Resumo em Inglês:

The epidemiology of tropical spastic paraparesis/human T lymphotropic virus I (HTLV-I)-associated myelopathy (TSP/HAM) is frequently inconsistent and suggests environmental factors in the etiology of these syndromes. The neuropathology corresponds to a toxometabolic or autoimmune process and possibly not to a viral disease. Some logical hypotheses about the etiology and physiopathology of TSP and HAM are proposed. Glutamate-mediated excitotoxicity, central distal axonopathies, cassava, lathyrism and cycad toxicity may explain most cases of TSP. The damage caused to astrocytes and to the blood-brain barrier by HTLV-I plus xenobiotics may explain most cases of HAM. Analysis of the HTLV-I/xenobiotic ratio clarifies most of the paradoxical epidemiology of TSP and HAM. Modern neurotoxicology, neuroimmunology and molecular biology may explain the neuropathology of TSP and HAM. It is quite possible that there are other xenobiotics implicated in the etiology of some TSP/HAMs. The prevention of these syndromes appears to be possible today.

Resumo em Inglês:

Chronic idiopathic urticaria (CIU) is a dermatological syndrome, characterized by raised erythematous skin lesions, that affects 20% of the general population and has been associated with autoimmunity. However, some reports have also suggested a close relationship between CIU and Helicobacter pylori infection, which is endemic in developing countries and associated with chronic gastritis, peptic ulcer disease, and gastric carcinoma. In the present study, we investigated the occurrence of autoantibodies in sera from 23 CIU subjects infected with H. pylori and from 23 CIU subjects without this infection. The presence of anti-thyroid antibodies was determined by indirect hemagglutination assay and the presence of autoantibodies to IgE and C1INH was determined by ELISA. Antibodies to thyroid antigens were detected at low titers from 100 to 400 in three of 23 (13%) CIU-infected subjects and in four of 23 (17%) CIU-noninfected subjects. The titers of anti-IgE autoantibodies were similar in these CIU groups, presenting absorbances of 1.16 ± 0.09 and 1.07 ± 0.16, respectively, while a titer of 1.14 ± 0.15 was detected in the healthy control group. The concentration of anti-C1INH autoantibodies was the same in the CIU-infected and -noninfected subjects (7.28 ± 1.31 and 7.91 ± 2.45 ng/ml, respectively), and was 7.20 ± 2.25 ng/ml in the healthy control group. However, the serum levels of complexed anti-C1INH antibodies were increased in CIU-infected subjects compared to CIU-noninfected subjects and healthy controls with an absorbance of 1.51 ± 0.21 vs 1.36 ± 0.16 and 1.26 ± 0.23, respectively (P < 0.05), indicating an impaired clearance of immune complexes in CIU-infected patients. In conclusion, no correlation was observed between H. pylori infection and autoantibody production in CIU patients consistent with reports of clinical studies.

Resumo em Inglês:

Neuron-specific enolase (NSE) is a glycolytic enzyme present almost exclusively in neurons and neuroendocrine cells. NSE levels in cerebrospinal fluid (CSF) are assumed to be useful to estimate neuronal injury and clinical outcome of patients with serious clinical manifestations such as those observed in stroke, head injury, anoxic encephalopathy, encephalitis, brain metastasis, and status epilepticus. We compared levels of NSE in serum (sNSE) and in CSF (cNSE) among four groups: patients with meningitis (N = 11), patients with encephalic injuries associated with impairment of consciousness (ENC, N = 7), patients with neurocysticercosis (N = 25), and normal subjects (N = 8). Albumin was determined in serum and CSF samples, and the albumin quotient was used to estimate blood-brain barrier permeability. The Glasgow Coma Scale score was calculated at the time of lumbar puncture and the Glasgow Outcome Scale (GOS) score was calculated at the time of patient discharge or death. The ENC group had significantly higher cNSE (P = 0.01) and albumin quotient (P = 0.005), but not sNSE (P = 0.14), levels than the other groups (Kruskal-Wallis test). Patients with lower GOS scores had higher cNSE levels (P = 0.035) than patients with favorable outcomes. Our findings indicate that sNSE is not sensitive enough to detect neuronal damage, but cNSE seems to be reliable for assessing patients with considerable neurological insult and cases with adverse outcome. However, one should be cautious about estimating the severity of neurological status as well as outcome based exclusively on cNSE in a single patient.

