RESUMEN
PURPOSE: There is increasing evidence that a defect of the gastrointestinal mucosal barrier is important for the development of inflammatory bowel diseases (IBD). The hydrophobicity of the colonic mucosal surface is a measure of its resistance to luminal antigens, e.g. of bacterial origin. Therefore, the purpose of this study was to determine this parameter in patients suffering from IBD. METHODS: Nineteen patients with ulcerative colitis (UC), ten patients with Crohn's disease (CD) and 20 controls were examined. All underwent colonic surgery at the University Hospital Heidelberg. Clinical disease activity was determined. From every subject, colonic tissue specimens were obtained, and hydrophobicity of the mucosal surface was determined with a goniometer by multiple plateau contact angle measurements. Histological evaluation of disease activity was performed in directly adjacent tissue specimens. RESULTS: Hydrophobicity of the colonic mucosal surface, expressed as plateau contact angles, was significantly reduced in patients with UC (mean ± SEM, 47.8° ± 3.4°) compared to those with CD (72.0° ± 5.2°) and controls (72.5° ± 5.6°; over-all P = 0.0004; UC versus controls, P < 0.001; UC versus CD, P < 0.05; CD versus controls, P > 0.05). Between mucosal hydrophobicity and clinical disease activity, as well as mucosal hydrophobicity and histological disease activity, no significant correlation was found. CONCLUSIONS: The results suggest a defective physicochemical barrier as an essential factor in the pathogenesis of UC, but not CD. The fact that no correlation was found between mucosal hydrophobicity and disease activity may indicate that the loss of mucosal hydrophobicity in UC is not exclusively a secondary effect due to inflammation.
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Colitis Ulcerosa/patología , Colon/patología , Interacciones Hidrofóbicas e Hidrofílicas , Mucosa Intestinal/patología , Adolescente , Adulto , Anciano , Estudios de Casos y Controles , Enfermedad de Crohn/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Propiedades de Superficie , Adulto JovenRESUMEN
Diarrhea predominant irritable bowel syndrome (IBS-D) is a complex disorder related to dysfunctions in the serotonergic system. As cis-regulatory variants can play a role in the etiology of complex conditions, we investigated the untranslated regions (UTRs) of the serotonin receptor type 3 subunit genes HTR3A and HTR3E. Mutation analysis was carried out in a pilot sample of 200 IBS patients and 100 healthy controls from the UK. The novel HTR3E 3'-UTR variant c.*76G>A (rs62625044) was associated with female IBS-D (P = 0.033, OR = 8.53). This association was confirmed in a replication study, including 119 IBS-D patients and 195 controls from Germany (P = 0.0046, OR = 4.92). Pooled analysis resulted in a highly significant association of c.*76G>A with female IBS-D (P = 0.0002, OR = 5.39). In a reporter assay, c.*76G>A affected binding of miR-510 to the HTR3E 3'-UTR and caused elevated luciferase expression. HTR3E and miR-510 co-localize in enterocytes of the gut epithelium as shown by in situ hybridization and RT-PCR. This is the first example indicating micro RNA-related expression regulation of a serotonin receptor gene with a cis-regulatory variant affecting this regulation and appearing to be associated with female IBS-D.
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Diarrea/genética , Síndrome del Colon Irritable/genética , MicroARNs/genética , Receptores de Serotonina/genética , Regiones no Traducidas 3'/genética , Adolescente , Adulto , Anciano , Estudios de Casos y Controles , Línea Celular , Estudios de Cohortes , Diarrea/metabolismo , Femenino , Expresión Génica , Alemania , Humanos , Mucosa Intestinal , Síndrome del Colon Irritable/metabolismo , Masculino , Persona de Mediana Edad , Mutación , Receptores de Serotonina/metabolismo , Receptores de Serotonina 5-HT3 , Especificidad de la Especie , Reino UnidoRESUMEN
Deleted in malignant brain tumors 1 (DMBT1) is a secreted glycoprotein displaying a broad bacterial-binding spectrum. Recent functional and genetic studies linked DMBT1 to the suppression of LPS-induced TLR4-mediated NF-kappaB activation and to the pathogenesis of Crohn's disease. Here, we aimed at unraveling the molecular basis of its function in mucosal protection and of its broad pathogen-binding specificity. We report that DMBT1 directly interacts with dextran sulfate sodium (DSS) and carrageenan, a structurally similar sulfated polysaccharide, which is used as a texturizer and thickener in human dietary products. However, binding of DMBT1 does not reduce the cytotoxic effects of these agents to intestinal epithelial cells in vitro. DSS and carrageenan compete for DMBT1-mediated bacterial aggregation via interaction with its bacterial-recognition motif. Competition and ELISA studies identify poly-sulfated and poly-phosphorylated structures as ligands for this recognition motif, such as heparansulfate, LPS, and lipoteichoic acid. Dose-response studies in Dmbt1(-/-) and Dmbt1(+/+) mice utilizing the DSS-induced colitis model demonstrate a differential response only to low but not to high DSS doses. We propose that DMBT1 functions as pattern-recognition molecule for poly-sulfated and poly-phosphorylated ligands providing a molecular basis for its broad bacterial-binding specificity and its inhibitory effects on LPS-induced TLR4-mediated NF-kappaB activation.
