Enhancing the Diagnostic Yield of Esophageal Manometry Using Distension Contraction Plots of Peristalsis & Artificial Intelligence.

BACKGROUND: Our prior study reveal that the distension-contraction profiles using high-resolution manometry impedance (HRMZ) recordings can distinguish patients with dysphagia symptom but normal esophageal function testing ("functional dysphagia") from controls. AIMS: To determine the diagnostic value of the recording protocol used in our prior studies (10cc swallows with subjects in the Trendelenburg position) against the standard clinical protocol (5cc swallows with subject in the supine position). We used advanced machine learning techniques and robust metrics for the classification purposes. METHODS: Studies were performed in 30 healthy subjects and 30 patients with functional dysphagia. A custom-built software was used to extract the relevant distension-contraction features of esophageal peristalsis. Ensemble methods, i.e., gradient boost, support vector machines (SVM), and logit boost were used as the primary machine learning algorithms. RESULTS: While the individual contraction features were marginally different between the two groups, the distension features of peristalsis were significantly different. The ROC curves values for the standard recording protocol, for the distension features ranged from 0.74 to 0.82; they were significantly better for the protocol used in our prior studies, ranged from 0.81-0.91. The ROC curve values using 3 machine learning algorithms were far superior for the distension than the contraction features of esophageal peristalsis, revealing value of 0.95 for the SVM algorithm. CONCLUSIONS: Current patient classification based on the contraction phase of peristalsis misses large number of patients who have abnormality in the distension phase of peristalsis. Distension contraction plots should be the standard of assessing esophageal peristalsis in clinical practice.

A Direct Link Implicating Loss of SLC26A6 to Gut Microbial Dysbiosis, Compromised Barrier Integrity, and Inflammation.

BACKGROUND & AIMS: Putative anion transporter-1 (PAT1, SLC26A6) plays a key role in intestinal oxalate and bicarbonate secretion. PAT1 knockout (PKO) mice exhibit hyperoxaluria and nephrolithiasis. Notably, diseases such as inflammatory bowel disease are also associated with higher risk of hyperoxaluria and nephrolithiasis. However, the potential role of PAT1 deficiency in gut-barrier integrity and susceptibility to colitis is currently elusive. METHODS: Age-matched PKO and wild-type littermates were administered 3.5% dextran sulfate sodium in drinking water for 6 days. Ileum and colon of control and treated mice were harvested. Messenger RNA and protein expression of tight junction proteins were determined by reverse transcription polymerase chain reaction and western blotting. Severity of inflammation was assessed by measuring diarrheal phenotype, cytokine expression, and H&E staining. Gut microbiome and associated metabolome were analyzed by 16S ribosomal RNA sequencing and mass spectrometry, respectively. RESULTS: PKO mice exhibited significantly higher loss of body weight, gut permeability, colonic inflammation, and diarrhea in response to dextran sulfate sodium treatment. In addition, PKO mice showed microbial dysbiosis and significantly reduced levels of butyrate and butyrate-producing microbes compared with controls. Co-housing wild-type and PKO mice for 4 weeks resulted in PKO-like signatures on the expression of tight junction proteins in the colons of wild-type mice. CONCLUSIONS: Our data demonstrate that loss of PAT1 disrupts gut microbiome and related metabolites, decreases gut-barrier integrity, and increases host susceptibility to intestinal inflammation. These findings, thus, highlight a novel role of the oxalate transporter PAT1 in promoting gut-barrier integrity, and its deficiency appears to contribute to the pathogenesis of inflammatory bowel diseases.

Fecal incontinence patients categorized based on anal pressure and electromyography: Anal sphincter damage and clinical symptoms.

