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- Novel FGFR1 mutations in Kallmann syndrome and normosmic idiopathic hypogonadotropic hypogonadism: evidence for the involvement of an alternatively spliced isoformPublication . Gonçalves, C; Bastos, M; Pignatelli, D; Borges, T; Aragüés, JM; Fonseca, F; Pereira, BD; Socorro, S; Lemos, MCOBJECTIVE: To determine the prevalence of fibroblast growth factor receptor 1 (FGFR1) mutations and their predicted functional consequences in patients with idiopathic hypogonadotropic hypogonadism (IHH). DESIGN: Cross-sectional study. SETTING: Multicentric. PATIENT(S): Fifty unrelated patients with IHH (21 with Kallmann syndrome and 29 with normosmic IHH). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Patients were screened for mutations in FGFR1. The functional consequences of mutations were predicted by in silico structural and conservation analysis. RESULT(S): Heterozygous FGFR1 mutations were identified in six (12%) kindreds. These consisted of frameshift mutations (p.Pro33-Alafs*17 and p.Tyr654*) and missense mutations in the signal peptide (p.Trp4Cys), in the D1 extracellular domain (p.Ser96Cys) and in the cytoplasmic tyrosine kinase domain (p.Met719Val). A missense mutation was identified in the alternatively spliced exon 8A (p.Ala353Thr) that exclusively affects the D3 extracellular domain of FGFR1 isoform IIIb. Structure-based and sequence-based prediction methods and the absence of these variants in 200 normal controls were all consistent with a critical role for the mutations in the activity of the receptor. Oligogenic inheritance (FGFR1/CHD7/PROKR2) was found in one patient. CONCLUSION(S): Two FGFR1 isoforms, IIIb and IIIc, result from alternative splicing of exons 8A and 8B, respectively. Loss-of-function of isoform IIIc is a cause of IHH, whereas isoform IIIb is thought to be redundant. Ours is the first report of normosmic IHH associated with a mutation in the alternatively spliced exon 8A and suggests that this disorder can be caused by defects in either of the two alternatively spliced FGFR1 isoforms
- Cholangiocarcinoma: from molecular biology to treatmentPublication . Brito, AF; Abrantes, AM; Encarnação, JC; Tralhão, JG; Botelho, MFCholangiocarcinoma is a rare tumor originating in the bile ducts, which, according to their anatomical location, is classified as intrahepatic, extrahepatic and hilar. Nevertheless, incidence rates have increased markedly in recent decades. With respect to tumor biology, several genetic alterations correlated with resistance to chemotherapy and radiotherapy have been identified. Here, we highlight changes in KRAS and TP53 genes that are normally associated with a more aggressive phenotype. Also IL-6 and some proteins of the BCL-2 family appear to be involved in the resistance that the cholangiocarcinoma presents toward conventional therapies. With regard to diagnosis, tumor markers most commonly used are CEA and CA 19-9, and although its use isolated appears controversial, their combined value has been increasingly advocated. In imaging terms, various methods are needed, such as abdominal ultrasound, computed tomography and cholangiopancreatography. Regarding therapy, surgical modalities are the only ones that offer chance of cure; however, due to late diagnosis, most patients cannot take advantage of them. Thus, the majority of patients are directed to other therapeutic modalities like chemotherapy, which, in this context, assumes a purely palliative role. Thus, it becomes urgent to investigate new therapeutic options for this highly aggressive type of tumor.
