Preferential association of hepatitis C virus with CD19+ B cells is mediated by complement system

Extrahepatic disease manifestations are common in chronic hepatitis C virus (HCV) infection. The mechanism of HCV-related lymphoproliferative disorders is not fully understood. Recent studies have found that HCV in peripheral blood mononuclear cells (PBMCs) from chronically infected patients is mainly associated with CD19+ B cells. To further elucidate this preferential association of HCV with B cells, we used in vitro cultured virus and uninfected PBMCs from healthy blood donors to investigate the necessary serum components that activate the binding of HCV to B cells. First, we found that the active serum components were present not only in HCV carriers, but also in HCV recovered patients and HCV negative healthy blood donors and that the serum components were heat labile. Second, the preferential binding activity of HCV to B cells could be blocked by anti-complement C3 antibodies. In experiments with complement-depleted serum and purified complement proteins, we demonstrated that complement proteins C1, C2, and C3 were required to activate such binding activity. Complement protein C4 was partially involved in this process. Third, using antibodies against cell surface markers, we showed that the binding complex mainly involved CD21 (complement receptor 2), CD19, CD20, and CD81; CD35 (complement receptor 1) was involved but had lower binding activity. Fourth, both anti-CD21 and anti-CD35 antibodies could block the binding of patient-derived HCV to B cells. Fifth, complement also mediated HCV binding to Raji cells, a cultured B cell line derived from Burkitt´s lymphoma.CONCLUSION:In chronic HCV infection, the preferential association of HCV with B cells is mediated by the complement system, mainly through complement receptor 2 (CD21), in conjunction with the CD19 and CD81 complex. This article is protected by copyright. All rights reserved.Fil: Wang, Richard. National Institutes of Health; Estados UnidosFil: Baré, Patricia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina. National Institutes of Health; Estados UnidosFil: De Giorgi, Valeria. National Institutes of Health; Estados UnidosFil: Matsuura, Kentaro. Nagoya City University Graduate School of Medicine; Japón. National Institutes of Health; Estados UnidosFil: Salam, Kazi Abdus. National Institutes of Health; Estados Unidos. University of Rajshahi; IndiaFil: Grandinetti, Teresa. National Institutes of Health; Estados UnidosFil: Schechterly, Cathy. National Institutes of Health; Estados UnidosFil: Alter, Harvey J.. National Institutes of Health; Estados Unido

An assessment of existing models for individualized breast cancer risk estimation in a screening program in Spain

Background: The aim of this study was to evaluate the calibration and discriminatory power of three predictive models of breast cancer risk. Methods: We included 13,760 women who were first-time participants in the Sabadell-Cerdanyola Breast Cancer Screening Program, in Catalonia, Spain. Projections of risk were obtained at three and five years for invasive cancer using the Gail, Chen and Barlow models. Incidence and mortality data were obtained from the Catalan registries. The calibration and discrimination of the models were assessed using the Hosmer-Lemeshow C statistic, the area under the receiver operating characteristic curve (AUC) and the Harrell’s C statistic. Results: The Gail and Chen models showed good calibration while the Barlow model overestimated the number of cases: the ratio between estimated and observed values at 5 years ranged from 0.86 to 1.55 for the first two models and from 1.82 to 3.44 for the Barlow model. The 5-year projection for the Chen and Barlow models had the highest discrimination, with an AUC around 0.58. The Harrell’s C statistic showed very similar values in the 5-year projection for each of the models. Although they passed the calibration test, the Gail and Chen models overestimated the number of cases in some breast density categories. Conclusions: These models cannot be used as a measure of individual risk in early detection programs to customize screening strategies. The inclusion of longitudinal measures of breast density or other risk factors in joint models of survival and longitudinal data may be a step towards personalized early detection of BC.This study was funded by grant PS09/01340 and The Spanish Network on Chronic Diseases REDISSEC (RD12/0001/0007) from the Health Research Fund (Fondo de Investigación Sanitaria) of the Spanish Ministry of Health

In-hospital mortality after stomach cancer surgery in Spain and relationship with hospital volume of interventions

