A lymphocyte chemoaffinity axis for lung, non-intestinal mucosae and CNS.

Tissue-selective chemoattractants direct lymphocytes to epithelial surfaces to establish local immune environments, regulate immune responses to food antigens and commensal organisms, and protect from pathogens. Homeostatic chemoattractants for small intestines, colon, and skin are known1 2, but chemotropic mechanisms selective for respiratory tract and other non-intestinal mucosal tissues (NIMT) remain poorly understood. Here we leveraged diverse omics datasets to identify GPR25 as a lymphocyte receptor for CXCL17, a chemoattractant cytokine whose expression by epithelial cells of airways, upper gastrointestinal and squamous mucosae unifies the NIMT and distinguishes them from intestinal mucosae. Single-cell transcriptomic analyses show that GPR25 is induced on innate lymphocytes prior to emigration to the periphery, and is imprinted in secondary lymphoid tissues on activated B and T cells responding to immune challenge. GPR25 characterizes B and T tissue resident memory and regulatory T lymphocytes in NIMT and lungs in humans and mediates lymphocyte homing to barrier epithelia of the airways, oral cavity, stomach, biliary and genitourinary tracts in mouse models. GPR25 is also expressed by T cells in cerebrospinal fluid and CXCL17 by neurons, suggesting a role in CNS immune regulation. We reveal widespread imprinting of GPR25 on regulatory T cells, suggesting a mechanistic link to population genetic evidence that GPR25 is protective in autoimmunity3,4. Our results define a GPR25-CXCL17 chemoaffinity axis with the potential to integrate immunity and tolerance at non-intestinal mucosae and the CNS.

Evaluation of the Vascular Endothelial Growth Factor and Smooth Muscle Actin Expression With Microvessel Density and Morphometric Analysis of Endometrial Vessels in Patients With Abnormal Uterine Bleeding.

BACKGROUND: Abnormal uterine bleeding (AUB) that occurs in a structurally normal uterus with regular menstrual cycles and without other identifiable etiology is often caused by a primary endometrial disorder (AUB-E). Altered vascular morphological changes and expression of markers of angiogenesis have been implicated as an underlying cause in these cases. OBJECTIVES:  The study was conducted to investigate the expression of vascular endothelial growth factor (VEGF) and smooth muscle actin-alpha (SMA-α), and to perform microvessel density (MVD), and morphometric evaluation of endometrial vessels in patients with AUB-E. MATERIAL AND METHODS: Endometrial biopsies and hysterectomy specimens of 40 patients clinically diagnosed with AUB-E were included in the study with 40 age-matched controls. Immunohistochemistry (IHC) with VEGF and SMA-α was performed, and the expression and staining pattern was recorded as the number of positive vessels per 10 high power fields and intensity scores. Morphometric analysis was performed on CD34 stained sections using Leica Application Suite, version 4.4.0 software (Leica Microsystems, Wetzlar, Germany). MVD was calculated by the vascular hotspot method. RESULTS: A statistically significant increase in VEGF vessel count (p-value<0.001) and a decline in SMA-α expression (p-value=0.23) was seen in cases as compared to the control group. There was a statistically significant increase in microvessel caliber (p-value=0.01) and MVD (p-value <0.001) in cases as compared to controls. CONCLUSION: These findings support aberrant vascular proliferation and impaired vessel maturation, contributing to the pathology of AUB-E. Alterations in angiogenesis in these patients reveal potential therapeutic targets for AUB.

The spectrum of microvascular patterns in adult diffuse glioma and their correlation with tumor grade.

