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PURPOSE: The diagnosis microscopic colitis (MC) consisting of collagenous colitis (CC) and lymphocytic colitis (LC) relies on histological assessment of mucosal biopsies from the colon. The optimal biopsy strategy for reliable diagnosis of MC is controversial. The aim of this study was to evaluate the distribution of histopathological features of MC throughout the colon. METHODS: Mucosal biopsies from multiple colonic segments of patients with MC who participated in one of the three prospective European multicenter trials were analyzed. Histological slides were stained with hematoxylin-and-eosin, a connective tissue stain, and CD3 in selected cases. RESULTS: In total, 255 patients were included, 199 and 56 patients with CC and LC, respectively. Both groups exhibited a gradient with more pronounced inflammation in the lamina propria in the proximal colon compared with the distal colon. Similarly, the thickness of the subepithelial collagenous band in CC showed a gradient with higher values in the proximal colon. The mean number of intraepithelial lymphocytes was > 20 in all colonic segments in patients within both subgroups. Biopsies from 86 to 94% of individual segments were diagnostic, rectum excluded. Biopsies from non-diagnostic segments often showed features of another subgroup of MC. CONCLUSION: Conclusively, although the severity of the histological changes in MC differed in the colonic mucosa, the minimum criteria required for the diagnosis were present in the random biopsies from the majority of segments. Thus, our findings show MC to be a pancolitis, rectum excluded, questioning previously proclaimed patchiness throughout the colon.
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Colite Colagenosa , Colite Microscópica , Colite , Biópsia , Colo , Humanos , Estudos ProspectivosRESUMO
BACKGROUND & AIMS: Lymphocytic colitis is a common cause of chronic, nonbloody diarrhea. However, the effects of treatment are unclear and randomized placebo-controlled trials were requested in a Cochrane review. We performed a randomized, placebo-controlled, multicenter study to evaluate budesonide and mesalazine as induction therapy for lymphocytic colitis. METHODS: Patients with active lymphocytic colitis were randomly assigned to groups given budesonide 9 mg once daily (Budenofalk granules), mesalazine 3 g once daily (Salofalk granules), or placebo for 8 weeks in a double-blind, double-dummy design. The primary endpoint was clinical remission, defined as ≤21 stools (including ≤6 watery stools), in the 7 days before week 8. RESULTS: The final analysis included 57 patients (19 per group). Most patients were female (72%) and the mean age was 59 years. The proportion of patients in clinical remission at week 8 was significantly higher in the budesonide group than in the placebo group (intention-to-treat analysis, 79% vs 42%; P = .01). The difference in proportions of patients in clinical remission at week 8 between the mesalazine (63%) and placebo groups was not significant (P = .09). The proportion of patients with histologic remission at week 8 was significantly higher in the budesonide group (68%) vs the mesalazine (26%; P = .02) or placebo (21%; P = .008) groups. The incidence of adverse events was 47.4% in the budesonide group, 68.4% in the mesalazine group, and 42.1% in the placebo group. CONCLUSIONS: In a randomized multicenter study, we found oral budesonide 9 mg once daily to be effective and safe for induction of clinical and histologic remission in patients with lymphocytic colitis, compared with placebo. Oral mesalazine 3 g once daily was not significantly better than placebo. ClinicalTrials.gov no: NCT01209208.
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Anti-Inflamatórios/uso terapêutico , Budesonida/uso terapêutico , Colite Linfocítica/tratamento farmacológico , Mesalamina/uso terapêutico , Administração Oral , Anti-Inflamatórios/administração & dosagem , Budesonida/administração & dosagem , Colite Linfocítica/patologia , Método Duplo-Cego , Esquema de Medicação , Feminino , Humanos , Quimioterapia de Indução , Masculino , Mesalamina/administração & dosagem , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
BACKGROUND: Over the past decade, treatment targets for ulcerative colitis (UC) have become more stringent, incorporating multiple parameters. Recently, the concept of 'disease clearance'-defined as combined clinical, endoscopic, and histological remission-has been proposed as an ultimate endpoint in treating UC. OBJECTIVE: To determine the rates of disease clearance in patients with mild-to-moderate UC treated with different doses of mesalazine granules as induction therapy. METHODS: In a post hoc analysis, data were pooled from four randomised, active-controlled, phase 3 clinical trials in patients with mild-to-moderate UC receiving 8-week induction therapy with mesalazine granules at daily doses of 1.5, 3.0 or 4.5 g. Rates of clinical, endoscopic, and histological remission were determined using stringent criteria and used to calculate rates of the composite endpoints of clinical plus endoscopic remission, endoscopic plus histological remission, and disease clearance (clinical plus endoscopic plus histological remission). RESULTS: A total of 860 patients were included in the analysis. Among the total population, 20.0% achieved disease clearance with mesalazine granules: 13.1% in patients receiving 1.5 g mesalazine granules/day, 21.8% in those receiving 3.0 g/day and 18.9% in those receiving 4.5 g/day. Among patients with moderate UC, 16.8% achieved disease clearance: 7.1% with 1.5 g/day, 18.8% with 3.0 g/day and 16.2% with 4.5 g/day. CONCLUSION: Disease clearance, proposed to be predictive of improved long-term outcomes, can be achieved in a clinically meaningful proportion of mild-to-moderate UC patients treated with mesalazine granules. A daily dose of 3.0 g appears optimal to reach this target.
