Miracle-dz/UniFAR-FTUs huggingface dataset:
Is there any difference in efficacy of oral sildenafil therapy in primary vs secondary Pulmonary Arterial Hypertension

Objective: Oral sildenafil, a phosphodiesterase 5 inhibitor,is now accepted mode of therapy for symptomatic Pulmonary arterial hypertension(PAH). As the pathobiologic mechanisms are different in primary and secondary PAH, we undertook this study to find out any significant difference in efficacy of oral sildenafil therapy in primary versus secondary PAH. Methods: It was an unicentric parallel group longitudinal study. After selection and baseline investigations,all the patients of primary and secondary PAH were given sildenafil in fixed doses (50 mg thrice daily). Study parameters: 1. Distance covered in 6 minute walk test (6MWT), 2.Pulmonary arterial pressure (PAP) by trans-thoracic Doppler echocardiography, 3.quality of life (QOL) score assessed by Minnesota living with heart disease questionnaire. At the end of 6 weeks, 6 MWT, PAP, QOL were compared to the baseline value. Results: 42 subjects completed the study.20 subjects had primary PAH and 22 had secondary PAH. Sildenafil therapy was effective in both groups in reducing PAP, increase in distance covered in 6 minute walk and reducing QOL score. Reduction of PAP is significantly more in primary PAH than secondary PAH but no such difference was found in 6 MWT and QOL score. Conclusion: Though lowering of pulmonary arterial pressure in primary PAH is significantly lower than secondary PAH, this is not translated in better symptomatic relief. Key words: primary pulmonary hypertension, secondary pulmonary hypertension, sildenafil, pulmonary arterial pressure, 6 minute walk test.
Thrombin-receptor antagonist vorapaxar in acute coronary syndromes.

BACKGROUND Vorapaxar is a new oral protease-activated-receptor 1 (PAR-1) antagonist that inhibits thrombin-induced platelet activation. METHODS In this multinational, double-blind, randomized trial, we compared vorapaxar with placebo in 12,944 patients who had acute coronary syndromes without ST-segment elevation. The primary end point was a composite of death from cardiovascular causes, myocardial infarction, stroke, recurrent ischemia with rehospitalization, or urgent coronary revascularization. RESULTS Follow-up in the trial was terminated early after a safety review. After a median follow-up of 502 days (interquartile range, 349 to 667), the primary end point occurred in 1031 of 6473 patients receiving vorapaxar versus 1102 of 6471 patients receiving placebo (Kaplan-Meier 2-year rate, 18.5% vs. 19.9%; hazard ratio, 0.92; 95% confidence interval [CI], 0.85 to 1.01; P=0.07). A composite of death from cardiovascular causes, myocardial infarction, or stroke occurred in 822 patients in the vorapaxar group versus 910 in the placebo group (14.7% and 16.4%, respectively; hazard ratio, 0.89; 95% CI, 0.81 to 0.98; P=0.02). Rates of moderate and severe bleeding were 7.2% in the vorapaxar group and 5.2% in the placebo group (hazard ratio, 1.35; 95% CI, 1.16 to 1.58; P<0.001). Intracranial hemorrhage rates were 1.1% and 0.2%, respectively (hazard ratio, 3.39; 95% CI, 1.78 to 6.45; P<0.001). Rates of nonhemorrhagic adverse events were similar in the two groups. CONCLUSIONS In patients with acute coronary syndromes, the addition of vorapaxar to standard therapy did not significantly reduce the primary composite end point but significantly increased the risk of major bleeding, including intracranial hemorrhage. (Funded by Merck; TRACER ClinicalTrials.gov number, NCT00527943.).
Dronedarone in high-risk permanent atrial fibrillation.

