Vitamin D Status and VDR Genotype in NF1 Patients: A Case-Control Study from Southern Brazil.

Neurofibromatosis type 1 (NF1) patients are more likely to have vitamin D deficiency when compared to the general population. This study aimed to determine the levels of 25-OH-vitamin D [25(OH)D] in individuals with NF1 and disease-unaffected controls and analyze FokI and BsmI VDR gene polymorphisms in a case and in a control group. Vitamin D levels were compared between a group of 45 NF1 patients from Southern Brazil and 45 healthy controls matched by sex, skin type, and age. Genotypic and allelic frequencies of VDR gene polymorphisms were obtained from the same NF1 patients and 150 healthy controls. 25(OH)D deficiency or insufficiency was not more frequent in NF1 patients than in controls (p = 0.074). We also did not observe an association between FokI and BsmI VDR gene polymorphisms and vitamin D levels in NF1 patients, suggesting that their deficient or insufficient biochemical phenotypes are not associated with these genetic variants. The differences between the groups in genotypic and allelic frequencies for FokI and BsmI VDR gene polymorphisms were small and did not reach statistical significance. These polymorphisms are in partial linkage disequilibrium and the haplotype frequencies also did not differ in a significant way between the two groups (p = 0.613).

Hypertension-related factors in patients with active and inactive acromegaly.

INTRODUCTION: There are several complications of the cardiovascular system caused by acromegaly, especially hypertension. OBJECTIVES: To evaluate hypertension characteristics in patients with cured/controlled acromegaly and with the active disease. PATIENTS AND METHODS: Cross-sectional study of the follow-up of forty-four patients with acromegaly submitted to clinical evaluation, laboratory tests and cardiac ultrasound. Patients with cured and controlled disease were evaluated as one group, and individuals with active disease as second one. RESULTS: Forty-seven percent of the patients had active acromegaly, and these patients were younger and had lower blood pressure levels than subjects with controlled/cured disease. Hypertension was detected in 50% of patients. Subjects with active disease showed a positive correlation between IGF-1 and systolic and diastolic blood pressure levels (r = 0.48, p = 0.03; and r = 0.42, p = 0.07, respectively), and a positive correlation between IGF-1 and urinary albumin excretion (UAE) rates. In patients with active disease, IGF-1 was a predictor of systolic blood pressure, although it was not independent of UAE rate. For individuals with cured/controlled disease, waist circumference and triglycerides were the predictors associated with systolic and diastolic blood pressure. CONCLUSIONS: Blood pressure (BP) levels in patients with active acromegaly dependent of the GH excess. However, once thedisease becomes controlled and IGF-1 levels decrease, their blood pressure levels are depend on the other cardiovascular riskfactors [corrected].

Hypertension-related factors in patients with active and inactive acromegaly / Fatores implicados com a hipertensão em pacientes com acromegalia ativa e inativa

INTRODUCTION: There are several complications of the cardiovascular system caused by acromegaly, especially hypertension. OBJECTIVES: To evaluate hypertension characteristics in patients with cured/controlled acromegaly and with the active disease. PATIENTS AND METHODS: Cross-sectional study of the follow-up of forty-four patients with acromegaly submitted to clinical evaluation, laboratory tests and cardiac ultrasound. Patients with cured and controlled disease were evaluated as one group, and individuals with active disease as second one. RESULTS: Forty-seven percent of the patients had active acromegaly, and these patients were younger and had lower blood pressure levels than subjects with controlled/cured disease. Hypertension was detected in 50 percent of patients. Subjects with active disease showed a positive correlation between IGF-1 and systolic and diastolic blood pressure levels (r = 0.48, p = 0.03; and r = 0.42, p = 0.07, respectively), and a positive correlation between IGF-1 and urinary albumin excretion (UAE) rates. In patients with active disease, IGF-1 was a predictor of systolic blood pressure, although it was not independent of UAE rate. For individuals with cured/controlled disease, waist circumference and triglycerides were the predictors associated with systolic and diastolic blood pressure. CONCLUSIONS: Our findings suggest that blood pressure levels in patients with active acromegaly are very similar, and depend on excess GH. However, once the disease becomes controlled and IGF-1 levels decrease, their blood pressure levels will depend on the other cardiovascular risk factors.

