L'objectif de cette thèse était de caractériser phénotypiquement et fonctionnellement les cellules NK activées par l'IL-21 et d'étudier leur interaction avec les lymphocytes T CD4*. Les lymphocytes Natural Killer (NK) sont essentiels pour la protection exercée par l'immunité innée. Les cellules NK, en plus de leurs fonctions cytotoxiques, peuvent orienter la réponse immunitaire adaptative vers un profile TH1 grâce à leur production d'IFN-y. Dans cette étude, nous avons montré que l'IL-21, une cytokine produite in vivo au cours de l'inflammation chronique ou de maladies infectieuses, induit la différenciation d'une sous-population spécifique de cellules NK co-exprimant ÇD86 et HLA-DR. Les cellules NK HLA-DR* induites par l'IL-21 sont capables d'apprêter et de présenter des antigènes aux lymphocytes T CD4*. De plus, ces cellules produisent MIF (Macrophage Migration Inhibitory Factor) et apportent un signal de costimulation durant le priming des lymphocytes T CD4 naïfs en induisant leur différenciation vers un profile central mémoire (Tcm) peu différencié. Les Tcm activés en présence des cellules NK HLA-DR" sont CXCR3' CCR4' CCR6' CXCR5' et produisent de PIL-2 et du TNF-a. La costimulation des lymphocytes T ÇD4 par les cellules NK HLA-DR" prévient l'acquisition d'un phénotype effecteur mémoire induit par l'IL-2. Ainsi, ces résultats montrent une nouvelle fonction pour l'IL-21 qui peut moduler l'interaction NK/CD4 et favoriser l'expansion des lymphocytes centraux mémoires. / Natural Killer lymphocytes are critical for innate immunity-mediated protection. Main roles of NK cell rely on their cytotoxic functions or depend on the tuning of TH1 adaptive immunity by IFN-y. Here, we provide evidence that 1L-21, a cytokine produced in vivo during chronic inflammation or infectious diseases, promotes the differentiation of a specifie subset of NK co-expressing CD86 and HLA-DR. IL-21-propagated HLA-DR' NK were able to process and present antigens to CD4' T lymphocytes. More importantly, IL-21-propagated HLA-DR' NK produced macrophage migration inhibitory factor and provided a co-stimulatory signaling during naive CD4* T cell priming inducing the differentiation of uncommitted central memory (Tcm) lymphocytes. Tcm expanded in the presence of HLA-DR* NK were CXCR3 CCR4" CCR6' CXCR5' and produced IL-2, as well as low levels of TNF-a. Co-stimulation of CD4* T cells by HLA-DR' NK prevented the acquisition of effector memory phenotype induced by IL-2. Altogether, these results demonstrate a novel function for IL-21 in tuning NK and CD4~ T cell interactions promoting a specifie expansion of central memory lymphocytes.

