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.)

Genotypic classification of patients with Wolfram syndrome: insights into the natural history of the disease and correlation with phenotype

Purpose: Wolfram syndrome is a degenerative, recessive rare disease with an onset in childhood. It is caused by mutations in WFS1 or CISD2 genes. More than 200 different variations in WFS1 have been described in patients with Wolfram syndrome, which complicates the establishment of clear genotype-phenotype correlation. The purpose of this study was to elucidate the role of WFS1 mutations and update the natural history of the disease. Methods: This study analyzed clinical and genetic data of 412 patients with Wolfram syndrome published in the last 15 years. Results: (i) 15% of published patients do not fulfill the current ­inclusion criterion; (ii) genotypic prevalence differences may exist among countries; (iii) diabetes mellitus and optic atrophy might not be the first two clinical features in some patients; (iv) mutations are nonuniformly distributed in WFS1; (v) age at onset of diabetes mellitus, hearing defects, and diabetes insipidus may depend on the patient"s genotypic class; and (vi) disease progression rate might depend on genotypic class. Conclusion: New genotype-phenotype correlations were established, disease progression rate for the general population and for the genotypic classes has been calculated, and new diagnostic criteria have been proposed. The conclusions raised could be important for patient management and counseling as well as for the development of treatments for Wolfram syndrome.

Efficacy and safety of once-daily aclidinium in chronic obstructive pulmonary disease

Background: The long-term efficacy and safety of aclidinium bromide, a novel, long-acting muscarinic antagonist, were investigated in patients with moderate to severe chronic obstructive pulmonary disease (COPD). Methods: In two double-blind, 52-week studies, ACCLAIM/COPD I (n = 843) and II (n = 804), patients were randomised to inhaled aclidinium 200 μg or placebo once-daily. Patients were required to have a postbronchodilator forced expiratory volume in 1 second (FEV1)/forced vital capacity ratio of ≤70% and FEV1 <80% of the predicted value. The primary endpoint was trough FEV1 at 12 and 28 weeks. Secondary endpoints were health status measured by St George"s Respiratory Questionnaire (SGRQ) and time to first moderate or severe COPD exacerbation. Results: At 12 and 28 weeks, aclidinium improved trough FEV1 versus placebo in ACCLAIM/COPD I (by 61 and 67 mL; both p < 0.001) and ACCLAIM/COPD II (by 63 and 59 mL; both p < 0.001). More patients had a SGRQ improvement ≥4 units at 52 weeks with aclidinium versus placebo in ACCLAIM/COPD I (48.1% versus 39.5%; p = 0.025) and ACCLAIM/COPD II (39.0% versus 32.8%; p = 0.074). The time to first exacerbation was significantly delayed by aclidinium in ACCLAIM/COPD II (hazard ratio [HR] 0.7; 95% confidence interval [CI] 0.55 to 0.92; p = 0.01), but not ACCLAIM/COPD I (HR 1.0; 95% CI 0.72 to 1.33; p = 0.9). Adverse events were minor in both studies. Conclusion: Aclidinium is effective and well tolerated in patients with moderate to severe COPD. Trial registration: ClinicalTrials.gov: NCT00363896 ACCLAIM/COPD I) and NCT00358436 (ACCLAIM/COPD II).

Incidence, prevalence and clinical significance of abnormal hematological indices in compensated cirrhosis.