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Carragenina/inmunología , Sulfato de Dextran/inmunología , Receptores de Superficie Celular/inmunología , Bacterias/inmunología , Bacterias/metabolismo , Proteínas de Unión al Calcio , Carragenina/farmacología , Carragenina/toxicidad , Línea Celular , Proteínas de Unión al ADN , Sulfato de Dextran/farmacología , Sulfato de Dextran/toxicidad , Células Epiteliales/inmunología , Células Epiteliales/metabolismo , Células Epiteliales/microbiología , Humanos , Mucosa Intestinal/metabolismo , Intestinos/inmunología , Intestinos/microbiología , Ligandos , Fosfatos/inmunología , Fosfatos/metabolismo , Receptores de Superficie Celular/antagonistas & inhibidores , Receptores de Superficie Celular/genética , Receptores de Superficie Celular/metabolismo , Proteínas Supresoras de TumorRESUMEN
BACKGROUND: In 2 preceding studies, delayed release phosphatidylcholine (rPC) was found to (a) improve disease activity and (b) withdraw steroids in patients with chronic-active ulcerative colitis. GOAL: Objective of the study was to determine the most effective rPC dose with least adverse events. STUDY: A randomized, dose-controlled, double-blinded study. Four groups of 10 patients each with nonsteroid-treated, chronic-active ulcerative pancolitis with a clinical activity index (CAI) and endoscopic activity index (EAI) >or=7. Patients were treated with oral rPC at doses of 0.5, 1, 3, and 4 g daily over 12 weeks. RESULTS: The CAI changes from baseline to the end of the study were 2.5 (0.5 g), 7.0 (1 g), 5.5 (3 g), and 6.0 (4 g dose arm). Significant improvement of the CAI was registered between the lowest rPC dose of 0.5 g (control group) and all higher doses of 1.0, 3.0, and 4.0-g rPC (P
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Colitis Ulcerosa/tratamiento farmacológico , Fosfatidilcolinas/uso terapéutico , Adulto , Enfermedad Crónica , Colitis Ulcerosa/fisiopatología , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Náusea/inducido químicamente , Fosfatidilcolinas/administración & dosificación , Fosfatidilcolinas/efectos adversos , Inducción de Remisión/métodos , Índice de Severidad de la Enfermedad , Factores de Tiempo , Resultado del TratamientoRESUMEN
PURPOSE: The death ligand tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and its receptors (TRAIL-R) are involved in immune surveillance and tumor development. Here, we studied a possible association between the expression of TRAIL/TRAIL-Rs and the prognosis in patients with renal cell carcinomas (RCC). EXPERIMENTAL DESIGN: A tissue microarray containing RCC tumor tissue samples and corresponding normal tissue samples from 838 patients was generated. Expression of TRAIL and TRAIL-Rs was examined by immunohistochemistry and the effect of TRAIL and TRAIL-R expression on disease-specific survival was assessed. RESULTS: High TRAIL-R2 expression levels were associated with high-grade RCCs (P < 0.001) and correlated negatively with disease-specific survival (P = 0.01). Similarly, high TRAIL expression was associated with a shorter disease-specific survival (P = 0.01). In contrast, low TRAIL-R4 expression was associated with high-stage RCCs (P < 0.001) as well as with the incidence of distant metastasis (P = 0.03) and correlated negatively with disease-specific survival (P = 0.02). In patients without distant metastasis, multivariate Cox regression analyses revealed that TRAIL-R2 and TRAIL are independent prognostic factors for cancer-specific survival (in addition to tumor extent, regional lymph node metastasis, grade of malignancy, and type of surgery). CONCLUSION: High TRAIL-R2, high TRAIL, and low TRAIL-R4 expression levels are associated with a worse disease-specific survival in patients with RCCs. Therefore, the assessment of TRAIL/TRAIL-R expression offers valuable prognostic information that could be used to select patients for adjuvant therapy studies. Moreover, our findings are of relevance for a potential experimental therapeutic administration of TRAIL-R agonists in patients with RCCs.