Resumo em Inglês:

No reports testing the efficacy of the use of the QT/RR ratio <1/2 for detecting a normal QTc interval were found in the literature. The objective of the present study was to determine if a QT/RR ratio <=1/2 can be considered to be equal to the normal QTc and to compare the QT and QTc measured and calculated clinically and by a computerized electrocardiograph. Ratios (140 QT/RR) of 28 successive electrocardiograms obtained from 28 consecutive patients in a tertiary level teaching hospital were analyzed clinically by 5 independent observers and by a computerized electrocardiograph. The QT/RR ratio provided 56% sensitivity and 78% specificity, with an area under the receiver operator characteristic curve of 75.8% (95%CI: 0.68 to 0.84). The divergence in QT and QTc interval measurements between clinical and computerized evaluation were 0.01 ± 0.03 s (95%CI: 0.04-0.02) and 0.01 ± 0.04 s (95%CI: -0.05-0.03), respectively. The QT and QTc values measured clinically and by a computerized electrocardiograph were similar. The QT/RR ratio <=1/2 was not a satisfactory index for QTc evaluation because it could not predict a normal QTc value.

Resumo em Inglês:

Alternative methods to assess ventricular diastolic function in the fetus are proposed. Fetal myocardial hypertrophy in maternal diabetes was used as a model of decreased left ventricular compliance (LVC), and fetal respiratory movements as a model of increased LVC. Comparison of three groups of fetuses showed that, in 10 fetuses of diabetic mothers (FDM) with septal hypertrophy (SH), the mean excursion index of the septum primum (EISP) (ratio between the linear excursion of the flap valve and the left atrial diameter) was 0.36 ± 0.09, in 8 FDM without SH it was 0.51 ± 0.09 (P = 0.001), and in the 8 normal control fetuses (NCF) it was 0.49 ± 0.12 (P = 0.003). In another study, 28 fetuses in apnea had a mean EISP of 0.39 ± 0.05 which increased to 0.57 ± 0.07 during respiration (P < 0.001). These two studies showed that the mobility of the septum primum was reduced when LVC was decreased and was increased when LVC was enhanced. Mean pulmonary vein pulsatility was higher in 14 FDM (1.83 ± 1.21) than in 26 NCF (1.02 ± 0.31; P = 0.02). In the same fetuses, mean left atrial shortening was decreased (0.40 ± 0.11) in relation to NCF (0.51 ± 0.09; P = 0.011). These results suggest that FDM may have a higher preload than normal controls, probably as a result of increased myocardial mass and LV hypertrophy. Prenatal assessment of LV diastolic function by fetal echocardiography should include analysis of septum primum mobility, pulmonary vein pulsatility, and left atrial shortening.

Resumo em Inglês:

We detected anti-human small nuclear ribonucleoprotein (snRNP) autoantibodies in chagasic patients by different immunological methods using HeLa snRNPs. ELISA with Trypanosoma cruzi total lysate antigen or HeLa human U small nuclear ribonucleoproteins (UsnRNPs) followed by incubation with sera from chronic chagasic and non-chagasic cardiac patients was used to screen and compare serum reactivity. Western blot analysis using a T. cruzi total cell extract was also performed in order to select some sera for Western blot and immunoprecipitation assays with HeLa nuclear extract. ELISA showed that 73 and 95% of chronic chagasic sera reacted with HeLa UsnRNPs and T. cruzi antigens, respectively. The Western blot assay demonstrated that non-chagasic cardiac sera reacted with high molecular weight proteins present in T. cruzi total extract, probably explaining the 31% reactivity found by ELISA. However, these sera reacted weakly with HeLa UsnRNPs, in contrast to the chagasic sera, which showed autoantibodies with human Sm (from Stefanie Smith, the first patient in whom this activity was identified) proteins (B/B', D1, D2, D3, E, F, and G UsnRNP). Immunoprecipitation reactions using HeLa nuclear extracts confirmed the reactivity of chagasic sera and human UsnRNA/RNPs, while the other sera reacted weakly only with U1snRNP. These findings agree with previously reported data, thus supporting the idea of the presence of autoimmune antibodies in chagasic patients. Interestingly, non-chagasic cardiac sera also showed reactivity with T. cruzi antigen and HeLa UsnRNPs, which suggests that individuals with heart disease of unknown etiology may develop autoimmune antibodies at any time. The detection of UsnRNP autoantibodies in chagasic patients might contribute to our understanding of how they develop upon initial T. cruzi infection.

