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BACKGROUND & AIMS: Although T-cell intrinsic expression of G9a has been associated with murine intestinal inflammation, mechanistic insight into the role of this methyltransferase in human T-cell differentiation is ill defined, and manipulation of G9a function for therapeutic use against inflammatory disorders is unexplored. METHODS: Human naive T cells were isolated from peripheral blood and differentiated in vitro in the presence of a G9a inhibitor (UNC0642) before being characterized via the transcriptome (RNA sequencing), chromatin accessibility (assay for transposase-accessible chromatin by sequencing), protein expression (cytometry by time of flight, flow cytometry), metabolism (mitochondrial stress test, ultrahigh performance liquid chromatography-tandem mas spectroscopy) and function (T-cell suppression assay). The in vivo role of G9a was assessed using 3 murine models. RESULTS: We discovered that pharmacologic inhibition of G9a enzymatic function in human CD4 T cells led to spontaneous generation of FOXP3+ T cells (G9a-inibitors-T regulatory cells [Tregs]) in vitro that faithfully reproduce human Tregs, functionally and phenotypically. Mechanistically, G9a inhibition altered the transcriptional regulation of genes involved in lipid biosynthesis in T cells, resulting in increased intracellular cholesterol. Metabolomic profiling of G9a-inibitors-Tregs confirmed elevated lipid pathways that support Treg development through oxidative phosphorylation and enhanced lipid membrane composition. Pharmacologic G9a inhibition promoted Treg expansion in vivo upon antigen (gliadin) stimulation and ameliorated acute trinitrobenzene sulfonic acid-induced colitis secondary to tissue-specific Treg development. Finally, Tregs lacking G9a expression (G9a-knockout Tregs) remain functional chronically and can rescue T-cell transfer-induced colitis. CONCLUSION: G9a inhibition promotes cholesterol metabolism in T cells, favoring a metabolic profile that facilitates Treg development in vitro and in vivo. Our data support the potential use of G9a inhibitors in the treatment of immune-mediated conditions including inflammatory bowel disease.
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Linfócitos T CD4-Positivos , Colite , Camundongos , Humanos , Animais , Metabolismo dos Lipídeos , Linfócitos T Reguladores/metabolismo , Colite/induzido quimicamente , Colite/tratamento farmacológico , Colite/genética , Cromatina , Inflamação , Colesterol , Lipídeos , Fatores de Transcrição Forkhead/metabolismoRESUMO
The etiology of inflammatory bowel disease (IBD) has yet to be fully understood; however, it is thought to be a result of genetic, immunologic, and environmental factors, including changes in the gut microbiome.1,2 Immune checkpoint inhibitors (ICI) have revolutionized treatment of advanced cancer. They activate the immune system by promoting cytotoxic T-cell survival and antitumor effects. A total of 7 ICIs currently are approved by the United States Food and Drug Administration, and target cytotoxic T lymphocyte-associated protein 4 (ipilimumab); anti-programmed cell death 1 (PD-1) (nivolumab, pembrolizumab, and cemiplimab), or anti-PD-ligand 1 (atezolizumab, durvalumab, and avelumab). However, by activating the immune system, these medications also can lead to off-target inflammation and autoimmunity, including ICI-induced colitis, which has been reported in up to 13.6% of patients.3.
