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1.
Sci Rep ; 9(1): 6653, 2019 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-31040306

RESUMO

Adenosine triphosphate binding cassette transporter, subfamily B member 4 (ABCB4) is the transporter of phosphatidylcholine at the canalicular membrane of hepatocytes. ABCB4 deficiency, due to genetic variations, is responsible for progressive familial intrahepatic cholestasis type 3 (PFIC3) and other rare biliary diseases. Roscovitine is a molecule in clinical trial that was shown to correct the F508del variant of cystic fibrosis transmembrane conductance regulator (CFTR), another ABC transporter. In the present study, we hypothesized that roscovitine could act as a corrector of ABCB4 traffic-defective variants. Using HEK and HepG2 cells, we showed that roscovitine corrected the traffic and localisation at the plasma membrane of ABCB4-I541F, a prototypical intracellularly retained variant. However, roscovitine caused cytotoxicity, which urged us to synthesize non-toxic structural analogues. Roscovitine analogues were able to correct the intracellular traffic of ABCB4-I541F in HepG2 cells. Importantly, the phospholipid secretion activity of this variant was substantially rescued by three analogues (MRT2-235, MRT2-237 and MRT2-243) in HEK cells. We showed that these analogues also triggered the rescue of intracellular traffic and function of two other intracellularly retained ABCB4 variants, i.e. I490T and L556R. Our results indicate that structural analogues of roscovitine can rescue genetic variations altering the intracellular traffic of ABCB4 and should be considered as therapeutic means for severe biliary diseases caused by this class of variations.

2.
J Pediatr ; 211: 120-125.e1, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31072651

RESUMO

OBJECTIVE: To identify predictors of and factors associated with the performance of antireflux surgery during the first year of life in children born with esophageal atresia. STUDY DESIGN: All patients were included in a French registry for esophageal atresia. All 38 multidisciplinary French centers completed questionnaires about perinatal characteristics and one-year outcome for children born with esophageal atresia. RESULTS: Of 835 infants with esophageal atresia born in France from 2010 to 2014, 682 patients, excluding those with long-gap esophageal atresia, were included. Three patients had type I, 669 had type III, and 10 had type IV esophageal atresia. Fifty-three children (7.8%) received fundoplication during the first year of life. The median age at the time of the end-to-end esophageal anastomosis was 1.1 day (range 0-15). Multivariate analysis identified three perioperative factors that predicted the need for early antireflux surgery: anastomotic tension (P = .004), associated malformations (P = .019), and low birth weight (P = .018). Six other factors, measured during the first year of life, were associated with the need for antireflux surgery: gastroesophageal reflux (P < .001), anastomotic stricture (P < .001), gastrostomy (P < .001), acute life-threatening event (P = .002), respiratory complications (P = .045), and poor nutritional status (P < .001). CONCLUSIONS: Gastroesophageal reflux disease, low birth weight, poor nutrition, and surgical anastomosis difficulties predicted the performance of antireflux surgery in the first year of life in infants with esophageal atresia.

3.
Prenat Diagn ; 39(5): 403-408, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30861154

RESUMO

OBJECTIVE: We developed a new balloon called "Smart-TO," which allows noninvasive and easy unplugging, thanks to a magnetic valve actuated by the magnetic fringe field of a magnetic resonance imaging (MRI) scanner. The objective of this feasibility study was to evaluate the operation of this new balloon in a nonhuman primate model. METHODS: Four pregnant rhesus monkeys underwent fetal endoscopic tracheal occlusion using the "Smart-TO" balloon. The pregnant monkeys were simply carried around the perimeter of an MRI scanner a few days later. Study outcomes were feasibility of fetal tracheal occlusion using the "Smart-TO" balloon, persistence of the balloon in the fetal trachea, and deflation of the balloon when subjected to the magnetic fringe field of an MRI. RESULTS: At the time of the unplug procedure, in all cases, the balloon was still in a correct position, and its shape did not change based on their ultrasound appearance. After bringing the pregnant monkeys into the fringe field of the MRI scanner, the balloon deflated in all cases. CONCLUSION: The balloon we developed allows noninvasive, easily triggered, and externally controlled reversal occlusion, based on the nonhuman primate model. Further tests evaluating occlusiveness and potential adverse effects are necessary.

