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1.
J Lipid Res ; 60(10): 1787-1800, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31315900

RESUMO

Dietary lipids are taken up as FAs by the intestinal epithelium and converted by diacylglycerol acyltransferase (DGAT) enzymes into triglycerides, which are packaged in chylomicrons or stored in cytoplasmic lipid droplets (LDs). DGAT1-deficient patients suffer from vomiting, diarrhea, and protein losing enteropathy, illustrating the importance of this process to intestinal homeostasis. Previously, we have shown that DGAT1 deficiency causes decreased LD formation and resistance to unsaturated FA lipotoxicity in patient-derived intestinal organoids. However, LD formation was not completely abolished in patient-derived organoids, suggesting the presence of an alternative mechanism for LD formation. Here, we show an unexpected role for DGAT2 in lipid metabolism, as DGAT2 partially compensates for LD formation and lipotoxicity in DGAT1-deficient intestinal stem cells. Furthermore, we show that (un)saturated FA-induced lipotoxicity is mediated by ER stress. More importantly, we demonstrate that overexpression of DGAT2 fully compensates for the loss of DGAT1 in organoids, indicating that induced DGAT2 expression in patient cells may serve as a therapeutic target in the future.

2.
Liver Int ; 39(9): 1768-1775, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31152478

RESUMO

BACKGROUND & AIMS: Sclerosing cholangitis (SC) is a severe liver disease leading to destruction of bile ducts. It is believed to run a milder course in children than in adults. To test this assumption, we evaluated time-to-complication curves in two independent paediatric-onset cohorts from the same geographical area. METHODS: Short-term disease outcomes were evaluated with an online clinical registry that was filled with data on children with SC diagnosed between 2000 and 2017 and who were followed bi-annually thereafter. Long-term disease outcomes were evaluated in a paediatric-onset subcohort derived from a previously published population-based study from the Netherlands. Time-to-complication in the first cohort was defined as the time from diagnosis until portal hypertension, biliary obstructions and infections, development of malignancy, or liver transplantation, whichever came first. In the second cohort time-to-complication was defined as the time until liver transplantation or PSC-related death. RESULTS: Median age at diagnosis in the first cohort (n = 86) was 12.3 years. In the first 5 years post-diagnosis 23% of patients developed complications. The patients in the population-based study (n = 683) were stratified into those diagnosed before the age of 18 years ('paediatric-onset' subcohort, n = 43) and those diagnosed after the age of 18 years ('adult-onset' subcohort, n = 640). Median age at diagnosis was 14.6 and 40.2 years, respectively. Median time-to-complication in the paediatric-onset and adult-onset subcohorts was not statistically different. CONCLUSION: Paediatric and adult-onset SC run a similar long-term disease course. Paediatricians who treat children with SC should monitor them closely to recognize early complications and control long-term sequelae.

3.
Liver Int ; 39(11): 2136-2152, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31206982

RESUMO

BACKGROUND & AIMS: Wilson disease (WD) is a rare disorder of copper metabolism. The objective of this systematic review was to determine the comparative effectiveness and safety of common treatments of WD. METHODS: We included WD patients of any age or stage and the study drugs D-penicillamine, zinc salts, trientine and tetrathiomolybdate. The control could be placebo, no treatment or any other treatment. We included prospective, retrospective, randomized and non-randomized studies. We searched Medline and Embase via Ovid, the Cochrane Central Register of Controlled Trials, and screened reference lists of included articles. Where possible, we applied random-effects meta-analyses. RESULTS: The 23 included studies reported on 2055 patients and mostly compared D-penicillamine to no treatment, zinc, trientine or succimer. One study compared tetrathiomolybdate and trientine. Post-decoppering maintenance therapy was addressed in one study only. Eleven of 23 studies were of low quality. When compared to no treatment, D-penicillamine was associated with a lower mortality (odds ratio 0.013; 95% CI 0.0010 to 0.17). When compared to zinc, there was no association with mortality (odds ratio 0.73; 95% CI 0.16 to 3.40) and prevention or amelioration of clinical symptoms (odds ratio 0.84; 95% CI 0.48 to 1.48). Conversely, D-penicillamine may have a greater impact on side effects and treatment discontinuations than zinc. CONCLUSIONS: There are some indications that zinc is safer than D-penicillamine therapy while being similarly effective in preventing or reducing hepatic or neurological WD symptoms. Study quality was low warranting cautious interpretation of our findings.

