HINTERGRUND: Die Leber nimmt bei der Regulierung und Aufrechterhaltung des Uridinplasmaspiegels eine zentrale Rolle ein. Die Synthese von Uridin hängt dabei wesentlich von der intakten Funktion hepatozytärer Mitochondrien und des mitochondrialen Enzymes Dihydroorotatdehydrogenase (DHODH) ab. Bei Patienten unter HIV-Therapie zeigten sich in Studien verminderte Uridinplasmaspiegel, wobei die dafür verantwortlich gemachte therapieassoziierte mitochondriale Toxizität durch Uridinsupplementation reduziert werden konnte. Schädigungen von Leber und Mitochondrien im Rahmen chronischer Lebererkrankungen wie Hepatitis C (CHC), B (CHB), alkoholischer und nichtalkoholischer Fettleber (AFLD und NAFLD) könnten ebenfalls zu einem Abfall des Uridinplasmaspiegels führen. METHODIK: Nach Etablierung einer HPLC-Methodik zur Evaluation von Uridin im menschlichen Serum wurden Uridinplasmaspiegel von Patienten mit oben genannten Erkrankungen mit denjenigen einer gesunden Kontrollgruppe verglichen. Ferner wurden die Spiegel mit Demografie, Genotypen, Viruslasten, antiviraler Therapie und Therapiedauer sowie mit sonographischen wie histologischen Leberbefunden und Laborparametern korreliert. ERGEBNISSE: Sämtliche 130 Patienten zeigten einen signifikant niedrigeren Uridinplasmaspiegel als die aus 14 Probanden bestehende gesunde Kontrollgruppe, lagen jedoch noch im physiologischen Normbereich gesunder Erwachsener. In absteigender Reihenfolge zeigten die grössten Unterschiede die Gruppen mit chronischer Hepatits C (n = 69), Hepatitis B (n = 37) sowie AFLD/AFLD (n = 24). Demographische Faktoren, chronischer Alkoholkonsum, histologischer Grad der Leberentzündung und -fibrose, sowie Diabetes mellitus zeigten keinen Einfluss. Spezifika der Virushepatitiden zeigten, abgesehen von der Viruslast bei CHC mit Tendenz zu eher niedrigen Uridinplasmasppiegeln bei hohen Lasten ebenfalls keine Signifikanzen. Eine Leberverfettung zeigte hinsichtlich des Uridinplasmaspiegels lediglich im Vergleich der Gruppe AFLD/NAFLD zur Kontrollgruppe signifikant reduzierte Werte. In Bezug auf das absolute wie relative Vorliegen einer Leberzirrhose zeigten sich ebenfalls signifikant erniedrigte Spiegel, und auch bei Korrelation des Child-Pugh-Index sowie laborchemischen Lebersynthesemarkern zeigten sich mit Zunahme der Leberschädigung reduzierte Uridinspiegel. SCHLUSSFOLGERUNG: Der Uridinplasmaspiegel scheint bei chronischen Lebererkrankungen wie Hepatitis C und B sowie alkoholischer und nichtalkoholischer Fettleber relativ erniedrigt zu sein, ebenso bei der Leberzirrhose. Um den Einfluss einer Mitochondrienschädigung genauer einzuordnen wären zukünftige Untersuchungen unter Einbezug oxidativer Marker ebenso interessant wie Überlegungen, Uridin bei fortgeschrittenen chronischen Lebererkrankungen zu substituieren. / BACKGROUND: The liver plays a pivotal role in regulating and maintaining uridine levels in plasma. Synthesis of uridine is mainly depending on the intact function of mitochondria and the mitochondrial enzyme dihydroorotate dehydrogenase in liver cells. HIV therapy associated mitochondrial toxicity, affecting reduced uridine plasma levels could be diminished by uridine supplementation. Moreover, in cases of liver or mitochondrial damage induced by chronic liver diseases such as hepatitis C (CHC) and B (CHB), alcoholic and non-alcoholic induced fatty liver (AFLD and NAFLD) can result in reduced uridine levels in plasma. METHODS: An HPLC-based method for evaluating uridine levels in human serum was established and utilized to compare uridine levels in patients suffering from the aforementioned diseases with controls. Moreover, uridine levels were evaluated with regard to (a) demographic data, (b) genotypes, (c) viral load, (d) antiviral treatment, (e) treatment duration, (f) sonographic and histological findings, and (g) laboratory values. RESULTS: Uridine levels in plasma of all 130 patients were significantly reduced compared to those of the 14 healthy individuals, however, were still within the physiological range observed in healthy