Dissertação (mestrado)—Universidade de Brasília, Faculdade de Medicina, 2007. / Submitted by Rebeca Araujo Mendes (bekinhamendes@gmail.com) on 2009-12-22T00:13:19Z No. of bitstreams: 1 2007_VanessaVianaCardoso.pdf: 1910167 bytes, checksum: a55c514050e76b694ea5803428ab0065 (MD5) / Approved for entry into archive by Carolina Campos(carolinacamposmaia@gmail.com) on 2010-01-07T18:45:04Z (GMT) No. of bitstreams: 1 2007_VanessaVianaCardoso.pdf: 1910167 bytes, checksum: a55c514050e76b694ea5803428ab0065 (MD5) / Made available in DSpace on 2010-01-07T18:45:04Z (GMT). No. of bitstreams: 1 2007_VanessaVianaCardoso.pdf: 1910167 bytes, checksum: a55c514050e76b694ea5803428ab0065 (MD5) Previous issue date: 2007 / A leishmaniose visceral é caracterizada pela visceralização da leishmânia pelo sistema fagocítico-mononuclear. A expressão clínica da doença depende de fatores como a espécie e virulência da cepa e o tipo de resposta do sistema imunitário, características individuais, genética e o meio ambiente em que o indivíduo está inserido. O glucantime continua sendo a droga de primeira escolha no tratamento desta doença e a resposta clínica ao tratamento depende da inter-relação de vários fatores. O objetivo deste trabalho foi avaliar a influência do glucantime sobre a função dos monócitos e neutrófilos de crianças com leishmaniose visceral. Foram avaliados os parâmetros clínico-evolutivos e a função dos fagócitos de 23 crianças com leishmaniose visceral e 18 crianças controles sem a doença. A capacidade fagocitária dos monócitos e neutrófilos e a capacidade microbicida foram avaliadas antes, após 48 h e ao final do tratamento com glucantime. O teste de fagocitose foi realizado utilizando-se Saccharomyces cerevisiae, pelos receptores que reconhecem padrões moleculares de patógenos e pelos receptores que reconhecem os componentes do complemento e porção Fc da IgG. A produção de ânions superóxido foi avaliada pelo teste do nitroblue tetrazolium. A desnutrição foi mais freqüente entre as crianças com leishmaniose visceral, e o escore z da estatura para idade (E/I) mostrou relação direta com a capacidade microbicida. Infecção bacteriana foi observada em 35% das crianças, sendo o pulmão o local mais freqüentemente acometido. Hepatite ocorreu em 74% dos casos e insuficiência hepática foi observada em uma criança. Provavelmente houve hepatotoxidade em 13% dos casos. O tamanho do baço mostrou relação inversa com a concentração de hemoglobina e com o índice fagocitário dos monócitos. Observou-se melhora da febre em 61% das crianças no sétimo dia de tratamento, redução do tamanho do baço e do fígado das crianças em 55% e 54%, respectivamente, na segunda semana, melhora da pancitopenia com aumento em 20% da concentração de hemoglobina, em 46% no número de glóbulos brancos e em 67% no número das plaquetas e tendência à diminuição das enzimas hepáticas na segunda semana de tratamento. Houve dois óbitos devidos a insuficiência respiratória e hepática. O índice fagocitário de neutrófilos e monócitos estava aumentado nas crianças com leishmaniose visceral antes do tratamento, devido ao aumento da média de levedura ingeridas por fagócito, o que sugere um aumento na expressão de receptores para complemento e porção Fc das IgG nestes fagócitos, induzidas pela infecção parasitária. Entretanto, observamos uma diminuição na capacidade microbicida dos fagócitos nas crianças com leishmaniose visceral antes do tratamento específico. O tratamento com o glucantime contribuiu para a melhora dos parâmetros clínicos e laboratoriais e aumentou a capacidade microbicida dos fagócitos. Entretanto, esta droga modulou negativamente a capacidade fagocitária. Mostramos a ação desta droga como moduladora da resposta do sistema de fagócitos. A aumentada capacidade fagocitária associada com a diminuída produção de moléculas microbicidas pode fazer parte dos mecanismos de escape do parasita da resposta imune do hospedeiro e o tratamento com o antimonial possivelmente está atuando como um mecanismo de contra-escape, aumentando a competência microbicida destas células. ___________________________________________________________________________________ ABSTRACT / Visceralizing of leishmaniasis is in part due to the mononuclear phagocyte system. The clinical manifestations depend on several factors as parasite and virulence of the strain, the type of immune response, genetic and environment. The meglumine antimoniate remains the first choice for the treatment of the disease and the cure depends on several factors. This work aimed to evaluate the influence of meglumine antimoniate on phagocytosis and superoxide production by phagocytes from visceral leishmaniasis children. Phagocytosis was assessed in 16 infected children, before, 9 children 48h after treatment and in 16 children at the end of the therapy, and in 18 normal control, using Saccharomyces