BACKGROUND: Disruption of external anal sphincter muscle (EAS) is an important factor in the multifactorial etiology of fecal incontinence (FI). OBJECTIVES: We categorize FI patients into four groups based on the location of lesion in neuromuscular circuitry of EAS to determine if there are differences with regards to fecal incontinence symptoms severity (FISI) score, age, BMI, obstetrical history, and anal sphincter muscle damage. METHODS: Female patients (151) without any neurological symptoms, who had undergone high-resolution manometry, anal sphincter EMG, and 3D ultrasound imaging of the anal sphincter were assessed. Patients were categorized into four groups: Group 1 (normal)-normal cough EMG (>10 µV), normal squeeze EMG (>10 µV), and normal anal squeeze pressure (>124 mmHg); Group 2 (cortical apraxia, i.e., poor cortical activation)-normal cough EMG, low squeeze EMG, and low anal squeeze pressure; Group 3 (muscle damage)-normal cough EMG, normal squeeze EMG, and low anal squeeze pressure; and Group 4 (pudendal nerve damage)-low cough EMG, low squeeze EMG, and low anal squeeze pressure. RESULTS: The four patient groups were not different with regards to the patient's age, BMI, parity, and FISI scores. 3D ultrasound images of the anal sphincter complex revealed significant damage to the internal anal sphincter, external anal sphincter, and puborectalis muscles in all four groups. CONCLUSION: The FI patients are a heterogeneous group; majority of these patients have significant damage to the muscles of the anal sphincter complex. Whether biofeedback therapy response is different among different patient groups requires study.

Epidemiological and Clinical Profile of Hand, Foot, and Mouth Disease in Children in a Tertiary Care Center in Jammu.

Background Hand, foot, and mouth disease (HFMD) is a viral illness commonly seen in children under five years of age, characterized by typical manifestations such as oral lesions and rashes on the hands and feet. Coxsackievirus A-16 (CV-A16) and Enterovirus A-71 (EV-A71) are the major etiological agents of this disease. Over the past two decades, there have been several outbreaks of HFMD all across India. As there is no chemoprophylaxis available for the disease, it becomes even more significant to conduct regular research and surveillance for HFMD. Aim and objective To observe the clinico-epidemiological profile along with constitutional symptoms in HFMD patients attending pediatric OPD. Methods This hospital-based prospective observational study was conducted in the Post Graduate Department of Pediatrics, Acharya Shri Chander College of Medical Sciences and Hospital (ASCOMS & H), Sidra, Jammu and Kashmir, India, over six months from April to September 2023. A total of 132 children with symptoms of HFMD visited the pediatric OPD. After using inclusive and exclusive criteria, we selected a sample size of 112 children with HFMD. The descriptive data were expressed in terms of percentages and proportions, and their graphical representation was done using MS Excel (Microsoft Corporation, Redmond, Washington, United States). Results Among the 112 HFMD patients examined, the highest peak was seen in August, followed by another one in September. Most of the cases were seen in the age group of zero to three years, and it was observed that there was a linear fall in the number of cases with the increase in age. Nearly 61% of cases were male, showing a slight male preponderance. Vesiculopapular rash on the hand and foot was the most common clinical characteristic, whereas painful deglutition was noted to be the most common constitutional symptom in HFMD patients. About 27% had a positive family history, and nail changes post-recovery were present in 1.79% of cases during their regular follow-ups. Conclusions This study reveals that HFMD cases surged in August and September, with a history of contact in one-fourth of cases. Disease is seen more commonly in children under three years of age, and the incidence of cases decreases with the increase in age. The illness is usually contagious and can spread quickly; therefore, more awareness programs should be done to educate parents and promote hygiene to prevent contact cases.

Leaf functional traits and resource use strategies facilitate the spread of invasive plant Parthenium hysterophorus across an elevational gradient in western Himalayas.

Parthenium hysterophorus L. (Asteraceae) is a highly prevalent invasive species in subtropical regions across the world. It has recently been seen to shift from low (subtropical) to high (sub-temperate) elevations. Nevertheless, there is a dearth of research investigating the adaptive responses and the significance of leaf functional traits in promoting the expansion to high elevations. The current study investigated the variations and trade-offs among 14 leaf traits (structural, photosynthetic, and nutrient content) of P. hysterophorus across different elevations in the western Himalayas, India. Plots measuring 20 × 40 m were established at different elevations (700 m, 1100 m, 1400 m, and 1800 m) to collect leaf trait data for P. hysterophorus. Along the elevational gradient, significant variations were noticed in leaf morphological parameters, leaf nutrient content, and leaf photosynthetic parameters. Significant increases were observed in the specific leaf area, leaf thickness, and chlorophyll a, total chlorophyll and carotenoid content, as well as leaf nitrogen and phosphorus content with elevation. On the other hand, there were reductions in the amount of chlorophyll b, photosynthetic efficiency, leaf dry matter content, leaf mass per area, and leaf water content. The trait-trait relationships between leaf water content and dry weight and between leaf area and dry weight were stronger at higher elevations. The results show that leaf trait variability and trait-trait correlations are very important for sustaining plant fitness and growth rates in low-temperature, high-irradiance, resource-limited environments at relatively high elevations. To summarise, the findings suggest that P. hysterophorus can expand its range to higher elevations by broadening its functional niche through changes in leaf traits and resource utilisation strategies.

