Selective autophagy of RIPosomes maintains innate immune homeostasis during bacterial infection.

The NOD1/2-RIPK2 is a key cytosolic signaling complex that activates NF-κB pro-inflammatory response against invading pathogens. However, uncontrolled NF-κB signaling can cause tissue damage leading to chronic diseases. The mechanisms by which the NODs-RIPK2-NF-κB innate immune axis is activated and resolved remain poorly understood. Here, we demonstrate that bacterial infection induces the formation of endogenous RIPK2 oligomers (RIPosomes) that are self-assembling entities that coat the bacteria to induce NF-κB response. Next, we show that autophagy proteins IRGM and p62/SQSTM1 physically interact with NOD1/2, RIPK2 and RIPosomes to promote their selective autophagy and limit NF-κB activation. IRGM suppresses RIPK2-dependent pro-inflammatory programs induced by Shigella and Salmonella. Consistently, the therapeutic inhibition of RIPK2 ameliorates Shigella infection- and DSS-induced gut inflammation in Irgm1 KO mice. This study identifies a unique mechanism where the innate immune proteins and autophagy machinery are recruited together to the bacteria for defense as well as for maintaining immune homeostasis.

Assessing cognitive impairment and disability in older adults through the lens of whole brain white matter patterns.

INTRODUCTION: This study aimed to explore the potential of whole brain white matter patterns as novel neuroimaging biomarkers for assessing cognitive impairment and disability in older adults. METHODS: We conducted an in-depth analysis of magnetic resonance imaging (MRI) and amyloid positron emission tomography (PET) scans in 454 participants, focusing on white matter patterns and white matter inter-subject variability (WM-ISV). RESULTS: The white matter pattern ensemble model, combining MRI and amyloid PET, demonstrated a significantly higher classification performance for cognitive impairment and disability. Participants with Alzheimer's disease (AD) exhibited higher WM-ISV than participants with subjective cognitive decline, mild cognitive impairment, and vascular dementia. Furthermore, WM-ISV correlated significantly with blood-based biomarkers (such as glial fibrillary acidic protein and phosphorylated tau-217 [p-tau217]), and cognitive function and disability scores. DISCUSSION: Our results suggest that white matter pattern analysis has significant potential as an adjunct neuroimaging biomarker for clinical decision-making and determining cognitive impairment and disability. HIGHLIGHTS: The ensemble model combined both magnetic resonance imaging (MRI) and amyloid positron emission tomography (PET) and demonstrated a significantly higher classification performance for cognitive impairment and disability. Alzheimer's disease (AD) revealed a notably higher heterogeneity compared to that in subjective cognitive decline, mild cognitive impairment, or vascular dementia. White matter inter-subject variability (WM-ISV) was significantly correlated with blood-based biomarkers (glial fibrillary acidic protein and phosphorylated tau-217 [p-tau217]) and with the polygenic risk score for AD. White matter pattern analysis has significant potential as an adjunct neuroimaging biomarker for clinical decision-making processes and determining cognitive impairment and disability.

Suppression of Chronic Unpredictable Stress-Persuaded Increased Monoamine Oxidase Activity by Taurine Promotes Significant Neuroprotection in Zebrafish Brain.

Neuropsychiatric upshots following chronic exposure to unpredictable adverse stressors have been well documented in the literature. Considering the significant impact of chronic unpredictable stress (CUS), the literature is elusive regarding the neuroprotective efficacy of taurine against CUS-induced oxidative stress and chromatin condensation in the zebrafish brain. In this study, to ameliorate CUS-persuaded neurological outcomes, waterborne treatment of taurine as a prophylactic intervention was undertaken. Further, our approach also focused on the gross neurobehavioral response of zebrafish, oxidative stress indices and neuromorphology of the zebrafish brain following CUS exposure with taurine treatment. Because taurine provides significant neuroprotection against oxidative insult, the cytosolic level of monoamine oxidase (MAO) in the zebrafish brain following CUS exposure is worth investigating. Further, as heightened MAO activity is associated with augmented oxidative and chromatin condensation, the focus of this study was on whether taurine provides neuroprotection by downregulating MAO levels in the brain. Our findings show that CUS-persuaded altered neurobehavioral response was significantly rescued by taurine. Moreover, our findings firmly support the hypothesis that taurine acts as a radical neuroprotector by restoring glutathione biosynthesis in the zebrafish brain subsequent to CUS exposure. Additionally, the rising level of brain MAO following chronic exposure to CUS is ameliorated by taurine treatment. These findings strongly advocate the role of taurine as a natural MAO inhibitor through the neuroprotection it provides against CUS-instigated oxidative stress in zebrafish. However, the fundamental neuroprotective mechanism of such natural compounds needs to be elucidated to determine their neuroprotective efficacy against stress regimens.

