unaccompanied by alteration in their number. Dietary αKG significantly reduced clot formation and leukocyte accumulation in various organs including lungs of mice treated with thrombosis-inducing agent carrageenan. Importantly, in SARS-CoV-2 infected hamsters, we observed a significant rescue effect of dietary αKG on inflamed lungs with significantly reduced leukocyte accumulation, clot formation and viral load alongside down-modulation of pAkt in the lung of the infected animals. INTERPRETATION: Our study suggests that dietary αKG supplementation prevents Akt-driven maladies such as thrombosis and inflammation and rescues pathology of COVID19-infected lungs. FUNDING: Study was funded by the Department of Biotechnology (DBT), Govt. of India (grants: BT/PR22881 and BT/PR22985); and the Science and Engineering Research Board, Govt. of India (CRG/000092).

Dermatological Disorders in the Intensive Care Unit: A Descriptive Study at a Tertiary Care Centre.

BACKGROUND: Dermatological disorders are common in patients being treated in intensive care units (ICU). However, they are often neglected in context of a critically ill patient. Very few studies focusing on these dermatoses have been undertaken. OBJECTIVES: To determine the prevalence and spectrum of dermatological disorders in patients being treated in medical ICU of a tertiary care centre. METHODS: This was a descriptive study conducted over a period of one year. All the patients admitted in the medical ICU were examined for the presence of any preexisting or newly developed dermatological disorder. Dermatological disorders were initially classified into infective and non-infective disorders. Patients with dermatological findings were classified into two groups: those who survived and those who died; which were compared with each other with respect to age and sex distribution, length of ICU stay and dermatological findings. RESULTS: Out of 776 cases admitted in ICU during the study period, dermatological disorders were observed in 164 (21.13%) cases. Life-threatening dermatological disorders were seen in 3.05% cases. Twenty nine (17.68%) patients with dermatological findings died. Amongst these cases, infectious dermatological disorders were significantly less common; while no significant difference was noticed in context of reactive dermatological disorders. CONCLUSION: Dermatological disorders in ICU are common and have a wide spectrum. They often need treatment and may be indicative of underlying potentially fatal systemic illness. Besides, a subset of cutaneous lesions may develop in response to various medical interventions, immunosuppression and immobility. Knowledge of such dermatoses is thus, essential, both for the intensivist and dermatologist.

Interplay between hypoxia and inflammation contributes to the progression and severity of respiratory viral diseases.

History of pandemics is dominated by viral infections and specifically respiratory viral diseases like influenza and COVID-19. Lower respiratory tract infection is the fourth leading cause of death worldwide. Crosstalk between resultant inflammation and hypoxic microenvironment may impair ventilatory response of lungs. This reduces arterial partial pressure of oxygen, termed as hypoxemia, which is observed in a section of patients with respiratory virus infections including SARS-CoV-2 (COVID-19). In this review, we describe the interplay between inflammation and hypoxic microenvironment in respiratory viral infection and its contribution to disease pathogenesis.