Exploring the intricacies of calcium dysregulation in ischemic stroke: Insights into neuronal cell death and therapeutic strategies.

Calcium ion (Ca2+) dysregulation is one of the main causes of neuronal cell death and brain damage after cerebral ischemia. During ischemic stroke, the ability of neurons to maintain Ca2+ homeostasis is compromised. Ca2+ regulates various functions of the nervous system, including neuronal activity and adenosine triphosphate (ATP) production. Disruptions in Ca2+ homeostasis can trigger a cascade of events, including activation of the unfolded protein response (UPR) pathway, which is associated with endoplasmic reticulum (ER) stress and mitochondrial dysfunction. This response occurs when the cell is unable to manage protein folding within the ER due to various stressors, such as a high influx of Ca2+. Consequently, the UPR is initiated to restore ER function and alleviate stress, but prolonged activation can lead to mitochondrial dysfunction and, ultimately, cell death. Hence, precise regulation of Ca2+ within the cell is mandatory. The ER and mitochondria are two such organelles that maintain intracellular Ca2+ homeostasis through various calcium-operating channels, including ryanodine receptors (RyRs), inositol trisphosphate receptors (IP3Rs), sarco/endoplasmic reticulum calcium ATPases (SERCAs), the mitochondrial Na+/Ca2+ exchanger (NCLX), the mitochondrial calcium uniporter (MCU) and voltage-dependent anion channels (VDACs). These channels utilize Ca2+ sequestering and release mechanisms to maintain intracellular Ca2+ homeostasis and ensure proper cellular function and survival. The present review critically evaluates the significance of Ca2+ and its physiological role in cerebral ischemia. We have compiled recent findings on calcium's role and emerging treatment strategies, particularly targeting mitochondria and the endoplasmic reticulum, to address Ca2+ overload in cerebral ischemia.

Esophageal Symptoms and Lumbosacral Back Pain.

BACKGROUND AND AIMS: Esophageal symptoms, that is, heartburn, regurgitation, dysphagia, and chest pain are common in the general population. Also common are symptoms of back pain related to pathology in the lumbosacral spine. The right crus of the diaphragm that forms the esophageal hiatus, originates from lumbar spine, may be affected by lumbar spine pathology resulting in esophageal symptoms. We studied whether there was an association between esophageal symptoms and spine symptoms. METHODS: Two patient groups of 150 each were investigated: group 1 (ES); patients referred to the esophageal manometry study for assessment of esophageal symptoms, group 2 (SC); patients undergoing screening colonoscopy (control group). Both groups completed standardized questionnaires assessing esophageal and spine symptoms. RESULTS: Back pain was reported by 74% of patients in the ES group as compared to 55% of patients in the SC group. Thirty percent of patients in the SC group reported one or more esophageal symptoms and these patients were regrouped with the ES group, resulting in 2 groups, ES1 and SC1, with and without esophageal symptoms, respectively. The ES1 group was 3.3 times more likely to experience back pain compared to the SC1 group (95% confidence interval: 1.95-5.46). Thoracolumbar was the most common site of pain in both groups. Pain score was greater for the group with esophageal symptoms compared to controls. Narcotic intake for most patients in the ES1 group was for back pain. CONCLUSION: A strong association between esophageal symptoms and thoracolumbar back pain raises the possibility that structural and functional changes in the esophageal hiatus muscles related to thoracolumbar spine pathology lead to esophageal dysmotility and symptoms.

Serotonin Transporter Deficiency Induces Metabolic Alterations in the Ileal Mucosa.