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Carcinoma de Células Renales/diagnóstico , Carcinoma de Células Renales/metabolismo , Regulación Neoplásica de la Expresión Génica , Neoplasias Renales/diagnóstico , Neoplasias Renales/metabolismo , Receptores del Ligando Inductor de Apoptosis Relacionado con TNF/metabolismo , Ligando Inductor de Apoptosis Relacionado con TNF/metabolismo , Anciano , Femenino , Perfilación de la Expresión Génica , Humanos , Masculino , Persona de Mediana Edad , Análisis de Secuencia por Matrices de Oligonucleótidos , Pronóstico , Modelos de Riesgos Proporcionales , Resultado del TratamientoRESUMEN
BACKGROUND: High-mobility group box-1 (HMGB1) is a nuclear factor released by necrotic cells and by activated immune cells. HMGB1 signals via members of the toll-like receptor family and the receptor for advanced glycation end products (RAGE). Although HMGB1 has been implicated in ischemia/reperfusion (I/R) injury of the liver and lung, its role in I/R injury of the heart remains unclear. METHODS AND RESULTS: Here, we demonstrate that HMGB1 acts as an early mediator of inflammation and organ damage in I/R injury of the heart. HMGB1 levels were already elevated 30 minutes after hypoxia in vitro and in ischemic injury of the heart in vivo. Treatment of mice with recombinant HMGB1 worsened I/R injury, whereas treatment with HMGB1 box A significantly reduced infarct size and markers of tissue damage. In addition, HMGB1 inhibition with recombinant HMGB1 box A suggested an involvement of the mitogen-activated protein kinases jun N-terminal kinase and extracellular signal-regulated kinase 1/2, as well as the nuclear transcription factor nuclear factor-kappaB in I/R injury. Interestingly, infarct size and markers of tissue damage were not affected by administration of recombinant HMGB1 or HMGB1 antagonists in RAGE(-/-) mice, which demonstrated significantly reduced damage in reperfused hearts compared with wild-type mice. Coincubation studies using recombinant HMGB1 in vitro induced an inflammatory response in isolated macrophages from wild-type mice but not in macrophages from RAGE(-/-) mice. CONCLUSIONS: HMGB1 plays a major role in the early event of I/R injury by binding to RAGE, resulting in the activation of proinflammatory pathways and enhanced myocardial injury. Therefore, blockage of HMGB1 might represent a novel therapeutic strategy in I/R injury.
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Proteína HMGB1/metabolismo , Isquemia Miocárdica/metabolismo , Daño por Reperfusión/prevención & control , Animales , Células Cultivadas , Ecocardiografía , Proteína HMGB1/antagonistas & inhibidores , Proteína HMGB1/farmacología , Inmunohistoquímica , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Isquemia Miocárdica/tratamiento farmacológico , Isquemia Miocárdica/patología , Unión Proteica , Receptor para Productos Finales de Glicación Avanzada , Receptores Inmunológicos/genética , Receptores Inmunológicos/metabolismo , Proteínas Recombinantes/farmacología , Daño por Reperfusión/inmunología , Daño por Reperfusión/patología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Transducción de Señal/inmunología , Regulación hacia Arriba/efectos de los fármacosRESUMEN
BACKGROUND & AIMS: T-cell receptor reactivity of intestinal lamina propria T cells (LP-T) critically depends on the capacity of local accessory cells to secrete cysteine. For T cells, cysteine is the limiting precursor for glutathione synthesis, a prerequisite for antigen-dependent proliferation. We aimed to determine the role of the redoxactive microenvironment for hyporeactivity of LP-T in normal human gut vs hyperreactivity of LP-T in inflammatory bowel disease. METHODS: Parameters relevant to cysteine production, determined as acid-soluble thiol, by intestinal lamina propria macrophages (LP-MO) vs peripheral blood monocytes were investigated (L-[(35)S]cystine uptake via system x(c)(-), messenger RNA, and protein expression of the cystine transporter subunit xCT). Glutathione levels in LP-T and peripheral blood T cells were analyzed both spectrophotometrically and by immunofluorescent staining in situ and in vitro. RESULTS: LP-MO from normal gut, unlike peripheral blood monocytes, are unable to take up cystine, which is due to a deficient expression of the transporter xCT in situ and in vitro. As a consequence, LP-MO do not secrete cysteine. The glutathione content in LP-T from normal gut is <50% of that in autologous peripheral blood T cells. In contrast, in inflammatory bowel disease, CD14(+)CD68(+) LP-MO express xCT and secrete substantial amounts of cysteine upon stimulation, which results in high glutathione levels and full T-cell receptor reactivity in LP-T. CONCLUSIONS: The antioxidative microenvironment of LP-T in inflammatory bowel disease and the prooxidative microenvironment in normal gut explain the differential T-cell receptor reactivities.
