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BACKGROUND & AIMS: Acute enteric infections are well known to result in long-term gastrointestinal (GI) disorders. Although COVID-19 is principally a respiratory illness, it demonstrates significant GI tropism, possibly predisposing to prolonged gut manifestations. We aimed to examine the long-term GI impact of hospitalization with COVID-19. METHODS: Nested within a large-scale observational cohort study of patients hospitalized with COVID-19 across North America, we performed a follow-up survey of 530 survivors 12-18 months later to assess for persistent GI symptoms and their severity, and for the development of disorders of gut-brain interaction (DGBIs). Eligible patients were identified at the study site level and surveyed electronically. The survey instrument included the Rome IV Diagnostic Questionnaire for DGBI, a rating scale of 24 COVID-related symptoms, the Gastrointestinal Symptoms Rating Scale, and the Impact of Events-Revised trauma symptom questionnaire (a measure of posttraumatic stress associated with the illness experience). A regression analysis was performed to explore the factors associated with GI symptom severity at follow-up. RESULTS: Of the 530 invited patients, 116 responded (52.6% females; mean age, 55.2 years), and 73 of those (60.3%) met criteria for 1 or more Rome IV DGBI at follow-up, higher than the prevalence in the US general population (P < .0001). Among patients who experienced COVID-related GI symptoms during the index hospitalization (abdominal pain, nausea, vomiting, or diarrhea), 42.1% retained at least 1 of these symptoms at follow-up; in comparison, 89.8% of respondents retained any (GI or non-GI) COVID-related symptom. The number of moderate or severe GI symptoms experienced during the initial COVID-19 illness by self-report correlated with the development of DGBI and severity of GI symptoms at follow-up. Posttraumatic stress disorder (Impact of Events-Revised score ≥33) related to the COVID-19 illness experience was identified in 41.4% of respondents and those individuals had higher DGBI prevalence and GI symptom severity. Regression analysis revealed that higher psychological trauma score (Impact of Events-Revised) was the strongest predictor of GI symptom severity at follow-up. CONCLUSIONS: In this follow-up survey of patients 12-18 months after hospitalization with COVID-19, there was a high prevalence of DGBIs and persistent GI symptoms. Prolonged GI manifestations were associated with the severity of GI symptoms during hospitalization and with the degree of psychological trauma related to the illness experience.
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INTRODUCTION: Variability in adherence rates to the Seattle protocol and to surveillance interval recommendations, established quality indicators (QIs) in Barrett's esophagus (BE), is unknown. METHODS: We evaluated endoscopist and site-based adherence rates to these QIs from January 2018 to May 2021 using the GI Quality Improvement Consortium national registry with matched endoscopy and pathology data. RESULTS: Across 153 practices with 572 endoscopists performing 20,155 endoscopies, adherence to the Seattle protocol varied by endoscopists (median 93.8%, IQR 18.9%) and by site (median 90.0%, IQR 20.1%). Adherence to appropriate surveillance intervals for nondysplastic BE also varied by endoscopist (median 82.4%, IQR 36.3%) and site (median 77.2%, IQR 29.8%). The overall dysplasia detection rate was 3.1% and varied among endoscopists and sites. DISCUSSION: These US population-based results can serve as a benchmark for quality initiatives and intervention trials aimed at improving outcomes for patients with BE.