Inhibition of IRGM establishes a robust antiviral immune state to restrict pathogenic viruses.

The type I interferon (IFN) response is the major host arsenal against invading viruses. IRGM is a negative regulator of IFN responses under basal conditions. However, the role of human IRGM during viral infection has remained unclear. In this study, we show that IRGM expression is increased upon viral infection. IFN responses induced by viral PAMPs are negatively regulated by IRGM. Conversely, IRGM depletion results in a robust induction of key viral restriction factors including IFITMs, APOBECs, SAMHD1, tetherin, viperin, and HERC5/6. Additionally, antiviral processes such as MHC-I antigen presentation and stress granule signaling are enhanced in IRGM-deficient cells, indicating a robust cell-intrinsic antiviral immune state. Consistently, IRGM-depleted cells are resistant to the infection with seven viruses from five different families, including Togaviridae, Herpesviridae, Flaviviverdae, Rhabdoviridae, and Coronaviridae. Moreover, we show that Irgm1 knockout mice are highly resistant to chikungunya virus (CHIKV) infection. Altogether, our work highlights IRGM as a broad therapeutic target to promote defense against a large number of human viruses, including SARS-CoV-2, CHIKV, and Zika virus.

Effect of endodontic treatment on endothelial dysfunction and subclinical atherosclerosis-a prospective intervention study.

OBJECTIVE: The objective of this study is to investigate the effect of endodontic treatment on flow-mediated dilatation (FMD) and carotid intima-media thickness (c-IMT) in patients with apical periodontitis (AP). MATERIAL AND METHOD: The study includes 32 young men having AP with a mean age of 25.78 years free from cardiovascular disease (CVD) and its risk factors, including periodontitis. All subjects underwent complete physical and dental examination, echocardiography, and ultrasound assessment of FMD on the brachial artery and c-IMT on the carotid artery at baseline and 12 months after the endodontic treatment. Data were analyzed using paired Student's t-test and Pearson's correlation coefficient (r) test using SPSS 26 version. RESULTS: Endodontic treatment leads to the improvement of FMD significantly from a pooled baseline value of 4.84 ± 1.55% to 7.68 ± 2.08% (p < 0.05). The study also depicts a statistically significant difference between c-IMT (mean = 0.62 ± 0.11 mm) before treatment as compared to 12 months after treatment (mean = 0.59 ± 0.11 mm) (p < 0.05). CONCLUSION: Endodontic treatment leads to improved FMD and decreased c-IMT suggesting that treating AP can be help revert the early stages of CVD. CLINICAL RELEVANCE: AP could be a potential etiological factor of future CVD and should be treated as soon as diagnosed.

Di-2-ethylhexyl phthalate-induced neurobehavioural transformation is associated with altered glutathione biosynthesis and neurodegeneration in zebrafish brain.

The contamination of life-sustaining environments with synthetic pollutants such as plastic-derived compounds has increased at an alarming rate in recent decades. Among such contaminants, di-2-ethylhexyl phthalate (DEHP) is an extensively used compound in plastics and plastic products to make them flexible. DEHP causes several adverse effects such as reproductive toxicity leading to infertility, miscarriage and litter size reduction, disruption of the thyroid endocrine system, oxidative stress, neurodevelopmental defect and cognitive impairment. An aquatic environment is a fragile site, where the accumulation of DEHP poses a significant threat to living organisms. In this context, the present study focused on whether the neurobehavioural transformation following exposure to DEHP is an outcome of augmented oxidative stress and neuromorphological alteration in the zebrafish brain. Our preliminary findings advocate that DEHP acts as a typical neurotoxicant in inducing neurobehavioural transformation in zebrafish. Furthermore, our study also supports the idea that DEHP itself acts as a potent neurotoxicant by altering the glutathione biosynthetic pathway through the induction of oxidative stress in the zebrafish brain. Similarly, our findings also link the abovementioned neurobehavioural transformation and oxidative stress with augmented neuronal pyknosis and chromatin condensation in the periventricular grey zone of the zebrafish brain following chronic exposure to DEHP. Therefore, the overall conclusion of the present study advocates the potential role of DEHP in inducing neuropathological manifestation in the zebrafish brain. Future research directed towards elucidating the neuroprotective efficacy of natural compounds against DEHP-induced neurotoxicity may provide a new line of intervention.