BACKGROUND Dronedarone restores sinus rhythm and reduces hospitalization or death in intermittent atrial fibrillation. It also lowers heart rate and blood pressure and has antiadrenergic and potential ventricular antiarrhythmic effects. We hypothesized that dronedarone would reduce major vascular events in high-risk permanent atrial fibrillation. METHODS We assigned patients who were at least 65 years of age with at least a 6-month history of permanent atrial fibrillation and risk factors for major vascular events to receive dronedarone or placebo. The first coprimary outcome was stroke, myocardial infarction, systemic embolism, or death from cardiovascular causes. The second coprimary outcome was unplanned hospitalization for a cardiovascular cause or death. RESULTS After the enrollment of 3236 patients, the study was stopped for safety reasons. The first coprimary outcome occurred in 43 patients receiving dronedarone and 19 receiving placebo (hazard ratio, 2.29; 95% confidence interval [CI], 1.34 to 3.94; P=0.002). There were 21 deaths from cardiovascular causes in the dronedarone group and 10 in the placebo group (hazard ratio, 2.11; 95% CI, 1.00 to 4.49; P=0.046), including death from arrhythmia in 13 patients and 4 patients, respectively (hazard ratio, 3.26; 95% CI, 1.06 to 10.00; P=0.03). Stroke occurred in 23 patients in the dronedarone group and 10 in the placebo group (hazard ratio, 2.32; 95% CI, 1.11 to 4.88; P=0.02). Hospitalization for heart failure occurred in 43 patients in the dronedarone group and 24 in the placebo group (hazard ratio, 1.81; 95% CI, 1.10 to 2.99; P=0.02). CONCLUSIONS Dronedarone increased rates of heart failure, stroke, and death from cardiovascular causes in patients with permanent atrial fibrillation who were at risk for major vascular events. Our data show that this drug should not be used in such patients. (Funded by Sanofi-Aventis; PALLAS ClinicalTrials.gov number, NCT01151137.).
Potassium channel KIR4.1 as an immune target in multiple sclerosis.

BACKGROUND Multiple sclerosis is a chronic inflammatory demyelinating disease of the central nervous system. Many findings suggest that the disease has an autoimmune pathogenesis; the target of the immune response is not yet known. METHODS We screened serum IgG from persons with multiple sclerosis to identify antibodies that are capable of binding to brain tissue and observed specific binding of IgG to glial cells in a subgroup of patients. Using a proteomic approach focusing on membrane proteins, we identified the ATP-sensitive inward rectifying potassium channel KIR4.1 as the target of the IgG antibodies. We used a multifaceted validation strategy to confirm KIR4.1 as a target of the autoantibody response in multiple sclerosis and to show its potential pathogenicity in vivo. RESULTS Serum levels of antibodies to KIR4.1 were higher in persons with multiple sclerosis than in persons with other neurologic diseases and healthy donors (P<0.001 for both comparisons). We replicated this finding in two independent groups of persons with multiple sclerosis or other neurologic diseases (P<0.001 for both comparisons). Analysis of the combined data sets indicated the presence of serum antibodies to KIR4.1 in 186 of 397 persons with multiple sclerosis (46.9%), in 3 of 329 persons with other neurologic diseases (0.9%), and in none of the 59 healthy donors. These antibodies bound to the first extracellular loop of KIR4.1. Injection of KIR4.1 serum IgG into the cisternae magnae of mice led to a profound loss of KIR4.1 expression, altered expression of glial fibrillary acidic protein in astrocytes, and activation of the complement cascade at sites of KIR4.1 expression in the cerebellum. CONCLUSIONS KIR4.1 is a target of the autoantibody response in a subgroup of persons with multiple sclerosis. (Funded by the German Ministry for Education and Research and Deutsche Forschungsgemeinschaft.).
Tendencia de las bacteremias y factores de riesgo de muerte en un hospital de tercer nivel de la Ciudad de México. 1981 a 1992

Objetivo: Describir la tendencia de las bacteremias y los factores de riesgo (FR) de muerte en adultos atendidos en un hospital de tercer nivel entre de 1981 a 1992. Material y metodos: Incluimos aleatoriamente el 20% de las bacteremias por ano. Resultados: Se tomaron 47, 618 hemocultivos de 19, 530 pacientes, de ellos 3, 428 (17.6%) con bacteremia (285 / ano). Incluimos 600 pacientes (50 / ano), 307 hombres; edad promedio 46 ± 19.8 anos; 88% mono microbiana y 61.3% de origen nosocomial (BN). Encontramos diabetes mellitus en 103 casos, cirrosis hepatica en 98, y SIDA en 33. Los microorganismos aislados fueron: E. Coli (177), K pneumoniae (53), Enterobacter (50), Salmonella (45) y P. Aeruginosa (35), estafilococos coagulasa negativa (ECN) (116), S. Aureus (56), enterococo (22) y Candida (20). Hubo disminucion de ECN (p<0.01), y aumento de Candida, Stenotro-phomonas maltophilia y enterococo (p<0.01), mortalidad cruda por BN de 70.8%, y comunitaria fue de 29.2%, con mortalidad atribuible a BN de 41.6%. Se definieron los siguientes FR: enfermedad valvular cardiaca (p<0.001), estancia en la UTI (p<0.001), sepsis (p<0.001) y neumonia (p<0.001). Discusion: La bacteremia es una de las infecciones asociadas con mayor mortalidad que no se ha modificado con la terapia oportuna. Enterococo y candida emergen como patogenos relevantes. Palabras clave: bacteremia, infeccion nosocomial, Pseudomonas aeruginosa, Stenotrophomonas maltophilia, enterococo, candida
Outbreak of salmonellosis linked to live poultry from a mail-order hatchery.