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Colite Ulcerativa , Mesalamina , Humanos , Colite Ulcerativa/diagnóstico , Colite Ulcerativa/tratamento farmacológico , Anti-Inflamatórios não Esteroides , Endoscopia , Indução de RemissãoRESUMO
BACKGROUND: In patients with mesalazine-refractory ulcerative colitis, systemic corticosteroids are the treatment of choice. OBJECTIVE: To evaluate the efficacy and safety of prolonged release budesonide granules for the induction of remission in patients with mesalazine-refractory ulcerative colitis. METHODS: Patients with mesalazine-refractory ulcerative colitis discontinued mesalazine at baseline and received 9 mg prolonged release budesonide granules daily for 8 weeks in this open-label, phase IIa study, followed by a 2-week follow-up phase wherein patients continued treatment on alternate days (EudraCT number 2014-005635-14; ClinicalTrials.gov identifier NCT02550418). The primary endpoint was clinical remission (Clinical Activity Index ≤4; stool frequency <18 per week; absence of rectal bleeding) at Week 8. Secondary endpoints included clinical, endoscopic and histological measures of disease at Week 8. A post hoc analysis assessed histo-endoscopic mucosal healing. Treatment-emergent adverse events and morning cortisol levels were assessed throughout the treatment and follow-up phases. RESULTS: A total of 61 patients were included in the intention-to-treat population; 50 were included in the follow-up analysis set. Clinical remission was achieved in 29 patients (47.5%; 95% confidence interval: 34.6-60.7%) by Week 8. Mean stool and bloody stool frequency decreased significantly from 32.5 to 22.9 per week (p<0.0001) and from 17.6 to 8.1 per week (p<0.0001), respectively. Rates of mucosal healing, endoscopic remission and histological remission were 58.0%, 54.0% and 36.0%, respectively. Histo-endoscopic mucosal healing was achieved by 34.0% of patients. Twenty-four patients (39.3%) experienced treatment-emergent adverse events, of which gastrointestinal disorders (16.4%) were the most common. Mean morning cortisol levels were not significantly suppressed by Week 8. CONCLUSIONS: Treatment with prolonged release budesonide granules for 8 weeks was associated with clinical, endoscopic and histological remission and demonstrated a favourable safety profile in patients with mesalazine-refractory ulcerative colitis. These results warrant further investigation into the potential of prolonged release budesonide granules as an alternative treatment for this patient population.
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Anti-Inflamatórios/administração & dosagem , Budesonida/administração & dosagem , Colite Ulcerativa/tratamento farmacológico , Mesalamina/farmacologia , Administração Oral , Adolescente , Adulto , Idoso , Anti-Inflamatórios/efeitos adversos , Anti-Inflamatórios não Esteroides , Budesonida/efeitos adversos , Budesonida/farmacologia , Budesonida/uso terapêutico , Colite Ulcerativa/diagnóstico , Colite Ulcerativa/imunologia , Colite Ulcerativa/patologia , Colo/diagnóstico por imagem , Colo/efeitos dos fármacos , Colo/imunologia , Colo/patologia , Colonoscopia , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/efeitos adversos , Esquema de Medicação , Resistência a Medicamentos , Feminino , Humanos , Mucosa Intestinal/diagnóstico por imagem , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/imunologia , Mucosa Intestinal/patologia , Masculino , Mesalamina/uso terapêutico , Pessoa de Meia-Idade , Estudo de Prova de Conceito , Indução de Remissão/métodos , Resultado do Tratamento , Adulto JovemRESUMO
Sprouting and invasive migration of endothelial cells are important steps of the angiogenic cascade. Vascular endothelial growth factor (VEGF) induces angiogenesis by activating intracellular signal transduction cascades, which regulate endothelial cell morphology and function. BTB-kelch proteins are intracellular proteins that control cellular architecture and cellular functions. The BTB-kelch protein KLEIP has been characterized as an actin-binding protein that interacts with the nucleotide exchange factor ECT2. We report that KLEIP is preferentially expressed in endothelial cells, suggesting that it may play a critical role in controlling the functions of migrating, proliferating, and invading endothelial cells during angiogenesis. KLEIP mRNA level in endothelial cells is strongly regulated by hypoxia which is controlled by hypoxia-inducible factor-1alpha. Functional analysis of KLEIP in endothelial cells revealed that it acts as an essential downstream regulator of VEGF- and basic fibroblast growth factor-induced migration and in-gel sprouting angiogenesis. Yet, it is not involved in controlling VEGF- or basic fibroblast growth factor-mediated proliferative responses. The depletion of KLEIP in endothelial cells blunted the VEGF-induced activation of the monomeric GTPase RhoA but did not alter the VEGF-stimulated activation of extracellular signal-regulated kinase 1/2. Moreover, VEGF induced a physical association of KLEIP with the guanine nucleotide-exchange factor ECT2, the depletion of which also blunted VEGF-induced sprouting. We conclude that the BTB-kelch protein KLEIP is a novel regulator of endothelial function during angiogenesis that controls the VEGF-induced activation of Rho GTPases.