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Inibidores de Checkpoint Imunológico , Doenças Inflamatórias Intestinais , Humanos , Doenças Inflamatórias Intestinais/tratamento farmacológico , Ipilimumab , Nivolumabe/efeitos adversos , Estudos RetrospectivosAssuntos
COVID-19/diagnóstico , Icterícia/etiologia , Fígado/patologia , Síndrome de Resposta Inflamatória Sistêmica/diagnóstico , Medula Óssea/patologia , Proteína C-Reativa/análise , COVID-19/complicações , Colestase/diagnóstico , Diagnóstico Diferencial , Humanos , Masculino , Pessoa de Meia-Idade , Prurido/etiologia , Síndrome de Resposta Inflamatória Sistêmica/complicaçõesRESUMO
BACKGROUND: It has been suggested that distal gastric carcinoma (GC) in younger patients has a more aggressive outcome than in older patients, however this is a controversial issue. The aim of this study was to compare clinicopathological features between younger and older patients with GC in Northeastern Brazil. METHODS: A total of 207 patients with distal GC (41 patients ≤45 years, considered younger group, and 166 > 45 years, considered older group) were evaluated prospectively during a 6 year period. RESULTS: The mean patient age in the young group was 37.41 years old and 64.43 years in the older group. No significant difference was found regarding gender, area of residence, history of alcohol consumption, chronic tobacco smoking. Prevalence of first-degree GC history was 12.5% (7.3% in younger group vs. 13.9% in older; p < 0.46). The most frequent symptom was gastric pain and weight loss. Diffuse infiltrative cancer was more frequently seen in younger patients (70.70% vs. 33.70%, respectively; p < 0.01), as was histologically less differentiated tumors (63.40% vs. 33.10%; p < 0.01) and stage IV of GC (48.80% vs. 30.70%; p < 0.015). Five-year survival, evaluated in 82 patients, was lower in younger patients (p = 0.045); however, after adjusting for stage of GC in the multivariate analysis, this association did not remain significant. Family history of GC and gender had no impact on survival. CONCLUSIONS: Younger patients showed higher prevalence of diffuse type of Lauren and lower survival that was attributed to higher rate of advanced stage of GC. Gastric cancer screening strategies should also be considered in younger individuals, especially in areas of high prevalence. Further studies are warranted to determine risk factors associated with gastric cancer in young adults.
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Medição de Risco/métodos , Medição de Risco/estatística & dados numéricos , Neoplasias Gástricas/patologia , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Brasil , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Estudos Prospectivos , Fatores de Risco , Análise de Sobrevida , Adulto JovemRESUMO
BACKGROUND: Clostridium difficile is an anaerobic bacterium that causes antibiotic-associated diarrhea. It produces toxin A and toxin B (TcdB), which cause injury to the gut epithelium. Glutamine is a fundamental fuel for enterocytes, maintaining intestinal mucosal health. Alanyl-glutamine (AQ) is a highly soluble dipeptide derivative of glutamine. We studied whether administration of AQ ameliorates the effects of TcdB in the intestinal cells and improves the outcome of C. difficile infection in mice. METHODS: WST-1 proliferation and cell-wounding-migration assays were assessed in IEC-6 cells exposed to TcdB, with or without AQ. Apoptosis and necrosis were assessed using Annexin V and flow cytometry. C57BL/6 mice were infected with VPI 10463 and treated with either vancomycin, AQ, or vancomycin with AQ. Intestinal tissues were collected for histopathologic analysis, apoptosis staining, and determination of myeloperoxidase activity. RESULTS: AQ increased proliferation in intestinal cells exposed to TcdB, improved migration at 24 and 48 hours, and reduced apoptosis in intestinal cells challenged with TcdB. Infected mice treated with vancomycin and AQ had better survival and histopathologic findings than mice treated with vancomycin alone. CONCLUSIONS: AQ may reduce intestinal mucosal injury in C. difficile-infected mice by partially reversing the effects of TcdB on enterocyte proliferation, migration, and apoptosis, thereby improving survival from C. difficile infection.
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Proteínas de Bactérias/genética , Toxinas Bacterianas/genética , Clostridioides difficile/efeitos dos fármacos , Dipeptídeos/farmacologia , Enterócitos/efeitos dos fármacos , Mucosa Intestinal/microbiologia , Animais , Apoptose/efeitos dos fármacos , Proteínas de Bactérias/metabolismo , Toxinas Bacterianas/metabolismo , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Clostridioides difficile/crescimento & desenvolvimento , Infecções por Clostridium/tratamento farmacológico , Infecções por Clostridium/microbiologia , Modelos Animais de Doenças , Enterócitos/metabolismo , Enterócitos/microbiologia , Mucosa Intestinal/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Necrose/tratamento farmacológico , Necrose/patologia , Ratos , Vancomicina/farmacologiaRESUMO
The integrity and permeability of epithelial and endothelial barriers depend on the formation of tight junctions, adherens junctions, and a junction-associated cytoskeleton. The establishment of this junction-cytoskeletal module relies on the correct folding and oligomerization of its protein components. Molecular chaperones are known regulators of protein folding and complex formation in different cellular compartments. Mammalian cells possess an elaborate chaperone network consisting of several hundred chaperones and co-chaperones. Only a small part of this network has been linked, however, to the regulation of intercellular adhesions, and the systematic analysis of chaperone functions at epithelial and endothelial barriers is lacking. This review describes the functions and mechanisms of the chaperone-assisted regulation of intercellular junctions. The major focus of this review is on heat shock protein chaperones, their co-chaperones, and chaperonins since these molecules are the focus of the majority of the articles published on the chaperone-mediated control of tissue barriers. This review discusses the roles of chaperones in the regulation of the steady-state integrity of epithelial and vascular barriers as well as the disruption of these barriers by pathogenic factors and extracellular stressors. Since cytoskeletal coupling is essential for junctional integrity and remodeling, chaperone-assisted assembly of the actomyosin cytoskeleton is also discussed.
