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1.
Intensive Care Med ; 2020 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-32025780

RESUMO

PURPOSE: Indications and optimal timing for tracheostomy in traumatic brain-injured (TBI) patients are uncertain. This study aims to describe the patients' characteristics, timing, and factors related to the decision to perform a tracheostomy and differences in strategies among different countries and assess the effect of the timing of tracheostomy on patients' outcomes. METHODS: We selected TBI patients from CENTER-TBI, a prospective observational longitudinal cohort study, with an intensive care unit stay ≥ 72 h. Tracheostomy was defined as early (≤ 7 days from admission) or late (> 7 days). We used a Cox regression model to identify critical factors that affected the timing of tracheostomy. The outcome was assessed at 6 months using the extended Glasgow Outcome Score. RESULTS: Of the 1358 included patients, 433 (31.8%) had a tracheostomy. Age (hazard rate, HR = 1.04, 95% CI = 1.01-1.07, p = 0.003), Glasgow coma scale ≤ 8 (HR = 1.70, 95% CI = 1.22-2.36 at 7; p < 0.001), thoracic trauma (HR = 1.24, 95% CI = 1.01-1.52, p = 0.020), hypoxemia (HR = 1.37, 95% CI = 1.05-1.79, p = 0.048), unreactive pupil (HR = 1.76, 95% CI = 1.27-2.45 at 7; p < 0.001) were predictors for tracheostomy. Considerable heterogeneity among countries was found in tracheostomy frequency (7.9-50.2%) and timing (early 0-17.6%). Patients with a late tracheostomy were more likely to have a worse neurological outcome, i.e., mortality and poor neurological sequels (OR = 1.69, 95% CI = 1.07-2.67, p = 0.018), and longer length of stay (LOS) (38.5 vs. 49.4 days, p = 0.003). CONCLUSIONS: Tracheostomy after TBI is routinely performed in severe neurological damaged patients. Early tracheostomy is associated with a better neurological outcome and reduced LOS, but the causality of this relationship remains unproven.

2.
Cancers (Basel) ; 11(9)2019 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-31527543

RESUMO

The present study applies for the first time as Matrix-Assisted Laser Desorption/Ionization (MALDI) Mass Spectrometry Imaging (MSI) on real thyroid Fine Needle Aspirations (FNAs) to test its possible complementary role in routine cytology in the diagnosis of thyroid nodules. The primary aim is to evaluate the potential employment of MALDI-MSI in cytopathology, using challenging samples such as needle washes. Firstly, we designed a statistical model based on the analysis of Regions of Interest (ROIs), according to the morphological triage performed by the pathologist. Successively, the capability of the model to predict the classification of the FNAs was validated in a different group of patients on ROI and pixel-by-pixel approach. Results are very promising and highlight the possibility to introduce MALDI-MSI as a complementary tool for the diagnostic characterization of thyroid nodules.

3.
Anal Bioanal Chem ; 411(20): 5007-5012, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31147760

RESUMO

MALDI-MSI represents an ideal tool to explore the spatial distribution of proteins directly in situ, integrating molecular and cytomorphological information, enabling the discovery of potential diagnostic markers in thyroid cytopathology. However, red cells present in the fine needle aspiration biopsy (FNAB) specimens caused ion suppression of other proteins during the MALDI-MSI analysis due to large amount of haemoglobin. Aim of this study was to set up a sample preparation workflow able to manage this haemoglobin interference. Three protocols were compared using ex vivo cytological samples collected from fresh thyroid nodules of 9 patients who underwent thyroidectomy: (A) conventional air-dried smears, (B) cytological smears immediately fixed in ethanol, and (C) ThinPrep liquid-based preparation. Protocols C and A were also evaluated using real FNABs. Results show that protocol C markedly decreased the amount of haemoglobin, with respect to protocols A and B. Protein profiles obtained with protocols A and B were characterised by high inter-patient variability, probably related to the abundance of the haemoglobin, whereas similar spectra were observed for protocol C, where haemoglobin contents were lower. Our findings suggest protocol C as the sample preparation method for MALDI-MSI analysis. Graphical abstract.


Assuntos
Biópsia por Agulha/métodos , Hemoglobinas/análise , Proteômica/métodos , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz/métodos , Glândula Tireoide/patologia , Artefatos , Humanos , Tireoidectomia
4.
Lancet Haematol ; 6(5): e239-e253, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30981783