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Cisteína/metabolismo , Cistina/metabolismo , Inmunidad Mucosa/fisiología , Enfermedades Inflamatorias del Intestino/inmunología , Enfermedades Inflamatorias del Intestino/metabolismo , Mucosa Intestinal/metabolismo , Estudios de Casos y Controles , Técnicas de Cultivo de Célula , Cisteína/genética , Cistina/genética , Glutatión/metabolismo , Humanos , Enfermedades Inflamatorias del Intestino/patología , Mucosa Intestinal/inmunología , Mucosa Intestinal/patología , ARN Mensajero/metabolismo , Linfocitos T/fisiologíaRESUMEN
We present a case of primary renal chondrosarcoma, its diagnosis and management.
Asunto(s)
Condrosarcoma/diagnóstico , Neoplasias Renales/diagnóstico , Adulto , Condrosarcoma/patología , Diagnóstico Diferencial , Femenino , Humanos , Neoplasias Renales/patología , Adulto JovenRESUMEN
BACKGROUND & AIMS: Impaired mucosal defense plays an important role in the pathogenesis of Crohn's disease (CD), one of the main subtypes of inflammatory bowel disease (IBD). Deleted in malignant brain tumors 1 (DMBT1) is a secreted scavenger receptor cysteine-rich protein with predominant expression in the intestine and has been proposed to exert possible functions in regenerative processes and pathogen defense. Here, we aimed at analyzing the role of DMBT1 in IBD. METHODS: We studied DMBT1 expression in IBD and normal tissues by quantitative reverse transcription-polymerase chain reaction, immunohistochemistry, and mRNA in situ hybridization. Genetic polymorphisms within DMBT1 were analyzed in an Italian IBD case-control sample. Dmbt1(-/-) mice were generated, characterized, and analyzed for their susceptibility to dextran sulfate sodium-induced colitis. RESULTS: DMBT1 levels correlate with disease activity in inflamed IBD tissues. A highly significant fraction of the patients with IBD displayed up-regulation of DMBT1 specifically in the intestinal epithelial surface cells and Paneth cells. A deletion allele of DMBT1 with a reduced number of scavenger receptor cysteine-rich domain coding exons is associated with an increased risk of CD (P = .00056; odds ratio, 1.75) but not for ulcerative colitis. Dmbt1(-/-) mice display enhanced susceptibility to dextran sulfate sodium-induced colitis and elevated Tnf, Il6, and Nod2 expression levels during inflammation. CONCLUSIONS: DMBT1 may play a role in intestinal mucosal protection and prevention of inflammation. Impaired DMBT1 function may contribute to the pathogenesis of CD.
Asunto(s)
Enfermedad de Crohn/genética , Enfermedad de Crohn/fisiopatología , Eliminación de Gen , Mucosa Intestinal/fisiopatología , Receptores de Superficie Celular/genética , Receptores de Superficie Celular/fisiología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Animales , Proteínas de Unión al Calcio , Estudios de Casos y Controles , Niño , Enfermedad de Crohn/inducido químicamente , Proteínas de Unión al ADN , Sulfato de Dextran , Susceptibilidad a Enfermedades , Exones/genética , Femenino , Humanos , Interleucina-6/metabolismo , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patología , Masculino , Ratones , Ratones Transgénicos , Persona de Mediana Edad , Mucinas/genética , Mucinas/fisiología , Proteína Adaptadora de Señalización NOD2/metabolismo , ARN Mensajero/metabolismo , Factores de Riesgo , Factor de Necrosis Tumoral alfa/metabolismo , Proteínas Supresoras de Tumor , Regulación hacia Arriba/genéticaRESUMEN
OBJECTIVES: To assess the protein expression of Livin, an apoptosis inhibitor, in renal cell carcinoma (RCC) and to determine its prognostic relevance. PATIENTS AND METHODS: Immunohistochemical staining for Livin was performed in tissue microarrays (TMAs), including tumour tissue cores, from patients with RCC who had undergone renal surgery. In 682 TMAs cytoplasmatic staining intensity and nuclear staining quantity were evaluated, and the association of Livin expression with progression-free survival (PFS) and cancer-specific survival (CSS) was analysed with a multivariate Cox regression model. RESULTS: Over a median (range) follow-up of 5.2 (0-16.1) years, 204 patients (28%) had died from their disease. The CSS rates at 1 and 5 years for the entire cohort was 88% and 71%. Cytoplasmatic Livin staining was absent in 516 (76%) specimens; staining was positive in 166 (24%) specimens. Weak nuclear Livin staining (
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Proteínas Adaptadoras Transductoras de Señales/metabolismo , Biomarcadores de Tumor/metabolismo , Carcinoma de Células Renales/patología , Proteínas Inhibidoras de la Apoptosis/metabolismo , Neoplasias Renales/patología , Proteínas de Neoplasias/metabolismo , Nefrectomía/métodos , Anciano , Carcinoma de Células Renales/mortalidad , Carcinoma de Células Renales/cirugía , Estudios de Cohortes , Femenino , Humanos , Neoplasias Renales/mortalidad , Neoplasias Renales/cirugía , Masculino , Persona de Mediana Edad , Análisis Multivariante , Pronóstico , Estudios Prospectivos , Factores de Riesgo , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
AIM: We describe the clinical features of a 6-year-old boy with sexual precocity caused by a somatic activating mutation of the luteinizing hormone (LH) receptor gene preceding gonadotropin-releasing hormone (GnRH)-dependent sexual precocity. STUDY DESIGN: Genomic DNA was extracted from the right testis and from the peripheral leukocytes followed by DNA amplification and sequencing of the LH receptor gene. We described the clinical characteristics including anthropometric parameters, bone age, and endocrine evaluation when the boy presented with sexual precocity. These data were compared with the clinical and hormonal evaluation after orchiectomy preceding GnRH-dependent sexual precocity and after subsequent treatment with GnRH agonist. RESULTS: No mutation was found in the sequence of the LH receptor gene extracted from peripheral leukocytes. Interestingly, sequencing of the tumor LH receptor gene revealed a heterozygous mutation in exon 11 encoding a replacement of Asp(578)His. Despite normalization of plasma testosterone, true precocious puberty was triggered within a year. CONCLUSIONS: Inmales with GnRH-independent sexual precocity the presence of small testicular Leydig cell tumorous lesions harboring a somatic mutation of the LH receptor gene should be considered. A close follow-up of affected patients should be instigated in order to monitor recurrence or subsequent true precocity.