adults. Maximum deviations decreased in the following order: Hepatitis C (n=69), hepatitis B (n=37) and AFLD/NAFLD (n=24). Demographic factors, chronic alcoholic diseases, histological grade of liver inflammation and fibrosis, as well as diabetes mellitus; had no impact on uridine plasma levels. Apart from CHC, which tends to reduce levels of uridine in plasma with a high viral load; specifics of the infectious hepatitis indicated no significant change. In cases of fatty liver, only when comparing the AFLD/NAFLD group to controls, significantly reduced levels of uridine in plasma could be confirmed. Additionally, in the case of existent relative or absolute cirrhosis, as well as with an increasing Child-Pugh-Index and decreasing liver synthesis products, significant reduced uridine plasma levels could be detected. CONCLUSION: The present data indicates reduced levels of uridine in plasma in cases of chronic liver diseases (such as hepatitis C and B), alcoholic and non-alcoholic steatohepatitis, as well as cirrhosis. To assess the impact of mitochondrial damage, future investigations should include oxidative markers and evaluate the potential of substituting uridine in cases of advanced chronic liver diseases.

acase@tulane.edu

Publicación a texto completo no autorizada por el autor / Determina la insulinoresistencia como marcador pronóstico en cirrosis hepática avanzada en pacientes que han acudido al consultorio externo de gastroenterología del Hospital Alberto Sabogal Sologuren, así como aquellos pacientes hospitalizados en el Servicio de Especialidades Médicas 2 a cargo de gastroenterología durante el periodo de marzo del 2013 a marzo del 2014. Estudio prospectivo, descriptivo, observacional, correlacional. Se analizaron 125 pacientes con un promedio de edad de 61,70 años (DS: 43,84). Obtiene que el 58% (73) del total de los pacientes bajo estudio fueron mujeres; el 65% (81) presentaron edades entre 61 a 80 años y el 24% (30) edades entre 51 a 60 años. El 50% (63) presentaron etiología de cirrosis hepática desconocida, el 15% (19) presentaron etiología alcohólica y hepatitis C crónica, respectivamente y el 12% (15) hepatitis crónica B; el 44% (55) presentaron como escala de Child Pugh la B y el 35% (44) la A; el 63% (79) tuvieron valores de HOMAR-IR, menor a 3,2; el 62% (78) presentaron como valores de potasio 3,7 a 5,2 mEq/l. El 77% (96) del total de pacientes bajo estudio tuvieron valores de fósforo sérico menor de 2,4 a 4,1 mg/dl, el 14% (17) mayor a 4,1 mg/dl y el 53% (10) del total de pacientes con cirrosis por alcohol tuvieron valores de fósforo sérico menor de 2,4 mg/dl y el 26% (5) mayor a 4,1 mg/dl. Existe relación y correlación moderada inversa entre los valores de HOMAR-IR y escala de Child Pugh; y, existe relación y correlación leve inversa entre los valores de potasio y escala de Child Pugh con un p=0.000, respectivamente. Concluye que la insulinoresistencia se encuentra en estadios Child Pugh avanzados, pudiéndose considerar como marcador pronóstico, La hipokalemia está presente en estadios avanzados, siendo mecanismo desencadenante en estos pacientes, la hipofosfatemia se encuentra presente en cirrosis alcohólica, siendo el mecanismo patogénico de Insulinoresistencia en estos pacientes. / Trabajo académico

People with hepatitis C (HCV) face stigma and discrimination because of the association of this disease with injecting drug use (IDU). Research has found that many instances of HCV-related discrimination occur in the health care sector. Health care workers' beliefs about their HCV positive clients are likely to influence how they relate to clients and their treatment delivery. This research assessed the implicit and explicit attitudes of both health care workers and their HCV positive injecting drug using (HCV+) clients toward each other and then established whether these affect the treatment experiences of health care workers and clients. The sample consisted of 60 health care workers (doctors and nurses), 120 HCV+ and 120 HCV- clients, recruited from the same