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Citoesqueleto , Junções Intercelulares , Animais , Citoesqueleto/metabolismo , Junções Intercelulares/metabolismo , Citoesqueleto de Actina/metabolismo , Actomiosina/metabolismo , Chaperonas Moleculares/metabolismo , Mamíferos/metabolismoRESUMO
Mosaic trisomy 14 is exceptionally rare and was first described in the 1970s with fewer than 100 known liveborn individuals. Information about complications and the natural history of the disease is rare, especially in adult patients. This case illustrates an adult patient with severe functional limitations from mosaic trisomy 14 who presented with abdominal pain and failure to thrive and was subsequently found to have intussusception and severe chronic constipation, which was successfully treated conservatively.
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Introduction: The aim of this case-control study was to determine if exposure to tumor necrosis factor alpha inhibitors (TNFIs) or immunomodulators (thiopurines or methotrexate) was associated with development of primary gastrointestinal lymphoma (PGIL) in patients with chronic inflammatory conditions. Methods: Patients with PGIL and controls evaluated at a tertiary care center over 20 years were matched 1:3 using a medical record informatics search engine based on their chronic inflammatory condition (Crohn's disease [CD], ulcerative colitis [UC], rheumatoid arthritis, ankylosing spondylitis, and psoriatic arthritis) and duration of follow-up. Patients who started on TNFI within 3 months of PGIL diagnosis were excluded. We extracted demographics, medical history, and medications used. Univariate models using conditional logistic regression were used due to the small number of matched pairs. Results: Twenty PGIL cases matched with 60 controls were followed for a mean 9.9â ±â 6.9 and 9.7â ±â 8.6 years, respectively. Mean age at time of PGIL diagnosis was 47.5â ±â 22.0 (standard deviation) years and the majority (75%) were males. The most common inflammatory diagnosis was inflammatory bowel disease (80% of cases; 45% with UC and 35% with CD). Development of PGIL was not associated with TNFI (odds ratio [OR]â =â 2.6; 95% confidence interval [CI] 0.69-11.01; Pâ =â .18), but with use of TNFI in combination with thiopurines (ORâ =â 8.93; 95% CI 1.43-80.25; Pâ =â .014). Risk of PGIL increased with every additional TNFI (2.277 (1.002-5.713); Pâ =â .0494). All cases exposed to multiple TNFI were also exposed to thiopurines. Use of thiopurines (alone or in combination) was the greatest risk factor (ORâ =â 6.32; 95% CI 1.55-37.05; Pâ =â 0.006) to develop PGIL. Conclusions: TNFI therapy was not associated with increased risk for PGIL unless used in combination with thiopurines and with every switch to a different TNFI.