Background & Aims: Patients with cirrhosis develop abnormal hematologic indices (HI) from multiple factors, including hypersplenism. We aimed to analyze the sequence of events and determine whether abnormal HI has prog-nostic significance. Methods: We analyzed a database of 213 subjects with compensated cirrhosis without esopha-geal varices. Subjects were followed for approximately 9 years until the development of varices or variceal bleeding or completion of the study; 84 subjects developed varices. Abnormal HI was defined as anemia at baseline (hemoglo-bin,<13.5 g/dL for men and 11.5 g/dL for women), leuko-penia (white blood cell counts,<4000/mm 3 ), or thrombo-cytopenia (platelet counts, < 150,000/mm 3 ). The primary end points were death or transplant surgery. Results: Most subjects had thrombocytopenia at baseline. Kaplan-Meier analysis showed that leukopenia occurred by 30 months (95% confidence interval, 18.5-53.6), and anemia occurred by 39.6 months (95% confidence interval, 24.1-49.9). Baseline thrombocytopenia (P .0191) and leukope-nia (P.0383) were predictors of death or transplant, after adjusting for baseline hepatic venous pressure gradient (HVPG), and Child-Pugh scores. After a median of 5 years,a significant difference in death or transplant, mortality,and clinical decompensation was observed in patients who had leukopenia combined with thrombocytopenia at base- line compared with patients with normal HI (P < .0001). HVPG correlated with hemoglobin and white blood cell count (hemoglobin, r 0.35, P < .0001; white blood cell count, r 0.31, P < .0001). Conclusions: Thrombocy-topenia is the most common and first abnormal HI to occurin patients with cirrhosis, followed by leukopenia and anemia. A combination of leukopenia and thrombocytopenia at baselin predicted increased morbidity and mortality.

Coexistence of protease sensitive and resistant prion protein in 129VV homozygous sporadic Creutzfeldt-Jakob disease: a case report

Introduction: The coexistence of different molecular types of classical protease-resistant prion protein in the same individual have been described, however, the simultaneous finding of these with the recently described protease-sensitive variant or variably protease-sensitive prionopathy has, to the best of our knowledge, not yet been reported. Case presentation: A 74-year-old Caucasian woman showed a sporadic Creutzfeldt-Jakob disease clinical phenotype with reactive depression, followed by cognitive impairment, akinetic-rigid Parkinsonism with pseudobulbar syndrome and gait impairment with motor apraxia, visuospatial disorientation, and evident frontal dysfunction features such as grasping, palmomental reflex and brisk perioral reflexes. She died at age 77. Neuropathological findings showed: spongiform change in the patient"s cerebral cortex, striatum, thalamus and molecular layer of the cerebellum with proteinase K-sensitive synaptic-like, dot-like or target-like prion protein deposition in the cortex, thalamus and striatum; proteinase K-resistant prion protein in the same regions; and elongated plaque-like proteinase K-resistant prion protein in the molecular layer of the cerebellum. Molecular analysis of prion protein after proteinase K digestion revealed decreased signal intensity in immunoblot, a ladder-like protein pattern, and a 71% reduction of PrPSc signal relative to non-digested material. Her cerebellum showed a 2A prion protein type largely resistant to proteinase K. Genotype of polymorphism at codon 129 was valine homozygous. Conclusion: Molecular typing of prion protein along with clinical and neuropathological data revealed, to the best of our knowledge, the first case of the coexistence of different protease-sensitive prion proteins in the same patient in a rare case that did not fulfill the current clinical diagnostic criteria for either probable or possible sporadic Creutzfeldt-Jakob disease. This highlights the importance of molecular analyses of several brain regions in order to correctly diagnose rare and atypical prionopathies

Undifferentiated and differentiated PC12 cells protected by huprines against injury induced by hydrogen peroxide

Oxidative stress is implicated in the pathogenesis of neurodegenerative disorders and hydrogen peroxide (H2O2) plays a central role in the stress. Huprines, a group of potent acetylcholinesterase inhibitors (AChEIs), have shown a broad cholinergic pharmacological profile. Recently, it has been observed that huprine X (HX) improves cognition in non transgenic middle aged mice and shows a neuroprotective activity (increased synaptophysin expression) in 3xTg-AD mice. Consequently, in the present experiments the potential neuroprotective effect of huprines (HX, HY, HZ) has been analyzed in two different in vitro conditions: undifferentiated and NGF-differentiated PC12 cells. Cells were subjected to oxidative insult (H2O2, 200 µM) and the protective effects of HX, HY and HZ (0.01 µM- 1 µM) were analyzed after a pre-incubation period of 24 and 48 hours. All huprines showed protective effects in both undifferentiated and NGF-differentiated cells, however only in differentiated cells the effect was dependent on cholinergic receptors as atropine (muscarinic antagonist, 0.1 µM) and mecamylamine (nicotinic antagonist, 100 µM) reverted the neuroprotection action of huprines. The decrease in SOD activity observed after oxidative insult was overcome in the presence of huprines and this effect was not mediated by muscarinic or nicotinic receptors. In conclusion, huprines displayed neuroprotective properties as previously observed in in vivo studies. In addition, these effects were mediated by cholinergic receptors only in differentiated cells. However, a non-cholinergic mechanism, probably through an increase in SOD activity, seems to be also involved in the neuroprotective effects of huprines.

