Intraductal administration of transferrin receptor-targeted immunotoxin clears ductal carcinoma in situ in mouse models of breast cancer-a preclinical study.

The human transferrin receptor (TFR) is overexpressed in most breast cancers, including preneoplastic ductal carcinoma in situ (DCIS). HB21(Fv)-PE40 is a single-chain immunotoxin (IT) engineered by fusing the variable region of a monoclonal antibody (HB21) against a TFR with a 40 kDa fragment of Pseudomonas exotoxin (PE). In humans, the administration of other TFR-targeted immunotoxins intrathecally led to inflammation and vascular leakage. We proposed that for treatment of DCIS, intraductal (i.duc) injection of HB21(Fv)-PE40 could avoid systemic toxicity while retaining its potent antitumor effects on visible and occult tumors in the entire ductal tree. Pharmacokinetic studies in mice showed that, in contrast to intravenous injection, IT was undetectable by enzyme-linked immunosorbent assay in blood following i.duc injection of up to 3.0 µg HB21(Fv)-PE40. We demonstrated the antitumor efficacy of HB21(Fv)-PE40 in two mammary-in-duct (MIND) models, MCF7 and SUM225, grown in NOD/SCID/gamma mice. Tumors were undetectable by In Vivo Imaging System (IVIS) imaging in intraductally treated mice within 1 wk of initiation of the regimen (IT once weekly/3 wk, 1.5 µg/teat). MCF7 tumor-bearing mice remained tumor free for up to 60 d of observation with i.duc IT, whereas the HB21 antibody alone or intraperitoneal IT treatment had minimal/no antitumor effects. These and similar findings in the SUM225 MIND model were substantiated by analysis of mammary gland whole mounts, histology, and immunohistochemistry for the proteins Ki67, CD31, CD71 (TFR), and Ku80. This study provides a strong preclinical foundation for conducting feasibility and safety trials in patients with stage 0 breast cancer.

HIV cure: Are we going to make history?

BACKGROUND: At present, combination antiretroviral therapy (cART) is the mainstay for the treatment of people living with HIV/AIDS. cART can suppress the viral load to a minimal level; however, the possibility of the emergence of full-blown AIDS is always there. In the latter part of the first decade of the 21st century, an HIV-positive person received stem cell transplantation (SCT) for treatment of his haematological malignancy. The patient was able to achieve remission of the haematological condition as well as of HIV following SCT. Thorough investigations of various samples including blood and biopsy could not detect the virus in the person's body. The person was declared to be the first cured case of HIV. LITERATURE SEARCH: Over the next decade, a few more similar cases were observed and have recently been declared cured of the infection. A comprehensive search was performed in PubMed, Cochrane library and Google Scholar. Four such additional cases were found in literature. DESCRIPTION & DISCUSSION: These cases all share a common proposed mechanism for the HIV cure, that is, transplantation of stem cells from donors carrying a homozygous mutation in a gene encoding for CCR5 (receptor utilized by HIV for entry into the host cell), denoted as CCR5△32. This mutation makes the host immune cells devoid of CCR5, causing the host to acquire resistance against HIV. To the best of our knowledge, this is the first review to look at relevant and updated information of all cured cases of HIV as well as the related landmarks in history and discusses the underlying mechanism(s).

Excess Mortality Risk Due to Heat Stress in Different Climatic Zones of India.