INTRODUÇÃO: Existem várias complicações no sistema cardiovascular causadas pela acromegalia, especialmente a hipertensão. OBJETIVOS: Avaliar as características da hipertensão em pacientes com acromegalia curada/controlada e com doença ativa. PACIENTES E MÉTODOS: Estudo transversal com 44 pacientes com acromegalia seguidos em nosso serviço. Eles foram submetidos a avaliação clínica, exames laboratoriais e ecocardiograma. Pacientes com doença curada/controlada foram avaliados como um grupo único e os indivíduos com doença ativa como outro grupo. RESULTADOS: Quarenta e sete por cento dos pacientes apresentaram acromegalia ativa. Esses indivíduos foram mais jovens e apresentaram níveis mais baixos de pressão arterial que os indivíduos com doença controlada/curada. A hipertensão foi detectada em 50 por cento da amostra. Indivíduos com doença ativa mostraram uma correlação positiva entre os níveis de IGF-1 e os níveis de pressão arterial sistólica e de pressão arterial diastólica (r = 0,48, p = 0,03; e r = 0,42, p = 0,07, respectivamente) e também apresentaram uma correlação positiva entre IGF-1 e excreção urinária de albumina (EUA). Em pacientes com doença ativa, o IGF-1 foi um preditor da pressão arterial sistólica, embora não tenha sido independente da taxa de EUA. Para indivíduos com doença curada/controlada, a circunferência da cintura e os triglicérides foram os preditores associados aos níveis de pressão arterial sistólica e diastólica. CONCLUSÕES: Nossos resultados sugerem que os níveis pressóricos em pacientes com acromegalia ativa dependem do excesso de GH. No entanto, uma vez que a doença torna-se controlada e os níveis de IGF-1 reduzem, os níveis de pressão arterial dependerão de outros fatores de risco cardiovasculares.

Betacellulin overexpression in mesenchymal stem cells induces insulin secretion in vitro and ameliorates streptozotocin-induced hyperglycemia in rats.

Betacellulin (BTC), a ligand of the epidermal growth factor receptor, has been shown to promote growth and differentiation of pancreatic ß-cells and to improve glucose metabolism in experimental diabetic rodent models. Mesenchymal stem cells (MSCs) have been already proved to be multipotent. Recent work has attributed to rat and human MSCs the potential to differentiate into insulin-secreting cells. Our goal was to transfect rat MSCs with a plasmid containing BTC cDNA to guide MSC differentiation into insulin-producing cells. Prior to induction of cell MSC transfection, MSCs were characterized by flow cytometry and the ability to in vitro differentiate into mesoderm cell types was evaluated. After rat MSC characterization, these cells were electroporated with a plasmid containing BTC cDNA. Transfected cells were cultivated in Dulbecco's modified Eagle medium high glucose (H-DMEM) with 10 mM nicotinamide. Then, the capability of MSC-BTC to produce insulin in vitro and in vivo was evaluated. It was possible to demonstrate by radioimmunoassay analysis that 10(4) MSC-BTC cells produced up to 0.4 ng/mL of insulin, whereas MSCs transfected with the empty vector (negative control) produced no detectable insulin levels. Moreover, MSC-BTC were positive for insulin in immunohistochemistry assay. In parallel, the expression of pancreatic marker genes was demonstrated by molecular analysis of MSC-BTC. Further, when MSC-BTC were transplanted to streptozotocin diabetic rats, BTC-transfected cells ameliorated hyperglycemia from over 500 to about 200 mg/dL at 35 days post-cell transplantation. In this way, our results clearly demonstrate that BTC overabundance enhances glucose-induced insulin secretion in MSCs in vitro as well as in vivo.

Secondary hyperparathyroidism is associated with increased risk of hospitalization or death in elderly adults living in a geriatric institution.