<p>Abstract</p> <p>Background</p> <p>There is no consensus about the possible relation between in-hospital mortality in surgery for gastric cancer and the hospital annual volume of interventions. The objectives were to identify factors associated to greater in-hospital mortality for surgery in gastric cancer and to analyze the possible independent relation between hospital annual volume and in-hospital mortality.</p> <p>Methods</p> <p>We performed a retrospective cohort study of all patients discharged after surgery for stomach cancer during 2001–2002 in four regions of Spain using the Minimum Basic Data Set for Hospital Discharges. The overall and specific in-hospital mortality rates were estimated according to patient and hospital characteristics. We adjusted a logistic regression model in order to calculate the in-hospital mortality according to hospital volume.</p> <p>Results</p> <p>There were 3241 discharges in 144 hospitals. In-hospital mortality was 10.3% (95% CI 9.3–11.4). A statistically significant relation was observed among age, type of admission, volume, and mortality, as well as diverse secondary diagnoses or the type of intervention. Hospital annual volume was associated to Charlson score, type of admission, region, length of stay and number of secondary diagnoses registered at discharge. In the adjusted model, increased age and urgent admission were associated to increased in-hospital mortality. Likewise, partial gastrectomy (Billroth I and II) and simple excision of lymphatic structure were associated with a lower probability of in-hospital mortality. No independent association was found between hospital volume and in-hospital mortality</p> <p>Conclusion</p> <p>Despite the limitations of our study, our results corroborate the existence of patient, clinical, and intervention factors associated to greater hospital mortality, although we found no clear association between the volume of cases treated at a centre and hospital mortality.</p

Effects of Anacetrapib in Patients with Atherosclerotic Vascular Disease

BACKGROUND: Patients with atherosclerotic vascular disease remain at high risk for cardiovascular events despite effective statin-based treatment of low-density lipoprotein (LDL) cholesterol levels. The inhibition of cholesteryl ester transfer protein (CETP) by anacetrapib reduces LDL cholesterol levels and increases high-density lipoprotein (HDL) cholesterol levels. However, trials of other CETP inhibitors have shown neutral or adverse effects on cardiovascular outcomes. METHODS: We conducted a randomized, double-blind, placebo-controlled trial involving 30,449 adults with atherosclerotic vascular disease who were receiving intensive atorvastatin therapy and who had a mean LDL cholesterol level of 61 mg per deciliter (1.58 mmol per liter), a mean non-HDL cholesterol level of 92 mg per deciliter (2.38 mmol per liter), and a mean HDL cholesterol level of 40 mg per deciliter (1.03 mmol per liter). The patients were assigned to receive either 100 mg of anacetrapib once daily (15,225 patients) or matching placebo (15,224 patients). The primary outcome was the first major coronary event, a composite of coronary death, myocardial infarction, or coronary revascularization. RESULTS: During the median follow-up period of 4.1 years, the primary outcome occurred in significantly fewer patients in the anacetrapib group than in the placebo group (1640 of 15,225 patients [10.8%] vs. 1803 of 15,224 patients [11.8%]; rate ratio, 0.91; 95% confidence interval, 0.85 to 0.97; P=0.004). The relative difference in risk was similar across multiple prespecified subgroups. At the trial midpoint, the mean level of HDL cholesterol was higher by 43 mg per deciliter (1.12 mmol per liter) in the anacetrapib group than in the placebo group (a relative difference of 104%), and the mean level of non-HDL cholesterol was lower by 17 mg per deciliter (0.44 mmol per liter), a relative difference of -18%. There were no significant between-group differences in the risk of death, cancer, or other serious adverse events. CONCLUSIONS: Among patients with atherosclerotic vascular disease who were receiving intensive statin therapy, the use of anacetrapib resulted in a lower incidence of major coronary events than the use of placebo. (Funded by Merck and others; Current Controlled Trials number, ISRCTN48678192 ; ClinicalTrials.gov number, NCT01252953 ; and EudraCT number, 2010-023467-18 .)

AVRAMI EQUATION INADEQUACY FOR MODELING THE HDPE ISOTHERMAL CRYSTALLIZATION RATES / Fallas de la ecuación de Avrami en el modelado de velocidades de cristalización isotérmica de Pead

The temperature dependence of the crystallization rate of polymers has been related to the classical nucleation and growthprocess. At temperatures slightly below the melting point, the controlling step is the nucleation process while, with largeundercoolings, the rate control shifts toward transport restrictions. With increasing degrees of crystallinity, a shift of thecontrolling step from nucleation towards transport resistances was also observed, which is frequently associated with asecondary crystallization process. This behavior has also been explained in terms of a separate geometric spreading of thesemi-crystalline superstructure followed by an increasing local crystallinity. The Avrami equation is known to be a goodmodel for the first process but rapidly fails with the appearance of a secondary crystallization process and the developmentof transport resistances. In this work, results of the crystallization rates of HDPE from 118 to 115&deg;C are presented andanalyzed of the light of the Avrami equation. It was observed that this model begins to fail with increasing degrees ofundercooling and crystallinity. The degree of fitting of the Avrami model, was analyzed processing different ranges ofrelative crystallinity at four different temperatures, and results are interpreted in terms of the possible rate controllingprocess. With the Avrami equation a good data fitting at 118&ordm;C was obtained, but it was observed that for increasingdegrees of undercooling and increasing degrees of crystallinity the degree of fitting deteriorates. It was found thatrestricting the use of the Avrami equation within the region of experimental data where it is more likely that the nucleationand the growing process of the semicrystalline superstructure are the controlling steps, very consistent values for Avramiparameters were obtained. Simulation results suggest the presence of a secondary crystallization process for which theVelisaris-Seferis parallel model was found satisfactory.RESUMENLa dependencia de la velocidad de cristalizaci&oacute;n de pol&iacute;meros ha sido relacionada con los procesos cl&aacute;sicos de nucleaci&oacute;ny crecimiento. A temperaturas ligeramente inferiores a la temperatura de fusi&oacute;n, la etapa controlante es el proceso denucleaci&oacute;n mientras que con un subenfriamento grande, el control es transferido hacia restricciones de transporte. Congrados de cristalinidad creciente tambi&eacute;n se observa un cambio de etapa controlante, entre el proceso de nucleaci&oacute;n alcomienzo, hacia los procesos de transferencia, lo cual frecuentemente se asocia con la aparici&oacute;n de un mecanismo secundariode cristalizaci&oacute;n. Este comportamiento tambi&eacute;n ha sido explicado en funci&oacute;n de un crecimiento geom&eacute;trico de superestructurascristalinas seguido de un aumento local de crystalinidad. Se sabe que el modelo de Avrami es un buen modelo para el primerproceso pero que r&aacute;pidamente falla con la aparici&oacute;n del proceso secundario de cristalizaci&oacute;n y el desarrollo de resistenciascrecientes de transporte. En este trabajo se presentan y analizan resultados de velocidades de cristalizaci&oacute;n del PEADdesde 118 hasta 115&ordm;C usando la ecuaci&oacute;n de avrami. El grado de ajuste logrado es analizado procesando diferentes rangosde cristalinidad relativa para cuatro niveles de temperatura, y los resultados se interpretan en t&eacute;rminos de las etapascontrolantes. A 118&ordm;C el modelo de Avrami ajusta satisfactoriamente los datos experimentales, pero se observa que congrados de subenfriamiento crecientes la calidad del ajuste se deteriora a medida que el grado de cristalinidad aumenta. Seencontr&oacute; que restringiendo el uso de la ecuaci&oacute;n de Avrami a los datos dentro de la regi&oacute;n donde el proceso de nucleaci&oacute;n,y de crecimiento de la superestructura semicristalina son las etapas controlantes, se obtiene valores consistentes para lospar&aacute;metros. Los resultados de simulaci&oacute;n sugieren la aparici&oacute;n de un mecanismo secundario de cristalizaci&oacute;n para el cualse encontr&oacute; satisfactorio el modelo de Velisaris-Seferis.Palabras clave: PEAD, cristalizaci&oacute;n, Modelo de Avrami, ajuste de datos, Modelo de Velisaris-Seferis

Occurrence and diversity of free-living protozoa on butterhead lettuce.

&lt;p&gt;The occurrence and diversity of free-living protozoa (FLP) on butterhead lettuce (Lactuca sativa L.) was investigated using four different sampling techniques (washing, swabbing, homogenization, and excising). FLP were recovered from all leaf samples (n=64), and cultures were FLP-positive after 1 week. Identification of FLP was performed by light microscopy and sequencing of denaturing gradient gel electrophoresis (DGGE)-separated 18S rRNA gene fragments. Bodo saltans, Spumella (-like) spp. and Cercozoa were the most common heterotrophic nanoflagellates. Amoebae belonged mainly to the Vannellida and Tubulinida. Colpoda steinii and Cyclidium glaucoma were the most common ciliates. The total number of FLP on middle leaves estimated by the Most Probable Number method ranged from 9.3 × 10(2)MPN/g to 2.4 × 10(5)MPN/g leaf, with flagellates (92 MPN/g to 2.4 ×10(5)MPN/g) being more abundant than amoebae (&lt;3 MPN/g to 9.3 × 10(3)MPN/g) and ciliates (&lt;3 MPN/g to 9.3 × 10(2)MPN/g). Washing or rinsing leaves followed by spin-drying in a household salad spinner reduced the protozoan number with maximum one log unit. Our survey shows that FLP on lettuce leaves are a common and diverse but largely unexplored group of microorganisms.&lt;/p&gt;</p