Glycosylation is one of the most abundant post-translational modifications of proteins. Glycoproteins participate in virtually all aspects of cellular functions. ST6Gal I is a glycosyltransferase highly expressed by B and T cells. Here, we interrogated the role of ST6Gal I in viral specific B and T cell immune responses, as well as examined how loss of this enzyme impacted viral pathogenesis. First, to understand how loss of ST6Gal I expression impacted viral specific humoral responses, we infected ST6Gal I-/- mice with influenza virus. We discovered that loss of ST6Gal I expression results in both reduced influenza specific antibodies levels and decreased viral-specific antibody secreting cells numbers. Following influenza infection, mice that received ST6Gal I-/- B cells showed reduced influenza-specific IgM responses compared to mice that received wild-type B cells. These experiments demonstrated that the expression of ST6Gal I by B cells is required for optimal viral-specific humoral response. We further examined how loss of ST6Gal I expression impacted the anti-influenza IgA response. We observed that immune ST6Gal I-/- mice displayed higher viral specific IgA levels and altered sialylation of IgG and IgA, which have been implicated in a human disease, IgA nephropathy. Moreover, ST6Gal I-/- mice exhibited increased immunoglobulin deposition in kidney glomeruli following influenza infection. These data suggest that ST6Gal I deficiency, together with influenza infection, may result in the initiation of a kidney disease. Finally, we examined how ST6Gal I expression regulated CD8 T cell responses. We discovered that ST6Gal I is differentially expressed during CD8 T cell activation. To understand its relevance, we infected ST6Gal I-/- mice and demonstrated that the early expansion of effector T cells was impaired in a cell intrinsic manner. Moreover, in the absence of ST6Gal I, the differentiation of CD8 T cells skewed towards memory precursor cells, whereas terminal effector cell expansion was impaired. Mechanistically, we identified delayed surface expression of IL-2Ralpha on ST6Gal I-/- CD8 T cells due to impaired IL-2/IL-2R signaling. These studies implicate that ST6Gal I expression enhances early proliferation of terminal effector CD8 T cells by promoting the rapid surface expression of IL2Ralpha during acute viral infection. 

Radiation therapy targets cancer cell death by overwhelming cells with harmful DNA damage. Understanding how cells repair radiation damage and in particular how they become resistant to radiation therapy is important for effective cancer treatment. Our lab made the novel discovery that Bcl10, a cytoplasmic protein important for NF-B activation, localizes to endogenous H2AX foci in the nucleus of breast cancer cells. We determined that following radiation treatment Bcl10 is recruited to ionizing radiation-induced foci in a dose-dependent matter and that it is important for the repair of radiation-induced DNA damage. We also observed that breast cancer cells are extremely sensitive to Bcl10 knockdown, causing cellular senescence, while normal breast epithelial cells are insensitive. Our findings identify Bcl10 as potent anti-cancer target. / Experimental Oncology

Graduation date: 1936

No description available.

Dem Geb�rbutterhals (Zervix) kommt als kaudalem bzw. unteren Anteil des Uterus w�hrend der Gravidit�t und Geburt eine besondere Rolle im Reproduktionstrakt zu. Einerseits fungiert die Zervix als uteriner Verschlussapparat, der den Schutz des Embryos bzw. Fetus und dessen Verbleiben im Uterus w�hrend der gesamten Gravidit�t gew�hrleistet. Andererseits muss die Zervix zum Zeitpunkt der Geburt in k�rzester Zeit erweichen und sich auf ein Vielfaches ihres Durchmessers erweitern k�nnen, um die Austreibung der Frucht zu erm�glichen (LEPPERT 1995; RATH et al. 1994; DANFORTH 1983). Um diesen gegens�tzlichen Aufgaben gerecht zu werden, bedarf es extremer geweberemodulierender Vorg�nge in diesem Organ, die unter endokriner Kontrolle von Hormonen wie z.B. �strogenen, Progesteron, Prostaglandinen, Oxytozin