BACKGROUND: The presence of secondary hyperparathyroidism is very frequent in the elderly population living in geriatric institutions. It has been associated with an increased mortality rate in previous studies. OBJECTIVES: To evaluate the association of secondary hyperparathyroidism with mortality or hospitalization or both (combined outcome) during a 6-month period in individuals living in geriatric institutions. METHODS: A cohort of 100 individuals aged between 65 and 102 years living in geriatric institutions in the city of Porto Alegre, Brazil, was prospectively studied. Serum levels of 25-hydroxyvitamin D [25(OH)D], parathyroid hormone (PTH), albumin, total calcium, phosphorus, magnesium, creatinine and alkaline phosphatase were measured. The glomerular filtration rate (GFR) was calculated using the Cockcroft-Gault equation. Secondary hyperparathyroidism was defined as serum PTH levels higher than 48 pg/ml and normal or reduced serum calcium levels. The deaths were verified by means of death certificates and hospitalization by the discharge summaries provided by the Brazilian health system hospitals. RESULTS: Fifty-eight percent of the individuals had secondary hyperparathyroidism, defined as serum PTH >48 pg/ml and normal or low serum calcium. Mean serum 25(OH)D levels were 12.5 +/- 8 ng/ml. The odds ratio of an individual with secondary hyperparathyroidism to die, to be hospitalized or to have the combined outcome within 6 months was 6.6 [confidence interval (CI) 95% 0.8-54.6; p = 0.07], 10.7 (CI 95% 1.3-85.9; p = 0.007) and 5.20 (CI 95% 1.10-27.7; p = 0.04), respectively. Secondary hyperparathyroidism and body mass index were independently associated with the combined outcome, after correction for the GFR and 25(OH)D. CONCLUSION: Secondary hyperparathyroidism could be an important prognostic factor for individuals living in geriatric institutions.

Effects of intermittent high-intensity exercise and carbohydrate supplementation on IGF-1 and glycogen of Wistar rats.

OBJECTIVE: The aim of this study was to analyze the association between glucose infusion during intermittent physical exercise and its metabolic effects on rats. DESIGN: Forty male rats were divided into eight groups based on training (intermittent), exercise and carbohydrate intake (glucose 20%): TEC (trained exercised with carbohydrate), TES (trained exercised without carbohydrate), TNC (trained non-exercised with carbohydrate), TNS (trained non-exercised without carbohydrate), UEC (untrained exercised with carbohydrate), UES (untrained exercised without carbohydrate), UNC (untrained non-exercised with carbohydrate) and UNS (untrained non-exercised without carbohydrate). The training and/or exercise protocol consisted of the rats running on a treadmill for 1 min above the lactate threshold, or running below the lactate threshold for 30s, intermittently for 30 min. Blood was analyzed for glycemia, lactate and IGF-1. Muscle and liver glycogen were measured (T2). RESULTS: Glycemia was found to be different in T2 compared to T1 in the TEC, TNC, UEC and UNC groups. Lactate was higher in T2 than in T1, but remained within the lactate threshold. Glycogen showed higher concentrations in the trained groups and, whether trained or not, in the supplemented groups. IGF-1 levels were higher in exercised rats independent of supplementation or glycogen levels. Trained rats showed lower IGF-1 when exercising than did the untrained animals. CONCLUSIONS: We conclude that intermittent exercise is beneficial in preventing a trained lactate pool, and that, in association with glucose supplementation, intermittent exercise will be efficient both in preventing a trained lactate pool and in maintaining sufficient glycemia levels. Exercise raises IGF-1 levels, whereas training inverts this relationship.

The effect of a single dose versus a daily dose of cholecalciferol on the serum 25-hydroxycholecalciferol and parathyroid hormone levels in the elderly with secondary hyperparathyroidism living in a low-income housing unit.

We designed a randomized, double-blind, controlled clinical trial to compare the effect of two regimens for administering cholecalciferol on the serum 25-hydroxycholecalciferol [25(OH)D] levels and in the reversion of secondary hyperparathyroidism in the elderly living in a low-income housing unit in the city of Porto Alegre, southern Brazil. We studied 28 individuals ranging in age from 65 to 102 years with serum parathyroid hormone (PTH) levels greater than 48 pg/ml and normal or reduced serum calcium levels. Subjects were randomized to receive oral cholecalciferol, as a single dose of 300 000 IU (group 1) or 800 IU (group 2) daily for 9 months. Both groups received 1250 mg calcium carbonate per day. Serum 25(OH)D and PTH levels were measured at baseline and after 1, 2, 3, 6, and 9 months. Serum 25(OH)D levels in group 1 were significantly higher than in group 2 during the study (P < 0.001). After 1 (P < 0.001) and 2 (P < 0.04) months of treatment, mean serum 25(OH)D levels were higher in group 1. The number of subjects who reached serum 25(OH)D levels >/=20 ng/dl was higher in group 1, after the first (P < 0.001) and third (P = 0.008) months. In the short term, a single 300 000 IU oral dose of vitamin D(3) was more effective than 800 IU per day to increase serum 25(OH)D levels in elderly persons, living in a low-income housing unit, who were taking 500 mg elementary calcium supplement per day.

