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1.
Int J Mol Sci ; 22(5)2021 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-33807944

RESUMO

Phosphodiesterases (PDEs) are a heterogeneous superfamily of enzymes which catalyze the degradation of the intracellular second messengers cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). Among PDEs, PDE4 is the most widely studied and characterized isoenzyme. PDE4 blocking can lead to increased levels of intracellular cAMP, which results in down-regulation of inflammatory responses by reducing the expression of tumor necrosis factor (TNF), interleukin (IL)-23, IL-17, interferon-γ, while increasing regulatory cytokines, such as IL-10. Therefore, PDE4 has been explored as a therapeutic target for the treatment of different chronic inflammatory conditions such as psoriatic arthritis (PsA) and inflammatory bowel disease (IBD). PsA shares clinical, genetic, and pathogenic features with IBD such as ulcerative colitis (UC) and Crohn's disease (CD), and enteropathic spondyloarthritis (eSpA) represent a frequent clinical evidence of the overlap between gut and joint diseases. Current therapeutic options in PsA patients and underlying UC are limited to synthetic immunosuppressants and anti-TNF. Apremilast is an oral PDE4 inhibitor approved for the treatment of active PsA patients with inadequate response to synthetic immunosuppressants. The efficacy and a good safety profile observed in randomized clinical trials with apremilast in PsA patients have been confirmed by few studies in a real-life scenario. In addition, apremilast led to significant improvement in clinical and endoscopic features in UC patients in a phase II RCT. By now there are no available data regarding its role in eSpA patients. In view of the above, the use of apremilast in eSpA patients is a route that deserves to be deepened.


Assuntos
Artrite Psoriásica/tratamento farmacológico , Colite Ulcerativa/tratamento farmacológico , Doença de Crohn/tratamento farmacológico , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/imunologia , Inibidores da Fosfodiesterase 4/uso terapêutico , Talidomida/análogos & derivados , Artrite Psoriásica/imunologia , Artrite Psoriásica/patologia , Colite Ulcerativa/imunologia , Colite Ulcerativa/patologia , Doença de Crohn/imunologia , Doença de Crohn/patologia , Citocinas/imunologia , Humanos , Talidomida/uso terapêutico
2.
Medicine (Baltimore) ; 100(14): e25340, 2021 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-33832109

RESUMO

ABSTRACT: Surgical resection is an unavoidable part of the current treatment options for Crohn's disease (CD), and more than half of patients develop recurrence. The aim of this study was to investigate the predictors for recurrence in the long-term follow-up of CD patients after surgery.Medical records of consecutive CD patients who were operated on between January 2003 and January 2015 were retrospectively analyzed. Data including demographic and clinical characteristics of the patients were recorded. Recurrence was evaluated based on the Crohn's Disease Activity Index or endoscopic findings.The majority of 112 patients were males (n = 64, 57.1%), and 61 (54.4%) of them were active smokers. The median follow-up was 113 (range: 61-197) months. Disease recurrence occurred in 16 (14.3%) patients at a median of 13.5 months. The endoscopic recurrence rate was 8% (n = 9) at 1 year, 12.5% (n = 14) at 5 years, and 13.4% (n = 15) at 10 years. One (0.9%) patient underwent colonoscopic balloon dilatation at 1 year, and 7 (6.3%) patients needed re-resection at a median of 36 months. The age of the patient at the time of diagnosis (P = .033), penetrating disease behavior (P = .011), intra-abdominal abscess (P = 0.040) and, concomitant fistula and intra-abdominal abscess (P = .017) were associated with disease recurrence.Our study results suggest that the patients' age at the time of diagnosis, penetrating disease, intra-abdominal abscess, and concomitant fistula and abscess are the risk factors for CD recurrence after surgery.