4.
Cell Rep ; 26(9): 2477-2493.e9, 2019 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-30811995

RESUMO

The role of brain cell-type-specific functions and profiles in pathological and non-pathological contexts is still poorly defined. Such cell-type-specific gene expression profiles in solid, adult tissues would benefit from approaches that avoid cellular stress during isolation. Here, we developed such an approach and identified highly selective transcriptomic signatures in adult mouse striatal direct and indirect spiny projection neurons, astrocytes, and microglia. Integrating transcriptomic and epigenetic data, we obtained a comprehensive model for cell-type-specific regulation of gene expression in the mouse striatum. A cross-analysis with transcriptomic and epigenomic data generated from mouse and human Huntington's disease (HD) brains shows that opposite epigenetic mechanisms govern the transcriptional regulation of striatal neurons and glial cells and may contribute to pathogenic and compensatory mechanisms. Overall, these data validate this less stressful method for the investigation of cellular specificity in the adult mouse brain and demonstrate the potential of integrative studies using multiple databases.

5.
J Pediatr Gastroenterol Nutr ; 69(1): 52-56, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30614952

RESUMO

BACKGROUND AND OBJECTIVE: Eosinophilic esophagitis (EoE) is an increasingly recognized childhood disease. Esophageal atresia (EA) is the most frequent congenital malformation of the esophagus. Recently, cases of EoE occurring in patients with EA have been reported, although the exact prevalence of EoE in EA remains unknown. The aim is to investigate the prevalence of EoE among EA in adolescents and to describe these patients' characteristics. METHODS: Systematic upper gastrointestinal endoscopies with multistage esophageal biopsies were prospectively performed in 63 adolescents with EA. A standardized form was used to collect clinical and endoscopic data. Diagnosis of EoE was made as ≥15 intraepithelial eosinophils/high power field, whatever the response on proton pump inhibitors therapy. RESULTS: Six patients (9.5%) presented an EoE (17-100 eosinophils/high power field). An atopic condition was reported more frequently in the eosinophil ≥15 group than in patients with no EoE (66% vs 16%; P = 0.014). Except for chest pain, symptoms and endoscopic features were similar in patients with EoE and patients with no EoE. CONCLUSION: In our series of 63 patients born with EA, mainly distal tracheoesophageal fistula, the prevalence of EoE is increased, and therefore should be considered in adolescents with EA.