Serum leptin, insulin resistance, and body fat after renal transplantation.

OBJECTIVE: Our objective was to evaluate serum levels of leptin, body mass index (BMI), body-fat percentage (BF%), and insulin resistance in the first year after renal transplantation. DESIGN: This study involved a prospective, observational cohort. SETTING: The setting was a transplant unit of a university teaching hospital in Porto Alegre, Brazil. PATIENTS: Thirty-two patients who underwent renal transplantation were prospectively followed for 1 year. A control group of 19 healthy individuals, matched by sex, age, and BMI, was included in the study. METHODS: Body mass index and BF% were measured according to anthropometric measures, serum leptin was measured by radioimmunoassay, and the homeostasis model assessment (HOMA) was used as an index of insulin resistance. Anthropometric measures and biochemical markers were evaluated prospectively, starting at transplant time and then every 3 months for up to 1 year. RESULTS: Leptin levels were increased before transplantation, and decreased significantly in the first year (median, 11.9 [interquartile range, 9.2 to 25.2] to 9.3 [4.9 to 16.4] ng/mL; P < .001). The HOMA values presented a similar pattern, decreasing from 2.4 +/- 1.5 (mean +/- SD) before transplantation, to 1.5 +/- 1.1 (P = .001) at 3 months after transplantation, but increasing to 2.0 +/- 1.7 at month 12 after transplantation (P = not significant). The BMI and BF% increased significantly in the first year after transplantation (23.3 +/- 2.7 kg/m(2) vs. 24.4 +/- 2.7 kg/m(2), P = .001, and 23.71% +/- 7.79% vs. 25.63% +/- 7.68%, P = .002, respectively). According to multivariate regression analysis, HOMA levels and BF% independently predicted leptin levels after transplantation. CONCLUSIONS: We found that leptin serum levels decreased significantly over the first posttransplant year. However, the effect of transplantation on insulin resistance appears to be transitory, and BF% also increases steadily in this period. The beneficial profile of leptin levels is counterbalanced by the detrimental effects of insulin resistance and BF% that may be related to the elevated cardiovascular risk observed after transplantation.

High prevalence of hypovitaminosis D and secondary hyperparathyroidism in elders living in nonprofit homes in South Brazil.

OBJECTIVES: Hypovitaminosis D (HD) and secondary hyperparathyroidism (SHP) are common in elders, and many factors could contribute to them. The objectives of this study were to estimate the prevalence of HD, SHP, and its associated factors, in individuals living in nonprofit homes for elders in south Brazil. Design Cross-sectional study. METHODS: Serum 25-hydroxyvitamin D 25(OH)D, intact parathyroid hormone (PTH), total calcium, phosphorus, alkaline phosphatase, magnesium, creatinine, and albumin levels were measured in late spring, November, 2005. The presence of factors potentially related with HD and SHP-age, sex, weight, height, skin phototype, sun exposure, exercise, smoking, use of < or = 5 medications or diuretics or alcohol, and daily calcium ingestion. RESULTS: 102 subjects age 77.8 +/- 9.0 were included in the study. HD was found in 85.7% and SHP in 53% of the subjects. The estimated daily calcium ingestion was 720 mg. There was no association between serum 25(OH)D levels and any of the risk factors evaluated. Serum 25(OH)D levels were correlated with serum PTH (r = -0.358, P = 0.000), calcium (r = 0.306, P = 0.002), and albumin (r = 0.253, P = 0.011) levels. In univariate analysis, SHP was positively associated with age (P = 0.006), and female sex (0.007); and negatively associated with sunlight exposure (P = 0.020), GFR (P = 0.000), Ln25(OH)D (P = 0.002), and total serum calcium (P = 0.024). After multivariate model adjustment, age [OR 1.09 (CI 1.01-1.18); P = 0.024], Ln25(OH)D [OR 0.92 (CI 0.08-0.74); P = 0.013], GFR [OR 0.96 (CI 0.92-0.99); P = 0.013], and hydrochlorothiazide treatment [OR 7.63 (CI 1.67-34.9); P = 0.008] were independently associated with SHP. CONCLUSIONS: HD and SHP are highly prevalent in elders living in old-age homes. No associations were established between common risk factors and low serum levels of 25(OH)D levels; however, SHP was independently related with age, 25(OH)D, GFR, and hydrochlorothiazide use.

