Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 122
Filtrar
2.
Am J Med Genet A ; 2019 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-31692235

RESUMO

Bohring-Opitz syndrome (BOS) has been described as a clinically recognizable genetic syndrome since 1999. Clinical diagnostic criteria were established in 2011 and include microcephaly, trigonocephaly, distinctive craniofacial dysmorphic features, facial nevus flammeus, failure to thrive, and severe developmental delays. The same year, different de novo heterozygous nonsense mutations in the ASXL1 were found in affected individuals. Since then, several cases have been reported confirming the association between this chromatin remodeling gene and BOS. Most affected individuals die in early childhood because of unexplained bradycardia, obstructive apnea, or pulmonary infections. Those that survive usually cannot walk independently and are nonverbal. Some have had success using walkers and braces in late childhood. While few are able to speak, many have been able to express basic needs using communication devices as well as gestures with associated basic vocalizations. In this article, we present a mild case of BOS with a de novo pathogenic mutation c.1720-2A>G (p.I574VfsX22) in ASXL1 detected on whole-exome sequencing and confirmed by functional analysis of the messenger RNA splicing pattern on the patient's fibroblasts. She has typical dysmorphic features and is able to run and walk independently as well as to communicate with basic sign language.

4.
Clin Genet ; 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31573083

RESUMO

Children with Neurofibromatosis Type 1 (NF1) may exhibit an incomplete clinical presentation, making difficult to reach a clinical diagnosis. A phenotypic overlap may exist with children with other RASopathies or with other genetic conditions if only multiple café-au-lait macules (CALMs) are present. The syndromes that can converge in these inconclusive phenotypes have different clinical courses. In this context, an early genetic testing has been proposed to be clinically useful to manage these patients. We present the validation and implementation into diagnostics of a custom NGS panel (I2HCP) for testing patients with a clinical suspicion of a RASopathy (n=48) and children presenting multiple CALMs (n=102). We describe the mutational spectrum and the detection rates identified in these two groups of individuals. We identified pathogenic variants in 21 out of 48 patients with clinical suspicion of RASopathy, with mutations in NF1 accounting for 10% of cases. Furthermore, we identified pathogenic mutations mainly in the NF1 gene, but also in SPRED1, in more than 50% of children with multiple CALMs, exhibiting a NF1 mutational spectrum different from a group of clinically diagnosed NF1 patients (n=80). An NGS panel strategy for the genetic testing of these two phenotype-defined groups outperforms previous strategies. This article is protected by copyright. All rights reserved.

5.
Eur J Hum Genet ; 2019 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-31477843

RESUMO

Following the publication of the article, it was noted that the last column in Table 1, the total % should have read 5/8 (62.5) for the 'Epilepsy' row, and not 5.7 (71.4). This has now been amended in the HTML and PDF of the original article.

6.
Heart Rhythm ; 16(10): 1506-1512, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31255846

RESUMO

BACKGROUND: Ventricular arrhythmias (VAs) can occur after continuous flow left ventricular assist device (LVAD) implantation as a single arrhythmic event or as electrical storm (ES) with multiple repetitive VA episodes. OBJECTIVE: We aimed at analyzing the incidence, predictors, and clinical impact of ES in LVAD recipients. METHODS: Patients analyzed were those included in the multicenter ASSIST-ICD observational study. ES was consensually defined as occurrence of ≥3 separate episodes of sustained VAs within a 24-hour interval. RESULTS: Of 652 patients with an LVAD, 61 (9%) presented ES during a median follow-up period of 9.1 (interquartile range [IQR] 2.5-22.1) months. The first ES occurred after 17 (IQR 4.0-56.2) days post LVAD implantation, most of them during the first month after the device implantation (63%). The incidence then tended to decrease during the initial years of follow-up and increased again after the third year post LVAD implantation. History of VAs before LVAD implantation and heart failure duration > 84 months were independent predictors of ES. The occurrence of ES was associated with an increased early mortality since 20 patients (33%) died within the first 2 weeks of ES. Twenty-two patients (36.1%) presented at least 1 recurrence of ES, occurring 43.0 (IQR 8.0-69.0) days after the initial ES. Patients experiencing ES had a significantly lower 1-year survival rate than did those free from ES (log-rank, P = .039). CONCLUSION: There is a significant incidence of ES in patients with an LVAD. The short-term mortality after ES is high, and one-third of patients will die within 15 days. Whether radiofrequency ablation of arrhythmias improves outcomes would require further studies.

