Biomedical subjects

A Prat

Publications and source records attributed to A Prat.

At least 19 recordsLinked to original sources

PubMed2026

Impact of BRCA2 pathogenic variants on outcomes to first-line CDK4/6 inhibitors plus endocrine therapy in HR-positive/HER2-negative metastatic breast cancer.

BACKGROUND: Currently, three cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) are approved in combination with endocrine therapy (ET) as first-line treatment of patients with hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC). The impact of homologous recombination repair (HRR) pathogenic variants (PV) on outcomes with first-line CDK4/6i plus ET in HR-positive/HER2-negative MBC remains uncertain. PATIENTS AND METHODS: We conducted a multicenter, real-world, case-control study including 233 patients with HR-positive/HER2-negative MBC treated with first-line CDK4/6i and ET. Among them, 116 presented HRR PVs and 117 were matched controls with negative germline testing. The primary objective was to compare progression-free survival (PFS) and overall survival among germline-BRCA2 PV carriers, other HRR PV carriers, and controls. To minimize baseline differences in prognostic factors between PV carriers and controls, inverse probability of treatment weighting was applied. Molecular analyses in pre-CDK4/6i samples among patients with BRCA2 PV were carried out, including RAD51-foci, PAM50 intrinsic subtype, and RB1 loss of heterozygosity (LOH). RESULTS: Among the included 233 patients, median age at diagnosis was 45 years (interquartile range 39-56) and 33% had de novo metastatic disease. Primary resistance to adjuvant ET was present in 10% and secondary resistance in 27%. After a median follow-up of 44 months, patients with germline-BRCA2 PVs (n = 67) had significantly shorter PFS [11 versus 27 months; adjusted hazard ratio (aHR) 2.73, 95% confidence interval (CI) 1.65-4.51, P < 0.001] compared with controls. Among patients with endocrine-sensitive disease, germline BRCA2 PV carriers had markedly shorter PFS (median PFS 12 versus 39 months; aHR 4.04; 95% CI 1.82-8.98, P < 0.001). Exploratory analyses revealed RB1 LOH before CDK4/6i-treatment in most evaluable BRCA2 tumors. CONCLUSIONS: BRCA2 PVs were independently associated with poorer outcomes to first-line CDK4/6i plus ET in HR-positive/HER2-negative MBC compared with controls, especially relevant among patients with endocrine-sensitive disease. These findings suggest that patients with a germline PV in BRCA2 may require alternative first-line strategies.

Humans↗

PubMed2006

Effectiveness of virosomal subunit influenza vaccine in preventing influenza-related illnesses and its social and economic consequences in children aged 3-14 years: a prospective cohort study.

To evaluate the effectiveness of a virosomal subunit influenza vaccine in preventing influenza-related illnesses and its social and economic consequences in children aged 3-14 years, a prospective cohort study was carried out during the 2004-2005 influenza season in 11 private pediatric clinics in the Barcelona metropolitan area. One dose of a virosomal subunit inactivated influenza vaccine (Inflexal V Berna) was given during September and October 2004 to healthy children aged 3-14 years attended in 5 of the 11 clinics. Who comprised the vaccinated cohort (n=966). The non-vaccinated cohort (n=985) was comprised of children attended in the other six clinics. Informed consent was obtained from all parents. The follow up was performed between 1 November 2004 and 31 March 2005. Using a self-administered questionnaire, information was collected from parents or guardians on any type of acute, febrile respiratory illness suffered by their children during the study period, including antibiotic use, and absence from school or work-loss of parents as a result of the illness. RT-PCR (influenza A+B+C) was carried out on pharyngeal and nasal samples obtained from children attended by pediatricians during this period in these clinics with the following symptoms: fever> or =38.5 degrees lasting at least 72h, cough or sore throat (influenza-like illness). Adjusted vaccination effectiveness was 58.6% (95% CI 49.2-66.3) in preventing acute febrile respiratory illnesses, 75.1% (95% CI 61.0-84.1) in preventing cases of influenza-like illnesses and 88.4% (95% CI 49.2-97.3) in preventing laboratory-confirmed cases of influenza A. The adjusted vaccination effectiveness in reducing antibiotic use (18.6%, 95% CI -4.2 to 3.64), absence from school (57.8%, 95% CI 47.9-65.9) and work-loss of parents (33.3%, 95% CI 8.9-51.2) in children affected by an acute febrile respiratory illness was somewhat lower. Vaccination of children aged 3-14 years in pediatric practices with one dose of virosomal subunit inactivated influenza vaccine has the potential to considerably reduce the health and social burdens caused by influenza-related illnesses.