4.
J Pediatr Gastroenterol Nutr ; 69(3): 310-316, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31124888

RESUMO

OBJECTIVE: Paediatric-onset inflammatory bowel disease (IBD) is different from adult-onset IBD with respect to disease severity and its effect on growth and development. Care of paediatric IBD patients in some countries is dispersed among paediatricians and adult care providers, which may result in different outcomes. This study aims to assess the effect of care setting (paediatric vs adult-oriented) on health care utilization in adolescent IBD patients. METHODS: This is a Dutch population-based cohort study based on an insurance claims database covering 4.2 million insurees (approximately 25% of the Dutch population). We identified IBD patients ages 16 to 18 years and followed them until the age of 19 years or transfer to adult care, whichever came first. We categorized patients according to care setting: paediatric versus adult-oriented. We defined outcomes as corticosteroid use, IBD-related hospital admission, IBD-related surgery, and biological use. We estimated Cox proportional hazards regression models to control for confounding by indication. RESULTS: Among 626 patients, 380 (61%) were in paediatric and 246 (39%) in adult-oriented care. In paediatric care, patients were less likely to be treated with corticosteroids (hazard ratio [HR] 0.72, 95% confidence interval [CI] 0.52-0.99) or biologicals (HR 0.57, 95% CI 0.34-0.97), and had fewer IBD-related hospital admissions (HR 0.58, 95% CI 0.37-0.92). CONCLUSION: In a large and representative community cohort of adolescents with IBD, treatment in paediatric care setting was associated with significantly lower steroid and biological use, without increase in hospital admissions. These results might be used to optimize clinical care for adolescents with IBD.

5.
Cell Rep ; 26(7): 1701-1708.e3, 2019 02 12.
Artigo em Inglês | MEDLINE | ID: mdl-30759382

RESUMO

In vitro drug tests using patient-derived stem cell cultures offer opportunities to individually select efficacious treatments. Here, we provide a study that demonstrates that in vitro drug responses in rectal organoids from individual patients with cystic fibrosis (CF) correlate with changes in two in vivo therapeutic endpoints. We measured individual in vitro efficaciousness using a functional assay in rectum-derived organoids based on forskolin-induced swelling and studied the correlation with in vivo effects. The in vitro organoid responses correlated with both change in pulmonary response and change in sweat chloride concentration. Receiver operating characteristic curves indicated good-to-excellent accuracy of the organoid-based test for defining clinical responses. This study indicates that an in vitro assay using stem cell cultures can prospectively select efficacious treatments for patients and suggests that biobanked stem cell resources can be used to tailor individual treatments in a cost-effective and patient-friendly manner.

6.
JAMA Neurol ; 76(3): 342-350, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30575854

RESUMO

Importance: The identification and understanding of the monogenic causes of neurodevelopmental disorders are of high importance for personalized treatment and genetic counseling. Objective: To identify and characterize novel genes for a specific neurodevelopmental disorder characterized by refractory seizures, respiratory failure, brain abnormalities, and death in the neonatal period; describe the outcome of glutaminase deficiency in humans; and understand the underlying pathological mechanisms. Design, Setting, and Participants: We performed exome sequencing of cases of neurodevelopmental disorders without a clear genetic diagnosis, followed by genetic and bioinformatic evaluation of candidate variants and genes. Establishing pathogenicity of the variants was achieved by measuring metabolites in dried blood spots by a hydrophilic interaction liquid chromatography method coupled with tandem mass spectrometry. The participants are 2 families with a total of 4 children who each had lethal, therapy-refractory early neonatal seizures with status epilepticus and suppression bursts, respiratory insufficiency, simplified gyral structures, diffuse volume loss of the brain, and cerebral edema. Data analysis occurred from October 2017 to June 2018. Main Outcomes and Measures: Early neonatal epileptic encephalopathy with glutaminase deficiency and lethal outcome. Results: A total of 4 infants from 2 unrelated families, each of whom died less than 40 days after birth, were included. We identified a homozygous frameshift variant p.(Asp232Glufs*2) in GLS in the first family, as well as compound heterozygous variants p.(Gln81*) and p.(Arg272Lys) in GLS in the second family. The GLS gene encodes glutaminase (Enzyme Commission 3.5.1.2), which plays a major role in the conversion of glutamine into glutamate, the main excitatory neurotransmitter of the central nervous system. All 3 variants probably lead to a loss of function and thus glutaminase deficiency. Indeed, glutamine was increased in affected children (available z scores, 3.2 and 11.7). We theorize that the potential reduction of glutamate and the excess of glutamine were a probable cause of the described physiological and structural abnormalities of the central nervous system. Conclusions and Relevance: We identified a novel autosomal recessive neurometabolic disorder of loss of function of glutaminase that leads to lethal early neonatal encephalopathy. This inborn error of metabolism underlines the importance of GLS for appropriate glutamine homeostasis and respiratory regulation, signal transduction, and survival.