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BACKGROUND: Metabolic syndrome and diabetes in obese individuals are strong risk factors for development of inflammatory bowel disease (IBD) and colorectal cancer. The pathogenic mechanisms of low-grade metabolic inflammation, including chronic hyperglycemic stress, in disrupting gut homeostasis are poorly understood. In this study, we sought to understand the impact of a hyperglycemic environment on intestinal barrier integrity and the protective effects of small molecular weight (35 kDa) hyaluronan on epithelial barrier function. METHODS: Intestinal organoids derived from mouse colon were grown in normal glucose media (5 mM) or high glucose media (25 mM) to study the impact of hyperglycemic stress on the intestinal barrier. Additionally, organoids were pretreated with 35 kDa hyaluronan (HA35) to investigate the effect of hyaluronan on epithelial barrier under high glucose stress. Immunoblotting as well as confocal imaging was used to understand changes in barrier proteins, quantitative as well as spatial distribution, respectively. Alterations in barrier function were measured using trans-epithelial electrical resistance and fluorescein isothiocyanate flux assays. Untargeted proteomics analysis was performed to elucidate mechanisms by which HA35 exerts a protective effect on the barrier. Intestinal organoids derived from receptor knockout mice specific to various HA receptors were utilized to understand the role of HA receptors in barrier protection under high glucose conditions. RESULTS: We found that high glucose stress decreased the protein expression as well as spatial distribution of two key barrier proteins, zona occludens-1 (ZO-1) and occludin. HA35 prevented the degradation or loss of ZO-1 and maintained the spatial distribution of both ZO-1 and occludin under hyperglycemic stress. Functionally, we also observed a protective effect of HA35 on the epithelial barrier under high glucose conditions. We found that HA receptor, layilin, was involved in preventing barrier protein loss (ZO-1) as well as maintaining spatial distribution of ZO-1 and occludin. Additionally, proteomics analysis showed that cell death and survival was the primary pathway upregulated in organoids treated with HA35 under high glucose stress. We found that XIAP associated factor 1 (Xaf1) was modulated by HA35 thereby regulating apoptotic cell death in the intestinal organoid system. Finally, we observed that spatial organization of both focal adhesion kinase (FAK) as well as F-actin was mediated by HA35 via layilin. CONCLUSION: Our results highlight the impact of hyperglycemic stress on the intestinal barrier function. This is of clinical relevance, as impaired barrier function has been observed in individuals with metabolic syndrome. Additionally, we demonstrate barrier protective effects of HA35 through its receptor layilin and modulation of cellular apoptosis under high glucose stress.
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The accuracy of a nested PCR in gastric DNA obtained by a string test for the diagnosis of Helicobacter pylori infection in asymptomatic children was 94.0%. The cagA-positive toxigenic vacAs1m1 strains were the most prevalent strains, indicating that this population is colonized early by the strains associated with gastric cancer.
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Mucosa Gástrica/microbiologia , Infecções por Helicobacter/diagnóstico , Helicobacter pylori/genética , Helicobacter pylori/patogenicidade , Reação em Cadeia da Polimerase/métodos , Fatores de Virulência/genética , Adolescente , Antígenos de Bactérias/genética , Doenças Assintomáticas , Proteínas de Bactérias/genética , Brasil , Criança , Feminino , Infecções por Helicobacter/microbiologia , Helicobacter pylori/isolamento & purificação , Humanos , MasculinoRESUMO
Disruption of the intestinal epithelial barrier is a hallmark of mucosal inflammation. It increases exposure of the immune system to luminal microbes, triggering a perpetuating inflammatory response. For several decades, the inflammatory stimuli-induced breakdown of the human gut barrier was studied in vitro by using colon cancer derived epithelial cell lines. While providing a wealth of important data, these cell lines do not completely mimic the morphology and function of normal human intestinal epithelial cells (IEC) due to cancer-related chromosomal abnormalities and oncogenic mutations. The development of human intestinal organoids provided a physiologically-relevant experimental platform to study homeostatic regulation and disease-dependent dysfunctions of the intestinal epithelial barrier. There is need to align and integrate the emerging data obtained with intestinal organoids and classical studies that utilized colon cancer cell lines. This review discusses the utilization of human intestinal organoids to dissect the roles and mechanisms of gut barrier disruption during mucosal inflammation. We summarize available data generated with two major types of organoids derived from either intestinal crypts or induced pluripotent stem cells and compare them to the results of earlier studies with conventional cell lines. We identify research areas where the complementary use of colon cancer-derived cell lines and organoids advance our understanding of epithelial barrier dysfunctions in the inflamed gut and identify unique questions that could be addressed only by using the intestinal organoid platforms.