Serotonin transporter (SERT) deficiency has been implicated in metabolic syndrome, intestinal inflammation, and microbial dysbiosis. Interestingly, changes in microbiome metabolic capacity and several alterations in host gene expression, including lipid metabolism, were previously observed in SERT-/- mice ileal mucosa. However, the precise host or microbial metabolites altered by SERT deficiency that may contribute to the pleiotropic phenotype of SERT KO mice are not yet understood. This study investigated the hypothesis that SERT deficiency impacts lipid and microbial metabolite abundances in the ileal mucosa, where SERT is highly expressed. Ileal mucosal metabolomics was performed by Metabolon on wild-type (WT) and homozygous SERT knockout (KO) mice. Fluorescent-activated cell sorting (FACS) was utilized to measure immune cell populations in ileal lamina propria to assess immunomodulatory effects caused by SERT deficiency. SERT KO mice exhibited a unique ileal mucosal metabolomic signature, with the most differentially altered metabolites being lipids. Such changes included increased diacylglycerols and decreased monoacylglycerols in the ileal mucosa of SERT KO mice compared to WT mice. Further, the ileal mucosa of SERT KO mice exhibited several changes in microbial-related metabolites known to play roles in intestinal inflammation and insulin resistance. SERT KO mice also had a significant reduction in the abundance of ileal group 3 innate lymphoid cells (ILC3). In conclusion, SERT deficiency induces complex alterations in the ileal mucosal environment, indicating potential links between serotonergic signaling, gut microbiota, mucosal immunity, intestinal inflammation, and metabolic syndrome.

A Sustainable and Regenerative Process for the Treatment of Textile Effluents Using Nonphotocatalytic Water Splitting by Nanoporous Oxygen-Deficient Ferrite.

Water is crucial for life. Being the world's third-largest industry, the textile industry pollutes 93 billion cubic meters of water each year. Only 28% of textile wastewater is treated by lower- to middle-income countries due to the costly treatment methods. The present work demonstrates the utilization of surface oxygen defects and nanopores in Mg0.8Li0.2Fe2O4 (Li-MgF) to treat textile effluents by a highly economical, scalable, and eco-friendly process. Nanoporous, oxygen-deficient Li-MgF splits water by a nonphotocatalytic process at room temperature to produce green electricity as hydroelectric cell. The adsorbent Li-MgF can be easily regenerated by heat treatment. A 70-90% reduction in the UV absorption intensity of adsorbent-treated textile effluents was observed by UV-visible spectroscopy. The oxygen defects on Li-MgF surface and nanopores were confirmed by X-ray photoelectron spectroscopy and Brunauer-Emmett-Teller (BET) measurements, respectively. To analyze the adsorption mechanism, three known organic water-soluble dyes, brilliant green, crystal violet, and congo red, were treated with nanoporous Li-MgF. The dye decolorization efficiency of Li-MgF was recorded to be 99.84, 99.27, and 99.31% at 250 µM concentrations of brilliant green, congo red, and crystal violet, respectively. The results of Fourier transform infrared (FTIR) spectroscopy confirmed the presence of dyes on the material surface attached through hydroxyl groups generated by water splitting on the surface of the material. Total organic carbon analysis confirmed the removal of organic carbon from the dye solutions by 82.8, 77.0, and 46.5% for brilliant green, Congo red, and crystal violet, respectively. Based on the kinetic and isotherm models, the presence of a large number of surface hydroxyl groups on the surface of the material and OH- ions in solutions generated by water splitting was found to be responsible for the complete decolorization of all of the dyes. Adsorption of chemically diverse dyes by the nanoporous, eco-friendly, ferromagnetic, economic, and reusable Li-MgF provides a sustainable and easy way to treat textile industry effluents in large amounts.

Urinary tract infections in pediatric orthopedic surgical patients: a Single Institution National Surgical Quality Improvement Program Study.

OBJECTIVE: Perioperative urinary tract infections (UTIs) are poorly studied among pediatric orthopedic surgical patients. We evaluated the incidence of and risk factors for UTI in a large volume of pediatric orthopedic surgical patients. METHODS: Children <18 who underwent orthopedic surgery between March 2015 and December 2018 were analyzed using our institution's National Surgical Quality Improvement Program (NSQIP) data. Demographic, perioperative and outcome data of patients who developed a UTI within 30 days of surgery were compared to patients without UTI. RESULTS: NSQIP data were available for 520 surgeries (324 girls and 196 boys). Median age at surgery was 13.5 years. A Foley was placed in 301/520 cases (88/196 boys and 213/324 girls) in 264 children. Six cases of UTI occurred within 30 days of surgery (1.2% of surgeries). The UTI rate among patients with a Foley was 2.3%, and among girls with a Foley was 2.8%. No UTIs occurred without a Foley, nor any in boys. All six occurred in the American Society of Anesthesiologists Class 2 females, ages 7-15 undergoing elective surgery with Foley for over 48 h. Factors associated with an increased odds of developing UTI included: higher BMI [OR, 1.12 (CI, 1.01-1.22; P  = 0.03)], developmental delay [OR, 7.82 (CI, 1.40-43.7; P  = 0.02)], structural central nervous system abnormality [OR, 17.5 (CI, 3.89-90.4; P  = 0.01)], longer duration with Foley [OR, 1.68 (CI, 1.22-2.32; P  = 0.002)] and hospital readmission within 30 days [OR 14.2 (CI, 2.32-87.3; P  = 0.004)]. CONCLUSION: Risk of UTI is low after pediatric orthopedic surgery. Girls with comorbidities including structural central nervous system abnormality, developmental delay and higher BMI with prolonged Foley catheterization may have higher postoperative UTI risk. Level of Evidence: II.