India is at a high risk of heat stress-induced health impacts and economic losses owing to its tropical climate, high population density, and inadequate adaptive planning. The health impacts of heat stress across climate zones in India have not been adequately explored. Here, we examine and report the vulnerability to heat stress in India using 42 years (1979-2020) of meteorological data from ERA-5 and developed climate-zone-specific percentile-based human comfort class thresholds. We found that the heat stress is usually 1-4 °C higher on heatwave (HW) days than on nonheatwave (NHW) days. However, the stress on NHW days remains considerable and cannot be neglected. We then showed the association of a newly formulated India heat index (IHI) with daily all-cause mortality in three cities - Delhi (semiarid), Varanasi (humid subtropical), and Chennai (tropical wet and dry), using a semiparametric quasi-Poisson regression model, adjusted for nonlinear confounding effects of time and PM2.5. The all-cause mortality risk was enhanced by 8.1% (95% confidence interval, CI: 6.0-10.3), 5.9% (4.6-7.2), and 8.0% (1.7-14.2) during "sweltering" days in Varanasi, Delhi, and Chennai, respectively, relative to "comfortable" days. Across four age groups, the impact was more severe in Varanasi (ranging from a 3.2 to 7.5% increase in mortality risk for a unit rise in IHI) than in Delhi (2.6-4.2% higher risk) and Chennai (0.9-5.7% higher risk). We observed a 3-6 days lag effect of heat stress on mortality in these cities. Our results reveal heterogeneity in heat stress impact across diverse climate zones in India and call for developing an early warning system keeping in mind these regional variations.

Quercetin in semen extenders curtails reactive oxygen and nitrogen species and improves functional attributes of cryopreserved buck semen.

Cryopreservation of goat spermatozoa is challenging due to several factors, including one of the most essential, i.e., oxidative stress. It is particularly essential in goat semen due to its scanty ejaculate volume and high sperm concentration. This leaves a narrow sperm-to-seminal plasma ratio owing to marginal antioxidant support; moreover, semen extension further dilutes the antioxidant level, leading to an imbalance of oxidant-antioxidant equilibrium. The present study aimed to evaluate the effect of quercetin on curtailing oxidative stress and its reflection on the post-thaw survivability and membrane integrity of goat spermatozoa. For this study, six bucks were selected. Six ejaculates from each buck totaling 36 ejaculates were collected, which were then split into five parts; furthermore, each part was added with a semen extender having a particular concentration of additive. Group C without quercetin and T1 containing Vit E at 3 mmol/mL were considered the control and positive control respectively, whereas T2, T3, and T4 contain 10, 20, and 30 µmol/mL of Quercetin respectively. The final sperm concentration of each group was kept at 200×106 spermatozoa/mL. All groups were subjected to equilibration at 4 °C for 4 hours, then filled in French mini (0.25 mL) straws, followed by sealing and cryopreservation. Samples after 72 hours of cryopreservation were subjected to evaluation of plasma membrane integrity and viability through staining, acrosomal integrity, and mitochondrial membrane activity through flowcytometry. Evaluation of sperm kinematics as well as the oxidant-antioxidant status of sperm (ROS and nitric oxide) and seminal plasma (SOD, CAT, GPx, FRAP, and lipid peroxidation through MDA estimation) were also carried out. Quercetin, when supplemented at 20 µmol/mL in buck semen extender, significantly (p<0.01) improved cryopreserved sperm functions in terms of plasma membrane integrity, viability, acrosomal integrity, mitochondrial membrane activity, and sperm kinematics of buck semen. Similarly, Quercetin supplementation at 20 µmol/mL significantly reduced reactive oxygen and nitrogen species (RONS) in sperm and improved the antioxidant status of seminal plasma, which was indicated by reduced oxidative damage and improved the antioxidant status of buck semen. In conclusion, Quercetin at 20 µmol/mL reduced oxidative stress, improved semen antioxidant status, and improved sperm membrane integrity and kinematics.

Precision mapping child undernutrition for nearly 600,000 inhabited census villages in India.

There are emerging opportunities to assess health indicators at truly small areas with increasing availability of data geocoded to micro geographic units and advanced modeling techniques. The utility of such fine-grained data can be fully leveraged if linked to local governance units that are accountable for implementation of programs and interventions. We used data from the 2011 Indian Census for village-level demographic and amenities features and the 2016 Indian Demographic and Health Survey in a bias-corrected semisupervised regression framework to predict child anthropometric failures for all villages in India. Of the total geographic variation in predicted child anthropometric failure estimates, 54.2 to 72.3% were attributed to the village level followed by 20.6 to 39.5% to the state level. The mean predicted stunting was 37.9% (SD: 10.1%; IQR: 31.2 to 44.7%), and substantial variation was found across villages ranging from less than 5% for 691 villages to over 70% in 453 villages. Estimates at the village level can potentially shift the paradigm of policy discussion in India by enabling more informed prioritization and precise targeting. The proposed methodology can be adapted and applied to diverse population health indicators, and in other contexts, to reveal spatial heterogeneity at a finer geographic scale and identify local areas with the greatest needs and with direct implications for actions to take place.