Resumo em Inglês:

Gastric dysrhythmias, such as tachy- or bradygastria, have been reported in patients with functional dyspepsia (FD), but their role in symptom production is uncertain. It is also not known whether gastric dysrhythmias in these patients can be elicited by physiological gastric distension with a meal. We investigated the relationships between symptoms after ingestion of different volumes of water following a test meal and gastric dysrhythmias in FD patients. Fourteen patients with dysmotility-like FD and 13 healthy volunteers underwent paired electrogastrography (EGG) studies. Fasted subjects ingested 150 ml of yoghurt with either 150 ml (low volume) or 300 ml (high volume) water in random order. Fasting and fed EGGs with monitoring of symptoms were performed in both studies. Ten FD patients (71.4%) reported upper abdominal discomfort and bloating after the low volume meal, but only one (7.1%) presented an abnormal EGG (dominant frequency in the 2-4-cpm range: 58%). Following the high volume meal, 7 patients (50%) had symptoms, but none had EGG abnormalities. No significant differences were found between FD patients and controls for any of the EGG variables, in any test. In FD patients with postprandial symptoms, the percentage of the EGG dominant frequency in the normal range (median, 84.6%; range, 76.0-100.0%) was similar (P > 0.20) to that in those without symptoms (88.5%; 75.0-100.0%). We conclude that disturbances of gastric myoelectrical activity are unlikely to play a role in the origin of postprandial upper abdominal discomfort and bloating in dysmotility-like FD.

Resumo em Inglês:

The aim of the present study was to determine the prevalence of celiac disease in children of short stature and to assess whether some of the routine laboratory examinations performed to determine the cause of short stature could suggest the presence of celiac disease. A total of 106 children of short stature and no gastrointestinal symptoms were studied. An extensive endocrine work-up had been negative for all of them and an additional investigation was performed by measuring the concentration of antiendomysial antibody. Patients who were positive for antiendomysial antibody ( > or = 1:10) or who exhibited IgA deficiency (less than 5 mg/dl) were referred for an endoscopic intestinal biopsy. We detected a pathological titer of antiendomysial IgA in six of these patients. Five of them showed histological abnormalities compatible with celiac disease and one had normal histology and was considered to have potential celiac disease. The prevalence of celiac disease in the population studied was 4.7% (with another 0.9% of the subjects being considered to have potential celiac disease). The children with celiac disease did not differ in any of the parameters tested when compared to those without celiac disease, though they showed an improvement in growth velocity after treatment with a gluten-free diet. We conclude that it is important to test all children with short stature for celiac disease by measuring antiendomysial IgA.

Resumo em Inglês:

The objective of the present study was to determine the effect of chronic calcitonin deficiency on bone mass development. The results of 11 patients with thyroid dysgenesis (TD) were compared to those of 17 normal individuals (C) and of 9 patients with other forms of hypothyroidism (OH): 4 with hypothyroidism due to inborn errors of thyroid hormone synthesis and 5 with Hashimoto's thyroiditis. The subjects received an intravenous calcium stimulus and blood was collected for the determination of ionized calcium (Ca2+), calcitonin, and intact parathyroid hormone. Bone mineral density (BMD) was determined by dual-energy X-ray absorptiometry. After calcium administration the levels of Ca2+ in the two groups of hypothyroidism were significantly higher than in the normal control group (10 min after starting calcium infusion: C = 1.29 ± 0.08 vs TD = 1.34 ± 0.03 vs OH = 1.34 ± 0.02 mmol/l; P < 0.05), and only the TD group showed no calcitonin response (5 min after starting calcium infusion: C = 27.9 ± 5.8 vs TD = 6.6 ± 0.3 vs OH = 43.0 ± 13.4 ng/l). BMD values did not differ significantly between groups (L2-L4: C = 1.116 ± 0.02 vs TD = 1.109 ± 0.03 vs OH = 1.050 ± 0.04 g/cm²). These results indicate that early deficiency of calcitonin secretion has no detrimental effect on bone mass development. Furthermore, the increased calcitonin secretion observed in patients with inborn errors of thyroid hormone biosynthesis does not confer any advantage in terms of BMD.