7.
Br J Nutr ; : 1-7, 2018 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-30442206

RESUMO

Pancreatic-insufficient children with cystic fibrosis (CF) receive age-group-specific vitamin D supplementation according to international CF nutritional guidelines. The potential advantageous immunomodulatory effect of serum 25-hydroxy vitamin D (25(OH)D) on pulmonary function (PF) is yet to be established and is complicated by CF-related vitamin D malabsorption. We aimed to assess whether current recommendations are optimal for preventing deficiencies and whether higher serum 25(OH)D levels have long-term beneficial effects on PF. We examined the longitudinal relationship between vitamin D intake, serum 25(OH)D and PF in 190 CF children during a 4-year follow-up period. We found a significant relationship between total vitamin D intake and serum 25(OH)D (ß = 0·02; 95 % CI 0·01, 0·03; P = 0·000). However, serum 25(OH)D decreased with increasing body weight (ß = -0·79; 95 % CI -1·28, -0·29; P = 0·002). Furthermore, we observed a significant relationship between serum 25(OH)D and forced expiratory volume in 1 s (ß = 0·056; 95 % CI 0·01, 0·102; P = 0·018) and forced vital capacity (ß = 0·045; 95 % CI 0·008, 0·082; P = 0·017). In the present large study sample, vitamin D intake is associated with serum 25(OH)D levels, and adequate serum 25(OH)D levels may contribute to the preservation of PF in children with CF. Furthermore, to maintain adequate levels of serum 25(OH)D, vitamin D supplementation should increase with increasing body weight. Adjustments of the international CF nutritional guidelines, in which vitamin D supplementation increases with increasing weight, should be considered.

8.
J Cyst Fibros ; 2018 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-30279125

RESUMO

OBJECTIVE: Disruption of the enterohepatic circulation of bile acids (BAs) is part of the gastrointestinal phenotype of cystic fibrosis (CF). Ivacaftor (VX-770), a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator, improves pulmonary function in CF patients with class III gating mutations. We studied the effect of ivacaftor on the enterohepatic circulation by assessing markers of BA homeostasis and their changes in CF patients. METHODS: In CF patients with an S1251N mutation (N = 16; age 9-35 years S125N study/NTR4873) or a G551D mutation (N = 101; age 10-24 years; GOAL study/ NCT01521338) we analyzed plasma fibroblast growth factor 19 (FGF19) and 7α-hydroxy-4-cholesten-3-one (C4) levels, surrogate markers for intestinal BA absorption and hepatic synthesis, respectively, before and after treatment with ivacaftor. RESULTS: At baseline, median FGF19 was lower (52% and 53%, P < .001) and median C4 higher (350% and 364%, P < .001), respectively, for the S1251 N and G551D mutation patient groups compared to healthy controls. Treatment with ivacaftor significantly increased FGF19 and reduced C4 levels towards normalization in both cohorts but this did not correlate with CFTR function in other organs, as measured by sweat chloride levels or pulmonary function. CONCLUSIONS: We demonstrate that patients with CFTR gating mutations display interruption of the enterohepatic circulation of BAs reflected by lower FGF19 and elevated C4 levels. Treatment with ivacaftor partially restored this disruption of BA homeostasis. The improvement did not correlate with established outcome measures of CF, suggesting involvement of modulating factors of CFTR correction in different organs.

9.
Artigo em Inglês | MEDLINE | ID: mdl-30236549

RESUMO

BACKGROUND AND AIMS: Progressive familial intrahepatic cholestasis (PFIC) is a heterogeneous group of rare genetic disorders associated with bile acid secretion or transport defects. This is the first systematic review of the epidemiology, natural history and burden of PFIC. METHODS: MEDLINE and Embase were searched for publications on PFIC prevalence, incidence or natural history, and the economic burden or health-related quality of life (HRQoL) of patients with PFIC. Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed. RESULTS: Of 1269 records screened, 20 were eligible (epidemiology, 17; humanistic burden, 5; both, 2). Incidence of intrahepatic cholestasis, including but not limited to PFIC, was 1/18 000 live births in one study that did not use genetic testing. In two studies of infants and children (2-18 years) with cholestasis, 12-13% had genetically diagnosed PFIC. Of the three main PFIC subtypes, PFIC2 was the most common (21-91% of patients). Common symptoms (e.g. pruritus, jaundice, hepatomegaly, splenomegaly) generally appeared at about 3 months of age and tended to emerge earliest in patients with PFIC2. Patients reported that pruritus was often severe and led to dermal damage and reduced HRQoL. Disease progression led to complications including liver failure and hepatocellular carcinoma, with 20-83% of patients requiring liver transplantation. Mortality was 0-87% across 10 studies (treatment varied among studies), with a median age at death of ~4 years in one study. CONCLUSIONS: Patients with PFIC face debilitating symptoms and poor prognosis. Further research is needed to inform patient management and clinical trial design. Published data on the epidemiology and socioeconomic burden of PFIC is limited.

