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1.
Exp Hematol ; 80: 36-41.e3, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31812712

RESUMO

Epidemiological sequencing studies have revealed that somatic mutations characteristic of myeloid neoplasms can be detected in the blood of asymptomatic individuals decades prior to presentation of any clinical symptoms. This premalignant condition is known as clonal hematopoiesis of indeterminate potential (CHIP). Despite the fact these mutant clones become readily detectable in the blood of elderly individuals (∼10% of people over the age of 65), the overall rate of disease progression remains relatively low. Thus, in addition to genetic mutations, there are likely environmental factors that contribute to clonal evolution in people with CHIP. One environmental stress that increases with age is inflammation. Although chronic inflammation is detrimental to the long-term function of normal hematopoietic stem cells, several recent studies in animal models have indicated hematopoietic stem cells with CHIP mutations may be resistant to these deleterious effects. However, direct evidence indicating a correlation between increased inflammation and accelerated CHIP in humans is currently lacking. In this study, we sequenced the peripheral blood cells of a cohort of patients with ulcerative colitis, an autoimmune disease characterized by increased levels of pro-inflammatory cytokines. This analysis revealed that the inflammatory environment of ulcerative colitis promoted CHIP with a distinct mutational spectrum, notably positive selection of clones with DNMT3A and PPM1D mutations. We also show a specific association between elevated levels of serum interferon gamma and DNMT3A mutations. These data add to our understanding of how cell extrinsic factors select for clones with specific mutations to promote clonal hematopoiesis.


Assuntos
Colite Ulcerativa/patologia , Hematopoese/genética , Interferon gama/sangue , Mutação , Fator de Necrose Tumoral alfa/análise , Idoso , Idoso de 80 Anos ou mais , Células Clonais/citologia , Colite Ulcerativa/sangue , Colite Ulcerativa/genética , DNA (Citosina-5-)-Metiltransferases/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Lesões Pré-Cancerosas/sangue , Lesões Pré-Cancerosas/genética , Lesões Pré-Cancerosas/patologia , Proteína Fosfatase 2C/genética
2.
Complement Ther Med ; 46: 36-43, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31519285

RESUMO

OBJECTIVE: The present study aimed to evaluate the possible effect of grounded flaxseed and flaxseed oil on serum levels of inflammatory markers, metabolic parameters, and the severity of disease in patients with UC. METHODS: In this open-labeled randomized controlled trial, 90 UC patients were randomly assigned to one of the 3 groups for 12 weeks: grounded flaxseed (GF; 30 g/day), flaxseed oil (FO; 10 g/day) and control group. The weight, waist circumference, systolic and diastolic blood pressure, serum inflammatory markers (interleukin-6 (IL-6), interferon gamma (INF-γ), transforming growth factor beta (TGF-ß), and Erythrocyte Sedimentation Rate (ESR)), and fecal calprotectin were measured at the baseline and end of the study. RESULTS: Totally, 75 patients (43 men and 32 women) with a mean age of 31.54 ±â€¯9.84 years participated in the present study. Comparing the change of the variables indicated a significant decrease in fecal calprotectin (P < 0.001), Mayo score (P < 0.001), ESR (P < 0.001), INF-γ (P < 0.001), IL-6 (P < 0.001), waist circumference (P = 0.02), Diastolic Blood Pressure (DBP) (P < 0.001), and Systolic Blood Pressure (SBP) (P < 0.001) and a significant increase in TGF-ß (P < 0.001) and Inflammatory Bowel Disease Questionnaire-Short form (IBDQ-9) score (P < 0.001) in the GF and FO groups compared to the control. No difference was obvious between the FO and GF groups except for TGF-ß. CONCLUSION: The present study showed that both flaxseed and flaxseed oil, attenuate inflammatory markers, disease severity, blood pressure, and WC. However, the effect of flaxseed on weight and BMI was not evident.


Assuntos
Biomarcadores/sangue , Colite Ulcerativa/tratamento farmacológico , Linho/química , Mediadores da Inflamação/sangue , Inflamação/sangue , Óleo de Semente do Linho/uso terapêutico , Adulto , Pressão Sanguínea/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Colite Ulcerativa/sangue , Suplementos Nutricionais , Feminino , Humanos , Óleo de Semente do Linho/farmacologia , Masculino , Estresse Oxidativo/efeitos dos fármacos , Índice de Gravidade de Doença , Circunferência da Cintura/efeitos dos fármacos
3.
Gastroenterology ; 157(6): 1584-1598, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31513797

RESUMO

BACKGROUND & AIMS: T-regulatory (Treg) cells suppress the immune response to maintain homeostasis. There are 2 main subsets of Treg cells: FOXP3 (forkhead box protein 3)-positive Treg cells, which do not produce high levels of effector cytokines, and type 1 Treg (Tr1) cells, which are FOXP3-negative and secrete interleukin (IL) 10. IL10 is an anti-inflammatory cytokine, so Tr1 cells might be used in the treatment of inflammatory bowel diseases. We aimed to develop methods to isolate and expand human Tr1 cells and define their functions. METHODS: We obtained blood and colon biopsy samples from patients with Crohn's disease or ulcerative colitis or healthy individuals (controls). CD4+ T cells were isolated from blood samples and stimulated with anti-CD3 and anti-CD28 beads, and Tr1 cells were purified by using an IL10 cytokine-capture assay and cell sorting. FOXP3-positive Treg cells were sorted as CD4+CD25highCD127low cells from unstimulated cells. Tr1 and FOXP3-positive Treg cells were expanded, and phenotypes and gene expression profiles were compared. T cells in peripheral blood mononuclear cells from healthy donors were stimulated with anti-CD3 and anti-CD28 beads, and the suppressive abilities of Tr1 and FOXP3-positive Treg cells were measured. Human colon organoid cultures were established, cultured with supernatants from Tr1 or FOXP3-positive cells, and analyzed by immunofluorescence and flow cytometry. T84 cells (human colon adenocarcinoma epithelial cells) were incubated with supernatants from Tr1 or FOXP3-positive cells, and transepithelial electrical resistance was measured to determine epithelial cell barrier function. RESULTS: Phenotypes of Tr1 cells isolated from control individuals vs patients with Crohn's disease or ulcerative colitis did not differ significantly after expansion. Tr1 cells and FOXP3-positive Treg cells suppressed proliferation of effector T cells, but only Tr1 cells suppressed secretion of IL1B and tumor necrosis factor from myeloid cells. Tr1 cells, but not FOXP3-positive Treg cells, isolated from healthy individuals and patients with Crohn's disease or ulcerative colitis secreted IL22, which promoted barrier function of human intestinal epithelial cells. Tr1 cell culture supernatants promoted differentiation of mucin-producing goblet cells in intestinal organoid cultures. CONCLUSIONS: Human Tr1 cells suppress proliferation of effector T cells (adaptive immune response) and production of IL1B and TNF by myeloid cells (inmate immune response). They also secrete IL22 to promote barrier function. They might be developed as a cell-based therapy for intestinal inflammatory disorders.


