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1.
Dig Liver Dis ; 51(8): 1179-1184, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30928422

RESUMO

OBJECTIVES: Non-cirrhotic portal vein thrombosis (PVT) is a main cause of portal hypertension in children. We describe the characteristics at presentation and outcome of a cohort of patients with PVT to determine clinical features and predictors of outcome. METHODS: We recorded: (1) Associated factors: prematurity, congenital malformations, neonatal illnesses, umbilical vein catheterization (UVC), deep infections, surgery; (2) congenital and acquired prothrombotic disorders; (3) features at last follow up including survival rate and need for surgery. RESULTS: 187 patients, mean age at diagnosis 4 ±â€¯3.7 years, had a history of prematurity (61%); UVC (65%); neonatal illnesses (79%). The diagnosis followed the detection of splenomegaly (40%), gastrointestinal bleeding (36%), hypersplenism (6%), or was incidental (18%). Of 71 patients who had endoscopy at presentation 62 (87%) had oesophageal varices. After 11.3 years' follow up 63 (34%) required surgery or TIPS. Ten-year survival rate was 98%, with 90% shunt patency. Spleen size, variceal bleeding and hypersplenism at presentation were predictors of surgery or TIPS (p < 0.05). CONCLUSION: PVT is associated with congenital and acquired co-morbidities. History of prematurity, neonatal illnesses and UVC should lead to rule out PVT. Large spleen, variceal bleeding and hypersplenism at presentation predict the need for eventual surgery in a third of cases.

2.
Ital J Pediatr ; 45(1): 27, 2019 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-30791938

RESUMO

BACKGROUND: paucity of interlobular bile ducts is an important observation at liver biopsy in the diagnostic work-up of neonatal cholestasis. To date, other than in the Alagille syndrome, syndromic paucity of interlobular bile ducts has been documented in four cholestatic neonates with HFN1ß mutations. A syndromic phenotype, known as renal cysts and diabetes syndrome (RCAD), has been identified. This is usually characterized by a wide clinical spectrum, including renal cysts, maturity-onset diabetes of the young, exocrine pancreatic insufficiency, urogenital abnormalities and a not well established liver involvement. Herein we report a novel case of paucity of interlobular bile ducts due to an HFN1ß defect. CASE PRESENTATION: A 5-week-old boy was admitted to our department for cholestatic jaundice with increased gamma-glutamyl transpeptidase and an unremarkable clinical examination. He had been delivered by Caesarian section at 38 weeks' gestation from unrelated parents, with a birth weight of 2600 g (3rd percentile). Screening for cholestatic diseases, including Alagille syndrome, was negative except for a minor pulmonary artery stenosis at echocardiography and a doubt of a thoracic butterfly hemivertebra. The finding of hyperechogenic kidneys with multiple bilateral cortical cysts at ultrasound examination, associated with moderately impaired renal function with proteinuria, polyuria and metabolic acidosis, was suggestive of ciliopathy. A liver biopsy was performed revealing paucity of interlobular bile ducts, thus the diagnosis of Alagille syndrome was reconsidered. Although genetic tests for liver cholestatic diseases were performed with negative results for Alagille syndrome (JAG1 and NOTCH2), a de-novo missense mutation of HNF1ß gene was detected. At 18 months of age our patient has persistent cholestasis and his itching is not under satisfactory control. CONCLUSIONS: Alagille syndrome may not be the only syndrome determining paucity of interlobular bile ducts in neonates presenting with cholestasis and renal impairment, especially in small for gestational age newborns. We suggest that HNF1ß deficiency should also be ruled out, taking into consideration HNF1ß mutations, together with Alagille syndrome, in next generation sequencing strategies in neonates with cholestasis, renal impairment and/or paucity of interlobular bile ducts at liver biopsy.