10.
Eur Respir J ; 52(3)2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30166324

RESUMO

Forskolin-induced swelling (FIS) of intestinal organoids from individuals with cystic fibrosis (CF) measures function of the cystic fibrosis transmembrane conductance regulator (CFTR), the protein mutated in CF.We investigated whether FIS corresponds with clinical outcome parameters and biomarkers of CFTR function in 34 infants diagnosed with CF. Relationships with FIS were studied for indicators of pulmonary and gastrointestinal disease.Children with low FIS had higher levels of immunoreactive trypsinogen (p=0.030) and pancreatitis-associated protein (p=0.039), more often had pancreatic insufficiency (p<0.001), had more abnormalities on chest computed tomography (p=0.049), and had lower z-scores for maximal expiratory flow at functional residual capacity (p=0.033) when compared to children with high FIS values. FIS significantly correlated with sweat chloride concentration (SCC) and intestinal current measurement (ICM) (r= -0.82 and r=0.70, respectively; both p<0.001). Individual assessment of SCC, ICM and FIS suggested that FIS can help to classify individual disease severity.Thus, stratification by FIS identified subgroups that differed in pulmonary and gastrointestinal outcome parameters. FIS of intestinal organoids correlated well with established CFTR-dependent biomarkers such as SCC and ICM, and performed adequately at group and individual level in this proof-of-concept study.

11.
Genet Med ; 2018 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-29875423

RESUMO

PURPOSE: Pathogenic variations in genes encoding aminoacyl-tRNA synthetases (ARSs) are increasingly associated with human disease. Clinical features of autosomal recessive ARS deficiencies appear very diverse and without apparent logic. We searched for common clinical patterns to improve disease recognition, insight into pathophysiology, and clinical care. METHODS: Symptoms were analyzed in all patients with recessive ARS deficiencies reported in literature, supplemented with unreported patients evaluated in our hospital. RESULTS: In literature, we identified 107 patients with AARS, DARS, GARS, HARS, IARS, KARS, LARS, MARS, RARS, SARS, VARS, YARS, and QARS deficiencies. Common symptoms (defined as present in ≥4/13 ARS deficiencies) included abnormalities of the central nervous system and/or senses (13/13), failure to thrive, gastrointestinal symptoms, dysmaturity, liver disease, and facial dysmorphisms. Deep phenotyping of 5 additional patients with unreported compound heterozygous pathogenic variations in IARS, LARS, KARS, and QARS extended the common phenotype with lung disease, hypoalbuminemia, anemia, and renal tubulopathy. CONCLUSION: We propose a common clinical phenotype for recessive ARS deficiencies, resulting from insufficient aminoacylation activity to meet translational demand in specific organs or periods of life. Assuming residual ARS activity, adequate protein/amino acid supply seems essential instead of the traditional replacement of protein by glucose in patients with metabolic diseases.

12.
Gastroenterology ; 155(1): 130-143.e15, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29604290

RESUMO

BACKGROUND & AIMS: Congenital diarrheal disorders are rare inherited intestinal disorders characterized by intractable, sometimes life-threatening, diarrhea and nutrient malabsorption; some have been associated with mutations in diacylglycerol-acyltransferase 1 (DGAT1), which catalyzes formation of triacylglycerol from diacylglycerol and acyl-CoA. We investigated the mechanisms by which DGAT1 deficiency contributes to intestinal failure using patient-derived organoids. METHODS: We collected blood samples from 10 patients, from 6 unrelated pedigrees, who presented with early-onset severe diarrhea and/or vomiting, hypoalbuminemia, and/or (fatal) protein-losing enteropathy with intestinal failure; we performed next-generation sequencing analysis of DNA from 8 patients. Organoids were generated from duodenal biopsies from 3 patients and 3 healthy individuals (controls). Caco-2 cells and patient-derived dermal fibroblasts were transfected or transduced with vectors that express full-length or mutant forms of DGAT1 or full-length DGAT2. We performed CRISPR/Cas9-guided disruption of DGAT1 in control intestinal organoids. Cells and organoids were analyzed by immunoblot, immunofluorescence, flow cytometry, chromatography, quantitative real-time polymerase chain reaction, and for the activity of caspases 3 and 7. RESULTS: In the 10 patients, we identified 5 bi-allelic loss-of-function mutations in DGAT1. In patient-derived fibroblasts and organoids, the mutations reduced expression of DGAT1 protein and altered triacylglycerol metabolism, resulting in decreased lipid droplet formation after oleic acid addition. Expression of full-length DGAT2 in patient-derived fibroblasts restored formation of lipid droplets. Organoids derived from patients with DGAT1 mutations were more susceptible to lipid-induced cell death than control organoids. CONCLUSIONS: We identified a large cohort of patients with congenital diarrheal disorders with mutations in DGAT1 that reduced expression of its product; dermal fibroblasts and intestinal organoids derived from these patients had altered lipid metabolism and were susceptible to lipid-induced cell death. Expression of full-length wildtype DGAT1 or DGAT2 restored normal lipid metabolism in these cells. These findings indicate the importance of DGAT1 in fat metabolism and lipotoxicity in the intestinal epithelium. A fat-free diet might serve as the first line of therapy for patients with reduced DGAT1 expression. It is important to identify genetic variants associated with congenital diarrheal disorders for proper diagnosis and selection of treatment strategies.