Assuntos
Doença de Crohn/patologia , Doença de Crohn/cirurgia , Abscesso Abdominal/epidemiologia , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Fumar Cigarros/epidemiologia , Feminino , Humanos , Fístula Intestinal/epidemiologia , Masculino , Pessoa de Meia-Idade , Recidiva , Estudos Retrospectivos , Fatores de Risco , Índice de Gravidade de Doença , Adulto Jovem
3.
Nat Commun ; 12(1): 2032, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33795670

RESUMO

Adherent-invasive Escherichia coli (AIEC) are pathogenic bacteria frequently isolated from patients who have Crohn's disease (CD). Despite the phenotypic differences between AIEC and commensal E. coli, comparative genomic approaches have been unable to differentiate these two groups, making the identification of key virulence factors a challenge. Here, we conduct a high-resolution, in vivo genetic screen to map AIEC genes required for intestinal colonization of mice. In addition, we use in vivo RNA-sequencing to define the host-associated AIEC transcriptome. We identify diverse metabolic pathways required for efficient gut colonization by AIEC and show that a type IV secretion system (T4SS) is required to form biofilms on the surface of epithelial cells, thereby promoting AIEC persistence in the gut. E. coli isolated from CD patients are enriched for a T4SS, suggesting a possible connection to disease activity. Our findings establish the T4SS as a principal AIEC colonization factor and highlight the use of genome-wide screens in decoding the infection biology of CD-associated bacteria that otherwise lack a defined genetic signature.


Assuntos
Doença de Crohn/patologia , Escherichia coli/genética , Perfilação da Expressão Gênica/métodos , Ensaios de Triagem em Larga Escala/métodos , Sistemas de Secreção Tipo IV/genética , Animais , Aderência Bacteriana/genética , Biofilmes , Células CACO-2 , Doença de Crohn/microbiologia , Células Epiteliais/metabolismo , Células Epiteliais/microbiologia , Escherichia coli/classificação , Escherichia coli/fisiologia , Infecções por Escherichia coli/microbiologia , Infecções por Escherichia coli/patologia , Feminino , Humanos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiologia , Camundongos Endogâmicos C57BL , Fatores de Virulência/genética
4.
J Comput Assist Tomogr ; 45(2): 171-176, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33661155

RESUMO

OBJECTIVE: The objective of this study was to determine if dual-energy computed tomography enterography (DECTE)-obtained iodine density can predict medical management change or surgery in Crohn disease patients. METHODS: The most active-appearing bowel segment on DECTE in 21 Crohn disease patients was retrospectively interrogated with prototype software determining the percentage of bowel wall (I) in specified ranges. Patients were categorized into 3 groups after DECTE: (1) no management change, (2) outpatient medication change, and (3) inpatient admission or surgery. Crohn's disease activity index was calculated. Group 3's percentage iodine density of >3 mg/mL and Crohn's disease activity index were compared with group 1/2. Crohn's disease activity index and percentage iodine density of >2 mg/mL were compared for groups 2/3 versus group 1 patients. RESULTS: There were 5 group 1, 6 group 2, and 10 group 3 patients. Group 3 patients had higher frequency of iodine density >3 mg/mL (27%) compared with groups 1/2 patients (12.6%) (P < 0.05). Crohn's disease activity index was similar (P = 0.98). Groups 2/3 patients had 60.5% iodine density of >2 mg/mL, whereas group 1 patients had 31.7% iodine density of >2 mg/mL (P < 0.05). Crohn's disease activity index was similar (P = 0.12). CONCLUSIONS: Iodine density from DECTE may predict medical or surgical Crohn disease management.


Assuntos
Doença de Crohn/diagnóstico por imagem , Intestino Delgado/diagnóstico por imagem , Tomografia Computadorizada por Raios X , Adulto , Idoso , Doença de Crohn/patologia , Feminino , Humanos , Intestino Delgado/patologia , Iodo , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos
5.
Nat Commun ; 12(1): 1921, 2021 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-33771991

RESUMO

Crohn's disease (CD) is a chronic transmural inflammation of intestinal segments caused by dysregulated interaction between microbiome and gut immune system. Here, we profile, via multiple single-cell technologies, T cells purified from the intestinal epithelium and lamina propria (LP) from terminal ileum resections of adult severe CD cases. We find that intraepithelial lymphocytes (IEL) contain several unique T cell subsets, including NKp30+γδT cells expressing RORγt and producing IL-26 upon NKp30 engagement. Further analyses comparing tissues from non-inflamed and inflamed regions of patients with CD versus healthy controls show increased activated TH17 but decreased CD8+T, γδT, TFH and Treg cells in inflamed tissues. Similar analyses of LP find increased CD8+, as well as reduced CD4+T cells with an elevated TH17 over Treg/TFH ratio. Our analyses of CD tissues thus suggest a potential link, pending additional validations, between transmural inflammation, reduced IEL γδT cells and altered spatial distribution of IEL and LP T cell subsets.