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Esôfago de Barrett , Neoplasias Esofágicas , Humanos , Esôfago de Barrett/diagnóstico , Esôfago de Barrett/patologia , Benchmarking , Esofagoscopia , Hiperplasia , Sistema de Registros , Neoplasias Esofágicas/patologiaRESUMO
BACKGROUND AND AIMS: Endoscopic eradication therapy for Barrett's esophagus (BE)-related neoplasia is increasingly being performed at tertiary and community centers. While it has been suggested that these patients should be evaluated at expert centers, the impact of this practice has not been evaluated. We aimed to assess the impact of referral of BE-related neoplasia patients to expert centers by assessing the proportion of patients with change in pathological diagnosis and visible lesions detected. METHODS: Multiple databases were searched until December 2021 for studies of patients with BE referred from the community to expert center. The proportions of pathology grade change and newly detected visible lesions at expert centers were pooled using a random-effects model. Subgroup analyses were performed based on baseline histology and other relevant factors. RESULTS: Twelve studies were included (1630 patients). The pooled proportion of pathology grade change after expert pathologist review was 47% (95% CI 34-59%) overall and 46% (95% CI 31-62%) among patients with baseline low-grade dysplasia. When upper endoscopy was repeated at an expert center, the pooled proportion of pathology grade change was still high 47% (95% 26-69%) overall and 40% (95% CI 34-45%) among patients with baseline LGD. The pooled proportion of newly detected visible lesions was 45% (95% CI 28-63%) and among patients referred with LGD was 27% (95% CI 22-32%). CONCLUSION: An alarmingly high proportion of newly detected visible lesions and pathology grade change were found when patients were referred to expert centers supporting the need for centralized care for BE-related neoplasia patients.
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Esôfago de Barrett , Neoplasias Esofágicas , Humanos , Esôfago de Barrett/patologia , Endoscopia Gastrointestinal , Neoplasias Esofágicas/patologia , Lesões Pré-Cancerosas/patologiaRESUMO
Lynch syndrome (LS) is the most common inherited colorectal cancer (CRC) syndrome with lifetime CRC risks of up to 70%.1 Conventionally, CRC specimens are screened for LS postoperatively but preoperative diagnosis of LS could impact decisions, such as the extent of resection and the need for additional risk-reducing surgeries for uterine and ovarian cancers. Few studies have addressed this issue2-5 and surveys indicate that most gastroenterologists are unsure that LS can be screened for preoperatively.6 We compared the yield of preoperative versus postoperative screening of LS by immunohistochemistry (IHC) and microsatellite instability (MSI) in unselected patients with newly diagnosed CRC who underwent testing under real-life laboratory conditions to mimic clinical practice.
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Neoplasias Colorretais Hereditárias sem Polipose , Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Neoplasias Colorretais Hereditárias sem Polipose/genética , Reparo de Erro de Pareamento de DNA , Detecção Precoce de Câncer , Testes Genéticos , Humanos , Programas de Rastreamento , Instabilidade de MicrossatélitesRESUMO
Several case reports and cohort studies have examined the use of (1,3)-beta-d-glucan measurement with cerebrospinal fluid to diagnose fungal meningitis. This systematic review aims to characterize the evidence regarding cerebrospinal fluid (1,3)-beta-d-glucan measurement to detect fungal meningitis. We searched PubMed for (1,3)-beta-d-glucan and each of several distinct fungi, cerebrospinal fluid, and meningitis. Summary data including diagnostic performance (where applicable) were recorded. A total of 939 records were examined via a PubMed search. One hundred eighteen records remained after duplicates were removed, and 104 records were excluded, as they did not examine cerebrospinal fluid, included animals, or focused on nonfungal infections. Fourteen studies were included in this systematic review. A variety of fungi, including species of Candida, Aspergillus, Exserohilum, Cryptococcus, Histoplasma, and Coccidioides, were studied, although most were case reports. Diagnostic accuracy was examined in 5 studies. Cerebrospinal fluid (CSF) (1,3)-beta-d-glucan measurement showed >95% sensitivity in the corticosteroid injection-related outbreak of Exserohilum rostratum One study in Histoplasma meningitis found 53% (53/87) sensitivity and 87% (133/153) specificity, while another study of Cryptococcus meningitis found 89% (69/78) sensitivity and 85% (33/39) specificity. CSF (1,3)-beta-d-glucan testing may be useful, primarily as a nonspecific marker of fungal meningitis. Although the FDA black box warning states that Cryptococcus spp. do not make (1,3)-beta-d-glucan, the current evidence shows that (1,3)-beta-d-glucan is detectable in cryptococcal meningitis. Organism-specific testing should be used in conjunction with (1,3)-beta-d-glucan measurement.