6.
Gastroenterology ; 155(6): 1951-1966.e26, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30165047

RESUMO

BACKGROUND & AIMS: We performed an integrated analysis to identify microRNAs (miRNAs) and messenger RNAs (mRNAs) with altered expression in liver tumors from 3 mouse models of hepatocellular carcinoma (HCC) and human tumor tissues. METHODS: We analyzed miRNA and mRNA expression profiles of liver tissues from mice with diethylnitrosamine-induced hepatocarcinogenesis, conditional expression of lymphotoxin alpha and lymphotoxin beta, or inducible expression of a Myc transgene (Tet-O-Myc mice), as well as male C57BL/6 mice (controls). miRNA mimics were expressed and miRNAs and mRNAs were knocked down in human (Huh7, Hep3B, JHH2) hepatoma cell lines; cells were analyzed for viability, proliferation, apoptosis, migration, and invasion. Cells were grown as xenograft tumors in nude mice and analyzed. We combined in silico target gene prediction with mRNA profiles from all 3 mouse models. We quantified miRNA levels in 146 fresh-frozen tissues from patients (125 HCCs, 17 matched nontumor tissues, and 4 liver samples from patients without cancer) and published human data sets and tested correlations with patient survival times using Kaplan-Meier curves and the log-rank test. Levels of NUSAP1 mRNA were quantified in 237 HCCs and 5 nontumor liver samples using the TaqMan assay. RESULTS: Levels of the miRNA 193a-5p (MIR193A-5p) were reduced in liver tumors from all 3 mouse tumor models and in human HCC samples, compared with nontumor liver tissues. Expression of a MIR193A-5p mimic in hepatoma cells reduced proliferation, survival, migration, and invasion and their growth as xenograft tumors in nude mice. We found nucleolar and spindle-associated protein 1 (NUSAP1) to be a target of MIR193A-5p; HCC cells and tissues with low levels of MIR193A-5p had increased expression of NUSAP1. Increased levels of NUSAP1 in HCC samples correlated with shorter survival times of patients. Knockdown of NUSAP1 in Huh7 cells reduced proliferation, survival, migration, and growth as xenograft tumors in nude mice. Hydrodynamic tail-vein injections of a small hairpin RNA against NUSAP1 reduced growth of Akt1-Myc-induced tumors in mice. CONCLUSIONS: MIR193A-5p appears to prevent liver tumorigenesis by reducing levels of NUSAP1. Levels of MIR193A-5p are reduced in mouse and human HCC cells and tissues, leading to increased levels of NUSAP1, associated with shorter survival times of patients. Integrated analyses of miRNAs and mRNAs in tumors from mouse models can lead to identification of therapeutic targets in humans. The currently reported miRNA and mRNA profiling data have been submitted to the Gene Expression Omnibus (super-series accession number GSE102418).

7.
Dis Markers ; 2018: 1983421, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29606984

RESUMO

Mixed lineage kinase domain-like (MLKL), a crucial regulator of necroptotic cell death, was shown to play a role in inflammatory diseases. However, its role as a biomarker in critical illness and sepsis is currently unknown. We analyzed serum levels of MLKL in 136 critically ill patients at admission to the intensive care unit (ICU) and after three days of ICU treatment. Results were compared with 36 healthy controls and correlated with clinical and laboratory patients' data. MLKL serum levels of critically ill patients at admission to the ICU were similar compared to healthy controls. At ICU admission, MLKL serum concentrations were independent of disease severity, presence of sepsis, and etiology of critical illness. In contrast, median serum levels of MLKL after three days of ICU treatment were significantly lower compared to those at admission to the ICU. While serum levels of MLKL at admission were not predictive for short-term survival during ICU treatment, elevated MLKL concentrations at day three were an independent negative predictor of patients' ICU survival. Thus, elevated MLKL levels after three days of ICU treatment were predictive for patients' mortality, indicating that sustained deregulated cell death is associated with an adverse prognosis in critical illness.


Assuntos
Biomarcadores/sangue , Estado Terminal/mortalidade , Proteínas Quinases/sangue , Sepse/mortalidade , Regulação para Cima , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Cuidados Críticos , Feminino , Humanos , Unidades de Terapia Intensiva , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Sepse/sangue , Análise de Sobrevida , Adulto Jovem
8.
J Vis Surg ; 4: 43, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29552525

RESUMO

Congenital diaphragmatic hernia (CDH) is a rare congenital disease requiring neonatal surgical treatment. The traditional surgical management of CDH consists of diaphragmatic repair by laparotomy. Thoracoscopic repair techniques have been well described for CDH with late presentation. Nevertheless, its feasibility for CDH treatment in neonates emerged only the past few years because the use of thoracoscopy with carbon dioxide insufflation remains controversial in these patients more vulnerable to hypothermia and acidosis. However, we think that thoracoscopy can be safely used to repair CDH in selected patients and the major limiting factor is pulmonary hypoplasia. Some patients should be excluded based on their higher potential need for patch closure with its technical difficulty and increased operative time. The close collaboration between pediatric surgeon, anesthetist and neonatologist is essential. We discuss here the patient selection criteria, expose the pre- and post-operative management, the procedure steps; regarding to our experience we deliver some tips to achieve the safest surgical procedure for the pediatric patient.