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Tumor de Células de Leydig/genética , Mutación Missense , Proteínas de Neoplasias/genética , Pubertad Precoz/genética , Receptores de HL/genética , Neoplasias Testiculares/genética , Sustitución de Aminoácidos , Niño , Exones/genética , Hormona Liberadora de Gonadotropina/sangre , Heterocigoto , Humanos , Tumor de Células de Leydig/sangre , Tumor de Células de Leydig/fisiopatología , Masculino , Proteínas de Neoplasias/metabolismo , Pubertad Precoz/sangre , Pubertad Precoz/fisiopatología , Receptores de HL/metabolismo , Neoplasias Testiculares/sangre , Neoplasias Testiculares/fisiopatologíaRESUMEN
BACKGROUND: Although long-term steroid treatment is discouraged in ulcerative colitis, alternatives are lacking when therapy with immunosuppressant drugs fails. An insufficient level of phosphatidylcholine in colonic mucus is a possible pathogenetic factor for ulcerative colitis. OBJECTIVE: To see whether steroid withdrawal is easier with retarded-release phosphatidylcholine or placebo in adults with chronic steroid-refractory ulcerative colitis. DESIGN: Randomized, double-blind, placebo-controlled trial conducted from March 2003 to January 2006. SETTING: University Hospital Heidelberg, a referral center for inflammatory bowel disease. PATIENTS: 60 patients with chronic steroid-refractory ulcerative colitis and high clinical and endoscopic disease activity indexes (score > or =5). INTERVENTION: Phosphatidylcholine or cellulose placebo was ingested 4 times daily for 12 weeks for a total dosage of 2 g/d. The follow-up rate was 97%. MEASUREMENTS: The number of patients achieving complete steroid withdrawal and either a low clinical activity index (< or =3) or improvement in the clinical activity index of 50% or more. RESULTS: The primary end point was achieved in 15 of 30 (50%) phosphatidylcholine recipients and in 3 of 30 (10%) placebo recipients (difference, 40% [95% CI, 19% to 61%]; P = 0.002). Twenty-four phosphatidylcholine recipients (80%) and 3 (10%) placebo recipients discontinued steroid therapy without disease exacerbation (difference, 70% [CI, 52% to 88%]; P <0.001). Mild bloating was a common adverse event. LIMITATIONS: The sample size was small, and the study was of short duration. CONCLUSION: Phosphatidylcholine reduced corticosteroid dependence more than placebo in patients with chronic steroid-refractory ulcerative colitis. The next step is long-term trials to evaluate the sustainability of steroid withdrawal in these patients. ClinicalTrials.gov registration number: NCT00259545.