und Relaxin stehen (LINDZEY u. KORACH 1999; BRYANT-GREENWOOD u. SCHWABE 1994). Anhand des in der reproduktionsbiologischen Forschung etablierten Primatenmodells Wei�b�schelaffe (Callithrix jacchus) sollte mit der vorliegenden Arbeit ein �berblick �ber hormonelle, durch Relaxin und �stradiol induzierte Ver�nderungen in der Struktur der Extrazellul�ren Matrix des Bindegewebes, der Expression kollagenolytischer Enzyme (Matrix-Metalloproteinasen, MMPs), der Rezeptorexpression sowie der Blutgef��versorgung in der Zervix mittels histologischer, immunhistochemischer und molekularbiologischer Methoden erarbeitet werden. Dazu soll einerseits die Wirkung lokal und systemisch applizierten Relaxins und andererseits die Wirkung systemisch applizierten Relaxins mit der ebenfalls systemisch verabreichten �stradiols verglichen sowie ein m�glicher Kombinations-effekt beider Hormone auf das Gewebe der Zervix untersucht werden. Um direkt einen erweichenden Effekt des Hormons Relaxin auf die Zervix zu untersuchen, wurde ein in vivo-Versuch zur Bestimmung des Zervix-Innendurchmessers vor und nach lokaler Applikation von rekombinantem humanen (rh)Relaxin mittels speziell angefertigter Messr�hrchen unter Allgemeinan�sthesie der Tiere durchgef�hrt. Desweiteren erfolgte die histologische, immunhistochemische und molekularbiologische Untersuchung von Zervices weiblicher Wei�b�schelaffen aus 3 unterschiedlichen Versuchs-gruppen: 1) anatomisch und physiologisch intakte, zyklische Wei�b�schelaffen, 2) intakte, lokal mit rhRelaxin behandelte Tiere und 3) zur Ausschaltung endogener Hormonquellen ovariektomierter Wei�b�schelaffen, denen systemisch rhRelaxin oder 17β-�stradiol bzw. eine Kombination beider Hormone verabreicht wurde sowie einer unbehandelten Kontroll-gruppe. Die Organe wurden nach Entnahme geteilt. Ein Teil wurde f�r die histologischen und immunhistochemischen Untersuchungen in 4%igem Formalin fixiert und in Paraffin eingebettet, wohingegen der andere Organteil f�r die molekularbiologischen Versuche kryokonserviert wurde. Als histologische F�rbemethoden wurden die H�malaun-Eosin-F�rbung f�r einen �berblick �ber die Morphologie der Zervix, die Masson-Trichrom- bzw. Pikrosiriusrot-F�rbung zur Beurteilung der Struktur der kollagenen Fasern der Extrazellul�ren Matrix sowie die Siriusrot-F�rbung zur spezifischen Darstellung der eosinophilen Granulozyten im Gewebe der Zervix durchgef�hrt. Weiterhin wurden durch die Methode der indirekten Immunhistochemie mittels spezifischer Antik�rper die Expression der �strogen- und Progesteronrezeptoren (ERα u. PR), des �strogensynthese-Enzyms 17β-Hydroxysteroid-Dehydrogenase-7 (17βHSD7), des Relaxins und des Relaxinrezeptors LGR7 sowie der kollagenolytischen Enzyme MMP-1, -2 und -9 dargestellt. Zur Ermittlung der Blutgef��anzahl im zervikalen Stroma wurde die Darstellung mittels Aktin-Antik�rpern angewendet. Zur Erg�nzung der immunhistochemischen Untersuchungen zur Proteinexpression der ge-nannten Parameter wurde die Expression des ERα und PR, des LGR7, des Relaxins und des vaskul�ren endothelialen Wachstumsfaktors (VEGF) auf mRNA-Ebene molekular-biologisch durch die Methode der Polymerase-Kettenreaktion (PCR) bestimmt. Die Ergebnisse der vorliegenden Untersuchungen zeigen deutlich, dass sowohl Relaxin als auch �stradiol einen geweberemodulierenden Einfluss auf die Zervix besitzen, wobei vermutlich unterschiedliche Mechanismen einerseits f�r Relaxin und �stradiol und andererseits f�r lokal bzw. systemisch wirkendes Relaxin von Bedeutung sind. Systemisch appliziertes �stradiol vermag die Sekretion des zervikalen Epithels, die Ein-wanderung von eosinophilen Granulozyten und die Expression von MMPs zu stimulieren. Es ist eine deutliche Auflockerung des Bindegewebes zu sehen. Diese Beobachtungen stimmen mit den Ergebnissen der intakten, zyklischen Tiere in der �strogen-dominierten sp�ten Follikelphase �berein. �stradiol scheint weiterhin die Sensibilit�t des zervikalen Gewebes gegen�ber Relaxin durch eine Stimulation der LGR7-Expression positiv zu beeinflussen. Die Behandlung mit Relaxin zeigt deutliche Unterschiede