Assuntos
Doença de Crohn/imunologia , Linfócitos Intraepiteliais/imunologia , Análise de Célula Única/métodos , Subpopulações de Linfócitos T/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Células Cultivadas , Doença de Crohn/patologia , Perfilação da Expressão Gênica/métodos , Humanos , Linfócitos Intraepiteliais/metabolismo , Contagem de Linfócitos , Subpopulações de Linfócitos T/metabolismo , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Células Th17/imunologia , Células Th17/metabolismo
6.
7.
Science ; 371(6534): 1154-1159, 2021 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-33707263

RESUMO

Alterations of the mycobiota composition associated with Crohn's disease (CD) are challenging to link to defining elements of pathophysiology, such as poor injury repair. Using culture-dependent and -independent methods, we discovered that Debaryomyces hansenii preferentially localized to and was abundant within incompletely healed intestinal wounds of mice and inflamed mucosal tissues of CD human subjects. D. hansenii cultures from injured mice and inflamed CD tissues impaired colonic healing when introduced into injured conventionally raised or gnotobiotic mice. We reisolated D. hansenii from injured areas of these mice, fulfilling Koch's postulates. Mechanistically, D. hansenii impaired mucosal healing through the myeloid cell-specific type 1 interferon-CCL5 axis. Taken together, we have identified a fungus that inhabits inflamed CD tissue and can lead to dysregulated mucosal healing.


Assuntos
Doença de Crohn/microbiologia , Doença de Crohn/patologia , /fisiologia , Mucosa Intestinal/microbiologia , Mucosa Intestinal/patologia , Anfotericina B/farmacologia , Animais , Antibacterianos/farmacologia , Antifúngicos/farmacologia , Quimiocina CCL5/metabolismo , Colo/microbiologia , Colo/patologia , Doença de Crohn/imunologia , Feminino , Microbioma Gastrointestinal , Vida Livre de Germes , Humanos , Íleo/microbiologia , Íleo/patologia , Inflamação , Interferon Tipo I/metabolismo , Mucosa Intestinal/imunologia , Macrófagos/imunologia , Macrófagos/microbiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL
8.
Methods Mol Biol ; 2212: 169-179, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33733356

RESUMO

In biology, the term "epistasis" indicates the effect of the interaction of a gene with another gene. A gene can interact with an independently sorted gene, located far away on the chromosome or on an entirely different chromosome, and this interaction can have a strong effect on the function of the two genes. These changes then can alter the consequences of the biological processes, influencing the organism's phenotype. Machine learning is an area of computer science that develops statistical methods able to recognize patterns from data. A typical machine learning algorithm consists of a training phase, where the model learns to recognize specific trends in the data, and a test phase, where the trained model applies its learned intelligence to recognize trends in external data. Scientists have applied machine learning to epistasis problems multiple times, especially to identify gene-gene interactions from genome-wide association study (GWAS) data. In this brief survey, we report and describe the main scientific articles published in data mining and epistasis. Our article confirms the effectiveness of machine learning in this genetics subfield.


Assuntos
Biologia Computacional/métodos , Mineração de Dados/métodos , Epistasia Genética , Aprendizado de Máquina , Característica Quantitativa Herdável , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Doença de Crohn/genética , Doença de Crohn/metabolismo , Doença de Crohn/patologia , Genoma Humano , Estudo de Associação Genômica Ampla , Humanos , Padrões de Herança , Degeneração Macular/genética , Degeneração Macular/metabolismo , Degeneração Macular/patologia , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patologia , Fenótipo , Plantas/genética , Polimorfismo de Nucleotídeo Único
9.
Am J Hum Genet ; 108(3): 431-445, 2021 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-33600772

