Elicitation and enhancement of T and B cell responses

The Major histocompatibility complex class I (MHC-I) has been characterized in such great depth that a number of its key properties are well understood and part of its behavior can even be predicted. It is therefore intriguing that the impact of small epitope modifications on immunogenicity and the elicitation of T-cell repertoires remain often unpredictable and full of surprises. Substitution of the secondary anchor residue at peptide position 3 from a serine to a proline (p3P) significantly increased the stabilization capacity and immunogenicity of the melanoma-associated H-2Db (Db)-restricted epitope gp100 (EGS). Despite this strong enhancement the conformation of the modified epitope (EGP) was not altered and vaccination with EGP generated T-cell responses that recognized cells expressing EGS with high functional avidity. Based on these promising results, the p3P modification was applied to the highly immunodominant Lymphocytic Choriomeningitis Virus epitope gp33 and the associated escape variants Y4F and Y4A. As for gp100, p3P was found to increase the MHC stabilization capacity and immunogenicity of the modified epitopes V3P, PA and PF, while not altering their structures. Accordingly, T-cell responses were cross-reactive between native and p3P enhanced epitopes and, when used for vaccination of C57BL/6 mice, PF elicited a focused T-cell response against Db/Y4F. In parallel, surface plasmon resonance (SPR) measurements revealed that p3P did not only enhance MHC stabilization capacity but also directly increased the affinity of the cognate T-cell receptors (TCRs). To fully characterize the molecular details underlying these two enhancing effects, the thermostability, TCR binding and molecular dynamics (MD) of Db/EGP were measured in comparison with Db/EGS. Furthermore, the contribution of Y159, a highly conserved tyrosine that is structurally juxtaposed to p3P, was assessed using a set of soluble Db-Y159 variants. In conclusion, these measurements clearly demonstrated that specific interactions of p3P with the aromatic ring of Y159 are responsible for the significantly increased MHC stabilization capacity. Surprisingly, the enhanced TCR binding was found to be entirely independent of Y159, suggesting a direct contribution of the buried proline residue to TCR binding. These findings underscore the potential to enhance MHC-I-restricted epitopes at secondary anchor residues, while specifically indicating that proline can directly increase TCR affinity, which could not have been anticipated from our current understanding of the factors shaping TCR recognition. Not entirely different from T-cell elicitation, the induction of broadly neutralizing antibodies against the Human Immunodeficiency Virus type 1 (HIV-1) is to date still an elusive goal despite extensive characterization of the respective antibody-epitope interactions. One of the central challenges is that the virus is highly adapted to immune pressure and the most relevant antibody epitopes on the HIV envelope proteins (Env) are the least immunogenic. Therefore, a highly heterologous prime-boost vaccination strategy was designed in which priming of rabbits with HIV-1 env plasmids was followed by a recombinant Simian Immunodeficiency Virus (SIV) Env boost. While the SIV Env trimers were inherently favorable because of their higher stability, the approach was specifically chosen to preferentially boost antibody responses against the few sites that are conserved in HIV and SIV Env. The described approach was generally validated and warrants future investigations as it lead to the elicitation of potent neutralizing antibodies even though it remains to be fully established if the highly heterologous nature of the prime boost strategy was solely responsible. In summary, the studies presented in this thesis provide the structural and functional platform for a novel and intriguing MHC-I peptide enhancement. Additionally, heterologous immunizations of rabbits offer a promising addition to existing vaccination strategies against HIV

What means "best practice" in addiction treatment?

The concept of best treatment practice is a response to the growing diversity of therapeutic experience and to the frequently inadequacy of service reality and guidelines. Ideally, best practice guidelines are based on the available research evidence about effi cacy and effectiveness of therapeutic approaches. But limitations of outcome research must be taken into consideration as well as limitations of guideline applicability. Circumstantial factors are also relevant for treatment outcomes, and clinicians are expected to adapt evidence-based recommendations to such factors in their daily practice with individual patients. In addition, availability and access to recommended treatments are in the responsibility of service planners and providers, thereby facilitating the implementation of best practices. We understand best practice not as treatment provided in some centres of excellence, but as a system providing all those in need of treatment in the best possible way. Finally, major changes are expected for the future, redirecting the focus from a traditional evaluation of clinical usefulness for populations to an assessment of individually optimised interventions (personalised medicine: 'treating the patient, not the disease')

¿Qué significa "mejores prácticas" en el tratamiento de las toxicomanías?

El concepto de las mejores prácticas en el tratamiento constituye una respuesta al aumento de la diversidad de las experiencias terapéuticas y a la frecuente insufi ciencia de la realidad y de las directrices de la asistencia. De forma ideal, las directrices de prácticas recomendables se fundamentan en los resultados disponibles de la investigación de la efi cacia y la efectividad de los enfoques terapéuticos. Sin embargo, es esencial tener en cuenta las limitaciones de la evaluación de resultados así como las limitaciones de la aplicabilidad de las directrices. Los factores circunstanciales también son relevantes en los resultados del tratamiento y se espera que los terapeutas clínicos adapten las recomendaciones fundamentadas en pruebas científi cas a dichos factores en su trato diario con los pacientes. Además, la disponibilidad y el acceso a los tratamientos recomendados son responsabilidad de los planifi cadores y proveedores de servicios, facilitando de este modo la implantación de las mejores prácticas. Consideramos que el término 'mejores prácticas' no signifi ca la asistencia proporcionada en ciertos centros de excelencia, sino el sistema que facilita la mejor asistencia posible a todos los que necesitan tratamiento. Por último, se esperan cambios importantes en el futuro, para reorientar el enfoque desde la evaluación tradicional de la utilidad clínica para las poblaciones hacia una evaluación de las intervenciones optimizadas individualmente (medicina personalizada: 'tratando al paciente, no la enfermedad')