Assuntos
Síndrome de Alagille/diagnóstico , Colestase Intra-Hepática/etiologia , Fator 1-beta Nuclear de Hepatócito/deficiência , Síndrome de Alagille/complicações , Humanos , Lactente , Masculino
5.
Minerva Pediatr ; 70(5): 476-487, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30021412

RESUMO

Although about 35 years have elapsed since the discovery of the Helicobacter pylori, its diagnosis and the choice of optimal eradication therapy are still to be defined. Over time, there has been an increase in interest, publications, recommendations and guidelines. Moreover, management of the disease in pediatric subjects differs somewhat to that of adults and requires a more delicate approach leading to alternative strategies for both diagnosis and treatment. Which patient should be investigated for H. pylori, when to perform noninvasive or invasive tests, what are the proper therapeutic options and best antibiotics regimen to eradicate the infection are practices changing with evidences through time. Therefore, an updated guideline was published by the European Society of Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) and the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) in 2017. The aim of this review is to highlight what is new and what differs between adult and pediatric population regarding the management of H. pylori infection after the ESPGHAN/NASPGHAN guidelines, enriched with updates from literature reviews published over the last two years.

7.
Transplantation ; 102(5): 823-828, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29377874

RESUMO

BACKGROUND: Hematopoietic stem cell transplantation (HSCT) is curative in patients with primary immunodeficiencies. However, pre-HSCT conditioning entails unacceptably high risks if the liver is compromised. The presence of a recurrent opportunistic infection affecting the biliary tree and determining liver cirrhosis with portal hypertension posed particular decisional difficulties in a 7-year-old child with X-linked CD40-ligand deficiency. We aim at adding to the scanty experience available on such rare cases, as successful management with sequential liver transplantation (LT) and HSCT has been reported in detail only in 1 young adult to date. METHODS: A closely sequential strategy, with a surgical complication-free LT, followed by reduced-intensity conditioning, allowed HSCT to be performed only one month after LT, preventing Cryptosporidium parvum recolonization of the liver graft. RESULTS: Combined sequential LT and HSCT resolved the cirrhotic evolution and corrected the immunodeficiency so that the infection responsible for the progressive sclerosing cholangitis did not recur. CONCLUSIONS: Hopefully, this report of the successful resolution of a potentially fatal combination of immunodeficiency and chronic opportunistic infection with end-stage organ damage in a child will encourage others to adapt a sequential transplant approach to this highly complex pathology. However, caution is to be exercised to carefully balance the risks intrinsic to transplant surgery and immunosuppression in primary immunodeficiencies.

8.
Pediatr Transplant ; 22(2)2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29369488

RESUMO

As graft survival in pediatric LT is often affected by progressive fibrosis, numerous centers carry out protocol liver biopsies. Follow-up biopsy protocols differ from center to center, but all biopsies are progressively spaced out, as time from transplant increases. Therefore, there is a need for non-invasive techniques to evaluate graft fibrosis progression in those children who have no clinical or serological signs of liver damage. Indirect markers, such as the APRI, should be relied on with caution because their sensitivity in predicting fibrosis can be strongly influenced by the etiology of liver disease, severity of fibrosis, and patient age. A valid alternative could be TE, a non-invasive technique already validated in adults, which estimates the stiffness of the cylindrical volume of liver tissue, 100-fold the size of a standard needle biopsy sample. The aims of this study were to evaluate the reliability of TE in children after LT and to compare both the TE and the APRI index results with the histological scores of fibrosis on liver biopsies. A total of 36 pediatric LT recipients were studied. All patients underwent both TE and biopsy within a year (median interval -0.012 months) at an interval from LT of 0.36 to 19.47 years (median 3.02 years). Fibrosis was assessed on the biopsy specimens at histology and staged according to METAVIR. There was a statistically significant correlation between TE stiffness values and METAVIR scores (P = .005). The diagnostic accuracy of TE for the diagnosis of significant fibrosis (F ≥ 2) was measured as the area under the curve (AUROC = 0.865), and it demonstrated that the method had a good diagnostic performance. APRI was not so accurate in assessing graft fibrosis when compared to METAVIR (AUROC = 0.592). A liver stiffness cutoff value of 5.6 kPa at TE was identified as the best predictor for a significant graft fibrosis (METAVIR F ≥ 2) on liver biopsy, with a 75% sensitivity, a 95.8% specificity, a 90% positive predictive value, and an 88.5% negative predictive value. These data suggest that TE may represent a non-invasive, reliable tool for the assessment of graft fibrosis in the follow-up of LT children, alerting the clinicians to the indication for a liver biopsy, with the aim of reducing the number of protocol liver biopsies.


