Noninvasive prognostic markers for cardiac death and ventricular arrhythmia in long-term follow-up of subjects with chronic Chagas' disease

The objective of the present study was to investigate clinical, echocardiographic and electrocardiographic (12-lead resting ECG, 24-h ambulatory ECG monitoring and signal-averaged ECG (SAECG)) parameters in subjects with chronic Chagas' disease in a long-term follow-up as prognostic markers for adverse outcomes. Fifty adult outpatients (34 to 74 years old, 31 females) staged according to Los Andes class I, II or III and complaining of palpitation were enrolled in a longitudinal study. SAECG was analyzed in time and frequency domains and the endpoint was a composite of cardiac death and ventricular tachycardia. During a follow-up of 84.2 ± 39.0 months, 34.0% of the patients developed adverse outcomes (9 cardiac deaths and 11 episodes of ventricular tachycardia). After optimal dichotomization, in a stepwise multivariate Cox-hazard regression model, apical aneurysm (HR = 3.7; 95% CI = 1.2-1.3; P = 0.02), left ventricular ejection fraction <62% (HR = 4.60; 95% CI = 1.39-15.24; P = 0.01) and incidence of ventricular premature contractions >614 per 24 h (hazard ratio = 6.1; 95% CI = 1.7-22.6; P = 0.006) were independent predictors of the composite endpoint. Although a high frequency content in SAECG demonstrated association with the presence of left ventricular dysfunction and myocardial fibrosis, its predictive value for the composite endpoint was not significant. Apical aneurysms, reduced left ventricular function and a high incidence of ventricular ectopic beats over a 24-h period have a strong predictive value for a composite endpoint of cardiac death and ventricular tachycardia in subjects with chronic Chagas' disease.

Activity of liver microsomal enzymes during the chronic phase of murine schistosomiasis

The effects of schistosomiasis on microsomal enzymes were studied on post-infection day 90 when accumulated damage and fibrosis are most intense but granulomatous reaction around the eggs harbored in the liver is smaller than during the earlier phases. Swiss Webster (SW) and DBA/2 mice of either sex (N = 12 per sex per group) were infected with 100 Schistosoma mansoni cercariae on postnatal day 10 and killed on post-infection day 90. Cytochrome P-450 (CYP) concentration and alkoxyresorufin-O-dealkylases (EROD, MROD, BROD, and PROD), p-nitrophenol-hydroxylase (PNPH), coumarin-7-hydroxylase (COH), and UDP-glucuronosyltransferase (UGT) activities were measured in hepatic microsomes. Age-matched mice of the same sex and strain were used as controls. In S. mansoni-infected mice, CYP1A- and 2B-mediated activities (control = 100%) were reduced in SW (EROD: male (M) 36%, female (F) 38%; MROD: M 38%, F 39%; BROD: M 46%, F 19%; PROD: M 50%, F 28%) and DBA/2 mice (EROD: M 64%, F 58%; MROD: M 60%; BROD: F 49%; PROD: M 73%) while PNPH (CYP2E1) was decreased in SW (M 31%, F 38%) but not in DBA/2 mice. COH did not differ between infected and control DBA/2 and UGT, a phase-2 enzyme, was not altered by infection. In conclusion, chronic S. mansoni infection reduced total CYP content and all CYP-mediated activities evaluated in SW mice, including those catalyzed by CYP2E1 (PNPH), CYP1A (EROD, MROD) and 2B (BROD, PROD). In DBA/2 mice, however, CYP2A5- and 2E1-mediated activities remained unchanged while total CYP content and activities mediated by other CYP isoforms were depressed during chronic schistosomiasis.