Resumo em Inglês:

The aim of the present study was to compare the clinical findings and polysomnography results obtained at public and private clinics in Brazil, the follow-up after diagnosis, and the therapeutic aspects related to continuous positive airway pressure. Patients who snore and who have obstructive sleep apnea were retrospectively divided into two groups, i.e., public clinic (N = 307) and private clinic (N = 317). Data concerning age, sex, body mass index (BMI), neck circumference, medical history, sleepiness scale, follow-up after diagnosis, and acceptance of continuous positive airway pressure therapy were collected. Mean age was 50 ± 12 (range: 15-80) for public patients and 48 ± 12 years (range: 19-91) for private patients. Mean BMI was 30 ± 6 (range: 19-67) for public patients and 31 ± 6 kg/m² (range: 21-59) for private patients. The public clinic had a significantly higher frequency of women than the private clinic (M:F ratio of 2.0:1 and 6.9:1, respectively). The condition of private patients (apnea-hypopnea index = 31 ± 25) was more severe than that of public patients (apnea-hypopnea index = 25 ± 24 events/h; P = 0.0004). In the public and private clinics, 19 and 15% of patients were snorers, respectively, and 81 and 85% of them had sleep apnea. After diagnosis, follow-up was longer in the private group. The continuous positive airway pressure acceptance was similar for both groups (32 vs 35%), but patients from the public clinic abandoned treatment more than private ones (65 vs 13%). Social status was significant in terms of the severity of obstructive sleep apnea age and gender distribution. Private patients look for a diagnosis earlier in the course of the disease than public patients, adhere more to follow-up, and abandon continuous positive airway pressure treatment less than public patients do.

Resumo em Inglês:

Typing techniques are essential for understanding hospital epidemiology, permitting the elucidation of the source of infection and routes of bacterial transmission. Although DNA-based techniques are the "gold standard" for the epidemiological study of Pseudomonas aeruginosa, antibiotic profiles and biochemical results are used because they are easy to perform and to interpret and relatively inexpensive. Antibiotypes (susceptibility profiles) and biotypes (biochemical profiles) were compared to genotypes established by DNA restriction enzyme analysis in 81 clinical isolates of P. aeruginosa from three hospitals in Porto Alegre, Brazil. The epidemiological relationship among patients was also evaluated. Susceptibility and restriction profiles were discrepant in more than 50% of the cases, and many antibiotypes were observed among isolates from the same genotype. Furthermore, susceptibility profiles did not allow the distinction of isolates from unrelated genotypes. Since a large number of isolates (63%) yielded the same biochemical results, only 10 biotypes were detected, showing that this typing method has a low discriminatory power. On the other hand, DNA restriction enzyme typing allowed us to establish 71 distinct types. Epidemiological data about the relation among P. aeruginosa isolates were not conclusive. The results of the present study indicate that the only method that can establish a clonal relation is DNA restriction enzyme typing, whereas the other methods may cause misleading interpretations and are inadequate to guide proper infection control measures.

Resumo em Inglês:

Estrogen (ER) and progesterone (PR) receptors in the normal uterine cervix, cervical intraepithelial neoplasia and invasive carcinoma were studied in consecutive samples from Hospital do Câncer, São Paulo, between 1996 and 1997. Tissue was collected by removing a fragment of the tumoral area using a 5-mm diameter biopsy punch, followed by removal of a macroscopically normal area as close as possible from the tumor. Histopathological confirmation was obtained for all specimens analyzed. A total of 24 normal tissues, 17 cases of cervical intraepithelial neoplasia and 7 of invasive carcinomas were studied. The ER/PR ratio was determined by immunohistochemistry using monoclonal antibodies specific for each receptor. Adjacent tissue slides were submitted to generic PCR for human papillomavirus (HPV) DNA detection followed by typing by dot blot hybridization. About half (45.8%) of the tumors were HPV DNA positive while 29.1% of the patients were also HPV positive in their respective normal tissue. ER was negative in the tumoral epithelium of 11 HPV-positive patients (P = 0.04). There was a trend in the ER distribution in normal tissue that was opposite to that from lesions, but it was not statistically significant (P = 0.069). No difference in ER distribution in stromal tissues was observed between HPV-positive and HPV-negative tissues. PR staining was negative in the epithelium of all cases studied. The results obtained from this small number of cases cannot be considered to be conclusive but do suggest that factors related to viral infection affect the expression of these ER/PR cervix receptors.