RESUMO

BACKGROUND: Wiskott-Aldrich syndrome is a rare, life-threatening, X-linked primary immunodeficiency characterised by microthrombocytopenia, infections, eczema, autoimmunity, and malignant disease. Lentiviral vector-mediated haemopoietic stem/progenitor cell (HSPC) gene therapy is a potentially curative treatment that represents an alternative to allogeneic HSPC transplantation. Here, we report safety and efficacy data from an interim analysis of patients with severe Wiskott-Aldrich syndrome who received lentiviral vector-derived gene therapy. METHODS: We did a non-randomised, open-label, phase 1/2 clinical study in paediatric patients with severe Wiskott-Aldrich syndrome, defined by either WAS gene mutation or absent Wiskott-Aldrich syndrome protein (WASP) expression or a Zhu clinical score of 3 or higher. We included patients who had no HLA-identical sibling donor available or, for children younger than 5 years of age, no suitable 10/10 matched unrelated donor or 6/6 unrelated cord blood donor. After treatment with rituximab and a reduced-intensity conditioning regimen of busulfan and fludarabine, patients received one intravenous infusion of autologous CD34+ cells genetically modified with a lentiviral vector encoding for human WAS cDNA. The primary safety endpoints were safety of the conditioning regimen and safety of lentiviral gene transfer into HSPCs. The primary efficacy endpoints were overall survival, sustained engraftment of genetically corrected HSPCs, expression of vector-derived WASP, improved T-cell function, antigen-specific responses to vaccinations, and improved platelet count and mean platelet volume normalisation. This interim analysis was done when the first six patients treated had completed at least 3 years of follow-up. The planned analyses are presented for the intention-to-treat population. This trial is registered with ClinicalTrials.gov (number NCT01515462) and EudraCT (number 2009-017346-32). FINDINGS: Between April 20, 2010, and Feb 26, 2015, nine patients (all male) were enrolled of whom one was excluded after screening; the age range of the eight treated children was 1·1-12·4 years. At the time of the interim analysis (data cutoff April 29, 2016), median follow-up was 3·6 years (range 0·5-5·6). Overall survival was 100%. Engraftment of genetically corrected HSPCs was successful and sustained in all patients. The fraction of WASP-positive lymphocytes increased from a median of 3·9% (range 1·8-35·6) before gene therapy to 66·7% (55·7-98·6) at 12 months after gene therapy, whereas WASP-positive platelets increased from 19·1% (range 4·1-31·0) to 76·6% (53·1-98·4). Improvement of immune function was shown by normalisation of in-vitro T-cell function and successful discontinuation of immunoglobulin supplementation in seven patients with follow-up longer than 1 year, followed by positive antigen-specific response to vaccination. Severe infections fell from 2·38 (95% CI 1·44-3·72) per patient-year of observation (PYO) in the year before gene therapy to 0·31 (0·04-1·11) per PYO in the second year after gene therapy and 0·17 (0·00-0·93) per PYO in the third year after gene therapy. Before gene therapy, platelet counts were lower than 20 × 109 per L in seven of eight patients. At the last follow-up visit, the platelet count had increased to 20-50 × 109 per L in one patient, 50-100 × 109 per L in five patients, and more than 100 × 109 per L in two patients, which resulted in independence from platelet transfusions and absence of severe bleeding events. 27 serious adverse events in six patients occurred after gene therapy, 23 (85%) of which were infectious (pyrexia [five events in three patients], device-related infections, including one case of sepsis [four events in three patients], and gastroenteritis, including one case due to rotavirus [three events in two patients]); these occurred mainly in the first 6 months of follow-up. No adverse reactions to the investigational drug product and no abnormal clonal proliferation or leukaemia were reported after gene therapy. INTERPRETATION: Data from this study show that gene therapy provides a valuable treatment option for patients with severe Wiskott-Aldrich syndrome, particularly for those who do not have a suitable HSPC donor available. FUNDING: Italian Telethon Foundation, GlaxoSmithKline, and Orchard Therapeutics.


Assuntos
Terapia Genética , Vetores Genéticos/genética , Células-Tronco Hematopoéticas/metabolismo , Lentivirus/genética , Síndrome de Wiskott-Aldrich/genética , Síndrome de Wiskott-Aldrich/terapia , Criança , Pré-Escolar , Feminino , Terapia Genética/métodos , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Lactente , Itália , Masculino , Mutação , Linfócitos T/imunologia , Linfócitos T/metabolismo , Condicionamento Pré-Transplante/métodos , Resultado do Tratamento , Síndrome de Wiskott-Aldrich/sangue , Síndrome de Wiskott-Aldrich/diagnóstico , Proteína da Síndrome de Wiskott-Aldrich/genética
5.
Nat Med ; 25(2): 234-241, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30664781