cerevisiae, through pattern recognition receptors and opsonin receptors. The production of superoxide was assessed by the nitroblue tetrazolium test. Clinical and laboratorial parameters of 23 children were evaluated and followed up. The malnutrition was frequent in children with visceral leishmaniasis and the z score height for age showed positive relationship with the microbicidal capacity. Bacterial infection was observed in 35% of the diseased children and the lung was the most frequent site of infection. Acute hepatitis was observed in 74% of the cases and hepatic insufficiency was present in one patient. In 13% of the cases hepatotoxicity was observed, probably secondary to meglumine antimoniate use. The spleen size showed negative relationship with the hemoglobin concentration and phagocytic index of monocytes. The fever decreased in 61% of the children in the seventh day of treatment. After two weeks there was 55% and 54% reduction of spleen and liver, respectively, 20% increase of hemoglobin concentration, 46% increase of leukocytes and 67% increase of platelets and showed tendency to reduction of hepatic enzymes. There were two deaths due to hepatic insufficiency and respiratory failure. The phagocytic index of monocytes and neutrophils was increased in children with visceral leishmaniasis before treatment due to an increase of the median of ingested S. cerevisiae by phagocyte. This suggests an increase of opsonin receptors expression induced by parasitic infection. However, it was observed reduction of microbicidal capacity of phagocytes in children with visceral leishmaniasis before specific treatment. The antimoniate treatment contributed to improve the clinical and laboratorial parameters and the microbicidal capacity of phagocytes. However, the antimoniate modulated negatively the phagocytic capacity. The increased phagocytic capacity associated with the reduction of microbicidal molecules may play a role in the escape mechanism of the parasite from the host immune response and the antimonial treatment is probably acting as a counter escape mechanism, therefore increasing the microbicidal capability of these cells.

Visceral leishmaniasis is a potentially lethal disease. It is clinically presented by viscerotropic dissemination to internal organs. The agents causing the disease are all grouped within the L. donovani "complex" (Lainson and Shaw, 1987). Many issues in the taxonomy within this complex are still controversial, such as the agents causing visceral leishmaniasis in Sudan and the validity and the identity of L. "archibaldi". The agents causing VL in Sudan are at present defined on the basis of an isoenzyme classification as Leishmania donovani, L. infantum and L. "archibaldi". L. "archibaldi" only differs from L. donovan; in the mobility of one enzyme (GOT). The presence of all three species in Sudan has been contested by many authors who suggested grouping the zymodemes belonging to these two taxa in a single group L. donovan; sensu lato (Ashford et al. 1992). In this study we have obtained the sequence of the chitinase gene of 37 stocks of these parasites from the Sudan and elsewhere to construct a phylogenetic tree. A panel of microsatellite markers suitable for classifying these species was also developed. Two strategies were used to develop the panel of microsatellites. Firstly, the Leishmania major genome sequence was used to identify microsatellite markers. Twenty-seven independent microsatellite loci were identified by BLAST search of the L. major genome. 13 out of 27 primers designed against the L. major sequences also amplified a single product of approximately the expected size from L. donovani. These 13 microsatellites were tested for variation in a panel of the L. donovan; "complex". Only two out of 13'loci that were polymorphic in L. major were also polymorphic in L. donovani. Almost all microsatellite peR products were significantly smaller in all the test strains than they were in L. major. Therefore, the use of the L. major genome sequence to identify microsatellite loci is unlikely to be an efficient method of identifying microsatellite loci in other Leishmania strains. Secondly, forty microsatellites were identified in L. donovani by an enrichment method (http://WWW.liv.ac.uk/-kempsj/genomics.htmI.).Primers for twenty of these amplified a single sharp band from L. donovani DNA and were found to be polymorphic between L. donovani stocks. Phylogenetic trees were constructed using microsatellite data. Both chitinase and microsatellite phylogenies showed that stocks of all three species isolated from Sudan form a single monophyletic group within the Leishmania donovani, / L. infantum clade. We conclude that L. "archibaldi" is not a valid species and the definitions of L. donovani and L. infantum may have to be revised in the light of this data.