Introdução: A doença de Alzheimer (DA) é considerada um dos importantes pro blemas de Saúde Pública, significando, portanto, grande desafio para a geron tologia e geriatria. É causa mais comum de demência que cursa com declínio cognitivo e funcional e alterações com portamentais, porém, poucos estudos relatam a correlação existente entre o declínio motor, considerando o equilíbrio, a força e a implicação na capacidade funcional e na ocorrência de quedas nessa população, principalmente na fase inicial da DA. Objetivos: Identificar o grau de capacidade funcional dos idosos portadores da DA e adequação do seu ambiente domiciliar propício às suas atividades de vida diária, e ocorrência de quedas, proporcionando, assim, melhor qualidade de vida. Métodos: Foi efetuado um estudo epide miológico descritivo, tipo inquérito pros pectivo. Foram estudados 30 pacientes portadores de DA, com idade acima de 60 anos. Foi utilizada avaliação pes soal do paciente, do ambiente e instru mento de avaliação da Medida de Inde pendência Funcional (MIF). Resultados e Conclusões: Dos pacientes estudados, 60% eram do sexo feminino, 47% a profissão era do lar, o intervalo modal do tempo de DA foi de 1,5 - 2 anos e 57% deles apresentaram pelo menos uma queda. Em relação aos cuidadores, 80% eram do sexo feminino e apresentaram média de idade de 59 anos. Em relação à MIF, foi observado grau 6 (independên cia modificada) nos parâmetros: função banho (70%), controle de esfíncter (27%), função transferência (90%), função locomoção (83%). Na função cognitiva, 100% dos pacientes apresentaram grau 5 em pelo menos uma função. Sobre o ambiente, observou-se que os principais fatores de risco foram calçados inadequados, móveis soltos pelo caminho, altura inadequada do vaso sanitário e ausência de barras de apoio. Através da MIF, pôde-se avaliar o grau de comprometimento das funções cognitivas/sociais e identificar a independência modificada das funções motoras dos pacientes com DA, na fase leve. Embora o número de pacientes estuda dos seja pequeno, contudo as evidências parecem mostrar que aumentou os riscos de quedas em função da MIF e do ambiente. / Alzheimer\'s disease is a major public health problem, meaning that it is considered a great challenge to Geria trics and Gerontology. It is the most common cause of dementia, which leads to cognitive and functional decline and behavioral changes. However, few studies report the existing relation between motor decline (balance), strength, and their influence on function abilities as well as the occurrence of falls among the population afflicted by AD, mainly in its early stage. Objectives: This study aimed to identify the functio nal ability level in AD senior citizens and home setting adjustment for a proper environment in which they could carry out daily activities. It also aimed to identify occurrence of falls in order to provide them with a better quality of life. Methods: A survey-like descriptive epidemiological study was conducted. Thirty AD patients over 60 years old were studied. An assessment of the patients and their environment using the Functional Independence Seale was made. Results: 60% of the patients studied were female and 47% were housewives. Their modal AD time interval was 1.5 - 2.0 years, and 57% of them had had at least one fall. As for caregivers, 80% of them were female and averaged 59 years of age. As for Functional Independence Scale, a level 6 (Altered Independence) was observed in the following parameters: Bathing function (70%), sphincter control (27%), transfer function (90%), and movement function (83%). Regarding cognitive function, 100% of the patients showed a 5 level for at least one function. As re gards environment, the main risk factors were inadequate footwear, pieces of furniture on the way, toilet height, and absence of supporting railing. Conclusion: It was possible to identify cognitive changes and altered independence motor functions through the IFS. Those changes, thus, increased risks of falls posed mainly by environ mental threats. Therefore, IFS is considered a good and important instrument to asses AD patients\' functional ability.

Introdução: A doença de Alzheimer (DA) é considerada um dos importantes pro blemas de Saúde Pública, significando, portanto, grande desafio para a geron tologia e geriatria. É causa mais comum de demência que cursa com declínio cognitivo e funcional e alterações com portamentais, porém, poucos estudos relatam a correlação existente entre o declínio motor, considerando o equilíbrio, a força e a implicação na capacidade funcional e na ocorrência de quedas nessa população, principalmente na fase inicial da DA. Objetivos: Identificar o grau de capacidade funcional dos idosos portadores da DA e adequação do seu ambiente domiciliar propício às suas atividades de vida diária, e ocorrência de quedas, proporcionando, assim, melhor qualidade de vida. Métodos: Foi efetuado um estudo epide miológico descritivo, tipo inquérito pros pectivo. Foram estudados 30 pacientes portadores de DA, com idade acima de 60 anos. Foi utilizada avaliação pes soal do paciente, do ambiente e instru mento de avaliação da Medida de Inde pendência Funcional (MIF). Resultados e Conclusões: Dos pacientes estudados, 60% eram do sexo feminino, 47% a profissão era do lar, o intervalo modal do tempo de DA foi de 1,5 - 2 anos e 57% deles apresentaram pelo menos uma queda. Em relação aos cuidadores, 80% eram do sexo feminino e apresentaram média de idade de 59 anos. Em relação à MIF, foi observado grau 6 (independên cia modificada) nos parâmetros: função banho (70%), controle de esfíncter (27%), função transferência (90%), função locomoção (83%). Na função cognitiva, 100% dos pacientes apresentaram grau 5 em pelo menos uma função. Sobre o ambiente, observou-se que os principais fatores de risco foram calçados inadequados, móveis soltos pelo caminho, altura inadequada do vaso sanitário e ausência de barras de apoio. Através da MIF, pôde-se avaliar o grau de comprometimento das funções cognitivas/sociais e identificar a independência modificada das funções motoras dos pacientes com DA, na fase leve. Embora o número de pacientes estuda dos seja pequeno, contudo as evidências parecem mostrar que aumentou os riscos de quedas em função da MIF e do ambiente. / Alzheimer\'s disease is a major public health problem, meaning that it is considered a great challenge to Geria trics and Gerontology. It is the most common cause of dementia, which leads to cognitive and functional decline and behavioral changes. However, few studies report the existing relation between motor decline (balance), strength, and their influence on function abilities as well as the occurrence of falls among the population afflicted by AD, mainly in its early stage. Objectives: This study aimed to identify the functio nal ability level in AD senior citizens and home setting adjustment for a proper environment in which they could carry out daily activities. It also aimed to identify occurrence of falls in order to provide them with a better quality of life. Methods: A survey-like descriptive epidemiological study was conducted. Thirty AD patients over 60 years old were studied. An assessment of the patients and their environment using the Functional Independence Seale was made. Results: 60% of the patients studied were female and 47% were housewives. Their modal AD time interval was 1.5 - 2.0 years, and 57% of them had had at least one fall. As for caregivers, 80% of them were female and averaged 59 years of age. As for Functional Independence Scale, a level 6 (Altered Independence) was observed in the following parameters: Bathing function (70%), sphincter control (27%), transfer function (90%), and movement function (83%). Regarding cognitive function, 100% of the patients showed a 5 level for at least one function. As re gards environment, the main risk factors were inadequate footwear, pieces of furniture on the way, toilet height, and absence of supporting railing. Conclusion: It was possible to identify cognitive changes and altered independence motor functions through the IFS. Those changes, thus, increased risks of falls posed mainly by environ mental threats. Therefore, IFS is considered a good and important instrument to asses AD patients\' functional ability.

