Western diet reduces small intestinal intraepithelial lymphocytes via FXR-Interferon pathway.

The prevalence of obesity in the United States has continued to increase over the past several decades. Understanding how diet-induced obesity modulates mucosal immunity is of clinical relevance. We previously showed that consumption of a high fat, high sugar "Western" diet (WD) reduces the density and function of small intestinal Paneth cells, a small intestinal epithelial cell type with innate immune function. We hypothesized that obesity could also result in repressed gut adaptive immunity. Using small intestinal intraepithelial lymphocytes (IEL) as a readout, we found that in non-inflammatory bowel disease (IBD) subjects, high body mass index correlated with reduced IEL density. We recapitulated this in wild type (WT) mice fed with WD. A 4-week WD consumption was able to reduce IEL but not splenic, blood, or bone marrow lymphocytes, and the effect was reversible after another 2 weeks of standard diet (SD) washout. Importantly, WD-associated IEL reduction was not dependent on the presence of gut microbiota, as WD-fed germ-free mice also showed IEL reduction. We further found that WD-mediated Farnesoid X Receptor (FXR) activation in the gut triggered IEL reduction, and this was partially mediated by intestinal phagocytes. Activated FXR signaling stimulated phagocytes to secrete type I IFN, and inhibition of either FXR or type I IFN signaling within the phagocytes prevented WD-mediated IEL loss. Therefore, WD consumption represses both innate and adaptive immunity in the gut. These findings have significant clinical implications in the understanding of how diet modulates mucosal immunity.

The diagnostic performance of mean neutrophil volume in neonatal sepsis: A systematic review and meta-analysis.

BACKGROUND: There is a need for reliable diagnostic tests for early identification of sepsis to prevent neonatal mortality and antibiotic misuse. During sepsis, many immature neutrophils came into the bloodstream, altering the mean neutrophil volume (MNV) shown in the previous studies. OBJECTIVES: To summarize the diagnostic performance of mean neutrophil volume (MNV) in neonatal sepsis from the published literature. METHOD: Databases such as PubMed, Scopus, and Web of Science were searched from January 1990 to April 2023 for studies reporting MNV as a diagnostic test in neonatal sepsis. The pooled sensitivity, specificity, diagnostic odds ratio (DOR), and area under the curve (AUC) of the summary receiver operating characteristic (SROC) curve of MNV were estimated with reference blood culture-positive sepsis and clinical sepsis for meta-analysis. RESULT: The diagnostic performance of MNV was analyzed in 1685 neonates, including 829 septic and 856 non-septic neonates, from six prospective studies. The pooled sensitivity and specificity of MNV were 0.87 and 0.75, respectively, for neonatal sepsis; the DOR was 20.01 (95% CI: 5.90-67.82); and the AUC of the SROC for MNV was 0.81 (95% CI: 0.69-0.88). Higgins I2 was 92.1% (95% CI: 85.5%-95.7%). The diagnostic performance of MNV was better during sub-group analysis of studies reporting culture-positive sepsis (DOR 85.61). CONCLUSION: The diagnostic performance of MNV is moderate for neonatal sepsis. As the evidence originated from a small number of studies with marked heterogeneity, further large-scale diagnostic accuracy studies are recommended to resolve heterogeneity in the future.

Progenitors of distinct lineages shape the diversity of mature type 2 conventional dendritic cells.

Conventional dendritic cells (cDC) are antigen-presenting cells comprising cDC1 and cDC2, responsible for priming naive CD8+ and CD4+ T cells, respectively. Recent studies have unveiled cDC2 heterogeneity and identified various cDC2 progenitors beyond the common DC progenitor (CDP), hinting at distinct cDC2 lineages. By generating Cd300ciCre-hCD2R26tdTomato reporter mice, we identified a bone marrow pro-cDC2 progenitor exclusively generating cDC2 in vitro and in vivo. Single-cell analyses and multiparametric flow cytometry demonstrated that pro-cDC2 encompasses myeloid-derived pre-cDC2 and lymphoid-derived plasmacytoid DC (pDC)-like precursors differentiating into a transcriptionally convergent cDC2 phenotype. Cd300c-traced cDC2 had distinct transcriptomic profiles, phenotypes, and tissue distributions compared with Ms4a3CreR26tdTomato lineage-traced DC3, a monocyte-DC progenitor (MDP)-derived subset that bypasses CDP. Mice with reduced Cd300c-traced cDC2 showed impaired humoral responses to T cell-dependent antigens. We conclude that progenitors of distinct lineages shape the diversity of mature cDC2 across tissues. Thus, ontogenesis may impact tissue immune responses.