Adolescent↗

PubMed2005

Cost-benefit and cost-effectiveness of the incorporation of the pneumococcal 7-valent conjugated vaccine in the routine vaccination schedule of Catalonia (Spain).

The health and economic costs and benefits of vaccinating a cohort of 60,000 children born in Catalonia in the year 2000 with the pneumococcal 7-valent conjugated vaccine were compared with the alternative of not implementing the vaccination programme. The time horizon fixed for the programme was 10 years for invasive disease, 2 years for all episodes of pneumonia and otitis media and 3.5 years for the placement of tympanostomy tubes. In the base case (incidence rate of invasive disease of 160 per 100,000 and price of the vaccine 50 euros) the net present value was negative, both from the societal perspective (-5.1million euros) and from the provider's perspective (-9.2million euros). The benefit-cost ratio was 0.59 euros from the societal perspective. The cost per disability adjusted life year (DALY) gained was 44,307 euros from the societal perspective and 80,291 euros from the provider's perspective.

Child, Preschool↗

PubMed2005

Efficiency of the incorporation of the hepatitis A vaccine as a combined A+B vaccine to the hepatitis B vaccination programme of preadolescents in schools.

In 1998, the Department of Health of Catalonia (Spain) began universal vaccination of preadolescents against hepatitis A by replacing the simple hepatitis B vaccine with a combined hepatitis A+B vaccine. Economic analyses were made of the two alternative strategies: to continue with the simple hepatitis B vaccination or to replace the simple vaccine with a combined hepatitis A+B vaccine. The analysis was made from the societal perspective and the time horizon considered was 25 years. In the base case, (estimated annual hepatitis A incidence of 15 per 100,000 and incremental price of the hepatitis A+B vaccine over the simple hepatitis B vaccine of 1.98) the net present value of the programme was positive (+533,708) and the benefit-cost ratio was 2.58. If the estimated disease incidence were reduced by half, the programme would still be efficient.

Child↗

PubMed2004

[Percutaneous treatment of obstructive lesions of the aortic bifurcation: results at 50 months from 28 patients].

OBJECTIVE: We conducted a retrospective analysis of short- and mid-term results of endoluminal treatment of obstruction lesions involving the terminal aorta and the initial portions of the iliac arteries in 28 patients. PATIENTS AND METHODS: Twenty-eight patients (9 women, 19 men, mean age 57.5 Years) presented 52 obstructive atheromatous lesions of the aorto-iliac bifurcation. The lesions were divided into three topographic groups (9 unilateral lesions, 19 bilateral ostial lesions, 5 widespread lesions of the terminal aorta) and identified as simple (44%) or complex (56%, more than 2 cm in length and/or calcified and/or eccentric). RESULTS: Technical success was achieved in 93% of the cases with only one hematoma of the puncture site. Primary and secondary patencies were 78.9% and 93% after a mean follow-up of 50 Months (range 4-85). Clinical outcome remained good at this term for all cases of technical success but complete resolution of the symptoms was more frequent when a stent was used (84%) than for simple balloon dilatation (49%). CONCLUSION: Percutaneous treatment of obstructive lesions of the aorto-iliac bifurcation may be proposed when possible as a first-line treatment.

Angioplasty, Balloon↗

PubMed2003

Oscillatory waves in inhomogeneous neural media.

In this Letter we show that an inhomogeneous input can induce wave propagation failure in an excitatory neural network due to the pinning of a stationary front or pulse solution. A subsequent reduction in the strength of the input can lead to a Hopf instability of the stationary solution resulting in breatherlike oscillatory waves.

Models, Neurological↗

PubMed2002

[Criteria for percutaneous non-closure of interatrial communications of the ostium secundum type by the Amplatzer septal occluder].