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Corticoesteroides/administración & dosificación , Colitis Ulcerosa/tratamiento farmacológico , Fosfatidilcolinas/administración & dosificación , Corticoesteroides/efectos adversos , Adulto , Colitis Ulcerosa/metabolismo , Colitis Ulcerosa/patología , Preparaciones de Acción Retardada , Método Doble Ciego , Endoscopía Gastrointestinal , Femenino , Estudios de Seguimiento , Humanos , Mucosa Intestinal/metabolismo , Masculino , Moco/metabolismo , Fosfatidilcolinas/efectos adversos , Fosfatidilcolinas/farmacocinética , Calidad de Vida , Tamaño de la Muestra , Resultado del TratamientoRESUMEN
The vascular type of Ehlers-Danlos syndrome (type IV) is an infrequent disease caused by heterozygous germline mutations in the procollagen 3A gene (COL3A1). Clinical signs include characteristic facial features, easy bruising, and a translucent skin. These signs are less obvious than the hyperflexibility of skin and joints seen in other types of Ehlers-Danlos syndrome. Therefore, diagnosis of Ehlers-Danlos syndrome type IV is usually not considered until complications have occurred. Complications include spontaneous ruptures of vessels and hollow organs, particularly the colon. We, herein, report pathologic findings in colon specimens from related Ehlers-Danlos syndrome type IV patients. Thorough examination revealed abnormalities of the large bowel architecture including abrupt changes in the caliber of the lamina muscularis, secondary diverticula formation, and strongly reduced expression of abnormal collagen 3. These findings are not seen in other diseases of the colon and should prompt the pathologist to include Ehlers-Danlos syndrome type IV in the differential diagnosis of spontaneous bowel perforation in younger patients.
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Colon/patología , Síndrome de Ehlers-Danlos/clasificación , Síndrome de Ehlers-Danlos/patología , Adulto , Colágeno Tipo III/metabolismo , Colon/metabolismo , Enfermedades del Colon/etiología , Enfermedades del Colon/patología , Diagnóstico Diferencial , Divertículo/etiología , Divertículo/patología , Síndrome de Ehlers-Danlos/complicaciones , Síndrome de Ehlers-Danlos/metabolismo , Femenino , Humanos , Inmunohistoquímica , Perforación Intestinal/diagnóstico , Masculino , Microscopía ElectrónicaRESUMEN
This leading article refers to the paper by Meier-Ruge WA, Muller-Lobeck H, Stoss F, Bruder E. The pathogenesis of idiopathic megacolon. Eur J Gastroenterol Hepatol 2006; 18:1209-1215. We apologise to all concerned for the dissociation between the two papers, which was due to an administrative error. The pathogenesis of idiopathic megacolon is still unclear. Besides abnormalities of the enteric nervous system, alterations in the function of intestinal smooth muscle cells and connective tissue elements might play an important role. A permanent extension of the bowel diameter without concrete hints to its aetiology is termed idiopathic megacolon. Evidence exists that idiopathic megacolon comprises a heterogeneous group of conditions characterized by alterations of the enteric nervous system, smooth muscle cells and/or connective tissue. Innovative molecular techniques are needed to get further insights into the pathogenesis of these intestinal motility disorders.
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Megacolon/fisiopatología , Tejido Conectivo/fisiopatología , Sistema Nervioso Entérico/fisiopatología , Motilidad Gastrointestinal , Humanos , Intestinos/fisiopatología , Megacolon/etiología , Músculo Liso/fisiopatologíaRESUMEN
AIM: To study susceptibility genes which may play a potential role in the pathogenesis and etiology of inflammatory bowel disease (IBD). METHODS: To identify potential susceptibility genes we performed global gene expression profiling in patients with IBD and control specimens. For determination of an intrinsic gene expression profile in ulcerative colitis (UC) and Crohn's disease (CD) compared to normal subjects, mucosal biopsies of non-inflamed regions of the colon and the terminal ileum were subjected to DNA microarray analysis. Real-time RT-PCR and immunohistochemistry were used for verification of selected regulated candidate genes and a genetic analysis was performed. RESULTS: We could show that aquaporin-8 (AQP8) mRNA and protein levels were significantly increased in the colon of UC patients compared to controls. Genetic analysis of the six exons and the promoter region of AQP8, however, revealed no mutations or polymorphisms in IBD patients. CONCLUSION: Our results suggest that upregulation of AQP8 in the colon of UC patients represents a secondary phenomenon which may, due to altered water exchange of the distal intestinal mucosa, disturb the physiologic colonic mucus barrier and thus lead to chronic inflammation and ulceration.
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Acuaporinas/metabolismo , Colitis Ulcerosa/metabolismo , Colon/metabolismo , Íleon/metabolismo , Adulto , Acuaporinas/genética , Biopsia , Estudios de Casos y Controles , Colitis Ulcerosa/etiología , Colon/patología , Susceptibilidad a Enfermedades/metabolismo , Susceptibilidad a Enfermedades/patología , Femenino , Regulación de la Expresión Génica , Humanos , Íleon/patología , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patología , Masculino , Persona de Mediana Edad , Análisis de Secuencia por Matrices de Oligonucleótidos , ARN Mensajero/genética , ARN Mensajero/metabolismoRESUMEN
BACKGROUND AND AIMS: Low anterior resection and abdominoperineal resection with total mesorectal excision are the standard treatment in patients with low rectal cancer. Rectal resection remains a surgical intervention with considerable morbidity and long-term impairment of quality of life. Local excision of low rectal cancer is regarded as an alternative to radical surgery; however, occurrence of lymph node metastasis even in patients with highly differentiated early-stage rectal cancer may be underestimated. PATIENTS AND RESULTS: In two patients with T1 rectal cancer, minimal-invasive partial excision of the mesorectum was performed after transanal excision of the tumor. The postoperative course was uneventful in both patients. Patients left the hospital on the fourth and fifth postoperative day without any complaints. In one patient, histo-pathological workup revealed a lymph node metastasis in the specimen. DISCUSSION: The technique of "Endoscopic posterior mesorectal resection" represents an interesting option in the surgical treatment of rectal cancer, as it allows for the first time an organ preserving resection of local lymph nodes in the small pelvis. It may evolve as an efficient new staging procedure to identify patients with metastatic disease who may benefit from multimodal treatment or extended surgery.