BACKGROUND: Primary brain tumors constitute the leading cause of cancer-related mortality. Among them, adult diffuse gliomas are the most common type, affecting the cerebral hemispheres and displaying a diffuse infiltrative pattern of growth in the surrounding neuropil that accounts for about 80% of all primary intracranial tumors. The hallmark feature of gliomas is blood vessel proliferation, which plays an important role in tumor growth, tumor biological behavior, and disease outcome. High-grade gliomas exhibit increased vascularity, the worst prognosis, and lower survival rates. Several angiogenic receptors and factors are upregulated in glioblastomas and stimulate angiogenesis signaling pathways by means of activating oncogenes and/or down-regulating tumor-suppressor genes. Existing literature has emphasized that different microvascular patterns (MVPs) are displayed in different subtypes of adult diffuse gliomas. METHODS: We examined the distribution and biological characteristics of different MVPs in 50 patients with adult diffuse gliomas. Haematoxylin and eosin staining results, along with periodic acid-Schiff and CD34 dual-stained sections, were examined to assess the vascular patterns and correlate with different grades of diffuse glioma. RESULTS: The present observational study on adult diffuse glioma evaluated tumor grade and MVPs. Microvascular sprouting was the most common pattern, while a bizarre pattern (type 2) was associated with the presence of a high-grade glioma. Vascular mimicry was observed in 6% of cases, all of which were grade 4 gliomas. CONCLUSIONS: This study supplements the role of neo-angiogenesis and aberrant vasculature patterns in the grading and progression of adult diffuse gliomas, which can be future targets for planning treatment strategies.

Understanding Perioperative Acute Myocardial Ischemia Following Coronary Artery Bypass Grafting.

Surgical revascularization and coronary artery bypass grafting are often pursued as treatment for obstructive coronary artery disease. Despite trends of increased referrals for complex percutaneous coronary intervention, surgical revascularization often remains the standard of care for patients with multivessel or complex coronary artery disease. Myocardial ischemia during the perioperative and postoperative periods during coronary artery bypass grafting remains a challenge. Nuanced consideration is necessary to decide on interventions that include conservative management and percutaneous or repeat surgical revascularization.

Cytological Perspective in a Case of Doege-Potter Syndrome With Hypoinsulinemic Hypoglycemia.

Solitary fibrous tumor (SFT) of the lung is a rare mesenchymal neoplasm of uncertain histogenesis, unknown molecular features, and unpredictable clinical behavior, characterized by NAB2-STAT6 fusion. Hypoglycemia accompanying SFT (Doege-Potter syndrome) is an uncommon presentation. We present the cytomorphological features on biopsy imprint smears of a histopathologically confirmed case of SFT of the lung with an uncommon presentation. A 76-year-old non-smoker, non-alcoholic, and non-diabetic man presented with complaints of intermittent episodes of confusion with syncopal attacks (>10 episodes) for six months. The patient had no respiratory complaints and no history of weight loss. Laboratory investigations revealed fasting blood sugar of 38 mg/dl with low serum insulin and C-peptide levels. Physical examination revealed reduced air entry on the left side of the chest. Chest X-ray showed left-sided homogenous opacity. High-resolution computed tomography (HRCT) of the chest showed a large left-sided lung mass. A biopsy was performed. Biopsy imprint smears were cellular and showed tumor cells arranged in clusters and fragments with traversing capillaries displaying monomorphic pump to oval nuclei, fine granular evenly dispersed chromatin, regular nuclear membrane, inconspicuous nucleoli, and a moderate amount of wispy cytoplasm. Foci of intercellular hyaline stromal material were noted. A cytodiagnosis of low-grade mesenchymal neoplasm was made. Histopathology revealed a cellular tumor comprising tightly packed round to fusiform cells arranged around blood vessels with intervening thick collagen, positive for CD99, vimentin, BCL2, CD34, and STAT6 and negative for EMA, CK AE1/AE3, S100, TLE1, and SMA. Familiarity with cytomorphology plays a pivotal role in clinching an early diagnosis of this rare neoplasm of the lung, particularly in the setting of presentation with hypoglycemia.

Application of Laser-Induced Acoustic Desorption for Molecular Rotational Resonance Spectroscopy.