Direct costs of asthma in Brazil: a comparison between controlled and uncontrolled asthmatic patients

Asthma is a common chronic illness that imposes a heavy burden on all aspects of the patient's life, including personal and health care cost expenditures. To analyze the direct cost associated to uncontrolled asthma patients, a cross-sectional study was conducted to determine costs related to patients with uncontrolled and controlled asthma. Uncontrolled patient was defined by daytime symptoms more than twice a week or nocturnal symptoms during two consecutive nights or any limitations of activities, or need for relief rescue medication more than twice a week, and an ACQ score less than 2 points. A questionnaire about direct cost stratification in health services, including emergency room visits, hospitalization, ambulatory visits, and asthma medications prescribed, was applied. Ninety asthma patients were enrolled (45 uncontrolled/45 controlled). Uncontrolled asthmatics accounted for higher health care expenditures than controlled patients, US$125.45 and US$15.58, respectively [emergency room visits (US$39.15 vs US$2.70) and hospitalization (US$86.30 vs US$12.88)], per patient over 6 months. The costs with medications in the last month for patients with mild, moderate and severe asthma were US$1.60, 9.60, and 25.00 in the uncontrolled patients, respectively, and US$6.50, 19.00 and 49.00 in the controlled patients. In view of the small proportion of uncontrolled subjects receiving regular maintenance medication (22.2%) and their lack of resources, providing free medication for uncontrolled patients might be a cost-effective strategy for the public health system.

Chronic obstructive pulmonary disease is underdiagnosed and undertreated in São Paulo (Brazil): results of the PLATINO study

Chronic obstructive pulmonary disease (COPD) is a common disease in adults over 40 years of age and has a great social and economic impact. It remains little recognized and undertreated even in developed countries. However, there are no data about its diagnosis and treatment in Brazil. The objectives of the present study were to evaluate the proportion of COPD patients who had never been diagnosed and to determine if the COPD patients who had been identified were receiving appropriate treatment. The Latin American Project for the Investigation of Obstructive Lung Disease (PLATINO) was a randomized epidemiological study of adults over 40 years living in five metropolitan areas, including São Paulo. The studied sample was randomly selected from the population after a division of the metropolitan area of São Paulo in clusters according to social characteristics. All subjects answered a standardized questionnaire on respiratory symptoms, history of smoking, previous diagnosis of lung disease, and treatments. All subjects performed spirometry. The criterion for the diagnosis of COPD was defined by a post-bronchodilator FEV1/FVC ratio lower than 0.7. A total of 918 subjects were evaluated and 144 (15.8%) met the diagnostic criterion for COPD. However, 126 individuals (87.5%) had never been diagnosed. This undiagnosed group of COPD patients had a lower proportion of subjects with respiratory symptoms than the previously diagnosed patients (88.9 vs 54.8%) and showed better lung function with greater FEV1 (86.8 ± 20.8 vs 68.5 ± 23.6% predicted) and FVC (106.6 ± 22.4 vs 92.0 ± 24.1% predicted). Among the COPD patients, only 57.3% were advised to stop smoking and 30.6% received the influenza vaccine. In addition, 82.3% did not receive any pharmacological treatment. In conclusion, COPD is underdiagnosed and a large number of COPD patients are not treated appropriately.

The emergence of YMDD mutants precedes biochemical flare by 19 weeks in lamivudine-treated chronic hepatitis B patients: an opportunity for therapy reevaluation

Given the loss of therapeutic efficacy associated with the development of resistance to lamivudine (LMV) and the availability of new alternative treatments for chronic hepatitis B patients, early detection of viral genotypic resistance could allow the clinician to consider therapy modification before viral breakthrough and biochemical relapse occur. To this end, 28 LMV-treated patients (44 ± 12 years; 24 men), on their first therapy schedule, were monitored monthly at four Brazilian centers for the emergence of drug resistance using the reverse hybridization-based INNO-LiPA HBV DR assay and occasionally sequencing (two cases). Positive viral responses (HBV DNA clearance) after 6, 12, and 18 months of therapy were achieved by 57, 68, and 53% of patients, while biochemical responses (serum alanine aminotransferase normalization) were observed in 82, 82, and 53% of cases. All viral breakthrough cases (N = 8) were related to the emergence of YMDD variants observed in 7, 21, and 35% of patients at 6, 12, and 18 months, respectively. The emergence of these variants was not associated with viral genotype, HBeAg expression status, or pretreatment serum alanine aminotransferase levels. The detection of resistance-associated mutations was observed before the corresponding biochemical flare (41 ± 14 and 60 ± 15 weeks) in the same individuals. Then, if highly sensitive LMV drug resistance testing is carried out at frequent and regular intervals, the relatively long period (19 ± 2 weeks) between the emergence of viral resistance and the onset of biochemical relapse can provide clinicians with ample time to re-evaluate drug therapy.