Non-analgesic benefits of combined thoracic epidural analgesia with general anesthesia in on-pump pediatric cardiac surgery: A prospective observational study.

Background: The use of thoracic epidural analgesia in infants and children could attenuate the stress response and thereby improve the outcomes associated with cardiac surgery. Methods: This study is a prospective observational study conducted on 118 patients admitted for cardiac surgery. All patients received thoracic epidural analgesia. Laboratory investigations including inflammatory markers, markers for different organ functions, and intensive care unit parameters were collected at different time points (preoperative, immediate postoperative, on day 1, and day 2). Results: Inflammatory markers such as IL6, IL8, and metabolic response as measured by serum cortisol and blood sugar were significantly high in the immediate postoperative period, which later stabilized in the next 48 h. There was also a sharp increase in the anti-inflammatory marker IL-10 in an immediate postoperative period, which settled later on but continued to be higher than baseline in the next 48 h. All these markers showed lower values when compared to published literature. The baseline renal oxygen saturation using near infrared spectroscopy (NIRS) value in our study was 59.3 + 19, which increased to 76.4 + 12.7 on day 2. Serum neutrophil gelatinase associated lipocalin (NGAL) remained well below normal levels in the perioperative period. PF (pO2/FiO2) ratio and pO2 consistently improved postoperatively with the maximum on day 2. The median mechanical ventilation (MV) duration was 18 h, and the mean length of stay that included intensive care unit stay was 12 days. No epidural-related adverse events were noted. Conclusions: Apart from good analgesia, patients receiving thoracic epidural analgesia displayed a reduction in perioperative stress, superior postoperative glycemic control, reduction in inflammatory markers, postoperative acute kidney injury, and pulmonary complications.

Evaluation of qCON and qNOX indices in pediatric surgery under general anesthesia.

Background and Aims: The objective of the study was to evaluate the performances of qCON and qNOX indices in pediatric populations undergoing surgery under general anesthesia (GA), focusing on the induction and recovery periods. Both the indices are derived from electroencephalogram (EEG) and implemented in the CONOX monitor (Fresenius Kabi, Germany). Material and Methods: After approval of the institutional ethics committee, this prospective observational study was conducted in pediatric patients of either sex in the age group of 1-12 years belonging to the American Society of Anesthesiology (ASA) grade I and II undergoing elective surgery under GA. Anesthetic technique was GA with or without regional analgesia (RA). All patients underwent inhalation induction and maintenance using sevoflurane. Patients were monitored with the use of a CONOX monitoring system (Fresenius Kabi, Germany), connected via a set of electrodes placed over the forehead. qCON and qNOX scores were recorded during awake (on operating table premedicated with oral midazolam 0.5 mg/kg), at induction, at loss of eyelash reflex, intubation/laryngeal mask airway (LMA) insertion, before and after regional anesthesia, surgical incision, at cessation of anesthesia, emergence, extubation, and eye-opening. Registered results were also analyzed compared with the minimum alveolar concentration of sevoflurane (MAC). Results: A total of 46 pediatric patients were enrolled in the study with a mean age of 5.6 years. All the patients were either ASA I or II. There was a simultaneous fall and rise of qCON and qNOX upon induction and recovery, respectively. There was a rise in qNOX with surgical incision irrespective of RA. However, there was a greater rise in qNOX following surgical incision in those who did not receive RA (P = 0.33) Also both qCON (P = 0.06) and qNOX (P = 0.41) were poorly correlated with MAC values of sevoflurane during GA in the pediatric population. Conclusions: Both qCON and qNOX values change predictably with changes in the conscious level and with different noxious stimuli. Further studies are required to confirm the findings taking into account the postoperative assessment of delirium and recall of intraoperative events.