treatment facility. Participants were given a series of attitude and treatment experiences measures to complete. Data illustrate that while health care workers' and HCV+ clients' explicit attitudes towards each other were positive, clients with HCV still rated their health care workers less highly and reported less satisfaction with their treatment than HCV- clients. Analyses also indicated that more conservative health care workers displayed greater prejudice toward their HCV+ clients because they believe that injecting drug use is controllable. This prejudice toward IDUs on the part of health care workers was associated with worry about the behaviour of IDU clients and this worry in turn predicted differences in treatment experiences reported by HCV+ and HCV- clients. These data support the contention that health care worker concerns, particularly those related to injecting drug use, underlie discriminatory treatment of people with HCV. Finally the research also addressed the impact of health care worker contact with HCV+ clients on their attitudes towards this group. Analysis revealed that while health care workers who have had more contact with people with HCV show more positive explicit attitudes, they also show less favourable implicit attitudes toward IDUs. This may reflect the difficulties and stresses associated in caring for IDUs and may provide insight into the hidden costs involved for health care workers working with a population that may be challenging and at times difficult to manage.

The use of mathematical models in studying disease epidemics can be diverse, from the focused study of the role of a single determinant of the epidemic, or to the overall estimation of morbidity and mortality. In using simple deterministic models, a balance is struck between biological and social complexities, and the high data input demands of mathematical models. This thesis aims to apply the use of deterministic mathematical models to the studies of HIV and hepatitis C epidemiology in the Asia-Pacific region. In Australia, about 85% of reported HIV cases are among homosexual men. Casual homosexual partnerships made up 40% of incident HIV cases in 1995 increasing to 65% in 2004. In the state of New South Wales, it was estimated that over 7,500 people were living with HIV/AIDS in 2005, increasing to over 10,000 by 2016 with existing levels of intervention. Intervention measures were estimated to have prevented some 44,500 cases, the majority being among injecting drug users through the Needle and Syringe Programmes. Models for the HIV epidemics in developing countries were also developed incorporating multiple routes of HIV transmission. For Papua New Guinea, it was estimated 64,000 people were living with HIV/AIDS in 2005, rising to over 500,000 by 2025 with current levels of intervention. High levels of interventions, in particular increased condom use, will be required to achieve a stabilisation or reduction in HIV prevalence. In East Timor, the HIV epidemic is still in the early stages with 138 people estimated to be living with HIV/AIDS, rising to 5,000 by 2025 with minimal intervention. For HCV, models of the epidemic in Australia showed HCV incidence peaking in 1999, followed by a decline reaching 9,700 incident cases in 2005. Of 197,000 estimated chronic HCV cases in 2005, 58% had stage F 0/1 liver disease, 15% F 2/3 liver disease, and 2% HCV-related cirrhosis. Models estimated 210 and 105 people developed HCV-related liver failure and hepatocellular carcinoma, respectively. Comparisons of modelled HCV long-term sequelae projections with linkage data showed relatively good agreement, despite discrepancies in liver-related deaths. To decrease the number of chronic HCV, at least a tripling of treatment coverage would be required. These models provide estimates of the current levels of epidemics as well as projections of future scenarios under different intervention strategies, which have an important role in the planning of strategies, as well as assessment of previous epidemic conditions.