RESUMO

ß-thalassemia is caused by ß-globin gene mutations resulting in reduced (ß+) or absent (ß0) hemoglobin production. Patient life expectancy has recently increased, but the need for chronic transfusions in transfusion-dependent thalassemia (TDT) and iron chelation impairs quality of life1. Allogeneic hematopoietic stem cell (HSC) transplantation represents the curative treatment, with thalassemia-free survival exceeding 80%. However, it is available to a minority of patients and is associated with morbidity, rejection and graft-versus-host disease2. Gene therapy with autologous HSCs modified to express ß-globin represents a potential therapeutic option. We treated three adults and six children with ß0 or severe ß+ mutations in a phase 1/2 trial ( NCT02453477 ) with an intrabone administration of HSCs transduced with the lentiviral vector GLOBE. Rapid hematopoietic recovery with polyclonal multilineage engraftment of vector-marked cells was achieved, with a median of 37.5% (range 12.6-76.4%) in hematopoietic progenitors and a vector copy number per cell (VCN) of 0.58 (range 0.10-1.97) in erythroid precursors at 1 year, in absence of clonal dominance. Transfusion requirement was reduced in the adults. Three out of four evaluable pediatric participants discontinued transfusions after gene therapy and were transfusion independent at the last follow-up. Younger age and persistence of higher VCN in the repopulating hematopoietic cells are associated with better outcome.


Assuntos
Transfusão de Sangue , Osso e Ossos/patologia , Terapia Genética , Transplante de Células-Tronco Hematopoéticas , Células-Tronco Hematopoéticas/citologia , Talassemia beta/genética , Talassemia beta/terapia , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Resultado do Tratamento
6.
J Allergy Clin Immunol ; 143(6): 2238-2253, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30660643

RESUMO

BACKGROUND: CD40 ligand (CD40L) deficiency, an X-linked primary immunodeficiency, causes recurrent sinopulmonary, Pneumocystis and Cryptosporidium species infections. Long-term survival with supportive therapy is poor. Currently, the only curative treatment is hematopoietic stem cell transplantation (HSCT). OBJECTIVE: We performed an international collaborative study to improve patients' management, aiming to individualize risk factors and determine optimal HSCT characteristics. METHODS: We retrospectively collected data on 130 patients who underwent HSCT for CD40L deficiency between 1993-2015. We analyzed outcome and variables' relevance with respect to survival and cure. RESULTS: Overall survival (OS), event-free survival (EFS), and disease-free survival (DFS) were 78.2%, 58.1%, and 72.3% 5 years after HSCT. Results were better in transplantations performed in 2000 or later and in children less than 10 years old at the time of HSCT. Pre-existing organ damage negatively influenced outcome. Sclerosing cholangitis was the most important risk factor. After 2000, superior OS was achieved with matched donors. Use of myeloablative regimens and HSCT at 2 years or less from diagnosis associated with higher OS and DFS. EFS was best with matched sibling donors, myeloablative conditioning (MAC), and bone marrow-derived stem cells. Most rejections occurred after reduced-intensity or nonmyeloablative conditioning, which associated with poor donor cell engraftment. Mortality occurred mainly early after HSCT, predominantly from infections. Among survivors who ceased immunoglobulin replacement, T-lymphocyte chimerism was 50% or greater donor in 85.2%. CONCLUSION: HSCT is curative in patients with CD40L deficiency, with improved outcome if performed before organ damage development. MAC is associated with better OS, EFS, and DFS. Prospective studies are required to compare the risks of HSCT with those of lifelong supportive therapy.

7.
J Ultrasound Med ; 38(7): 1713-1720, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30480833

RESUMO

OBJECTIVES: The aim of this study was to evaluate the application of shear wave elastography (SWE) in the routine management of thyroid nodules, as a possible additional tool to the standard sonographic triage. METHODS: A total of 248 consecutive patients scheduled for ultrasound-guided thyroid fine-needle aspiration were included in the study. The presence of a pure colloid lesion was an exclusion criterion. Absolute and relative SWE stiffness measurements on color-coded elastograms, expressed in kilopascals and meters per second, were correlated with radiologic and pathologic features. RESULTS: SWE values in thyroid nodules were significantly higher than normal thyroid tissue (P = .0001), proving the different elastic properties of the pathologic tissues. Regarding the radiologic characteristics of the nodules, SWE highest values were associated with the largest lesions (P = .0105) but independent from sonographic and Doppler findings. The SWE elasticity was not influenced by the characteristics of the biopsy smears. The final correlation between the SWE results and the pathologic diagnoses showed a trend in stiffness from tender tumors (follicular adenoma) to papillary thyroid carcinoma (P = .016). CONCLUSIONS: SWE allows the identification of nodules within normal parenchyma; however, the present study does not confirm the potential role in differentiating between benign and malignant thyroid nodules.