Streptococcus pneumoniae[italicized everytime] (S. pneumoniae) causes a spectrum of disease severity, and human host factors likely play a role in this variation. One candidate factor is macrophage migration inhibitory factor (MIF), a pro-inflammatory cytokine and upstream regulator of innate immunity. The MIF[italicized when not in parenthesis] promoter contains two functional polymorphisms, a tetranucleotide (CATT) repeat such that MIF expression increases with repeat number from 5-8 and a single nucleotide polymorphism (SNP) leading to a G-to-C transition, which results in increased MIF expression in cell line reporter assays. Emerging data suggest an association between high-expression MIF alleles and inflammatory disease. This study comprised two parts. For the in vitro portion, we hypothesized that peripheral blood monocytic cells (pBMCs) cultured from healthy individuals with low-expressing MIF genotypes (5-CATT alleles or SNP-GG) would have lower MIF content and release than those from individuals with high-expressing MIF genotypes (7-CATT or SNP-C alleles). For the in vivo study, we hypothesized that individuals with low-expressing MIF genotypes would have less severe systemic inflammatory responses than individuals with high-expressing MIF genotypes in response to S. pneumoniae infection. Blood samples and chart findings were collected prospectively at three Connecticut hospitals from 30 inpatients with documented invasive S. pneumoniae infections. Genomic DNA was isolated from host blood, amplified, and genotyped using fragment analysis (CATT repeat) and allelic discrimination (SNP) methods. Fishers exact tests were used to compare genotypes and disease severity. For the in vitro experiments, there were no differences observed in serum MIF levels or MIF content or release from pBMCs based on MIF genotype. In the cohort of patients infected with S. pneumoniae, serum MIF levels among enrolled subjects were significantly higher than the reported normal values, but levels did not vary with genotype or disease severity. The SNP genotype was not correlated with disease severity or occurrence of meningitis. The CATT genotype did not correlate significantly with disease severity or occurrence of meningitis, although there was a trend suggesting an association between the 7-CATT allele and meningitis (p = 0.1188, 8% without meningitis had a 7-CATT allele vs. 40% with meningitis). More patient samples will need to be analyzed in order to definitively elucidate the role of MIF genetics in infection with S. pneumoniae