BACKGROUND Outbreaks of human salmonella infections are increasingly associated with contact with live poultry, but effective control measures are elusive. In 2005, a cluster of human salmonella Montevideo infections with a rare pattern on pulsed-field gel electrophoresis (the outbreak strain) was identified by PulseNet, a national subtyping network. METHODS In cooperation with public health and animal health agencies, we conducted multistate investigations involving patient interviews, trace-back investigations, and environmental testing at a mail-order hatchery linked to the outbreak in order to identify the source of infections and prevent additional illnesses. A case was defined as an infection with the outbreak strain between 2004 and 2011. RESULTS From 2004 through 2011, we identified 316 cases in 43 states. The median age of the patient was 4 years. Interviews were completed with 156 patients (or their caretakers) (49%), and 36 of these patients (23%) were hospitalized. Among the 145 patients for whom information was available, 80 (55%) had bloody diarrhea. Information on contact with live young poultry was available for 159 patients, and 122 of these patients (77%) reported having such contact. A mail-order hatchery in the western United States was identified in 81% of the trace-back investigations, and the outbreak strain was isolated from samples collected at the hatchery. After interventions at the hatchery, the number of human infections declined, but transmission continued. CONCLUSIONS We identified a prolonged multistate outbreak of salmonellosis, predominantly affecting young children and associated with contact with live young poultry from a mail-order hatchery. Interventions performed at the hatchery reduced, but did not eliminate, associated human infections, demonstrating the difficulty of eliminating salmonella transmission from live poultry.
Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib.

BACKGROUND Approximately 50% of melanomas harbor activating (V600) mutations in the serine-threonine protein kinase B-RAF (BRAF). The oral BRAF inhibitor vemurafenib (PLX4032) frequently produced tumor regressions in patients with BRAF V600-mutant metastatic melanoma in a phase 1 trial and improved overall survival in a phase 3 trial. METHODS We designed a multicenter phase 2 trial of vemurafenib in patients with previously treated BRAF V600-mutant metastatic melanoma to investigate the efficacy of vemurafenib with respect to overall response rate (percentage of treated patients with a tumor response), duration of response, and overall survival. The primary end point was the overall response rate as ascertained by the independent review committee; overall survival was a secondary end point. RESULTS A total of 132 patients had a median follow-up of 12.9 months (range, 0.6 to 20.1). The confirmed overall response rate was 53% (95% confidence interval [CI], 44 to 62; 6% with a complete response and 47% with a partial response), the median duration of response was 6.7 months (95% CI, 5.6 to 8.6), and the median progression-free survival was 6.8 months (95% CI, 5.6 to 8.1). Primary progression was observed in only 14% of patients. Some patients had a response after receiving vemurafenib for more than 6 months. The median overall survival was 15.9 months (95% CI, 11.6 to 18.3). The most common adverse events were grade 1 or 2 arthralgia, rash, photosensitivity, fatigue, and alopecia. Cutaneous squamous-cell carcinomas (the majority, keratoacanthoma type) were diagnosed in 26% of patients. CONCLUSIONS Vemurafenib induces clinical responses in more than half of patients with previously treated BRAF V600-mutant metastatic melanoma. In this study with a long follow-up, the median overall survival was approximately 16 months. (Funded by Hoffmann-La Roche; ClinicalTrials.gov number, NCT00949702.).
Identificación de marcadores moleculares y dianas terapéuticas relacionadas con la respuesta a inhibidores de la ruta EGFR/PI3K/AKT en gliomas