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Meningite Criptocócica , Meningite Fúngica , Ascomicetos , Líquido Cefalorraquidiano , Testes Diagnósticos de Rotina , Glucanos , Histoplasma , Humanos , Meningite Criptocócica/diagnóstico , Meningite Fúngica/diagnósticoRESUMO
Pulmonary endothelial prostacyclin appears to be involved in the pathogenesis of chronic obstructive pulmonary disease (COPD). The effect of treatment with a prostacyclin analog in animal models of previously established COPD is unknown. We evaluated the short- and long-term effect of iloprost on inflammation and airway hyperresponsiveness (AHR) in a murine model of COPD. Nineteen mice were exposed to LPS/elastase, followed by either three doses of intranasal iloprost or saline. In the long-term treatment experiment, 18 mice were exposed to LPS/elastase and then received 6 wk of iloprost or were left untreated as controls. In the short-term experiment, iloprost did not change AHR but significantly reduced serum IL-5 and IFN-γ. Long-term treatment with iloprost for both 2 and 6 wk significantly improved AHR. After 6 wk of iloprost, there was a reduction in bronchoalveolar lavage (BALF) neutrophils, serum IL-1ß (30.0 ± 9.2 vs. 64.8 ± 7.4 pg/ml, P = 0.045), IL-2 (36.5 ± 10.6 vs. 83.8 ± 0.4 pg/ml, P = 0.01), IL-10 (75.7 ± 9.3 vs. 96.5 ± 3.5 pg/ml, P = 0.02), and nitrite (15.1 ± 5.4 vs. 30.5 ± 10.7 µmol, P = 0.01). Smooth muscle actin (SMA) in the lung homogenate was also significantly reduced after iloprost treatment (P = 0.02), and SMA thickness was reduced in the small and medium blood vessels after iloprost (P < 0.001). In summary, short- and long-term treatment with intranasal iloprost significantly reduced systemic inflammation in an LPS/elastase COPD model. Long-term iloprost treatment also reduced AHR, serum nitrite, SMA, and BALF neutrophilia. These data encourage future investigations of prostanoid therapy as a novel treatment for COPD patients.
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Anti-Inflamatórios/administração & dosagem , Iloprosta/administração & dosagem , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Administração Intranasal , Animais , Citocinas/metabolismo , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Lipopolissacarídeos/farmacologia , Masculino , Camundongos Endogâmicos C57BL , Infiltração de Neutrófilos , Doença Pulmonar Obstrutiva Crônica/imunologia , Hipersensibilidade Respiratória/tratamento farmacológico , Hipersensibilidade Respiratória/imunologiaRESUMO
BACKGROUND: We reported that DNA-dependent protein kinase (DNA-PK) is critical for the expression of nuclear factor κB-dependent genes in TNF-α-treated glioblastoma cells, suggesting an involvement in inflammatory diseases. OBJECTIVE: We sought to investigate the role of DNA-PK in asthma. METHODS: Cell culture and ovalbumin (OVA)- or house dust mite-based murine asthma models were used in this study. RESULTS: DNA-PK was essential for monocyte adhesion to TNF-α-treated endothelial cells. Administration of the DNA-PK inhibitor NU7441 reduced airway eosinophilia, mucus hypersecretion, airway hyperresponsiveness, and OVA-specific IgE production in mice prechallenged with OVA. Such effects correlated with a marked reduction in lung vascular cell adhesion molecule 1 expression and production of several cytokines, including IL-4, IL-5, IL-13, eotaxin, IL-2, and IL-12 and the chemokines monocyte chemoattractant protein 1 and keratinocyte-derived chemokine, with a negligible effect on IL-10/IFN-γ production. DNA-PK inhibition by gene heterozygosity of the 450-kDa catalytic subunit of the kinase (DNA-PKcs(+/-)) also prevented manifestation of asthma-like traits. These results were confirmed in a chronic model of asthma by using house dust mite, a human allergen. Remarkably, such protection occurred without causing severe combined immunodeficiency. Adoptive transfer of TH2-skewed OT-II wild-type CD4(+) T cells reversed IgE and TH2 cytokine production but not airway hyperresponsiveness in OVA-challenged DNA-PKcs(+/-) mice. DNA-PK inhibition