miRNA expression profiles in chronic lymphocytic and acute lymphocytic leukemia

MicroRNAs (miRNAs) are a class of small endogenous RNAs that play important regulatory roles by targeting mRNAs for cleavage or translational repression. miRNAs act in diverse biological processes including development, cell growth, apoptosis, and hematopoiesis, suggesting their association with cancer. We determined the miRNA expression profile of chronic and acute lymphocytic leukemias (CLL and ALL) using the TaqMan® MicroRNA Assays Human Panel (Applied Biosystems). Pooled leukemia samples were compared to pooled CD19+ samples from healthy individuals (calibrator) by the 2-DDCt method. Total RNA input was normalized based on the Ct values obtained for hsa-miR-30b. The five most highly expressed miRNAs were miR-128b, miR-204, miR-218, miR-331, and miR-181b-1 in ALL, and miR-331, miR-29a, miR-195, miR-34a, and miR-29c in CLL. To our knowledge, this is the first report associating miR-128b, miR-204 and miR-331 to hematological malignancies. The miR-17-92 cluster was also found to be up-regulated in ALL, as previously reported for some types of lymphomas. The differences observed in gene expression levels were validated for miR-331 and miR-128b in ALL and CD19+ samples. These miRNAs were up-regulated in ALL, in agreement with our initial results. A brief target analysis was performed for miR-331. One of its putative targets, SOCS1, promotes STAT activation, which is a known mediator of cell proliferation and survival, suggesting the possibility of an association between miR-331 and these processes. This initial screening provided information on miRNA differentially expressed in normal and malignant B-cells that could suggest the potential roles of these miRNAs in hematopoiesis and leukemogenesis.

Examining life-course influences on chronic disease: the Ribeirão Preto and São Luís birth cohort studies (Brazil)

More than any other low- and middle-income country, Brazil has the longest research tradition of establishing, maintaining and exploiting birth cohort studies. This research pedigree is highlighted in the present issue of the Brazilian Journal of Medical and Biological Research, which contains a series of twelve papers from the Ribeirão Preto and São Luis birth cohort studies from the Southeast and Northeast of Brazil, respectively. The topics covered in this raft of reports vary and include predictors of perinatal health and maternal risk factors, early life determinants of cardiovascular risk factors in childhood and adolescence, use of health services, and a description of dietary characteristics of young adults, amongst other topics. There is also a guide to the background, objectives, sampling and protocols employed across these studies, which, together with similar pieces published in past issues of the Brazilian Journal, serve as a very useful starting point, particularly for potential collaborators. In the fervent hope that further follow-up of these cohorts will take place - we provide our own justification for cohort maintenance and extension in this issue - future data collection could include: genetic material, atherosclerosis, ascertained, for instance, by intima-media thickness, and IQ testing in children - scores from which are emerging as potentially important predictors of adult health outcomes up to six decades later.