Why so Many Patients With Dysphagia Have Normal Esophageal Function Testing.

Esophageal peristalsis involves a sequential process of initial inhibition (relaxation) and excitation (contraction), both occurring from the cranial to caudal direction. The bolus induces luminal distension during initial inhibition (receptive relaxation) that facilitates smooth propulsion by contraction travelling behind the bolus. Luminal distension during peristalsis in normal subjects exhibits unique characteristics that are influenced by bolus volume, bolus viscosity, and posture, suggesting a potential interaction between distension and contraction. Examining distension-contraction plots in dysphagia patients with normal bolus clearance, ie, high-amplitude esophageal peristaltic contractions, esophagogastric junction outflow obstruction, and functional dysphagia, reveal 2 important findings. Firstly, patients with type 3 achalasia and nonobstructive dysphagia show luminal occlusion distal to the bolus during peristalsis. Secondly, patients with high-amplitude esophageal peristaltic contractions, esophagogastric junction outflow obstruction, and functional dysphagia exhibit a narrow esophageal lumen through which the bolus travels during peristalsis. These findings indicate a relative dynamic obstruction to bolus flow and reduced distensibility of the esophageal wall in patients with several primary esophageal motility disorders. We speculate that the dysphagia sensation experienced by many patients may result from a normal or supernormal contraction wave pushing the bolus against resistance. Integrating representations of distension and contraction, along with objective assessments of flow timing and distensibility, complements the current classification of esophageal motility disorders that are based on the contraction characteristics only. A deeper understanding of the distensibility of the bolus-containing esophageal segment during peristalsis holds promise for the development of innovative medical and surgical therapies to effectively address dysphagia in a substantial number of patients.

Eco-safe composite edible coating of hydrocolloids with papaya leaf extract improves postharvest quality and shelf life of papaya fruit under ambient storage.

Papaya postharvest management using low-temperature storage is discouraged as it is a tropical fruit. Extensive research is going on to preserve papaya quality at ambient storage using edible coatings and its composites. The present investigation examined the effects of an eco-safe composite edible coating consisting of hydrocolloid carboxymethyl cellulose (CMC) (1%), guar gum (1.5%), xanthan gum (0.3%), and Gum Arabic (10%) combined with papaya leaf extract (PLE) (1:1 ratio by volume) applied as dip treatment on "Red Lady" papaya fruit at ambient storage condition. Among all the attempted treatments, "PLE incorporated with CMC (1%)" was found to be the best, as the treated fruit exhibited the highest levels of biochemicals, whereas the lowest levels of physiological and enzymatic activity, which positively affected the shelf life. The "CMC + PLE" treatment enhanced the fruit gloss score by 70.1%, phenolics by 6.1%, ascorbic acid by 22.3%, total carotenoid content by 7.4%, and fruit predilection score by 22.0% over the control fruit. However, it lowered (controlling) the physiological loss in weight by 51.0%, decay incidence by 66.6%, and polygalacturonase and pectin methylesterase activity by 24.92% and 35.29%, respectively, over control. Moreover, this treatment exhibited the highest fruit purchase predilection score and prolonged the storage life for >3 days on the physiological loss standard basis (≤10%). This study indicates that "CMC (1%) with PLE (1:1)" composite coating application on papaya under ambient conditions might be an effective, environmentally friendly, and health-friendly way to retain the quality and extend the storage life.