zwischen lokaler und systemischer Hormoneinwirkung. W�hrend eine systemische Relaxinapplikation durch Stimulation der LGR7-Expression im Gewebe die Wirkung lokal produzierten und auto- bzw. parakrin wirkenden Relaxins positiv zu modulieren scheint, ist v.a. nach lokaler Applikation dieses Hormons eine Erh�hung der Gef��anzahl sowie eine deutliche Auflockerung des Binde-gewebes zu sehen, die f�r eine Erweichung des Gewebes spricht, was durch die Erweiterung des Zervix-Innendurchmessers im in vivo-Versuch best�tigt werden konnte. Eine Kombination aus beiden Hormonen f�hrte in bezug auf die untersuchten Parameter zu durchgehend positiven und teilweise die einzeln erzielten Wirkungen �bertreffenden Ergebnissen. Dies l�sst den Schluss zu, dass sich Relaxin und �stradiol in ihren Wirkungen auf die Zervix des Wei�b�schelaffen gegenseitig erg�nzen und best�tigt die Feststellung von HUANG et al. (1997), dass diese beiden Hormone einen synergistischen Effekt auf das Gewebe der Zervix haben, der v.a w�hrend der Geburt eine Rolle spielt und hinsichtlich einer therapeutischen Anwendungen des Relaxins zur Geburtserleichterung bei den Primaten einschlie�lich des Menschen. / The cervix as the caudal or lower part of the uterus plays an important role within the female reproductive tract during pregnancy and parturition. On the one hand it has to protect the intrauterine from the outside milieu and to hold the embryo or fetus in the uterine cavity. On the other hand the cervix has to soften and widen immediately during parturition to deliver the fetus (LEPPERT 1995; RATH et al. 1994; DANFORTH 1983). For these opposed functions of the cervix an extreme tissue remodelling is essential, which is under endocrine control of hormones like estrogen, progesterone, prostaglandins, oxytocin and relaxin (LINDZEY u. KORACH 1999; BRYANT-GREENWOOD u. SCHWABE 1994). The aim of the presented study was to give an overview of the effects of the hormones relaxin and estradiol on the cervical tissue of the Common Marmoset, a well established primate model in reproductive sciences. Especially changes in the structure of the extracellular matrix (ECM) of the connective tissue, the expression of collagenolytic enzymes (matrix metalloproteinases, MMPs), receptor expression and blood vessel supply in the cervix should be analysed using histological, immunohistochemical and molecular biological methods. Therefore on the one hand the effect of locally versus systemically applied recombinant human (rh) relaxin and on the other hand the effect of systemically applied rh relaxin versus systemically applied 17β-estradiol as well as a combined effect of both hormones was to be investigated. First an in vivo experiment was carried out to show directly the softening or widening effect of relaxin on the cervix by measuring the intracervical diameter with special tubes under anesthesia before and after local relaxin treatment. Furthermore cervices from female marmosets of 3 different experimental groups were histologically, immunohistochemically and molecular biologically investigated: 1) anatomically and physiologically intact, cyclic Common Marmosets, 2) intact animals treated locally with rh relaxin and 3) ovariectomized animals systemically treated with rh relaxin, 17β-estradiol or with a combination of both hormones as well as an untreated control group. After euthanasia the organs were taken and separated. One part was fixated in 4% formalin and embedded in paraffin for the histological and immunohistochemical experiments, the other part was conserved at -80�C for the molecular biological investigations. To get an overview of the morphology of the cervix haematoxylin and eosin (H&E)-staining was used. Massons trichrom and picrosiriusred-stainings were used to investigate changes in the ECM-structure, especially the collagen fibres, siriusred stainig to show differences in the numbers of eosinophile granulocytes in the cervical tissue. Furthermore the indirect immunohistochemical method by means of specific antibodies was used to investigate the expression of estrogen