The aim of the study is to recognise the criteria preventing the percutaneous closure of an interatrial communication of the ostium secundum type for the Amplatzer septal occluder device. From January 1999 to December 2000, 121 consecutive patients with an average age of 24.8 +/- 19 years affected with an interatrial communication of the ostium secundum type underwent echocardiographic examination with transthoracic Doppler to evaluate the maximal diameter of the communication, the border dimensions, and the length of the interatrial septum; 92.5% of them underwent haemodynamic investigation to evaluate the shunt and the stretched diameter. Comparison of the umbrella group averages with the surgical group was performed by the Student test, and the frequencies by the Chi 2 test. ROC curves were drawn for the numeric parameters. After these 2 examinations, 68 patients underwent an attempt at percutaneous closure with 61 successful (84.7%) and 53 had a surgical closure straight off. The surgical group was younger, with a more significant shunt and a wider communication. The criteria for non-closure apart from abnormal pulmonary venous reflux were: insufficient border (59% of cases), diameter too wide (16%), multiperforate septum (16%) and insufficient septum length (9%). Percutaneous closure could be performed in 2/3 of interatrial communications without abnormal pulmonary venous reflux. Candidates for surgery were younger, with a more significant shunt and a wider diameter. In retrospect 8 patients of the surgical group could have had percutaneous closure and 7 patients of the umbrella group could have been sent straight for surgery.

Adolescent↗

PubMed2001

Anterior chordal transection impairs not only regional left ventricular function but also regional right ventricular function in mitral regurgitation.

BACKGROUND: Preservation of annuloventricular continuity through the chordae tendinae aims to maintain left ventricular (LV) function and thus improve postoperative prognosis. This study was designed to prospectively investigate the effect of anterior chordal transection on global and regional LV and right ventricular (RV) function in mitral regurgitation (MR). METHODS AND RESULTS: Sixty-five patients with severe MR underwent radionuclide angiography before and after either mitral valve (MV) repair (42 patients) or replacement with anterior chordal transection (23 patients). LV and RV ejection fractions (EF) were determined at rest. Both ventricles were divided into 9 regions to analyze regional EF and the effect of anteromedial translation related to surgery. After surgery there was a significant decrease in LVEF (P=0.038) and an increase in RVEF (P=0.036). However, LVEF did not change after MV repair (63.8+/-9.9% to 62.6+/-10.3%), whereas RVEF improved (40.7+/-10.1% to 44.5+/-8.1%, P=0.027). In contrast, LVEF decreased after MV replacement (61.7+/-10.1% to 57.2+/-9.9%, P=0.03), and RVEF was unchanged (40.9+/-10.9% to 41.3+/-9.1%). LVEF 4 and 5, in the area of anterior papillary muscle insertion, were impaired after MV replacement compared with MV repair (region 4, 77.6+/-16.7% versus 87.7+/-10.8%, P=0.005, and region 5, 73.9+/-19.3% versus 89.9+/-13.1%, P<0.001). Moreover, anterior chordal transection led to a significant impairment in the apicoseptal region of the RV (RVEF 4, 50.3+/-15.6% versus 59.3+/-13.8%, P=0.02). CONCLUSIONS: Anterior chordal transection during MV replacement for MR impairs not only regional LV function but also regional RV function.

Cardiac Surgical Procedures↗

PubMed2001

N-arginine dibasic convertase is a specific receptor for heparin-binding EGF-like growth factor that mediates cell migration.

Heparin-binding epidermal growth factor-like growth factor (HB-EGF), a mitogen and chemotactic factor, binds to two receptor tyrosine kinases, erbB1 and erbB4. Now we demonstrate that HB-EGF also binds to a novel 140 kDa receptor on MDA-MB 453 cells. Purification of this receptor showed it to be identical to N-arginine dibasic convertase (NRDc), a metalloendopeptidase of the M16 family. Binding to cell surface NRDc and NRDc in solution was highly specific for HB-EGF among EGF family members. When overexpressed in cells, NRDc enhanced their migration in response to HB-EGF but not to EGF. Conversely, inhibition of endogenous NRDc expression in cells by antisense morpholino oligonucleotides inhibited HB-EGF-induced cell migration. Anti-erbB1 neutralizing antibodies completely abrogated the ability of NRDc to enhance HB-EGF-dependent migration, demonstrating that this NRDc activity was dependent on erbB1 signaling. Although NRDc is a metalloproteinase, enzymatic activity was not required for HB-EGF binding or enhancement of cell migration; neither did NRDc cleave HB-EGF. Together, these results suggest that NRDc is a novel specific receptor for HB-EGF that modulates HB-EGF-induced cell migration via erbB1.