Elucidating the role of chemokines in inflammaging associated atherosclerotic cardiovascular diseases.

Age-related inflammation or inflammaging is a critical deciding factor of physiological homeostasis during aging. Cardiovascular diseases (CVDs) are exquisitely associated with aging and inflammation and are one of the leading causes of high mortality in the elderly population. Inflammaging comprises dysregulation of crosstalk between the vascular and cardiac tissues that deteriorates the vasculature network leading to development of atherosclerosis and atherosclerotic-associated CVDs in elderly populations. Leukocyte differentiation, migration and recruitment holds a crucial position in both inflammaging and atherosclerotic CVDs through relaying the activity of an intricate network of inflammation-associated protein-protein interactions. Among these interactions, small immunoproteins such as chemokines play a major role in the progression of inflammaging and atherosclerosis. Chemokines are actively involved in lymphocyte migration and severe inflammatory response at the site of injury. They relay their functions via chemokine-G protein-coupled receptors-glycosaminoglycan signaling axis and is a principal part for the detection of age-related atherosclerosis and related CVDs. This review focuses on highlighting the detailed intricacies of the effects of chemokine-receptor interaction and chemokine oligomerization on lymphocyte recruitment and its evident role in clinical manifestations of atherosclerosis and related CVDs. Further, the role of chemokine mediated signaling for formulating next-generation therapeutics against atherosclerosis has also been discussed.

Anti-Vascular Endothelial Growth Factor (Anti-VEGF) for the Treatment of Type I ROP.

This retrospective study evaluated the trends in the use of anti-vascular endothelial growth factor (anti-VEGF) for the treatment of type-1 retinopathy of prematurity (ROP) during two periods - 2016-2019 (epoch A) and 2020-2022 (epoch B) in a neonatal unit of India. The study also compared the efficacy of anti-VEGF and laser therapies. Anti-VEGF was used in 8 (12.2%) out of 66 eyes treated during epoch A and 54 (75%) out of 72 eyes during epoch B (P = 0.001). The proportion of eyes in which ROP regressed with a single attempt of laser and anti-VEGF therapies was 8/20 (40%) and 7/15 (46.6%) respectively for the disease in zone 1 and aggressive-posterior ROP (P = 0.70) and 46/66 (69.6%) and 17/37 (45.9%) respectively for the disease in zone 2 (P = 0.018). There was a trend towards an increase in the use of anti-VEGF for ROP management over time. Anti-VEGF showed equal efficacy as laser for zone 1 ROP and AP-ROP, but laser therapy was better for zone 2 ROP.

Screening and Management of Congenital Hypothyroidism - Guidelines by American Academy of Pediatrics, 2023.

Guidelines for screening and management of congenital hypothyroidism in neonates have been recently updated by the American Academy of Pediatrics (AAP). This article compares new AAP guideline with the Indian Society for Pediatric and Adolescent Endocrinology (ISPAE) Guidelines, 2018 and lists the changes in screening, diagnosis, and management of congenital hypothyroidism suggested in the new guidelines, along with clinical utilization in the Indian scenario.

Pregnancy-induced differential expression of SARS-CoV-2 and influenza a viral entry factors in the lower respiratory tract.

Despite differences in the clinical presentation of coronavirus disease-19 and pandemic influenza in pregnancy, fundamental mechanistic insights are currently lacking because of the difficulty in recruiting critically ill pregnant subjects for research studies. Therefore, to better understand host-pathogen interaction during pregnancy, we performed a series of foundational experiments in pregnant rats at term gestation to assess the expression of host entry factors for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and influenza A virus (IAV) and genes associated with innate immune response in the lower respiratory tract. We report that pregnancy is characterized by a decrease in host factors mediating SARS-CoV-2 entry and an increase in host factors mediating IAV entry. Furthermore, using flow cytometric assessment of immune cell populations and immune provocation studies, we show an increased prevalence of plasmacytoid dendritic cells and a Type I interferon-biased environment in the lower respiratory tract of pregnancy, contrary to the expected immunological indolence. Our findings, therefore, suggest that the dissimilar clinical presentation of COVID-19 and pandemic influenza A in pregnancy could partly be due to differences in the extent of innate immune activation from altered viral tropism and indicate the need for comparative mechanistic investigations with live virus studies.