Orientador: Marcos Augusto de Moraes Silva / Banca: Marcos Augusto de Moraes Silva / Banca: Antonio S. Martins / Banca: Mônica Oliveira Orsi Gameiro / Banca: João Carlos Braga / Banca: Edson Lopes Lavado / Resumo: Os serviços de saúde acompanhando o desenvolvimento econômico e alta competitividade direcionam atenção à qualidade com que os serviços estão sendo realizados. A avaliação de um serviço de saúde está ligada à percepção do paciente na medida em que suas expectativas foram atendidas na efetividade e na qualidade das intervenções. O objetivo deste estudo consistiu em avaliar a funcionalidade e a qualidade de serviço em pacientes de cirurgia cardíaca no período pré-operatório e pós-operatório recente 6ºPO. Buscou-se ainda relacionar o nível de funcionalidade e de qualidade do serviço com: gênero, faixa etária e uso de circulação extra-corpórea (CEC). Foram estudados 82 pacientes, submetidos à cirurgia cardíaca eletiva, operados por toracotomia médio esternal, de ambos os gêneros, com idade entre 31 e 83 anos. Os pacientes entraram no estudo consecutivamente, de acordo com os critérios de inclusão e exclusão, a partir de março a setembro de 2006. Os pacientes foram divididos em subgrupos de acordo com: gênero, faixa etária, tipo de cirurgia, primeira cirurgia cardíaca ou reoperação e uso de CEC. O nível de funcionalidade foi avaliado pela escala MIF e a qualidade dos serviços prestados pela escala SERVQUAL-Card, escala modificada da SERVQUAL. A funcionalidade foi prejudicada após a cirurgia cardíaca até o 6º PO. Os níveis mais elevados de perda funcional ocorreram na categoria de locomoção, concentrando-se na atividade de subir escadas. No pré-operatório os pacientes mais jovens apresentaram níveis mais elevados de funcionalidade. Os níveis diminuíram com o aumento da idade dos pacientes e a menor funcionalidade foi na faixa etária de 70 a 85 anos. Tanto no aspecto motor como no cognitivo a utilização de CEC não esteve relacionada com o grau de perda funcional no pós-operatório recente. A qualidade dos serviços percebida pelo paciente foi satisfatória. / Abstract: The health services, following the economical development and the high competition, focus its attention on the quality of services. The evaluation of a health service is related to the patient perception as his expectations are met in the quality and effectiveness of the interventions.This paper was aimed at evaluating the service functionality and quality in cardiac surgery patients during the preoperative and recent postoperative periods (6° PO). It was also aimed at relating the service level of functionality and quality with the following: gender, age, and use of extra-corporal circulation (ECC). Eight two patients (men and women), subjected to elective cardiac surgery, were studied; they were operated by means of sternal medium thoracotomy and their ages ranged from 31 to 83 years. The patients were entered the study consecutively, according to the criteria of inclusion and exclusion, from March to September, 2006. The patients were divided into sub-groups in accordance with gender, age, type of surgery, first cardiac surgery or re-operation and use of ECC. The functionality level was assessed by using the MIF scale and the quality of the services was measured by the SERVQUAL scale-Card, modified SERQUAL scale. The functionality was harmed after the cardiac surgery until the 6° PO. The most elevated levels of functional losses occurred in the locomotion category, concentrating on the activity of climbing stairs. During the preoperative period, the youngest patients presented more elevated levels of functionality. The levels were decreased according to the increase in the patients’ ages and the smallest functionality was found in the ages of 70 to 85 years. Both in the motor aspect and in the cognitive aspect, the use of ECC was not related to the degree of functional loss during the recent postoperative period. The quality of the services watched by the patients was considered satisfactory. / Doutor

No description available.