Serum neuron-specific enolase as early predictor of outcome after in-hospital cardiac arrest: a cohort study.

INTRODUCTION: Outcome after cardiac arrest is mostly determined by the degree of hypoxic brain damage. Patients recovering from cardiopulmonary resuscitation are at great risk of subsequent death or severe neurological damage, including persistent vegetative state. The early definition of prognosis for these patients has ethical and economic implications. The main purpose of this study was to investigate the prognostic value of serum neuron-specific enolase (NSE) in predicting outcomes in patients early after in-hospital cardiac arrest. METHODS: Forty-five patients resuscitated from in-hospital cardiac arrest were prospectively studied from June 2003 to January 2005. Blood samples were collected, at any time between 12 and 36 hours after the arrest, for NSE measurement. Outcome was evaluated 6 months later with the Glasgow outcome scale (GOS). Patients were divided into two groups: group 1 (unfavorable outcome) included GOS 1 and 2 patients; group 2 (favorable outcome) included GOS 3, 4 and 5 patients. The Mann-Whitney U test, Student's t test and Fisher's exact test were used to compare the groups. RESULTS: The Glasgow coma scale scores were 6.1 +/- 3 in group 1 and 12.1 +/- 3 in group 2 (means +/- SD; p < 0.001). The mean time to NSE sampling was 20.2 +/- 8.3 hours in group 1 and 28.4 +/- 8.7 hours in group 2 (p = 0.013). Two patients were excluded from the analysis because of sample hemolysis. At 6 months, favorable outcome was observed in nine patients (19.6%). Thirty patients (69.8%) died and four (9.3%) remained in a persistent vegetative state. The 34 patients (81.4%) in group 1 had significantly higher NSE levels (median 44.24 ng/ml, range 8.1 to 370) than those in group 2 (25.26 ng/ml, range 9.28 to 55.41; p = 0.034). CONCLUSION: Early determination of serum NSE levels is a valuable ancillary method for assessing outcome after in-hospital cardiac arrest.

Simultaneous detection of Neisseria meningitidis, Haemophilus influenzae and Streptococcus sp. by polymerase chain reaction for the diagnosis of bacterial meningits

Avaliamos o desempenho da reação em cadeia da polimerase (PCR) para detecção simultânea da Neisseria meningitidis, Haemophilus influenzae e Streptococcus sp. no diagnóstico das meningites bacterianas e sua aplicabilidade na rotina diagnóstica. Foi realizado um estudo de coorte com 182 crianças apresentando suspeita de meningite bacteriana. Em 84, havia alterações clínicas e laboratoriais sugestivas de meningite bacteriana. Destas, 65 tiveram o agente etiológico identificado pelos métodos laboratoriais de rotina e 19 ficaram sem diagnóstico etiológico. Em 98 pacientes foi excluído o diagnóstico de meningite bacteriana. Analisando o desempenho da PCR encontramos sensibilidade de 88,1%, especificidade de 99,0% e valores preditivos positivo e negativo de 98,7% e 90,1% respectivamente. Nos 19 pacientes com meningite bacteriana mas sem diagnóstico etiológico a PCR detectou microrganismos em 14, sendo 12 N. meningitidis, um H. influenzae e um Streptococcus sp. A PCR possui o potencial de poder aumentar os índices de identificação das técnicas tradicionais, principalmente nas situações onde a microscopia direta, cultura ou identificação antigênica são negativos ou inconclusivos.

Simultaneous detection of Neisseria meningitidis, Haemophilus influenzae and Streptococcus sp. by polymerase chain reaction for the diagnosis of bacterial meningitis.