9.
Cell Death Dis ; 9(3): 344, 2018 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-29497041

RESUMO

Cell-cell adhesions constitute the structural "glue" that retains cells together and contributes to tissue organisation and physiological function. The integrity of these structures is regulated by extracellular and intracellular signals and pathways that act on the functional units of cell adhesion such as the cell adhesion molecules/adhesion receptors, the extracellular matrix (ECM) proteins and the cytoplasmic plaque/peripheral membrane proteins. In advanced cancer, these regulatory pathways are dysregulated and lead to cell-cell adhesion disassembly, increased invasion and metastasis. The Metastasis suppressor protein 1 (MTSS1) plays a key role in the maintenance of cell-cell adhesions and its loss correlates with tumour progression in a variety of cancers. However, the mechanisms that regulate its function are not well-known. Using a system biology approach, we unravelled potential interacting partners of MTSS1. We found that the secretory carrier-associated membrane protein 1 (SCAMP1), a molecule involved in post-Golgi recycling pathways and in endosome cell membrane recycling, enhances Mtss1 anti-invasive function in HER2+/ER-/PR- breast cancer, by promoting its protein trafficking leading to elevated levels of RAC1-GTP and increased cell-cell adhesions. This was clinically tested in HER2 breast cancer tissue and shown that loss of MTSS1 and SCAMP1 correlates with reduced disease-specific survival. In summary, we provide evidence of the cooperative roles of MTSS1 and SCAMP1 in preventing HER2+/ER-/PR- breast cancer invasion and we show that the loss of Mtss1 and Scamp1 results in a more aggressive cancer cell phenotype.

10.
J Pediatr ; 193: 204-210, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29212620

RESUMO

OBJECTIVE: To evaluate the status of congenital diaphragmatic hernia (CDH) management in France and to assess predictors of adverse outcomes. STUDY DESIGN: We reviewed the first-year outcome of all cases of CDH reported to the French National Register in 2011. RESULTS: A total of 158 cases were included. Of these, 83% (131) were prenatally diagnosed, with a mortality rate of 39% (44 of 112) for live born infants with a known outcome at hospital discharge. Mortality increased to 47% (60 of 128) including those with termination of pregnancy and fetal loss. This contrasts with the 7% (2 of 27) mortality rate of the patients diagnosed postnatally (P = .002). Mortality worsened with 1 prenatal marker of CDH severity (OR 3.38 [1.30-8.83] P = .013) and worsened further with 2 markers (OR 20.64 [5.29-80.62] P < .001). Classic postnatal risk factors of mortality such as side of hernia (nonleft P = .001), prematurity (P < .001), low birth weight (P = .002), and size of the defect (P < .001) were confirmed. Of the 141 live births (114 prenatal and 27 postnatal diagnosis) with known outcomes, 93 (67%) survived to hospital discharge, 68 (60%) with a prenatal diagnosis and 25 (93%) with a postnatal diagnosis. The median time to hospital discharge was 34 days (IQR, 19.25-62). Of these survivors, 71 (76%) were followed up for 1 year. CONCLUSIONS: Despite advances in management of CDH, mortality was high and associated with prenatal risk factors. Postnatally, severe persistent pulmonary hypertension was difficult to predict and presented persistent challenges in management.

11.
ACS Appl Mater Interfaces ; 10(9): 7574-7580, 2018 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-28914050

RESUMO

The deposition of polydopamine (PDA) films on surfaces, a versatile deposition method with respect to the nature of the used substrate, is unfortunately accompanied by deposition of insoluble precipitates in solution after a prolonged oxidation time of dopamine solutions. Therefore, there is evident interest to find methods able to stop the deposition of PDA on surfaces and to simultaneously control the self-assembly of PDA in solution to get stable colloidal aggregates. In addition to proposed methods relying on the use of polymers like poly(vinyl alcohol) and proteins like human serum albumin, we show herein that boric acid is an efficient adjuvant that is simultaneously able to stop the self-assembly of PDA in solution as well as on surfaces and to change the adhesive properties of the resulting PDA coatings.