and progesterone receptors (ERα, PR), the estrogen synthesizing enzyme 17β-hydroxysteroid dehydrogenase-7 (17βHSD7), relaxin and the relaxin receptor (LGR7) as well as the collagenolytic enzymes MMP-1, -2 and -9. The number of blood vessels in the cervical tissue was determined using specific Actin-antibodies. The immuno-histochemical results were completed by molecular biological investigation of the mRNA-expression of ERα, PR, LGR7, relaxin and the vascular endothelial growth factor (VEGF) using reverse transcription-polymerase chain reaction (RT-PCR). The results of the presented study show an explicit tissue remodelling effect of both hormones, relaxin and estradiol, whereas different mechanisms for relaxin and estradiol on the one hand and for local and systemically acting relaxin on the other hand could probably exist. Systemically applied estradiol stimulates the secretion of the cervical epithelial cells, the immigration of eosinophile granulocytes and the expression of MMPs. An obvious loosening of the structure of the connective tissue is to be seen. These observations accord with the results from the intact, cyclic animals in the estrogene dominated late follicular phase. Estradiol further seems to have a positive impact on the sensibility of the cervical tissue towards relaxin by stimulating the expression of LGR7. The treatment with rh relaxin shows significant differences between local and systemic hormone application. Systemically applied relaxin seems to induce LGR7-expression and a local relaxin synthesis in the cervical tissue as a mechanism for a positive regulation of local relaxin effects. After local application of rh-relaxin an increased number of blood vessels could be detected as well as a loosening of the connective tissue structure validating an increase in the cervical diameter in the in vivo experiment. The combination of both hormones led to continuous positive and sometimes maximum results compared with the effects of relaxin and estradiol alone with regard to the investigated parameters. In conclusion, relaxin and estradiol seem to interact in their effects on the cervical tissue thus proving the possibility to act synergistically, which is important in physiological situations, especially during the parturition, and for treatment with relaxin under birth for uncomplicated delivery in primates including humans.

Thesis (M.A.)--University of Hawaii at Manoa, 2003. / Includes bibliographical references (leaves 121-125). / iv, 126 leaves, bound 29 cm

INTRODUCCIÓN:Diversos estudios epidemiológicos han mostrado la infección crónica por el virus de la hepatitis B (VHB) como factor etiológico del cáncer hepático (CH) y en las dos últimas décadas se ha constatado un incremento de la incidencia de éste en los países industrializados. Sin embargo, los factores de progresión a CH en portadores del VHB han sido estudiados mayoritariamente en países asiáticos, por lo que es importante determinar cuál es su incidencia en Catalunya. OBJETIVOSDeterminar: i) la tendencia de la incidencia y la mortalidad por cirrosis y cáncer hepático en Catalunya en el período 1980-1997; ii) la mortalidad por enfermedad hepática en una cohorte de 2.352 donantes de sangre infectados por el VHB; iii) los factores de riesgo de desarrollar enfermedad hepática en individuos infectados por el VHB.METODOLOGÍAi) los datos de incidencia y mortalidad por cirrosis y CH en Catalunya se recogieron a partir del Registro de Cáncer Poblacional de Tarragona y del Registro de Mortalidad de Catalunya. Las tendencias se evaluaron mediante el análisis joinpoint y el análisis edad-período-cohorte; ii) como grupo control se escogió a 15.504 donantes de sangre no infectados por el VHB. La cohorte y el grupo control se cruzaron con el Registro de Mortalidad de Catalunya para determinar el estado vital y la causa de defunción de los individuos fallecidos. El exceso de mortalidad de la cohorte respecto al grupo control se determinó mediante la Razón de la Mortalidad Estandarizada; iii) se invitó a la cohorte a una visita médica en el periodo 1994-1996, que