Assuntos
Técnicas de Imagem por Elasticidade/métodos , Cirrose Hepática/diagnóstico por imagem , Transplante de Fígado , Complicações Pós-Operatórias/diagnóstico por imagem , Adolescente , Criança , Pré-Escolar , Estudos de Viabilidade , Feminino , Humanos , Lactente , Cirrose Hepática/etiologia , Masculino , Curva ROC , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Adulto Jovem
9.
JIMD Rep ; 38: 97-100, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-28643274

RESUMO

We report on a 12-year-old adopted boy with psychomotor disability, absence seizures, and normal brain MRI. He showed increased (but initially, at 5 months, normal) serum cholesterol, increased alkaline phosphatases, transiently increased transaminases and hypoceruloplasminemia with normal serum and urinary copper. Blood levels of immunoglobulins, haptoglobin, antithrombin, and factor XI were normal. A type 2 serum transferrin isoelectrofocusing and hypoglycosylation of apoCIII pointed to a combined N- and O-glycosylation defect. Neither CDG panel analysis with 79 CDG-related genes, nor whole exome sequencing revealed the cause of this CDG. Whole genome sequencing was not performed since the biological parents of this adopted child were not available.

10.
Ital J Pediatr ; 43(1): 88, 2017 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-28946922

RESUMO

BACKGROUND: Pediatric acute-liver-failure due to acetaminophen (APAP) administration at therapeutic dosage is rare, while viral infections and metabolic defects are the prevalent causes. Yet, as acetaminophen is routinely used in febrile illnesses, it may be mistakenly held responsible for the acute liver damage. CASE PRESENTATION: An 11 month old boy had been on acetaminophen for 10 days (total dose 720 mg = 72 mg/kg) when he developed acute-liver-failure with encephalopathy. As he rapidly improved on N-acetylcysteine (NAC) infusion, it was concluded that chronic acetaminophen administration in an infant had lead to acute-liver-failure even at therapeutic doses, that N-acetylcysteine infusion had been life-saving and should be immediately started in similar circumstances. The child, however, had two further episodes of acute liver damage over a 34-month period, without having been given acetaminophen, as the parents carefully avoided using it. His clinical, laboratory and radiological findings between the acute episodes were unremarkable. His features and skeletal surveys were not suggestive of a syndromic condition. He then went on to suffer another episode of acute-liver-failure with multi-organ failure, necessitating an urgent liver transplant. All efforts to come to a diagnosis for the causes of his recurrent episodes of liver failure had been unsuccessful, until a biallelic mutation in the NBAS gene was reported to be associated with recurrent acute-liver-failure in children. The boy's DNA analysis revealed compound heterozygous pathogenic mutations in the NBAS gene. Liver failure episodes in these patients are triggered and worsened by fever, most likely due to thermal susceptibility of hepatocytes, hence APAP, rather than being a culprit, is part of the supportive treatment. CONCLUSIONS: We suggest that, in acute-liver-failure with a history of acetaminophen exposure at therapeutic dosage, clinicians should not be contented with administering NAC, but should consider an alternative etiology, above all if the episodes are recurrent, and actively start supportive and antipyretic treatment while seeking the advice of a specialist unit.


Assuntos
Acetaminofen/efeitos adversos , Acetaminofen/uso terapêutico , Falência Hepática Aguda/genética , Transplante de Fígado/métodos , Proteínas de Neoplasias/genética , Diagnóstico Diferencial , Progressão da Doença , Febre/tratamento farmacológico , Predisposição Genética para Doença , Sobrevivência de Enxerto , Humanos , Lactente , Falência Hepática Aguda/induzido quimicamente , Falência Hepática Aguda/diagnóstico , Masculino , Mutação , Prognóstico , Medição de Risco , Resultado do Tratamento
11.
J Clin Virol ; 91: 36-41, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28414949

RESUMO

BACKGROUND: Epstein-Barr virus (EBV) infects 90% of the world population, commonly causing self-limiting infectious mononucleosis or rarely inciting a range of malignancies. EBV microRNAs (miRNAs) were discovered by sequencing libraries of small RNAs generated from several EBV-positive cell lines. Little is known about their roles, but their high stability and easy quantification make these molecules potential biomarkers. OBJECTIVES: In this study a stem-loop MGB real-time RT-PCR has been used to detect and quantify miR-BART2-5p, miR-BART15 and miR-BART22 EBV miRNAs levels. STUDY DESIGNS: The profiles of EBV miRNAs levels were evaluated in 51 serum samples of 37 pediatric liver transplant patients subdivided in 3 study groups: EBV seronegative, EBV seropositive and PCR negative, EBV seropositive and PCR positive. RESULTS: miR-BART22 serum levels in patients with positive EBV PCR were significantly higher than those in patients with negative EBV PCR (p=0.0005). On the contrary, miR-BART2-5p and miR-BART15 did not exhibit significant difference in positive and negative EBV PCR patients (p=0.5511 and p=0.3523, respectively). CONCLUSION: This study described a method for quantitative detection of miR-BART 22, miR-BART2-5p and miR-BART15 EBV miRNAs in liver transplanted patients, and suggests the use of miR-BART22 as a potential biomarker for EBV reactivation.