Silicon Palliates Chromium Toxicity through the Formation of Root Hairs in Rice (Oryza sativa) Mediated by GSH and IAA.

Along with the rapidly increasing environmental contamination by heavy metals, the exposure of plants to chromium has also magnified, resulting in a declined productivity. Hexavalent chromium [Cr(VI)], the most toxic form of Cr, brings about changes in plant processes at morpho-physiological and biochemical levels. However, silicon (Si) is known to mitigate the impact of abiotic stresses in plants. Here, we demonstrate Si-mediated alleviation of Cr(VI) toxicity and its effects on root hair formation in rice seedlings. Reduced glutathione (GSH) and indole-3 acetic acid (IAA, an important auxin) were assessed for their involvement in root hair formation after the application of Si to Cr(VI)-stressed plants, and our results confirmed their crucial significance in such developmental processes. The expression analysis of genes involved in GSH biosynthesis (OsGS2) and regeneration (OsGR1), and auxin biosynthesis (OsTAA1 and OsYUCCA1) and transport (OsAUX1 and OsPIN1) corroborated their positive role in Si-mediated root hair formation in Cr(VI)-stressed rice seedlings. Moreover, the results indicated that nitric oxide (NO) seems a probable but not fundamental component in Si-mediated formation of roots in rice during exposure to Cr(VI) stress. In this study, the indispensable role of GSH and IAA, redox homeostasis of GSH and IAA biosynthesis and transport are discussed with regard to Si-mediated formation of root hairs in rice under Cr(VI) stress. The results of the study suggest that Si is a protective agent against Cr(VI) stress in rice, and the findings can be used to develop Cr(VI) stress-tolerant varieties of rice with enhanced productivity.

Japanese Encephalitis Virus Infection Causes an Imbalance in the Activation of Mitochondrial Fusion/Fission Genes and Triggers the Activation of NOX2-mediated Oxidative Stress and Neuronal Cell Death.

Mitochondria dysfunction may be an important contributor to Japanese encephalitis (JE) viral infection disease pathogenesis. In the current study, we define whether changes in mitochondrial DNA copy number (which is the biomarker for mitochondrial function) and alteration in mitochondria dynamics (fusion and fission) contribute to the pathology of the JE virus in vivo mice model. We found decreased mitochondria copy number, reduced activation of mitochondrial fission (FIS1/DRP1), and increased activation of mitochondrial fusion (MFN1/MFN2/OPA1) genes that are associated with increased NOX2-mediated ROS generation and neuronal cell death following JE virus infection. Furthermore, we found that antioxidant glutathione level decreases. In summary, the following study demonstrates that JE viral infection causes an imbalance in mitochondrial fission/fusion gene activation and promotes NOX2-mediated oxidative stress and cell death, suggesting that intervention in mitochondrial dynamics might be a potential therapeutic strategy for combating oxidative stress and inflammatory process in JE viral infection.

Addressing Biases in Ambient PM2.5 Exposure and Associated Health Burden Estimates by Filling Satellite AOD Retrieval Gaps over India.

Ambient PM2.5 exposure statistics in countries with limited ground monitors are derived from satellite aerosol optical depth (AOD) products that have spatial gaps. Here, we quantified the biases in PM2.5 exposure and associated health burden in India due to the sampling gaps in AOD retrieved by a Moderate Resolution Imaging Spectroradiometer. We filled the sampling gaps and derived PM2.5 in recent years (2017-2022) over India, which showed fivefold cross-validation R2 of 0.92 and root mean square error (RMSE) of 11.8 µg m-3 on an annual scale against ground-based measurements. If the missing AOD values are not accounted for, the exposure would be overestimated by 19.1%, translating to an overestimation in the mortality burden by 93,986 (95% confidence interval: 78,638-110,597) during these years. With the gap-filled data, we found that the rising ambient PM2.5 trend in India has started showing a sign of stabilization in recent years. However, a reduction in population-weighted exposure balanced out the effect of the increasing population and maintained the mortality burden attributable to ambient PM2.5 for 2022 (991,058:798,220-1,183,896) comparable to the 2017 level (1,014,766:812,186-1,217,346). Therefore, a decline in exposure alone is not sufficient to significantly reduce the health burden attributable to ambient PM2.5 in India.