Autoimmunity gene IRGM suppresses cGAS-STING and RIG-I-MAVS signaling to control interferon response.

Activation of the type 1 interferon response is extensively connected to the pathogenesis of autoimmune diseases. Loss of function of Immunity Related GTPase M (IRGM) has also been associated to several autoimmune diseases, but its mechanism of action is unknown. Here, we found that IRGM is a master negative regulator of the interferon response. Several nucleic acid-sensing pathways leading to interferon-stimulated gene expression are highly activated in IRGM knockout mice and human cells. Mechanistically, we show that IRGM interacts with nucleic acid sensor proteins, including cGAS and RIG-I, and mediates their p62-dependent autophagic degradation to restrain interferon signaling. Further, IRGM deficiency results in defective mitophagy leading to the accumulation of defunct leaky mitochondria that release cytosolic DAMPs and mtROS. Hence, IRGM deficiency increases not only the levels of the sensors, but also those of the stimuli that trigger the activation of the cGAS-STING and RIG-I-MAVS signaling axes, leading to robust induction of IFN responses. Taken together, this study defines the molecular mechanisms by which IRGM maintains interferon homeostasis and protects from autoimmune diseases.

Comparative evaluation of the force required to fracture coronal segments reattached using different methods.

BACKGROUND/AIM: Anterior teeth are prone to traumatic injuries. Their management is necessary in order to maintain the pulp and esthetics. Various methods have been reported for fragment reattachment of fractured teeth but there is no consensus on which is the best technique. The aim of this study was to compare the force required to fracture reattached fragments using polyethylene fibers in vertical grooves on the external surface of teeth, fiber-reinforced composite post and circumferential chamfer. MATERIAL AND METHODS: Forty-eight extracted maxillary central incisors were sectioned using a disk and randomly divided into 4 groups (n = 12): Group 1: control group, Group 2: reattachment followed by placement of two external vertical grooves on the labial surface and restored with polyethylene fibers and hybrid composite, Group 3: reattachment followed by two external vertical grooves and filled with fiber posts and composite, and Group 4: reattachment followed by circumferential chamfer at the fracture line and restored with composite. The forces required to fracture the reattached fragments were measured using a Universal testing machine. Data were analyzed using the Kruskal-Wallis test. Pairwise multiple comparison procedure was done using the Student-Newman-Keuls Method. RESULTS: The highest values for force required to fracture were observed in the fiber post group and the lowest in the Ribbond group (p < .05). The fiber post group had significantly different results compared to the Ribbond and Chamfer preparation groups (p < .05). However, the difference of rank between the fiber post and control groups was not significantly different (p > .05). CONCLUSION: The force required to fracture the fiber post group was closest to that of intact teeth followed by the chamfer and Ribbond groups, respectively.

Pulmonary embolism and gastric bleed with disseminated mucormycosis - treading dangerous waters.

Mucormycosis is an opportunistic infection seen in immunocompromised patients or in surgical and trauma settings with Mucorales wound contamination. In immunocompetent people, disseminated mucormycosis is uncommon. To ensure survival, patients with mucormycosis require early diagnosis and aggressive treatment using a multi-modality approach. We present a case of disseminated mucormycosis in an immunocompetent patient who also had pulmonary embolism and gastrointestinal bleeding. A recent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, identified retrospectively by a positive IgM against SARS-CoV-2, was the only risk factor present. This report emphasizes the increased risk of mucormycosis and thromboembolic complications following a recent SARS-CoV-2 infection, as well as its successful treatment with medical therapy alone.