12.
J Laparoendosc Adv Surg Tech A ; 28(1): 106-110, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29072964

RESUMO

OBJECTIVE: The authors present a multicenter retrospective series of different benign rib lesions in children operated on using thoracoscopy. MATERIALS AND METHODS: Between 2005 and 2015, 17 rib resections were performed thoracoscopically, in four French departments of pediatric surgery. Of these 17 cases, 13 exostoses, 2 endochondromas, 1 synostosis, and 1 Cyriax's syndrome were noted. Inclusion criteria were benign tumors or rib anomalies such as synostosis, in children younger than the age of 18 years, and thoracoscopy. Open surgery and malignant tumors were excluded. Thoracoscopy was put forward using one optical port as well as one or two operative ports. RESULTS: Ten patients presented with chest pain, dyspnea, or unexplained cough. Six tumors were incidentally diagnosed. One patient presented with a chest wall deformation. Single-lung ventilation was required in 2 cases. In 1 case of endochondroma, a segmental rib resection was performed, leaving a part of the periosteum and the intercostal vessels and nerve. In this case, rib resection was performed using an endoscopic shaver drill system. As for the other cases, a simple resection of the tumor or of the bridge between two ribs (synostosis) was performed. In these cases, a Codman Kerrison laminectomy rongeur was used. There was no complication during or after surgery. Nevertheless, 2 years after surgery, pain did not disappear in 1 case, probably due to a definitive intercostal nerve damage. CONCLUSION: Benign rib lesions in children are rare. Thoracoscopy may be offered to reduce the functional deleterious consequences of an open surgery. It may be put forward especially in case of hereditary multiple exostoses where redo procedures may be required.


Assuntos
Doenças Ósseas/cirurgia , Costelas/cirurgia , Toracoscopia/métodos , Adolescente , Cistos Ósseos/cirurgia , Criança , Pré-Escolar , Exostose/cirurgia , Feminino , Humanos , Masculino , Estudos Retrospectivos , Costelas/anormalidades , Sinostose/cirurgia , Toracoscopia/instrumentação
13.
Sci Rep ; 7(1): 16975, 2017 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-29208940

RESUMO

Cholangiocarcinoma (CCA) represents a rare form of primary liver cancer with increasing incidence but dismal prognosis. Surgical treatment has remained the only potentially curative treatment option, but it remains unclear which patients benefit most from liver surgery, highlighting the need for new preoperative stratification strategies. In clinical routine, CA19-9 represents the most widely used tumor marker in CCA patients. However, data on the prognostic value of CA19-9 in CCA patients are limited and often inconclusive, mostly due to small cohort sizes. Here, we investigated the prognostic value of CA19-9 in comparison with other standard laboratory markers in a large cohort of CCA patients that underwent tumor resection. Of note, while CA19-9 and CEA were able to discriminate between CCA and healthy controls, CEA showed a higher accuracy for the differentiation between CCA and patients with primary sclerosing cholangitis (PSC) compared to CA19-9. Furthermore, patients with elevated levels of C-reactive protein (CRP), CA19-9 or CEA showed a significantly impaired survival in Kaplan-Meier curve analysis, but surprisingly, only CEA but not CA19-9 represented an independent predictor of survival in multivariate Cox-regression analysis. Our data suggest that CEA might help to identify CCA patients with an unfavourable prognosis after tumor resection.