Los gliomas, que son los tumores primarios mas frecuentes del sistema nervioso central, constituyen uno de los tipos de cancer con peor pronostico, por su dificil tratamiento y su alta tasa de recidivas. La forma mas agresiva de los gliomas es el glioblastoma (GBM) que cuenta con bajas tasas de supervivencia y una rapida progresion. El tratamiento principal de los GBM consiste en la reseccion quirurgica del tumor siempre que sea posible, seguido por radioterapia y un tratamiento adjuvante de quimioterapia, que usa principalmente compuestos intercalantes como la carmustina o la temozolamida. Sin embargo, ante la respuesta poco satisfactoria de este tratamiento, hay diversas diversas lineas secundarias de tratamiento en investigacion, siendo una de ellas el uso de inhibidores de tirosina quinasa. En la presente tesis doctoral, se ha estudiado el efecto de cuatro inhibidores de la ruta EGFR/PI3K/Akt (gefitinib, erlotinib, LY294002, temsirolimus), utilizando modelos celulares. Previamente, se han caracterizado molecularmente las 11 lineas celulares derivadas de gliomas utilizadas, comparando las aberraciones genomicas de estas lineas con las alteraciones mas comunes en gliomas primarios. Mediante la utilizacion de tecnicas de analisis genico masivo se ha podido comprobar que las lineas celulares derivadas de gliomas conservan las perdidas genicas habitualmente encontradas en tumores primarios (PTEN, CDKN2A y CDKN2B), asi como ganancias de bajo nivel (EGFR, PI3KCA), pero no conservan las amplificaciones. Ademas, los estudios de expresion han permitido establecer distintos perfiles de expresion segun la respuesta al inhibidor de EGFR, erlotinib y se han propuesto varios genes (PIK3R3, HRAS, CTGF, HDAC3 y ERCC5) como posibles candidatos para predecir la respuesta a este inhibidor. Por otra parte, se ha comprobado que erlotinib causa detencion del ciclo celular en lineas celulares derivadas de gliomas mediante la represion de E2F1, BIRC5 y PLK1 y la induccion de GAS5, principalmente.
Early surgery versus conventional treatment for infective endocarditis.

BACKGROUND The timing and indications for surgical intervention to prevent systemic embolism in infective endocarditis remain controversial. We conducted a trial to compare clinical outcomes of early surgery and conventional treatment in patients with infective endocarditis. METHODS We randomly assigned patients with left-sided infective endocarditis, severe valve disease, and large vegetations to early surgery (37 patients) or conventional treatment (39). The primary end point was a composite of in-hospital death and embolic events that occurred within 6 weeks after randomization. RESULTS All the patients assigned to the early-surgery group underwent valve surgery within 48 hours after randomization, whereas 30 patients (77%) in the conventional-treatment group underwent surgery during the initial hospitalization (27 patients) or during follow-up (3). The primary end point occurred in 1 patient (3%) in the early-surgery group as compared with 9 (23%) in the conventional-treatment group (hazard ratio, 0.10; 95% confidence interval [CI], 0.01 to 0.82; P=0.03). There was no significant difference in all-cause mortality at 6 months in the early-surgery and conventional-treatment groups (3% and 5%, respectively; hazard ratio, 0.51; 95% CI, 0.05 to 5.66; P=0.59). The rate of the composite end point of death from any cause, embolic events, or recurrence of infective endocarditis at 6 months was 3% in the early-surgery group and 28% in the conventional-treatment group (hazard ratio, 0.08; 95% CI, 0.01 to 0.65; P=0.02). CONCLUSIONS As compared with conventional treatment, early surgery in patients with infective endocarditis and large vegetations significantly reduced the composite end point of death from any cause and embolic events by effectively decreasing the risk of systemic embolism. (EASE ClinicalTrials.gov number, NCT00750373.).
Protective role of necrostatin‐1 in acute myocardial infarction

Following a tradition, the Council of the European Society of Clinical Investigation (ESCI) will award at the next Meeting in Paris (April 27(th) -29(th) 2016) the best basic research article published in the European Journal of Clinical Investigation (EJCI) from November 2014 to October 2015. In the final selection round four outstanding articles were selected on the basis of their scientific impact, quality and novelty [1-4]. Among those finalists, the article by Koudstaal et al. obtained the highest consideration and was elected as the winner of the 2016 ESCI Award for the Best Basic Research Article [1]. This article is protected by copyright. All rights reserved.
Biological roles of glycans

Abstract Simple and complex carbohydrates (glycans) have long been known to play major metabolic, structural and physical roles in biological systems. Targeted microbial binding to host glycans has also been studied for decades. But such biological roles can only explain some of the remarkable complexity and organismal diversity of glycans in nature. Reviewing the subject about two decades ago, one could find very few clear-cut instances of glycan-recognition-specific biological roles of glycans that were of intrinsic value to the organism expressing them. In striking contrast there is now a profusion of examples, such that this updated review cannot be comprehensive. Instead, a historical overview is presented, broad principles outlined and a few examples cited, representing diverse types of roles, mediated by various glycan classes, in different evolutionary lineages. What remains unchanged is the fact that while all theories regarding biological roles of glycans are supported by compelling evidence, exceptions to each can be found. In retrospect, this is not surprising. Complex and diverse glycans appear to be ubiquitous to all cells in nature, and essential to all life forms. Thus, >3 billion years of evolution consistently generated organisms that use these molecules for many key biological roles, even while sometimes coopting them for minor functions. In this respect, glycans are no different from other major macromolecular building blocks of life (nucleic acids, proteins and lipids), simply more rapidly evolving and complex. It is time for the diverse functional roles of glycans to be fully incorporated into the mainstream of biological sciences.
Combination chemotherapy in advanced adrenocortical carcinoma.