Resumo em Inglês:

Several investigators have identified Epstein-Barr virus (EBV) particles in breast carcinomas, a fact that supports a role for EBV in mammary tumorigenesis. The possible mechanism involved in this process is not clear. The present study was carried out in an attempt to determine whether there is a relationship between latent infection with EBV and p53 and p63 expression in breast carcinomas. Immunohistochemistry developed with 3.3-diaminobenzidine tetrahydrochloride was performed in 85 formalin-fixed paraffin-embedded breast carcinomas using anti-EBV EBNA-1, anti-p63, anti-p53, anti-estrogen receptor (ER) and anti-progesterone receptor (PR) antibodies. The cases were selected to represent each of the various histologic types: intraductal carcinoma (N = 12), grade I invasive ductal carcinoma (N = 15), grade II invasive ductal carcinoma (N = 15), grade III invasive ductal carcinoma (N = 15), tubular carcinoma (N = 8), lobular carcinoma (N = 10), and medullary carcinoma (N = 10). The ductal breast carcinomas were graded I, II and III based on the Scarff-Bloom and Richardson grading system modified by Elston and Ellis. One slide containing at least 1000 neoplastic cells was examined in each case. ER, PR, p63, p53 and EBNA-1 were positive in 60, 40, 11.8, 21.2 and 37.6% of carcinomas, respectively. There was a correlation between EBNA-1 and p63 expression (P < 0.001), but not between EBNA-1 and p53 (P = 0.10). These data suggest a possible role for p63 in the mammary tumorigenesis associated with Epstein-Barr virus infection.

Resumo em Inglês:

A recent study from our laboratory has provided evidence for the generation of slow potentials occurring in anticipation to task-performance feedback stimuli, in multiple association cortical areas, consistently including two prefrontal areas. In the present study, we intended to determine whether these slow potentials would indicate some abnormality (topographic) in schizophrenic patients, and thus serve as an indication of abnormal association cortex activity. We recorded slow potentials while subjects performed a paired-associates memory task. A 123-channel EEG montage and common average reference were used for 20 unmedicated schizophrenic (mean duration of illness: 11.3 ± 9.2 years; mean number of previous hospitalizations: 1.2 ± 1.9) and 22 healthy control subjects during a visual paired-associates matching task. For the topographic analysis, we used a simple index of individual topographic deviation from normality, corrected for absolute potential intensities. Slow potentials were observed in all subjects. Control subjects showed a simple spatial pattern of voltage extrema (left central positive and right prefrontal negative), whereas schizophrenic patients presented a more complex, fragmented pattern. Topographic deviation was significantly different between groups (P < 0.001). The increased topographic complexity in schizophrenics could be visualized in grand averages computed across subjects. Increased topographic complexity could also be seen when grand averages were computed for subgroups of patients assembled either according to task-performance (high versus low) or by their scores on psychopathological scales. There was no significant correlation between topographic deviation and psychopathology scores. We conclude that the slow potential topographic abnormalities of schizophrenia indicate an abnormality in the configuration of large-scale electrical activity in association cortices.