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Proteínas de Transporte/fisiologia , Movimento Celular/fisiologia , Células Endoteliais/fisiologia , Proteínas dos Microfilamentos/fisiologia , Neovascularização Fisiológica/fisiologia , Células Cultivadas , Células Endoteliais/citologia , HumanosRESUMO
Background: The novel oral antibiotic formulation Rifamycin SV-MMX®, with a targeted delivery to the distal small bowel and colon, was superior to placebo in treating travellers' diarrhea (TD) in a previous study. Thus, a study was designed to compare this poorly absorbed antibiotic with the systemic agent ciprofloxacin. Methods: In a randomized double-blind phase 3 study (ERASE), the efficacy and safety of Rifamycin SV-MMX® 400 mg twice daily (RIF-MMX) was compared with ciprofloxacin 500 mg twice daily in the oral treatment of TD. Overall, 835 international visitors to India, Guatemala or Ecuador with acute TD were randomized to receive a 3-day treatment with RIF-MMX (n = 420) or ciprofloxacin (n = 415). Primary endpoint was time to last unformed stool (TLUS), after which clinical cure was declared. Stools samples for microbiological evaluation were collected at the baseline visit and the end of treatment visit. Results: Median TLUS in the RIF-MMX group was 42.8 h versus 36.8 h in the ciprofloxacin group indicating non-inferiority of RIF-MMX to ciprofloxacin (P = 0.0035). Secondary efficacy endpoint results including clinical cure rate, treatment failure rate, requirement of rescue therapy as well as microbiological eradication rate confirmed those of the primary analysis indicating equal efficacy for both compounds. While patients receiving ciprofloxacin showed a significant increase of Extended Spectrum Beta Lactamase Producing-Escherichia coli (ESBL-E. Coli) colonization rates after 3-days treatment (6.9%), rates did not increase in patients receiving RIF-MMX (-0.3%). Both drugs were well-tolerated and safe. Conclusion: The novel multi-matrix formulation of the broad-spectrum, poorly absorbed antibiotic Rifamycin SV was found non-inferior to the systemic antibiotic ciprofloxacin in the oral treatment of non-dysenteric TD with the advantage of a lower risk of ESBL-E. Coli acquisition.
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Antibacterianos/administração & dosagem , Ciprofloxacina/administração & dosagem , Diarreia/tratamento farmacológico , Farmacorresistência Bacteriana Múltipla , Infecções por Escherichia coli/tratamento farmacológico , Rifamicinas/administração & dosagem , Administração Oral , Adulto , Diarreia/microbiologia , Diarreia/prevenção & controle , Equador , Escherichia coli Enterotoxigênica/efeitos dos fármacos , Infecções por Escherichia coli/prevenção & controle , Feminino , Guatemala , Humanos , Índia , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Viagem , Resultado do TratamentoRESUMO
BACKGROUND: Adherence to mesalazine treatment is essential for the successful treatment of ulcerative colitis. OBJECTIVE: The objective of this study was to compare the efficacy, safety and preference of a novel high-dose 1000 mg mesalazine tablet versus conventional treatment for ulcerative colitis remission. METHODS: This pivotal phase III trial compared one 1000 mg mesalazine tablet (M1000 group) versus two registered 500 mg mesalazine tablets (M2x500 group), both taken three times daily, in patients with mild to moderately active ulcerative colitis. The primary efficacy variable was clinical remission at week 8. RESULTS: A total of 306 patients were considered for intent-to-treat analysis. Clinical remission was achieved in 45.0% of the patients in the M1000 group versus 41.9% in the M2x500 group (P < 0.001 for non-inferiority). Mucosal healing was achieved by 68.9% of the patients in the M1000 group and 68.4% in the M2x500 group. The majority of patients preferred the intake of one high-dose tablet (47.7%) over two low-dose tablets (10.5%). Oral treatment with high-dose 1000 mg mesalazine tablets was well tolerated without new safety signals. CONCLUSIONS: The novel high-dose 1000 mg mesalazine tablet is effective, non-inferior to the registered 500 mg mesalazine tablet, and safe for ulcerative colitis treatment. It was preferred by a majority of patients and may improve ulcerative colitis treatment adherence.