Assuntos
Diacilglicerol O-Aciltransferase/genética , Duodeno/metabolismo , Fibroblastos/metabolismo , Hipoalbuminemia/genética , Transtornos do Metabolismo dos Lipídeos/genética , Organoides/metabolismo , Enteropatias Perdedoras de Proteínas/genética , Células CACO-2 , Estudos de Casos e Controles , Caspase 3/metabolismo , Caspase 7/metabolismo , Criança , Pré-Escolar , Consanguinidade , Derme/citologia , Diacilglicerol O-Aciltransferase/deficiência , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Países Baixos , Forbóis , Reação em Cadeia da Polimerase em Tempo Real , Análise de Sequência de DNA , Turquia
13.
APMIS ; 126(3): 186-190, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29383769

RESUMO

Current diagnostic guidelines for celiac disease (CD) in pediatric patients require a duodenal biopsy if the IgA anti-tissue transglutaminase (tTG) is below 10x the upper limit of normal (ULN). Additional markers may enable a noninvasive diagnosis in this group. Serum intestinal-fatty acid-binding protein (I-FABP), a marker for intestinal epithelial damage, could be useful in this respect. A total of 95 children with a clinical suspicion of CD and tTG 1-10x ULN were investigated. All had a duodenal biopsy and analysis of serum I-FABP. A control group of 161 children with familial short stature and normal tTG was included. I-FABP levels in the 71 patients with tTG 1-10x ULN and biopsy-proven CD (median 725 pg/mL) were not significantly different (p = 0.13) from the levels in the 24 patients with a tTG 1-10x ULN but a normal biopsy (median 497 pg/mL). However, when combining tTG and I-FABP levels, 11/24 patients could have been diagnosed noninvasively if tTG is ≥ 50 U/mL and I-FABP ≥880 pg/mL or in 12/19 patients if tTG is ≥ 60 U/mL and I-FABP ≥ 620 pg/mL. Therefore, addition of I-FABP to the diagnostic procedure of CD may provide a noninvasive diagnosis in patients with a tTG ≥ 50 U/mL.


Assuntos
Doença Celíaca/diagnóstico , Doença Celíaca/patologia , Proteínas de Ligação a Ácido Graxo/sangue , Proteínas de Ligação ao GTP/imunologia , Imunoglobulina A/sangue , Transglutaminases/imunologia , Adolescente , Doença Celíaca/sangue , Criança , Pré-Escolar , Duodeno/patologia , Proteínas de Ligação a Ácido Graxo/metabolismo , Feminino , Antígenos HLA-DQ/sangue , Humanos , Imunoglobulina A/imunologia , Lactente , Mucosa Intestinal/patologia , Masculino
14.
J Pediatr Gastroenterol Nutr ; 65(4): 425-429, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28945207

RESUMO

OBJECTIVES: To evaluate the effect of immunomodulators on formation of antibodies to infliximab (ATI) in paediatric patients with Crohn disease (CD) and the association of ATI and loss of response. METHODS: Retrospective multicentre observational study (January 2009-December 2014) among Dutch children with CD treated with infliximab (IFX). ATI formation was analysed with Chi-square test and time-to-ATI formation with Kaplan-Meier and log-rank test. RESULTS: A total of 229 children were identified. ATIs were measured in 162 patients (70.7%) and 25 (15%) developed ATIs: 6 of 62 (10%) on continuous combined immunosuppression (CCI), 11 of 81 (14%) on early combined immunosuppression (ECI), and 8 of 19 (42%) on IFX monotherapy. ATI formation was higher in patients on IFX monotherapy compared to CCI (P = 0.003) and ECI (P = 0.008), whereas no significant difference was found between CCI and ECI. Sixteen out of 25 patients (64%) with ATIs had loss of response, compared with 32 of 137 patients (19%) without ATIs (P < 0.00002, log rank 0.02). Among patients treated with ECI, 10 of 55 (18%) developed ATIs within the first 12 months, compared to 1 of 26 (4%) after more than 12 months. CONCLUSIONS: In children with CD combination therapy is associated with significant reduction of antibody formation and prolonged effectivity compared to IFX monotherapy. ECI for at least 12 months, followed by IFX monotherapy, may be an equally effective alternative to CCI.