Molecular Rotational Resonance (MRR) spectroscopy is a uniquely precise tool for the determination of molecular structures of volatile compounds in mixtures, as the characteristic rotational transition frequencies of a molecule are extremely sensitive to its 3D structure through the moments of inertia in a three-dimensional coordinate system. This enables identification of the compounds based on just a few parameters that can be calculated, as opposed to, for example, mass spectrometric data, which often require expert analysis of 10-20 different signals and the use of many standards/model compounds. This paper introduces a new sampling technique for MRR, laser-induced acoustic desorption (LIAD), to allow the vaporization of nonvolatile and thermally labile analytes without the need for excessive heating or derivatization. In this proof-of-concept study, LIAD was successfully coupled to an MRR instrument to conduct measurements on seven compounds with differing polarities, molecular weights, and melting and boiling points. Identification of three isomers in a mixture was also successfully performed using LIAD/MRR. Based on these results, LIAD/MRR is demonstrated to provide a powerful approach for the identification of nonvolatile and/or thermally labile analytes with molecular weights up to 600 Da in simple mixtures, which does not require the use of reference compounds. In the future, applications to more complex mixtures, such as those relevant to pharmaceutical research, and quantitative aspects of LIAD/MRR will be reported.

Impact of COVID-19 outbreak on healthcare workers in a Tertiary Healthcare Center in India: a cross sectional study.

Numerous speculations have continually emerged, trying to explore the association between COVID-19 infection and a varied range of demographic and clinical factors. Frontline healthcare workers have been the primary group exposed to this infection, and there have been limited global research that examine this cohort. However, while there are a few large studies conducted on Indian healthcare professionals to investigate their potential risk and predisposing factors to COVID-19 infection, to our knowledge there are no studies evaluating the development of long COVID in this population. This cross-sectional study systematically utilized the demographic and clinical data of 3329 healthcare workers (HCW) from a tertiary hospital in India to gain significant insights into the associations between disease prevalence, severity of SARS-Cov-2 infection and long COVID. Most of the study population was found to be vaccinated (2,615, 78.5%), while 654 (19.65%) HCWs were found to be SARS-CoV-2 positive at least once. Of the infected HCWs, 75.1% (491) did not require hospitalization, whereas the rest were hospitalized for an average duration of 9 days. A total of 206 (6.19%) individuals were found to be suffering from long COVID. Persistent weakness/tiredness was the most experienced long-COVID symptom, while females (1.79, 1.25-2.57), individuals who consumed alcohol (1.85, 1.3-2.64) or had blood group B (1.9, 1.33-2.7) were at a significantly higher risk for developing long COVID.

Unusual Manifestation of Mercuric Chloride Poisoning as Intratubular Nephrocalcinosis - A Rare Case Report.

Mercuric chloride salts are highly toxic compounds that have been linked to suicidal or accidental poisoning. Because of their high solubility, mercuric chloride salts can cause acute tubular injury, corrosive effects in the gastrointestinal system, hematemesis and hematochezia, circulatory collapse, and death. Here, we report an unusual case of mercuric chloride poisoning in a 17-year-old girl who manifested with acute tubular necrosis in association with intratubular nephrocalcinosis and emphasize the role of hemodialysis in the patient's successful recovery.

Current challenges in treatment and management of spontaneous coronary artery dissection.

Though an infrequent cause of acute coronary syndrome, spontaneous coronary artery dissection is an increasingly recognized cardiovascular condition predominantly seen in middle-aged females. Its pathophysiology is defined by separation of coronary arterial wall layers which cause acute coronary syndrome-like presentations with relatively high recurrence rates. Overall, there is a lack of reported literature and understanding of the short- and long-term management for spontaneous coronary artery dissection. Therapeutic approaches include, but are not limited to, percutaneous coronary intervention, surgical revascularization, antithrombotic therapy, and beta-blocker therapy. There is a significant absence of randomized control trials to help guide both interventional and medical management for spontaneous coronary artery dissection. This review is aimed to review the current literature regarding risk factors and considerations for the short- and long-term management of spontaneous coronary artery dissection.

Spontaneous coronary artery dissection is a condition commonly found in middle-aged females with symptoms that mimic a traditional 'heart-attack.' The condition differs where it is without actual arterial blood clot formation within the coronary arteries. In general, spontaneous coronary artery dissection involves the tearing of certain layers within coronary artery walls causing the expansion of layers with bleeding in between, consequently causing arterial blockage. In general, there is a lack of consensus on therapeutic strategy for this condition given a limited amount of data. This review article expands on the current data regarding the management of spontaneous coronary artery dissection including interventional versus medical management. Despite being rare, this acute disease process can have significant implications; however, it has been found that a more conservative approach with close monitoring is generally recommended.