incluyó una exploración médica, análisis de sangre (función hepática y marcadores serológicos de los virus hepatotrópicos) y un cuestionario epidemiológico. El cuestionario recogió la exposición a diversos factores de riesgo asociados a enfermedad hepática. Los sujetos diagnosticados de hepatopatía fueron los casos y los sujetos con función hepática normal los controles del estudio caso-control anidado en la cohorte. La asociación de cada factor de riesgo y la enfermedad hepática se determinó mediante la razón de las odds (OR). RESULTADOS i) En el período de estudio se constató una disminución de la mortalidad por cirrosis (- 3% anual) en ambos sexos, a excepción de los hombres de 25 a 35 años en que la mortalidad por esta causa aumentó (4.5% de incremento anual). La mortalidad y la incidencia del CH permanecieron estables en ambos sexos y en todos los grupos de edad. Se constató un incremento de la mortalidad por colangiocarcinoma en ambos sexos (10% de incremento anual). ii) Exceso de mortalidad por CH y cirrosis en los hombres infectados por el VHB respecto a los del grupo control (RME CH: 17.7; RME cirrosis: 10.5). En las mujeres, solo se evidenció un exceso de muertes por cirrosis respecto a las del grupo control (RME: 7.2). iii) Los factores de progresión a enfermedad hepática en individuos infectados por el VHB fueron: la replicación del VHB (OR: 20.5 IC95%: 7.9-53.0), historia de episodios de hepatitis agudas (OR: 2.3 IC 95%: 1.3-4.2), el consumo de alcohol (OR: 2.4 IC 95%: 1.5-4.1), la infección por el VHC (OR: 6.9 IC95%: 2.3-20.5). Se constató una interacción entre el consumo de alcohol y la historia de episodios de hepatitis agudas, y posiblemente, entre el consumo de alcohol y diabetes.CONCLUSIONESi) No se ha constatado en Catalunya un aumento de la incidencia y de la mortalidad por CH como en otros países industrializados. Si se ha constatado un incremento de la mortalidad por colangiocarcinoma; ii) Los individuos infectados por el VHB tienen un exceso de mortalidad por enfermedad hepática respecto a los individuos no infectados por el VHB; iii) La replicación del VHB, los antecedentes de episodios de hepatitis agudas, el consumo de alcohol y la coinfección por el VHC incrementan el riesgo de desarrollar enfermedad hepática en individuos infectados por el VHB. / GOALS:To Determine: i) time trends on incidence and mortality by cirrhosis and liver cancer in Catalonia during the period 1980-1997; ii) the mortality by liver disease in a cohort of 2352 blood donors infected by the Hepatitis B Virus (HBV); iii) risk factors to develop liver disease in HBV infected individuals.METHODS: i) Liver cancer incidence and mortality and cirrhosis mortality data were extracted from the population-based cancer registry of Tarragona and from the Catalan Mortality Registry. Statistical analysis: joinpoint analysis and an age-period-cohort modeling. ii) Control Group: 15504 blood donors non-infected by HBV. Record Linkage of the cohort and the control group with the Catalan Mortality Registry. Statistical Analysis: Standardized Mortality Ratios for all causes of death in the cohort. iii) Nested case-control study in the cohort. Cases: ndividuals with liver disease. Controls: individuals without liver disease. Statistical analysis: logistic regression in order to estimate the odds ratios.RESULTS AND CONCLUSIONS:i) During the period of study it has been shown: stability of the incidence and mortality by liver cancer in Catalonia, and a decrease in the mortality by cirrhosis in both sexes excluding males aged 25-35 years old in which mortality by this cause of death increased, and an increase by death of cholangiocarcinoma in both sexes. ii) An excess of risk of death by liver cancer and cirrhosis in the cohort men when they were compared with the control group. It has been observed an excess mortality by cirrhosis in the cohort women. iii) Risk factors associated to de development of liver disease in individuals infected by HBV were replication of HBV, acute hepatitis history, alcohol consumption and Hepatitis C virus infection.