Examining life-course influences on chronic disease: the importance of birth cohort studies from low- and middle- income countries. An overview

The objectives of this overview are to describe the past and potential contributions of birth cohorts to understanding chronic disease aetiology; advance a justification for the maintenance of birth cohorts from low- and middle-income countries (LMIC); provide an audit of birth cohorts from LMIC; and, finally, offer possible future directions for this sphere of research. While the contribution of birth cohorts from affluent societies to understanding disease aetiology has been considerable, we describe several reasons to anticipate why the results from such studies might not be directly applied to LMIC. More than any other developing country, Brazil has a tradition of establishing, maintaining and exploiting birth cohort studies. The clear need for a broader geographical representation may be precipitated by a greater collaboration worldwide in the sharing of ideas, fieldwork experience, and cross-country cohort data comparisons in order to carry out the best science in the most efficient manner. This requires the involvement of a central overseeing body - such as the World Health Organization - that has the respect of all countries and the capacity to develop strategic plans for `global' life-course epidemiology while addressing such issues as data-sharing. For rapid progress to be made, however, there must be minimal bureaucratic entanglements.

Interrelationship between serum and sputum inflammatory mediators in chronic obstructive pulmonary disease

Little is known about airway inflammatory markers in chronic obstructive pulmonary disease (COPD). The objective of the present study was to identify and try to correlate pulmonary and peripheral blood inflammatory markers in COPD. In a cross-sectional study on patients with stable COPD, induced sputum and blood samples were collected for the determination of C-reactive protein, eosinophilic cationic protein, serum amyloid A protein, a-1 antitrypsin (a-1AT), and neutrophil elastase. Twenty-two patients were divided into two groups according to post-bronchodilator forced expiratory volume in the first second (%FEV1): group 1 (N = 12, FEV1 <40%) and group 2 (N = 10, FEV1 ³40%). An increase in serum elastase, eosinophilic cationic protein and a-1AT was observed in serum markers in both groups. Cytology revealed the same total number of cells in groups 1 and 2. There was a significantly higher number of neutrophils in group 1 compared to group 2 (P < 0.05). No difference in eosinophils or macrophages was observed between groups. Serum elastase was positively correlated with serum a-1AT (group 1, r = 0.81, P < 0.002 and group 2, r = 0.83, P < 0.17) and negatively correlated with FEV1 (r = -0.85, P < 0.03 and -0.14, P < 0.85, respectively). The results indicate the presence of chronic and persistent pulmonary inflammation in stable patients with COPD. Induced sputum permitted the demonstration of the existence of a subpopulation of cells in which neutrophils predominated. The serum concentration of all inflammatory markers did not correlate with the pulmonary functional impairment.

Relationship between disease severity and quality of life in patients with chronic obstructive pulmonary disease

Few studies have evaluated the relationship between Airways Questionnaire 20 (AQ20), a measure of the quality of life, scores and physiological outcomes or with systemic markers of disease in patients with chronic obstructive pulmonary disease (COPD). The aim of the present study was to investigate the relationship of forced expiratory volume in 1 s (FEV1), body mass index, fat-free mass index, 6-min walk test (6MWT) results, dyspnea sensation and peripheral oxygen saturation (SpO2) with the quality of life of COPD patients. Ninety-nine patients with COPD (mean age: 64.2 ± 9.2 years; mean FEV1: 60.4 ± 25.2% of predicted) were evaluated using spirometry, body composition measurement and the 6MWT. The baseline dyspnea index (BDI) and the Modified Medical Research Council (MMRC) scale were used to quantify dyspnea. Quality of life was assessed using the AQ20 and the St. George's Respiratory Questionnaire (SGRQ). The Charlson index was used to determine comorbidity. The body mass index/airflow obstruction/dyspnea/exercise capacity (BODE) index was also calculated. AQ20 and SGRQ scores correlated significantly with FEV1, SpO2, 6MWT, MMRC and BDI values as did with BODE index. In the multivariate analyses, MMRC or BDI were identified as predictors of AQ20 and SGRQ scores (P < 0.001 in all cases). Thus, the relationship between AQ20 and disease severity is similar to that described for SGRQ. Therefore, the AQ20, a simple and brief instrument, can be very useful to evaluate the general impact of disease when the time allotted for measurement of the quality of life is limited.