Assuntos
Colite Ulcerativa/imunologia , Doença de Crohn/imunologia , Interleucina-10/metabolismo , Mucosa Intestinal/patologia , Linfócitos T Reguladores/imunologia , Adulto , Idoso , Biópsia , Comunicação Celular/imunologia , Proliferação de Células , Células Cultivadas , Colite Ulcerativa/sangue , Colite Ulcerativa/terapia , Colo/citologia , Colo/imunologia , Colo/patologia , Doença de Crohn/sangue , Doença de Crohn/terapia , Feminino , Fatores de Transcrição Forkhead/imunologia , Fatores de Transcrição Forkhead/metabolismo , Voluntários Saudáveis , Humanos , Interleucina-10/imunologia , Interleucinas/imunologia , Interleucinas/metabolismo , Mucosa Intestinal/citologia , Mucosa Intestinal/imunologia , Masculino , Pessoa de Meia-Idade , Cultura Primária de Células , Linfócitos T Citotóxicos/imunologia , Linfócitos T Reguladores/metabolismo , Linfócitos T Reguladores/transplante
4.
Biol Pharm Bull ; 42(8): 1419-1422, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31366877

RESUMO

The pathogenic relationship of ulcerative colitis and rheumatoid arthritis is not known. Therefore, we examined dextran sodium sulfate (DSS)-induced colitis separately and in combination with a mouse arthritis model that mimics rheumatoid arthritis and evaluated the deterioration-related factors of each condition. Arthritis was induced in a collagen-induced arthritis mouse model using DBA/1JJmsSlc mice and ulcerative colitis was induced by the administration of drinking water containing 3.0% (w/v) DSS. The arthritis/DSS-treated mice developed worse colitis scores compared to that of the other groups of mice. The arthritis/DSS-treated mice did not demonstrate changes in hind foot volumes or in the concentration of matrix metalloproteinase-3 (MMP-3) in the plasma; however, plasma levels of interleukin-6 (IL-6) and tumor necrosis factor (TNF)-α were increased. Our results showed that IL-6 and TNF-α may influence the deterioration effect of colitis in arthritic mice.


Assuntos
Artrite Experimental/imunologia , Colite Ulcerativa/imunologia , Interleucina-6/sangue , Fator de Necrose Tumoral alfa/sangue , Animais , Artrite Experimental/sangue , Artrite Experimental/patologia , Colite Ulcerativa/sangue , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/patologia , Colo/patologia , Sulfato de Dextrana , Edema/sangue , Edema/imunologia , Edema/patologia , Pé/patologia , Metaloproteinase 3 da Matriz/sangue , Camundongos Endogâmicos DBA
5.
Ann Hematol ; 98(9): 2053-2061, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31256218

RESUMO

Aplastic anemia (AA) has been reported to be associated with inflammatory bowel disease (IBD), but mostly with ulcerative colitis (UC). Little is known about the associations between AA and Crohn's disease (CD). We aim to determine the portraits of patients with AA-CD. Among a total of 657 patients with CD registered in Xijing Hospital of Digestive Diseases IBD center from January 2008 to October 2018, the patients diagnosed with concurrent AA were reviewed. Clinical presentation, medical history, endoscopic features, response to treatment, and prognosis in this set of patients were collected. Six male patients confirmed as CD associated with AA were identified. The incidence rate was 0.91% for CD associated with AA in our series. Average age at diagnosis of CD and AA was 41.5 and 39.2 years old, respectively. Abdominal pain and hyperpyrexia were the most common symptoms. Endoscopic findings showed discontinued severe inflammation, and all these patients presented with deformed ileocecal valve. Conventional pharmacotherapy failed to achieve a favorable effect. Four of six patients died from CD progression and its complications. None of these patients received bone marrow transplantation treatment because of poverty. Concurrence of AA and CD is a relatively rare condition. Immunologic impairment may play an important pathogenic role and deserves further attention. Males are more susceptible to this condition. Patients with AA-CD are prone to a severe clinical course and poor prognosis. Conventional therapy achieves no potent effect, and allogeneic stem cell transplantation may be a potentially efficient therapy.