Determinants, risk factors and spatial analysis of multi-drug resistant pulmonary tuberculosis in Jodhpur, India.

This study was planned to estimate the proportion of confirmed multi-drug resistance pulmonary tuberculosis (TB) cases out of the presumptive cases referred to DTC (District Tuberculosis Center) Jodhpur for diagnosis; to identify clinical and socio-demographic risk factors associated with the multidrug-resistant pulmonary TB and to assess the spatial distribution to find out clustering and pattern in the distribution of pulmonary TB with the help of Geographic Information System (GIS). In the Jodhpur district, 150 confirmed pulmonary multi-drug resistant tuberculosis (MDR-TB) cases, diagnosed by probe-based molecular drug susceptibility testing method and categorized as MDR in DTC's register (District Tuberculosis Center), were taken. Simultaneously, 300 control of confirmed non-MDR or drug-sensitive pulmonary TB patients were taken. Statistical analysis was done with logistic regression. In addition, for spatial analysis, secondary data from 2013-17 was analyzed using Global Moran's I and Getis and Ordi (Gi*) statistics. In 2012-18, a total of 12563 CBNAAT (Cartridge-based nucleic acid amplification test) were performed. 2898 (23%) showed M. TB positive but rifampicin sensitive, and 590 (4.7%) showed rifampicin resistant. Independent risk factors for MDR TB were ≤60 years age (AOR 3.0, CI 1.3-7.1); male gender (AOR 3.4, CI 1.8-6.7); overcrowding (AOR 1.6, CI 1.0-2.7); using chulha (smoke appliance) for cooking (AOR 2.5, CI 1.2-4.9), past TB treatment (AOR 5.7, CI 2.9-11.3) and past contact with MDR patient (AOR 10.7, CI 3.7-31.2). All four urban TUs (Tuberculosis Units) had the highest proportion of drug-resistant pulmonary TB. There was no statistically significant clustering, and the pattern of cases was primarily random. Most of the hotspots generated were present near the administrative boundaries of TUs, and the new ones mostly appeared in the area near the previous hotspots. A random pattern seen in cluster analysis supports the universal drug testing policy of India. Hotspot analysis helps cross administrative border initiatives with targeted active case finding and proper follow-up.

Unravelling the potential of gut microbiota in sustaining brain health and their current prospective towards development of neurotherapeutics.

Increasing incidences of neurological disorders, such as Parkinson's disease (PD), multiple sclerosis (MS), Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS) are being reported, but an insight into their pathology remains elusive. Findings have suggested that gut microbiota play a major role in regulating brain functions through the gut-brain axis. A unique bidirectional communication between gut microbiota and maintenance of brain health could play a pivotal role in regulating incidences of neurodegenerative diseases. Contrarily, the present life style with changing food habits and disturbed circadian rhythm may contribute to gut homeostatic imbalance and dysbiosis leading to progression of several neurological disorders. Therefore, dysbiosis, as a primary factor behind intestinal disorders, may also augment inflammation, intestinal and blood-brain barrier permeability through microbiota-gut-brain axis. This review primarily focuses on the gut-brain axis functions, specific gut microbial population, metabolites produced by gut microbiota, their role in regulating various metabolic processes and role of gut microbiota towards development of neurodegenerative diseases. However, several studies have reported a decrease in abundance of a specific gut microbial population and a corresponding increase in other microbial family, with few findings revealing some contradictions. Reports also showed that colonization of gut microbiota isolated from patients suffering from neurodegenerative disease leads to the development of enhance pathological outcomes in animal models. Hence, a systematic understanding of the dominant role of specific gut microbiome towards development of different neurodegenerative diseases could possibly provide novel insight into the use of probiotics and microbial transplantation as a substitute approach for treating/preventing such health maladies.

Suppression of bisphenol A-induced oxidative stress by taurine promotes neuroprotection and restores altered neurobehavioral response in zebrafish (Danio rerio).