Distribution of the human leukocyte antigen class II alleles in Brazilian patients with chronic hepatitis C virus infection

Hepatitis C virus (HCV) infection is a global medical problem. The current standard of treatment consists of the combination of peginterferon plus ribavirin. This regimen eradicates HCV in 55% of cases. The immune response to HCV is an important determinant of disease evolution and can be influenced by various host factors. HLA class II may play an important role in immune response against HCV. The objective of the present study was to determine the distribution of HLA class II (DRB1 and DQB1) alleles, their association with chronic HCV infection and their response to interferon therapy. One hundred and two unrelated white Brazilian patients with chronic HCV infection, 52 responders (45 males and 7 females) and 50 non-responders (43 males and 7 females) to antiviral treatment, were included in the study. Healthy Brazilian bone marrow donors of Caucasian origin from the same geographic area constituted the control group (HLA-DRB1, N = 99 and HLA-DQB1, N = 222 individuals). HLA class II genotyping was performed using a low-resolution DRB1, DQB1 sequence-specific primer amplification. There were higher frequencies of HLA-DRB1*13 (26.5 vs 14.1%) and HLA-DQB1*02 (52.9 vs 38.7%) in patients compared with controls; however, these were not significantly different after P correction (Pc = 0.39 and Pc = 0.082, respectively). There was no significant difference between the phenotypic frequencies of HLA-DRB1 (17.3 vs 14.0%) and HLA-DQB1 alleles in responder and non-responder HCV patients. The HLA-DRB1*07 allele was significantly more common in HCV patients (33.3 vs 12.1%) than in controls (Pc = 0.0039), suggesting that the HLA-DRB1*07 allele is associated with chronic HCV infection.

Are the current chronic allograft nephropathy grading systems sufficient to predict renal allograft survival?

A major problem in renal transplantation is identifying a grading system that can predict long-term graft survival. The present study determined the extent to which the two existing grading systems (Banff 97 and chronic allograft damage index, CADI) correlate with each other and with graft loss. A total of 161 transplant patient biopsies with chronic allograft nephropathy (CAN) were studied. The samples were coded and evaluated blindly by two pathologists using the two grading systems. Logistic regression analyses were used to evaluate the best predictor index for renal allograft loss. Patients with higher Banff 97 and CADI scores had higher rates of graft loss. Moreover, these measures also correlated with worse renal function and higher proteinuria levels at the time of CAN diagnosis. Logistic regression analyses showed that the use of angiotensin-converting enzyme inhibitor (ACEI), hepatitis C virus (HCV), tubular atrophy, and the use of mycophenolate mofetil (MMF) were associated with graft loss in the CADI, while the use of ACEI, HCV, moderate interstitial fibrosis and tubular atrophy and the use of MMF were associated in the Banff 97 index. Although Banff 97 and CADI analyze different parameters in different renal compartments, only some isolated parameters correlated with graft loss. This suggests that we need to review the CAN grading systems in order to devise a system that includes all parameters able to predict long-term graft survival, including chronic glomerulopathy, glomerular sclerosis, vascular changes, and severity of chronic interstitial fibrosis and tubular atrophy.

Effect of melatonin administration on subjective sleep quality in chronic obstructive pulmonary disease

Disturbed sleep is common in chronic obstructive pulmonary disease (COPD). Conventional hypnotics worsen nocturnal hypoxemia and, in severe cases, can lead to respiratory failure. Exogenous melatonin has somnogenic properties in normal subjects and can improve sleep in several clinical conditions. This randomized, double-blind, placebo-controlled study was carried out to determine the effects of melatonin on sleep in COPD. Thirty consecutive patients with moderate to very severe COPD were initially recruited for the study. None of the participants had a history of disease exacerbation 4 weeks prior to the study, obstructive sleep apnea, mental disorders, current use of oral steroids, methylxanthines or hypnotic-sedative medication, nocturnal oxygen therapy, and shift work. Patients received 3 mg melatonin (N = 12) or placebo (N = 13), orally in a single dose, 1 h before bedtime for 21 consecutive days. Sleep quality was assessed by the Pittsburgh Sleep Quality Index (PSQI) and daytime sleepiness was measured by the Epworth Sleepiness Scale. Pulmonary function and functional exercise level were assessed by spirometry and the 6-min walk test, respectively. Twenty-five patients completed the study protocol and were included in the final analysis. Melatonin treatment significantly improved global PSQI scores (P = 0.012), particularly sleep latency (P = 0.008) and sleep duration (P = 0.046). No differences in daytime sleepiness, lung function and functional exercise level were observed. We conclude that melatonin can improve sleep in COPD. Further long-term studies involving larger number of patients are needed before melatonin can be safely recommended for the management of sleep disturbances in these patients.