Commotio Cordis: A Comprehensive Review.

Commotio cordis is a rare, however, potentially fatal, cardiovascular phenomenon arising from direct chest wall trauma, causing sudden cardiac arrest and potentially death. It is primarily seen in young athletes who participate in contact and organized sports. Though debated, the cause of commotio cordis is believed to involve specific timing of chest impact during ventricular electrical activity leading to severe arrhythmic events. Due to sudden onset, the first step in management is immediate and effective basic life support with automated external defibrillation, followed by advanced cardiac life support. Future considerations should include secondary prevention measures such as protective padding in contact sports. It is paramount that clinicians are vigilant in recognizing potential cases of commotio cordis in the field and provide immediate care. This review consolidates the current understanding of commotio cordis, emphasizing the importance of awareness and early intervention. Future research is warranted, including retrospective and observational studies to identify high-risk patterns or trends associated with the condition.

Review and Key Takeaways of the 2021 Percutaneous Coronary Intervention Guidelines.

The 2021 Percutaneous Coronary Intervention guidelines completed by American College of Cardiology/American Heart Association/Society for Cardiovascular Angiography and Interventions provide a set of guidelines regarding revascularization strategies. With emphasis on equity of care, multidisciplinary heart team use, revascularization for acute coronary syndrome, and stable ischemic heart disease, the guidelines create a thorough framework with recommendations regarding therapeutic strategies. In this comprehensive review, our aim is to summarize the 2021 revascularization guidelines and analyze key points regarding each recommendation.

Aortopathy: Effects of Lipid-Lowering Therapy.

Aortopathies can be congenital or acquired. Aortic atherosclerosis, abdominal aortic aneurysm, and degenerative aortic stenosis are some of the major manifestations of acquired aortopathy. Dyslipidemia, an imbalance of plasma lipid levels, is strongly associated with common aortopathies. A relationship between abdominal aortic aneurysm, degenerative aortic stenosis, and dyslipidemia has been identified in the literature but finding effective preventive strategies has been challenging. Nevertheless, lipid-lowering therapy remains a mainstay of both treatment and prevention. In patients with aortic atheroma, statins were found to be protective through the review of this study. There is currently no place for statins in the treatment or prevention of disease progression in patients with calcific aortic stenosis. Their low cost, widespread availability, and strong safety profile tip the risk-to-benefit ratio toward statins for abdominal aortic aneurysms but more research is needed. A review of proprotein convertase subtilisin/kexin type 9 inhibitors may yield similar benefits for all aortopathy patients; however, those results are not yet available.

Bronchoalveolar Lavage in Diagnostic Evaluation of Pulmonary Diseases- An Institutional Experience.

Background: Bronchoalveolar lavage (BAL) is a widely accepted investigative tool for the diagnosis of pulmonary lesions. This study was done to find out the usefulness of BAL in diagnosis of pulmonary lesions from central Indian patient population. Methods: A cross-sectional prospective study was performed over a period of three years. All the BAL specimens of patients presenting to Department of Pulmonary Medicine and Tuberculosis during a period of January 2017 to December 2019 were included in the study. Cyto-histopathologic correlation was done, wherever available. Results: Of total 277 cases, there were 178 (64.5%) males and 99 (35.5%) females. The age of patients ranged from 4 years to 82 years. In 92 (33%) cases, specific infective etiology could be identified on BAL cytology, the most common being tuberculosis (26%) followed by fungal infections (2%). Rarely, infections like nocardia, actinomycosis, and hydatidosis were also identified. Eight cases (3%) of malignancy were identified which included two cases of adenocarcinoma, one case of small cell carcinoma, three cases of poorly differentiated carcinoma, and two cases suspicious for malignancy. Some rare diagnoses like diffuse alveolar damage, pulmonary alveolar microlithiasis, and pulmonary alveolar proteinosis could be identified on BAL. Conclusion: BAL is useful in primary diagnosis of infections and malignancies of lower respiratory tract. BAL may aid in diagnostic workup of diffuse lung diseases. A combination of clinical information, high-resolution computed tomography, and BAL analysis may furnish an assured diagnosis to the clinician and obviate need for invasive procedures.