reduced IL-4, IL-5, IL-13, eotaxin, IL-8, and monocyte chemoattractant protein 1 production without affecting IL-2, IL-12, IFN-γ, and interferon-inducible protein 10 production in CD3/CD28-stimulated human CD4(+) T cells, potentially by blocking expression of Gata3. These effects occurred without significant reductions in T-cell proliferation. In mouse CD4(+) T cells in vitro DNA-PK inhibition severely blocked CD3/CD28-induced Gata3 and T-bet expression in CD4(+) T cells and prevented differentiation of TH1 and TH2 cells under respective TH1- and TH2-skewing conditions. CONCLUSION: Our results suggest DNA-PK as a novel determinant of asthma and a potential target for the treatment of the disease.
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Asma/imunologia , Linfócitos T CD4-Positivos/imunologia , Proteína Quinase Ativada por DNA/antagonistas & inibidores , Mucosa Respiratória/imunologia , Transferência Adotiva , Alérgenos/imunologia , Animais , Asma/metabolismo , Asma/patologia , Hiper-Reatividade Brônquica/imunologia , Hiper-Reatividade Brônquica/metabolismo , Hiper-Reatividade Brônquica/patologia , Adesão Celular , Citocinas/metabolismo , Proteína Quinase Ativada por DNA/genética , Proteína Quinase Ativada por DNA/metabolismo , Modelos Animais de Doenças , Eosinófilos/imunologia , Eosinófilos/metabolismo , Células Epiteliais/metabolismo , Fator de Transcrição GATA3/genética , Fator de Transcrição GATA3/metabolismo , Expressão Gênica , Heterogeneidade Genética , Humanos , Imunoglobulina E/imunologia , Ativação Linfocitária , Masculino , Camundongos , Camundongos Knockout , Tamanho do Órgão , Ovalbumina/efeitos adversos , Ovalbumina/imunologia , Fenótipo , Plasmócitos/imunologia , Plasmócitos/metabolismo , Pyroglyphidae/imunologia , Receptores de Antígenos de Linfócitos T/metabolismo , Mucosa Respiratória/metabolismo , Mucosa Respiratória/patologia , Imunodeficiência Combinada Severa , Baço/anatomia & histologia , Baço/imunologia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Células Th2/imunologia , Células Th2/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Molécula 1 de Adesão de Célula Vascular/genética , Molécula 1 de Adesão de Célula Vascular/metabolismoRESUMO
Our laboratory established a role for poly(ADP-ribose)polymerase (PARP) in asthma. To increase the clinical significance of our studies, it is imperative to demonstrate that PARP is actually activated in human asthma, to examine whether a PARP inhibitor approved for human testing such as olaparib blocks already-established chronic asthma traits in response to house dust mite (HDM), a true human allergen, in mice and to examine whether the drug modulates human cluster of differentiation type 4 (CD4(+)) T-cell function. To conduct the study, human lung specimens and peripheral blood mononuclear cells (PBMCs) and a HDM-based mouse asthma model were used. Our results show that PARP is activated in PBMCs and lung tissues of asthmatics. PARP inhibition by olaparib or gene knockout blocked established asthma-like traits in mice chronically exposed to HDM including airway eosinophilia and hyper-responsiveness. These effects were linked to a marked reduction in T helper 2 (Th2) cytokine production without a prominent effect on interferon (IFN)-γ or interleukin (IL)-10. PARP inhibition prevented HDM-induced increase in overall cellularity, weight and CD4(+) T-cell population in spleens of treated mice whereas it increased the T-regulatory cell population. In CD3/CD28-stimulated human CD4 (+)T-cells, olaparib treatment reduced Th2 cytokine production potentially by modulating GATA binding protein-3 (gata-3)/IL-4 expression while moderately affecting T-cell proliferation. PARP inhibition inconsistently increased IL-17 in HDM-exposed mice and CD3/CD28-stimulated CD4(+) T cells without a concomitant increase in factors that can be influenced by IL-17. In the present study, we provide evidence for the first time that PARP-1 is activated in human asthma and that its inhibition is effective in blocking established asthma in mice.