BACKGROUND Adrenocortical carcinoma is a rare cancer that has a poor response to cytotoxic treatment. METHODS We randomly assigned 304 patients with advanced adrenocortical carcinoma to receive mitotane plus either a combination of etoposide (100 mg per square meter of body-surface area on days 2 to 4), doxorubicin (40 mg per square meter on day 1), and cisplatin (40 mg per square meter on days 3 and 4) (EDP) every 4 weeks or streptozocin (streptozotocin) (1 g on days 1 to 5 in cycle 1; 2 g on day 1 in subsequent cycles) every 3 weeks. Patients with disease progression received the alternative regimen as second-line therapy. The primary end point was overall survival. RESULTS For first-line therapy, patients in the EDP-mitotane group had a significantly higher response rate than those in the streptozocin-mitotane group (23.2% vs. 9.2%, P<0.001) and longer median progression-free survival (5.0 months vs. 2.1 months; hazard ratio, 0.55; 95% confidence interval [CI], 0.43 to 0.69; P<0.001); there was no significant between-group difference in overall survival (14.8 months and 12.0 months, respectively; hazard ratio, 0.79; 95% CI, 0.61 to 1.02; P=0.07). Among the 185 patients who received the alternative regimen as second-line therapy, the median duration of progression-free survival was 5.6 months in the EDP-mitotane group and 2.2 months in the streptozocin-mitotane group. Patients who did not receive the alternative second-line therapy had better overall survival with first-line EDP plus mitotane (17.1 month) than with streptozocin plus mitotane (4.7 months). Rates of serious adverse events did not differ significantly between treatments. CONCLUSIONS Rates of response and progression-free survival were significantly better with EDP plus mitotane than with streptozocin plus mitotane as first-line therapy, with similar rates of toxic events, although there was no significant difference in overall survival. (Funded by the Swedish Research Council and others; FIRM-ACT ClinicalTrials.gov number, NCT00094497.).
A gene cluster at an unusual chromosomal location responsible for the novel O-antigen synthesis in Escherichia coli O62 by the ABC transporter-dependent pathway

The O-antigen is a part of the outer membrane of Gram-negative bacteria and is related to bacterial virulence. It is one of the most variable cell constituents, and its structural diversity is almost entirely due to genetic variation of the O-antigen gene cluster. In this study, the O-antigen structure of Escherichia coli O62 was elucidated by chemical analysis and nuclear magnetic resonance spectroscopy, but showing not consistent with the O-antigen gene cluster between conserved genes galF and gnd reported earlier. The complete genome of E. coli O62 was then sequenced and analyzed, and another O-antigen gene cluster was found and characterized that correlated perfectly with the established O-antigen structure. A deletion and complementation experiment confirmed the functionality of the novel gene cluster and demonstrated that the O62-antigen is synthesized by the ABC transporter-dependent system. To our knowledge, this is the first report that the O-antigen gene cluster is positioned at a novel locus in E. coli. Comparative analysis indicated that E. coli O62 likely originated from E. coli O68 via an IS event resulting in the repression of the O68-antigen synthesis, followed by the acquisition of a novel O-antigen gene cluster from Enterobacter aerogenes.
LASIK vs. LASEK desde la perspectiva morfométrica corneal in vivo

Objetivo: Comparar los cambios en la morfometría corneal de pacientes operados de LASIK y LASEK, evaluados mediante microscopía confocal in vivo. Método: Se realizó una investigación observacional, descriptiva, longitudinal y prospectiva. Se evaluaron 146 pacientes intervenidos con láser de excímeros para la corrección de ametropías por el autor, con las técnicas quirúrgicas: LASIK con microquerátomo pendular y LASEK, en el Hospital Abel Santamaría Cuadrado en Pinar del Río, Cuba, desde noviembre del 2010 a junio del 2011. La muestra quedó constituida por 134 pacientes, que cumplieron con los criterios de selección establecidos. Se formaron dos grupos: uno de 78 pacientes (151 ojos) operados con LASIK ◗ Abstract