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Members of the BTB-kelch superfamily play important roles during fundamental cellular processes, such as the regulation of cell morphology, migration, and gene expression. The BTB-kelch protein LZTR-1 is deleted in the majority of DiGeorge syndrome patients and is believed to act as a transcriptional regulator. However, functional and expression profiling studies of LZTR-1 have not been performed thus far. Therefore, we examined the subcellular localization and function of LZTR-1 to gain insights into its biological role. Analysis of the primary structure of the protein revealed six N-terminal kelch motifs and two BTB/POZ domains at the C terminus within LZTR-1. Confocal analysis of the subcellular distribution of LZTR-1 using the Golgi markers GM130, Golgin-97, and TGN46 identified a localization of LZTR-1 exclusively on the cytoplasmic surface of the Golgi network that is mediated by its second BTB/POZ domain. In contrast to most other BTB-kelch proteins, LZTR-1 did not co-localize with actin. Treatment with brefeldin A did not lead to redistribution of LZTR-1 to the endoplasmic reticulum but caused its relocalization in dispersed, punctuated structures that were also positive for GM130. These data demonstrate that LZTR-1 is a Golgi matrix-associated protein. Upon induction of apoptosis, LZTR-1 was phosphorylated on tyrosine residues and subsequently degraded; that could be rescued partially by the addition of the caspase inhibitor Z-VAD-fmk and the proteasome inhibitors lactacystin and MG132. Taken together, our experiments identify LZTR-1 as the first BTB-kelch protein that exclusively localizes to the Golgi network, and the binding of LZTR-1 to the Golgi complex is mediated by its second BTB/POZ domain.
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Apoptose , Complexo de Golgi/metabolismo , Fatores de Transcrição/química , Fatores de Transcrição/fisiologia , Actinas/química , Clorometilcetonas de Aminoácidos/farmacologia , Motivos de Aminoácidos , Sequência de Aminoácidos , Aorta/metabolismo , Autoantígenos/farmacologia , Northern Blotting , Western Blotting , Brefeldina A/farmacologia , Linhagem Celular , Células Cultivadas , Clonagem Molecular , Retículo Endoplasmático/metabolismo , Endotélio Vascular/metabolismo , Proteínas da Matriz do Complexo de Golgi , Células HeLa , Humanos , Leupeptinas/farmacologia , Glicoproteínas de Membrana/farmacologia , Proteínas de Membrana/farmacologia , Microscopia Confocal , Dados de Sequência Molecular , Complexo de Endopeptidases do Proteassoma/metabolismo , Estrutura Terciária de Proteína , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transcrição Gênica , Transfecção , Tirosina/química , Ubiquitina/química , Veias Umbilicais/citologiaRESUMO
The dickkopf (dkk) gene family encodes secreted antagonists of Wnt signalling proteins, which have important functions in the control of cell fate, proliferation, and cell polarity during development. Here, we report the isolation, from a regeneration-specific signal peptide screen, of a novel dickkopf gene from the fresh water cnidarian Hydra. Comparative sequence analysis demonstrates that the Wnt antagonistic subfamily Dkk1/Dkk2/Dkk4 and the non-modulating subfamily Dkk3 separated prior to the divergence of cnidarians and bilaterians. In steady-state Hydra, hydkk1/2/4-expression is inversely related to that of hywnt3a. hydkk1/2/4 is an early injury and regeneration responsive gene, and hydkk1/2/4-expressing gland cells are essential for head regeneration in Hydra, although once the head has regenerated they are excluded from it. Activation of Wnt/beta-Catenin signalling leads to the complete downregulation of hydkk1/2/4 transcripts. When overexpressed in Xenopus, HyDkk1/2/4 has similar Wnt-antagonizing activity to the Xenopus gene Dkk1. Based on the corresponding expression patterns of hydkk1/2/4 and neuronal genes, we suggest that the body column of Hydra is a neurogenic environment suppressing Wnt signalling and facilitating neurogenesis.