Assuntos
Anemia Aplástica , Doença de Crohn , Índice de Gravidade de Doença , Adulto , Idoso , Anemia Aplástica/sangue , Anemia Aplástica/diagnóstico , Anemia Aplástica/etiologia , Colite Ulcerativa/sangue , Colite Ulcerativa/complicações , Colite Ulcerativa/diagnóstico , Doença de Crohn/sangue , Doença de Crohn/complicações , Doença de Crohn/diagnóstico , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos
6.
Mediators Inflamm ; 2019: 5256460, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31148945

RESUMO

The associations between serum total bilirubin (sTB) levels, inflammatory marker levels, and disease activity are not well understood in patients with inflammatory bowel disease (IBD). The present study investigated the association between sTB levels and disease activity in patients with IBD. We conducted a retrospective study with a total of 242 consecutive patients with Crohn's disease (CD) and 211 consecutive patients with ulcerative colitis (UC). The Crohn's Disease Activity Index (CDAI) score was used to assess disease activity in patients with CD and the Mayo score of patients with UC. 255 clinically healthy subjects comprised the control group, which come from the same geographic area as the IBD group. We retrieved the clinical and laboratory parameters of patients with IBD from the medical records. Patients with IBD displayed significantly lower sTB levels than controls. sTB levels were negatively associated with C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), fecal calprotectin (FC), and hemoglobin (Hb) levels in patients with IBD. Additionally, there was a negative association between sTB levels and the CDAI score of patients with CD. sTB levels were also negatively associated with the Mayo score of patients with UC. IBD patients had lower sTB levels when compared with controls, and there was a negative correlation between sTB levels and disease activity in patients with IBD. Increased reactive oxygen species production in IBD is likely to be responsible for increased consumption of bilirubin in patients with IBD, leading to further intestinal injury. Reducing oxidative stress may be therapeutic for these patients.


Assuntos
Bilirrubina/sangue , Colite Ulcerativa/sangue , Doenças Inflamatórias Intestinais/sangue , Adulto , Proteína C-Reativa/metabolismo , Feminino , Hemoglobinas/metabolismo , Humanos , Complexo Antígeno L1 Leucocitário/sangue , Testes de Função Hepática , Masculino , Pessoa de Meia-Idade , Espécies Reativas de Oxigênio/metabolismo , Estudos Retrospectivos
7.
Mol Med Rep ; 20(2): 1321-1332, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31173225

RESUMO

Artesunate (ART) is a semi­synthetic derivative of artemisinin used in the treatment of patients with malaria, which has also been reported to have immunoregulatory, anticancer and anti­inflammatory properties. The aim of the present study was to investigate the possible beneficial effects of ART on ulcerative colitis (UC) rats and to detect the possible mechanisms underlying these effects. A UC rat model was established using dextran sulfate sodium (DSS). Rats were randomly divided into the following groups: Normal control, UC model group, UC rats treated with a low, medium or high dose of ART (10, 30 and 50 mg/kg/day, respectively), and the positive control group (50 mg/kg/day 5­aminosalicylic acid). The damage status of colonic mucosal epithelial tissue was investigated by hematoxylin and eosin staining, and then the weight, colon length and disease activity index (DAI) were measured. Western blotting and reverse transcription­quantitative polymerase chain reaction analysis were used to detect the levels of cytokines associated with UC and proteins associated with Toll­like receptor 4 (TLR4)­nuclear factor (NF)­κB pathway. ELISA was also performed to measure the levels of inflammatory cytokines. In addition, the viability and infiltration of RAW264.7 cells were examined using Cell Counting Kit­8 and Transwell assays. The results demonstrated that treatment with ART significantly alleviated the UC symptoms induced by DSS in the rat model, lowered the DAI, ameliorated pathological changes, attenuated colon shortening, inhibited the levels of pro­inflammatory mediators and myeloperoxidase activity, and increased hemoglobin expression. Additionally, inflammatory and apoptotic markers were found to be significantly downregulated following treatment with ART in UC rats and RAW264.7 cells. To the best of our knowledge, the present study is the first to demonstrate that ART exerts anti­inflammatory effects via regulating the TLR4­NF­κB signaling pathway in UC.


Assuntos
Artesunato/uso terapêutico , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/metabolismo , NF-kappa B/metabolismo , Substâncias Protetoras/uso terapêutico , Transdução de Sinais , Receptor 4 Toll-Like/metabolismo , Animais , Artesunato/farmacologia , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Colite Ulcerativa/sangue , Colite Ulcerativa/patologia , Colo/efeitos dos fármacos , Colo/patologia , Sulfato de Dextrana , Hemoglobinas/metabolismo , Mediadores da Inflamação/sangue , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Macrófagos/patologia , Masculino , Camundongos , Peroxidase/metabolismo , Substâncias Protetoras/farmacologia , Células RAW 264.7 , Ratos Sprague-Dawley
8.
Medicina (Kaunas) ; 55(6)2019 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-31159239

RESUMO

Background and objectives: Inflammatory bowel disease (IBD) mainly includes Crohn's disease (CD) and ulcerative colitis (UC). Both conditions are associated with an exacerbated intestinal immune response to harmless stimuli, leading to upregulation of pro-inflammatory mediators. Materials and Methods: The subjects of the study were 55 patients with IBD. The control group consisted of 35 healthy subjects. The researched material consisted of peripheral blood lymphocytes collected from the subjects. Expression of the genes BAX, BCL2, CASP3 and CASP9 was assessed at the mRNA level in the peripheral blood lymphocytes of patients with ulcerative colitis and Crohn's disease relative to the healthy subjects. The expression of the genes was determined by rtPCR using TaqMan probes specific for these genes. Results: The group of patients diagnosed with CD had statistically significantly higher expression of the genes BAX (p = 0.012), BCL2 (p = 0.022), CASP3 (p = 0.003) and CASP9 (p = 0.029) than healthy subjects. Expression of BAX, BCL2, CASP3 and CASP9 in UC patients in the active phase of the disease was significantly lower than in patients in remission: BAX (p = 0.001), BCL2 (p = 0.038) and CASP9 (p = 0.007). In patients with UC, the BAX/BCL2 ratio was significantly correlated (r = 0.473) with the duration of the disease. In the group of CD patients treated biologically, a significantly lower BAX/BCL2 ratio was demonstrated than in patients that were not biologically treated. Conclusions: Our research has shown a simultaneous increase in the expression of the anti-apoptotic BCL2 gene and the proapoptotic BAX gene, which suggests the dysregulation of apoptosis mechanisms in IBD. Significantly higher expression of BAX and BCL2 in UC patients in remission as compared to CD may suggest differences in these diseases in terms of prognosis and treatment. Our results may suggest that an underlying imbalance in factors controlling apoptosis in peripheral blood lymphocytes may be the response of the immune system to inflammation of the intestinal mucosa. Modulation of apoptosis may become an important therapeutic mechanism in IBD.