Long-term postnatal treatment of rats with SCH 23390 is associated with a reduction in the development of dopamine D1 receptors in the striatum. Because the tripeptide, l-prolyl-l-leucylglycinamide (PLG) attenuates the neuroleptic-induced increase in D2 receptors in the striatum in adult rats, this study was undertaken with the objective of determining whether PLG could modulate a developmental alteration in the D1 subtype of receptor. Rats were treated with the dopamine D1 receptor antagonist, SCH 23390 (R[+]-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1-H-3benzazepine) (0.30 mg/kg/d i.p.) for 32 successive days from birth, while D1 receptors in the striatum were assessed at 5 and 8 weeks from birth. Postnatal treatment with SCH 23390 reduced in vitro binding of [3H]SCH 23390 to homogenates in the striatum by 70% at 8 weeks. Scatchard analysis at 5 weeks determined that the Bmax for the binding of [3H]SCH 23390 was reduced by 78%, while the Kd was unaltered. When PLG (1.0 mg/kg/d i.p.) was administered together with SCH 23390 for the initial 32 days from birth, the binding of [3H]SCH 23390 to homogenates of the striatum was unchanged from that of the control group at 8 weeks. Also, at 5 weeks the Bmax and Kd were unaltered from control in the group that was treated with both SCH 23390 and PLG. The binding of [3H]SCH 23390 was not altered from control in the group treated with PLG alone. Also, PLG given in vitro did not alter the binding of [3H]SCH 23390 to control homogenates of the striatum. These findings indicate that PLG is able to attenuate neuroleptic-induced alterations in dopamine d1 receptors in the striatum.

Long-term postnatal treatment of rats with the dopamine D2 receptor antagonist, spiroperidol, results in the impaired development of striatal D2 receptors. Because the tripeptide prolyl-leucyl-glycinamide (MIF-1) attenuates haloperidol-induced up-regulation of striatal dopamine D2 receptors in adult rats, we studied the effect of MIF-1 on the spiroperidol-induced alteration of striatal D2 ontogeny. Postnatal treatment of rats with spiroperidol (1.0 mg/kg/day, IP, ×32 days from birth) resulted in a 74% decrease in the Bmax for [3H]spiroperidol binding with no change in the Kd at 5 weeks. When rats were studied at 8 weeks, in the absence of additional treatment, total specific [3H]spiroperidol binding was reduced by 59%. While MIF-1 alone (1.0 mg/kg/day, IP, ×32 days from birth) had no effect on [3H]spiroperidol binding, MIF-1 completely attenuated the ontogenic impairment of striatal D2 receptors that was produced by spiroperidol treatment. At 5 weeks the Bmax for [3H]spiroperidol binding was at the saline control level in the group of rats cotreated with spiroperidol and MIF-1. At 8 weeks, with no additional treatments, the specific binding of [3H]spiroperidol to striatum was also at control levels in the group cotreated with spiroperidol and MIF-1. These findings demonstrate that MIF-1 attenuates spiroperidol-induced impairment of development of striatal dopamine D2 receptors in rats.

Our previous report showed that the brain peptide Tyr-MIF-1 (Tyr-Pro-Leu-Gly-NH2) blocks the inhibitory effect of morphine sulfate on E-rosette formation by human peripheral blood lymphocytes (PBL). In this study, additional in vitro effects of Tyr-MIF-1 on human PBL were studied. The percentages of positive cells for CD 2, a sheep erythrocyte receptor, CD 4 and CD 8 were unchanged after incubation of PBL with morphine or morphine plus Tyr-MIF-1. Tyr-MIF-1 was not mitogenic by itself. The addition of Tyr-MIF-1 did not increase the proliferative response of PBL to Con A, although morphine did. Tyr-MIF-1 did not activate PBL to produce IL 2 nor did it affect the production of IL 2 by Con A-stimulated PBL. The results suggest that Tyr-MIF-1 does not directly modulate CD 2, CD 4 and CD 8 expression, does not alter the proliferative response of PBL, and does not affect the production of IL 2.

Because of conflicting reports of the actions of the antiparkinsonian agent L-prolyl-L-leucyl-glycine amide (PLG, MIF-I) on the turnover of Striatal dopamine (DA), this process was reinvestigated. In the present series of studies, it was found that neither our MIF-I (200 ng ICV) nor the MIF-I used by Versteeg et al. [25]was effective in altering the rate of decline of endogenous DA in the caudate nucleus of rats pretreated with α-methyl-p-tyrosine (300 mg/kg IP). In addition, our MIF-I (1 mg/kg IP) did not change endogenous dihydroxyphenylacetic acid (DOPAC) or homovanillic acid (HVA) in rat striatum. These studies indicate that MIF-I does not alter the turnover rate of DA in nigrostriatal neurons. It is possible that MIF-I or some substance released by MIF-I acts at a posfsynaptic receptor site.