967 resultados para functional methods
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Since the first experimental evidences of active conductances in dendrites, most neurons have been shown to exhibit dendritic excitability through the expression of a variety of voltage-gated ion channels. However, despite experimental and theoretical efforts undertaken in the past decades, the role of this excitability for some kind of dendritic computation has remained elusive. Here we show that, owing to very general properties of excitable media, the average output of a model of an active dendritic tree is a highly non-linear function of its afferent rate, attaining extremely large dynamic ranges (above 50 dB). Moreover, the model yields double-sigmoid response functions as experimentally observed in retinal ganglion cells. We claim that enhancement of dynamic range is the primary functional role of active dendritic conductances. We predict that neurons with larger dendritic trees should have larger dynamic range and that blocking of active conductances should lead to a decrease in dynamic range.
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Background: Major depression is one of the leading causes of disability worldwide, yet epidemiologic data are not available for many countries, particularly low- to middle-income countries. In this paper, we present data on the prevalence, impairment and demographic correlates of depression from 18 high and low-to middle-income countries in the World Mental Health Survey Initiative. Methods: Major depressive episodes (MDE) as defined by the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DMS-IV) were evaluated in face-to-face interviews using the World Health Organization Composite International Diagnostic Interview (CIDI). Data from 18 countries were analyzed in this report (n = 89,037). All countries surveyed representative, population-based samples of adults. Results: The average lifetime and 12-month prevalence estimates of DSM-IV MDE were 14.6% and 5.5% in the ten high-income and 11.1% and 5.9% in the eight low- to middle-income countries. The average age of onset ascertained retrospectively was 25.7 in the high-income and 24.0 in low- to middle-income countries. Functional impairment was associated with recency of MDE. The female: male ratio was about 2: 1. In high-income countries, younger age was associated with higher 12-month prevalence; by contrast, in several low-to middle-income countries, older age was associated with greater likelihood of MDE. The strongest demographic correlate in high-income countries was being separated from a partner, and in low- to middle-income countries, was being divorced or widowed. Conclusions: MDE is a significant public-health concern across all regions of the world and is strongly linked to social conditions. Future research is needed to investigate the combination of demographic risk factors that are most strongly associated with MDE in the specific countries included in the WMH.
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Background and Purpose: A nonfunctioning inflammatory kidney is a challenging surgical condition for urologists. Some investigators recommend open surgery because of the surgical difficulties caused by the inflammatory process, whereas others try to apply the advantages of a ""simple"" non-hand-assisted laparoscopic approach. We report our experience with simple laparoscopic nephrectomy for inflammatory kidney management. Patients and Methods: From July 2002 through December 2006, 50 pure laparoscopic nephrectomies were performed for inflammatory kidney ( 43 because of pyelonephritis, 5 for xanthogranulomatous pyelonephritis (XGP), and 2 for pyonephrosis). Histopathologic analysis was the criterion used for inflammatory kidney diagnosis. Pain or recurrent urinary tract infection associated with a nonfunctioning excluded kidney was the eligibility criterion for the procedure. Preoperatively, all patients underwent complete image and functional renal assessment. Morcellation was used to remove surgical specimens. Conversion index, surgical difficulties, operative time, and postoperative complications were evaluated. Results: Conversion was performed in 14 of 50 (28%) patients, including two with XGP and one with pyonephrosis. Adhesions, vascular (two inferior vena cava) lesions, and intestinal lesions (two colon) were the main causes of conversion. Acute pancreatitis developed in one patient, and one patient had a wound infection. Reoperations were unnecessary, and no deaths occurred. Conclusion: Pure laparoscopic nephrectomy was successful in 72% of patients with inflammatory kidneys. The laparoscopic dissection was useful even in those cases converted to open surgery. This is a high-risk procedure, however, and both surgeon and patient must be aware of that before the decision is made for this approach.
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Background: The beneficial actions of exercise training on lipid, glucose and energy metabolism and insulin sensitivity appear to be in part mediated by PGC-1 alpha. Previous studies have shown that spontaneously exercised rats show at rest enhanced responsiveness to exogenous insulin, lower plasma insulin levels and increased skeletal muscle insulin sensitivity. This study was initiated to examine the functional interaction between exercise-induced modulation of skeletal muscle and liver PGC-1 alpha protein expression, whole body insulin sensitivity, and circulating FFA levels as a measure of whole body fatty acid (lipid) metabolism. Methods: Two groups of male Wistar rats (2 Mo of age, 188.82 +/- 2.77 g BW) were used in this study. One group consisted of control rats placed in standard laboratory cages. Exercising rats were housed individually in cages equipped with running wheels and allowed to run at their own pace for 5 weeks. At the end of exercise training, insulin sensitivity was evaluated by comparing steady-state plasma glucose (SSPG) concentrations at constant plasma insulin levels attained during the continuous infusion of glucose and insulin to each experimental group. Subsequently, soleus and plantaris muscle and liver samples were collected and quantified for PGC-1 alpha protein expression by Western blotting. Collected blood samples were analyzed for glucose, insulin and FFA concentrations. Results: Rats housed in the exercise wheel cages demonstrated almost linear increases in running activity with advancing time reaching to maximum value around 4 weeks. On an average, the rats ran a mean (Mean +/- SE) of 4.102 +/- 0.747 km/day and consumed significantly more food as compared to sedentary controls (P < 0.001) in order to meet their increased caloric requirement. Mean plasma insulin (P < 0.001) and FFA (P < 0.006) concentrations were lower in the exercise-trained rats as compared to sedentary controls. Mean steady state plasma insulin (SSPI) and glucose (SSPG) concentrations were not significantly different in sedentary control rats as compared to exercise-trained animals. Plantaris PGC-1 alpha protein expression increased significantly from a 1.11 +/- 0.12 in the sedentary rats to 1.74 +/- 0.09 in exercising rats (P < 0.001). However, exercise had no effect on PGC-1 alpha protein content in either soleus muscle or liver tissue. These results indicate that exercise training selectively up regulates the PGC-1 alpha protein expression in high-oxidative fast skeletal muscle type such as plantaris muscle. Conclusion: These data suggest that PGC-1 alpha most likely plays a restricted role in exercise-mediated improvements in insulin resistance (sensitivity) and lowering of circulating FFA levels.