Assuntos
Morte Celular/fisiologia , Colite Ulcerativa/sangue , Doença de Crohn/sangue , Linfócitos/patologia , Adulto , Idoso , Caspase 3/genética , Caspase 9/genética , Morte Celular/genética , Colite Ulcerativa/genética , Colite Ulcerativa/fisiopatologia , Doença de Crohn/genética , Doença de Crohn/fisiopatologia , Feminino , Humanos , Mucosa Intestinal/fisiopatologia , Masculino , Pessoa de Meia-Idade , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteína X Associada a bcl-2/genética
9.
Pediatr Int ; 61(7): 720-725, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31102555

RESUMO

BACKGROUND: Laboratory data in children with newly diagnosed inflammatory bowel disease (IBD) have been reported from Europe and North America, but not Asia. The aim of this study was to clarify laboratory data in Japanese children with newly diagnosed IBD, and to compare them with those in Western reports. METHODS: We retrospectively reviewed patients <16 years old, newly diagnosed with ulcerative colitis (UC) or Crohn's disease (CD) at Kurume University Hospital between January 2008 and December 2015. RESULTS: UC and CD patients numbered 31 and 15, respectively. The percentages of patients with normal values for hemoglobin (Hb), platelet count (Plt), albumin (Alb), C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR) in the UC and CD groups were 45% and 47%; 68% and 53%; 84% and 40%; 81% and 7%; and 35% and 0%, respectively. The frequency of normal results for these five tests were similar to Western findings except for the greater frequency of normal CRP in UC. Alb and ESR differed significantly between UC and CD in both mild and moderate-severe cases. Plt, Alb, CRP, and ESR differed significantly between diseases in late-onset IBD, whereas early onset IBD showed no differences. In UC, ESR correlated positively, while Hb and Alb correlated negatively, with disease activity. In CD, CRP and ESR correlated positively with activity. CONCLUSIONS: The proportion of Japanese children with IBD having normal values at diagnosis was mostly similar to that in Western reports. In early onset cases, UC parameters may be similar to CD. Of the five tests, ESR was particularly indicative of disease activity at diagnosis in both pediatric UC and CD.


Assuntos
Biomarcadores/sangue , Colite Ulcerativa/diagnóstico , Doença de Crohn/diagnóstico , Adolescente , Criança , Pré-Escolar , Colite Ulcerativa/sangue , Doença de Crohn/sangue , Feminino , Humanos , Japão , Masculino , Estudos Retrospectivos , Ocidente
10.
PLoS One ; 14(5): e0217238, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31120977

RESUMO

OBJECTIVES: Vitamin D deficiency predicts unfavorable disease outcomes in inflammatory bowel disease. Endogenous vitamin D synthesis is affected by seasonal factors including sunlight exposure, raising the question whether seasonality determines the risk of vitamin D deficiency and may mask other clinical risk factors. METHODS: Univariable and multiple regression analyses were performed in a retrospective cohort of 384 patients to determine risk factors for vitamin D deficiency. Since the observed 25-hydroxyvitamin D [25(OH)D] concentrations followed a sinusoidal pattern over the year, all 25(OH)D concentrations were normalized for the predicted variability of the respective day of analysis based on a sinusoidal regression analysis of 25(OH)D test results obtained in more than 86,000 control serum samples. RESULTS: Vitamin D deficiency was highly prevalent in patients with Crohn's disease or ulcerative colitis (63% and 55%, respectively) and associated with winter/spring seasons. After normalization of 25(OH)D concentrations for the day of analysis, vitamin D deficiency was associated with histories of complications related to inflammatory bowel disease, surgery, smoking and ongoing diarrhea while initial disease manifestation during adulthood, ongoing vitamin D supplementation and diagnosis of ulcerative colitis vs. Crohn's disease appeared to be protective. Multiple regression analyses revealed that vitamin D deficiency was associated with disease activity in Crohn's disease and anemia in ulcerative colitis patients. Only few deficient patients achieved sufficient 25(OH)D concentrations over time. However, increasing 25(OH)D concentrations correlated with improved Crohn's disease activity. CONCLUSIONS: Vitamin D deficiency was highly prevalent in patients with Crohn's disease and ulcerative colitis and dependent on the season of the year. Following normalization for seasonality by sinusoidal regression analysis, vitamin D deficiency was found to be associated with parameters of complicated disease course while increasing 25(OH)D concentrations over time correlated with reduced activity of Crohn's disease.


Assuntos
Doenças Inflamatórias Intestinais/sangue , Vitamina D/análogos & derivados , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Colite Ulcerativa/sangue , Colite Ulcerativa/complicações , Doença de Crohn/sangue , Doença de Crohn/complicações , Suplementos Nutricionais , Feminino , Alemanha/epidemiologia , Humanos , Doenças Inflamatórias Intestinais/complicações , Masculino , Pessoa de Meia-Idade , Prevalência , Estudos Retrospectivos , Fatores de Risco , Estações do Ano , Vitamina D/administração & dosagem , Vitamina D/sangue , Deficiência de Vitamina D/sangue , Deficiência de Vitamina D/complicações , Deficiência de Vitamina D/epidemiologia , Adulto Jovem
11.
Medicine (Baltimore) ; 98(18): e15233, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31045762