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Leishmaniasis, a protozoan infection caused by Leishmania parasites is a neglected disease affecting millions across the world. It is exhibited by diverse clinical presentations that broadly classified as visceral (VL) and cutaneous (CL) leishmaniasis. Both CL and VL are endemic to Ethiopia, which the later is generally considered as fatal, if left untreated. Leishmania donovani is the sole agent of Ethiopian human VL. In Africa, the worst VL affected regions are found in Sudan and Ethiopia. VL is considered as an endemic and at the same time emerging disease in north, northwest, south and southwest with sporadic cases in Eastern Ethiopia. The epidemiology is more or less associated with seasonal migration to endemic areas and HIV/AIDS. The transmission of CL in Ethiopia is known to involve zoonotic cycle while VL transmission isn't clearly understood despite traditional generalization of anthroponosis in East African platform. The aim of this dissertation is to determine VL transmission cycle and study variability L. donovani and P. orientalis in Ethiopia. Studies on human and non-human hosts were conducted to determine the transmission dynamics. To assess the role of symptomatic and asymptomatic L. donovani infected persons in the epidemiology of VL, a community based cohort was conducted. As the...

De acordo com dado da OrganizaÃÃo Mundial de SaÃde (OMS) existem cerca de 12 milhÃes de pessoas no mundo com leishmaniose. No Brasil o agente etiolÃgico da Leishmaniose visceral (LV) à a Leishmania chagasi, e a principal forma de transmissÃo do parasita ao homem e outros hospedeiros mamÃferos à por meio da picada do mosquito fÃmea de insetos dÃpteros da famÃlia Psychodidae, cujo vetor principal à o Lutzomyia (Lutzomyia) longipalpis (Lutz & Neiva). O calazar ou leishmaniose visceral à uma doenÃa tropical que se caracteriza pela presenÃa de febre, anemia, hepatoesplenomegalia, manifestaÃÃes hemorrÃgicas, alÃm de linfoadenomegalia, perda de peso, taquicardia, tosse seca, diarrÃia, febre, pancitopenia e hipergamaglobulinemia. O envolvimento hematolÃgico à comum nos pacientes com LV, sendo a anemia a anormalidade mais freqÃente decorrente de natureza multifatorial e com prevalÃncia variÃvel conforme a populaÃÃo analisada. Consiste em avaliar o padrÃo das alteraÃÃes hematolÃgicas perifÃricas dos pacientes com Leishmaniose Visceral. As amostras de sangue foram colhidas apÃs o diagnÃstico laboratorial de pesquisa de formas amastigotas de Leishmania sp em aspirado medular nos pacientes (n=30) do Hospital SÃo Josà de DoenÃas Infecciosas, em Fortaleza, CearÃ, no perÃodo de Janeiro de 2007 a Julho de 2008 e de um grupo controle (n=30) constituÃdo de doadores de sangue do HEMOCE. As anÃlises laboratoriais foram realizadas no LaboratÃrio de AnÃlises ClÃnicas do Hospital Geral de Fortaleza e no LaboratÃrio Louis Pasteur Medicina DiagnÃstica. As contagens dos elementos sanguÃÃneos foram realizadas em contador hematolÃgico Pentra 120 ABX, seguido de avaliaÃÃo citomorfolÃgica. As dosagens bioquÃmicas foram realizadas em Analisador bioquÃmico HITACHI Modular P800 e Modulo E/RocheÂ. A comparaÃÃo entre os grupos, em relaÃÃo à mÃdia das variÃveis quantitativas foi realizada atravÃs do Teste t de Student, para os dados com hipÃtese de distribuiÃÃo normal e Mann-Whitney, no caso de nÃo normalidade dos dados. Foram considerados estatisticamente significantes valores de p < 0,05. Das anÃlises (n=30) pacientes, observou-se que 63%(19) dos pacientes sÃo do interior do Estado do Cearà e 37%(11) pacientes sÃo da capital, Fortaleza. Que 80%(24) dos pacientes sÃo do sexo masculino e 20(8%) do sexo feminino. A maioria dos pacientes, 57% apresentavam-se na faixa etÃria entre 31 a 45 anos de idade. Com relaÃÃo ao tempo da doenÃa atà a data do diagnÃstico laboratorial, 47%(14) dos pacientes jà apresentavam sinais clÃnicos da doenÃa com 30 a 90 dias. Obtivemos para o sexo masculino contagem das HemÃcias, uma mÃdia de 3,69 0,6644 (x106/mm3), Hemoglobina de 