Non-metabolic role of alpha-enolase in virus replication.

Viruses are extremely complex and highly evolving microorganisms; thus, it is difficult to analyse them in detail. The virion is believed to contain all the essential components required from its entry to the establishment of a successful infection in a susceptible host cell. Hence, the virion composition is the principal source for its transmissibility and immunogenicity. A virus is completely dependent on a host cell for its replication and progeny production. Occasionally, they recruit and package host proteins into mature virion. These incorporated host proteins are believed to play crucial roles in the subsequent infection, although the significance and the molecular mechanism regulated are poorly understood. One such host protein which is hijacked by several viruses is the glycolytic enzyme, Enolase (Eno-1) and is also packaged into mature virion of several viruses. This enzyme exhibits a highly flexible nature of functions, ranging from metabolic to several non-metabolic activities. All the glycolytic enzymes are known to be moonlighting proteins including enolase. The non-metabolic functions of this moonlighting protein are also highly diverse with respect to its cellular localization. Although very little is known about the virological significance of this enzyme, several of its non-metabolic functions have been observed to influence the virus replication cycle in infected cells. In this review, we have attempted to provide a comprehensive picture of the non-metabolic role of Eno-1, its significance in the virus replication cycle and to stimulate interest around its scope as a therapeutic target for treating viral pathologies.

A scalable health system model to achieve high coverage and quality of Kangaroo mother care in Uttar Pradesh, India.

AIM: To design a health system model for scaling-up Kangaroo mother care (KMC) and assess its impact on the population-level coverage and quality of KMC in Uttar Pradesh, India. METHODS: We co-developed the model with mothers and health system stakeholders using human-centred design over multiple cycles of implementation, learning and data-driven refinement. Infants with birthweight <2000 g in the study district were prospectively followed to assess the 'effective coverage' of KMC. Effective coverage referred to the proportion of eligible infants receiving ≥8 h of daily skin-to-skin contact and exclusive breastfeeding. RESULTS: High delivery load facilities were equipped with a KMC Lounge to ensure comfort, respectful care of mothers and high-quality KMC over prolonged periods. Systems to ensure weighing at birth, referral of infants with birthweight <2000 g to KMC facilities, initiation of KMC for all stable low birthweight infants, improving quality of care within KMC facilities and supporting families to continue KMC at home post discharge, were integrated into existing services. KMC was initiated in 93.3% of eligible infants with effective coverage of 52.7% and 64.8% at discharge and 7 days post discharge, respectively. CONCLUSION: The model addressed critical barriers to KMC implementation and adoption, contributing to its scale-up across the state.

Geochemical characteristics of the Rajmahal coals in Dhulia North Block, Eastern India: implication to their utilization and environment.

The borehole coal samples of Dhulia North Block from the Rajmahal Basin, Eastern India, were systematically analyzed based on the chemical composition and concentration of major and trace elements (including rare earth elements, REEs) to assess the distribution of REEs and their environmental implications with utilization potential. The Dhulia North Block coals are characterized by the predominant major oxides of SiO2, Al2O3, and Fe2O3, accounting for 94% of the total ash composition, indicating the presence of quartz, clay-rich minerals, and pyrite. Compared with the average world coal ash, the total REE content in the analyzed samples ranged from 341.0 to 810.4 ppm, which is substantially higher. Hot humid climate conditions with intermediate igneous source rocks of the basin were demonstrated by the major oxide ratios (Al2O3/TiO2 < 20) and plots of TiO2 with Al2O3 and Zr. The redox-sensitive elements such as V, Ni, Cr, and Co found in the Dhulia North Block coal indicate that an oxic sedimentary environment existed in the basin when coal was formed. The low sulfur content (1% in most samples) indicates freshwater conditions in the basin at the time of organic matter deposition. The outlook coefficient (Coutl) varies between 0.7 and 1.6, indicating that the Dhulia North Block coals are a prospective source of REEs. The Dhulia North Block coals are characterized by low H/C and O/C atomic ratios ranging from 0.56 to 0.90 and 0.10 to 0.22, respectively, and contain type-III kerogens, indicating gas-prone source rock. Further, the basic-to-acid oxide ratio suggested that Dhulia North Block coals were suitable for utilization during combustion processes.