RESUMO

Whether or not populations diverge with respect to the genetic contribution to risk of specific complex diseases is relevant to understanding the evolution of susceptibility and origins of health disparities. Here, we describe a large-scale whole-genome sequencing study of inflammatory bowel disease encompassing 1,774 affected individuals and 1,644 healthy control Americans with African ancestry (African Americans). Although no new loci for inflammatory bowel disease are discovered at genome-wide significance levels, we identify numerous instances of differential effect sizes in combination with divergent allele frequencies. For example, the major effect at PTGER4 fine maps to a single credible interval of 22 SNPs corresponding to one of four independent associations at the locus in European ancestry individuals but with an elevated odds ratio for Crohn disease in African Americans. A rare variant aggregate analysis implicates Ca2+-binding neuro-immunomodulator CALB2 in ulcerative colitis. Highly significant overall overlap of common variant risk for inflammatory bowel disease susceptibility between individuals with African and European ancestries was observed, with 41 of 241 previously known lead variants replicated and overall correlations in effect sizes of 0.68 for combined inflammatory bowel disease. Nevertheless, subtle differences influence the performance of polygenic risk scores, and we show that ancestry-appropriate weights significantly improve polygenic prediction in the highest percentiles of risk. The median amount of variance explained per locus remains the same in African and European cohorts, providing evidence for compensation of effect sizes as allele frequencies diverge, as expected under a highly polygenic model of disease.


Assuntos
Calbindina 2/genética , Predisposição Genética para Doença , Doenças Inflamatórias Intestinais/genética , Receptores de Prostaglandina E Subtipo EP4/genética , Afro-Americanos/genética , Idoso , Idoso de 80 Anos ou mais , Colite Ulcerativa/genética , Colite Ulcerativa/patologia , Doença de Crohn/genética , Doença de Crohn/patologia , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Frequência do Gene , Estudo de Associação Genômica Ampla , Humanos , Doenças Inflamatórias Intestinais/patologia , Masculino , Herança Multifatorial/genética , Polimorfismo de Nucleotídeo Único/genética , Sequenciamento Completo do Genoma
10.
Methods Mol Biol ; 2224: 133-146, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33606212

RESUMO

Crohn's disease (CD) and ulcerative colitis are two main clinically defined forms of chronic inflammatory bowel disease (IBD). Chronic intestinal inflammation is inextricably linked to colitis-associated colon carcinogenesis (CAC). Patients with ulcerative colitis (UC) and Crohn's disease (CD) have an increased risk of colon cancer. Our understanding of IBD and IBD-associated colon carcinogenesis depends largely on rodent models. AOM-DSS-induced colitis-associated colon cancer in mice is the most widely used and accepted model that can recapitulate the human IBD-associated colon cancer. Here, we have provided detailed protocols of this mouse model of experimentally induced chronic intestinal inflammation-associated colon cancer. We will also discuss the protocols for the isolation and analysis of inflammatory immune cells from the colon.


Assuntos
Colite Ulcerativa/patologia , Neoplasias do Colo/patologia , Animais , Colite Ulcerativa/induzido quimicamente , Colo/patologia , Doença de Crohn/induzido quimicamente , Doença de Crohn/patologia , Sulfato de Dextrana/farmacologia , Modelos Animais de Doenças , Feminino , Doenças Inflamatórias Intestinais/induzido quimicamente , Doenças Inflamatórias Intestinais/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL
11.
BMJ Case Rep ; 14(2)2021 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-33541992

RESUMO

A 14-year-old girl presented to the ophthalmology clinic with progressive diminution of vision, redness, pain and photophobia in both eyes for the last 1 month. She had abdominal pain, diarrhoea and weight loss during that period. Ocular examination revealed features of anterior uveitis, vitritis and retinal vasculitis. In view of gastrointestinal symptoms, abdominal imaging was done, which showed multiple enhancing bowel wall thickening with skip lesions in the terminal ileum and ascending colon. Colonoscopy showed ulcers in the ascending colon, caecum and terminal ileum. Histopathology revealed microgranulomas in lamina propria and submucosal granulomas suggestive of Crohn's disease. The patient was started on topical steroid eye drops and oral budesonide and mesalazine. Her vision improved after 3 weeks and bowel symptoms attained remission after 8 weeks, and at present, she is doing well.


Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Budesonida/uso terapêutico , Doença de Crohn/diagnóstico , Mesalamina/uso terapêutico , Pan-Uveíte/diagnóstico , Dor Abdominal/etiologia , Adolescente , Colonoscopia , Doença de Crohn/patologia , Feminino , Humanos , Tomografia de Coerência Óptica
12.
BMJ Case Rep ; 14(2)2021 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-33558378

RESUMO

Few cases of pouch-related cancers have been reported in inflammatory bowel disease, and squamous cell carcinoma (SCC) is very rare. We have reviewed the published literature searching the online databases PubMed and Medline. Since 1979, there have been eight cases of SCC developing after restorative proctocolectomy in ulcerative colitis. To date, there have been no reported cases of SCC of the ileo-anal pouch in Crohn's disease. We present the case of a 59-year-old woman who underwent colectomy with ileal pouch-anal anastomosis for Crohn's disease during the 1990s. The patient was noted to be anaemic and was experiencing significant weight loss with poor pouch function in 2019. Endoscopy with histology and radiological investigation revealed the presence of SCC of the pouch. This was subsequently treated with surgical therapy and chemoradiotherapy.


Assuntos
Carcinoma de Células Escamosas/patologia , Neoplasias do Colo/patologia , Bolsas Cólicas/patologia , Doença de Crohn/patologia , Carcinoma de Células Escamosas/complicações , Carcinoma de Células Escamosas/terapia , Quimiorradioterapia Adjuvante , Neoplasias do Colo/complicações , Neoplasias do Colo/terapia , Doença de Crohn/complicações , Doença de Crohn/cirurgia , Feminino , Humanos , Ileostomia , Pessoa de Meia-Idade , Terapia Neoadjuvante , Proctocolectomia Restauradora
13.
Nat Commun ; 12(1): 261, 2021 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-33431850

RESUMO

Intestinal microfold cells are the primary pathway for translocation of secretory IgA (SIgA)-pathogen complexes to gut-associated lymphoid tissue. Uptake of SIgA/commensals complexes is important for priming adaptive immunity in the mucosa. This study aims to explore the effect of SIgA retrograde transport of immune complexes in Crohn's disease (CD). Here we report a significant increase of SIgA transport in CD patients with NOD2-mutation compared to CD patients without NOD2 mutation and/or healthy individuals. NOD2 has an effect in the IgA transport through human and mouse M cells by downregulating Dectin-1 and Siglec-5 expression, two receptors involved in retrograde transport. These findings define a mechanism of NOD2-mediated regulation of mucosal responses to intestinal microbiota, which is involved in CD intestinal inflammation and dysbiosis.


Assuntos
Doença de Crohn/metabolismo , Imunoglobulina A Secretora/metabolismo , Proteína Adaptadora de Sinalização NOD2/metabolismo , Animais , Colite/microbiologia , Colite/patologia , Doença de Crohn/patologia , Humanos , Lectinas Tipo C/metabolismo , Camundongos Knockout , Modelos Biológicos , Mutação/genética , Proteína Adaptadora de Sinalização NOD2/deficiência , Proteína Adaptadora de Sinalização NOD2/genética , Nódulos Linfáticos Agregados/metabolismo , Transporte Proteico , Salmonella/fisiologia , Lectinas Semelhantes a Imunoglobulina de Ligação ao Ácido Siálico/metabolismo , Transcitose
14.
BMJ Case Rep ; 13(12)2020 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-33318260

RESUMO

A 57-year-old man underwent emergency laparoscopic loop colostomy for acute recto-sigmoid obstruction. He was hospitalised 2 months previously, at another facility for diabetic ketoacidosis (DKA) and hyperkalaemia. He had no gastrointestinal symptoms prior to the hospitalisation. Both surgical exploration and intraoperative sigmoidoscopy showed ulcerations of sigmoid colon and proximal rectum with a pinhole stricture in mid-rectum. After ruling out all aetiologies, and due to persistence of the colonic ulcerations on a follow-up colonoscopy, a diagnosis of Crohn's colitis was made, and the patient was started on infliximab and 6-mercaptopurine (6-MP). Six months later, on rereview of all the biopsies, it was noted that a key element of presence of crystals suggestive of Kayexalate on the initial colorectal biopsies was missed. It was later found out that the patient had received rectal Kayexalate for treatment of DKA at the other facility. Hence, infliximab and 6-MP were both discontinued. All the colonoscopies, following the discontinuation of the medications, showed complete resolution of colitis but persistence of the mid-rectum stricture. This was treated with a fully covered metal stent for 12 weeks with only partial improvement of the stricture. He was hence referred for ultra-low anterior resection of rectum and take down of colostomy.