Assuntos
Doença de Crohn/tratamento farmacológico , Fármacos Gastrointestinais/imunologia , Fatores Imunológicos/uso terapêutico , Infliximab/imunologia , Adolescente , Formação de Anticorpos , Criança , Doença de Crohn/imunologia , Quimioterapia Combinada , Feminino , Fármacos Gastrointestinais/efeitos adversos , Fármacos Gastrointestinais/uso terapêutico , Humanos , Fatores Imunológicos/efeitos adversos , Infliximab/efeitos adversos , Infliximab/uso terapêutico , Masculino , Estudos Retrospectivos , Análise de Sobrevida , Resultado do Tratamento
15.
Curr Opin Pulm Med ; 23(6): 551-555, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28787381

RESUMO

PURPOSE OF REVIEW: Several new therapeutic modalities have recently become available to be used in patients with cystic fibrosis such as potentiators, modulators, and probiotics. Although the effects on pulmonary function have been well documented, gastrointestinal outcomes have been addressed only rarely. RECENT FINDINGS: Both the potentiator (ivacaftor) and the potentiator/modulator combination (ivacaftor/lumacaftor) that are currently on the market have a positive effect on BMI. Young patients (2-5 years of age) with a gating mutation may show improvement of exocrine pancreatic function on ivacaftor. In this specific patient population this agent also seems to improve intestinal pH and reflux. The effect of these medications on other gastrointestinal outcomes, such as intestinal inflammation and cystic fibrosis liver disease, has not been described so far. Furthermore, the results of several trials suggest that probiotics might reduce intestinal inflammation. Finally, organoids might be used to predict in vitro the clinical effect of potentiators and modulators. SUMMARY: The effect of new interventions on the gastrointestinal outcomes studied so far is favourable. Future studies should address the effect on other gastrointestinal parameters.


Assuntos
Aminofenóis/farmacologia , Aminopiridinas/farmacologia , Benzodioxóis/farmacologia , Agonistas dos Canais de Cloreto/farmacologia , Fibrose Cística/tratamento farmacológico , Sistema Digestório/efeitos dos fármacos , Probióticos/farmacologia , Quinolonas/farmacologia , Aminofenóis/uso terapêutico , Aminopiridinas/uso terapêutico , Benzodioxóis/uso terapêutico , Índice de Massa Corporal , Agonistas dos Canais de Cloreto/uso terapêutico , Fibrose Cística/complicações , Fibrose Cística/fisiopatologia , Combinação de Medicamentos , Refluxo Gastroesofágico/tratamento farmacológico , Refluxo Gastroesofágico/etiologia , Humanos , Concentração de Íons de Hidrogênio/efeitos dos fármacos , Enteropatias/tratamento farmacológico , Enteropatias/etiologia , Hepatopatias/tratamento farmacológico , Hepatopatias/etiologia , Probióticos/uso terapêutico , Quinolonas/uso terapêutico , Resultado do Tratamento , Ganho de Peso/efeitos dos fármacos
16.
N Engl J Med ; 377(1): 52-61, 2017 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-28657829

RESUMO

BACKGROUND: Studies of monogenic gastrointestinal diseases have revealed molecular pathways critical to gut homeostasis and enabled the development of targeted therapies. METHODS: We studied 11 patients with abdominal pain and diarrhea caused by early-onset protein-losing enteropathy with primary intestinal lymphangiectasia, edema due to hypoproteinemia, malabsorption, and less frequently, bowel inflammation, recurrent infections, and angiopathic thromboembolic disease; the disorder followed an autosomal recessive pattern of inheritance. Whole-exome sequencing was performed to identify gene variants. We evaluated the function of CD55 in patients' cells, which we confirmed by means of exogenous induction of expression of CD55. RESULTS: We identified homozygous loss-of-function mutations in the gene encoding CD55 (decay-accelerating factor), which lead to loss of protein expression. Patients' T lymphocytes showed increased complement activation causing surface deposition of complement and the generation of soluble C5a. Costimulatory function and cytokine modulation by CD55 were defective. Genetic reconstitution of CD55 or treatment with a complement-inhibitory therapeutic antibody reversed abnormal complement activation. CONCLUSIONS: CD55 deficiency with hyperactivation of complement, angiopathic thrombosis, and protein-losing enteropathy (the CHAPLE syndrome) is caused by abnormal complement activation due to biallelic loss-of-function mutations in CD55. (Funded by the National Institute of Allergy and Infectious Diseases and others.).