Socioeconomic Disparity and Risk Factors of Non-communicable Diseases: Analysis of Longitudinal Ageing Study in India using a Decomposition Approach.

INTRODUCTION: Many countries prioritize health-related research and policy around socioeconomic inequality. In India, data on socioeconomic disparity and risk factors for noncommunicable diseases (NCDs) are limited. The study provides empirical information on socioeconomic disparities in NCD risk factors in India as part of a preventative and policy initiative. METHODS: The study used nationally representative data from wave 1 of the Longitudinal Ageing Study in India which adopted a multistage random sampling design. To achieve the objectives of the study, binary logistic regression was used to demonstrate the association between socioeconomic status and NCD risk factors, and further analysis was conducted employing the decomposition method approach using STATA 14 software to assess socioeconomic disparity. RESULTS: Concentration Indices (CIs) revealed that overweight/obesity (CI = 0.157) was more prevalent among the nonpoor, whereas smoking (CI = -0.067) and alcohol consumption (CI = -0.014) were more prevalent among the poor. Wealth status was identified as the primary contributor to socioeconomic inequality for all of the risk factors of NCDs. Education was also the leading cause of socioeconomic inequality with respect to alcohol, smoking, high blood pressure, and obesity. CONCLUSION: Identifying the specific needs of impoverished and nonpoor populations is necessary for addressing NCD risk factors and inequalities. It is essential to implement interventions that address the underlying social determinants of health and promote health equality to reduce the burden of NCDs and enhance health outcomes for all.

Pro-inflammatory and anti-inflamatory cytokine genes polymorphisms and susceptibility to Japanese encephalitis disease in the North Indian population.

BACKGROUND: Japanese encephalitis virus (JEV) is the major cause of viral encephalitis in many regions of Asia. Cytokines, including pro-inflammatory and anti-inflammatory are key regulators playing a detrimental role in the host response to JE infection, pathogenesis and disease outcome. Evidently, the host's cytokine response is genetically determined, representing the complexity of interindividual differences regarding immune response to viral infection. The current study assesses the association of single nucleotide polymorphisms of classical interleukin IL-1ß and IL-10 with JEV susceptibility and disease severity in north Indian population. METHODS: We performed a case-control study using 85 JE patients and 85 healthy controls. Polymorphisms in the IL-1ß (-511 C/T) and IL-10 (-1082 A/G) genes were genotyped using PCR-RFLP. All continuous variables were expressed as mean ± standard deviation, and categorical variables were expressed in percentage. RESULTS: The mRNA level of IL-1ß and IL-10 were found significantly increased in JE patients. In severe JE patients, IL-1ß mRNA level was significantly higher with heterozygous (C/T) and homozygous (C/C) genotype compared to wild (T/T) genotype and mRNA level of IL-10 was higher in heterozygous genotype (A/G) compared to wild genotype (A/A). The C/T and C/C genotypes of IL-1ß were significantly associated with higher risk of JE infection (p < 0.05, OR = 7.25 and 4.40) whereas, the A/G genotype of IL-10 was associated with a reduced risk of JEV infection (p < 0.05, OR = 0.30). The C allele of IL-1ß was associated with fever and neck stiffness (p < 0.05) and CT genotype was associated with disease severity and worse outcomes in JE patients. Along with this, IL-10 polymorphism was found associated with fever, and AG genotype was found to be associated with worse disease outcomes such as neurological sequelae (p < 0.05). CONCLUSION: Mutant allele and genotype at IL-1ß (-511 C/T) and IL-10 (-1082 A/G) gene polymorphism show increased expression of IL-1ß and IL-10 in JE patients which contribute to disease severity as well as adverse outcomes of disease. Overall this is the first report from northern India, which shows the association of IL-1ß and IL-10 polymorphisms with JEV infection.

Immune metabolism in PD-1 blockade-based cancer immunotherapy.

