Helicobacter pylori infection in infant rhesus macaque monkeys is associated with an altered lung and oral microbiome.

It is estimated that more than half of the world population has been infected with Helicobacter pylori. Most newly acquired H. pylori infections occur in children before 10 years of age. We hypothesized that early life H. pylori infection could influence the composition of the microbiome at mucosal sites distant to the stomach. To test this hypothesis, we utilized the infant rhesus macaque monkey as an animal model of natural H. pylori colonization to determine the impact of infection on the lung and oral microbiome during a window of postnatal development. From a cohort of 4-7 month-old monkeys, gastric biopsy cultures identified 44% of animals infected by H. pylori. 16S ribosomal RNA gene sequencing of lung washes and buccal swabs from animals showed distinct profiles for the lung and oral microbiome, independent of H. pylori infection. In order of relative abundance, the lung microbiome was dominated by the phyla Proteobacteria, Firmicutes, Bacteroidota, Fusobacteriota, Campilobacterota and Actinobacteriota while the oral microbiome was dominated by Proteobacteria, Firmicutes, Bacteroidota, and Fusobacteriota. In comparison to the oral cavity, the lung was composed of more genera and species that significantly differed by H. pylori status, with a total of 6 genera and species that were increased in H. pylori negative infant monkey lungs. Lung, but not plasma IL-8 concentration was also associated with gastric H. pylori load and lung microbial composition. We found the infant rhesus macaque monkey lung harbors a microbiome signature that is distinct from that of the oral cavity during postnatal development. Gastric H. pylori colonization and IL-8 protein were linked to the composition of microbial communities in the lung and oral cavity. Collectively, these findings provide insight into how H. pylori infection might contribute to the gut-lung axis during early childhood and modulate future respiratory health.

Implementation of a Novel Prehospital Clinical Decision Tool and ECG Transmission for STEMI Significantly Reduces Door-to-Balloon Time and Sex-Based Disparities.

BACKGROUND: An important method employed to reduce door to balloon time (DTBT) for ST segment elevation Myocardial Infarctions (STEMIs) is a prehospital MI alert. The purpose of this retrospective study was to examine the effects of an educational intervention using a novel decision support method of STEMI notification and prehospital electrocardiogram (ECG) transmission on DTBT. METHODS: An ongoing database (April 4, 2000 - present) is maintained to track STEMI alerts. In 2007, an MI alert program began; emergency medicine physicians could activate a "prehospital MI alert". In October 2015, modems were purchased for Emergency Medical Services personnel to transmit ECGs. There was concurrent implementation of a decision support tool for identifying STEMI. Sex was assigned as indicated in the medical record. Data were analyzed in two groups: Pre-2016 (PRE) and 2016-2022 (POST). RESULTS: In total, 3,153 patients (1,301 PRE; 1,852 POST) were assessed; the average age was 65.2 years, 32.6% female, 87.7% white with significant differences in age and race between the two cohorts. Of the total 3,153 MI alerts, 239 were false activations, leaving 2,914 for analysis. 2,115 (72.6%) had cardiac catheterization while 16 (6.7%) of the 239 had a cardiac catheterization. There was an overall decrease in DTBT of 27.5% PRE to POST of prehospital ECG transmission (p < 0.001); PRE median time was 74.5 min vs. 55 min POST. There was no significant difference between rates of cardiac catheterization PRE and POST for all patients. After accounting for age, race, and mode of arrival, DTBT was 12.2% longer in women, as compared to men (p < 0.001) PRE vs. POST. DTBT among women was significantly shorter when comparing PRE to POST periods (median 77 min vs. 60 min; p = 0.0001). There was no significant sex difference in the proportion of those with cardiac catheterization between the two cohorts (62.5% vs. 63.5%; p = 0.73). CONCLUSION: Introduction of a decision support tool with prehospital ECG transmission with prehospital ECG transmission decreased overall DTBT by 20 min (27.5%). Women in the study had a 17-minute decrease in DTBT (22%), but their DTBT remained 12.2% longer than men for reasons that remain unclear.

The Impact of Coronary Artery Disease on Outcomes in Patients With Peripartum Cardiomyopathy.