9,383Â1,3002 (g/dL), HematÃcrito de 28,6708Â4,0687(%),para o sexo feminino contagem das HemÃcias, uma mÃdia de 3,525 0,6233(x106/mm3), Hemoglobina de 8,5666Â1,6561(g/dL), HematÃcrito de 26,9666Â3,9026(%). Com relaÃÃo aos Ãndices hematimÃticros observamos para ambos os sexo, um Volume Corpuscular MÃdio(VCM) de 78,1Â7,0 (fL), Hemoglobina Corpuscular MÃdia(HCM) de 25,42Â2,51 (pg), ConcentraÃÃo de Hemoglobina Corpuscular MÃdia(CHCM) de 32 2,15 (%), DistribuiÃÃo de amplitude das hemÃcias(RDW) de 15,337Â2,435 (%), Contagem de reticulÃcitos de 20.636,63Â20.300,39 (/mm3). Das anÃlises citomorfolÃgica, Das anÃlises morfolÃgicas evidenciou-se um perfil laboratorial caracterÃstico de anemia do tipo microcÃtica e hipocrÃmica seguido de normocÃtica e normocrÃmica e em 65% das amostras observamos a presenÃa de ârouleauxâ. Para as determinaÃÃes do Ferro sÃrico obtivemos uma mÃdia de 32,53Â17,31 (Âg/dL), Transferrina de 146,83Â42,19 (mg/dL), Ferritina de 1339,47Â599,05 (ng/mL), Vitamina B12 de 573,5Â253,94 (pg/mL). Ãcido FÃlico de 10Â3,47 (ng/mL). Para as contagens dos leucÃcitos a mÃdia observada foi de 2802,33 Â2322,16 (nÂ/mm3), neutrÃfilos de 1.426,33Â1.348,88(nÂ/mm3), linfÃcitos de 982,60Â576,47x(nÂ/mm3), monÃcitos de 350,13Â283,47(nÂ/mm3), plaquetas de 120,233,33Â90.640,89 (nÂ/mm3). Para as determinaÃÃes do VHS ao diagnÃstico, os pacientes apresentaram uma mÃdia de 81,77 mm na primeira hora de observaÃÃo. As determinaÃÃes do TAP nos mostrou que ao diagnÃstico os pacientes apresentaram uma mÃdia de 67,87% de atividade de protrombina. Das anÃlises observou-se que na LV existe um comprometimento na hematopoese traduzindo no sangue perifÃrico por uma pancitopenia a favor principalmente da linhagem eritrÃide, sendo a anemia nestes pacientes de natureza provavelmente crÃnica / According to World Health Organization (WHO) data there are some 12 million people worldwide with leishmaniasis. In Brazil the etiological agent of visceral leishmaniasis (VL) is Leishmania chagasi, and is the main means of transmission from the parasite to human beings and other hosts mammals is through the biting of the female mosquito of the order diptera insects belonging to the Psychodidae family, whose main vector is the Lutzomyia (Lutzomyia) longipalpis (Lutz & Neiva). The visceral leishmaniasis or kala azar is a tropical disease that is characterized by the presence of fever, anemia, hepatosplenomegaly, hemorrhagic manifestations, and linfoadenomegaly, weight loss, tachycardia, dry cough, diarrhea, fever, pancytopenia and hypergammaglobulinemia. The hematological involvement is common in patients with VL, with anemia the most frequent abnormality due to its multifactor nature and prevalence varies depending on the population being studied. It is meant to evaluate the pattern of peripheral alterations of patients with hematological Visceral Leishmaniasis. Blood samples were collected after the diagnosis of researches seeking ways of amastigotes Leishmania sp in bone marrow aspirate in patients (n = 30), Hospital of Infectious Diseases SÃo JosÃ, in Fortaleza, in the state of CearÃ, in the period from January 2007 to July 2008 and a control group (n = 30) consists of blood donors from HEMOCE. Laboratory tests were performed at the Clinical Analysis Laboratory of the General Hospital of Fortaleza and the Louis Pasteur Medical Diagnosis Laboratory. The counting of blood elements were measured with an ABX blood Pentre 60 gauge, followed by cytomorphology assessment. The biochemical measurements were made in a HITACHI biochemical analyzer Module P800 and Roche  Modular I. The comparison between the groups, for the average of quantitative variables was performed by Student t-test, for the normal distribution and Mann â Whitney hypothesis data, in case of non-normality of the data. We have statistically considered meaningful values of 0.05. The analysis (n = 30) patients, the study showed that 63% (19) of the patients are from within the State of Cearà and 37% (11)of the patients are from the capital of the state of