RESUMO

Patients with inflammatory bowel disease have an increased risk of vitamin D deficiency and this may impact upon the disease activity. This study explored the association between serum vitamin D levels and inflammatory bowel disease in a Chinese population.Sixty-five patients with ulcerative colitis (UC) and 50 with Crohn's disease (CD) were investigated between January 2015 and December 2016 at the Kunshan Second People's Hospital, China. A control group of 120 healthy volunteers was also selected. Serum vitamin D levels were detected and compared between groups and among patients with different disease activity.The serum vitamin D levels in the UC (10.27 ±â€Š4.05 ng/mL) and CD (11.13 ±â€Š3.96 ng/mL) groups were lower than in the control group (12.96 ±â€Š5.18 ng/mL) (P < .05). In the UC group, during the moderate (9.21 ±â€Š3.26 ng/mL) and severe (7.58 ±â€Š3.81 ng/mL) periods, serum vitamin D levels were significantly lower compared with during remission (12.18 ±â€Š3.69 ng/mL) and the mild period (11.35 ±â€Š4.08 ng/mL) (P < .05). In the CD group, serum vitamin D levels were significantly lower during the moderate (10.28 ±â€Š3.57 ng/mL) and severe (8.52 ±â€Š3.72 ng/mL) periods compared with remission (13.97 ±â€Š5.61 ng/mL) (P < .05).Patients with UC and CD are both prone to vitamin D deficiency. Serum vitamin D was significantly lower with aggravating disease status. Therefore, vitamin D may be involved in the development of inflammatory bowel disease in a Chinese population.


Assuntos
Doenças Inflamatórias Intestinais/sangue , Deficiência de Vitamina D/etiologia , Vitamina D/sangue , Adulto , China/epidemiologia , Colite Ulcerativa/sangue , Colite Ulcerativa/complicações , Colite Ulcerativa/diagnóstico , Colite Ulcerativa/fisiopatologia , Doença de Crohn/sangue , Doença de Crohn/complicações , Doença de Crohn/diagnóstico , Doença de Crohn/fisiopatologia , Feminino , Humanos , Doenças Inflamatórias Intestinais/complicações , Doenças Inflamatórias Intestinais/diagnóstico , Doenças Inflamatórias Intestinais/fisiopatologia , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Vitamina D/uso terapêutico , Vitaminas/uso terapêutico
12.
Turk J Gastroenterol ; 30(5): 408­414, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31060995

RESUMO

BACKGROUND/AIMS: It is unclear whether IgG4-related immune responses to food can play a role in the pathogenesis of inflammatory bowel disease (IBD). The aim of the present study was to investigate the serum levels of IgG4 to common food antigens in patients with ulcerative colitis (UC), Crohn's disease (CD), and healthy controls. MATERIALS AND METHODS: Thirty-six patients with CD (n=12) or UC (n=24) and 36 sex- and age-matched healthy individuals (mean age, 49 years) participated in the study. Serum levels of IgG4 to 90 common food antigens were measured. The number of subjects with positivity, defined by cut-off values ≥0.7 U/mL, was compared. RESULTS: Serum titers of IgG4 to salmon, onion, shrimp, cuttlefish, eel, millet, gluten, soybean, and coconut in patients with IBD were significantly or tended to be higher than those in the control group. Serum levels of IgG4 to salmon, millet, and onion in patients with CD were significantly or tended to be higher than those in the control group. Serum titers of IgG4 to cuttlefish and onion in patients with UC tended to be higher than those in the control group. The number of subjects with positivity to cod, tuna, mackerel, oat, pea, peanut, and coconut was significantly higher in patients with CD than in healthy controls. The number of subjects with positivity to kiwi and cuttlefish was significantly higher in patients with UC than in controls. CONCLUSION: Patients with IBD shows higher serum levels of IgG4 to diverse food antigens. Patients with CD present IgG4-related immune reactions to more foods than patients with UC.


Assuntos
Colite Ulcerativa/sangue , Doença de Crohn/sangue , Hipersensibilidade Alimentar/imunologia , Antígenos de Histocompatibilidade Classe II/sangue , Imunoglobulina G/sangue , Adulto , Estudos de Casos e Controles , Colite Ulcerativa/imunologia , Doença de Crohn/imunologia , Feminino , Antígenos de Histocompatibilidade Classe II/imunologia , Humanos , Imunoglobulina G/imunologia , Masculino , Pessoa de Meia-Idade
13.
Med Sci Monit ; 25: 3303-3315, 2019 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-31055592

RESUMO

BACKGROUND Ulcerative colitis is a chronic, idiopathic inflammatory disease that destroys the colon structure. Nevertheless, the exact pathogenesis is not clear and needs to be fully elucidated. MATERIAL AND METHODS Stool and plasma samples were used for 16S ribosomal RNA sequencing and liquid chromatography mass spectrometry, respectively. In addition, we detected the level of trimethylamine N-oxide. Finally, we performed Pearson correlation analysis between the microbiome and the metabolome. RESULTS Twenty-three active ulcerative colitis, 25 inactive ulcerative colitis, and 30 control cases were included. Thirty-four significantly different metabolites were found between the active ulcerative colitis and control groups, 38 were found between the inactive ulcerative colitis and control groups, and only 1 was found between the active ulcerative colitis and inactive ulcerative colitis groups. The plasma trimethylamine N-oxide level of the inactive ulcerative colitis and active ulcerative colitis groups was significantly higher than that of the control group. Moreover, we identified significant changes in 24, 18, and 12 bacterial genera for active ulcerative colitis-control, inactive ulcerative colitis-control, and active ulcerative colitis-inactive ulcerative colitis, respectively. Cross-correlation indicated an association between sphingosine 1-phosphate and Roseburia, Klebsiella, and Escherichia-Shigella. Through the pathway analysis, we found sphingolipid metabolism was one of the most significantly increased pathways. CONCLUSIONS Although levels of trimethylamine N-oxide were higher in ulcerative colitis patients, they did not achieve statistical significance in active ulcerative colitis and inactive ulcerative colitis groups. Sphingosine 1-phosphate was increased in ulcerative colitis patients and there were several microbiota associated with it. Although further study is still needed, sphingosine 1-phosphate will probably become a new target for treatment of ulcerative colitis.