Role of neonatal cerebrospinal fluid cytology in correlation to C-reactive protein, blood culture, risk factors and clinical outcomes in neonatal intensive care.

Introduction: The number of neonatal cerebrospinal fluid (CSF) samples sent from the neonatal intensive care unit (NICU) for cytologic examination is rising, warranting accurate analysis and interpretation of the same. This study was taken up to assess the usefulness of CSF cell count and cytology in NICU settings, as it can be used even in a resource-limited setting. Aim and Objective: 1) To study the prevalence of cell count and cytologic changes in CSF from NICU and assess their usefulness in correlation to C-reactive protein, CSF neutrophil percentage, blood, CSF culture, and other biochemical parameters. 2) To correlate cell counts and cytology with age, period of gestation, presence, and absence of sepsis, seizures, intracranial hemorrhage, and their clinical follow-up. Materials and Methods: A retrospective study was done on neonatal CSF samples submitted for cytology over one year (January-December 2016) in the Department of Pathology. CSF cell counts were retrieved, and cytosmears were reviewed for cellularity, cell type, proportion, and background and correlated with the biochemical, microbiological, and clinicoradiological findings. Results: A total of 213 samples were included with 140 males and 73 females with an age range of 0-28 (mean: 7.3) days. The mean CSF cell count was 5.48/cu.mm (0-90 cells/cu.mm). The most frequent cytologic finding was occasional lymphocytes or acellular CSF (63.9%). The CSF leucocyte count and protein levels showed a significant correlation with s C-reactive protein. The CSF cytology showed a significant correlation between the age of the neonate and blood neutrophil percentage (P = 0.0158). History of intracranial hemorrhage showed a significantly higher frequency of the presence of red blood cells (P = 0.0147). Conclusion: Accurate cell counts, cytology of neonatal CSF, and biochemical and microbiological workup can help diagnose and manage neonates in intensive care.

Gendered Pattern and Predictors of Tobacco use in India: Evidence from the Second Round of Global adult Tobacco Survey.

Background: India has completed the second round of the Global Adult Tobacco Survey (GATS) to monitor adult tobacco use and progress in tobacco control efforts. This study assesses the gendered pattern of tobacco use and its predictors in the second rounds of GATS. Material and Methods: Publicly available GATS-2 (2016-2017) data was analyzed which contains self-reported tobacco use information of ≥15 years Indians (n = 74,037). The independent predictors of "smoking only," "smokeless only," and "dual use" among current male and female tobacco users were assessed using the multinomial regression model. Results: The burden of "smoking only," "smokeless only," and "dual-use" of tobacco were 8.9% (8.74-9.15), 16.69% (16.42-16.96), and 3.89% (3.75-4.03), respectively, in the second round with wide regional variation as well as male dominance in use. Region, age, education, caste, and religion were significantly and consistently associated with different types of tobacco use in both genders. Other contextual predictors of tobacco use were residence, marital status, occupation, awareness, and wealth index (WI). Conclusions: Tobacco use predictors and their gendered patterns are contextual. Monitoring the predictors for tobacco use, which may change over time, should be given priority in the national tobacco control program.

Alternations of Fertility Parameters by Graded Dose of Inorganic Arsenic in Adult Male White Pekin Ducks.