7.
Artigo em Inglês | MEDLINE | ID: mdl-31242521

RESUMO

BACKGROUND: In patients with secondary mitral regurgitation (MR) associated with low ejection fraction or previous heart surgery, minimally invasive mitral valve surgery without aortic cross-clamp (MIMVS-WAC) has shown promising results. We report our experience for this strategy in our centers. METHODS: Between August 2011 and April 2017, 46 patients (mean age 69 ± 11 years, 76% males) received MIMVS-WAC. Indications for this technique were prior coronary bypass surgery (26%), severe or recent left ventricular (LV) dysfunction (30%), or both (39%). The mean EuroSCORE II was 12 ± 10. RESULTS: For each procedure, we conducted right minithoracotomy and hypothermic cardiopulmonary bypass (CPB) after peripheral cannulation. Mean CPB time was 159 ± 39 minutes. A mitral valve replacement (MVR) was performed in 23 cases (50%), an annuloplasty in 22 cases (48%), and a prosthesis pannus removal in 1 case (2%). Mean hospital length of stay was 12 ± 5.4 days. We report no sternotomy conversions, six reoperations for bleeding, and three deaths at 30 days. Transfusion was requested in 62% (mean infusion 2 ± 2.4 packed red blood cells). The postoperative echocardiography showed an LV function preservation in 69% of cases and a reduction of pulmonary arterial pressure in 73% of cases. Four additional deaths occurred in the long-term follow-up (mean 637 ± 381 days, median 593 days). No mitral reoperation was required, with a MR ≤ 2 in 90% of patients. CONCLUSION: In high-risk patients, the MIMVS-WAC is a safe technique. It avoids hard dissections while ensuring excellent preservation of cardiac function.

8.
Am Heart J ; 214: 69-76, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31174053

RESUMO

BACKGROUND: Left ventricular assist device (LVAD)-associated infections may be life-threatening and impact patients' outcome. We aimed to identify the characteristics, risk factors, and prognosis of LVAD-associated infections. METHODS: Patients included in the ASSIST-ICD study (19 centers) were enrolled. The main outcome was the occurrence of LVAD-associated infection (driveline infection, pocket infection, or pump/cannula infection) during follow-up. RESULTS: Of the 652 patients enrolled, 201 (30.1%) presented a total of 248 LVAD infections diagnosed 6.5 months after implantation, including 171 (26.2%), 51 (7.8%), and 26 (4.0%) percutaneous driveline infection, pocket infection, or pump/cannula infection, respectively. Patients with infections were aged 58.7 years, and most received HeartMate II (82.1%) or HeartWare (13.4%). Most patients (62%) had implantable cardioverter-defibrillators (ICDs) before LVAD, and 104 (16.0%) had ICD implantation, extraction, or replacement after the LVAD surgery. Main pathogens found among the 248 infections were Staphylococcus aureus (n = 113' 45.4%), Enterobacteriaceae (n = 61; 24.6%), Pseudomonas aeruginosa (n = 34; 13.7%), coagulase-negative staphylococci (n = 13; 5.2%), and Candida species (n = 13; 5.2%). In multivariable analysis, HeartMate II (subhazard ratio, 1.56; 95% CI, 1.03 to 2.36; P = .031) and ICD-related procedures post-LVAD (subhazard ratio, 1.43; 95% CI, 1.03-1.98; P = .031) were significantly associated with LVAD infections. Infections had no detrimental impact on survival. CONCLUSIONS: Left ventricular assist device-associated infections affect one-third of LVAD recipients, mostly related to skin pathogens and gram-negative bacilli, with increased risk with HeartMate II as compared with HeartWare, and in patients who required ICD-related procedures post-LVAD. This is a plea to better select patients needing ICD implantation/replacement after LVAD implantation.