Estudios realizados en diversos países han llegado a la conclusión de que las personas ingresadas en prisión deben ser consideradas como grupos de riesgo de infección por virus de la hepatitis B (VHB). El objetivo fundamental del presente trabajo ha sido investigar la utilidad de las campañas de vacunación anti-hepatitis B en la población reclusa, considerando: l. La inmunogenicidad de la vacuna, y 2. La factibilidad del propio programa (aceptación del cribaje serológico prevacunal y adeherencia al calendario vacunal establecido). Los objetivos adicionales fueron: 1º. Esclarecer si la permanencia en prisión constituye en sí misma un factor de riesgo de infección por los virus de la hepatitis B y D. 2º. Describir el papel que juegan determinadas características personales y otros factores de riesgo de los reclusos sobre la infección por VHB. 3º. Valorar la importancia relativa del consumo de drogas por vía parenteral (CDVP) sobre la infección por VHB y virus de la hepatitis Delta (VHD), y 4º. Interpretar el significado de la presencia aislada de anti-HBc y de anti-HBs, en el examen prevacunal.Previamente a la vacunación, se ha estudiado la prevalencia de marcadores del VHB (HBsAg, anti-HBc y anti-HBs) en 1742 reclusos varones de tres centros penitenciarios (CP) de Cataluña de diferentes características. Ello representa más del 98% de la población total de estos CP (reclusos presentes el día de inicio del estudio, más nuevos ingresos durante un periodo de 4, 5 y 6 meses). En los casos simultáneamente positivos para HBsAg y anti-HBc, se determinó además anti-HBc-IgM, HBeAg, anti-HBe y anti-HD. La presencia de marcadores se ha re1acionado con una serie de vbriab1es (demográficas, penitenciarias y factores de riesgo de infección), obtenidas mediante entrevista personal dirigida.Los reclusos ca1ificados como susceptibles a la infección por VHB (n=705, inc1uyendo 68 casos anti-HBs positivo aislado), fueron vacunados con vacuna recombinante antihepatitis B (20 microgramos, pauta de 0, 1 y 6 meses), practicándose extracciones postvacunales (6º y 9º mes del inicio), para determinar el título de anti-HBs alcanzado.En el examen prevacunal, el 63% de los reclusos presentaron algún marcador del VHB, el 7'1% HBsAg. Tanto el análisis simple como el estratificado (Mantel-Haenszel), mostró que el consumo de drogas por vía parenteral (COVP) era, en cada CP, el factor más fuertemente asociado a la infección por VHB, (para el conjunto de CP, CDVP seropositivos 83'6%, no CDVP seropositivos 41%, OR cruda 7'35, IC 95% 5'84+9'27). Los distintos patrones sero1ógicos de los seropositivos (excepto la prevalencia aislada de anti-HBs), fueron significativamente más comunes en el grupo drogadicto. El 53'9% de los reclusos portadores de HBsAg presentaron anticuerpos anti-HB (65'3% los CDVP vs. 26'7% los no CDVP, OR 5.17).Se consigue vacunar con 2 dosis a 2/3, y con 3 dosis a 1/3 de los reclusos susceptibles, obteniéndose tasas de seroconversión (80% al 9º mes) y títulos de anti-HBs moderadamente más bajos a los logrados en grupos de población sana. Son causa de peor respuesta la mayor edad, el CDVP y la infección por VIH. No inf1uye la presencia previa, aislada, de anti-HBs.La baja adherencia vacunal es fundamentalmente debida a la excarcelación del recluso antes de completar la pauta establecida de 0, l y 6 meses, proponiéndose para mejorar esta adherencia el empleo de pautas flexibles, y la de 0, 1 y 2 meses como pauta de referencia. La vacunación antihepatitis B de los reclusos permite actuar sobre grupos de población muy poco accesibles, de otro modo, a las redes sanitarias convencionales, protegiendo a estas personas dentro de la cárcel y fuera de ella.Se concluye además que el estilo de vida antes, o durante el encarcelamiento, especialmente el CDVP, es la principal causa de propagación de la infección por VHB y VHD, y que el mayor riesgo de los reclusos gitanos se relaciona probablemente con transmisión vertical y horizontal precoz en la infancia. / The fundamental purpose of this study was to investigate the usefulness of anti-hepatitis B vaccination campaigns in the prison population, considering: 1) the vaccine's immunogenicity and 2) the feasibility of the programme itself (acceptance of pre-vaccination serologic screening and compliance of the vaccination schedule).Prior to vaccination, the prevalence of hepatitis B virus (BBV) markers was studied in 1,742 male prisoners in 3 different types of prison centre (PC) in Catalonia. This number of prisoners represents over 98% of these PC's total population. Marker presence was related to a series of variables (demographic, prison and infection risk factors), obtained by means of personal guided interviews.In 63% of prisoners, some kind of HBV marker was detected, which was HBsAg in 7.1%. Parenteral drug consumption (POC) was the factor most strongly associated with BBV infection (raw OR 7.35, IC95% 5.84+9.27) .The different serologic patterns of the seropositive subjects (except the prevalence of anti-HBs alone), were more common in those practising PDC.It was possible to give two thirds of the prisoners 2 vaccine doses, and one-third 3 doses, obtaining seroconversion rates and anti-HBs titres moderately lower than those obtained in groups of healthy population. Advanced age, PDC and BIV infection cause a worse response. The prior presence of anti-HBs alone does not have any influence.Vaccination of prisoners against hepatitis B allows the conventional health networks to act on population groups that otherwise would be difficult to reach, thus protecting these people both inside and outside the prison. In order to improve vaccination schedule compliance, the use of flexible systems is suggested, 0, 1 and 2 months being the reference system.