The simultaneous detection of Neisseria meningitidis, Haemophilus influenzae, and Streptococcus sp. was assessed by polymerase chain reaction (PCR) for the diagnosis of bacterial meningitis, as well as the applicability of PCR as a routine test. A cohort study was carried out with 182 children (2 months to 12 years of age) with suspicion of bacterial meningitis. Routine tests identified the etiologic agent in 65/84 children whose clinical status and laboratory findings suggested the presence of bacterial meningitis. Bacterial meningitis was ruled out in 98 children. In 19 children, the etiologic diagnosis was not possible using standard methods; in 14 of these patients, the etiologic agent was identified by PCR (N. meningitidis=12; H. influenzae=1; Streptococcus sp.=1). The sensitivity of PCR was 88.1%; specificity, 99.0%; positive predictive value, 98.7%; and negative predictive, 90.1%. PCR is a useful complementary diagnostic technique, especially when Gram stain, culture, or antigenic detection are negative or inconclusive.

Polymerase chain reaction for the laboratory diagnosis of aseptic meningitis and encephalitis

A protocol for testing cerebrospinal fluid specimens using a range of PCR assays for the diagnosis of central nervous system infection was developed and used to test prospectively 383 specimens. PCR assays were used for the detection of adenovirus, Borrelia burgdorferi, enteroviruses, Epstein Barr virus, cytomegalovirus, herpes simplex virus, human herpes virus type 6, JC virus, Leptospira interrogans, Listeria monocytogenes, lymphocytic choriomeningitis virus, measles virus, mumps virus, Mycobacterium sp., Mycoplasma pneumoniae, Toxoplasma gondii and varicella zoster virus. Of the 383 specimens tested in this study, 46 (12.0 percent) were found to be positive. The microorganisms detected were CMV, enterovirus, Epstein Barr virus, herpes simplex virus, human herpes virus type 6, JC virus, L. monocytogenes, Mycobacterium genus, Toxoplasma gondii and varicella zoster virus. The introduction of the PCR protocol described has improved the diagnosis of a range of central nervous system infections in our laboratory. We believe however that further evaluation of these assays in immunocompromised patients is necessary to better determine the predictive value of positive PCR results in these patient groups

Diagnóstico molecular das infecçöes do Sistema Nervoso Central pela Reaçäo em Cadeia da Polimerase (PCR) / Molecular diagnosis of Central Nervous System infections by Polimerase Chain Reaction (PCR)

A identificaçäo do agente etiológico é de fundamental importância no tratamento e prognóstico das infecçöes do Sistema Nervoso Central (SNC) porém, os métodos convencionais de diagnóstico tem limitado sucesso. A Reaçäo em Cadeia da Polimerase (PCR) tem possibilitado o diagnóstico de infecçöes virais,bacterianas e por protozoários de maneira mais rápida e precisa. O objetivo deste estudo foi implantar, em nosso serviço, uma rotina ágil para o diagnóstico molecular dos microorganismos que mais freqüentemente acometem o SNC. As amostras de líquor (LCR) foram testadas para 20 agentes infecciosos: Herpes simplex, Herpes zooster, Enterovírus, vírus da Linfocoriomeningite, vírus Epstein-Barr, Adenovírus, Herpes hominis tipo 6, Sarampo, Caxumba, Mycobacterium sp, Citomegalovírus, Toxoplasma gondii, vírus JC, Listeria monocytogenes, Borrelia burgdorferi, Mycoplasma pneumoniae, Leptospira interrogans, Neisseria meningitidis, Haemophylus influenzae e Streptococcus sp. A técnica usada foi o PCR "nested" com extraçäo do RNA ou DNA das amostras pelo método de Boom modificado. Em algumas reaçöes utilizou-se a combinaçäo de "primers" de patógenos diferentes ("multiplex"), possibilitando a pesquisa de até três microrganismos na mesma reaçäo, agilizando os resultados. Foram testadas 281 amostras de LCR suspeitos de meningite ou meningo-encefalite linfocitária ou asséptica. A PCR foi positiva em 18 amostras (6,4 porcento). microrganismos detectados foram: Mycobacterium sp, Herpes simplex, Citomegalovírus, Herpes hominis tipo 6 e Toxoplasma gondii. Em estudo paralelo com 22 amostras liquóricas de pacientes com meningite bacteriana, a PCR foi positiva em 21 casos (95,4 porcento). Os microrganismos encontrados foram: H. influenzae, Streptococcus sp e N. meningitidis. Em quatro pacientes com PCR positiva a cultura do LCR foi negativa. A introduçäo da técnica de PCR em nosso laboratório otimizou o diagnóstico etiológico das infecçöes do SNC e tem se revelado de grande importância clínica.