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Antialérgicos/farmacologia , Antiasmáticos/farmacologia , Antígenos de Dermatophagoides , Asma/prevenção & controle , Pulmão/efeitos dos fármacos , Ftalazinas/farmacologia , Piperazinas/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Poli(ADP-Ribose) Polimerases/metabolismo , Animais , Asma/enzimologia , Asma/imunologia , Asma/fisiopatologia , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Citocinas/metabolismo , Modelos Animais de Doenças , Ativação Enzimática , Humanos , Mediadores da Inflamação/metabolismo , Pulmão/enzimologia , Pulmão/imunologia , Pulmão/fisiopatologia , Ativação Linfocitária/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Poli(ADP-Ribose) Polimerase-1 , Poli(ADP-Ribose) Polimerases/deficiência , Poli(ADP-Ribose) Polimerases/genética , Receptores de Antígenos de Linfócitos T/metabolismo , Transdução de Sinais/efeitos dos fármacos , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/enzimologia , Linfócitos T Reguladores/imunologia , Células Th2/efeitos dos fármacos , Células Th2/enzimologia , Células Th2/imunologiaRESUMO
PDZ domain containing 1 (PDZK1) is a scaffold protein that plays a role in the fate of several proteins. Estrogen can induce PDZK1 gene expression; however, our recent report showed that PDZK1 expression in the breast cancer cell line MCF-7 is indirect and involves insulin-like growth factor (IGF)-1 receptor function. Such a relationship was established in cell culture systems and human breast cancer tissues. Here we show that overexpression of PDZK1 promoted an increase in cyclin D1 and enhanced anchorage-independent growth of MCF-7 cells in the absence of 17ß-estradiol, suggesting that PDZK1 harbors oncogenic activity. Indeed, PDKZ1 overexpression enhanced epidermal growth factor receptor (EGFR)-stimulated MEK/ERK1/2 signaling and IGF-induced Akt phosphorylation. PDZK1 appeared to play this role, in part, by stabilizing the integrity of the growth promoting factors Akt, human epidermal growth factor receptor 2 (Her2/Neu) and EGFR. Increased Akt levels occurred via a decrease in the ubiquitination of the kinase. PDZK1 overexpression was associated with resistance to paclitaxel/5-fluorouracil/etoposide only at low concentrations. Although the increased stability of Akt was sensitive to heat shock protein 90 (HSP90) inhibition, increased levels of the cochaperone cell division cycle 37 (Cdc37), as well as its ability to bind PDZK1, appear to play a larger role in kinase stability. Using human tissue microarrays, we show strong positive correlation between PDZK1, Akt and Cdc37 protein levels, and all correlated with human breast malignancy. There were no positive correlations between PDZK1 and Cdc37 at the mRNA levels, confirming our in vitro studies. These results demonstrate a relationship between PDZK1, Akt and Cdc37, and potentially Her2/Neu and EGFR, in breast cancer, representing a new axis that can be targeted therapeutically to reduce the burden of human breast cancer.