3T3 Cells↗

PubMed2001

Inhibition of proprotein convertases is associated with loss of growth and tumorigenicity of HT-29 human colon carcinoma cells: importance of insulin-like growth factor-1 (IGF-1) receptor processing in IGF-1-mediated functions.

Proprotein convertases (PCs) of the subtilisin/kexin family are responsible for the activation of prohormones, protrophic factors, and their receptors. We sought to determine whether loss of PC-mediated activities might affect the malignant phenotypes of cancer cells. Stable transfectants of alpha(1)-antitrypsin Portland (alpha(1)-PDX) cDNA, coding for a potent PC inhibitor, were analyzed in model HT-29 cells (HT-29/PDX) and in other cell lines. Expression of alpha(1)-PDX resulted in a proinsulin-like growth factor-1 receptor (pro-IGF-1R) processing blockade, hence inhibiting the ability of exogenous IGF-1 to induce tyrosine phosphorylation of its beta-subunit and insulin-related substrate-1. Coexpression of IGF-1R with four different PCs or the novel convertase SKI-1 in the furin-defective LoVo-C5 cells demonstrated that pro-IGF-1R ( approximately 200 kDa) cleavage into IGF-1R (beta-subunit, approximately 105 kDa) can be achieved by furin and PC5A, but not by PACE4, PC7, or SKI-1. Expression of alpha(1)-PDX resulted in reduction of DNA synthesis and in anchorage-independent growth. Following serum deprivation, the alpha(1)-PDX transfectants exhibited an enhanced apoptotic phenotype and were insensitive to IGF-1-mediated [(3)H]thymidine incorporation and protection against apoptosis. These cells showed reduced invasiveness that paralleled decreased mRNA levels of urokinase-type plasminogen activator and its receptor, tissue-type plasminogen activator, and plasminogen activator inhibitor-1. Comparative subcutaneous inoculation of cells in nude mice revealed that animals injected with HT-29/PDX cells exhibited delayed and lower incidence of tumor development as well as reduced tumor size. Immunohistochemical analysis of CD31 antigen expression, a marker of endothelial cells, revealed reduced HT-29/PDX tumor vascularization. These findings indicate that PCs actively contribute to the growth and malignant phenotypes of HT-29 tumors, suggesting that PC inhibition strategies may be a useful adduct to the arsenal of colorectal anticancer gene therapies.

Animals↗

PubMed2001

T lymphocytes conditioned with Interferon beta induce membrane and soluble VCAM on human brain endothelial cells.

Vascular cell adhesion molecule (VCAM)-1 plays a critical role in mediating inflammatory cell adhesion and migration. Factors regulating the expression of membrane (m)VCAM and its cleaved counterpart soluble (s)VCAM are poorly understood. We previously demonstrated that serum sVCAM levels are increased in multiple sclerosis (MS) patients treated with interferon beta 1b (IFNbeta1b), which correlated with a reduction in gadolinium enhancing lesions on magnetic resonance imaging. However, subsequent studies have shown that IFNbeta does not directly induce VCAM expression on endothelial cells. We demonstrate here that co-culture with IFNbeta-conditioned T cells induces mVCAM on human brain endothelial cells (HBEC). Further, rapid shedding of sVCAM occurs, which mirrors the response after in vivo IFNbeta treatment. The VCAM induction is mediated partially through tumor necrosis factor (TNF)alpha and can be abrogated by sTNF receptor. VCAM could also be induced on astroglioma lines using IFNbeta-conditioned T cells, which suggests the effect is not specific for HBEC. Kinetic studies demonstrated an increase in the sVCAM to mVCAM ratio over time, which may contribute to the ultimate therapeutic effect of IFNbeta in patients. These data have important implications for understanding the events occurring at the blood brain barrier in vivo, and for determining the mechanism of action of IFNbeta in MS.

Adult↗

PubMed2001

Glial cell influence on the human blood-brain barrier.