Selective Quantification of Chemotropic Responses of Fusarium graminearum.

Chemotropism refers to the directional growth of a living organism toward a chemical stimulus. Molecular mechanisms underlying chemotropism of fungal pathogens have recently been enabled by advancements in biological chemotropic assays, with a particular focus on the roles of G-protein-coupled receptors and their plant-derived ligands in chemotropism. Here we describe in detail an assay that enables quantification of chemotropic responses of Fusarium graminearum, with variations recently reported for Fusarium oxysporum and Trichoderma atroviride.

Dual antiplatelet therapy with concomitant anticoagulation: current perspectives on triple therapy.

Anticoagulation and antiplatelet therapy are individually mainstays of treatment for multiple cardiovascular conditions. Antiplatelet therapy, most commonly with dual agents, is vital in the setting of coronary artery disease with acute coronary syndrome requiring percutaneous coronary intervention to prevent in-stent complications. A multitude of cardiovascular conditions with increased thromboembolic risk also require anticoagulation, including atrial fibrillation, venous or arterial thrombosis, and prosthetic heart valves to name a few. There is often an overlap in comorbidities as our patient population ages and becomes more complex, frequently necessitating a combination of both anticoagulation and antiplatelet agents, known as "triple therapy". To reduce or treat thromboembolic disease states as well as reduce platelet aggregation for coronary stent protection, many patients are placed at an increased bleeding risk without compelling evidence of reduction in major adverse cardiac events. With this comprehensive review of the existing literature, we aim to analyse different strategies and durations of triple therapy medication regimens.

Bland Urine Sediment in a Child with Acute Kidney Injury.

Tubulointerstitial nephritis (TIN) or acute interstitial nephritis (AIN) is a renal lesion characterized by inflammatory infiltrate limited to the renal interstitium and tubules. Three-fourths of the cases are drug induced, other causes being systemic and autoimmune diseases, and infections. Various drugs have been implicated, the most common being antibiotics such as ß-lactams. Cephalosporins causing AIN have been reported uncommonly, particularly in children. Although renal biopsy confirms the diagnosis, urinalysis provides pertinent diagnostic clues against the backdrop of the clinico-laboratory profile. The presence of white blood cells, white cell casts, and red blood cells in urine sediment have been described in literature. However, a relatively normal urinalysis may be present in some cases and may pose a diagnostic challenge. We present a case of ceftriaxone-induced AIN in a child with bland urine sediment at initial presentation. To the best of our knowledge, this is the first report of ceftriaxone-induced AIN in the pediatric age group.

Genome profiling of uropathogenic E. coli from strictly defined community-acquired UTI in paediatric patients: a multicentric study.

BACKGROUND: Urinary tract infection (UTI) in children is a common bacterial infection. The emergence of extended-spectrum beta-lactamases (ESBLs) poses a major challenge against the treatment of uropathogens. We aimed to characterize the E. coli isolates recovered from children with UTI for their resistance profile and circulating sequence types (ST). METHODS: Children (> 1.5-18 years of age) from different community health centres of India with symptoms of UTI were enrolled. Isolates causing significant bacteriuria were identified by Matrix-Assisted Laser Desorption Ionization Time of Flight Mass Spectrometry (MALDI-TOF MS) and tested for antimicrobial susceptibility by the automated system, VITEK-2 (Biomeriux, Durhum, US). Nineteen E. coli isolates (15 ESBL positive and 4 ESBL negative) were sequenced in Oxford Nanopore platform followed by core-genome phylogeny, accessory genome cluster analysis, identification of sequence types, mobile genetic elements, genetic antimicrobial resistance markers. The correlation between detection of antimicrobial resistance genes with phenotypic resistance profiles was also investigated. RESULTS: Eleven percent of children had significant bacteriuria [male:female-1:1, > 50% were 11-18 years of age group]. E. coli was predominant (86%) followed by K. pneumoniae (11%). Susceptibility of E. coli was highest against fosfomycin (100%) followed by carbapenems (90.7%) and nitrofurantoin (88.8%). ST131 (15.8%) and ST167 (10.5%) found as high-risk clones with the presence of plasmid [IncFIB (63.1%), IncFIA (52.6%)], and composite transposon [Tn2680 (46.6%)] in many isolates. Few isolates coharboured multiple beta-lactamases including blaNDM-5 (33.3%), blaOXA-1 (53.3%), blaCTX-M-15 (60%) and blaTEM-4 (60%). CONCLUSIONS: This study highlights horizontal transmission of resistance genes and plasmids in paediatric patients at community centers across the nation harbouring multidrug-resistant genes such as blaNDM-5 and blaCTX-M-15 associated with high-risk clones ST131 and ST167. The data is alarming and emphasizes the need for rapid identification of resistance markers to reduce the spread in community. To our knowledge, this is the first multicentric study targeting paediatric UTI patients from the community setting of India.