Introduction The purpose of this study was to determine the prevalence of coronary artery disease (CAD) among patients admitted with peripartum cardiomyopathy (PPCM) as well as to analyze the independent association of CAD with in-hospital outcomes among PPCM patients. Methods Data were obtained from the National Inpatient Sample from January 2016 to December 2019. We assessed the independent association of CAD with outcomes in patients admitted with PPCM. Predictors of mortality in patients admitted with PPCM were also analyzed. Results There was a total of 4,730 patients with PPCM, 146 of whom had CAD (3.1%). Multivariate analysis demonstrated that CAD in patients with PPCM was independently associated with several outcomes, and, among them, ST-segment elevation myocardial infarction (STEMI) (adjusted odds ratio (aOR): 58.457, 95% CI: 5.403-632.504, p= 0.001) was positively associated with CAD. CAD was found to be protective against preeclampsia (aOR: 0.351, 95% CI: 0.126-0.979, p = 0.045). Predictors of in-hospital mortality for patients with PPCM include cardiogenic shock (aOR: 12.818, 95% CI: 7.332-22.411, p = 0.001), non-ST elevation myocardial infarction (NSTEMI) (OR: 3.429, 95% CI: 1.43-8.22, p = 0.006), chronic kidney disease (OR: 2.851, 95% CI: 1.495-5.435, p = 0.001), and atrial fibrillation (OR: 2.326, 95% CI: 1.145-4.723, p = 0.020). Conclusion In a large cohort of patients admitted with PPCM, we found the prevalence of CAD to be 3.1%. CAD was associated with several adverse outcomes, including STEMI, but protective against preeclampsia.

Alzheimer's disease-related presenilins are key to intestinal epithelial cell function and gut immune homoeostasis.

OBJECTIVE: Mutations in presenilin genes are the major cause of Alzheimer's disease. However, little is known about their expression and function in the gut. In this study, we identify the presenilins Psen1 and Psen2 as key molecules that maintain intestinal homoeostasis. DESIGN: Human inflammatory bowel disease (IBD) and control samples were analysed for Psen1 expression. Newly generated intestinal epithelium-specific Psen1-deficient, Psen2-deficient and inducible Psen1/Psen2 double-deficient mice were used to dissect the functional role of presenilins in intestinal homoeostasis. RESULTS: Psen1 expression was regulated in experimental gut inflammation and in patients with IBD. Induced deletion of Psen1 and Psen2 in mice caused rapid weight loss and spontaneous development of intestinal inflammation. Mice exhibited epithelial barrier disruption with bacterial translocation and deregulation of key pathways for nutrient uptake. Wasting disease was independent of gut inflammation and dysbiosis, as depletion of microbiota rescued Psen-deficient animals from spontaneous colitis development but not from weight loss. On a molecular level, intestinal epithelial cells lacking Psen showed impaired Notch signalling and dysregulated epithelial differentiation. CONCLUSION: Overall, our study provides evidence that Psen1 and Psen2 are important guardians of intestinal homoeostasis and future targets for barrier-promoting therapeutic strategies in IBD.

Early Detection of Myeloid-Derived Suppressor Cells in the Lung Pre-Metastatic Niche by Shortwave Infrared Nanoprobes.

Metastatic breast cancer remains a significant source of mortality amongst breast cancer patients and is generally considered incurable in part due to the difficulty in detection of early micro-metastases. The pre-metastatic niche (PMN) is a tissue microenvironment that has undergone changes to support the colonization and growth of circulating tumor cells, a key component of which is the myeloid-derived suppressor cell (MDSC). Therefore, the MDSC has been identified as a potential biomarker for PMN formation, the detection of which would enable clinicians to proactively treat metastases. However, there is currently no technology capable of the in situ detection of MDSCs available in the clinic. Here, we propose the use of shortwave infrared-emitting nanoprobes for the tracking of MDSCs and identification of the PMN. Our rare-earth albumin nanocomposites (ReANCs) are engineered to bind the Gr-1 surface marker of murine MDSCs. When delivered intravenously in murine models of breast cancer with high rates of metastasis, the targeted ReANCs demonstrated an increase in localization to the lungs in comparison to control ReANCs. However, no difference was seen in the model with slower rates of metastasis. This highlights the potential utility of MDSC-targeted nanoprobes to assess PMN development and prognosticate disease progression.

Effect of Co-Reactants on Interfacial Oxidation in Atomic Layer Deposition of Oxides on Metal Surfaces.

We have examined the atomic layer deposition (ALD) of Al2O3 using TMA as the precursor and t-BuOH and H2O as the co-reactants, focusing on the effects of the latter on both the ALD process and the possible modification of the underlying substrate. We employed a quartz crystal microbalance (QCM) to monitor ALD in situ and in real time, and the deposited thin films have been characterized using X-ray photoelectron spectroscopy, spectroscopic ellipsometry, X-ray reflectivity, and atomic force microscopy. Growth of thin films of Al2O3 using TMA and either t-BuOH or H2O as the co-reactant at T = 285 °C produces thin films of similar physical properties (density, stoichiometry, minimal carbon incorporation), and the growth rate per cycle is similar for the two co-reactants at this temperature. At a lower temperature of T = 120 °C, the behavior is starkly different, where growth occurs with H2O but not with t-BuOH. At either process temperature, we find no evidence for significant coverages of a long-lived tert-butoxy species from the reaction of t-BuOH. Deposition of thin films of Al2O3 on metal surfaces of Cu and Co has been examined for evidence of interfacial oxidation. While growth with either co-reactant does not lead to the oxidation of the underlying Cu substrate, use of H2O leads to the oxidation of Co, but use of t-BuOH as the co-reactant does not. Thermodynamic factors may affect the early stages of growth, as Al species will likely scavenge all free O species. In contrast, at later times, diffusion of species through the deposited Al2O3 thin film could result in oxidation at the Al2O3|metal interface, a process that is strongly hindered in the case of t-BuOH due to its size. This observation highlights the importance of the choice of the co-reactant concerning ALD of oxides on metal surfaces.

Myenteric Plexus Immune Cell Infiltrations and Neurotransmitter Expression in Crohn's Disease and Ulcerative Colitis.

BACKGROUND AND AIMS: Pain is a cardinal symptom in inflammatory bowel disease [IBD]. An important structure in the transduction of pain signalling is the myenteric plexus [MP]. Nevertheless, IBD-associated infiltration of the MP by immune cells lacks in-depth characterisation. Herein, we decipher intra- and periganglionic immune cell infiltrations in Crohn´s disease [CD] and ulcerative colitis [UC] and provide a comparison with murine models of colitis. METHODS: Full wall specimens of surgical colon resections served to examine immune cell populations by either conventional immuno-histochemistry or immunofluorescence followed by either bright field or confocal microscopy. Results were compared with equivalent examinations in various murine models of intestinal inflammation. RESULTS: Whereas the MP morphology was not significantly altered in IBD, we identified intraganglionic IBD-specific B cell- and monocyte-dominant cell infiltrations in CD. In contrast, UC-MPs were infiltrated by CD8+ T cells and revealed a higher extent of ganglionic cell apoptosis. With regard to the murine models of intestinal inflammation, the chronic dextran sulphate sodium [DSS]-induced colitis model reflected CD [and to a lesser extent UC] best, as it also showed increased monocytic infiltration as well as a modest B cell and CD8+ T cell infiltration. CONCLUSIONS: In CD, MPs were infiltrated by B cells and monocytes. In UC, mostly CD8+ cytotoxic T cells were found. The chronic DSS-induced colitis in the mouse model reflected best the MP-immune cell infiltrations representative for IBD.

Guardians of the gut: influence of the enteric nervous system on the intestinal epithelial barrier.