The blood-brain barrier (BBB) is a specialized structure of the central nervous system (CNS) that restricts immune cell migration and soluble molecule diffusion from the systemic compartment into the CNS. Astrocytes and microglia are resident cells of the CNS that contribute to the formation of the BBB. In this article, we consider the influence of these glial cells on the immune regulatory functions of the microvascular endothelium, with special emphasis on the human BBB. A series of in vitro studies demonstrate that soluble factors produced by glial cells, under basal culture conditions, help restrict development of inflammation within the CNS. These soluble factor effects include upregulating expression of molecules including HT7, UEA-1 lectin-binding sites, and angiotensin receptors that help define the phenotype of endothelial cells. These factors also induce tight junction formation between brain endothelial cells, contributing to the restricted permeability of the BBB. In contrast, these factors have little effect on expression of molecules by ECs that either promote lymphocyte migration, such as chemokines and adhesion molecules or molecules that are required for competent antigen presentation, such as MHC and co-stimulatory molecules. Glial cells that become activated in response to signals derived from the immune system or generated within the CNS, produce an array of inflammatory molecules that increase permeability and promote lymphocyte trafficking and persistence. These observations emphasize the bidirectional nature of neural-immune interactions; this dynamic system should be amenable to therapeutic interventions.

Animals↗

PubMed2001

NG2 immunoreactivity on human brain endothelial cells.

In this study, we evaluated the expression of NG2 on human brain endothelial cells derived from temporal lobe tissue resected as a treatment for intractable epilepsy. Using dissociated cell cultures, we found expression of NG2 on both proliferating and non-proliferating cells, at the mRNA level by reverse transcription-polymerase chain reaction analyses, and at the protein level by immunocytochemistry and immunoblotting. We further observed that human cerebral microvessels in nonmalignant CNS tissues immunoreacted with NG2. NG2 protein was detected using both a rabbit antibody raised against the rodent NG2 and a monoclonal antibody raised against the human NG2 (9.2.27). Our findings further define the range of resident cells of the CNS that can express NG2 and indicate that expression of NG2 by endothelial cells is not restricted to proliferating CNS endothelial cells or to endothelial cells found in brain tumors.

Adult↗

PubMed2001

Outcome and follow-up of aortic valve replacement with the freestyle stentless bioprosthesis.

BACKGROUND: The aim of this study was to determine the morbidity, mortality, and hemodynamics after implantation of the Freestyle stentless bioprosthesis in the aortic position. METHODS: A total of 280 patients were operated on from June 1993 to July 1999 as part of a multicenter investigation. Factors influencing hospital mortality and long-term survival were assessed by logistic regression and Cox proportional hazards analysis. Patients were evaluated postoperatively at discharge, at 3 to 6 months, and yearly by clinical examination and color flow Doppler echocardiography. RESULTS: Hospital mortality in this group was relatively high (9.6%). Logistic regression analysis showed that cross-clamp time, age, myocardial infarction, diabetes, left ventricular hypertrophy, coronary artery disease, New York Heart Association class III or IV and female gender were the independent predictive factors. According to the Kaplan-Meier method, the 4-year survival for hospital survivors was 94%. In the multivariate Cox proportional hazard analysis, only coronary artery disease proved to be prognostic. During follow-up, 11 patients developed paravalvular leakage due to prosthetic dehiscence at the side of the noncoronary cusp. Performance of the prosthesis as assessed by echocardiography was excellent. Mean gradient decreased significantly between discharge and follow-up at 3 to 6 months. At 1-year follow-up trivial regurgitation was found in 6 patients (3%) and mild regurgitation in 4 (2%). Regurgitation did not increase with time. The effective orifice area increased significantly from discharge to follow-up at 3 to 6 months. CONCLUSIONS: Hospital mortality after implantation of a stentless bioprosthesis was higher compared to conventional prosthesis. A high incidence of prosthesis dehiscence at the proximal suture line was found, which was probably due to technique. Hemodynamic performance up to 3 years showed low transvalvular gradients. There is echocardiographic evidence for reduction of left ventricular hypertrophy and improvement of left ventricular function.

Actuarial Analysis↗

PubMed2001

Ross operation for active culture-positive aortic valve endocarditis with extensive paravalvular involvement.