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Adenocarcinoma/cirugía , Endoscopía , Escisión del Ganglio Linfático , Procedimientos Quirúrgicos Mínimamente Invasivos , Proctoscopía , Neoplasias del Recto/cirugía , Adenocarcinoma/patología , Anciano , Terapia Combinada , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Invasividad Neoplásica , Estadificación de Neoplasias , Neoplasias del Recto/patología , Recto/patología , Recto/cirugía , ReoperaciónRESUMEN
BACKGROUND/AIMS: Severe gastric inflammation or ulcer disease can alter gastric motility and influence sufficient glycemic control in patients with type 2 diabetes mellitus. However, visceral neuropathy may reduce the perception of typical gastrointestinal symptoms in these patients. The aim of the present study was to evaluate the prevalence of silent severe acute gastritis, gastric ulcers or erosions in asymptomatic patients with diabetes mellitus and to determine potential predictive parameters. METHODOLOGY: Seventy-two patients with type 2 diabetes mellitus and little or no dyspeptic symptoms were investigated by endoscopy of the upper gastrointestinal tract under screening conditions. Before endoscopy the presence of gastrointestinal symptoms and standard laboratory parameters were determined. In addition, the presence of Helicobacter pylori infection was investigated by rapid urease test and histology. RESULTS: Highly active gastric inflammation was found in 34 patients (gastric ulcers in 10, gastric erosions in 21, and histologically acute, grade two or three gastritis in 3 patients). Episodic heartburn was significantly associated with highly active gastric inflammation (odds ratio 2.96 (1.05-8.32), p = 0.036). Elevated levels of C-reactive-protein and blood leukocyte counts proved to be of positive predictive value for highly active gastric inflammation in patients without other causes of acute inflammatory diseases (odds ratio 3.52 (p = 0.026) and 7.64 (p = 0.007) respectively). No significant association was found for gender, age, duration of disease, BMI, considerably raised HbA1c (>8.5%), complications of diabetic disease, general gastrointestinal symptoms, Helicobacter pylori infections and therapy with acetylsalicylic acid on 100 mg/d. CONCLUSIONS: The results of this study indicate that severe acute gastric inflammation or ulcer disease can occur with high prevalence in patients with diabetes mellitus with little or no dyspeptic symptoms. Additional endoscopic investigations might be of particular diagnostic value in patients with inexplicable raised levels of inflammatory parameters like C-reactive-protein or blood leukocyte counts.
Asunto(s)
Diabetes Mellitus Tipo 2/epidemiología , Gastritis/epidemiología , Úlcera Gástrica/epidemiología , Enfermedad Aguda , Adulto , Anciano , Anciano de 80 o más Años , Pruebas Respiratorias , Proteína C-Reactiva/metabolismo , Comorbilidad , Estudios Transversales , Neuropatías Diabéticas/epidemiología , Endoscopía del Sistema Digestivo , Femenino , Alemania , Pirosis/epidemiología , Infecciones por Helicobacter/epidemiología , Helicobacter pylori , Humanos , Recuento de Leucocitos , Masculino , Tamizaje Masivo , Persona de Mediana Edad , Estudios Prospectivos , Estadística como AsuntoRESUMEN
Gata-3 has been shown to specifically alter its expression patterns in different types of cancers. Recent evidence suggests that an interference of Gata-3 exists in the TGF-beta signaling pathway. To determine the role of Gata-3 in pancreatic cancer, pancreatic cancer samples were analyzed in comparison to normal pancreatic tissues. Furthermore, four different pancreatic cancer cell lines with different alterations of the TGF-beta pathway were studied. To evaluate if a potential relationship with TGF-beta signaling pathway exists, we correlated mRNA expression levels with the expression of TGF-betas, TGF-beta receptors, and Smad-3. Finally, we analyzed the influence of TGF-beta on Gata-3 expression in vitro. All pancreatic cancer samples demonstrated a marked overexpression of Gata-3 mRNA and protein. Immunohistochemical staining revealed strong and persistent cytoplasmic Gata-3 immunoreactivity in cancer cells. In an electrophoretic mobility shift assay, a disturbed nuclear translocation was confirmed. The expression of Gata-3 showed a significant correlation with the expression of TGF-betas, TGF-beta receptors, and Smad-3. TGF-beta responsive cell lines showed a downregulation of Gata-3 mRNA upon TGF-beta exposure, whereas in TGF-beta-unresponsive cell lines, Gata-3 mRNA expression persisted at high levels. Furthermore, strong specific upregulation of Gata-3 impaired nuclear translocation and its cooperative action with the TGF-beta pathway, suggesting that Gata-3 plays a central role in human pancreatic cancer.