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Neoplasias do Colo , Mucosite , Humanos , Inflamação , Linhagem Celular , Células Epiteliais , OrganoidesRESUMO
BACKGROUND: Upadacitinib is a selective Janus kinase inhibitor approved for the management of ulcerative colitis and is under evaluation for the management of Crohn's disease [CD] in Phase 3 clinical trials. AIMS: Our goal was to describe our real-world experience with upadacitinib in CD. METHODS: This is a two-centre retrospective cohort study of adult patients with moderate to severe CD on upadacitinib. The primary outcome was clinical response and remission as determined by stool frequency and abdominal pain scores. Secondary endpoints included endoscopic response and remission as determined by change in Simple Endoscopic Score for CD. Outcomes were assessed at 3 months after starting upadacitinib and at the patient's most recent follow-up. We further evaluated adverse events and dose-related response. RESULTS: A total of 45 CD patients received upadacitinib and were included in the safety analysis. Thirty-six patients received upadacitinib for CD, whereas nine received it for inflammatory arthritis [nâ =â 8] or pyoderma [nâ =â 1]. Thirty-three patients received upadacitinib for 3 months or longer and were included in the efficacy analysis. At the 3-month follow-up, 21 patients achieved clinical response [63.6%] and nine achieved clinical remission [27.2%]. At time of last follow-up, 23 patients had clinical response [69.7%], ten achieved clinical remission [30.3%] and four [28.6%] achieved endoscopic remission. Adverse events occurred in 12 patients [26.7%]. Two patients had a serious adverse event [4.5%] without associated mortality. CONCLUSION: In this real-world cohort of highly refractory CD patients, upadacitinib was effective in inducing remission and had an acceptable safety profile.
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Doença de Crohn , Compostos Heterocíclicos com 3 Anéis , Inibidores de Janus Quinases , Doença de Crohn/tratamento farmacológico , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Inibidores de Janus Quinases/uso terapêutico , Estudos Retrospectivos , Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
BACKGROUND: The development of Crohn's disease [CD] involves immune cell signalling pathways regulated by epigenetic modifications. Aberrant DNA methylation has been identified in peripheral blood and bulk intestinal tissue from CD patients. However, the DNA methylome of disease-associated intestinal CD4+ lymphocytes has not been evaluated. MATERIALS AND METHODS: Genome-wide DNA methylation sequencing was performed from terminal ileum CD4+ cells from 21 CD patients and 12 age- and sex-matched controls. Data were analysed for differentially methylated CpGs [DMCs] and methylated regions [DMRs]. Integration was performed with RNA-sequencing data to evaluate the functional impact of DNA methylation changes on gene expression. DMRs were overlapped with regions of differentially open chromatin [by ATAC-seq] and CCCTC-binding factor [CTCF] binding sites [by ChIP-seq] between peripherally derived Th17 and Treg cells. RESULTS: CD4+ cells in CD patients had significantly increased DNA methylation compared to those from the controls. A total of 119 051 DMCs and 8113 DMRs were detected. While hypermethylated genes were mostly related to cell metabolism and homeostasis, hypomethylated genes were significantly enriched within the Th17 signalling pathway. The differentially enriched ATAC regions in Th17 cells [compared to Tregs] were hypomethylated in CD patients, suggesting heightened Th17 activity. There was significant overlap between hypomethylated DNA regions and CTCF-associated binding sites. CONCLUSIONS: The methylome of CD patients shows an overall dominant hypermethylation yet hypomethylation is more concentrated in proinflammatory pathways, including Th17 differentiation. Hypomethylation of Th17-related genes associated with areas of open chromatin and CTCF binding sites constitutes a hallmark of CD-associated intestinal CD4+ cells.
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Doença de Crohn , Metilação de DNA , Humanos , Doença de Crohn/genética , Doença de Crohn/metabolismo , Células Th17 , Linfócitos T CD4-Positivos/metabolismo , Cromatina/metabolismoRESUMO
BACKGROUND: Helicobacter pylori infection is acquired predominantly in childhood. There is also evidence that children loss the infection. Therefore, factors that account for children remain infected need to be investigated because once established the infection persists throughout the life unless treated. METHODS: This study aimed to evaluate the H. pylori infection in children of a low-income community at baseline and 8years later to determine the predictor factors linked to the maintenance, acquisition, and loss of the infection using regression models of generalized estimating equations. H. pylori status was determined by (13) C-urea breath test. RESULTS: Data from 37.7% (133/353) of the children were available. No difference between the characteristics of the included and nonincluded children was observed. The prevalence of infection increased from 53.4 to 64.7%. Thirty-nine children (29.3%) remained noninfected, 47.4% remained infected, 17.3% became infected, and 6.0% lost the infection. Factors associated with to remain infected compared with to remain noninfected included the age, increased number of children in the household, and the use of well water instead of municipal water. The acquisition of the infection was associated with the male gender. CONCLUSION: Factors linked to remain and to gain H. pylori infection in a poor region were increased number of children in the household and the male gender. Also, the acquisition rates were higher than the loss rates, which lead to an increase in the infection prevalence with age.