BACKGROUND: We evaluated the midterm results of the Ross operation in active advanced endocarditis. METHODS: Between June 1994 and June 2000 a pulmonary autograft aortic root replacement was performed in 11 consecutive patients who had urgent or emergent procedures for active endocarditis with extensive involvement of the aortic root (10 native, 1 prosthetic). Patients ranged in age from 26 to 45 years (median, 33 years). Indications for operation were uncontrolled infection (n = 5), hemodynamic deterioration (n = 3), or both (n = 3). Four patients were in the New York Heart Association class III, 6 in class IV, and 1 was operated on while in cardiogenic shock. Four patients (36%) suffered an embolic cerebrovascular accident preoperatively. The endocarditis affected the mitral valve in 2 patients and the tricuspid valve in 1 patient. RESULTS: There was no early or late death. Recurrent endocarditis was not detected in any of the patients during the follow-up period ranging up to 72 months (median, 40 months). CONCLUSIONS: The autograft may well be the best substitute for aortic root reconstruction in advanced endocarditis.

Adult↗

PubMed2001

Regulation of Th1 and Th2 lymphocyte migration by human adult brain endothelial cells.

Endothelial cells of the blood-brain barrier (BBB) have the ability to regulate and restrict the passage of cells and molecules from the periphery to the CNS. We have used an in vitro assay of lymphocyte migration across monolayers of human adult brain endothelial cells (HBEC) as a model of lymphocyte migration across the BBB. We found that human allogeneic or MBP-reactive Th2-polarized lymphocytes migrate more avidly than Th1-polarized lymphocytes. Migration of Th2 but not Th1 cells across brain endothelium was inhibited by antibodies directed at MCP-1, a chemokine produced by HBECs. We could detect CCR2, a chemokine receptor that recognizes MCP-1 on Th2 but not Th1 lymphocytes. ICAM-1 and VCAM-1 molecules were expressed on the surface of HBECs under basal conditions and were upregulated by Th1 but not Th2 cell-derived supernatants. Migration of both lymphocyte subsets was dependent on LFA-1/ICAM-1 interactions. Blocking VLA-4/VCAM-1 binding did not influence actual trans-endothelial migration. These results suggest that HBECs composing the BBB favor the migration of Th2 cells. We postulate that this selectivity may help prevent activated Th1 lymphocytes, the putative CNS autoimmune disease initiating cells, from reaching the CNS parenchyma and favor entry of Th2 cells, a putative means to induce bystander suppression in the CNS.

Adult↗

PubMed2001

A recovery model of partial cardiopulmonary bypass in the rat.

This study was undertaken to develop a recovery model of cardiopulmonary bypass (CPB) in rats. Twenty male Wistar rats (475-550 g) were anaesthetized, mechanically ventilated and the femoral vessels cannulated. The extracorporeal circulation circuit comprised a roller pump, a venous reservoir and a modified Capiox 308 paediatric membrane oxygenator. Priming consisted of 20 ml of fresh homologous blood and 15 ml of colloid. Anticoagulation was achieved with heparin (500 IU/kg). Blood gas analysis, blood pressure monitoring and survival studies were performed in CPB (n=10) and Sham (n=10) rats. Partial CPB was always easily established and was conducted at a flow rate of 100 ml/kg/min for 90 min Blood gas analysis and blood pressure data did not differ between the two groups. All CPB rats survived and the 3-week follow-up period remained uneventful. The rat model of CPB was easy to perform and was associated with excellent survival. This recovery model should allow us to study the pathophysiological processes underlying post-CPB multiple organ dysfunction.

Animals↗

PubMed2000

Endovascular treatment for dissection of the descending aorta.

Surgery for acute ischaemia complicating dissection of the descending aorta is associated with high mortality. We used an endovascular fenestration approach (scissor technique) to treat seven of 12 patients with ischaemic complications of descending aortic dissection; the remaining five patients were treated by stent implantation. Four of the 12 patients died (two in the fenestration group and two in the stenting group) in the days after the procedure. The remaining eight were symptom-free a mean of 9.4 (SD 8) months later. We suggest that the fenestration approach is a promising addition to endovascular treatment for patients with ischaemic complications of descending aortic dissection.

Adult↗