11.
J Inherit Metab Dis ; 2019 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-30942483

RESUMO

There are many metabolic disorders that present with bone phenotypes. In some cases, the pathological bone symptoms are the main features of the disease whereas in others they are a secondary characteristic. In general, the generation of the bone problems in these disorders is not well understood and the therapeutic options for them are scarce. Bone development occurs in the early stages of embryonic development where the bone formation, or osteogenesis, takes place. This osteogenesis can be produced through the direct transformation of the pre-existing mesenchymal cells into bone tissue (intramembranous ossification) or by the replacement of the cartilage by bone (endochondral ossification). In contrast, bone remodeling takes place during the bone's growth, after the bone development, and continues throughout the whole life. The remodeling involves the removal of mineralized bone by osteoclasts followed by the formation of bone matrix by the osteoblasts, which subsequently becomes mineralized. In some metabolic diseases, bone pathological features are associated with bone development problems but in others they are associated with bone remodeling. Here, we describe three examples of impaired bone development or remodeling in metabolic diseases, including work by others and the results from our research. In particular, we will focus on hereditary multiple exostosis (or osteochondromatosis), Gaucher disease, and the susceptibility to atypical femoral fracture in patients treated with bisphosphonates for several years.

13.
Sci Rep ; 9(1): 4677, 2019 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-30886234

RESUMO

In this paper, we propose a very innovative designed system that enables optimal length adjustment during transapical neochordae implantation for mitral valve repair, increasing accuracy and reproducibility of neochordae length adjustment. Also, such a new device allowed real-time measurement and recording of chordae tension, producing original physiological data. To the best of our knowledge, the tension of chordae had never been measured previously as precisely, especially in in vivo human clinical trials. Preliminary experimental data have been collected on 10 selected patients, giving us the opportunity to assess for the first time the tension applied on the chordae implanted in beating human hearts. The final goal of our measuring device is to provide reliable objective intraoperative data to improve the understanding of changes occurring after mitral valve repair (MVR). This novel measuring instrument may bring change in the paradigm of MVR by allowing repair with strong objective and quantitative, instead of qualitative anatomical analysis.

14.
Bone ; 123: 39-47, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30878523

RESUMO

Genome-wide association studies (GWAS) have repeatedly identified genetic variants associated with bone mineral density (BMD) and osteoporotic fracture in non-coding regions of C7ORF76, a poorly studied gene of unknown function. The aim of the present study was to elucidate the causality and molecular mechanisms underlying the association. We re-sequenced the genomic region in two extreme BMD groups from the BARCOS cohort of postmenopausal women to search for functionally relevant variants. Eight selected variants were tested for association in the complete cohort and 2 of them (rs4342521 and rs10085588) were found significantly associated with lumbar spine BMD and nominally associated with osteoporotic fracture. cis-eQTL analyses of these 2 SNPs, together with SNP rs4727338 (GWAS lead SNP in Estrada et al., Nat Genet. 44:491-501, 2012), performed in human primary osteoblasts, disclosed a statistically significant influence on the expression of the proximal neighbouring gene SLC25A13 and a tendency on the distal SHFM1. We then studied the functionality of a putative upstream regulatory element (UPE), containing rs10085588. Luciferase reporter assays showed transactivation capability with a strong allele-dependent effect. Finally, 4C-seq experiments in osteoblastic cell lines showed that the UPE interacted with different tissue-specific enhancers and a lncRNA (LOC100506136) in the region. In summary, this study is the first one to analyse in depth the functionality of C7ORF76 genomic region. We provide functional regulatory evidence for the rs10085588, which may be a causal SNP within the 7q21.3 GWAS signal for osteoporosis.