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Infecções por Helicobacter/epidemiologia , Infecções por Helicobacter/patologia , Brasil/epidemiologia , Testes Respiratórios , Criança , Estudos de Coortes , Características da Família , Feminino , Seguimentos , Helicobacter pylori/patogenicidade , Humanos , Masculino , Prevalência , Fatores de Risco , Fatores SocioeconômicosRESUMO
BACKGROUND: To evaluate the prevalence of more virulent H. pylori genotypes in relatives of gastric cancer patients and in patients without family histories of gastric cancer. METHODS: We evaluated prospectively the prevalence of the infection by more virulent H. pylori strains in 60 relatives of gastric cancer patients comparing the results with those obtained from 49 patients without family histories of gastric cancer. H. pylori status was determined by the urease test, histology and presence of H. pylori ureA. The cytotoxin associated gene (cagA), the cagA-EPIYA and vacuolating cytotoxin gene (vacA) were typed by PCR and the cagA EPIYA typing was confirmed by sequencing. RESULTS: The gastric cancer relatives were significant and independently more frequently colonized by H. pylori strains with higher numbers of CagA-EPIYA-C segments (OR = 4.23, 95%CI = 1.53-11.69) and with the most virulent s1m1 vacA genotype (OR = 2.80, 95%CI = 1.04-7.51). Higher numbers of EPIYA-C segments were associated with increased gastric corpus inflammation, foveolar hyperplasia and atrophy. Infection by s1m1 vacA genotype was associated with increased antral and corpus gastritis. CONCLUSIONS: We demonstrated that relatives of gastric cancer patients are more frequently colonized by the most virulent H. pylori cagA and vacA genotypes, which may contribute to increase the risk of gastric cancer.
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Antígenos de Bactérias/metabolismo , Proteínas de Bactérias/metabolismo , Carcinoma/microbiologia , Infecções por Helicobacter/microbiologia , Helicobacter pylori/patogenicidade , Neoplasias Gástricas/microbiologia , Adulto , Sequência de Aminoácidos , Antígenos de Bactérias/genética , Proteínas de Bactérias/genética , Sequência de Bases , Carcinoma/epidemiologia , Carcinoma/metabolismo , Carcinoma/patologia , Família , Feminino , Infecções por Helicobacter/epidemiologia , Infecções por Helicobacter/patologia , Helicobacter pylori/genética , Helicobacter pylori/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Fosforilação , Prevalência , Estudos Prospectivos , Análise de Sequência de DNA , Neoplasias Gástricas/epidemiologia , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Urease/análiseRESUMO
The implementation of biologic therapy has improved the treatment and clinical course of patients with inflammatory bowel disease since the initial approval of infliximab for Crohn's disease in 1998. However, the efficacy and safety profiles of currently available therapies are still less than optimal in several ways, highlighting the need for novel therapeutic targets. Several new drug classes (Janus kinase inhibitors, anti-integrins, sphingosine-1-phosphate receptor modulators, anti-interleukin-23 antibodies, and stem cell therapies) are currently being studied in Crohn's disease and ulcerative colitis with promising results. This article reviews the current literature and provides an updated overview of the emerging therapies.