Assuntos
Antígenos CD55/genética , Ativação do Complemento/genética , Proteínas do Sistema Complemento/metabolismo , Mutação , Enteropatias Perdedoras de Proteínas/genética , Trombose/genética , Antígenos CD55/sangue , Criança , Pré-Escolar , Ativação do Complemento/efeitos dos fármacos , Inativadores do Complemento/farmacologia , Feminino , Homozigoto , Humanos , Imunoglobulina A/sangue , Lactente , Intestino Delgado/patologia , Masculino , Linhagem , Enteropatias Perdedoras de Proteínas/complicações , Estatísticas não Paramétricas , Síndrome , Linfócitos T/metabolismo
17.
J Biol Chem ; 292(19): 7904-7920, 2017 05 12.
Artigo em Inglês | MEDLINE | ID: mdl-28302725

RESUMO

Infantile-onset inflammatory bowel disease (IO IBD) is an invalidating illness with an onset before 2 years of age and has a complex pathophysiology in which genetic factors are important. Homozygosity mapping and whole-exome sequencing in an IO IBD patient and subsequent sequencing of the candidate gene in 12 additional IO IBD patients revealed two patients with two mutated ankyrin repeat and zinc-finger domain-containing 1 (ANKZF1) alleles (homozygous ANKZF1 R585Q mutation and compound heterozygous ANKZF1 E152K and V32_Q87del mutations, respectively) and two patients with one mutated ANKZF1 allele. Although the function of ANKZF1 in mammals had not been previously evaluated, we show that ANKZF1 has an indispensable role in the mitochondrial response to cellular stress. ANKZF1 is located diffusely in the cytoplasm and translocates to the mitochondria upon cellular stress. ANKZF1 depletion reduces mitochondrial integrity and mitochondrial respiration under conditions of cellular stress. The ANKZF1 mutations identified in IO IBD patients with two mutated ANKZF1 alleles result in dysfunctional ANKZF1, as shown by an increased level of apoptosis in patients' lymphocytes, a decrease in mitochondrial respiration in patient fibroblasts with a homozygous ANKZF1 R585Q mutation, and an inability of ANKZF1 R585Q and E152K to rescue the phenotype of yeast deficient in Vms1, the yeast homologue of ANKZF1. These data indicate that loss-of-function mutations in ANKZF1 result in deregulation of mitochondrial integrity, and this may play a pathogenic role in the development of IO IBD.


Assuntos
Repetição de Anquirina/genética , Proteínas de Transporte/genética , Doenças Inflamatórias Intestinais/genética , Dedos de Zinco , Idade de Início , Alelos , Apoptose , Proteínas de Transporte/metabolismo , Linhagem Celular Tumoral , Pré-Escolar , Exoma , Feminino , Fibroblastos/metabolismo , Genoma Humano , Células HEK293 , Homozigoto , Humanos , Lactente , Inflamação , Doenças Inflamatórias Intestinais/metabolismo , Linfócitos/citologia , Masculino , Mitocôndrias/metabolismo , Mutação , Fenótipo , RNA Interferente Pequeno/metabolismo , Análise de Sequência de DNA , Zinco/química
18.
J Cyst Fibros ; 16(3): 410-417, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28283399

RESUMO

BACKGROUND: Cystic fibrosis (CF) patients are advised to derive 35% of their daily energy intake from dietary fat. Whether this high fat intake is associated with dyslipidaemia is unknown. We described the lipid profile and dietary intake in paediatric patients with CF. METHODS: 110 fasting lipid concentrations of 110 Dutch patients with CF were studied, along with 86 measurements of dietary intake. For the total group and for boys and girls separately, the lipid profile and the dietary intake were investigated. The cross-sectional relationship between the lipid concentrations and dietary intake was determined. RESULTS: The mean dietary fat intake was ≥35% of the total energy intake, along with a considerable consumption of saturated fat. We found lower concentrations of cholesterol, high-density lipoprotein cholesterol and low-density lipoprotein cholesterol, and increased concentrations of triglyceride and triglyceride to high-density lipoprotein cholesterol ratios. Lipid concentrations were not associated with dietary fat intake. CONCLUSION: This study lacks variation in dietary fat intake to exclude an effect on lipid concentrations as the distribution of dietary fat intake remained constant at a high level. Elevated triglyceride concentrations and triglyceride to high-density lipoprotein cholesterol ratios suggest an increased risk of cardiovascular disease. Any negative consequences of a high dietary fat intake on the overall lipid profile later in life cannot be excluded.