CearÃ, Fortaleza. That 80% (24) of patients are male and 20 (8%) were females. Most of the patients, 57% were aged between 31 to 45 years old. In what concerns the period of time of the disease until the date of laboratory diagnosis, 47% (14) of the patients already had signs of clinical disease with 30 to 90 days. We have to count the male of red blood cells, an average of 3.69  0.6644 (x106/mm3), hemoglobin of 9383  1.3002 (g/dL), Hematocrit of 28.6708  4.0687 (%) for the female count of red blood cells, an average of 3525  0.6233 (x106/mm3), hemoglobin from 8.5666  1.6561 (g/dL), Hematocrit of 26.9666  3.9026 (%) . With regard to RBC indices observed for both sex, cell volume Medium (MCV) of 78.1  7.0 (fL), mean corpuscular hemoglobin (MCH) of 25.42  2.51 (pg), mean corpuscular hemoglobin concentration (MCHC) of 32  2.15 (%), distribution of amplitude of red blood cells (RDW) of 15,337  2435 (%), reticulocyte count of 20.636.63  20.300.39 (/ mm3). Of the morphological analysis showed up a laboratory profile characteristic of the type of anemia and microcytic normocytic and hypochromic followed by normochromic and 65% of the samples found the presence of "rouleax". For the determinations of serum iron had a average of 32.53  17.31 (Âg/dL), Transferrin of 146.83  42.19 (mg/dL), Ferritin of 1.339.47  599.05 (ng /ml), Vitamin B12 from 573.5  253.94 (pg/mL), Folic Acid, 10  3.47 (ng/mL). For the average counts of leukocytes observed was 2802.33  2322.16 (nÂ/mm3), of neutrophils 1426.33  1348.88 (nÂ/mm3), lymphocytes from 982.60  576.47 (nÂ/ mm3); monocytes of 350.13  283.47 (nÂ/mm3), platelet count 120.233.33  90640.89 (n Â/mm3). For the determinations of the VHS diagnosis, the patients had an average of 81.77 mm in the first hours of observation. The determination of TAP showed us that the diagnosis of the patients showed an average of 67.87% of activity prothrombin. The analysis it was observed that there is an impairment in VL hematopoese in translating in peripheral blood by a pancytopenia mainly in favor of the erythroid lineage, and the anemia in patients with chronic nature probably

The exact mechanism underlying the coupling between breathing and locomotion is still unknown; the visceral piston theory is a putative mechanism but has gone largely untested. The study assessed the visceral piston theory by examining the effect of perturbations (vocalization and fluid ingestion) on the coupling of breathing and locomotion. 10 experienced runners performed a speed running trial (6.5 to 8.0 mph in 0.5 mph increments), followed by a vocalization trial and a fluid ingestion trial at their preferred running speed while on a treadmill. Continuous recordings of respiratory flow and single leg, tibial acceleration was acquired (500 Hz). Rating of perceived exertion for breathing (RPEB), effort (RPEE), stitch (RPES) and heart rate (HR) were also recorded during the trials. The magnitude (SIFTMAG) and timing (SIFTT) of step induced flow transients were determined, along with the breath cycle duration (BCD) and respiratory locomotor entrainment (RLE) ratios. RPEB, and HR showed an increase in all three trials, RPEE showed an increase in the speed trial and the fluid ingestion trial but not the vocalization trial. SIFTMAG had a significant increase post perturbation (vocalization and fluid ingestion). SIFTT increased significantly post fluid ingestion but not after the vocalization perturbation. RLE ratios were increased post fluid ingestion but not post vocalization perturbation, however BCD was reduced after vocalization trials. The SIFTMAG was increased as result of perturbations corresponding to respiratory flow suppression which could lead to increased respiratory load. A shift in timing after fluid ingestion is consistent with an increased mass of a visceral spring mass system. Four of ten runners experienced a stitch after fluid ingestion. These findings strongly support the visceral piston theory of RLE, and this becomes a plausible mechanism for the induction of a stitch in the side.