Spermiogenesis and spermatozoon of the liver fluke Mediogonimus jourdanei (Microphalloidea: Prosthogonimidae), a parasite of Myodes glareolus (Rodentia: Cricetidae)

Spermatological characters of the liver fluke Mediogonimus jourdanei Mas-Coma et Rocamora, 1978 were studied by means of transmission and scanning electron microscopy. Spermiogenesis begins with the formation of the differentiation zone containing two centrioles associated with striated rootlets and an intercentriolar body. These two centrioles originate two free flagella that undergo a 90 degrees rotation before fusing with the median cytoplasmic process. Both nuclear and mitochondrial migrations toward the median cytoplasmic process occur before the proximodistal fusion of flagella. Finally, the constriction of the ring of arched membranes gives rise to the young spermatozoon. The mature sperm of M. jourdanei measures about 260 microm and presents two axonemes of different lengths with the typical pattern of the Trepaxonemata, two bundles of parallel cortical microtubules, one mitochondrion, a nucleus and granules of glycogen. An analysis of all the microphalloidean species studied to date emphasised some differences in certain characters found in Maritrema linguilla Jägerskiöld, 1908 and Ganeo tigrinum Mehra et Negi, 1928 in comparison to those in the remaining microphalloideans. The presence and variability of such ultrastructural characters according to family, superfamily or order have led several authors to propose their use in the analysis of trematode relationships and phylogeny. Therefore, apart from producing new data on the family Prosthogonimidae, the present study also compares the spermatological organization of M jourdanei with other available ultrastructural studies focusing on the Microphalloidea.

NADPH oxidase NOX4 mediates stellate cell activation and hepatocyte cell death during liver fibrosis development.

A role for the NADPH oxidases NOX1 and NOX2 in liver fibrosis has been proposed, but the implication of NOX4 is poorly understood yet. The aim of this work was to study the functional role of NOX4 in different cell populations implicated in liver fibrosis: hepatic stellate cells (HSC), myofibroblats (MFBs) and hepatocytes. Two different mice models that develop spontaneous fibrosis (Mdr2−/−/p19ARF−/−, Stat3Δhc/Mdr2−/−) and a model of experimental induced fibrosis (CCl4) were used. In addition, gene expression in biopsies from chronic hepatitis C virus (HCV) patients or non-fibrotic liver samples was analyzed. Results have indicated that NOX4 expression was increased in the livers of all animal models, concomitantly with fibrosis development and TGF-β pathway activation. In vitro TGF-β-treated HSC increased NOX4 expression correlating with transdifferentiation to MFBs. Knockdown experiments revealed that NOX4 downstream TGF-β is necessary for HSC activation as well as for the maintenance of the MFB phenotype. NOX4 was not necessary for TGF-β-induced epithelial-mesenchymal transition (EMT), but was required for TGF-β-induced apoptosis in hepatocytes. Finally, NOX4 expression was elevated in patients with hepatitis C virus (HCV)-derived fibrosis, increasing along the fibrosis degree. In summary, fibrosis progression both in vitro and in vivo (animal models and patients) is accompanied by increased NOX4 expression, which mediates acquisition and maintenance of the MFB phenotype, as well as TGF-β-induced death of hepatocytes.

Spermiogenesis and ultrastructure of the spermatozoon of Wardula capitellata (Digenea, Mesometridae), an intestinal parasite of the sparid teleost Sarpa salpa in Senegal

The spermiogenesis process in Wardula capitellata begins with the formation of a differentiation zone containing two centrioles associated with striated rootlets and an intercentriolar body. Each centriole develops into a free flagellum orthogonal to a median cytoplasmic process. Later these flagella rotate and become parallel to the median cytoplasmic process, which already exhibits two electron-dense areas and spinelike bodies before its proximodistal fusion with the flagella. The final stage of the spermiogenesis is characterized by the constriction of the ring of arched membranes, giving rise to the young spermatozoon, which detaches from the residual cytoplasm. The mature spermatozoon of W. capitellata presents most of the classical characters reported in digenean spermatozoa such as two axonemes of different lengths of the 9 + '1' trepaxonematan pattern, nucleus, mitochondrion, two bundles of parallel cortical microtubules and granules of glycogen. However, some peculiarities such as two lateral expansions accompanied by external ornamentation of the plasma membrane and spinelike bodies characterize the mature sperm. Moreover, a new spermatological character is described for the first time, the so-called cytoplasmic ornamented buttons.

Dificultad en la comunicación del riesgo de padecer cáncer hereditario.

Diferentes estudios han demostrado que, en ocasiones, los pacientes tienen dificultades a la hora de entender lo que el médico quiere comunicarles. El presente artículo intenta reflexionar sobre cuáles son los determinantes que pueden influir en el proceso de comunicación del riesgo en pacientes que tienen antecedentes familiares de cáncer y acuden a las Unidades de Consejo Genético en busca de asesoramiento. Existen estudios que señalan que los pacientes con antecedentes familiares de cáncer se preocupan por padecer dicha enfermedad. Sólo algunos de ellos han explorado cómo los pacientes entienden y perciben el concepto de riesgo y los posibles sesgos asociados a él. Como primeras aproximaciones, creemos que es necesario utilizar un lenguaje sencillo, claro y fácil de entender por parte de los pacientes, huyendo del lenguaje epidemiológico o médico. Del mismo modo es importante diseñar programas de formación psicoeducativos y material de soporte adecuado, así como el correcto manejo del counselling como herramienta principal de trabajo por parte de los profesionales y fomentar futuras investigaciones en este área determinada.

Personalidad premórbida y factores de riesgo en la enfermedad de Alzheimer

El presente artículo hace un repaso de los principales estudios respecto a los factores de riesgo para la enfermedad de Alzheimer, priorizando los factores psicosociales y especialmente los que se refieren a la personalidad premórbida. Entre los factores psicosociales de riesgo, aparecen como los más destacados un bajo nivel educativo y una actividad-relación social restringida. Necesidad de protección, tutelaje y dependencia de otras personas, relación social e interpersonal restringida e introversión, son los elementos de riesgo más relevantes para la personalidad premórbida. Los factores que aparecen en los estudios mencionados tienen relación con la hipótesis de trabajo de la investigación que se desarrolla actualmente, acerca de los perfiles de riesgo en la personalidad premórbida. Esta hipótesis los sitúa en el campo de lo emocional y de la relación interpersonal: fragilidad de la identidad personal y sostenimiento del yo a través de una relación simbiótica con el otro.

Factores de riesgo psicosocial y personalidad premórbida en enfermos con demencia: un estudio de casos y controles

Objetivos: Explorar los factores de riesgo no-biológicos para las demencias, plantear probables perfiles de riesgo para la enfermedad de Alzheimer y sugerir elementos para un posible desarrollo de intervenciones preventivas. Metodología: Se administró un cuestionario sobre eventos vitales y factores de personalidad, elaborado específicamente, a un grupo de enfermos (108 personas con demencia) y un grupo control (49 personas mayores sin demencia), identificando las diferencias significativas con un nivel alfa de 0.05 para todas las pruebas estadísticas. Resultados: Como probables factores de riesgo para la enfermedad de Alzheimer señalar: 1) Aspectos psíquicos: mayor número de trastornos psíquicos familiares graves y mayor respuesta psicosomática personal; 2) Aspectos familiares: mayor número de muertes precoces del padre y estilo educativo más dominante; 3) Educación y trabajo: menor nivel educativo y menor cualificación en el trabajo; 4) Eventos vitales: mayor problemática familiar; 5) Factores de personalidad según el criterio de los cinco grandes: Energía (Evitación, dependencia general y de relación e inhibición), Afabilidad (Introversión), Estabilidad emocional (Afectación, pesimismo e impulsividad), Apertura mental (Indiferencia y rigidez). Conclusiones: Destacar la relevancia del porcentaje de muertes precoces del padre y el déficit de personalidad en el factor I (Energía): Imitación, evitación y dependencia. Como posibles medidas de prevención se sugieren intervenciones que potencien la autonomía personal, la capacidad de afrontamiento y la relación social. Palabras clave: Alzheimer, Demencia, Factores de riesgo, Personalidad premórbida, Psicosocial