Background: The most recent estimate for the number of Australians living with chronic hepatitis B virus (HBV) infection is 150,000, with over one million ever having been infected. One in four people with chronic infection will die as a result. Worldwide, the burden of chronic HBV infection is great. As many as 400 million people are chronically infected, and the World Health Organisation estimates that as a result HBV infection is the tenth leading cause of death. / Aim: The aim of the research presented in this thesis is to improve the accuracy and relevance of our understanding of the epidemiology and control of HBV infection in Australia, through the development of new methodological approaches to the collection and analysis of relevant epidemiological data. / Methods: Three novel approaches were adopted. First, a serosurvey of a randomised, age-structured convenience sample of over 3200 specimens was performed spanning the period from 1995 to 2005 to estimate the prevalence of markers of infection with, and immunity to HBV. Secondly, a comparative analysis of the serosurvey results with national surveillance notifications since 1971 and migration records since 1945 was undertaken. Finally, a complex deterministic mathematical model of HBV infection in Australia was constructed simulating the entire population between 1951 and 2050. / Results: The serosurvey indicates that chronic infection with HBV is more common in the Victorian population than existing national serosurvey estimates suggest, and the coverage of immunisation programs (particularly of adolescents) is far from universal. Significant geographic, age, and gender disparities in the prevalence of chronic HBV infection were identified in the serosurvey, which appear in part to relate to historical migration patterns and which could be used to develop a targeted and effective public health response. The comparative analysis of the serosurvey results with notifications and migration data demonstrates coherence of these disparate sources of information, and suggest that knowledge of migration patterns can lead to robust predictions of future notifications. The novel regression model developed implies that at least 50,000 people with chronic HBV infection are undiagnosed. The mathematical model of HBV infection in the Australian population is unique in many respects, and has been validated against external data to provide reassurance regarding the accuracy of the simulated outcomes. Some of these outcomes include an estimated 160,000 Australians living with chronic HBV infection in 2009, increasing by several thousand people every year, and that less than 5 per cent of chronic infections entering the population are able to be addressed by domestic vaccination or other prevention programs. / Conclusion: The new insights into the epidemiology of HBV infection in Australia provided by the approaches described all suggest a large and increasing burden of chronic HBV infection. New approaches are needed to provide essential policy outcomes to assist and empower Australians living with chronic HBV infection. If this does not occur, the economic and human costs to our community are likely to become great.

Thesis (Ph.D.)--Memorial University of Newfoundland, 2005. / Bibliography: leaves 268-300.

No description available.

Hintergrund: Die Datenlage zur Substitutionstherapie Opiatabhängiger ist defizitär. Vor diesem markant defizitären Erkenntnishintergrund erscheint es sinnvoll und notwendig, eine versorgungsepidemiologische Studie zur aktuellen Versorgungslage opiatabhängiger Substitutionspatienten durchzuführen, um offene Fragen zu klären. Hierfür haben wir ein mehrstufiges Forschungsprojekt unter dem Akronym COBRA initiiert. COBRA steht für "Cost-Benefit and Risk Appraisal of Substitution Treatments" und signalisiert, dass wir uns in umfassender Weise um eine Evaluation der Risiken, Vor- und Nachteile verschiedener Interventionsstrategien und Modalitäten in der Substitutions- und Versorgungspraxis Opiatabhängiger in Deutschland bemühen. Zielsetzungen des COBRA-Projekts sind: • Die Charakterisierung von bestehenden Einrichtungsformen und -modellen; • Die Charakterisierung von: – Merkmalen opiatabhängiger Patienten in diesen Einrichtungen (Schwere, Dauer/ Stadium, Komorbidität, Delinquenz, Desintegration etc.), – der Diagnostik sowie den Indikations- und Allokationsentscheidungen in der Versorgungsrealität sowie – den eingesetzten Interventionsmethoden (Substitutionsmittel, Therapie komorbider Störungen, psychotherapeutische und soziale Interventionen) • Die Ermittlung von Problemen der