Resumo em Inglês:

The aim of the present study was to measure full epidermal thickness, stratum corneum thickness, rete length, dermal papilla widening and suprapapillary epidermal thickness in psoriasis patients using a light microscope and computer-supported image analysis. The data obtained were analyzed in terms of patient age, type of psoriasis, total body surface area involvement, scalp and nail involvement, duration of psoriasis, and family history of the disease. The study was conducted on 64 patients and 57 controls whose skin biopsies were examined by light microscopy. The acquired microscopic images were transferred to a computer and measurements were made using image analysis. The skin biopsies, taken from different body areas, were examined for different parameters such as epidermal, corneal and suprapapillary epidermal thickness. The most prominent increase in thickness was detected in the palmar region. Corneal thickness was more pronounced in patients with scalp involvement than in patients without scalp involvement (t = -2.651, P = 0.008). The most prominent increase in rete length was observed in the knees (median: 491 µm, t = 10.117, P = 0.000). The difference in rete length between patients with a positive and a negative family history was significant (t = -3.334, P = 0.03), being 27% greater in psoriasis patients without a family history. The differences in dermal papilla distances among patients were very small. We conclude that microscope-supported thickness measurements provide objective results.

Resumo em Inglês:

The introduction of highly active antiretroviral therapy (HAART) for patients infected with HIV has significantly prolonged the life expectancy and to some extent has restored a functional immune response. However, the premature introduction of HAART has led to a significant and alarming increase in cardiovascular complications, including myocardial infarction and the appearance of abnormal distribution of body fat seen as lipodystrophy. One key element in the development of ischemic coronary artery disease is the presence of circulating and tissue-fixed modified low density lipoprotein (mLDL) that contributes to the initiation and progression of arterial lesions and to the formation of foam cells. Even though not completely elucidated, the most likely mechanism involves mLDL in the inflammatory response and the induction of a specific immune response against mLDL. Circulating antibodies against mLDL can serve as an indirect marker of the presence of circulating and vessel-fixed mLDL. In the present study, we measured antibodies to mLDL and correlated them with immune status (i.e., number of CD4+ T cells) in 59 HIV patients and with the clinical manifestation of lipodystrophy in 10 patients. We observed a significant reduction in anti-mLDL antibody levels related both to lipodystrophy and to an immunocompromised state in HIV patients. We speculate that these antibodies may explain in part the rapid development of ischemic coronary artery disease in some patients.

Resumo em Inglês:

Human herpesvirus 8 (HHV-8) is a newly described herpesvirus that is etiologically associated with all forms of Kaposi's sarcoma (KS). Seroepidemiological studies have shown high prevalence rates of HHV-8 antibodies among men who have sex with men (MSM) and AIDS patients, African children, Brazilian Amerindians, and elderly individuals in certain regions of Europe. The aim of the present study was to determine the prevalence of HHV-8 antibodies in healthy children and young adults from different cities in São Paulo State, and in a population at high risk for HHV-8 infection: HIV-negative MSM, and AIDS patients with and without KS. Antibodies to HHV-8 latency-associated nuclear antigen and lytic-phase antigens were detected by immunofluorescence assays. In 643 healthy children and young adults from the general population attending a vaccination program for yellow fever in ten different cities in São Paulo State, the prevalence of HHV-8 antibodies detected by the presence of latent or lytic antigens ranged from 1.0 to 4.1% in the different age groups (mean = 2.5%). In the MSM group, the prevalence was 31/95 (32.6%). In the group of patients with AIDS, the prevalence was 39.2% (51/130) for non-KS patients and 98.7% (77/78) for AIDS patients with the diagnosis of KS confirmed by histopathological examination. We conclude that HHV-8 has a restricted circulation among healthy children and young adults in the general population of São Paulo State and a high prevalence among MSM and AIDS patients.

Resumo em Inglês:

The factors determining the development or not of visceral leishmaniasis (VL) have not been completely identified, but a Leishmania-specific cellular immune response seems to play a fundamental role in the final control of infection. Few studies are available regarding the production of cytokines in the subclinical form of VL, with only the production of IFN-g and TNF-a known. The aim of the present study was to identify immunological markers for the oligosymptomatic or subclinical form of VL. A prospective cohort study was conducted on 784 children aged 0 to 5 years from an endemic area in the State of Maranhão, Brazil, between January 1998 and December 2001. During 30 consecutive months of follow-up, 33 children developed the oligosymptomatic form of the disease and 12 the acute form. During the clinical manifestations, serum cytokine levels were determined in 27 oligosymptomatic children and in nine patients with the acute form using a quantitative sandwich enzyme immunoassay. In the subclinical form of VL, variable levels of IL-2 were detected in 52.3% of the children, IL-12 in 85.2%, IFN-g in 48.1%, IL-10 in 88.9%, and TNF-a in 100.0%, with the last two cytokines showing significantly lower levels than in the acute form. IL-4 was not detected in oligosymptomatic individuals. Multiple discriminant analysis used to determine the profile or combination of cytokines predominating in the subclinical form revealed both a Leishmania resistance (Th1) and susceptibility (Th2) profile. The detection of both Th1 and Th2 cytokine profiles explains the self-limited evolution accompanied by the discrete alterations observed for the subclinical form of VL.