Spermiogenesis and ultrastructure of the spermatozoon of Wardula capitellata (Digenea, Mesometridae), an intestinal parasite of the sparid teleost Sarpa salpa in Senegal

The spermiogenesis process in Wardula capitellata begins with the formation of a differentiation zone containing two centrioles associated with striated rootlets and an intercentriolar body. Each centriole develops into a free flagellum orthogonal to a median cytoplasmic process. Later these flagella rotate and become parallel to the median cytoplasmic process, which already exhibits two electron-dense areas and spinelike bodies before its proximodistal fusion with the flagella. The final stage of the spermiogenesis is characterized by the constriction of the ring of arched membranes, giving rise to the young spermatozoon, which detaches from the residual cytoplasm. The mature spermatozoon of W. capitellata presents most of the classical characters reported in digenean spermatozoa such as two axonemes of different lengths of the 9 + '1' trepaxonematan pattern, nucleus, mitochondrion, two bundles of parallel cortical microtubules and granules of glycogen. However, some peculiarities such as two lateral expansions accompanied by external ornamentation of the plasma membrane and spinelike bodies characterize the mature sperm. Moreover, a new spermatological character is described for the first time, the so-called cytoplasmic ornamented buttons.

GSK3 is involved in the relief of mitochondria pausing in a tau-dependent manner.

Mitochondrial trafficking deficits have been implicated in the pathogenesis of several neurological diseases, including Alzheimer's disease (AD). The Ser/Thre kinase GSK3β is believed to play a fundamental role in AD pathogenesis. Given that GSK3β substrates include Tau protein, here we studied the impact of GSK3β on mitochondrial trafficking and its dependence on Tau protein. Overexpression of GSK3β in neurons resulted in an increase in motile mitochondria, whereas a decrease in the activity of this kinase produced an increase in mitochondria pausing. These effects were dependent on Tau proteins, as Tau (−/−) neurons did not respond to distinct GSK3β levels. Furthermore, differences in GSK3β expression did not affect other parameters like mitochondria velocity or mitochondria run length. We conclude that GSK3B activity regulates mitochondrial axonal trafficking largely in a Tau-dependent manner.

Integrin-Specific Mechanoresponses to Compression and Extension Probed by Cylindrical Flat-Ended AFM Tips in Lung Cells

Cells from lung and other tissues are subjected to forces of opposing directions that are largely transmitted through integrin-mediated adhesions. How cells respond to force bidirectionality remains ill defined. To address this question, we nanofabricated flat-ended cylindrical Atomic Force Microscopy (AFM) tips with ~1 µm2 cross-section area. Tips were uncoated or coated with either integrin-specific (RGD) or non-specific (RGE/BSA) molecules, brought into contact with lung epithelial cells or fibroblasts for 30 s to form focal adhesion precursors, and used to probe cell resistance to deformation in compression and extension. We found that cell resistance to compression was globally higher than to extension regardless of the tip coating. In contrast, both tip-cell adhesion strength and resistance to compression and extension were the highest when probed at integrin-specific adhesions. These integrin-specific mechanoresponses required an intact actin cytoskeleton, and were dependent on tyrosine phosphatases and Ca2+ signaling. Cell asymmetric mechanoresponse to compression and extension remained after 5 minutes of tip-cell adhesion, revealing that asymmetric resistance to force directionality is an intrinsic property of lung cells, as in most soft tissues. Our findings provide new insights on how lung cells probe the mechanochemical properties of the microenvironment, an important process for migration, repair and tissue homeostasis.