Assuntos
Herpesvirus Humano 4/genética , Transplante de Fígado , MicroRNAs/sangue , RNA Viral/sangue , Adolescente , Biomarcadores/sangue , Proteínas de Transporte/sangue , Criança , Infecções por Vírus Epstein-Barr/diagnóstico , Infecções por Vírus Epstein-Barr/virologia , Feminino , Perfilação da Expressão Gênica , Herpesvirus Humano 4/fisiologia , Humanos , Mononucleose Infecciosa/virologia , Masculino , Reação em Cadeia da Polimerase em Tempo Real/métodos , Ativação Viral
12.
Br J Clin Pharmacol ; 83(6): 1252-1262, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28044353

RESUMO

AIM: The aim of the present study was to investigate the influence of the cytochrome P450 (CYP) 3A4/5 genotype in paediatric liver transplant recipients and donors, and the contribution of age and gender to tacrolimus disposition on the first day after transplantation. METHODS: The contribution of the CYP3A4/5 genotype in paediatric liver transplant recipients and donors to the tacrolimus blood trough concentrations (C0 ) and the tacrolimus concentration/weight-adjusted dose ratio on day 1 was evaluated in 67 liver-transplanted children: 33 boys and 34 girls, mean age 4.5 years. RESULTS: Donor CYP3A5 genotype appears to be significantly associated with tacrolimus disposition on the first day after liver transplantation (P < 0.0002). Other physiological factors, such as recipient age and donor gender may also play a role and lead to significant differences in tacrolimus C0 and tacrolimus concentration/weight-adjusted dose ratio on day 1. However, according to the general linear model, only recipient age appears to be independently associated with tacrolimus disposition on the first day after liver transplantation (P < 0.03). Indeed, there was a faster tacrolimus metabolism in children under 6 years of age (P < 0.02). CONCLUSIONS: Donor CYP3A5 genotype, recipient age and, to a lesser extent, donor gender appear to be associated with tacrolimus disposition on day 1 after transplant. This suggests that increasing the starting tacrolimus doses in paediatric patients under 6 years of age who receive a graft from a male extensive metabolizer may enhance the possibility of their tacrolimus levels reaching the therapeutic range sooner.


Assuntos
Citocromo P-450 CYP3A/genética , Imunossupressores/farmacocinética , Transplante de Fígado , Tacrolimo/farmacocinética , Doadores de Tecidos , Adolescente , Envelhecimento , Peso Corporal , Criança , Pré-Escolar , Feminino , Variação Genética , Genótipo , Humanos , Lactente , Modelos Lineares , Masculino , Caracteres Sexuais
13.
J Mass Spectrom ; 52(3): 187-195, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-28098395

RESUMO

Tacrolimus (TAC, FK-506) and everolimus (EVE, RAD001) are immunosuppressors used to treat pediatric patients undergoing liver transplantation. Their hematic TDM by liquid chromatography became standard practice. However, it does not always reflect concentrations at their active site. Our aim was to develop and validate a new method for the simultaneous TAC and EVE quantification into target cells: peripheral blood mononuclear cells (PBMCs). Peripheral blood mononuclear cells were collected using cell preparation tubes; cells number and mean cell volume were evaluated by an automatic cell counter. TAC and EVE were quantified using UHPLC-MS/MS coupled with an automated online solid-phase extraction platform. Chromatographic run was performed on an Acquity UPLC® BEH C18 1.7 µm (2.1 × 50 mm) column at 45 °C, for 6 min at 0.5 ml/min. Mobile phases were water and methanol, both with 2 mm ammonium acetate and 1 ml/l formic acid). XBridge® C8 10 µm (1 × 10 mm) SPE cartridges were used, and the internal standard was ascomycin. Following Food and Drug Administration guidelines, method validation resulted in high sensitivity and specificity. Calibration curves were linear (r2  = 0.998) and intra-day and inter-day imprecision and inaccuracy were <15%. A reproducible matrix effect was observed, with a good recovery for all compounds. Drug amounts in 15 'real' PBMCs samples from five pediatric patients in co-treatment resulted within the calibration range (0.039-5 ng). Concentrations from each patient were standardized using their evaluated mean cell volume: intra-PBMCs concentration was meanly 19.23 and 218.61 times higher than the hematic one for TAC and EVE, respectively. This method might be useful in clinical routine, giving reliable data on drugs concentration at the active site. Copyright © 2017 John Wiley & Sons, Ltd.