- Surgical Treatment of Posterior Mitral Valve Prolapse: Towards 100% RepairPublication . Correia, PM; Coutinho, GF; Branco, C; Garcia, A; Antunes, MJBACKGROUND: The study aim was to evaluate the immediate and long-term results of surgical treatment of isolated posterior mitral valve leaflet prolapse (PLP), focusing on survival and freedom from recurrent mitral regurgitation (MR). METHODS: Between January 1998 and December 2012, a total of 492 consecutive patients (375 males, 117 females; mean age 61.8 ± 12.1 years; range: 13-86 years) with isolated PLP [304 (61.8%) with myxomatous degeneration; 188 (38.2%) with fibroelastic deficiency] were treated at the authors' institution. Of these patients, 202 (41.1%) were in NYHA class III-IV, and atrial fibrillation was present in 104 (21.1%). Mitral valve repair was achieved in 484 patients (98.4%), resection was performed in 419 (85.2%), and prosthetic ring annuloplasty was used in 436 (88.6%). Concomitant procedures were performed in 153 patients (31.1%), including tricuspid valve repair in 50 (10.2%), aortic valve surgery in 34 (6.9%), and coronary artery bypass grafting (CABG) in 64 (13%). RESULTS: The hospital mortality rate was 0.2%, and the mean follow up was 7.1 ± 3.9 years. There were 71 late deaths (14.4%), and overall survival at five, 10 and 15 years was 91.7 ± 1.3%, 82.1 ± 2.3% and 64.7 ± 6.1%, respectively. There was no significant difference in long-term survival compared with the age- and gender-matched general population (p = 0.146). Multivariate Cox-proportional hazard analysis showed older age (HR 1.03 per annum), left ventricular dysfunction (HR 2.44), atrial fibrillation (HR 1.96), left ventricular end-diastolic dimension (HR 1.05 per mm) and non-use of prosthetic ring (HR 3.03) as significant predictors of late mortality. Recurrence of moderate or severe MR occurred in 31 patients, six of whom underwent mitral valve reoperation. Predictors of late recurrence of MR were fibroelastic deficiency (HR 2.38), mitral calcification (HR 5.26), posterior leaflet plication (HR 3.58), absence of complete ring annuloplasty (HR 3.84) and systolic pulmonary artery pressure at discharge (HR 1.10 per mmHg). Freedom from mitral valve reoperation at 15 years was 97.4 ± 1.1% CONCLUSIONS: Mitral valve repair in isolated PLP can be achieved in virtually all cases with a very low operative risk and a high durability of repair. Atrial fibrillation or large left ventricles are associated with a poor prognosis. Failure to use a complete ring annuloplasty carries a risk not only for the return of MR but also for survival.
- Lysophosphatidic acid enhances survival of human CD34(+) cells in ischemic conditionsPublication . Kostic, I; Fidalgo-Carvalho, I; Aday, S; Vazão, H; Carvalheiro, T; Grãos, M; Duarte, A; Cardoso, C; Gonçalves, L; Carvalho, L; Paiva, A; Ferreira, LSeveral clinical trials are exploring therapeutic effect of human CD34(+) cells in ischemic diseases, including myocardial infarction. Unfortunately, most of the cells die few days after delivery. Herein we show that lysophosphatidic acid (LPA)-treated human umbilical cord blood-derived CD34(+) cells cultured under hypoxic and serum-deprived conditions present 2.2-fold and 1.3-fold higher survival relatively to non-treated cells and prostaglandin E2-treated cells, respectively. The pro-survival effect of LPA is concentration- and time-dependent and it is mediated by the activation of peroxisome proliferator-activator receptor γ (PPARγ) and downstream, by the activation of pro-survival ERK and Akt signaling pathways and the inhibition of mitochondrial apoptotic pathway. In hypoxia and serum-deprived culture conditions, LPA induces CD34(+) cell proliferation without maintaining the their undifferentiating state, and enhances IL-8, IL-6 and G-CSF secretion during the first 12 h compared to non-treated cells. LPA-treated CD34(+) cells delivered in fibrin gels have enhanced survival and improved cardiac fractional shortening at 2 weeks on rat infarcted hearts as compared to hearts treated with placebo. We have developed a new platform to enhance the survival of CD34(+) cells using a natural and cost-effective ligand and demonstrated its utility in the preservation of the functionality of the heart after infarction.