Detection and treatment of HIV and hepatitis virus infections in Swiss correctional facilities

Summary: Objectives:: The aim of the study was to obtain an overview on diagnostic and therapeutic activities concerning hepatitis A, B, C virus and HIV in Swiss prisons. Methods:: A standardized questionnaire was sent to 91 prisons in the German and Italian speaking parts in October 2004; 41 institutions (45%) answered the questionnaire. Results:: In almost all prisons serological examinations were not done routinely, but were provided when demanded by inmates or recommended by the medical service. Vaccination against hepatitis A or B infection and initiation of antiviral therapy was possible in most institutions. Conclusions:: Most of the prisons investigated offered diagnostic and antiviral treatment for hepatitis virus and HIV infections. A reported problem was the discontinuation of ongoing treatments or vaccination cycles after discharge. In some cases deficient funding was an obstacl

Predicting mixing trends in mine-receiving waters using water quality modeling

Complete mixing of the water column of lakes is important to ensure that nutrients and dissolved oxygen are replenished and equalized throughout the lake. This ensures that organisms within the lake at all trophic levels can perform necessarily metabolism and have a maximized habitat range. Lakes that receive effluent high in total dissolved solids from mine operations can be prevented from performing complete water column turnover. When this occurs the lake is termed meromictic. Two lakes, one naturally remediating and the other actively receiving effluent discharge, have both exhibited historical meromictic conditions (meromixis). Over a three year period, the water quality in both lakes was analyzed and related to their current meromictic state. The CE-QUAL-W2 model was calibrated to predict total dissolved solids concentrations within the active receiver lake and one-year predictive simulations were run with total dissolved solids reductions of 10%, 25%, 50% and 75% at the lake inflow. The lake undergoing natural remediation exhibited substantial breakdown of meromictic stability during the study and was deemed monomictic while the active receiver demonstrated meromictic stability and variability in mixolimnion turnover depth. Calibration of CE-QUAL-W2 revealed that fluctuations in surface total dissolved solid concentrations and dissolved organic carbon from natural and effluent inputs had substantial influences on heat distribution in the effluent receiver. Reducing total dissolved solids inputs into the active receiver lake only elicited change in mixolimnion total dissolved solids concentrations but little change in monimolimnion concentrations. The 50% and 75% reduction simulations resulted in a much shallower mixolimnion depth and stronger meromictic stability in the lake

Prevalence of hepatitis and HIV infections and vaccination rates in patients entering the heroin-assisted treatment in Switzerland between 1994 and 2002

Background::  Hepatitis C virus (HCV) remains very prevalent in injection drug users (IDUs). In spite of recommended vaccinations against hepatitis A virus (HAV) and hepatitis B virus (HBV), many IDUs remain susceptible to HAV and HBV. Study population and methods::  Patients entering heroin-assisted treatment between 2000 and 2002 (N=210) were compared for infectious disease status with patients entering this treatment in 1998 (N=243) and between 1994 and 1996 (N=1035). Infection status was determined with the aid of questionnaires and blood tests for antibodies against HAV, HBV core antigen, HCV and HIV. Results::  In the cohort 2000-2002 78.3% of the patients were HCV positive, 53.3% were HBV positive, 41.2% were HAV positive and 12.6% were HIV positive. In comparison to the cohorts entering the heroin- assisted treatment at an earlier time, there was a significant reduction of HBV and HAV infections, but not of HCV and HIV infections. 15.6% of the patients entering between 2000 and 2002 were vaccinated against HBV and 10.3% against HAV. 31.1% of patients at entrance were susceptible for HBV and 48.5% for HAV. In comparison to patients entering treatment in 1998 there was no significant increase in patients who were vaccinated against HBV. Conclusions:: This data illustrates the need for improving HCV prevention and more consequent vaccination against HBV and HAV in IDU

Development of a monitoring system for heroin-assisted substitution treatment in Switzerland

Summary: Objectives: Switzerland introduced heroin-assisted treatment as a routine treatment for drug addicts. As a result the evaluation instruments were changed from a detailed scientific project to a routine monitoring system. The process for developing this monitoring system is described. Methods: The questionnaires and assessment instruments were restyled with staff of the treatment agencies. Indicators measuring quality of treatment and measures from the future national statistic on the addiction support system were integrated into admission, course and discharge questionnaires. Currently a system for feedback to treatment agencies is being developed. Results: All 21 treatment agencies are participating in the monitoring. Assessment quality is high. Conclusions: The described monitoring should provide continuous delivery of basic relevant data on patient

Detection and treatment of HIV and hepatitis virus infections in Swiss correctional facilities

OBJECTIVES: The aim of the study was to obtain an overview on diagnostic and therapeutic activities concerning hepatitis A, B, C virus and HIV in Swiss prisons.METHODS: A standardized questionnaire was sent to 91 prisons in the German and Italian speaking parts in October 2004; 41 institutions (45%) answered the questionnaire.RESULTS: In almost all prisons serological examinations were not done routinely, but were provided when demanded by inmates or recommended by the medical service. Vaccination against hepatitis A or B infection and initiation of antiviral therapy was possible in most institutions.CONCLUSIONS: Most of the prisons investigated offered diagnostic and antiviral treatment for hepatitis virus and HIV infections. A reported problem was the discontinuation of ongoing treatments or vaccination cycles after discharge. In some cases deficient funding was an obstacle