A systematic review of 454 randomized controlled trials using the Dermatology Life Quality Index: experience in 69 diseases and 43 countries.

BACKGROUND: Over 29 years of clinical application, the Dermatology Life Quality Index (DLQI) has remained the most used patient-reported outcome (PRO) in dermatology due to its robustness, simplicity and ease of use. OBJECTIVES: To generate further evidence of the DLQI's utility in randomized controlled trials (RCTs) and to cover all diseases and interventions. METHODS: The methodology followed PRISMA guidelines and included seven bibliographical databases, searching articles published from 1 January 1994 until 16 November 2021. Articles were reviewed independently by two assessors, and an adjudicator resolved any opinion differences. RESULTS: Of 3220 screened publications, 454 articles meeting the eligibility criteria for inclusion, describing research on 198 190 patients, were analysed. DLQI scores were primary endpoints in 24 (5.3%) of studies. Most studies were of psoriasis (54.1%), although 69 different diseases were studied. Most study drugs were systemic (85.1%), with biologics comprising 55.9% of all pharmacological interventions. Topical treatments comprised 17.0% of total pharmacological interventions. Nonpharmacological interventions, mainly laser therapy and ultraviolet radiation treatment, comprised 12.2% of the total number of interventions. The majority of studies (63.7%) were multicentric, with trials conducted in at least 42 different countries; 40.2% were conducted in multiple countries. The minimal clinically importance difference (MCID) was reported in the analysis of 15.0% of studies, but only 1.3% considered full score meaning banding of the DLQI. Forty-seven (10.4%) of the studies investigated statistical correlation of the DLQI with clinical severity assessment or other PRO/quality of life tools; and 61-86% of studies had within-group scores differences greater than the MCID in 'active treatment arms'. The Jadad risk-of-bias scale showed that bias was generally low, as 91.8% of the studies had Jadad scores of ≥ 3; only 0.4% of studies showed a high risk of bias from randomization. Thirteen per cent had a high risk of bias from blinding and 10.1% had a high risk of bias from unknown outcomes of all participants in the studies. In 18.5% of the studies the authors declared that they followed an intention-to-treat protocol; imputation for missing DLQI data was used in 34.4% of studies. CONCLUSIONS: This systematic review provides a wealth of evidence of the use of the DLQI in clinical trials to inform researchers' and -clinicians' decisions for its further use. Recommendations are also made for improving the reporting of data from future RCTs using the DLQI.

Selective dysfunction of the crural diaphragm in patients with chronic restrictive and obstructive lung disease.

BACKGROUND: Gastroesophageal reflux (GER) is known to be associated with chronic lung diseases. The driving force of GER is the transdiaphragmatic pressure (Pdi) generated mainly by costal and crural diaphragm contraction. The latter also enhances the esophagogastric junction (EGJ) pressure to guard against GER. METHODS: The relationship between Pdi and EGJ pressure was determined using high resolution esophageal manometry in patients with interstitial lung disease (ILD, n = 26), obstructive lung disease (OLD, n- = 24), and healthy subjects (n = 20). KEY RESULTS: The patient groups did not differ with respect to age, gender, BMI, and pulmonary rehabilitation history. Patients with ILD had significantly higher Pdi but lower EGJ pressures as compared to controls and OLD patients (p < 0.001). In control subjects, the increase in EGJ pressure at all-time points during inspiration was greater than Pdi. In contrast, the EGJ pressure during inspiration was less than Pdi in 14 patients with ILD and 7 patients with OLD. The drop in EGJ pressure was usually seen after the peak Pdi in ILD group (p < 0.0001) and before the peak Pdi in OLD group, (p = 0.08). Nine patients in the ILD group had sliding hiatus hernia, compared to none in control subjects (p = 0.003) and two patients in the OLD, (p = 0.04). CONCLUSIONS AND INFERENCES: A higher Pdi and low EGJ pressure, and dissociation between Pdi and EGJ pressure temporal relationship suggests selective dysfunction of the crural diaphragm in patients with chronic lung diseases and may explain the higher prevalence of GERD in ILD as seen in previous studies.

Linking NLRP3 inflammasome and pulmonary fibrosis: mechanistic insights and promising therapeutic avenues.