Assuntos
Biópsia por Agulha Fina , Técnicas de Imagem por Elasticidade/métodos , Biópsia Guiada por Imagem , Nódulo da Glândula Tireoide/diagnóstico por imagem , Nódulo da Glândula Tireoide/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Viabilidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Triagem
8.
Proteomics Clin Appl ; 13(1): e1700170, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30411853

RESUMO

PURPOSE: MALDI-MS imaging (MALDI-MSI) is an emerging technology that enables the spatial distribution of biomolecules within tissue to be combined with the traditional morphological information familiar to clinicians. Thus, for diagnostic or prognostic purposes, along with predicting response to therapeutic treatment, it is important to properly collect and handle biological specimens in order to avoid degradation or the formation of artifacts in the morphological structure and proteomic profile. EXPERIMENTAL DESIGN: In this work, the morphological and proteomic stability of thyroid fine needle aspiration biopsies in PreservCyt (up to 14 days) and CytoLyt (up to 7 days) solutions at 4 °C has been verified, by MALDI-MSI analysis. Moreover, a new measure has been introduced in order to assess the similarity of the obtained MALDI-MSI spectra, by equally taking into account the number of signals (fit and retrofit), and their intensities (Spearman's correlation and spectra overlap). RESULTS: Results show no degradation of the cellular morphology and a good stability of the samples up to 14 days in PreservCyt solution. CONCLUSIONS AND CLINICAL RELEVANCE: Moreover, this protocol can be easily implemented in pathological units, allowing simple sample collection and shipment to be used not only for the proteomic MALDI-MSI analysis of thyroid FNABs but also for other biological liquid based specimens.


Assuntos
Biópsia por Agulha Fina , Proteômica/métodos , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Glândula Tireoide/metabolismo , Glândula Tireoide/patologia , Estudos de Viabilidade , Humanos
9.
Expert Rev Proteomics ; 15(11): 937-948, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30290700

RESUMO

INTRODUCTION: An accurate diagnostic classification of thyroid lesions remains an important clinical aspect that needs to be addressed in order to avoid 'diagnostic' thyroidectomies. Among the several 'omics' techniques, proteomics is playing a pivotal role in the search for diagnostic markers. In recent years, different approaches have been used, taking advantage of the technical improvements related to mass spectrometry that have occurred. Areas covered: The review provides an update of the recent findings in diagnostic classification, in genetic definition and in the investigation of thyroid lesions based on different proteomics approaches and on different type of specimens: cytological, surgical and biofluid samples. A brief section will discuss how these findings can be integrated with those obtained by metabolomics investigations. Expert commentary: Among the several proteomics approaches able to deepen our knowledge of the molecular alterations of the different thyroid lesions, MALDI-MSI is strongly emerging above all. In fact, MS-imaging has also been demonstrated to be capable of distinguishing thyroid lesions, based on their different molecular signatures, using cytological specimens. The possibility to use the material obtained by the fine needle aspiration makes MALDI-MSI a highly promising technology that could be implemented into the clinical and pathological units.


Assuntos
Proteômica/métodos , Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/patologia , Biópsia por Agulha Fina , Proteínas Sanguíneas/análise , Técnicas Genéticas , Humanos , Imunoquímica , Metabolômica/métodos , Inclusão em Parafina , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz/métodos , Glândula Tireoide/metabolismo , Glândula Tireoide/cirurgia , Neoplasias da Glândula Tireoide/metabolismo , Neoplasias da Glândula Tireoide/cirurgia
10.
JAMA Neurol ; 75(1): 35-43, 2018 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-29150995

RESUMO

Importance: Chronic cerebrospinal venous insufficiency (CCSVI) is characterized by restricted venous outflow from the brain and spinal cord. Whether this condition is associated with multiple sclerosis (MS) and whether venous percutaneous transluminal angioplasty (PTA) is beneficial in persons with MS and CCSVI is controversial. Objective: To determine the efficacy and safety of venous PTA in patients with MS and CCSVI. Design, Setting, and Participants: We analyzed 177 patients with relapsing-remitting MS; 62 were ineligible, including 47 (26.6%) who did not have CCSVI on color Doppler ultrasonography screening. A total of 115 patients were recruited in the study timeframe. All patients underwent a randomized, double-blind, sham-controlled, parallel-group trial in 6 MS centers in Italy. The trial began in August 2012 and concluded in March 2016; data were analyzed from April 2016 to September 2016. The analysis was intention to treat. Interventions: Patients were randomly allocated (2:1) to either venous PTA or catheter venography without venous angioplasty (sham). Main Outcomes and Measures: Two primary end points were assessed at 12 months: (1) a composite functional measure (ie, walking control, balance, manual dexterity, postvoid residual urine volume, and visual acuity) and (2) a measure of new combined brain lesions on magnetic resonance imaging, including the proportion of lesion-free patients. Combined lesions included T1 gadolinium-enhancing lesions plus new or enlarged T2 lesions. Results: Of the included 115 patients with relapsing-remitting MS, 76 were allocated to the PTA group (45 female [59%]; mean [SD] age, 40.0 [10.3] years) and 39 to the sham group (29 female [74%]; mean [SD] age, 37.5 [10.6] years); 112 (97.4%) completed follow-up. No serious adverse events occurred. Flow restoration was achieved in 38 of 71 patients (54%) in the PTA group. The functional composite measure did not differ between the PTA and sham groups (41.7% vs 48.7%; odds ratio, 0.75; 95% CI, 0.34-1.68; P = .49). The mean (SD) number of combined lesions on magnetic resonance imaging at 6 to 12 months were 0.47 (1.19) in the PTA group vs 1.27 (2.65) in the sham group (mean ratio, 0.37; 95% CI, 0.15-0.91; P = .03: adjusted P = .09) and were 1.40 (4.21) in the PTA group vs 1.95 (3.73) in the sham group at 0 to 12 months (mean ratio, 0.72; 95% CI, 0.32-1.63; P = .45; adjusted P = .45). At follow-up after 6 to 12 months, 58 of 70 patients (83%) in the PTA group and 22 of 33 (67%) in the sham group were free of new lesions on magnetic resonance imaging (odds ratio, 2.64; 95% CI, 1.11-6.28; P = .03; adjusted P = .09). At 0 to 12 months, 46 of 73 patients (63.0%) in the PTA group and 18 of 37 (49%) in the sham group were free of new lesions on magnetic resonance imaging (odds ratio, 1.80; 95% CI, 0.81-4.01; P = .15; adjusted P = .30). Conclusion and Relevance: Venous PTA has proven to be a safe but largely ineffective technique; the treatment cannot be recommended in patients with MS. Trial Registration: clinicaltrials.gov Identifier: NCT01371760.