Role of Medicinal Plants in the Management of Inflammatory Disorders: An Overview.

Owing to the enhanced toxicity as well as consequences of allopathic medication, the research on herbal therapies is developing progressively. As a result, medicinal herbs are beginning to play a substantial role in the advancement of the dominant therapeutic medications. Since ancient times, the use of herbs has performed a vital part in human well-being as well in the invention of cutting-edge pharmaceuticals. Inflammation and related illnesses are a major health concern for the entire human population. Pain-inducing drugs including opiates, non-steroidal anti-inflammatory drugs, glucocorticoids, and corticosteroids have severe side effects and these therapies suffer from the recurrence of symptoms too after discontinuing the treatment. As a result, the diagnosis along with the advancement of medications with anti-inflammatory properties is the priority to conquer the drawbacks of the existing therapies. The present review article provides insight into the literature comprising promising phytochemicals from various medicinal plants tested through different model systems and employed for alleviating inflammation in several inflammatory disorders as well as clinical status of the herbal products.

Fusarium graminearum Ste3 G-Protein Coupled Receptor: A Mediator of Hyphal Chemotropism and Pathogenesis.

Fungal hyphal chemotropism has been shown to be a major contributor to host-pathogen interactions. Previous studies on Fusarium species have highlighted the involvement of the Ste2 G-protein-coupled receptor (GPCR) in mediating polarized hyphal growth toward host-released peroxidase. Here, the role of the opposite mating type GPCR, Ste3, is characterized with respect to Fusarium graminearum chemotropism and pathogenicity. Fgste3Δ deletion strains were found to be compromised in the chemotropic response toward peroxidase, development of lesions on germinating wheat, and infection of Arabidopsis thaliana leaves. In the absence of FgSte3 or FgSte2, F. graminearum cells exposed to peroxidase showed no phosphorylation of the cell-wall integrity, mitogen-activated protein kinase pathway component Mgv1. In addition, transcriptomic gene expression profiling yielded a list of genes involved in cellular reorganization, cell wall remodeling, and infection-mediated responses that were differentially modulated by peroxidase when FgSte3 was present. Deletion of FgSte3 yielded the downregulation of genes associated with mycotoxin biosynthesis and appressorium development, compared to the wild-type strain, both in the presence of peroxidase. Together, these findings contribute to our understanding of the mechanism underlying fungal chemotropism and pathogenesis while raising the novel hypothesis that FgSte2 and FgSte3 are interdependent on each other for the mediation of the redirection of hyphal growth in response to host-derived peroxidase. IMPORTANCE Fusarium head blight of wheat, caused by the filamentous fungus Fusarium graminearum, leads to devastating global food shortages and economic losses. Fungal hyphal chemotropism has been shown to be a major contributor to host-pathogen interactions. Here, the role of the opposite mating type GPCR, Ste3, is characterized with respect to F. graminearum chemotropism and pathogenicity. These findings contribute to our understanding of the mechanisms underlying fungal chemotropism and pathogenesis.