Energy metabolism plays an important role in proliferating cells. Recent reports indicate that metabolic regulation or metabolic products can control immune cell differentiation, fate and reactions. Cancer immunotherapy based on blockade of programmed cell death protein 1 (PD-1) has been used worldwide, but a significant fraction of patients remain unresponsive. Therefore, clarifying the mechanisms and overcoming the unresponsiveness are urgent issues. Because cancer immunity consists of interactions between the cancer and host immune cells, there has recently been a focus on the metabolic interactions and/or competition between the tumor and the immune system to address these issues. Cancer cells render their microenvironment immunosuppressive, driving T-cell dysfunction or exhaustion, which is advantageous for cancer cell survival. However, accumulating mechanistic evidence of T-cell and cancer cell metabolism has gradually revealed that controlling the metabolic pathways of either type of cell can overcome T-cell dysfunction and reprogram the metabolic balance in the tumor microenvironment. Here, we summarize the role of immune metabolism in T-cell-based immune surveillance and cancer immune escape. This new concept has boosted the development of combination therapy and predictive biomarkers in cancer immunotherapy with immune checkpoint inhibitors.

Influence of genetic polymorphism in renin-angiotensin system-candidate genes on urinary trefoil family factor 3 levels in children with congenital anomalies of kidney and urinary tract.

BACKGROUND: This cross-sectional study aimed to determine the influence of genetic polymorphism in two renin-angiotensin system (RAS)-candidate genes on urinary trefoil family factor 3 (TFF3) levels in children with congenital anomalies of kidney and urinary tract (CAKUT). METHODS: The study included fifty children with CAKUT (PUV, VUR, and PUJO) and twenty age-matched controls. Urinary TFF3 levels were measured by enzyme-linked immunosorbent assay. Detection of genetic polymorphisms in two genes, i.e., I/D polymorphism (SNP at rs4340) in angiotensin-converting enzyme (ACE) and A/T polymorphism in the angiotensin II receptor type-2 (AT2R) due to point mutation at rs3736556 was performed by polymerase chain reaction. Progressive deterioration in kidney function was defined as fall in GFR to < 60 ml/min/1.73 m2 and/or progressive scarring. RESULTS: In our cohort, the genotypic distribution of patients and controls showed no difference. Progressive functional deterioration was significantly associated with the presence of D allele (p = 0.0004), A allele (p = 0.005), and both (p < 0.0001) in patients. Significantly raised TFF3 levels were detected in the urine of children having D allele (D/D > I/D > I/I; p < 0.0001) and A allele (A/A > A/T > TT; p < 0.0001). Also, children with both D/D and A/A allelic genotypes had significantly elevated urinary TFF3 compared to those having either of them. CONCLUSIONS: The presence of D allele and/or A allele is significantly associated with progressive functional deterioration and elevated urinary TFF3 levels. These findings support the role of angiotensin II-AT2R-NF-κB interaction in progressive deterioration of kidney function and subsequent TFF3 expression in CAKUT.

Comparison of clinical profile and outcome of de novo convulsive status epilepticus with those with a past history of epilepsy in the elderly populace.

AIM: To compare the clinical characteristics and etiological differences between de novo convulsive status epilepticus (CSE) with those with a past history of epilepsy in the elderly populace and the predictors of in-hospital mortality. METHODS: One hundred twenty-two elderly (≥60 years of age) hospitalized patients with CSE were evaluated for clinical profile, etiologies and predictors of in-hospital mortality. RESULTS: The mean age of the study population was 67.2±7.7 years. Among them, 77 (63.1%) cases were of de novo CSE and 45 (36.9%) cases had a past history of epilepsy. Most common etiologies in de novo CSE were acute symptomatic in 68.8%, followed by remote symptomatic in 24.7% of cases. Inhospital mortality in de novo CSE was 38.9 % and on multivariate analysis, it was found variables significantly related to mortality in CSE were the presence of comorbidities (odds ratio (OR) = 0.229, 95% confidence interval (CI) = 0.059- 0.897; p=0.03) low Glasgow Coma Scale (GCS) (OR =0.045 , 95% CI =0.013- 0.160 ; p= 0.01) and de novo CSE ( OR= 0.093, 95% CI = 0.017- 0.503 ;p= 0.01 ). CONCLUSIONS: De novo CSE in the elderly was associated with poorer outcomes in comparison to those with a past history of epilepsy. In-hospital mortality in CSE was related to the presence of comorbidities, low GCS and de novo CSE. Prompt and aggressive management of de novo CSE is the most effective way of preventing in-hospital mortality in the elderly.