Assuntos
HDL-Colesterol/sangue , LDL-Colesterol/sangue , Colesterol/sangue , Fibrose Cística , Gorduras na Dieta/análise , Triglicerídeos/sangue , Adolescente , Criança , Estudos Transversais , Fibrose Cística/sangue , Fibrose Cística/epidemiologia , Fibrose Cística/fisiopatologia , Ingestão de Energia/fisiologia , Comportamento Alimentar/fisiologia , Feminino , Humanos , Masculino , Países Baixos/epidemiologia
19.
Nutr Clin Pract ; 32(1): 130-132, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27094687

RESUMO

BACKGROUND: Height evaluation is an integral part of cystic fibrosis (CF) care. Height is compared with reference values by converting it to height-for-age (HFA) z scores. However, HFA z scores do not adjust for genetic potential (ie, target height [TH]), which could result in an incorrect estimation of the height. MATERIALS AND METHODS: To evaluate the magnitude of this potential problem, we assessed the agreement between HFA and HFA-adjusted-for-TH (HFA/TH) z scores in 474 Dutch children with CF. RESULTS: In this study sample, HFA z scores were -0.07 (95% confidence interval, -0.02 to -0.12) lower than HFA/TH z scores. When HFA and HFA/TH z scores were subdivided into 4 categories (≥0, <0 and ≥-1, <-1 and ≥-2, and ≤-2), a moderate agreement was found. HFA z scores were classified lower than HFA/TH z scores in 21% of the measurements and higher in 15% of the measurements. CONCLUSION: In clinical routine, height evaluation based on HFA may result in underestimation or overestimation of height growth, which may induce inappropriate nutrition interventions.


Assuntos
Fenômenos Fisiológicos da Nutrição do Adolescente , Fenômenos Fisiológicos da Nutrição Infantil , Fibrose Cística/fisiopatologia , Erros de Diagnóstico/prevenção & controle , Transtornos do Crescimento/diagnóstico , Desnutrição/diagnóstico , Estado Nutricional , Adolescente , Desenvolvimento do Adolescente , Fatores Etários , Estatura , Criança , Desenvolvimento Infantil , Pré-Escolar , Estudos Transversais , Transtornos do Crescimento/etiologia , Transtornos do Crescimento/fisiopatologia , Humanos , Desnutrição/etiologia , Desnutrição/fisiopatologia , Países Baixos , Avaliação Nutricional , Sistema de Registros , Índice de Gravidade de Doença
20.
Surg Endosc ; 31(7): 2910-2917, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-27804042

RESUMO

BACKGROUND: Esophageal intraluminal baseline impedance reflects the conductivity of the esophageal mucosa and may be an instrument for in vivo evaluation of mucosal integrity in children with gastroesophageal reflux disease (GERD). Laparoscopic antireflux surgery (LARS) is a well-established treatment option for children with proton pump inhibitory (PPI) therapy resistant GERD. The effect of LARS in children on baseline impedance has not been studied in detail. The aim of this study was to evaluate the effect of LARS on baseline impedance in children with GERD. METHODS: This is a prospective, multicenter, nationwide cohort study (Dutch national trial registry: NTR2934) including 25 patients [12 males, median age 6 (range 2-18) years] with PPI-resistant GERD scheduled to undergo LARS. Twenty-four hour multichannel intraluminal impedance pH monitoring (MII-pH monitoring) was performed before and 3 months after LARS. Baseline impedance was evaluated during consecutive 2-h intervals in the 24-h tracings. RESULTS: LARS reduced acid exposure time from 8.5 % (6.0-16.2 %) to 0.8 % (0.2-2.8 %), p < 0.001. Distal baseline impedance increased after LARS from 2445 Ω (1147-3277 Ω) to 3792 Ω (3087-4700 Ω), p < 0.001. Preoperative baseline impedance strongly correlated with acid exposure time (r -0.76, p < 0.001); however, no association between symptomatic outcome and baseline impedance was identified. CONCLUSIONS: LARS significantly increased baseline impedance likely reflecting recovery of mucosal integrity. As the change in baseline impedance was not associated with the clinical outcome of LARS, other factors besides mucosal integrity may contribute to symptom perception in children with GERD.


Assuntos
Mucosa Esofágica/fisiopatologia , Fundoplicatura , Refluxo Gastroesofágico/cirurgia , Laparoscopia , Adolescente , Criança , Pré-Escolar , Impedância Elétrica , Monitoramento do pH Esofágico/métodos , Feminino , Seguimentos , Fundoplicatura/métodos , Refluxo Gastroesofágico/diagnóstico , Refluxo Gastroesofágico/fisiopatologia , Humanos , Masculino , Estudos Prospectivos , Resultado do Tratamento
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