14.
ACS Comb Sci ; 19(12): 715-737, 2017 12 11.
Artigo em Inglês | MEDLINE | ID: mdl-29035557

RESUMO

With microwave irradiation, the submonomer synthesis of dipeptoids on functionalized cellulose can be accelerated with good yields and purity. Optimization provided a library of 96 dipeptoids. From these, 29 compounds were found with an antibacterial activity against MRSA at a concentration of 25 µM. Large nonpolar residues, such as undecylamine and dehydroabiethylamine, are the key components engendering the observed antibacterial activity of these peptoids.


Assuntos
Antibacterianos/síntese química , Micro-Ondas , Peptoides/síntese química , Antibacterianos/farmacologia , Técnicas de Química Combinatória , Humanos , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Peptoides/farmacologia , Bibliotecas de Moléculas Pequenas
15.
Int J Biochem Cell Biol ; 89: 101-109, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28587926

RESUMO

Genetic variations of the phosphatidylcholine transporter, ABCB4 cause several biliary diseases. The large number of reported variations makes it difficult to foresee a comprehensive study of each variation. To appreciate the reliability of in silico prediction programs, 1) we confronted them with the assessment in cell models of two ABCB4 variations (E528D and P1161S) identified in patients with low phospholipid-associated cholelithiasis (LPAC); 2) we extended the confrontation to 19 variations that we had previously characterized in cellulo. Four programs (Provean, Polyphen-2, PhD-SNP and MutPred) were used to predict the degree of pathogenicity. The E528D and P1161S variants were studied in transfected HEK293 and HepG2 cells by immunofluorescence, immunoblotting and measurement of phosphatidylcholine secretion. All prediction tools qualified the P1161S variation as deleterious, but provided conflicting results for E528D. In cell models, both mutants were expressed and localized as the wild type but their activity was significantly reduced, by 48% (P1161S) and 33% (E528D). These functional defects best correlated with MutPred predictions. MutPred program also proved the most accurate to predict the pathogenicity of the 19 ABCB4 variants that we previously characterized in cell models, and the most sensitive to predict the pathogenicity of 65 additional mutations of the Human Gene Mutation Database. These results confirm the pathogenicity of E528D and P1161S variations and suggest that even a moderate decrease (by less than 50%) of phosphatidylcholine secretion can cause LPAC syndrome. They highlight the reliability of in silico prediction tools, most notably MutPred, as a first approach to predict the pathogenicity of ABCB4 variants.


Assuntos
Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Colelitíase/genética , Simulação por Computador , Variação Genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/química , Sequência de Aminoácidos , Animais , Colelitíase/metabolismo , Feminino , Regulação da Expressão Gênica , Células HEK293 , Células Hep G2 , Humanos , Masculino , Modelos Moleculares , Mutação , Fosfatidilcolinas/metabolismo , Conformação Proteica
16.
Mol Cell Oncol ; 4(3): e1304191, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28616581

RESUMO

Receptor interacting protein kinase 1 (RIPK1) represents a key molecule in cell death. Here, we discuss our recent data on RIPK1 in liver injury and hepatocellular carcinoma development and put these into relation to previous experimental findings to underpin that it exerts opposing kinase-dependent and kinase independent functions in liver cells.