Background: Physical activity (PA) reduces visceral adipose tissue (VAT) in adults; however, the dose to reduce VAT in youth is unclear. Objective: To examine whether high intensity PA preferentially reduces waist circumference (WC) and VAT compared to lower intensity PA. Design: Randomized controlled trial. Participants: Youth were 13-18yrs, overweight, with one additional risk factor for type 2 diabetes (T2DM). Intervention: 6-months, exercising 3 times/week at a high intensity (70-85% of Heart Rate Reserve HRR), or low intensity (40-55% HRR). Primary outcome: VAT (cm2) measured by MRI at L4-L5, and WC at the height of the iliac crest (cm). Results: 94 Youth were randomized to either high intensity (n=30); low intensity (n=32) or control (n=32). Changes in WC and VAT were not significant across groups. A trend towards a reduction in VAT in the training groups, compared to controls was demonstrated in sub-analysis (-14.3 ± 9.6 % vs. +0.01 ± 0.4 %, p= 0.059). Peak fitness increased significantly in both the high and low intensity arms (1.3 ± 0.6 and 1.4 ± 0.6 ml/kg/min, p < 0.05). Conclusions: Training at 55-65% HRR improves fitness by ~10%, and ~2 days/week elicits modest non-significant reductions in VAT in overweight youth.

The exact mechanism underlying the coupling between breathing and locomotion is still unknown; the visceral piston theory is a putative mechanism but has gone largely untested. The study assessed the visceral piston theory by examining the effect of perturbations (vocalization and fluid ingestion) on the coupling of breathing and locomotion. 10 experienced runners performed a speed running trial (6.5 to 8.0 mph in 0.5 mph increments), followed by a vocalization trial and a fluid ingestion trial at their preferred running speed while on a treadmill. Continuous recordings of respiratory flow and single leg, tibial acceleration was acquired (500 Hz). Rating of perceived exertion for breathing (RPEB), effort (RPEE), stitch (RPES) and heart rate (HR) were also recorded during the trials. The magnitude (SIFTMAG) and timing (SIFTT) of step induced flow transients were determined, along with the breath cycle duration (BCD) and respiratory locomotor entrainment (RLE) ratios. RPEB, and HR showed an increase in all three trials, RPEE showed an increase in the speed trial and the fluid ingestion trial but not the vocalization trial. SIFTMAG had a significant increase post perturbation (vocalization and fluid ingestion). SIFTT increased significantly post fluid ingestion but not after the vocalization perturbation. RLE ratios were increased post fluid ingestion but not post vocalization perturbation, however BCD was reduced after vocalization trials. The SIFTMAG was increased as result of perturbations corresponding to respiratory flow suppression which could lead to increased respiratory load. A shift in timing after fluid ingestion is consistent with an increased mass of a visceral spring mass system. Four of ten runners experienced a stitch after fluid ingestion. These findings strongly support the visceral piston theory of RLE, and this becomes a plausible mechanism for the induction of a stitch in the side.