Pulmonary fibrosis is a devastating disorder distinguished by redundant inflammation and matrix accumulation in the lung interstitium. The early inflammatory cascade coupled with recurring tissue injury orchestrates a set of events marked by perturbed matrix hemostasis, deposition of matrix proteins, and remodeling in lung tissue. Numerous investigations have corroborated a direct correlation between the NLR family pyrin domain-containing 3 (NLRP3) activation and the development of pulmonary fibrosis. Dysregulated activation of NLRP3 within the pulmonary microenvironment exacerbates inflammation and may incite fibrogenic responses. Nevertheless, the precise mechanisms through which the NLRP3 inflammasome elicits pro-fibrogenic responses remain inadequately defined. Contemporary findings suggest that the pro-fibrotic consequences stemming from NLRP3 signaling primarily hinge on the action of interleukin-1ß (IL-1ß). IL-1ß instigates IL-1 receptor signaling, potentiating the activity of transforming growth factor-beta (TGF-ß). This signaling cascade, in turn, exerts influence over various transcription factors, including SNAIL, TWIST, and zinc finger E-box-binding homeobox 1 (ZEB 1/2), which collectively foster myofibroblast activation and consequent lung fibrosis. Here, we have connected the dots to illustrate how the NLRP3 inflammasome orchestrates a multitude of signaling events, including the activation of transcription factors that facilitate myofibroblast activation and subsequent lung remodeling. In addition, we have highlighted the prominent role played by various cells in the formation of myofibroblasts, the primary culprit in lung fibrosis. We also provided a concise overview of various compounds that hold the potential to impede NLRP3 inflammasome signaling, thus offering a promising avenue for the treatment of pulmonary fibrosis.

Role of NLRP3 Inflammasome in Stroke Pathobiology: Current Therapeutic Avenues and Future Perspective.

Neuroinflammation is a key pathophysiological feature of stroke-associated brain injury. A local innate immune response triggers neuroinflammation following a stroke via activating inflammasomes. The nucleotide-binding oligomerization domain leucine-rich repeat and pyrin domain-containing protein 3 (NLRP3) inflammasome has been heavily implicated in stroke pathobiology. Following a stroke, several stimuli have been suggested to trigger the assembly of the NLRP3 inflammasome. Recent studies have advanced the understanding and revealed several new players regulating NLRP3 inflammasome-mediated neuroinflammation. This article discussed recent advancements in NLRP3 assembly and highlighted stroke-induced mitochondrial dysfunction as a major checkpoint to regulating NLRP3 activation. The NLRP3 inflammasome activation leads to caspase-1-dependent maturation and release of IL-1ß, IL-18, and gasdermin D. In addition, genetic or pharmacological inhibition of the NLRP3 inflammasome activation and downstream signaling has been shown to attenuate brain infarction and improve the neurological outcome in experimental models of stroke. Several drug-like small molecules targeting the NLRP3 inflammasome are in different phases of development as novel therapeutics for various inflammatory conditions, including stroke. Understanding how these molecules interfere with NLRP3 inflammasome assembly is paramount for their better optimization and/or development of newer NLRP3 inhibitors. In this review, we summarized the assembly of the NLRP3 inflammasome and discussed the recent advances in understanding the upstream regulators of NLRP3 inflammasome-mediated neuroinflammation following stroke. Additionally, we critically examined the role of the NLRP3 inflammasome-mediated signaling in stroke pathophysiology and the development of therapeutic modalities to target the NLRP3 inflammasome-related signaling for stroke treatment.

Comparative Evaluation of the Antimicrobial Efficacy of Chemical and Phytomedicinal Agents When Used As Intracanal Irrigants: An In Vitro Study.