A significant health issue, reproductive toxicity is mostly linked to exposure to various environmental heavy metals. A pervasive toxin that occurs naturally in the environment is arsenic (As). This research was done to determine the effects of various doses of inorganic As supplements on the reproductive organs of adult male white Pekin ducks. A total of 240 numbers of 14-days-old male white Pekin ducks were weighed and randomly assigned into 4 experimental groups with six replicates (10 ducklings in each replicate). The experimental groups were as follows: (T-1) basal diet along with normal drinking water (control group); (T-2 to T-4) basal diet along with As in the form of sodium-meta-arsenite at 7, 14, and 28 ppm of drinking water respectively. The results showed reduction in body weight and testicular weight, disruption of spermatogenesis, reduction in follicular-stimulating hormone (FSH), leutinizing hormone (LH), and testosterone levels and histopathological alterations as compared to control. Additionally, there was not only a significant decrease in various antioxidant parameters in testis tissue, like catalase (CAT), reduced glutathione (GSH), super oxide dismutase (SOD), and ferric-reducing antioxidant power (FRAP), but also a significant increase in oxidative parameters of testis like lipid peroxidation (LPO), myloperoxidase (MPO), nitric oxide (NO), and super oxide anion radical (O2-) in As-treated groups, in comparison with T-1. A significantly higher level of As content in testis was observed in all the 3 As-treated groups, with highest level recorded in T-4 birds. Besides that, there was upregulation of nuclear factor kappa B (NF-κB), heat shock proteins (Hsps) and pro-inflammatory cytokines like interlukin (IL) series, i.e., IL-2, IL-6, IL-18, IL-1ß and tumor necrosis factor- α (TNF-α) levels, whereas anti-inflammatory parameters like IL-4 and IL-10 levels showed downregulation in testis of As-treated groups. Together, these findings provide deeper understandings of the roles played by oxidative stress, NF-κB and Hsps in the progression of testicular injury, which may help to explain how the As induced male sterility, in ducks, due to exposure.

Repression of the aryl-hydrocarbon receptor prevents oxidative stress and ferroptosis of intestinal intraepithelial lymphocytes.

The aryl-hydrocarbon receptor (AHR) is a ligand-activated transcription factor that buoys intestinal immune responses. AHR induces its own negative regulator, the AHR repressor (AHRR). Here, we show that AHRR is vital to sustaining intestinal intraepithelial lymphocytes (IELs). AHRR deficiency reduced IEL representation in a cell-intrinsic fashion. Single-cell RNA sequencing revealed an oxidative stress profile in Ahrr-/- IELs. AHRR deficiency unleashed AHR-induced expression of CYP1A1, a monooxygenase that generates reactive oxygen species, increasing redox imbalance, lipid peroxidation, and ferroptosis in Ahrr-/- IELs. Dietary supplementation with selenium or vitamin E to restore redox homeostasis rescued Ahrr-/- IELs. Loss of IELs in Ahrr-/- mice caused susceptibility to Clostridium difficile infection and dextran sodium-sulfate-induced colitis. Inflamed tissue of inflammatory bowel disease patients showed reduced Ahrr expression that may contribute to disease. We conclude that AHR signaling must be tightly regulated to prevent oxidative stress and ferroptosis of IELs and to preserve intestinal immune responses.

Comparison between Phenobarbitone and Levetiracetam as the initial anticonvulsant in preterm neonatal seizures - a pilot randomized control trial in developing country setup.

This study aimed to compare the efficacy and safety of intravenous Levetiracetam and Phenobarbitone in the treatment of seizures in preterm neonates. It was an open-labeled, parallel randomized controlled trial conducted in a tertiary Neonatal Intensive Care Unit, India. Total 48 preterm neonates (28-36+6 weeks) with clinical seizures were randomized to receive either Levetiracetam (LEV; 40 mg/kg, then 20 mg/kg) or Phenobarbitone (PB; 15 mg/kg, then 10 mg/kg) intravenously as first loading dose in ratio 1:1; second loading was given for persistent seizure. Efficacy was denoted by cessation of clinical seizures with first or second doses of the allotted antiepileptic, and remaining seizure-free for the next 24 h. The demographic characteristics of preterm neonates and seizure types were comparable between both groups. Clinical seizure was controlled in 19 (79%) neonates in LEV group and 17 (70%) neonates in PB group, RR 1.12 (95% CI: 0.80 to 1.55), p = 0.504. There was increased respiratory support in PB group 9 (38%) vs. 3 (13%) in LEV group, RR 3.0 (95% CI: 0.92 to 9.74), p = 0.06.  Conclusion: Levetiracetam and Phenobarbitone were equally efficacious for clinical neonatal seizure control, but increased respiratory support was found with Phenobarbitone use. What is Known: • Preterm neonates are at higher risk of neonatal seizure and Phenobarbitone is commonly used as the first line antiepileptic drugs in treating them. What is New: • Levetiracetam found equally efficacious as Phenobarbitone for cessation of clinical seizures in preterm neonates, with less adverse effect.