Assuntos
Colite Ulcerativa/sangue , Colite Ulcerativa/microbiologia , Fezes/microbiologia , Adolescente , Adulto , Idoso , Estudos de Casos e Controles , Doença de Crohn/sangue , Doença de Crohn/microbiologia , Feminino , Microbioma Gastrointestinal/fisiologia , Humanos , Masculino , Metaboloma , Metilaminas/análise , Metilaminas/sangue , Microbiota , Pessoa de Meia-Idade , Plasma/química , RNA Ribossômico 16S/genética
14.
Gut ; 68(8): 1386-1395, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31030191

RESUMO

OBJECTIVE: We have previously described a prognostic transcriptional signature in CD8 T cells that separates patients with IBD into two phenotypically distinct subgroups, termed IBD1 and IBD2. Here we sought to develop a blood-based test that could identify these subgroups without cell separation, and thus be suitable for clinical use in Crohn's disease (CD) and ulcerative colitis (UC). DESIGN: Patients with active IBD were recruited before treatment. Transcriptomic analyses were performed on purified CD8 T cells and/or whole blood. Phenotype data were collected prospectively. IBD1/IBD2 patient subgroups were identified by consensus clustering of CD8 T cell transcriptomes. In a training cohort, machine learning was used to identify groups of genes ('classifiers') whose differential expression in whole blood recreated the IBD1/IBD2 subgroups. Genes from the best classifiers were quantitative (q)PCR optimised, and further machine learning was used to identify the optimal qPCR classifier, which was locked down for further testing. Independent validation was sought in separate cohorts of patients with CD (n=66) and UC (n=57). RESULTS: In both validation cohorts, a 17-gene qPCR-based classifier stratified patients into two distinct subgroups. Irrespective of the underlying diagnosis, IBDhi patients (analogous to the poor prognosis IBD1 subgroup) experienced significantly more aggressive disease than IBDlo patients (analogous to IBD2), with earlier need for treatment escalation (hazard ratio=2.65 (CD), 3.12 (UC)) and more escalations over time (for multiple escalations within 18 months: sensitivity=72.7% (CD), 100% (UC); negative predictive value=90.9% (CD), 100% (UC)). CONCLUSION: This is the first validated prognostic biomarker that can predict prognosis in newly diagnosed patients with IBD and represents a step towards personalised therapy.


Assuntos
Linfócitos T CD8-Positivos/metabolismo , Colite Ulcerativa , Doença de Crohn , Adulto , Biomarcadores/sangue , Colite Ulcerativa/sangue , Colite Ulcerativa/diagnóstico , Doença de Crohn/sangue , Doença de Crohn/diagnóstico , Diagnóstico Diferencial , Feminino , Expressão Gênica , Perfilação da Expressão Gênica/métodos , Humanos , Aprendizado de Máquina , Masculino , Pessoa de Meia-Idade , Fenótipo , Valor Preditivo dos Testes , Prognóstico , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Índice de Gravidade de Doença
15.
Dig Dis Sci ; 64(7): 2031-2038, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30945037

RESUMO

BACKGROUND: Studies have shown the efficacy of hepatitis B (HBV) vaccination in patients with inflammatory bowel disease (IBD) is impaired, but few data exist regarding the effectiveness of revaccination strategies following primary vaccination failure. Our aim was to analyze the association between administration of additional vaccine doses and hepatitis B surface antibody (HBsAb) seroconversion. METHODS: This is a retrospective cohort study. Inclusion criteria are as follows: age ≥ 18, diagnosis of Crohn's disease (CD) or ulcerative colitis (UC), inadequate HBsAb < 10 IU/L following initial HBV vaccination series, subsequent administration of 1-3 additional doses of HBV vaccine with follow-up serum HBsAb measurements. Patients were stratified into groups of ≤ 2 or 3 doses received. Primary outcome was achieving HBsAb > 10 IU/L. Outcomes were stratified by age ≥ or < 40 years. We performed logistic and linear multivariable regression analyses for categorical and continuous data. RESULTS: The study cohort consists of (n = 149) 54.4% women; 77.9% white; 72.6% with CD, with mean age: 46.2. Patients of all ages and age ≥ 40 years, who received 3 additional doses of vaccine, were more likely to achieve seroprotective HBsAb levels than patients who received 1 or 2 doses (OR 1.77, P = 0.01; OR 1.9, P = 0.03, respectively, after adjusting for age, sex, race, immunosuppressive medication exposure, time between vaccine/titer). CONCLUSIONS: Following initial HBV vaccination failure, patients with IBD of all ages are more likely to develop seroprotective levels of HBsAb following 3 additional vaccine doses, rather than 1 or 2 alone. In patients who fail primary HBV vaccination, providers should consider a more aggressive revaccination strategy with an additional 3-dose series.


Assuntos
Corticosteroides/efeitos adversos , Colite Ulcerativa/tratamento farmacológico , Doença de Crohn/tratamento farmacológico , Anticorpos Anti-Hepatite B/sangue , Vacinas contra Hepatite B/administração & dosagem , Imunização , Imunogenicidade da Vacina , Imunossupressores/efeitos adversos , /efeitos adversos , Adulto , Biomarcadores/sangue , Colite Ulcerativa/sangue , Colite Ulcerativa/imunologia , Doença de Crohn/diagnóstico , Doença de Crohn/imunologia , Feminino , Humanos , Hospedeiro Imunocomprometido , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Tempo , Falha de Tratamento
16.
Adv Clin Exp Med ; 28(7): 955-960, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30929318