17.
Clin Sci (Lond) ; 131(15): 1971-1987, 2017 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-28646120

RESUMO

BACKGROUND: Dysregulation of miRNAs has been described in tissue and serum from patients with acute and chronic liver diseases. However, only little information on the role of miR-223 in the pathophysiology of acute liver failure (ALF) and liver cirrhosis is available. METHODS: We analysed cell and tissue specific expression levels as well as serum concentrations of miR-223 in mouse models of acute (hepatic ischaemia and reperfusion, single CCl4 injection) and chronic (repetitive CCl4 injection, bile duct ligation (BDL)) liver diseases. Results were validated in patients and correlated with clinical data. The specific hepatic role of miR-223 was analysed by using miR-223-/- mice in these models. RESULTS: miR-223 expression was significantly dysregulated in livers from mice after induction of acute liver injury and liver fibrosis as well as in liver samples from patients with ALF or liver cirrhosis. In acute and chronic models, hepatic miR-223 up-regulation was restricted to hepatocytes and correlated with degree of liver injury and hepatic cell death. Moreover, elevated miR-223 expression was reflected by significantly higher serum levels of miR-223 during acute liver injury. However, functional in vitro and in vivo experiments revealed no differences in the degree of liver cell death and liver fibrosis as miR-223-/- mice behaved identical with wild-type (wt) mice in all tested models. CONCLUSION: miR-223 represents a promising diagnostic marker in a panel of serum markers of liver injury. Together with previously published data, our results highlight that the role of miR-223 in the pathophysiology of the liver is complex and needs further analysis.


Assuntos
Cirrose Hepática/metabolismo , Falência Hepática/metabolismo , MicroRNAs/metabolismo , Doença Aguda , Animais , Biomarcadores/metabolismo , Doença Crônica , Feminino , Humanos , Cirrose Hepática/diagnóstico , Cirrose Hepática/genética , Falência Hepática/diagnóstico , Falência Hepática/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/genética
18.
J Hepatol ; 67(5): 966-978, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28645739

RESUMO

BACKGROUND AND AIMS: Patient outcome in acute liver failure (ALF) is crucially determined by the appropriate balance between cell death and compensatory cell proliferation. MicroRNAs (miRNAs) - small non-coding RNAs that function as guide molecules in RNA silencing - have evolved as crucial mediators of nearly all developmental and pathological processes, including the physiology and pathology of the liver. We investigated the role of miR-1224 during ALF. METHODS: We measured miR-1224 in livers of mice in various acute liver disease murine models and in, patients with ALF, using quantitative real-time PCR. We studied the regulation of miR-1224 in AML12 cells and primary hepatocytes upon H2O2 stimulation. Cell proliferation and cell death were analysed by 5-bromo-2'-deoxyuridine and terminal deoxynucleotide transferase nick end labelling stainings, respectively. RESULTS: We found that miR-1224 was up-regulated in hepatocytes upon ischaemia-reperfusion in vivo and in vitro. This was accompanied by impaired proliferation and elevated apoptosis. This function of miR-1224 was mediated by repressing the anti-apoptotic gene Nfib in hepatocytes. Strikingly, miR-1224 was also up-regulated in human livers and the serum of patients with ALF and indicated an unfavourable prognosis with an excellent prognostic value compared to other known serum markers in this clinical setting. CONCLUSIONS: miR-1224 is a previously unrecognised regulator of proliferation after ALF in hepatocytes and represents a novel and specific biomarker of liver injury with prognostic value in ALF. Thus, miR-1224 may represent a target for novel therapeutic and diagnostic strategies in the context of ALF and warrants further testing as a biomarker in prospective trials. Lay summary: In acute liver failure, miR-1224 expression is modulated by oxidative stress. This leads to a decrease in hepatocyte cell proliferation and increase in apoptosis. Increased serum levels of miR-1224 could be a useful diagnostic marker in patients with acute liver failure.


Assuntos
Hepatócitos/metabolismo , Falência Hepática Aguda , MicroRNAs/metabolismo , Traumatismo por Reperfusão , Adulto , Animais , Biomarcadores/metabolismo , Bromodesoxiuridina/metabolismo , Morte Celular/fisiologia , Proliferação de Células/fisiologia , DNA Nucleotidilexotransferase/metabolismo , Feminino , Humanos , Falência Hepática Aguda/etiologia , Falência Hepática Aguda/genética , Falência Hepática Aguda/metabolismo , Masculino , Camundongos , Pessoa de Meia-Idade , Traumatismo por Reperfusão/complicações , Traumatismo por Reperfusão/metabolismo , Reprodutibilidade dos Testes , Regulação para Cima
19.
J Pediatr Surg ; 52(9): 1465-1470, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28185630