15.
Medicine (Baltimore) ; 98(8): e14524, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30813157

RESUMO

RATIONALE: Trio family-based whole exome sequencing (WES) is a powerful tool in the diagnosis of rare neurodevelopmental diseases, even in patients with the unclear diagnosis. There have been previous reports of variants in the phosphatidylinositol glycan anchor biosynthesis class T (PIGT) gene associated with multiple congenital anomalies, with a total of 14 affected individuals across 8 families. PATIENT CONCERNS: An 18-month-old boy of Greek ancestry presented with global developmental delay, generalized tonic-clonic seizures, hypotonia, renal cysts, esotropia, bilateral undescended testes, bilateral vesicoureteric reflux, marked cardiac dextroposition, bilateral talipes equinovarus, and dysmorphic features. DIAGNOSIS: WES revealed 2 compound heterozygous variants in the PIGT gene, c.[494-2A>G]; [547A>C]/p.[Asp122Glyfs*35]; [Thr183Pro]. The splicing mutation was demonstrated to lead to the skipping of exon 4. INTERVENTIONS: Seizures, infections, and other main symptoms were treated. OUTCOMES: The patient died at 2 years of age before the molecular diagnosis was achieved. Genetic counseling has been offered to the family. LESSONS: Most of the clinical features of the patient are in agreement with the previously described PIGT cases corroborating the usefulness of WES as a diagnostic tool.


Assuntos
Anormalidades Múltiplas/genética , Aciltransferases/genética , Técnicas de Cultura de Células , Deficiências do Desenvolvimento/genética , Diagnóstico Diferencial , Evolução Fatal , Humanos , Lactente , Masculino , Hipotonia Muscular/genética , Mutação , Reação em Cadeia da Polimerase em Tempo Real , Convulsões/genética , Síndrome , Sequenciamento Completo do Exoma/métodos
16.
Eur J Hum Genet ; 2019 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-30877278

RESUMO

DPH1 variants have been associated with an ultra-rare and severe neurodevelopmental disorder, mainly characterized by variable developmental delay, short stature, dysmorphic features, and sparse hair. We have identified four new patients (from two different families) carrying novel variants in DPH1, enriching the clinical delineation of the DPH1 syndrome. Using a diphtheria toxin ADP-ribosylation assay, we have analyzed the activity of seven identified variants and demonstrated compromised function for five of them [p.(Leu234Pro); p.(Ala411Argfs*91); p.(Leu164Pro); p.(Leu125Pro); and p.(Tyr112Cys)]. We have built a homology model of the human DPH1-DPH2 heterodimer and have performed molecular dynamics simulations to study the effect of these variants on the catalytic sites as well as on the interactions between subunits of the heterodimer. The results show correlation between loss of activity, reduced size of the opening to the catalytic site, and changes in the size of the catalytic site with clinical severity. This is the first report of functional tests of DPH1 variants associated with the DPH1 syndrome. We demonstrate that the in vitro assay for DPH1 protein activity, together with structural modeling, are useful tools for assessing the effect of the variants on DPH1 function and may be used for predicting patient outcomes and prognoses.

17.
Int J Technol Assess Health Care ; 35(1): 45-49, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30744730

RESUMO

OBJECTIVES: Cardiac surgery has seen substantial scientific progress over recent decades. Health economic evaluations have become important tools for decision makers to prioritize scarce health resources. The present study aimed to identify and critically appraise the reporting quality of health economic evaluations conducted in the field of cardiac surgery. METHODS: A literature search was performed to identify health economic evaluations in cardiac surgery. The consolidated Health Economic Evaluation Reporting Standards (CHEERS) statement was used to assess the quality of reporting of studies. RESULTS: A total 4,705 articles published between 1981 and 2016 were identified; sixty-nine studies fulfilled the inclusion criteria. There was a trend toward a greater number of publications and reporting quality over time. Six (8.7 percent) studies were conducted between 1981 and 1990, nine (13 percent) between 1991 and 2000, twenty-four (34.8 percent) between 2001 and 2010, and thirty (43.5 percent) after 2011. The mean CHEERS score of all articles was 16.7/24; for those published between 1980 and 1990 the mean (SD) score was 10.2 (±1.4), for those published between 1991 and 2000 it was 11.2 (±2.4), between 2001 and 2010 it was 15.3 (±4.8), and after 2011 it was 19.9 (±2.9). The quality of reporting was still insufficient for several studies after 2000, especially concerning items "characterizing heterogeneity," "assumptions," and "choice of model." CONCLUSIONS: The present study suggests that, even if the quantity and the quality of health economics evaluation in cardiac surgery has increased, there remains a need for improvement in several reporting criteria to ensure greater transparency.