Assuntos
Angioplastia/métodos , Esclerose Múltipla Recidivante-Remitente/cirurgia , Resultado do Tratamento , Adolescente , Adulto , Idoso , Método Duplo-Cego , Feminino , Seguimentos , Humanos , Processamento de Imagem Assistida por Computador , Itália , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla Recidivante-Remitente/diagnóstico por imagem , Fatores de Tempo , Ultrassonografia Doppler em Cores , Adulto Jovem
11.
JNCI Cancer Spectr ; 2(4): pky069, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31360884

RESUMO

Background: The aim of this study was to assess whether minimal residual disease (MRD) at the end of induction front-line treatment can serve as a surrogate endpoint for event-free survival (EFS) in childhood B-lineage acute lymphoblastic leukemia. Methods: The analysis was based on individual data of 4830 patients from two large phase III trials that asked a randomized question on the effect of different corticosteroids (dexamethasone vs prednisone) during induction chemotherapy on EFS. The association between MRD classified in three ordered categories [negative = 0, low positive = (>0 and <5 × 10-4), and positive = (≥5 × 10-4)] and EFS at the individual and trial levels was evaluated with the meta-analytic approach based on the Plackett copula model. Centers within trial were grouped according to geographical area, and a total of 28 units were identified for the analysis. Results: MRD at the end of induction was a poor surrogate for treatment effect on EFS at the trial level, with R trial 2 = 0.09 (95% confidence interval [CI] = 0.00 to 0.29), whereas at the individual level it was strongly associated with EFS, with an odds ratio of 3.90 (95% CI = 3.35 to 4.44) of failure for patients with higher compared with lower MRD levels. Additional sensitivity and relevant subgroup analyses confirmed these findings at both trial- and patient-level association. Conclusions: Although MRD is a robust biomarker highly predictive of outcome for individual patients, clinicians and regulatory bodies should be cautious in using early MRD response in the context of complex multiagent acute lymphoblastic leukemia therapy as an early surrogate endpoint to predict the effect of a randomized treatment intervention on long-term EFS.

12.
Mol Ther Methods Clin Dev ; 6: 143-158, 2017 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-28932756

RESUMO

In vivo gene therapy with adeno-associated viral (AAV) vectors is safe and effective in humans. We recently demonstrated that AAV8-mediated liver gene transfer is effective in animal models of mucopolysaccharidosis type VI (MPS VI), a rare lysosomal storage disease that is caused by arylsulfatase B (ARSB) deficiency. In preparing for a first-in-human trial, we performed non-clinical studies to assess the safety of intravenous administrations of AAV2/8.TBG.hARSB produced under good manufacturing practice-like conditions. No toxicity was observed in AAV-treated mice, except for a transient increase in alanine aminotransferase in females and thyroid epithelial hypertrophy. AAV2/8.TBG.hARSB biodistribution and expression confirmed the liver as the main site of both infection and transduction. Shedding and breeding studies suggest that the risk of both horizontal and germline transmission is minimal. An AAV dose-response study in MPS VI mice was performed to define the range of doses to be used in the clinical study. Overall, these data support the non-clinical safety and efficacy of AAV2/8.TBG.hARSB and pave the way for a phase I/II clinical trial based on intravascular infusions of AAV8 in patients with MPS VI.

13.
J Obstet Gynecol Neonatal Nurs ; 46(5): 686-695, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28806537

RESUMO

OBJECTIVE: To evaluate the effect of oral hydration on the success rate of external cephalic version (ECV). DESIGN: Randomized controlled and single-blind trial. SETTING: Academic tertiary hospital with approximately 3,000 births annually. PARTICIPANTS: One hundred sixty-four women at a gestational age of at least 37 weeks with breech-presenting fetuses and normal amniotic fluid indexes (AFIs). METHODS: Participants were randomly assigned to drink 2000 ml or no more than 100 ml of water in the 2 hours before undergoing ECV. The AFIs were assessed before and after treatment by the same sonographer, who was blinded to the treatment group. Data were collected on relevant maternal and fetal characteristics and ECV success. RESULTS: The mean AFI after hydration was significantly greater than that in the control group (15.5 cm vs. 13.4 cm, p = .003). The ECV success rate was 53.7% in the hydration group and 46.3% in the control group (odds ratio: 1.34, 95% confidence interval [0.69, 2.59]; p = .349). Hydration was well tolerated and there were no serious adverse events. CONCLUSION: Oral hydration significantly increased the AFIs but did not affect the success rate of ECVs.


Assuntos
Apresentação Pélvica , Hidratação/métodos , Versão Fetal/métodos , Adulto , Líquido Amniótico , Apresentação Pélvica/diagnóstico , Apresentação Pélvica/terapia , Feminino , Idade Gestacional , Humanos , Monitorização Fisiológica/métodos , Gravidez , Cuidado Pré-Natal/métodos , Nascimento a Termo , Resultado do Tratamento
14.
Ann. hepatol ; 16(3): 451-456, May.-Jun. 2017. tab, graf
Artigo em Inglês | LILACS-Express | ID: biblio-887258

RESUMO

ABSTRACT Background and Aim. HFE-related Hemochromatosis (HH) is characterized by marked phenotype heterogeneity, probably due to the combined action of acquired and genetic factors. Among them, GNPATrs11558492 was proposed as genetic modifier of iron status, but results are still controversial. To shed light on these discrepancies, we genotyped 298 Italian p.C282Y homozygotes and 169 healthy controls. Material and methods. Allele and genotype frequencies were analysed and compared with those reported in Exorne Variant Server (EVS). To explore the role of rs11558492 as a potential modifier of iron status, serum ferritin (SF), liver iron concentration (LIC) and iron removed (IR) were studied according to allele and genotype frequencies. In addition, the effect of the SNP on liver fibrosis was examined comparing patients with absent/mild-moderate fibrosis to those with severe fibrosis-cirrhosis. Results. GNPAT rs11558492 minor allele (G) frequency (MAF) was 20.3% in HFE- HH, 17.2% in controls and 20.6% in EVS database. Genotype frequencies were 64% and 69.2% (AA), 31.2% and 27.2% (AG), 4.8% and 3.6% (GG) in HFE-HH and controls, respectively. No significant differences were found comparing genotype and allele frequencies even selecting subgroups of only-males with extreme phenotypes and low alcohol intake. SF, IR and LIC levels did not significantly differ according to rs11558492 genotypes. Also, MAF did not differ between patients with absent/mild fibrosis and severe fibrosis/cirrhosis. Conclusions. Our findings indicate that GNPAT rs11558492 is not a major modifier of iron status and is not associated with liver fibrosis in HFE- HH patients.

15.
Ann Hepatol ; 16(3): 451-456, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28425416

RESUMO

BACKGROUND AND AIM: HFE-related Hemochromatosis (HH) is characterized by marked phenotype heterogeneity, probably due to the combined action of acquired and genetic factors. Among them, GNPAT rs11558492 was proposed as genetic modifier of iron status, but results are still controversial. To shed light on these discrepancies, we genotyped 298 Italian p.C282Y homozygotes and 169 healthy controls. MATERIAL AND METHODS: Allele and genotype frequencies were analysed and compared with those reported in Exome Variant Server (EVS). To explore the role of rs11558492 as a potential modifier of iron status, serum ferritin (SF), liver iron concentration (LIC) and iron removed (IR) were studied according to allele and genotype frequencies. In addition, the effect of the SNP on liver fibrosis was examined comparing patients with absent/mild-moderate fibrosis to those with severe fibrosis-cirrhosis. RESULTS: GNPAT rs11558492 minor allele (G) frequency (MAF) was 20.3% in HFE-HH, 17.2% in controls and 20.6% in EVS database. Genotype frequencies were 64% and 69.2% (AA), 31.2% and 27.2% (AG), 4.8% and 3.6% (GG) in HFE-HH and controls, respectively. No significant differences were found comparing genotype and allele frequencies even selecting subgroups of only-males with extreme phenotypes and low alcohol intake. SF, IR and LIC levels did not significantly differ according to rs11558492 genotypes. Also, MAF did not differ between patients with absent/mild fibrosis and severe fibrosis/cirrhosis. CONCLUSIONS: Our findings indicate that GNPAT rs11558492 is not a major modifier of iron status and is not associated with liver fibrosis in HFE-HH patients.