The intestinal mucosal surface forms one of the largest areas of the body, which is in direct contact with the environment. Co-ordinated sensory functions of immune, epithelial, and neuronal cells ensure the timely detection of noxious queues and potential pathogens and elicit proportional responses to mitigate the threats and maintain homeostasis. Such tuning and maintenance of the epithelial barrier is constantly ongoing during homeostasis and its derangement can become a gateway for systemic consequences. Although efforts in understanding the gatekeeping functions of immune cells have led the way, increasing number of studies point to a crucial role of the enteric nervous system in fine-tuning and maintaining this delicate homeostasis. The identification of immune regulatory functions of enteric neuropeptides and glial-derived factors is still in its infancy, but has already yielded several intriguing insights into their important contribution to the tight control of the mucosal barrier. In this review, we will first introduce the reader to the current understanding of the architecture of the enteric nervous system and the epithelial barrier. Next, we discuss the key discoveries and cellular pathways and mediators that have emerged as links between the enteric nervous, immune, and epithelial systems and how their coordinated actions defend against intestinal infectious and inflammatory diseases. Through this review, the readers will gain a sound understanding of the current neuro-immune-epithelial mechanisms ensuring intestinal barrier integrity and maintenance of intestinal homeostasis.

Helicobacter pylori Infection in Infant Rhesus Macaque Monkeys is Associated with an Altered Lung and Oral Microbiome.

Background: It is estimated that more than half of the world population has been infected with Helicobacter pylori. Most newly acquired H. pylori infections occur in children before 10 years of age. We hypothesized that early life H. pylori infection could influence the composition of the microbiome at mucosal sites distant to the stomach. To test this hypothesis, we utilized the infant rhesus macaque monkey as an animal model of natural H. pylori colonization to determine the impact of infection on the lung and oral microbiome during a window of postnatal development. Results: From a cohort of 4-7-month-old monkeys, gastric biopsy cultures identified 44% of animals infected by H. pylori. 16S ribosomal RNA gene sequencing of lung washes and buccal swabs from animals showed distinct profiles for the lung and oral microbiome, independent of H. pylori infection. In relative order of abundance, the lung microbiome was dominated by the phyla Proteobacteria, Firmicutes, Bacteroidota, Fusobacteriota, Campilobacterota and Actinobacteriota while the oral microbiome was dominated by Proteobacteria, Firmicutes, Bacteroidota, and Fusobacteriota. Relative to the oral cavity, the lung was composed of more genera and species that significantly differed by H. pylori status, with a total of 6 genera and species that were increased in H. pylori negative infant monkey lungs. Lung, but not plasma IL-8 concentration was also associated with gastric H. pylori load and lung microbial composition. Conclusions: We found the infant rhesus macaque monkey lung harbors a microbiome signature that is distinct from that of the oral cavity during postnatal development. Gastric H. pylori colonization and IL-8 protein were linked to the composition of microbial communities in the lung and oral cavity. Collectively, these findings provide insight into how H. pylori infection might contribute to the gut-lung axis during early childhood and modulate future respiratory health.

The Immunolocalization of Mast Cells in the Pathology of Oral Submucous Fibrosis.

Background Oral submucous fibrosis (OSMF) is a prevalent precancerous condition of the oral cavity and an ambiguity to clinicians because of its indistinguishable etiopathogenesis. Previous studies could not establish a definite role of mast cells (MCs) in the fibrosis of stroma. The present study was done to study the histopathological changes in OSMF and to determine the association of mast cells (MCs) and their degranulated components with vascularity. Methods A retrospective case-control study involved 40 cases of various histopathological grades of OSMF and was compared with 10 cases of normal buccal mucosa by using a cluster of differentiation 117 (CD117) kit for the identification of MCs and Masson's trichrome stain to study the number of blood vessels (BVs). Results The present study indicated that advanced cases of OSMF had keratinized epithelium with atrophic changes and moderate to advanced fibrosis of stroma with the involvement of underlying muscles. The MC density and the number of blood vessels were progressively reduced in OSMF as the grade advanced compared to healthy controls. Conclusion An increase in the mast cell density in the initial stages of OSMF suggests their definite role in the initiation of fibrosis and secondary changes to the epithelium such as atrophy.

Vaccination with Helicobacter pylori attachment proteins protects against gastric cancer.