Assuntos
Procedimentos Cirúrgicos Cardíacos/economia , Economia Médica/organização & administração , Publicações Periódicas como Assunto/normas , Bibliometria , Análise Custo-Benefício , Economia Médica/normas , Humanos , Projetos de Pesquisa
18.
J Card Surg ; 34(2): 74-81, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30636172

RESUMO

BACKGROUND AND AIM OF THE STUDY: Extracorporeal life support (ECLS) may be necessary in refractory postcardiotomy cardiogenic shock (PCS) unresponsive to optimal medical treatment. We sought to analyze the results and temporal outcomes of ECLS for PCS. METHODS: We performed an observational analysis of our prospective database. In order to analyze the temporal trends of ECLS for PCS, patients were divided into two groups according to the period of ECLS implantation: Group I from January 2007-June 2012, Group II from July 2012-December 2017. The primary endpoint was survival to hospital discharge. RESULTS: During the study period, 90 patients required ECLS for PCS (Group I n = 29, 32%; Group II n = 61, 68%). Mean age was 57.5 ± 15.0 years with 62% of males. Preoperative characteristics were comparable over the two periods. A high proportion of patients were in NYHA class III/IV (61%) or cardiogenic shock (22%). Group II showed a significantly higher proportion of miscellaneous cardiac surgery operations (23 vs 3%, P = 0.031). Crossclamp and cardiopulmonary bypass times were significantly shorter in Group II (85.4 vs 114.2 min, P = 0.023 and 135.2 vs 184.2 min, P = 0.022, respectively). The complication rate during ECLS support was comparable between both groups. Successful weaning from ECLS could be accomplished in 45 (50%) patients (Group I = 52% vs Group II = 49%, P = 0.822) after a mean support of 6.4 days. Thirty-five (39%) patients survived to hospital discharge (Group I = 41% vs Group II = 38%, P = 0.738). CONCLUSIONS: Outcomes following ECLS remained stable over an 11-year period. ECLS may be limited in patients with severe preoperative cardiac dysfunction. Our data suggest that these patients may be better served with less invasive, percutaneous procedures.


Assuntos
Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Oxigenação por Membrana Extracorpórea/métodos , Choque Cardiogênico/terapia , Feminino , Seguimentos , França/epidemiologia , Cardiopatias/cirurgia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Choque Cardiogênico/etiologia , Choque Cardiogênico/mortalidade , Taxa de Sobrevida/tendências , Resultado do Tratamento
20.
PLoS One ; 13(11): e0208131, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30485349

RESUMO

MicroRNAs (miRNAs) are important regulators of many cellular processes, including the differentiation and activity of osteoblasts, and therefore, of bone turnover. MiR-320a is overexpressed in osteoporotic bone tissue but its role in osteoblast function is unknown. In the present study, functional assays were performed with the aim to elucidate the mechanism of miR-320a action in osteoblastic cells. MiR-320a was either overexpressed or inhibited in human primary osteoblasts (hOB) and gene expression changes were evaluated through microarray analysis. In addition, the effect of miR-320a on cell proliferation, viability, and oxidative stress in hOB was evaluated. Finally, matrix mineralization and alkaline phosphatase activity were assessed in order to evaluate osteoblast functionality. Microarray results showed miR-320a regulation of a number of key osteoblast genes and of genes involved in oxidative stress. Regulation of osteoblast differentiation and ossification appeared as the best significant biological processes (PANTHER P value = 3.74E-05; and P value = 3.06E-04, respectively). The other enriched pathway was that of the cellular response to cadmium and zinc ions, mostly by the overexpression of metallothioneins. In hOBs, overexpression of miR-320a increased cell proliferation and oxidative stress levels whereas mineralization capacity was reduced. In conclusion, overexpression of miR-320a increased stress oxidation levels and was associated with reduced osteoblast differentiation and functionality, which could trigger an osteoporotic phenotype.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA