Total synthesis of entecavir

Entecavir (BMS-200475) was synthesized from 4-trimethylsilyl-3-butyn-2-one and acrolein. The key features of its preparation are: (i) a stereoselective boron-aldol reaction to afford the acyclic carbon skeleton of the methylenecylopentane moiety; (ii) its cyclization by a Cp2TiCl-catalyzed intramolecular radical addition of an epoxide to an alkyne; and (iii) the coupling with a purine derivative by a Mitsunobu reaction.

Immunologic work up of subjects who didn't respond appropriately to a rabies post exposure prophylaxis

Background New recommendations for rabies postexposure prophylaxis (rPEP) were published by the Centers for Disease Control and Prevention and the World Health Organization in 2010. In view of these new recommendations, the adequacy of rPEP among patients consulting the travel clinic of the University Hospital of Lausanne has been investigated and 6,8% of patients have been identified as non-responders with the new rPEP regimen. In this study we have selected the non-responders for a complete immunologic work up. Method Clinical and paraclinical immunologic investigations have been done to the non- responders patients. Those investigations have been conducted to look for an increased susceptibility to infections and an immunodeficiency. The investigations included a clinical evaluation, a full blood count, measurement of the immunoglobulin levels, a numeration of the subpopulations of the lymphocytes, a HIV test and an evaluation of the humoral response to tetanus, pneumococcal, and hepatitis B vaccinations. A lymphocyte proliferation assay with rabies antigen was performed to assess the cellular immune response. Results 9 subjects with rabies antibody titers ≤0,5 IU/ml after an rPEP with 4 doses were included in this study (=non-responders). 8/9 of these non-responders had an unremarkable medical history. 9/9 of them had normal paraclinical tests that did not suggest an immunodeficiency. The results of the lymphocyte proliferation assay with rabies antigen showed a significant correlation between the level of the humoral and cellular response. Conclusion These results suggest that a 4 dose intramuscular rPEP elicits in some patients a relatively poor humoral and cellular response, even in the absence of any immunosuppression. A serology on day 21 of the rPEP seems therefore useful to identify the patients who don't respond appropriately. Those non-responders should receive additional doses until they reach an antibody titer above 0.5 IU/ml.

Manejo terapêutico do hepatocarcinoma fibrolamelar

Fibrolamellar carcinoma of the liver is a distinct variant of hepatocellular carcinoma characterized by the lack of association with cirrhosis or other underlying liver diseases, as hepatitis B virus. The serum alpha-fetoprotein level is often not elevated, occuring typically in young patients. Distinction from conventional hepatocellular carcinoma is of clinical significance, because prognosis is far better due to higher ressecability and more indolent growth. We describe a case of a 26-year-old woman free of other liver diseases presenting with a large abdominal palpable mass. After ressection by vascular exclusion technique, the pathologic examination revealed fibrolamellar carcinoma. The former should not be confused with the hepatocellular carcinoma, since it is related with a more favorable prognosis.

Physical Attractiveness as a Signal of Biological Quality

It has been commonly thought that standards of beauty are arbitrary cultural conventions that vary between cultures and time. In my thesis I found that it is not so. Instead, I show that attractiveness and preferred traits serve as cues to phenotypic qualities that provide selective benefits for those who choose their mates based on these criteria. In the first study I show that attractive men have a stronger antibody response to the hepatitis b vaccine and higher levels of testosterone than their less attractive peers. Men with low levels of testosterone also tend to have high levels of the stress hormone cortisol, suggesting that their immune responses may have been inhibited by stress hormones. Thus, facial attractiveness may serve as an honest cue of the strength of immune defence in men. In the second study, I show that the attractiveness of the male body is also a cue of better immunity. In addition, I show that adiposity, both in men’s faces and bodies, is a better cue of the strength of immunity and attractiveness than of masculinity. In the third study, I test the preferences of women from 13 countries for facial cues of testosterone and cortisol. I show that there is cross-cultural variation in women’s preference for cues of testosterone and cortisol in male faces. I found a relationship between the health of a nation and women’s preferences for cues of testosterone in the male face and the interaction between preferences for cues of testosterone and cortisol. I show also a relationship between preferences for cues of testosterone and a societal-level measure of parasite stress. Thus, it seems that societal-level ecological factors influence the relative value of traits as revealed by combinations of testosterone and stress hormones. In the fourth study, I show that women’s immune responsiveness (amount of antibodies produced) does not predict facial attractiveness. Instead, plasma cortisol level is negatively associated with attractiveness, indicating that stressed women look less attractive. Fat percentage is curvilinearly associated with facial attractiveness, indicating that being too thin or too fat reduces attractiveness. This study suggests that in contrast to men, facial attractiveness in women does not indicate the strength of immune defence, but is associated with other aspects of long-term health and fertility: circulating levels of the stress hormone cortisol and the percentage of body fat. In the last study I show that the attractiveness of men’s body odor is positively correlated with stress hormone levels, suggesting also that the attractiveness of body odors may signal the phenotypic quality of males to females. However, the attractiveness of men’s body odor was not associated with testosterone levels. My thesis suggests that the standard of beauty is not in the eye of the beholder. Instead, our standard of beauty is hardwired in our brains by genes that are selected by natural selection and also influenced by current environmental conditions.

Prevalence and risk factors for HBV, HCV and HDV infections among injecting drug users from Rio de Janeiro, Brazil

Viral hepatitis constitutes a major health issue, with high prevalence among injecting drug users (IDUs). The present study assessed the prevalence and risk determinants for hepatitis B, C and D viruses (HBV, HCV and HDV) infections among 102 IDUs from Rio de Janeiro, Brazil. Serological markers and HCV-RNA were detected by enzyme immunoassay and nested PCR, respectively. HCV genotyping was determined by restriction fragment length polymorphism analysis (RFLP). HBsAg, anti-HBc and anti-HBs were found in 7.8, 55.8 and 24.7% of IDUs, respectively. In the final logistic regression, HBV infection was independently associated with male homosexual intercourse within the last 5 years (odds ratio (OR) 3.1; 95% confidence interval (CI) 1.1-8.8). No subject presented anti-delta (anti-HD). Anti-HCV was detected in 69.6% of subjects, and was found to be independently associated with needle sharing in the last 6 months (OR 3.4; 95% CI 1.3-9.2) and with longer duration of iv drug use (OR 3.1; 95% CI 1.1-8.7). These data demonstrate that this population is at high risk for both HBV and HCV infection. Among IDUs from Rio de Janeiro, unprotected sexual intercourse seems to be more closely associated with HBV infection, whereas HCV is positively correlated with high risk injecting behavior. Comprehensive public health interventions targeting this population and their sexual partners must be encouraged.

HBV vaccination of HCV-infected patients with occult HBV infection and anti-HBc-positive blood donors

Anti-HBc positivity is a frequent cause of donation rejection at blood banks. Hepatitis B virus (HBV) infection may also occur in HBsAg-negative patients, a situation denoted occult infection. Similarly, very low levels of HBV-DNA have also been found in the sera of patients with chronic hepatitis C virus (HCV) infection, even in the absence of serum HBsAg. Initially we searched for HBV-DNA in serum of 100 blood donors and 50 HCV-infected patients who were HBsAg negative/anti-HBc positive by nested-PCR and by an HBV monitor commercial test for HBV-DNA. Anti-HBs seroconversion rates were measured in 100 blood donors and in 22 patients with chronic HCV infection after HBV vaccination to determine if the HBV vaccination could eliminate an occult HBV infection in these individuals. Occult HBV infection was detected in proportionally fewer blood donors (6/100 = 6%) than chronic hepatitis C patients (12/50 = 24%) (P < 0.05). We noted seroconversion in 6/6 (100%) HBV-DNA(+) and in 84/94 (89.4%) HBV-DNA(-) blood donors (P > 0.05). All subjects who were HBV-DNA(+) before the first dose of HBV vaccine (D1), became HBV-DNA(-) after D1, D2, and D3. Among 22 HCV-positive patients, 10 HBV-DNA(+) and 12 HBV-DNA(-), seroconversion was observed in 9/10 (90%) HBV-DNA(+) and in 9/12 (75%) HBV-DNA(-) subjects (P > 0.05). The disappearance of HBV-DNA in the majority of vaccinated patients suggests that residual HBV can be eliminated in patients with occult infection.

Does hepatocellular carcinoma in non-alcoholic steatohepatitis exist in cirrhotic and non-cirrhotic patients?

Non-alcoholic steatohepatitis (NASH) has been associated with hepatocellular carcinoma (HCC) often arising in histologically advanced disease when steatohepatitis is not active (cryptogenic cirrhosis). Our objective was to characterize patients with HCC and active, histologically defined steatohepatitis. Among 394 patients with HCC detected by ultrasound imaging over 8 years and staged by the Barcelona Clinic Liver Cancer (BCLC) criteria, we identified 7 cases (1.7%) with HCC occurring in the setting of active biopsy-proven NASH. All were negative for other liver diseases such as hepatitis C, hepatitis B, autoimmune hepatitis, Wilson disease, and hemochromatosis. The patients (4 males and 3 females, age 63 ± 13 years) were either overweight (4) or obese (3); 57% were diabetic and 28.5% had dyslipidemia. Cirrhosis was present in 6 of 7 patients, but 1 patient had well-differentiated HCC in the setting of NASH without cirrhosis (fibrosis stage 1) based on repeated liver biopsies, the absence of portal hypertension by clinical and radiographic evaluations and by direct surgical inspection. Among the cirrhotic patients, 71.4% were clinically staged as Child A and 14.2% as Child B. Tumor size ranged from 1.0 to 5.2 cm and 5 of 7 patients were classified as early stage; 46% of all nodules were hyper-echoic and 57% were <3 cm. HCC was well differentiated in 1/6 and moderately differentiated in 5/6. Alpha-fetoprotein was <100 ng/mL in all patients. HCC in patients with active steatohepatitis is often multifocal, may precede clinically advanced disease and occurs without diagnostic levels of alpha-fetoprotein. Importantly, HCC may occur in NASH in the absence of cirrhosis. More aggressive screening of NASH patients may be warranted.

Differential gene expression profiles of hepatocellular carcinomas associated or not with viral infection

Chronic hepatitis B (HBV) and C (HCV) virus infections are the most important factors associated with hepatocellular carcinoma (HCC), but tumor prognosis remains poor due to the lack of diagnostic biomarkers. In order to identify novel diagnostic markers and therapeutic targets, the gene expression profile associated with viral and non-viral HCC was assessed in 9 tumor samples by oligo-microarrays. The differentially expressed genes were examined using a z-score and KEGG pathway for the search of ontological biological processes. We selected a non-redundant set of 15 genes with the lowest P value for clustering samples into three groups using the non-supervised algorithm k-means. Fisher’s linear discriminant analysis was then applied in an exhaustive search of trios of genes that could be used to build classifiers for class distinction. Different transcriptional levels of genes were identified in HCC of different etiologies and from different HCC samples. When comparing HBV-HCC vs HCV-HCC, HBV-HCC/HCV-HCC vs non-viral (NV)-HCC, HBC-HCC vs NV-HCC, and HCV-HCC vs NV-HCC of the 58 non-redundant differentially expressed genes, only 6 genes (IKBKβ, CREBBP, WNT10B, PRDX6, ITGAV, and IFNAR1) were found to be associated with hepatic carcinogenesis. By combining trios, classifiers could be generated, which correctly classified 100% of the samples. This expression profiling may provide a useful tool for research into the pathophysiology of HCC. A detailed understanding of how these distinct genes are involved in molecular pathways is of fundamental importance to the development of effective HCC chemoprevention and treatment.

Evaluación a la implementación de un modelo de atención para riesgo biológico en una administradora de riesgos profesionales en Colombia en el periodo de enero a octubre de 2009

Debido al alto riesgo que presentan los trabajadores que están expuestos a adquirir enfermedades infecto contagiosas en nuestro medio, se determina la necesidad de evaluar el modelo administrativo de atención para riesgo biológico que se implemento en una Administradora de Riesgos Profesionales (ARP) en Colombia, con el fin de establecer medidas para el manejo pertinente y oportuno del evento, así como el seguimiento de los trabajadores, buscando disminuir la incidencia y prevalencia de enfermedades de alto costo como VIH, Hepatitis B y Hepatitis C, y de esta manera generar un impacto positivo en la atención y administración de los recursos. Para ello se realiza un análisis de datos de la población afiliada a la ARP que reportaron un accidente de riesgo biológico durante el 2009, y se realizan comparaciones de variables entre los casos positivos del primer período, comprendido entre los meses de enero y junio de 2009, y los que se presentaron posterior a la implementación del nuevo modelo de atención, período comprendido desde julio hasta octubre del 2009. Se encontró que el género masculino fue el más afectado, los departamentos con mayor reporte de casos fueron Atlántico y Bolívar, el sector económico más afectado fue el de recolección de basura y las lesiones fueron provocadas en su mayoría por objeto cortopunzantes. Con el nuevo modelo se evidenció un cambio positivo en términos de pertinencia, oportunidad de aviso y calificación del evento, en cuanto a costos se encontró que, por el momento, los períodos no son comparables por la variabilidad en tiempo, sin embargo, se proyecta un cambio positivo, no solo por los costos cuantificables, sino por los costos indirectos.

Molecular mechanism involved in the mutagenicity induced by Aflatoxin B1

The aflatoxin B1 (AFB1) is a mycotoxin that has been identified as the most potent hepatocarcinogen. The metabolite resulting from detoxification process of AFB1 in liver, has the ability to react with the genomic DNA, generating AFB1-DNA adducts; during DNA replication process, this adduct induced the G:C→T:A transversion. Polymorphism in genes encoding for enzymes involved in the activation and detoxification of AFB1 and DNA repair enzymes has been associated with the risk of hepatocellular carcinoma (HCC) development. Additionally, in populations of high exposure to aflatoxin and high prevalence of hepatitis B virus (HBV) infection, has been demonstrated a synergism between these two risk factors for the development of HCC.

Análisis económico de las vacunas 10-valente y 13-valente contra neumococo: revisión sistemática

Introducción: Las vacunas clásicamente han representado un método económico y eficaz para el control y prevención de múltiples enfermedades infecciosas. En los últimos años se han introducido nuevas vacunas contra neumococo a precios elevados, y los diferentes análisis económicos a nivel mundial de estas vacunas no muestran tendencias. El objetivo de este trabajo era resumir la evidencia existente a través de los diferentes estudios económicos evaluando las dos vacunas de segunda generación contra neumococo en la población a riesgo. Metodología: En este trabajo se realizo una revisión sistemática de la literatura en 8 bases de datos localizadas en diferentes partes del mundo y también que tuvieran literatura gris. Los artículos fueron inicialmente evaluados acorde a su titulo y resumen, posteriormente los elegidos se analizaron en su totalidad. Resultados: Se encontraron 404 artículos, de los cuales 20 fueron incluidos en el análisis final. Se encontró que la mayoría de los estudios se realizaron en áreas donde la enfermedad tiene una carga baja, como es Norte América y Europa, mientras que en los lugares del mundo donde la carga es mas alta, se realizaron pocos estudios. De igual manera se observo que la mayoría de los estudios mostraron por los menos ser costo efectivos respecto a la no vacunación, y en su totalidad las dos vacunas de segunda generación mostraron costo efectividad respecto a la vacunación con PCV-7. Los resultados de los estudios son muy heterogéneos, hasta dentro del mismo país, señalando la necesidad de guías para la conducción de este tipo de estudios. De igual manera, la mayoría de los estudios fueron financiados por farmacéuticas, mientras en un numero muy reducido por entes gubernamentales. Conclusiones: La mayoría de los estudios económicos sobre las vacunas de segunda generación contra neumococo han sido realizados en países con un alto índice de desarrollo económico y patrocinados por farmacéuticas. Dado que la mayoría de la carga de la enfermedad se encuentran en regiones con un menor nivel de desarrollo económico se deberían realizar mas en estas zonas. De igual manera, al ser la vacunación un asunto de salud publica y con un importante impacto económico los gobiernos deberían estar mas involucrados en los mismos.

Diagnóstico de bioseguridad y elaboración de protocolo para el personal de salud del dispensario médico de la fuerza Aérea Colombiana (A.M.E.F.A.) en 1999

La toma de conciencia por parte del personal de salud a nivel mundial a cerca del reporte de los Accidentes de trabajo con factor de riesgo biológico, ha permitido que las estadísticas mundiales cada vez sean más reales pero a la vez más alarmantes.

Evaluación de la aplicación de los programas de bioseguridad en los estudiantes de Ciencias básicas de la Salud de la Universidad del Rosario de Bogotá

A raíz de la aparición y desmesurado aumento de enfermedades infectocontagiosas con amenaza para la salud integral del personal involucrado en la atención de pacientes tales como la hepatitis B y el síndrome de inmunodeficiencia adquirida, la comunid

Influencia del bajo peso al nacer en el cumplimiento del esquema de vacunación en Colombia

INTRODUCCION. En Colombia y a nivel mundial la vacunación es una estrategia que ha reducido la mortalidad infantil, sin embargo existen bajas coberturas en algunas zonas del país, dentro de las causas de la no vacunación se encuentra el bajo peso al nacer, tema de gran importancia y poco estudiado, encontrándose como una causa controlable y que permitiría a la población acceder a la protección frente a enfermedades inmunoprevenibles. MATERIALES Y METODOS. Se realizó un estudio de tipo observacional de corte trasversal, la muestra fue tomada de la ENDS realizada por Profamilia en el año 2010, se tomó el número total de los encuestados que cumplían con los criterios de inclusión, en total fueron 9694 registros a los que se les realizo; análisis descriptivo, bivariado y multivariado. RESULTADOS. Los niños con bajo peso al nacer tienen menor probabilidad de estar vacunados con el esquema completo con respecto a los niños con peso normal, OR 0762 (IC 95% 0,650; 0,895), se observó que las vacunas en forma individual tienen un comportamiento similar al esquema completo, específicamente en la aplicación en el tiempo indicado para su aplicación, exceptuando triple viral donde no se encontró asociación. CONCLUSION. El bajo peso es un factor determinante en la vacunación a tiempo de los menores y del cumplimiento posterior del esquema, se encontraron variables asociadas al no cumplimiento como el lugar del parto, el índice de pobreza y pertenecer a la etnia afrodescendiente.

Riesgo de accidentes biológicos en estudiantes de la salud: revisión de la literatura en los últimos 14 años.

Introducción: Todos los trabajadores del área de la salud están en riesgo de padecer un accidente biológico. No obstante los estudiantes de estas aéreas, pueden presentar más riesgo porque apenas están en formación y no tienen la práctica o experiencia suficiente. Existen varios artículos que han estudiado la incidencia y prevalencia de accidentes biológicos en los trabajadores del área de la salud, Sin embargo, sobre esta problemática de la población estudiantil del área de la salud, se encuentra menos literatura. Por lo tanto con esta revisión sistemática se busca analizar y actualizar este tema. Métodos: Se realizó una revisión de la literatura científica de artículos publicados en los últimos 14 años, en relación con la prevalencia de accidentes biológicos en estudiantes de medicina, odontología, enfermería y residentes del área de la salud a nivel mundial. Se llevó a cabo la búsqueda en la base de datos de Pubmed, encontrando un total de 100 artículos, escritos en inglés, francés, español o portugués. Resultados: Las prevalencias encontradas sobre accidentes biológicos en estudiantes fueron las siguientes: en países europeos a nivel de enfermería los valores oscilan entre 10.2 % a 32%, en medicina fueron del 16%-58.8%, y en odontología del 21 %. En países asiáticos, se encontró que en enfermería el porcentaje varía de 49%-96 %, en medicina van del 35% -68%, y en odontología varia de 68.a 75.4%. En Norte América, en medicina las cifras fluctúan alrededor del 11-72.7 % y en odontología giran alrededor del 19.1%. Finalmente respecto a Suramérica la prevalencia fue de 31.2 a 46.7% en medicina, y del 40% en enfermería. Conclusiones: Por lo anterior se pudo concluir que, la prevalencia de accidentes biológicos en los estudiantes del área de la salud es elevada y varía según el continente en el que se encuentren.