Rationale: The serotonergic system is involved in the modulation of emotion and plays an important role for personality and vulnerability for psychiatric disorders. In the papers included in this thesis, we investigate three biological factors that have been studied in relation to psychiatric symptoms: Platelet monoamine oxidase B (MAO-B) activity, and variations in the MAO-A and the serotonin transporter (5HTT) genes. We also study intensity dependent auditory evoked potentials (IAEP) as an intermediate phenotype for serotonergic capacity. Platelet MAO-B has been shown to be a biological marker for the properties of monoamine systems, with low activity being associated with vulnerability for high scores of sensation seeking, monotony avoidance, and impulsiveness, as well as for susceptibility for alcoholism. Functional polymorphisms in the promoter of the genes encoding MAO-A and the serotonin transporter result in high- or low- activity alleles that have been associated with numerous psychiatric symptoms. One hypothesis for the shaping of personality is that these genotype variants have prenatal effects on the wiring of the brain. Thus, exploring how the development of the brain is affected by different prenatal serotonin levels is relevant in this context. Observations: (i) Platelet MAOB activity was associated with monoamine metabolites in cerebrospinal fluid from cisterna magna in monkeys, as well as with voluntary alcohol intake, alcohol-induced aggression, and alcohol sensitivity. (ii) The long 5HTTLPR allele was associated with increased IAEP. (iii) The functional MAOA and 5HTT polymorphisms were associated with symptoms of ADHD-related traits in a population based sample of Swedish adolescents. Associations of these candidate genes with ADHD scores were strenghtened when the platelet MAOB activity was combined with genotype. (iv) Our pilot data showed that treatment of pregnant mice with 5HTT blocking antidepressives resulted in more serotonergic cellbodies in lateral wings of dorsal raphe in the offspring, when compared to saline treatment. Conclusions: Our studies support the notion that platelet MAOB activity and IAEP are endophenotypes for monoaminergic capacity and related behaviours. The functional candidate polymorphisms in MAOA and 5HTT were linked to behaviour, however, the cause-relationship is unclear and the explanation for the associations need to be further investigated, possibly with focus on prenatal effects of the polymorphisms.

La Leucèmia Limfàtica Crònica (LLC), la més freqüent de les leucèmies en el món occidental, és una malaltia produïda per la proliferació i cúmul de limfòcits B madurs, actualment incurable. Aproximadament el 50 de les LLCs presenten hipermutacions al gen de les immunoglobulines (IgVH), el que indica que podrien representar un subgrup diferent de cèl·lules que passen pel centre germinal, el lloc fisiològic de les hipermutacions.6. A més a més, els pacients sense hipermutacions tenen un pitjor pronòstic. L'anàlisi de les immunoglobulines és de gran interès pel pronòstic dels malalts d'LLC. Malauradament aquest és costós i llarg. És per això que una de les prioritats a la recerca en LLC és identificar marcadors relacionats amb les hipermutacions de les immunoglobulines. Recentment s'ha descrit la presència de la proteïna ZAP-70 en cèl·lules de LLC sense mutacions a les immunoglobulines. ZAP-70 és una kinasa de la família de tirosines kinases Syk/ZAP-70 que s'expressa normalment en limfòcits T i NK, on participa en la senyalització a través del TCR. També es troba en limfòcits pro/pre-B de ratolí, però no s'ha descrit en limfòcits B humans.La hipòtesi de treball del present projecte consisteix en que la expressió de ZAP-70 podria estar relacionada amb l'estat mutacional de les immunoglobulines i, per tant, amb la progressió de la LLC cap a estadis més avançats. Aquesta proteïna podria trobar-se en limfòcits pro/pre-B humans i en les neoplàsies que en deriven, les leucèmies agudes limfoblàstiques B.RESULTATS I CONCLUSIONS:- El 57 % dels casos de LLC tenen una elevada expressió de ZAP-70. La determinació de ZAP-70 per citometria és un factor pronòstic ràpid i fiable i de gran utilitat clínica en la LLC.