Assuntos
Resinas de Troca de Cátion/efeitos adversos , Colite/induzido quimicamente , Colite/patologia , Constrição Patológica/induzido quimicamente , Poliestirenos/efeitos adversos , Reto/patologia , Anastomose Cirúrgica , Colonoscopia , Colostomia , Constrição Patológica/cirurgia , Doença de Crohn/diagnóstico , Doença de Crohn/patologia , Cetoacidose Diabética/complicações , Cetoacidose Diabética/terapia , Humanos , Hiperpotassemia/complicações , Hiperpotassemia/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Reto/cirurgia , Stents
15.
APMIS ; 128(12): 621-625, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32956512

RESUMO

Surgeons, who documented what they had seen and felt in the abdomen of the patient, made the earliest descriptions of Crohn's disease (CD). Dalziel wrote the first pathology description in 1913. Crohn and his coworkers reinvented what Dalziel had written about and called it by a different name, 'regional enteritis'. Later others elaborated on the histologic features, at first the lymphoid follicles, later the granulomas. Some thought the latter were comprised of lymphatic endothelial cells and that endothelial plugs obstructed the lymphatics. Tonelli and others recognized that lymphedema was important and caused by obstructions to lymphatic vasculature. Some lymphatics they described contained lymphocyte plugs and others granulomas. Immunohistochemistry (IHC) has now shown that endothelial cells are not the cause of lymphatic obstruction, but rather CD68-positive macrophages, concluding that the 'lymphocyte thrombi' are passive, caught upstream of granuloma-obstructed lymphatics. Numerous authors recognized that transmural edema was the most significant change in Crohn's disease and that this was later followed by fibrosis and contracture of the diseased segment. Key descriptive papers spoke of the segmental lymphedema. Most recently, attention has been given to attachments of the intralymphatic CD68+ granulomas to a focal point where endothelial damage occurred, damage suggesting infectious penetration of the mucosa, necrosis of lymphatic endothelium and then granulomatous response, both inside and outside the lymphatics, of submucosa, muscularis, and subserosa. D2-40 IHC outlines the endothelium, and anti-CD68 shows the granulomas. IHC adds a valuable perspective when reviewing CD resections.


Assuntos
Doença de Crohn/história , Doença de Crohn/patologia , Patologistas/história , Doença de Crohn/genética , Doença de Crohn/imunologia , Células Endoteliais/imunologia , Células Endoteliais/patologia , História do Século XX , História do Século XXI , Humanos , Imuno-Histoquímica/história
17.
PLoS One ; 15(8): e0236657, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32760089

RESUMO

Crohn's disease is a pathological condition of the gastro-intestinal tract, causing severe transmural inflammation in the ileum and/or colon. Cigarette smoking is one of the best known environmental risk factors for the development of Crohn's disease. Nevertheless, very little is known about the effect of prolonged cigarette smoke exposure on inflammatory modulators in the gut. We examined the effect of cigarette smoke on cytokine profiles in the healthy and inflamed gut of human subjects and in the trinitrobenzene sulphonic acid mouse model, which mimics distal Crohn-like colitis. In addition, the effect of cigarette smoke on epithelial expression of transient receptor potential channels and their concurrent increase with cigarette smoke-augmented cytokine production was investigated. Active smoking was associated with increased IL-8 transcription in ileum of controls (p < 0,001; n = 18-20/group). In the ileum, TRPV1 mRNA levels were decreased in never smoking Crohn's disease patients compared to healthy subjects (p <0,001; n = 20/group). In the colon, TRPV1 mRNA levels were decreased (p = 0,046) in smoking healthy controls (n = 20/group). Likewise, healthy mice chronically exposed to cigarette smoke (n = 10/group) showed elevated ileal Cxcl2 (p = 0,0075) and colonic Kc mRNA levels (p = 0,0186), whereas TRPV1 mRNA and protein levels were elevated in the ileum (p = 0,0315). Although cigarette smoke exposure prior to trinitrobenzene sulphonic acid administration did not alter disease activity, increased pro-inflammatory cytokine production was observed in the distal colon (Kc: p = 0,0273; Cxcl2: p = 0,104; Il1-ß: p = 0,0796), in parallel with the increase of Trpv1 mRNA (p < 0,001). We infer that CS affects pro-inflammatory cytokine expression in healthy and inflamed gut, and that the simultaneous modulation of TRPV1 may point to a potential involvement of TRPV1 in cigarette smoke-induced production of inflammatory mediators.