Assuntos
Everolimo/sangue , Imunossupressores/sangue , Leucócitos Mononucleares/química , Tacrolimo/sangue , Adolescente , Criança , Pré-Escolar , Cromatografia Líquida de Alta Pressão/métodos , Humanos , Transplante de Fígado , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Extração em Fase Sólida , Espectrometria de Massas em Tandem/métodos
14.
Int J Cardiol ; 209: 60-5, 2016 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-26882184

RESUMO

BACKGROUND: In patients with Fontan circulation, the liver is profoundly affected by chronic venous stasis. Little is known about early hepatic changes in this population. METHODS: We performed echocardiography, abdominal ultrasound, liver elastography, cardiac catheterization, esophago-gastro-duodenoscopy and calculated MELD-XI score in 64 Fontan patients (69% minors), at an interval of 1-15years since Fontan. RESULTS: Cardiac output remained stable in the first 5years after Fontan, then significantly decreased (r=-0.45, p(r=0)=0.003). NYHA class significantly increased after Fontan. Patients in NYHA class II/III (n=21, 14 minors) had significantly higher hepatic pressures, but normal ventricular function and pulmonary vascular resistances (PVR). Patients with pulmonary arterial pressure (PAP) ≥15mmHg (n=12, 6 minors) and those with PVR≥2WU*m(2) (n=27, 25 minors), had higher hepatic pressures (p<0.0001), a higher incidence of liver collaterals and/or esophageal varices (p<0.0001) and splenomegaly (p<0.02). Liver stiffness (LS) was elevated in most patients (median, 25th-75th percentile:17.3KPa, 14.1-21.4). It rapidly increased during the first 5-years after Fontan, compared to the following 5-years (from 12.2KPa, 9.8-14.1 to 17.5KPa, 14.3-24.5, p=0.007), then remained stable (19.1KPa, 16.9-22.6, p=0.60). MELD-XI score increased linearly with the time interval since Fontan (r=0.31, p(r=0)=0.01). For patients above 12years we found a linear correlation between LS and MELD-XI score in the 6-15years period after Fontan (r=0.40. p(r=0)=0.04). The overall incidence of established liver cirrhosis was 22%. CONCLUSIONS: This is the largest study showing that Fontan circulation prompts early, progressive and eventually irreversible liver damage. Precautions should be taken immediately after Fontan, to protect this fragile population.


Assuntos
Técnica de Fontan/efeitos adversos , Hepatopatias/diagnóstico por imagem , Hepatopatias/etiologia , Índice de Gravidade de Doença , Adolescente , Criança , Técnicas de Imagem por Elasticidade , Feminino , Humanos , Masculino , Fatores de Risco , Ultrassonografia
15.
Am J Hum Genet ; 98(2): 322-30, 2016 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-26833330

RESUMO

Congenital disorders of glycosylation (CDGs) form a genetically and clinically heterogeneous group of diseases with aberrant protein glycosylation as a hallmark. A subgroup of CDGs can be attributed to disturbed Golgi homeostasis. However, identification of pathogenic variants is seriously complicated by the large number of proteins involved. As part of a strategy to identify human homologs of yeast proteins that are known to be involved in Golgi homeostasis, we identified uncharacterized transmembrane protein 199 (TMEM199, previously called C17orf32) as a human homolog of yeast V-ATPase assembly factor Vph2p (also known as Vma12p). Subsequently, we analyzed raw exome-sequencing data from families affected by genetically unsolved CDGs and identified four individuals with different mutations in TMEM199. The adolescent individuals presented with a mild phenotype of hepatic steatosis, elevated aminotransferases and alkaline phosphatase, and hypercholesterolemia, as well as low serum ceruloplasmin. Affected individuals showed abnormal N- and mucin-type O-glycosylation, and mass spectrometry indicated reduced incorporation of galactose and sialic acid, as seen in other Golgi homeostasis defects. Metabolic labeling of sialic acids in fibroblasts confirmed deficient Golgi glycosylation, which was restored by lentiviral transduction with wild-type TMEM199. V5-tagged TMEM199 localized with ERGIC and COPI markers in HeLa cells, and electron microscopy of a liver biopsy showed dilated organelles suggestive of the endoplasmic reticulum and Golgi apparatus. In conclusion, we have identified TMEM199 as a protein involved in Golgi homeostasis and show that TMEM199 deficiency results in a hepatic phenotype with abnormal glycosylation.