- L'expressió de ZAP-70 es troba en limfòcits pro/pre-B normals i desapareix en estadis maduratius posteriors. - El 56% de les leucèmies agudes limfoblàstiques B expressen ZAP-70, probablement com a reflex del seu orígen cel·lular- La proteïna ZAP-70 es troba expressada de manera aberrant en aproximadament un trenta per cent de les leucèmies/limfomes de Burkitt, ja que no es troba el limfòcits B de fenotip madur- la proteïna ZAP-70 i d'altres elements senyalitzadors del pre-TCR/TCR es troben expressats i fosforilats en les cèl·lules de leucèmia aguda limfoblàstica B, possiblement col·laborant amb altres proteïnes senyalitzadores en garantir la senyalització a través del pre-BCR. / BACKGROUND: The mutational status of immunoglobulin variable region genes (IgVH) is an important prognostic parameter in chronic lymphocytic leukemia (CLL). Unfortunately, no good surrogates for IgVH mutations have as yet been identified. The ZAP-70 gene is overexpressed in a subset of CLL cases, this change correlating with the lack of mutations of IgVH.METHODS: To probe the suggestive link between ZAP-70 expression and IgVH mutations, ZAP-70 was analyzed in different cell lines and in 56 CLL pacients using flow cytometry, Western Blot, and/or immunohistochemistry methods. The results were correlated with the IgVH mutational status and patients outcome.RESULTS: Using flow cytometry ZAP-70 expression was higher in IgVH unmutated CLL (n=35) (48 percent of cells ± 21 percent) than in mutated cells (n=21) (5.7 percent of cells ± 3.8 percent). All CLL patients with ZAP-70 expression > 20 percent (n=32) lacked IgVH mutations, whereas 21/24 CLL with ZAP-70 < 20 percent exhibited IgVH mutations. Finally, ZAP-70 expression had prognostic significance for progression and survival in Binet A cases.CONCLUSIONS: ZAP-70 expression by flow cytometry correlated with the IgVH mutational status and had prognostic significance in CLL patients. Therefore, ZAP-70 analysis can be considered a reliable surrogate for the IgVH mutational status in CLL and a useful tool for assessing prognosis in this disease.PURPOSE: ZAP-70 gene is normally expressed in T and NK cells, where is required for the T-cell receptor signaling. It has been described that ZAP-70 contributes to the B-cell development at early stages of B-cell differentiation in mice. The purpose was to investigate the presence of ZAP-70 in normal pro/pre B-cells and mature B-cells, and in tumoral cells from B-acute lymphoblastic leukemias (B-ALLs).EXPERIMENTAL DESIGN: ZAP-70 expression was ascertained by flow cytometry, immunofluorescence, Western blot, and quantitative RT-PCR. Analysis of ZAP-70 and other signalling proteins of the pre-TCR/TCR was performed by Western Blot.RESULTS: ZAP-70 was expressed in pro/pre B-cells, but not in normal mature B-cells derived from bone marrow, peripheral blood or tonsil. Among tumoral cells, ZAP-70 was expressed in 56% of B-ALLs with pro/pre B-cell phenotype and in 4/6 Burkitt/ALL lymphomas. Moreover, other elements of the pre-TCR/TCR signaling pathway, like LAT and Lck, were also found in B-ALL cells.CONCLUSIONS: Amongst normal B-cell subsets, ZAP-70 was found expressed in normal pro/pre B-cells, but not in a significant proportion of normal B-cells with mature phenotype. Moreover, the presence of ZAP-70 in B-ALLs probably reflects their cellular origin. The lack of ZAP-70 expression in normal mature B-cells suggests that its expression in mature-derived neoplasms with different cellular origin, such as Burkitt's lymphoma and chronic lymphocytic leukemia, might be due to an aberrant phenomenon.