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Neoplasias da Mama/metabolismo , Proteínas de Transporte/metabolismo , Proteínas de Ciclo Celular/metabolismo , Chaperoninas/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proliferação de Células , Feminino , Humanos , Células MCF-7 , Proteínas de MembranaRESUMO
Purpose of review: Endoscopic eradication therapy is an effective and durable treatment for Barrett's esophagus (BE) related neoplasia, but even after achieving successful eradication, these patients remain at risk for recurrence and require ongoing routine examinations. The optimal surveillance protocol including endoscopic technique, sampling strategy, and timing are still being refined. The aim of this review is to discuss current management principles for the post ablation patient and emerging technologies to guide clinical practice. Recent findings: There is increasing evidence to support less frequent surveillance exams in the first year after complete eradication of intestinal metaplasia and a move towards targeted biopsies of visible lesions and sampling high-risk locations such as the gastroesophageal junction. Promising technologies on the horizon that could impact management include novel biomarkers, personalized surveillance intervals, and non-endoscopic approaches. Summary: Ongoing high-quality examinations after endoscopic eradication therapy are key to limiting recurrent BE. Surveillance intervals should be based on the pretreatment grade of dysplasia. Future research should focus on technologies and surveillance practices that are most efficient for patients and the healthcare system.
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Microvascular dysfunction is an important component of the pathologic processes that occur in diabetic foot disease. The endothelial abnormalities observed in patients with diabetes mellitus are poorly understood, and evidence suggests that endothelial dysfunction could be involved in the pathogenesis of diabetic macroangiopathy and microangiopathy. With the advent of insulin replacement in the early 1900s and increased efforts toward metabolic control of diabetes, long-term complications of this disease have become apparent. These late-term complications are primarily disorders of the vascular system. This article reviews the process of microvascular dysfunction and how it may relate to the pathogenesis of diabetic foot problems.
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Angiopatias Diabéticas/fisiopatologia , Pé/irrigação sanguínea , Pé Diabético/fisiopatologia , Endotélio Vascular/fisiopatologia , Humanos , Hiperglicemia/fisiopatologia , MicrocirculaçãoRESUMO
We previously showed that DNA fragmentation factor, which comprises a caspase-3-activated DNase (CAD) and its inhibitor (ICAD), may influence the rate of cell death by generating PARP-1-activating DNA breaks. Here we tested the hypothesis that ICAD-deficient colon epithelial cells exhibiting resistance to death stimuli may accumulate additional genetic modifications, leading to a tumorigenic phenotype. We show that ICAD deficiency may be associated with colon malignancy in humans. Indeed, an examination of ICAD expression using immunohistochemistry in an array of both colon cancer and normal tissues revealed that ICAD expression levels were severely compromised in the cancerous tissues. Upon DNA damage caused by a low dose of irradiation, ICAD cells acquire a tumorigenic phenotype. Colon epithelial cells derived from ICAD mice showed a significant resistance to death induced by the colon carcinogen dimethylhydrazine in vitro and in mice. Such resistance was associated with a decrease in PARP-1 activation. In an animal model of dimethylhydrazine-induced colon tumorigenesis, ICAD(-/-) mice developed significantly higher numbers of tumors with markedly larger sizes than the wild-type counterparts. Interestingly, the phenotype of the ICAD(-/-) mice was not associated with a significant increase in the precancerous aberrant crypt foci suggesting a potential link to tumor progression rather than initiation. More importantly, ICAD deficiency was associated with severe genomic instability as assessed by array comparative genomic hybridization. Such genomic instability consisted most prominently of amplifications but with sizable deletions as compared to the wild-type counterparts affecting several cancer-related genes including RAF-1, GSN, LMO3, and Fzd6 independently of p53. Altogether, our results present a viable case for the involvement of ICAD deficiency in colon carcinogenesis and show that apoptosis and genomic instability may comprise the means by which such deficiency may contribute to the process of increasing susceptibility to carcinogen-induced tumorigenesis.