Resumo em Inglês:

Several genes that influence the development and function of the hypothalamic-pituitary-gonadal-axis (HPG) have been identified. These genes encode an array of transcription factors, matrix proteins, hormones, receptors, and enzymes that are expressed at multiple levels of the HPG. We report the experience of a single Endocrinology Unit in the identification and characterization of naturally occurring mutations in families affected by HPG disorders, including forms of precocious puberty, hypogonadism and abnormal sexual development due to impaired gonadotropin function. Eight distinct genes implicated in HPG function were studied: KAL, SF1, DAX1, GnRH, GnRHR, FSHß, FSHR, and LHR. Most mutations identified in our cohort are described for the first time in literature. New mutations in SF1, DAX1 and GnRHR genes were identified in three Brazilian patients with hypogonadism. Eight boys with luteinizing hormone- (LH) independent precocious puberty due to testotoxicosis were studied, and all have their LH receptor (LHR) defects elucidated. Among the identified LHR molecular defects, three were new activating mutations. In addition, these mutations were frequently associated with new clinical and hormonal aspects, contributing significantly to the knowledge of the molecular basis of reproductive disorders. In conclusion, the naturally occurring genetic mutations described in the Brazilian families studied provide important insights into the regulation of the HPG.

Resumo em Inglês:

In most mammals, male development is triggered by the transient expression of the SRY gene, which initiates a cascade of gene interactions ultimately leading to the formation of a testis from the indifferent fetal gonad. Mutation studies have identified several genes essential for early gonadal development. We report here a molecular study of the SRY, DAX1, SF1 and WNT4 genes, mainly involved in sexual determination, in Brazilian 46,XX and 46,XY sex-reversed patients. The group of 46,XX sex-reversed patients consisted of thirteen 46,XX true hermaphrodites and four 46,XX males, and was examined for the presence of the SRY gene and for the loss of function (inactivating mutations and deletions) of DAX1 and WNT4 genes. In the second group consisting of thirty-three 46,XY sex-reversed patients we investigated the presence of inactivating mutations in the SRY and SF1 genes as well as the overexpression (duplication) of the DAX1 and WNT4 genes. The SRY gene was present in two 46,XX male patients and in none of the true hermaphrodites. Only one mutation, located outside homeobox domain of the 5' region of the HMG box of SRY (S18N), was identified in a patient with 46,XY sex reversal. A novel 8-bp microdeletion of the SF1 gene was identified in a 46,XY sex-reversed patient without adrenal insufficiency. The dosage of DAX1 and WNT4 was normal in the sex-reversed patients studied. We conclude that these genes are rarely involved in the etiology of male gonadal development in sex-reversed patients, a fact suggesting the presence of other genes in the sex determination cascade.

Resumo em Inglês:

Autologous and allogeneic bone marrow transplantation (BMT) recipients lose immune memory of exposure to infectious agents and vaccines accumulated through a lifetime and therefore need to be revaccinated. Diphtheria toxoid, tetanus toxoid, pertussis vaccine (children <7 years old), Haemophilus influenzae type b conjugate, 23-valent pneumococcal polysaccharide, inactivated influenza vaccine, inactivated polio vaccine and live-attenuated measles-mumps-rubella vaccine are the currently recommended vaccines to be included in a vaccination program after BMT. For most of them, the best time to vaccinate, the number of vaccine doses and/or the duration of immunity after vaccination have not been established. Vaccination protocols vary greatly among BMT centers, suggesting that the lack of sufficient data has not permitted the formulation of reliable recommendations. The use of other vaccines and the perspectives for different vaccination protocols are analyzed in this review.