Delta sleep instability in children with chronic arthritis

The objective of the present study was to evaluate the expression of a cyclic alternating pattern (CAP) in slow wave sleep (SWS) in children with the well-defined chronic syndrome juvenile idiopathic arthritis (JIA). Twelve patients (9-17 years of age), 7 girls, with JIA were compared to matched controls by age, pubertal stage and gender. After one night of habituation in the sleep laboratory, sleep measurements were obtained by standard polysomnography with conventional sleep scoring and additional CAP analyses. The sleep parameters of the JIA and control groups were similar for sleep efficiency (91.1 ± 6.7 vs 95.8 ± 4.0), sleep stage in minutes: stage 1 (16.8 ± 8.5 vs 17.8 ± 4.0), stage 2 (251.9 ± 41 vs 262.8 ± 38.1), stage 3 (17.0 ± 6.0 vs 15.1 ± 5.7), stage 4 (61.0 ± 21.7 vs 77.1 ± 20.4), and rapid eye movement sleep (82.0 ± 27.6 vs 99.0 ± 23.9), respectively. JIA patients presented nocturnal disrupted sleep, with an increase in short awakenings, but CAP analyses showed that sleep disruption was present even during SWS, showing an increase in the overall CAP rate (P < 0.01). Overall CAP rate during non-rapid eye movement sleep was significantly higher in pediatric patients who were in chronic pain. This is the first study of CAP in pediatric patients with chronic arthritis showing that CAP analyses can be a powerful tool for the investigation of disturbance of SWS in children, based on sleep EEG visual analysis.

Breathing pattern and thoracoabdominal motion during exercise in chronic obstructive pulmonary disease

Subjects with chronic obstructive pulmonary disease (COPD) present breathing pattern and thoracoabdominal motion abnormalities that may contribute to exercise limitation. Twenty-two men with stable COPD (FEV1 = 42.6 ± 13.5% predicted; age 68 ± 8 years; mean ± SD) on usual medication and with at least 5 years of diagnosis were evaluated at rest and during an incremental cycle exercise test (10 watts/2 min). Changes in respiratory frequency, tidal volume, rib cage and abdominal motion contribution to tidal volume and the phase angle that measures the asynchrony were analyzed by inductive respiratory plethysmography at rest and during three levels of exercise (30-50, 70-80, and 100% maximal work load). Repeated measures ANOVA followed by pre-planned contrasts and Bonferroni corrections were used for analyses. As expected, the greater the exercise intensity the higher the tidal volume and respiratory frequency. Abdominal motion contributed to the tidal volume increase (rest: 49.82 ± 11.19% vs exercise: 64.15 ± 9.7%, 63.41 ± 10%, and 65.56 ± 10.2%, respectively, P < 0.001) as well as the asynchrony [phase angle: 11.95 ± 7.24° at rest vs 22.2 ± 15° (P = 0.002), 22.6 ± 9° (P < 0.001), and 22.7 ± 8° (P < 0.001), respectively, at the three levels of exercise]. In conclusion, the increase in ventilation during exercise in COPD patients was associated with the major motion of the abdominal compartment and with an increase in the asynchrony independent of exercise intensity. It suggests that cycling exercise is an effective way of enhancing ventilation in COPD patients.