Bisphenol A (BPA) has been documented as a mediator for a number of health effects, including inflammation, oxidative stress, carcinogenicity, and mood dysfunction. The literature on the role of BPA in inducing altered neurobehavioral response and brain morphology and plausible neuroprotective role of taurine against BPA induced oxidative stress mediated neurotoxicity is limited. Therefore, the present experimental paradigm was set for 21 days to expound the neuroprotective efficacy of taurine against BPA-induced neurotoxicity in zebrafish (Danio rerio) following waterborne exposure. Neurobehavioral studies were conducted by light-dark preference test (LDPT) and novel tank diving test (NTDT). To validate that the neuroprotective efficacy of taurine against BPA-induced neurotoxicity is associated with the modulation of the antioxidant defense system, we have conducted biochemical studies in zebrafish brain. Changes in brain morphology leading to neurobehavioral variations following co-supplementation of BPA and taurine were evaluated by Hoechst staining and cresyl violet staining (CVS) in periventricular gray zone (PGZ) of zebrafish brain. Our findings show that taurine co-supplementation significantly improved the BPA-induced altered scototaxis and explorative behavior of zebrafish. Further, BPA-induced augmented oxidative stress was considerably ameliorated by taurine co-supplementation. Subsequently, our observation also points toward the neuroprotective role of taurine against BPA-induced neuronal pyknosis and chromatin condensation in PGZ of zebrafish brain. In a nutshell, the findings of the current study show the neuroprotective efficacy of taurine against BPA-induced oxidative stress-mediated neurotoxicity. Elucidation of the underlying signaling mechanism of taurine-mediated neuroprotection would provide novel strategies for the prevention/treatment of BPA-persuaded serious neurological consequences.

Revisiting bronchoscopic intratumoral chemotherapy in malignant central airway obstruction via EUS-B approach and its review of literature.

Critical central airway obstruction has always been a dreaded complication to which interventional pulmonologist commonly encounters. There have been various modalities which are used for the management and palliation, which includes mechanical coring, laser, cryoextraction, electrocautery and airway stenting. Rigid bronchoscopy with or without jet ventilation has been corner stone of therapeutics and palliation of central airway obstruction. There are only a few conditions where it is not possible to use rigid bronchoscopy. Here we report a case of metastatic tracheal tumour which presented with critical airway obstruction in a patient who had atlantoaxial instability (AAI) due to rheumatoid arthritis. Here we used endobronchial ultrasound scope (EBUS) via esophageal route, i.e. EUS-B guided approach for sampling of the tracheal tumour, and intratumoral chemotherapy was instilled in multiple sessions, which resulted in shrinking of tumour, thus relieving the critical airway obstruction. This is the first report of using EUS-B approach for intratumoral chemotherapy for tracheal tumors. Bronchoscopic intratumoral chemotherapy therapy (BITC) in tracheal tumors is also one of the options but has not been explored much and there has been a dearth of literature for it.

Pancreatic pleural effusion masquerading as right sided tubercular pleural effusion.

Pleural effusion is easily diagnosed often managed optimally with standard protocols. It at times, is a diagnostic dilemma as it comes with big list of differential diagnosis. Pleural effusion due to pancreaticopleural fistula (PPF) is a rare and on right side is even rarer. Detailed history along with high index of suspicion in required to diagnose PPF, which is confirmed by increased level of pleural fluid amylase and lipase along with magnetic resonance cholangiopancreatography (MRCP) or endoscopic retrograde cholangiopancreatography (ERCP) demonstrating fistula tract. Here we report the case of a young patient who presented with respiratory distress and was wrongly diagnosed as right sided tubercular effusion which later turned out to be pancreatic effusion. Management in our case was multi-disciplinary involving pulmonologist, gastroenterologist, radiologist and thoracic surgeon.

A Rare Case of Neurogenic Pulmonary Edema Following High-voltage Electrical Injury.

Electrical injuries though infrequent, are potentially devastating form of injuries which are associated with high morbidity and mortality. The severity of the injury depends upon intensity of the electrical current which is determined by the voltage and the resistance offered by the victim. These injuries vary from trivial burns to death. There have been few reports about pulmonary injuries due to electrical current but none mentioning neurogenic pulmonary edema (NPE). Here we report a young boy who when exposed to high-voltage current developed neurogenic pulmonary edema and was successfully managed. Though there is no specific protocol for electrical injury but identifying the organs involved along with type of disease facilitates the management. HOW TO CITE THIS ARTICLE: Chawla G, Dutt N, Ramniwas, Chauhan NK, Sharma V. A Rare Case of Neurogenic Pulmonary Edema Following High-voltage Electrical Injury. Indian J Crit Care Med 2019;23(10):486-488.