RESUMO

BACKGROUND: A common feature in the etiology of inflammatory bowel disease (IBD) and osteoporosis is a complex genetic background. Moreover, it has been shown that some of the susceptibility loci overlap for both diseases. One of the genes that may be involved in the pathogenesis of IBD as well as decreased bone mass is the vitamin D receptor (VDR) gene. OBJECTIVES: The aim of this study was to investigate the association of the TaqI polymorphism (rs731236, c.1056T >C) in the VDR gene with serum vitamin D concentration and bone mineral density (BMD) in patients with IBD. MATERIAL AND METHODS: A total of 172 IBD patients (85 with Crohn's disease (CD) and 87 with ulcerative colitis (UC)) and 39 healthy controls were enrolled in the study. Polymorphism was determined with polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP). Bone mineral density was measured at the lumbar spine (L2-L4) and the femoral neck (FN) using dual-energy x-ray absorptiometry (DEXA). Serum concentrations of 25-hydroxyvitamin D were determined using electrochemiluminescence binding assay (ECLIA). RESULTS: Our studies revealed that serum vitamin D concentration in IBD patients was not lowered in comparison with healthy controls. Patients with CD presented more advanced osteopenia and osteoporosis. Individuals with UC carrying the TaqI tt genotype of VDR gene showed significantly higher FN BMD than carriers of TT and Tt genotypes (p = 0.02). Moreover, tt genotype was present with higher frequency in UC patients than in controls and CD patients (23% vs 7.7% and 16.5%, respectively). CONCLUSIONS: The tt genotype may have a protective effect on BMD in UC patients.


Assuntos
Densidade Óssea/genética , Doenças Ósseas Metabólicas/etiologia , Colo do Fêmur/diagnóstico por imagem , Doenças Inflamatórias Intestinais/complicações , Vértebras Lombares/diagnóstico por imagem , Receptores de Calcitriol/genética , Vitamina D/sangue , Absorciometria de Fóton , Doenças Ósseas Metabólicas/sangue , Doenças Ósseas Metabólicas/diagnóstico por imagem , Estudos de Casos e Controles , Colite Ulcerativa/sangue , Colite Ulcerativa/complicações , Colite Ulcerativa/genética , Doença de Crohn/sangue , Doença de Crohn/complicações , Doença de Crohn/genética , Feminino , Humanos , Doenças Inflamatórias Intestinais/sangue , Doenças Inflamatórias Intestinais/genética , Reação em Cadeia da Polimerase , Polimorfismo Genético , Polimorfismo de Fragmento de Restrição , Vitamina D/genética
17.
Gut Liver ; 13(5): 541-548, 2019 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-30970435

RESUMO

Background/Aims: Infliximab (IFX) often loses its therapeutic effect in initial responders with inflammatory bowel disease (IBD) over time. Low serum IFX trough levels (TLs) are linked to poor clinical response and outcomes. Maintenance of optimal therapeutic IFX concentrations is important for sustaining response and achieving good clinical outcomes. Measurement of serum IFX TLs is helpful for determining a further proper therapeutic plan. However, adequate therapeutic IFX TLs in pediatric IBD is uncertain. We aimed to identify the cutoff values for IFX TLs associated with laboratory response to IFX maintenance therapy. Methods: Patients with pediatric IBD who had received IFX infusions between December 2008 and March 2015 at Samsung Medical Center were retrospectively investigated. We analyzed 239 blood samples that were collected from 103 pediatric patients. We measured IFX TLs at induction (6 and 14 weeks) and during maintenance therapy (>22 weeks, 8 weeks interval) by fluid-phase radioimmunoassays. Results: A significant association was found between the erythrocyte sedimentation rate (ESR) and IFX TLs during maintenance (correlation coefficient, -0.11; p=0.0005). A cutoff value of 18 mm/hr for ESR was used to define higher levels. Receiver operating characteristic analysis identified optimal cutoff values: IFX TL >1.58 µg/mL (sensitivity 82% and specificity 73%). Conclusions: Cutoff values are considered a prerequisite for further investigating the clinical usefulness of measurements of IFX in patients maintained with IFX treatment.


Assuntos
Colite Ulcerativa/tratamento farmacológico , Doença de Crohn/tratamento farmacológico , Fármacos Gastrointestinais/farmacocinética , Infliximab/farmacocinética , Adolescente , Biomarcadores/metabolismo , Sedimentação Sanguínea , Proteína C-Reativa/metabolismo , Colite Ulcerativa/sangue , Doença de Crohn/sangue , Monitoramento de Medicamentos , Feminino , Fármacos Gastrointestinais/sangue , Hematócrito , Humanos , Infliximab/sangue , Masculino , Estudos Retrospectivos , Albumina Sérica/metabolismo , Equivalência Terapêutica
18.
Medicine (Baltimore) ; 98(15): e15172, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30985701

RESUMO

The incidence of inflammatory bowel disease (IBD) is increasing and the pathogenesis is still not completely understood. Micronutrients like vitamin D [25 (OH)D] and zinc play an important role in enzyme activities and the immune system. As the 25 (OH)D-receptor has been shown to be downregulated in patients with IBD, 25 (OH)D may emerge as a predictive marker for disease improvement. Studies on relationship of both micronutrients in IBD patients are lacking.We retrospectively evaluated serum levels of 25(OH)D and zinc together with baseline characteristics of 232 IBD patients. Uni- and multivariate analyses were performed for association between serum levels of 25(OH)D and zinc with clinical and deep remission (CR and DR).155 Crohn's disease (CD) and 77 ulcerative colitis (UC) patients were included. 54% (n = 125) and 6% (n = 14) of IBD patients showed deficient serum 25(OH)D levels below 20 ng/mL and zinc levels below 7 µmol/L. Serum 25(OH)D levels were significantly higher in IBD patients with CR (P = .02) and DR (P < .001) but not serum zinc levels, respectively. Serum 25(OH)D levels (P = .008), anti-tumor-necrosis-factor-α-trough-concentration (anti-TNF-α-TC) (P = .02) and CRP level (P = .02) were independently associated with CR in CD patients. Serum 25(OH)D threshold of 19 ng/mL discriminated CD patients with or without CR, having an area under the receiver operating curve analysis (AUROC) of 0.77 [95%-confidence interval (CI): 0.68-0.85]. In multivariate analysis serum 25(OH)D levels (P = .04) and anti-TNF-α-TC (P = .04) were associated with DR in CD patients. Serum 25(OH)D threshold of 26 ng/mL discriminated CD patients with or without DR, having an AUROC of 0.75 (95%-CI: 0.68-0.83).Serum 25(OH)D (P = .04) and fecal calprotectin levels (P = .04) were independently correlated with CR in UC patients. Serum 25(OH)D threshold of 32 ng/mL discriminated UC patients in CR with an AUROC of 0.83 (95%-CI: 0.71-0.95). Zinc levels did not correlate with disease activity status in CD or UC patients either.In conclusion, beside CRP and fecal calprotectin, serum 25(OH)D levels, but not serum zinc levels, may be an additional useful and noninvasive marker for characterizing different disease activity status of IBD patients. Measurement of serum 25(OH)D in IBD patients may be warranted. 25(OH)D supplementation in deficient IBD patients is recommended.