Assuntos
Aciltransferases/genética , Doadores de Sangue , Proteína da Hemocromatose/genética , Hemocromatose/genética , Ferro/sangue , Cirrose Hepática/genética , Polimorfismo de Nucleotídeo Único , Adulto , Biomarcadores/sangue , Estudos de Casos e Controles , Feminino , Ferritinas/sangue , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Hemocromatose/sangue , Hemocromatose/diagnóstico , Hemocromatose/enzimologia , Heterozigoto , Homozigoto , Humanos , Itália , Fígado/metabolismo , Cirrose Hepática/sangue , Cirrose Hepática/diagnóstico , Cirrose Hepática/enzimologia , Masculino , Pessoa de Meia-Idade , Fenótipo , Fatores de Risco
16.
Ann Hepatol ; 16(3): 451-456, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-31153447

RESUMO

BACKGROUND AND AIM: HFE-related Hemochromatosis (HH) is characterized by marked phenotype heterogeneity, probably due to the combined action of acquired and genetic factors. Among them, GNPAT rs11558492 was proposed as genetic modifier of iron status, but results are still controversial. To shed light on these discrepancies, we genotyped 298 Italian p.C282Y homozygotes and 169 healthy controls. MATERIAL AND METHODS: Allele and genotype frequencies were analysed and compared with those reported in Exome Variant Server (EVS). To explore the role of rs11558492 as a potential modifier of iron status, serum ferritin (SF), liver iron concentration (LIC) and iron removed (IR) were studied according to allele and genotype frequencies. In addition, the effect of the SNP on liver fibrosis was examined comparing patients with absent/mild-moderate fibrosis to those with severe fibrosis-cirrho-sis. RESULTS: GNPAT rs11558492 minor allele (G) frequency (MAF) was 20.3% in HFE-HH, 17.2% in controls and 20.6% in EVS database. Genotype frequencies were 64% and 69.2% (AA), 31.2% and 27.2% (AG), 4.8% and 3.6% (GG) in HFE-HH and controls, respectively. No significant differences were found comparing genotype and allele frequencies even selecting subgroups of only-males with extreme phenotypes and low alcohol intake. SF, IR and LIC levels did not significantly differ according to rs11558492 genotypes. Also, MAF did not differ between patients with absent/mild fibrosis and severe fibrosis/cirrhosis. CONCLUSIONS: Our findings indicate that GNPAT rs11558492 is not a major modifier of iron status and is not associated with liver fibrosis in HFE-HH patients.

17.
J Gastroenterol Hepatol ; 31(7): 1342-8, 2016 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-26868056

RESUMO

BACKGROUND AND AIM: p.Cys282Tyr homozygosity is the prevalent genotype in (HFE)-related Hereditary Hemochromatosis with low penetrance and variable expression. However, liver cirrhosis and hepatocellular carcinoma remain the main causes of mortality in these patients. Detection of genetic modifiers identifying patients at risk for liver damage would be relevant for their clinical management. We evaluated proprotein convertase 7 (PCSK7) rs236918 as genetic marker of risk of liver fibrosis in an Italian cohort of p.Cys282Tyr homozygotes. METHODS: Liver fibrosis was histologically assessed by Ishak score. We evaluated PCSK7 alleles and genotypes frequencies according to single or grouped staging scores: absent/mild fibrosis (stage: 0-2), moderate (stage: 3-4), and severe fibrosis/cirrhosis (stage: 5-6). Single nucleotide polymorphism genotyping was performed by restriction fragment length polymorphism or Taqman 5'-nuclease assays. RESULTS: The rs236918 allele C frequency increased from stages 0-2 to 5-6 (7.1% vs 13.6%, vs 21.9%, P = 0.003). The wild-type genotype was significantly more frequent in the absent/mild fibrosis group (54.2%) compared with only 17% in patients with severe fibrosis/cirrhosis. At univariate proportional odds model, patients with GC + CC genotypes were 2.77 times (P = 0.0018) more likely to have worse liver staging scores than wild-type patients. In the adjusted analysis, odds ratio was 2.37 (P = 0.0218), and 2.56 (P = 0.0233) when the analysis was restricted to males. An exploratory mediation analysis suggested a direct effect of genotype on severe fibrosis/cirrhosis (odds ratio = 3.11, P = 0.0157), and a mild non-significant indirect effect mediated through iron accounting for 28%. CONCLUSIONS: These findings confirm that PCSK7 rs236918 C allele is a risk factor for cirrhosis development in Italian patients with HFE-Hemochromatosis.