Assuntos
Colo/metabolismo , Doença de Crohn/metabolismo , Íleo/metabolismo , Canais de Cátion TRPV/metabolismo , Fumar Tabaco/efeitos adversos , Adulto , Idoso , Animais , Células CACO-2 , Colo/patologia , Doença de Crohn/induzido quimicamente , Doença de Crohn/patologia , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Células HT29 , Humanos , Íleo/patologia , Inflamação/metabolismo , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Pesquisa Médica Translacional , Ácido Trinitrobenzenossulfônico
18.
PLoS One ; 15(7): e0236421, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32716958

RESUMO

BACKGROUND: NOD2 variants are the strongest genetic predictors for susceptibility to Crohn's disease (CD). However, the clinical value of NOD2 on an individual patient level remains controversial. We aimed to define the predictive power of the major NOD2 mutations regarding complicated CD in a large single center cohort. METHODS: 1076 CD patients were prospectively genotyped for the three common CD-associated NOD2 mutations rs2066844, rs2066845, and rs2066847, followed by detailed genotype-phenotype analyses. RESULTS: Overall, 434 CD patients (40.3%) carried at least one of the three main NOD2 mutations. A significantly higher minor allele frequency (15.6%) of the NOD2 frameshift mutation p.Leu1007fsX1008 (rs2066847) was seen in patients with aggressive disease compared to 8.2% in patients with mild disease (p = 2.6 x 10-5). Moreover, a total of 54 CD patients (5.0%) were homozygous for this NOD2 frameshift mutation. 100% of these patients had ileal disease compared to 82% of NOD2 wild-type carriers (p<0.0001). In homozygous carriers of the NOD2 frameshift mutation, 87% presented with ileal stenosis, 68.5% had fistulas, and 72.2% required CD-related surgery despite immunosuppressive therapy in 87% of these patients. All homozygous carriers of the 1007fs mutation who were active smokers had ileal stenosis and required CD-related surgery. CONCLUSION: Homozygosity for Leu1007fsX1008 is an excellent biomarker for predicting complicated CD on an individual patient level. Active smoking and homozygosity for this mutation is associated with a 100% risk for developing ileal stenosis requiring CD-related surgery. In these patients, smoking cessation and early initiation of immunosuppressive strategies may be beneficial.


Assuntos
Doença de Crohn/genética , Doença de Crohn/patologia , Doenças do Íleo/cirurgia , Obstrução Intestinal/etiologia , Obstrução Intestinal/cirurgia , Mutação/genética , Proteína Adaptadora de Sinalização NOD2/genética , Fumar/efeitos adversos , Adolescente , Adulto , Estudos de Coortes , Doença de Crohn/complicações , Feminino , Dosagem de Genes , Frequência do Gene/genética , Marcadores Genéticos , Predisposição Genética para Doença , Heterozigoto , Homozigoto , Humanos , Doenças do Íleo/etiologia , Modelos Logísticos , Masculino , Fenótipo , Fatores de Risco , Índice de Gravidade de Doença , Adulto Jovem
20.
Cesk Patol ; 56(2): 95-98, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32493026

RESUMO

Amoebic colitis represents a common parasitic infection in developing countries. In western world, it is encountered only sporadically. The clinical presentation is usually non-specific, non-invasive laboratory tests are often false negative and endoscopic and histopathological appearance may mimic other illnesses, especially Crohns disease. The disease therefore harbours a huge risk of misdiagnosing and a proper diagnosis is usually challenging. We present a case of an amoebic colitis with Crohn-like features and negative parasitological testing in a 53-years-old woman, in which the final diagnosis was established on the basis of its histopathological examination.


Assuntos
Doença de Crohn , Disenteria Amebiana , Doença de Crohn/complicações , Doença de Crohn/diagnóstico , Doença de Crohn/patologia , Diagnóstico Diferencial , Disenteria Amebiana/complicações , Disenteria Amebiana/diagnóstico , Disenteria Amebiana/patologia , Feminino , Humanos , Pessoa de Meia-Idade
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