A Rare Case of Neurogenic Pulmonary Edema Following High-voltage Electrical Injury.

Electrical injuries though infrequent, are potentially devastating form of injuries which are associated with high morbidity and mortality. The severity of the injury depends upon intensity of the electrical current which is determined by the voltage and the resistance offered by the victim. These injuries vary from trivial burns to death. There have been few reports about pulmonary injuries due to electrical current but none mentioning neurogenic pulmonary edema (NPE). Here we report a young boy who when exposed to high voltage current developed neurogenic pulmonary edema and was successfully managed. Though there is no specific protocol for electrical injury but identifying the organs involved along with type of disease facilitates the management. HOW TO CITE THIS ARTICLE: Chawla G, Dutt N, Ramniwas, Chauhan N, Sharma V. A Rare Case of Neurogenic Pulmonary Edema Following High-voltage Electrical Injury. Indian J Crit Care Med 2019;23(8):384-386.

Heat stress modulated gastrointestinal barrier dysfunction: role of tight junctions and heat shock proteins.

Increased environmental temperature exerts a visible impact on an individual's physiology. At the onset of heat stress, there is an increase in core body temperature which triggers peripheral vasodilation and sweating in an effort to dissipate the elevated body heat. The increase in peripheral circulation however reduces blood flow to the internal organs which are thus adversely affected. In particular, the gastrointestinal (GI) tract gets adversely affected during hyperthermia resulting in loosening of the tight junctions (TJs) that finally leads to higher intestinal permeability. At the cellular level, elevated levels of heat shock proteins (HSPs) induced in response to heat stress mediated cytoprotection by maintaining proper protein folding, releasing survival signals and preserving cytoskeleton integrity. Recent studies have indicated that HSPs play a crucial role in maintaining the localization of TJ proteins. Dietary supplements have also shown to have a positive effect on the maintenance of intestinal TJs. Therefore, it becomes imperative to understand the cellular, molecular and physiological alterations in response to heat stress in GI tract. In the present report, the effect of thermal stress on GI tract has been summarized. Specific role of HSPs along with mitogen activated protein (MAP) kinase signaling pathway in response to hyperthermia has also been discussed.

Effect of Laser Therapy on Postoperative Pain and Endodontic Retreatment: A Systematic Review and Meta-Analysis.

BACKGROUND: Root canal re-treatment (RCR) cases are considered some of the most challenging cases in the field of endodontics, as they are mostly associated with various iatrogenic errors such as ledge formation, incomplete biomechanical preparation, file separation, and incomplete obturation. These iatrogenic errors lead to defective niches within root canals that may act as reservoirs for various viable microorganisms. Such residual microbial niches may cause postoperative pain even after thorough debridement and reshaping the canals, ultimately leading to a poor prognosis for the tooth. Nowadays, prevention of postoperative pain in re-treatment cases and prognosis are effectively managed by photobiomodulation therapy (PBMT). METHOD: Relevant studies in the English language published before November 2022 were identified using electronic databases like PubMed, SCOPUS, and EBSCO to conduct bibliographic research. This systematic review is based on 3 studies that were found eligible as per the inclusion and exclusion criteria. This systematic review is in accordance with PRISMA guidelines. RESULTS: The systematic review indicated a positive impact by significantly decreasing postoperative pain in RCR cases when treated with PBMT. The variation was statistically significant at 24 hours (P = .0002), 48 hours (P = .03), and 72 hours (P = .02). The mean difference at 24 hours was 0.65 (95% CI, 0.32-0.99), at 48 hours was 0.46 (95% CI, 0.05-0.87), and at 72 hours was 0.40 (95% CI, 0.07-0.74). There was no statistical heterogenicity at 24 hours (P > .05), but a medium heterogenicity was observed at 48 hours and 72 hours. PRACTICAL IMPLICATION: PBMT or low-level laser therapy has shown superior results as compared to the conventional pharmacologic approach in postoperative pain management in RCR cases.