Assuntos
Fosfatase Alcalina/metabolismo , Colesterol/metabolismo , Complexo de Golgi/genética , Homeostase , Proteínas de Membrana/deficiência , Transaminases/metabolismo , Adulto , Sequência de Aminoácidos , Ceruloplasmina/metabolismo , Retículo Endoplasmático/metabolismo , Exoma , Fibroblastos/metabolismo , Genótipo , Glicosilação , Complexo de Golgi/metabolismo , Humanos , Masculino , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Dados de Sequência Molecular , Mutação , Fenótipo , Adulto Jovem
16.
Clin Res Hepatol Gastroenterol ; 40(1): 83-9, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26138133

RESUMO

BACKGROUND AND OBJECTIVE: Giant cell hepatitis with autoimmune hemolytic anemia (GCH-AHA) is a rare disease of infancy, of possible autoimmune mechanism with poor prognosis due to its scarce response to immunosuppressive drugs. The aim of this retrospective multicenter study was to evaluate the efficacy and safety of intravenous immunoglobulin (IVIg) treatment in inducing and maintaining remission of the liver disease, in patients with GCH-AHA. METHODS: Seven children with GCH-AHA, four newly diagnosed, and three in relapse, being treated with different therapies, received one to three IVIg infusions (0.5 to 2g/kg) in association with other immunosuppressive drugs. Subsequently five of them received monthly sequential IVIg infusions (mean 13.4, range 7-24). RESULTS: IVIg infusions as first-line therapy associated with prednisone and other immunosuppressive drugs significantly (P=0.04) reduced the aminotransferase activity in all patients and normalized prothrombin activity in the only patient with severe liver dysfunction. Sequential monthly IVIg infusions determined a steroid-sparing effect and allowed a complete or partial remission in all patients, although with temporary efficacy, since relapse of the hemolytic anemia and/or of liver disease occurred in all patients. IVIg infusions were associated with mild side effects in two patients. CONCLUSIONS: IVIg infusion can be safely and effectively administered in patients with severe GCH-AHA at diagnosis, or in case of relapse, in association with other immunosuppressive drugs. Repeated IVIg infusions may help maintain remission, however, due to their temporary efficacy, they should not be routinely employed.


Assuntos
Anemia Hemolítica Autoimune/complicações , Hepatite/complicações , Hepatite/tratamento farmacológico , Imunoglobulinas Intravenosas/uso terapêutico , Feminino , Humanos , Lactente , Masculino , Indução de Remissão , Estudos Retrospectivos , Resultado do Tratamento
18.
Pediatrics ; 136(1): e252-6, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-26077484

RESUMO

With conventional dietary treatment, the clinical course of methylmalonic acidemia due to cobalamin-unresponsive methylmalonyl-CoA mutase (MCM) deficiency is characterized by the persistent risk of recurrent life-threatening decompensation episodes with metabolic acidosis, hyperammonemia, and coma. Liver transplant has been proposed as an alternative treatment and anecdotally attempted in the last 2 decades with inconsistent results. Most criticisms of this approach have been directed at the continuing risk of neurologic and renal damage after transplant. Here, we report the perioperative and postoperative clinical and biochemical outcomes of 2 patients with severe MCM deficiency who underwent early liver transplant. In both cases, liver transplant allowed prevention of decompensation episodes, normalization of dietary protein intake, and a marked improvement of quality of life. No serious complications have been observed at 12 years' and 2 years' follow-up, respectively, except for mild kidney function impairment in the older patient. On the basis of our experience, we strongly suggest that liver transplant should be offered as a therapeutic option for children with cobalamin-unresponsive MCM deficiency at an early stage of the disease.


Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/cirurgia , Transplante de Fígado/métodos , Ácido Metilmalônico/sangue , Erros Inatos do Metabolismo dos Aminoácidos/sangue , Humanos , Recém-Nascido , Masculino , Fatores de Tempo
19.
J Pharm Biomed Anal ; 107: 512-7, 2015 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-25698619

RESUMO

BACKGROUND: Tacrolimus is an immunosuppressor used to treat patients undergoing liver transplantation. TDM of hematic tacrolimus by liquid chromatography became standard practice, but it does not necessarily reflect its concentration at its active site. Our aim was to validate a new method for tacrolimus quantification into target cells (peripheral blood mononuclear cells, PBMCs) and testing it on 100 real samples from 37 pediatric patients. METHODS: PBMCs were collected using cell-preparation-tubes; cells number and MCV were evaluated. Tacrolimus was quantified using UPLC-MS/MS coupled with a new automated on-line SPE platform. Chromatographic run was performed on an Acquity UPLC(®) BEH C18 1.7 µm (2.1 mm × 50 mm) column for 5 min, with a gradient of water and methanol (both with 2 mM/L ammonium acetate and 1 mL/L formic acid). XBridge(®) C8 10 µm (1 mm × 10 mm) SPE cartridges were used. The internal standard was 6,7-dimethyl-2,3-di(2-pyridyl)quinoxaline. RESULTS: Full validation following FDA guidelines was performed: the method showed high sensitivity and specificity (LLOQ of 0.010 ng; LLOD of 0.005 ng). Intra- and inter-day imprecision and inaccuracy were <15%. A positive and stable matrix effect was observed, with a good recovery for tacrolimus. All drug amounts in real samples resulted within the calibration range and calibration curves were linear (r(2)=0.998). Concentrations from each patient were standardized using their evaluated MCV: intra-PBMCs concentration was meanly 12.7 times higher than the hematic one. CONCLUSION: This method might be eligible and useful for a clinical routine use, giving more reliable data on drug concentration at the active site.


Assuntos
Imunossupressores/sangue , Imunossupressores/química , Leucócitos Mononucleares/química , Tacrolimo/sangue , Tacrolimo/química , Adolescente , Calibragem , Criança , Pré-Escolar , Cromatografia Líquida de Alta Pressão/métodos , Humanos , Padrões de Referência , Sensibilidade e Especificidade , Espectrometria de Massas em Tandem/métodos
20.
J Pediatr Gastroenterol Nutr ; 58(5): 666-8, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24792632

RESUMO

OBJECTIVE: Recent genome-wide association studies performed in adults correlated single-nucleotide polymorphisms (SNPs rs12979860 and rs8099917) located on chromosome 19, upstream of the interleukin 28B gene, with spontaneous clearance of hepatitis C virus and with response to treatment with paginated interferon and ribavirin. The aim of the present collaborative study was to evaluate the rs12979860 SNP in a large cohort of Italian children with perinatal acquisition of hepatitis C. METHODS: Children were prospectively enrolled in 2 Italian centers. The interleukin 28B rs12979860 SNP was studied according to the diagnosis of chronic infection or spontaneous clearance. RESULTS: One hundred thirty children (86.7%) with chronic infection and 23 (13.3%) with spontaneous clearance of the virus were enrolled. Overall, the interleukin 28B C/C and C/T-T/T genotypes were found in 57 (37.3%) and 96 (62.7%) children, respectively. The proportion of C/C genotype was higher among children who cleared infection (14/23; 60.9%) compared with children with chronic infection (43/130; 33.1%; P = 0.01; odds ratio 3.15; 90% confidence intervals 1.34-7.53). CONCLUSIONS: The present study showed that, as already demonstrated in adults, children with the rs12979860 C/C SNP of the interleukin 28B gene have a higher probability of spontaneous clearance of hepatitis C virus.


Assuntos
Hepacivirus , Hepatite C Crônica/virologia , Interleucinas/genética , Polimorfismo de Nucleotídeo Único , Adolescente , Criança , Pré-Escolar , Feminino , Genótipo , Hepatite C Crônica/imunologia , Humanos , Lactente , Itália , Masculino , Remissão Espontânea , Viremia/genética , Viremia/imunologia , Adulto Jovem
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