Asunto(s)
Factor de Transcripción GATA3/biosíntesis , Neoplasias Pancreáticas/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Línea Celular Tumoral , Núcleo Celular/metabolismo , Citoplasma/metabolismo , Ensayo de Cambio de Movilidad Electroforética , Femenino , Factor de Transcripción GATA3/genética , Humanos , Inmunohistoquímica , Masculino , Microscopía Confocal , Persona de Mediana Edad , Estadificación de Neoplasias , Páncreas/metabolismo , Transporte de Proteínas , ARN Mensajero/biosíntesis , Transducción de Señal , Factor de Crecimiento Transformador beta/farmacología , Factor de Crecimiento Transformador beta/fisiología , Regulación hacia ArribaRESUMEN
BACKGROUND: CD4+CD25+ regulatory T cells have been shown to prevent immune-mediated colitis in mice; however, it is unclear whether the absence of CD4+CD25+ in the normal CD4+ T cell pool is responsible for the development of chronic colitis. Using the T cell-deficient Tgepsilon26 mouse model, we show that CD4+CD25- cells but not CD4+CD25+ cells induce a severe intestinal inflammation. Transfer of CD4+CD25+ cells, together with CD4+CD25- cells, ameliorated intestinal inflammation, and reconstitution with the whole mesenteric lymph node cell pool did not induce colitis in recipients. Transferred CD4+CD25- cells were found mainly in the mesenteric lymph nodes, where they showed an activated TH1-like phenotype. In the absence of regulatory CD4+CD25+ T cells, recipient CD4 cells secreted IFN-gamma in response to stimulation with intestinal bacterial antigen that was prevented in vivo and in vitro by regulatory CD4+CD25+ cells. These studies suggest that CD4+CD25- cells have a strong colitogenic effect in the Tgepsilon26 colitis model and that CD4+CD25+ cells may be the main regulators that prevent or downregulate the proinflammatory effect of colitogenic T cells in the Tgepsilon26 mouse model.
Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Colitis/inmunología , Tolerancia Inmunológica , Intestinos/inmunología , Receptores de Interleucina-2/análisis , Subgrupos de Linfocitos T/inmunología , Animales , Linfocitos T CD4-Positivos/patología , Enfermedad Crónica , Colitis/microbiología , Colitis/patología , Modelos Animales de Enfermedad , Huésped Inmunocomprometido , Intestinos/microbiología , Intestinos/patología , Ganglios Linfáticos/inmunología , Ganglios Linfáticos/patología , Depleción Linfocítica , Mesenterio/inmunología , Mesenterio/patología , Ratones , Bazo/inmunología , Bazo/patología , Subgrupos de Linfocitos T/patologíaRESUMEN
Independent of the severity, phenotypes and clinical outcomes of myocardial infarction may vary considerably in patients, suggesting a strong genetic influence on healing and adaptive processes. Since little is known about these genetic determinants, we examined the tissue response to myocardial injury in seven inbred mouse strains, including those employed for gene targeting or transgenic overexpression. Myocardial necrosis was produced by non-ischemic, trans-diaphragmal freeze-thaw injury in strains C57BL/6, C3H/He, DBA/2, BALB/c, 129S1, FVB/n and A/J. Two days after injury, necrotic cardiomyocytes calcified in C3H/He, DBA/2, BALB/c and 129S1, a phenotype known as dystrophic cardiac calcinosis (DCC). The susceptibility to DCC of 129S1 was determined by Dyscalc1, a locus on chromosome 7, which was identified previously in C3H/He and DBA/2. DCC was also observed in C3H/He following ischemic injury by permanent coronary artery ligation, indicating that DCC was independent of the mode of injury. In contrast, strains C57BL/6, FVB and A/J were resistant to DCC, showing formation of a fibrous scar without calcification. The development of DCC was studied in detail in C3H/He and C57BL/6. In both strains, no calcium deposition and only little structural disintegration were noted in necrotic myocardium 24 h after injury upon calcium-sensitive fluorescence staining. Ultrastructural examination revealed calcified mitochondria in C3H/He that may have served later as a nidus for rapid intracellular calcification of cardiomyocytes. We concluded that the susceptibility to calcification of myocardial necrosis may be common among inbred strains and should be recognised as a strong genetic modifier of experimental myocardial injury.