Substitutionstherapie bei verschiedenen Risikogruppen (z.B. Hepatitis-C- und HIVPatienten) • Die Beschreibung des Kurzzeitverlaufs und Outcomes hinsichtlich verschiedener klinischer und sozialer Kriterien Methodik: Die Studie teilt sich in einen deskriptiv-klinisch-epidemiologischen und einen analytisch-evaluativen Teil. Der deskriptive Teil soll zunächst darüber Auskunft geben, wie viele und welche Arten von Substitutionseinrichtungen in Deutschland wie viele Opiatabhängige erreichen und behandeln. Auf dieser Grundlage soll dann im evaluativen Teil an möglichst repräsentativen Einrichtungen und Patienten beurteilt werden, wie und mit welchen Methoden welche Arten von Patienten und Problemlagen versorgt werden. Durch Abgleich mit den wissenschaftlichen Bewertungsmaßstäben können daraus Defizite, Probleme und mögliche verbesserte Allokationsstrategien abgeleitet werden. Ergebnisse: Es werden erste Vorstudienbefunde und Ihre Design- Konsequenzen vorgestellt und diskutiert. / In the present paper, we will describe aims, methods, and design along with selected pre-study findings of an epidemiological study in a nationally representative sample of substitution doctors (N = 381) and their patients (n = 2500) in Germany. The project has three major components: (a) Pre-study: We sent mailed questionnaires to a sample of over 1000 substitution doctors to describe qualification and setting characteristics, treatment profiles and attitudes of substitution doctors in Germany. (b) Cross-sectional study: With a two-step epidemiological design (target day assessment of the patients, clinical appraisals by the doctors), our main aims were (1) to determine the number of opiate addicts treated by methadone or buprenorphine or other substitution drugs; (2) to find predictors and correlates for treatment, taking into account doctors, patients, and system variables; and (3) to evaluate cross-sectional differences between groups with regard to clinical presentation (comorbidity), clinical course, acceptance/compliance, critical incidences, and social integration. (c) Furthermore, the study includes a prospective-longitudinal cohort study of a total of 1000 patients sampled from this data base. The cohort will be followed-up over a period of three months to investigate whether buprenorphine patients have a more favorable course and outcome in terms of clinical, psychosocial, pharmaco-economic, and related measures. Selected pre-study findings are summarized, highlightening that current registers include a considerable proportion of doctors and a considerable heterogeneity of setting characteristics in terms of the number of patients, choice of substitution drugs and involvement in hepatitis- C treatment.

El virus de l’hepatitis A (HAV), el prototip del gènere Hepatovirus, té una sèrie de característiques que el diferencien de la resta de membres de la família Picornaviridae, entre aquestes l’existència d’un únic serotip del virus, a pesar de que replica seguint una dinàmica de quasiespècies. La falta de correlació entre la variabilitat a nivell de nucleòtids i a nivell d’aminoàcids fa pensar que l’HAV presenta unes fortes constriccions estructurals i biològiques a nivell de la càpsida. Cal tenir en compte que el virus ha de superar el pH àcid de l’estómac en la fase d’entrada, l’eliminació de sang en la fase virèmica i l’acció de proteases i detergents, especialment sals biliars, en la fase de sortida. Per fer front al pH àcid, les proteases i les sals biliars, l’HAV disposa d’una càpsida altament estable i cohesiva. Respecte l’eliminació de sang, l’HAV s’uneix a la glicoforina A dels eritròcits, la qual s’ha descrit que pot actuar com a receptor esquer interaccionant amb els patògens i impedint que arribin al seu teixit o òrgan diana, però la interacció és ineficient a pH fisiològic. Com que aquesta interacció és òptima a pH àcid, es creu que l’HAV ha adoptat una conformació de la càpsida que li permet evadir la interacció amb l’eritròcit i evitar així ser eliminat de sang. Per tant, aquest seria un factor que contribuiria a la baixa variabilitat antigènica de la càpsida, ja que els mutants amb canvis d’aminoàcids en la regió d’unió a la glicoforina A podrien ser més fàcilment eliminats de sang. De fet, en aquest treball s’ha observat com una única mutació en aquesta regió genera un mutant amb una capacitat de replicació in vitro idèntica a la del virus parental però amb una reducció del fitness in vivo pel fet de presentar una cinètica d’eliminació en sang més ràpida. Una altra característica única de l’HAV és que presenta un ús de codons altament deoptimitzat i