AIM: This study aimed to compare and evaluate the antimicrobial efficacy of chemical and phytomedicinal agents when used as intracanal irrigants against Candida albican (C. albican) and Enterococcus faecalis (E. faecalis). Materials and methods: This study was conducted at Kothiwal Dental College and Research Centre, Moradabad, India. One-hundred human tooth roots with a standardized length of 12±0.5 mm were divided into two groups (A and B, 50 each) inoculated with C. albican and E. faecalis, respectively. The groups were further divided according to the irrigants: A1 (11% ethanolic extract of propolis), A2 (2% chlorhexidine gluconate (CHX)), A3 (0.5% metronidazole), A4 (10% babool), and A5 (sterile saline (control) for the C. albican group and E. faecalis group (B1 to B5, respectively). The samples of different specimens were taken at subsequent intervals. The first collection was taken two days and 21 days after inoculation in group A and group B, respectively. The second collection was taken post irrigation, and the third collection seven days after different irrigants were used in both the groups. Microbiological samples were grown in a culture medium and incubated at 37°C for 24 hours for C. albican and 48 hours for E. faecalis (Sabouraud dextrose agar for C. albican and brain heart fusion for E. faecalis). The results were submitted for analysis of variance (ANOVA) and post-hoc test for statistical analysis. RESULTS: In group A, 2% chlorhexidine gluconate showed a highly significant percentage reduction of colony-forming unit (CFU) count (p≤0.001) with respect to the time interval against C. albican, followed by metronidazole, babool, propolis, and saline, whereas in group B, propolis showed a significant percentage reduction of CFU count (p<0.001) with respect to time interval against E. faecalis, followed by 2% CHX, metronidazole, babool, and saline. CONCLUSION: Two percent chlorhexidine gluconate showed the highest antimicrobial efficacy against C. albican, whereas propolis showed the highest antimicrobial efficacy against E. faecalis. Chemical irrigants proved effective over herbal irrigants against C. albican, whereas herbal irrigants showed better antimicrobial efficacy over chemical irrigants against E. faecalis.

Potential Dietary and Therapeutic Strategies Involving Indole-3-Carbinole in Preclinical Models of Intestinal Inflammation.

Diet-microbiota interactions are emerging as important contributors in the pathogenesis of inflammatory bowel diseases (IBD), characterized by chronic inflammation of the GI tract. The aryl hydrocarbon receptor (AhR) transcription factor regulates xenobiotic metabolism and is activated by exogenous ligands, including indole-3-carbinole (I3C), which is found in cruciferous vegetables. However, studies investigating the impact of dietary I3C and AhR in preclinical models resembling human IBD are lacking. Mice (WT or AhR KO in IECs, 6-8 weeks) or SAMP/YitFC and AKR/J control (4 weeks, m/f) were fed an AhR ligand-depleted or I3C (200 ppm)-supplemented diet. There were increased levels of LPS and exacerbated inflammation, resulting in increased mortality in AhRΔIEC mice fed the AhR ligand-depleted diet in response to chronic DSS. The mechanisms underlying the protective effects of I3C supplementation during colonic colitis involved amelioration of intestinal inflammation and restoration of the altered gut microbiota, particularly the families of clostridicae and lachnospriaceae. Furthermore, the AhR-depleted diet led to the emergence of pathobiont Parvibacter caecicola in WT mice. SAMP/YitFc mice with spontaneous ileitis showed significant recovery in epithelial abnormalities when fed dietary I3C. These data demonstrate the critical role of AhR and the mechanisms of dietary I3C in maintaining epithelial homeostasis and ameliorating inflammation.

Serum metabolomic analysis in cirrhotic alcohol-associated liver disease patients identified differentially altered microbial metabolites and novel potential biomarkers for disease severity.

BACKGROUND: Alcohol-Associated Liver Disease (ALD) is a leading cause of liver mortality. Mechanisms responsible for severe ALD and the roles of gut microbiota are not fully understood. Multi-omics tools have enabled a better understanding of metabolic alterations and can aid in identifying metabolites as biomarkers for severe ALD. AIMS: Examine differences between cirrhotic and non-cirrhotic ALD, investigate microbial contributions to such changes, and identify potential diagnostic and prognostic metabolites for severe ALD. METHODS: Untargeted metabolomics were performed on the serum of 11 non-cirrhotic and 11 cirrhotic ALD patients. Data were analyzed using MetOrigin and Metaboanalyst to identify enriched pathways. RESULTS: Increased methylated nucleotides, gamma-glutamyl amino acids, bile acids, and specific metabolites kynurenine and campesterol were increased in ALD cirrhosis, whereas branched-chain amino acids, serotonin, and xanthurenate were decreased. Microbial contributions included increases in the short-chain fatty acid indolebutyrate and methionine sulfoxide in ALD cirrhosis. The analysis also identified the potential for serum levels of 3-ureidopropionate, cis-3,3-methyleneheptanoylglycine, retinol, and valine to be used as biomarkers for clinical assessment of alcohol-associated cirrhosis. CONCLUSION: We have identified a set of metabolites that are differentially altered in cirrhotic compared to non-cirrhotic ALD that can potentially be used as biomarkers for the severity of the disease.