Assuntos
Colite Ulcerativa/sangue , Doença de Crohn/sangue , Vitamina D/sangue , Zinco/sangue , Adulto , Biomarcadores/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Estudos Retrospectivos , Índice de Gravidade de Doença
19.
Medicina (Kaunas) ; 55(4)2019 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-30986917

RESUMO

Background and objectives: Oxidative stress signalling plays a monumental role in inflammatory bowel disease (IBD). Reduction of oxidative stress might control inflammation, block tissue damage, and reverse natural history of IBD. We assessed the serum concentrations of free thiols (FT) and uric acid (SUA), together constituting a large part of nonenzymatic serum antioxidant capacity, as well as total antioxidant status (TAS) with reference to IBD phenotype, activity, co-occurrence of anemia, and treatment with azathioprine (AZA) and corticosteroids (CS). Additionally, we appraised the potential of uric acid, thiol stress, and TAS as mucosal healing (MH) markers in ulcerative colitis. Materials and methods: SUA, FT, and TAS were measured colorimetrically using, respectively, uricase, Ellman's and 2,2'-azino-bis-3-ethylbenzthiazoline-6-sulphonic acid (ABTS) methods. Results: The study group consisted of 175 individuals: 57 controls, 71 ulcerative colitis (UC), and 47 Crohn's disease (CD) patients. When compared to controls, SUA levels were significantly lower in patients with CD, and FT and TAS levels were significantly lower in patients with CD and UC. In UC patients, SUA, FT, and TAS inversely correlated with the severity of bowel inflammation. As MH markers, SUA displayed better overall accuracy and higher specificity than FT. In active CD, FT, and SUA were significantly lower in patients with anemia. FT was significantly lower in patients treated with corticosteroids. Conclusions: IBD patients, regardless the disease phenotype, have systemic thiol stress, depleted total antioxidant capacity, and reduced concentrations of uric acid, reflecting, to various degrees, clinical and local disease activity as well as presence of anaemia, the most common extraintestinal manifestation of IBD. Evaluation of systemic total antioxidant status may be useful in noninvasive assessment of mucosal healing. Our findings on thiol stress provide an additional aspect on adverse effects of corticosteroids therapy.


Assuntos
Corticosteroides/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Colite Ulcerativa/sangue , Colite Ulcerativa/tratamento farmacológico , Doença de Crohn/sangue , Doença de Crohn/tratamento farmacológico , Estresse Oxidativo , Corticosteroides/efeitos adversos , Adulto , Análise de Variância , Anemia/sangue , Anemia/complicações , Anti-Inflamatórios/efeitos adversos , Azatioprina/uso terapêutico , Biomarcadores/sangue , Estudos de Casos e Controles , Colite Ulcerativa/complicações , Doença de Crohn/complicações , Feminino , Hospitais Universitários , Humanos , Imunossupressores/uso terapêutico , Masculino , Pessoa de Meia-Idade , Polônia , Estatísticas não Paramétricas , Compostos de Sulfidrila/sangue , Ácido Úrico/sangue
20.
Medicina (Kaunas) ; 55(4)2019 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-30965640

RESUMO

Background and objectives: The anemia is the most common extra-intestinal manifestation of the ulcerative colitis. Taking into account, that meat products are perceived as factor, that may promote relapses, the crucial is to indicate the dietary recommendations to prevent anemia development but without high animal products intake. Aim of the study was to analyze the influence of animal products intake on the red blood cell count results in remission ulcerative colitis individuals and pair-matched control group, during 6 weeks of observation. Materials and Methods: The intake of nutrients associated with anemia development (iron, vitamin B12, protein, animal protein, calcium) and the products being their sources (meat, meat products, dairy beverages, cottage cheese, rennet cheese) were analyzed. Results: In spite of the higher meat products intake in the group of ulcerative colitis individuals, the iron intake did not differ between groups. The positive correlations between intakes of meat, meat products, total protein, animal protein, iron, vitamin B12 and red blood cell count results were stated for ulcerative colitis individuals, while in control group were not observed, that may have resulted from higher susceptibility for the diet-influenced changes. Conclusions: The positive correlation between red blood cell count results and energy value of diet, and daily iron intake observed in ulcerative colitis individuals, accompanied by negative correlation for iron intake per 1000 kcal of diet, may indicate, that higher iron intake may be beneficial, but only while accompanied by high energy value of diet.


Assuntos
Anemia/dietoterapia , Colite Ulcerativa/sangue , Colite Ulcerativa/dietoterapia , Ingestão de Alimentos/fisiologia , Contagem de Eritrócitos , Adulto , Instituições de Assistência Ambulatorial , Estudos de Casos e Controles , Feminino , Hospitais Universitários , Humanos , Ferro , Masculino , Produtos da Carne/efeitos adversos , Proteínas de Carne/efeitos adversos , Pessoa de Meia-Idade , Nutrientes , Polônia , Estatísticas não Paramétricas , Vitamina B 12 , Adulto Jovem
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