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Background: Microscopic colitis (MC) is suspected to result from increased immune activity in gut mucosa. Immune checkpoint inhibitors (ICIs) treat cancer by activating the immune system, and further investigation is needed regarding their role in the development of MC. Methods: A retrospective case series investigated cases of endoscopically and histologically confirmed MC developing after administration of ICIs. Clinical notes and medication administration records were reviewed for demographics, symptom duration, and treatment response. Results: Nineteen cases of de novo MC were identified, with 95% of cases requiring steroid treatment, 53% presenting with hospitalization, and colitis-related mortality in 1 individual. Symptom onset occurred a median of 160 days after initiation of ICI therapy and 53 days after their most recent dose of therapy. Patients had a median of 125 days of symptoms, and ICI therapy was held in 70% of individuals due for treatment. Conclusions: MC can develop after ICI administration, and presents with severe symptoms, often requiring hospitalization and steroid treatment. In certain individuals this can require a prolonged treatment course of steroid therapy or immunomodulators. Individuals developing diarrhea after ICI therapy warrant thorough workup including endoscopy and rapid treatment initiation given the disease severity observed in this series.
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BACKGROUND: This study conducted in Northeastern Brazil, evaluated the prevalence of H. pylori infection and the presence of gastritis in HIV-infected patients. METHODS: There were included 113 HIV-positive and 141 age-matched HIV-negative patients, who underwent upper gastrointestinal endoscopy for dyspeptic symptoms. H. pylori status was evaluated by urease test and histology. RESULTS: The prevalence of H. pylori infection was significantly lower (p < 0.001) in HIV-infected (37.2%) than in uninfected (75.2%) patients. There were no significant differences between H. pylori status and gender, age, HIV viral load, antiretroviral therapy and the use of antibiotics. A lower prevalence of H. pylori was observed among patients with T CD4 cell count below 200/mm3; however, it was not significant. Chronic active antral gastritis was observed in 87.6% of the HIV-infected patients and in 780.4% of the control group (p = 0.11). H. pylori infection was significantly associated with chronic active gastritis in the antrum in both groups, but it was not associated with corpus chronic active gastritis in the HIV-infected patients. CONCLUSION: We demonstrated that the prevalence of H. pylori was significantly lower in HIV-positive patients compared with HIV-negative ones. However, corpus gastritis was frequently observed in the HIV-positive patients, pointing to different mechanisms than H. pylori infection in the genesis of the lesion.
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Infecções por HIV/etnologia , Infecções por HIV/epidemiologia , Infecções por Helicobacter/etnologia , Infecções por Helicobacter/epidemiologia , Adolescente , Adulto , Idoso , Brasil/epidemiologia , Estudos de Casos e Controles , Comorbidade , Endoscopia Gastrointestinal , Feminino , Gastrite/diagnóstico , Gastrite/epidemiologia , Gastrite/etnologia , Infecções por Helicobacter/diagnóstico , Helicobacter pylori/isolamento & purificação , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Fatores de Risco , Trato Gastrointestinal Superior/microbiologia , Adulto JovemRESUMO
BACKGROUND: Methotrexate treatment has been associated to intestinal epithelial damage. Studies have suggested an important role of nitric oxide in such injury. The aim of this study was to investigate the role of nitric oxide (NO), specifically iNOS on the pathogenesis of methotrexate (MTX)-induced intestinal mucositis. METHODS: Intestinal mucositis was carried out by three subcutaneous MTX injections (2.5 mg/kg) in Wistar rats and in inducible nitric oxide synthase knock-out (iNOS-/-) and wild-type (iNOS+/+) mice. Rats were treated intraperitoneally with the NOS inhibitors aminoguanidine (AG; 10 mg/Kg) or L-NAME (20 mg/Kg), one hour before MTX injection and daily until sacrifice, on the fifth day. The jejunum was harvested to investigate the expression of Ki67, iNOS and nitrotyrosine by immunohistochemistry and cell death by TUNEL. The neutrophil activity by myeloperoxidase (MPO) assay was performed in the three small intestine segments. RESULTS: AG and L-NAME significantly reduced villus and crypt damages, inflammatory alterations, cell death, MPO activity, and nitrotyrosine immunostaining due to MTX challenge. The treatment with AG, but not L-NAME, prevented the inhibitory effect of MTX on cell proliferation. MTX induced increased expression of iNOS detected by immunohistochemistry. MTX did not cause significant inflammation in the iNOS-/- mice. CONCLUSION: These results suggest an important role of NO, via activation of iNOS, in the pathogenesis of intestinal mucositis.