Most cases of gastric cancer are caused by chronic Helicobacter pylori infection, but the lack of early onco-diagnostics and a high risk for antibiotic resistance hampers early intervention through eradication of H. pylori infection by antibiotics. We reported on a protective mechanism where H. pylori gastric mucosal attachment can be reduced by natural antibodies that block the binding of its attachment protein BabA. Here we show that challenge infection with H. pylori induced response of such blocking antibodies in both human volunteers and in rhesus macaques, that mucosal vaccination with BabA protein antigen induced blocking antibodies in rhesus macaques, and that vaccination in a mouse model induced blocking antibodies that reduced gastric mucosal inflammation, preserved the gastric juice acidity, and fully protected the mice from gastric cancer caused by H. pylori.

Breaking bad: necroptosis in the pathogenesis of gastrointestinal diseases.

A delicate balance between programmed cell death and proliferation of intestinal epithelial cells (IEC) exists in the gut to maintain homeostasis. Homeostatic cell death programs such as anoikis and apoptosis ensure the replacement of dead epithelia without overt immune activation. In infectious and chronic inflammatory diseases of the gut, this balance is invariably disturbed by increased levels of pathologic cell death. Pathological forms of cell death such as necroptosis trigger immune activation barrier dysfunction, and perpetuation of inflammation. A leaky and inflamed gut can thus become a cause of persistent low-grade inflammation and cell death in other organs of the gastrointestinal (GI) tract, such as the liver and the pancreas. In this review, we focus on the advances in the molecular and cellular understanding of programmed necrosis (necroptosis) in tissues of the GI tract. In this review, we will first introduce the reader to the basic molecular aspects of the necroptosis machinery and discuss the pathways leading to necroptosis in the GI system. We then highlight the clinical significance of the preclinical findings and finally evaluate the different therapeutic approaches that attempt to target necroptosis against various GI diseases. Finally, we review the recent advances in understanding the biological functions of the molecules involved in necroptosis and the potential side effects that may occur due to their systemic inhibition. This review is intended to introduce the reader to the core concepts of pathological necroptotic cell death, the signaling pathways involved, its immuno-pathological implications, and its relevance to GI diseases. Further advances in our ability to control the extent of pathological necroptosis will provide better therapeutic opportunities against currently intractable GI and other diseases.

Proteolytic Activity of the Paracaspase MALT1 Is Involved in Epithelial Restitution and Mucosal Healing.

The paracaspase MALT1 is a crucial regulator of immune responses in various cellular contexts. Recently, there is increasing evidence suggesting that MALT1 might represent a novel key player in mucosal inflammation. However, the molecular mechanisms underlying this process and the targeted cell population remain unclear. In this study, we investigate the role of MALT1 proteolytic activity in the context of mucosal inflammation. We demonstrate a significant enrichment of MALT1 gene and protein expression in colonic epithelial cells of UC patients, as well as in the context of experimental colitis. Mechanistically we demonstrate that MALT1 protease function inhibits ferroptosis, a form of iron-dependent cell death, upstream of NF-κB signaling, which can promote inflammation and tissue damage in IBD. We further show that MALT1 activity contributes to STAT3 signaling, which is essential for the regeneration of the intestinal epithelium after injury. In summary, our data strongly suggests that the protease function of MALT1 plays a critical role in the regulation of immune and inflammatory responses, as well as mucosal healing. Understanding the mechanisms by which MALT1 protease function regulates these processes may offer novel therapeutic targets for the treatment of IBD and other inflammatory diseases.

Pruritogens in pemphigoid diseases: Possible therapeutic targets for a burdensome symptom.

Pruritus is a hallmark feature in pemphigoid diseases, where it can be severe and greatly impact the quality of life of affected patients. Despite being a key symptom, the exact pathophysiological mechanisms involved in pruritus in pemphigoid are yet to be fully elucidated and effective therapies addressing them are limited. This review summarizes the present understanding of pruritus specific to pemphigoid diseases, especially the pruritogens that induce it, and the therapeutic options that have been explored so far. The majority of the available evidence is on bullous pemphigoid and epidermolysis bullosa acquisita. Histamine derived from basophils correlates with pruritus severity, with omalizumab demonstrating promising efficacy in pruritus for bullous pemphigoid. IL-4/-13 contribute to itch in bullous pemphigoid with dupilumab being evaluated in clinical trials. Other pruritogens of interest include substance P, tryptase, and thymic stromal lymphopoetin, with therapies targeting them requiring further investigation. Scratching behaviors contribute directly to blister formation through various mechanisms, such as pathological autoantibody recruitment, T helper cell type 1 polarization, and exposure of intracellular autoantigens. Treatments addressing these pathways may contribute to decreasing disease severity. Additional studies are needed to fully characterize how pruritus is regulated in pemphigoid diseases, to help pave the way to develop novel and effective therapeutics that will not only address pruritic symptoms but also decrease disease severity.