Early Evidence on Genetic Polymorphisms in Conferring A "Two-Hit" Propensity to Renal Injury in Asian Indian Children.

Background: Congenital anomalies of the kidney and urinary tract (CAKUT) are a common cause of end-stage renal disease in children. While certain nephrogenic genes have been incriminated in these malformations, data to identify the frequency of gene polymorphisms in Asian Indian children with CAKUT are scarce. This study was done to identify the effect of polymorphisms in paired-box gene 2 (PAX2), bone morphogenetic protein (BMP)-4, angiotensin-converting enzyme (ACE), and angiotensin II receptor Type 2 (AGTR2) nephrogenic genes on the development of CAKUT. Materials and Methods: In this prospective cohort study, 158 children <12 years old (86 cases with CAKUT and 72 age-matched controls) were analyzed. DNA from both sets was extracted from peripheral blood using the Keygen DNA extraction kit, and single-nucleotide gene polymorphisms (SNPs) in PAX2, BMP-4, ACE, and AGTR2 nephrogenic genes were detected by polymerase chain reaction (PCR) using previously published primers and PCR conditions. Results: The presence of A allele SNP for AGTR2 gene at rs3736556 was found to be significantly correlated with the development of ureteropelvic junction obstruction and vesicoureteral reflux (VUR) with the TT allelic genotype having a lower incidence of pelviureteric junction obstruction (odds ratio [OR] 0.18 [95% confidence interval [CI], 0.06-0.55], P = 0.01) and VUR (OR 0.31 [95% CI, 0.11-0.91], P = 0.03). Furthermore, on substratification of the patients with the presence of the A allele of AGTR2, 24 out of 27 patients with scarring were found to harbor the D allele of the ACE gene, thus predisposing them to further renal damage. Conclusion: This study points to early evidence in the implication of nephrogenic genes in development as well as predisposition to renal injury in Asian Indian patients with CAKUT.

Comparison of the predictive value of thromboelastography and Sonoclot analysis for postoperative bleeding in children undergoing corrective surgery for cyanotic congenital heart disease.

Background: The aim of the study was to compare the predictive value of Sonoclot analysis and thromboelastography (TEG) for postoperative bleeding in children younger than 12 years coming for cardiac surgery for congenital cyanotic heart disease. Methods: This is a prospective, observational study carried out in a single tertiary care military hospital. Ninety patients of the paediatric age group undergoing bypass cardiac surgery for correction of congenital cyanotic heart defect were included in the study. Laboratory-derived values to assess coagulation status (prothrombin time, international normalisation ratio, activated partial thromboplastin time) and point-of-care Sonoclot- and TEG-derived parameters were noted at the start of surgery and postoperatively in all patients. Bleeders were predefined on the basis of chest tube drainage. Results: The incidence of bleeders was 42.2% (38/90 patients), whereas 57.8% (52/90 patients) were non-bleeders. The postoperative R value and preoperative gbPF test were predictive for postoperative bleeders on multivariate analysis. Postoperative gbPF had the highest area under the curve (0.72), with a cut-off value of 1.75, and gbPF had 82% sensitivity and 71% specificity in predicting significant postoperative bleeding in paediatric cyanotic congenital heart surgeries. Transfusion requirements and mechanical ventilation duration were higher in bleeders; however; length of intensive care unit stay, incidence of sepsis and mortality were similar in both the groups. Conclusion: Bleeding in patients undergoing corrective surgery for cyanotic congenital heart disease could be predicted by the preoperative gbPF and postoperative R value. Among these, preoperative gbPF has the maximum predictive value.