RESUMO

BACKGROUND: The management of nonparasitic splenic cysts (NPSC) remains controversial. Surgical resection is indicated for symptomatic or complicated forms, but no guidelines are available for asymptomatic NPSC. The aims of this study were to evaluate the management of NPSC in French hospitals and to analyze the results of management. METHODS: We conducted a retrospective multicenter study from January 2004 to December 2014 in 16 university hospitals in France. Patients with a follow-up less than 6months were excluded. Data were extracted from the medical reports. RESULTS: One hundred patients were included. Median follow-up was 12.8months. No complications were observed for NPSC smaller than 5cm. The size of NPSC increased significantly between the ages of 10 and 12years. Fifteen patients were under observation; 58.3% of cysts decreased in size and 41.7% remained stable. Among the 85 operated patients, no recurrence occurred in the splenectomy group, while 11 recurrences were observed in the cystectomy group (57.9%), 3 of which required redo surgery. CONCLUSIONS: Observation is a safe treatment option for asymptomatic NPSC smaller than 5cm. Surgery is indicated for symptomatic patients, and can be proposed for asymptomatic NPSC larger than 5cm. Laparoscopic partial splenectomy is the technique of choice. Follow-up must be continued until the end of puberty. LEVELS OF EVIDENCE RATING: Level III.


Assuntos
Cistectomia/métodos , Cistos/cirurgia , Esplenopatias/cirurgia , Adolescente , Criança , Feminino , França , Humanos , Laparoscopia/métodos , Masculino , Estudos Retrospectivos , Esplenectomia/métodos
20.
J Laparoendosc Adv Surg Tech A ; 27(3): 318-321, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28055334

RESUMO

BACKGROUND: Intestinal malrotations with midgut volvulus are surgical emergencies that can lead to life-threatening intestinal necrosis. This study evaluates the feasibility and the outcomes of laparoscopic treatment of midgut volvulus compared with classic open Ladd's procedure in neonates. MATERIALS AND METHODS: The medical records of all neonates with diagnosis of malrotation and volvulus, who underwent surgery between January 1993 and January 2014, were reviewed. We considered the group of neonates laparoscopically treated (Group A, n = 20) and we compared it with an equal number of neonates treated with the classical open Ladd's procedure (Group B, n = 20). RESULTS: The median age at surgery was 8.4 days and the mean weight was 3.340 kg. The suspicion of volvulus was documented by plain abdominal radiograph, upper gastrointestinal contrast study, and/or ultrasound scanning of the mesenteric vessels. All the patients were treated according to the Ladd's procedure. Conversion to an open procedure was necessary in 25% of the patients. The mean operative time was 80 minutes (28-190 minutes) in Group A and 61 minutes (40-130 minutes) in Group B (P = .04). The median time to full diet (P = .02) and hospital stay (P = .04) was better in Group A. Rehospitalization because of recurrence of occlusive symptoms occurred in 30% of patients in Group A (n = 6) and in 40% of patients in Group B (n = 8). Among these, all the 6 patients of Group A underwent redo surgery for additional division of Ladd's bands or debridement; instead in Group B, 4 of 8 patients underwent open redo surgery. CONCLUSIONS: Laparoscopic exploration is the procedure of choice in case of suspicion of intestinal malrotation and volvulus. Laparoscopic treatment is feasible and safe even in neonatal age without additional risks compared with classical open Ladd's procedure.


Assuntos
Anormalidades do Sistema Digestório/cirurgia , Volvo Intestinal/cirurgia , Laparoscopia , Laparotomia , Conversão para Cirurgia Aberta/estatística & dados numéricos , Estudos de Viabilidade , Feminino , Seguimentos , Humanos , Recém-Nascido , Tempo de Internação/estatística & dados numéricos , Masculino , Duração da Cirurgia , Recidiva , Estudos Retrospectivos , Resultado do Tratamento
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