en certa manera antagònic al de la cèl•lula. Com a conseqüència, el virus utilitza molts codons rars, que s’aparellen amb tRNAs poc abundants, ja que utilitza com a codons rars els codons que són rars per la cèl•lula però també els que la cèl•lula utilitza freqüentment, i que, per tant, no estan disponibles per al virus. Aquesta estratègia li permet minimitzar la competència que ha d’establir amb la cèl•lula hoste pels tRNAs, ja que no posseeix d’un mecanisme específic per induir shut-off de la síntesi proteïca cel•lular. S’ha demostrat que els codons rars tenen un paper important en la regulació de la cinètica de traducció, ja que causen pauses del ribosoma degudes a la dificultat de trobar el tRNA correcte, que es troba en concentracions baixes. Aquestes pauses permeten el correcte plegament de les proteïnes, que té lloc de forma co-traduccional. En el cas de l’HAV, la importància de mantenir les pauses de la traducció per assegurar el correcte plegament de les proteïnes de la càpsida és tal que quan es feia replicar el virus en condicions de shut-off cel•lular artificial, el virus re-deoptimitzava l’ús de codons, al contrari del que s’esperaria en aquestes condicions de major disponibilitat de tRNAs. En aquest treball s’ha estudiat la relació entre les pèrdues i recuperacions del fitness del virus en les diferents condicions de shut-off cel•lular i els canvis en la conformació de la càpsida, els quals afectaven l’estabilitat i la eficiència amb que aquesta interaccionava amb el receptor i/o desencapsidava. Durant l’adaptació a aquestes condicions, els canvis en l’ús de codons que experimentava el virus li permetien recobrar un plegament de la càpsida per a recuperar la interacció amb el receptor o augmentar la eficiència de desencapsidació. A més, les poblacions adaptades a les condicions de shut-off cel•lular presentaven un increment de la infectivitat específica i una replicació més ràpida que el virus parental. Tot plegat ens dona una idea de com la càpsida de l’HAV s’adapta a colls d’ampolla imposats pel seu cicle biològic. / Hepatitis A virus (HAV) is a hepatotropic member of the Picornaviridae family. A single serotype exists, in spite of similar nucleotide diversity to that of the other picornaviruses. This discrepancy between nucleotide and amino acid variability suggests capsid structural and biological constraints. For the development of an infection cycle, HAV has to overcome the challenges posed by the acid pH of the stomach and the action of intestinal proteases and detergents (particularly biliary salts) during the entry phase, the decoy factors during the viremic phase, and again the action of proteases and detergents during the exit phase. HAV binds erythrocytes through the interaction with glycophorin A, however hemagglutination at physiological pH is highly inefficient. As erythrocyte glycoproteins may function as decoy receptors, attracting pathogens and keeping them away from target tissues, the actual virion conformation could represent an escape mechanism from blood clearance due to inefficient erythrocyte binding at physiological pH. The G1217D mutant, with a single mutation in the glycophorin A binding site, binds more efficiently to erythrocytes than the parental strain. In a rat model, it is eliminated from serum more rapidly and consequently reaches the liver with a certain delay compared to the parental strain, suggesting a low fitness phenotype which could explain the lack of natural antigenic variants of the glycophorin A binding site. Another unique characteristic of HAV is the codon usage. HAV don’t induce cellular shut-off and has adopted a deoptimazed codon usage, in order to reduce the competence for the cellular tRNAs. A consequence of this deoptimazed codon usage is an increase of the number of rare codons used by HAV. Adaptation of HAV to replicate in changing conditions of artificially induced cellular shut-off, results in dynamic adjustments of codon usage and in alternate capsid conformations which in turn influence the effectiveness of the initiation of the replicative cycle and the capsid stability. The adaptation processes also involve significant increases in virus specific infectivity and enable the selection of fast growing populations. Fine-tuning translation kinetics selection, i.e., the proper combination of abundant and rare codons in order to get a controlled translation speed and a proper capsid folding plays a critical role in HAV evolution during adaptation in conditions of cellular shut-off. These results suggest and adaptation of the capsid to bottlenecks during the replication cycle.