Assuntos
Marcadores Genéticos/genética , Proteína da Hemocromatose/genética , Hemocromatose/genética , Homozigoto , Cirrose Hepática/genética , Subtilisinas/genética , Alelos , Carcinoma Hepatocelular , Estudos de Coortes , Genótipo , Humanos , Itália , Neoplasias Hepáticas , Masculino , Pessoa de Meia-Idade , Fatores de Risco
18.
Nephrology (Carlton) ; 21(1): 35-45, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26132414

RESUMO

BACKGROUND: The glomerulocentric International Society of Nephrology/Renal Pathology Society (ISN/RPS) classification is the gold standard for the evaluation of lupus nephritis, while tubulointerstitial (TIN) parameters are often under-recognized in pathological reports. METHODS: Renal biopsies from 142 patients who underwent repeat biopsy (RB) were evaluated for the following histological parameters: (i) inflammatory interstitial infiltrates; (ii) interstitial fibrosis; (iii) tubulitis; and (iv) tubular atrophy. The inter-relationships between the four TIN variables were explored by multivariate analysis. A linear mixed model was used to investigate the potential impact of TIN variables on eGFR and proteinuria at the two biopsy occasions. RESULTS: The study showed that moderate-severe lesions were not so frequent at the reference biopsy, but more extensively represented upon RB. A strong association was found between the two inflammatory indices and between those related to chronic damage, while the relationship with the ISN/RPS classification was present at RB. If class IV-G was the most related with TIN (especially at RB), the existence of primary TIN in class II patients was also confirmed. Finally, our results support the hypothesis that tubulitis is an independent predictive factor for eGFR. CONCLUSIONS: We recommend that the standard histological evaluation of SLE nephritis also includes TIN features.


Assuntos
Rim/patologia , Nefrite Lúpica/patologia , Nefrite Intersticial/patologia , Adulto , Atrofia , Biópsia , Distribuição de Qui-Quadrado , Feminino , Fibrose , Taxa de Filtração Glomerular , Humanos , Rim/fisiopatologia , Modelos Lineares , Modelos Logísticos , Nefrite Lúpica/fisiopatologia , Masculino , Análise Multivariada , Nefrite Intersticial/fisiopatologia , Valor Preditivo dos Testes , Prognóstico , Proteinúria/patologia , Proteinúria/fisiopatologia , Estudos Retrospectivos , Índice de Gravidade de Doença , Adulto Jovem
19.
Stat Med ; 34(28): 3648-60, 2015 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-26215851

RESUMO

In survival analysis, the absolute measure of cumulative risk provided by the Kaplan-Meier estimator is still the most used quantity for its easy calculation and direct interpretability. However, for describing the survival after an intervention that may occur at different times from baseline observation, the Kaplan-Meier estimator generally yields to biased results if intervention is considered as fixed at baseline. The main focus of the present paper is to extend the use of a multiple timescale model in the presence of a time dependent intervention. The aim is to obtain 1) an estimate of treatment effect in terms of hazard ratios by flexible modeling, 2) a valid prediction tool, i.e. estimate of prognosis for a patient who changes treatment later in time, and 3) an appropriate graphical representation of survival in the presence of a time dependent treatment change, accounting for different timescales. We will show the advantages of this approach on the comparison of chemotherapy versus transplant in children with high-risk acute lymphoblastic leukemia in first remission. We considered a model with two timescales that accounts for the change in treatment at different times in the disease course. An alternative approach to survival estimates is also proposed which has some advantages over the traditional landmark approach: it uses all the data available to plot survival from the date of remission, it avoids the arbitrary choice of a landmark time and explicitly models the change in hazard due to transplant.


Assuntos
Modelos Estatísticos , Intervalo Livre de Doença , Estudos de Avaliação como Assunto , Humanos , Distribuição de Poisson , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Modelos de Riscos Proporcionais , Fatores de Tempo
20.
Scand J Gastroenterol ; 50(4): 429-38, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25633726

RESUMO

OBJECTIVE: Hyperferritinemia is frequent in chronic liver diseases of any cause, but the extent to which ferritin truly reflects iron stores is variable. In these patients, both liver iron and fat are found in variable amount and association. Liver biopsy is often required to quantify liver fat and iron, but sampling variability and invasiveness limit its use. We aimed to assess single breath-hold multiecho magnetic resonance imaging (MRI) for the simultaneous lipid and iron quantification in patients with hyperferritinemia. MATERIAL AND METHODS: We compared MRI results for both iron and fat with their respective gold standards - liver iron concentration and computer-assisted image analysis for steatosis on biopsy. We prospectively studied 67 patients with hyperferritinemia and other 10 consecutive patients were used for validation. We estimated two linear calibration equations for the prediction of iron and fat based on MRI. The agreement between MRI and biopsy was evaluated. RESULTS: MRI showed good performances in both the training and validation samples. MRI information was almost completely in line with that obtained from liver biopsy. CONCLUSION: Single breath-hold multiecho MRI is an accurate method to obtain a valuable measure of both liver iron and steatosis in patients with hyperferritinemia.


Assuntos
Tecido Adiposo , Fígado Gorduroso/patologia , Ferro/análise , Fígado/química , Fígado/patologia , Imagem por Ressonância Magnética , Biópsia , Feminino , Humanos , Ferro/sangue , Imagem por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos
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