Epithelial presenilin-1 drives colorectal tumour growth by controlling EGFR-COX2 signalling.

OBJECTIVE: Psen1 was previously characterised as a crucial factor in the pathogenesis of neurodegeneration in patients with Alzheimer's disease. Little, if any, is known about its function in the gut. Here, we uncovered an unexpected functional role of Psen1 in gut epithelial cells during intestinal tumourigenesis. DESIGN: Human colorectal cancer (CRC) and control samples were investigated for PSEN1 and proteins of theγ-secretase complex. Tumour formation was analysed in the AOM-DSS and Apc min/+ mouse models using newly generated epithelial-specific Psen1 deficient mice. Psen1 deficient human CRC cells were studied in a xenograft tumour model. Tumour-derived organoids were analysed for growth and RNA-Seq was performed to identify Psen1-regulated pathways. Tumouroids were generated to study EGFR activation and evaluation of the influence of prostanoids. RESULTS: PSEN1 is expressed in the intestinal epithelium and its level is increased in human CRC. Psen1-deficient mice developed only small tumours and human cancer cell lines deficient in Psen1 had a reduced tumourigenicity. Tumouroids derived from Psen1-deficient Apc min/+ mice exhibited stunted growth and reduced cell proliferation. On a molecular level, PSEN1 potentiated tumour cell proliferation via enhanced EGFR signalling and COX-2 production. Exogenous administration of PGE2 reversed the slow growth of PSEN1 deficient tumour cells via PGE2 receptor 4 (EP4) receptor signalling. CONCLUSIONS: Psen1 drives tumour development by increasing EGFR signalling via NOTCH1 processing, and by activating the COX-2-PGE2 pathway. PSEN1 inhibition could be a useful strategy in treatment of CRC.

The Role of Programmed Necrosis in Colorectal Cancer.

For quite a long time, necrosis was considered a chaotic and unorganized form of cell death. However, studies conducted during the past few decades unveiled multiple types of programmed necrosis, such as necroptosis, pyroptosis and ferroptosis. These types of programmed necrosis have been shown to play crucial roles in mediating pathological processes, including tumorigenesis. Almost all key mediators, such as RIPK3 and MLKL in necroptosis, GSDMD and caspase 1/11 in pyroptosis and GPX4 in ferroptosis, are highly expressed in intestinal epithelial cells (IECs). An aberrant increase or decrease in programmed necrosis in IECs has been connected to intestinal disorders. Here, we review the pathways of programmed necrosis and the specific consequences of regulated necrosis in colorectal cancer (CRC) development. Translational aspects of programmed necrosis induction as a novel therapeutic alternative against CRC are also discussed.

Smart soft contact lenses for continuous 24-hour monitoring of intraocular pressure in glaucoma care.

Continuous monitoring of intraocular pressure, particularly during sleep, remains a grand challenge in glaucoma care. Here we introduce a class of smart soft contact lenses, enabling the continuous 24-hour monitoring of intraocular pressure, even during sleep. Uniquely, the smart soft contact lenses are built upon various commercial brands of soft contact lenses without altering their intrinsic properties such as lens power, biocompatibility, softness, transparency, wettability, oxygen transmissibility, and overnight wearability. We show that the smart soft contact lenses can seamlessly fit across different corneal curvatures and thicknesses in human eyes and therefore accurately measure absolute intraocular pressure under ambulatory conditions. We perform a comprehensive set of in vivo evaluations in rabbit, dog, and human eyes from normal to hypertension to confirm the superior measurement accuracy, within-subject repeatability, and user comfort of the smart soft contact lenses beyond current wearable ocular tonometers. We envision that the smart soft contact lenses will be effective in glaucoma care.