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Background: Cardiac remodeling is generally an adverse sign and is associated with heart failure (HF) progression. NFkB, an important transcription factor involved in many cell survival pathways, has been implicated in the remodeling process, but its role in the heart is still controversial. Recently, a promoter polymorphism associated with a lesser activation of the NFKB1 gene was also associated with Dilated Cardiomyopathy. The purpose of this study was to evaluate the association of this polymorphism with clinical and functional characteristics of heart failure patients of different etiologies. Methods: A total of 493 patients with HF and 916 individuals from a cohort of individuals from the general population were investigated. The NFKB1-94 insertion/deletion ATTG polymorphism was genotyped by High Resolution Melt discrimination. Allele and genotype frequencies were compared between groups. In addition, frequencies or mean values of different phenotypes associated with cardiovascular disease were compared between genotype groups. Finally, patients were prospectively followed-up for death incidence and genotypes for the polymorphism were compared regarding disease onset and mortality incidence in HF patients. Results: We did not find differences in genotype and allelic frequencies between cases and controls. Interestingly, we found an association between the ATTG(1)/ATTG(1) genotype with right ventricle diameter (P = 0.001), left ventricle diastolic diameter (P = 0.04), and ejection fraction (EF) (P = 0.016), being the genotype ATTG(1)/ATTG(1) more frequent in patients with EF lower than 50% (P = 0.01). Finally, we observed a significantly earlier disease onset in ATTG(1)/ATTG(1) carriers. Conclusion: There is no genotype or allelic association between the studied polymorphism and the occurrence of HF in the tested population. However, our data suggest that a diminished activation of NFKB1, previously associated with the ATTG(1)/ATTG(1) genotype, may act modulating on the onset of disease and, once the individual has HF, the genotype may modulate disease severity by increasing cardiac remodeling and function deterioration.
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Background: Changes in the proteoglycans glypican and syndecan-4 have been reported in several pathological conditions, but little is known about their expression in the heart during diabetes. The aim of this study was to investigate in vivo heart function changes and alterations in mRNA expression and protein levels of glypican-1 and syndecan-4 in cardiac and skeletal muscles during streptozotocin (STZ)-induced diabetes. Methods: Diabetes was induced in male Wistar rats by STZ administration. The rats were assigned to one of the following groups: control (sham injection), after 24 hours, 10 days, or 30 days of STZ administration. Echocardiography was performed in the control and STZ 10-day groups. Western and Northern blots were used to quantify protein and mRNA levels in all groups. Immunohistochemistry was performed in the control and 30-day groups to correlate the observed mRNA changes to the protein expression. Results: In vivo cardiac functional analysis performed using echocardiography in the 10-day group showed diastolic dysfunction with alterations in the peak velocity of early (E) diastolic filling and isovolumic relaxation time (IVRT) indices. These functional alterations observed in the STZ 10-day group correlated with the concomitant increase in syndecan-4 and glypican-1 protein expression. Cardiac glypican-1 mRNA and skeletal syndecan-4 mRNA and protein levels increased in the STZ 30-day group. On the other hand, the amount of glypican in skeletal muscle was lower than that in the control group. The same results were obtained from immunohistochemistry analysis. Conclusion: Our data suggest that membrane proteoglycans participate in the sequence of events triggered by diabetes and inflicted on cardiac and skeletal muscles.
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Background: The MASS IV-DM Trial is a large project from a single institution, the Heart Institute (InCor), University of Sao Paulo Medical School, Brazil to study ventricular function and coronary arteries in patients with type 2 diabetes mellitus. Methods/Design: The study will enroll 600 patients with type 2 diabetes who have angiographically normal ventricular function and coronary arteries. The goal of the MASS IV-DM Trial is to achieve a long-term evaluation of the development of coronary atherosclerosis by using angiograms and coronary-artery calcium scan by electron-beam computed tomography at baseline and after 5 years of follow-up. In addition, the incidence of major cardiovascular events, the dysfunction of various organs involved in this disease, particularly microalbuminuria and renal function, will be analyzed through clinical evaluation. In addition, an effort will be made to investigate in depth the presence of major cardiovascular risk factors, especially the biochemical profile, metabolic syndrome inflammatory activity, oxidative stress, endothelial function, prothrombotic factors, and profibrinolytic and platelet activity. An evaluation will be made of the polymorphism as a determinant of disease and its possible role in the genesis of micro- and macrovascular damage. Discussion: The MASS IV-DM trial is designed to include diabetic patients with clinically suspected myocardial ischemia in whom conventional angiography shows angiographically normal coronary arteries. The result of extensive investigation including angiographic follow-up by several methods, vascular reactivity, pro-thrombotic mechanisms, genetic and biochemical studies may facilitate the understanding of so-called micro- and macrovascular disease of DM.
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Background: Spinal muscular atrophy (SMA) is an autosomal recessive disorder that affects the motoneurons of the spinal anterior horn, resulting in hypotonia and muscle weakness. The disease is caused by deletion or mutation in the telomeric copy of SMN gene (SMN1) and clinical severity is in part determined by the copy number of the centromeric copy of the SMN gene (SMN2). The SMN2 mRNA lacks exon 7, resulting in a production of lower amounts of the full-length SMN protein. Knowledge of the molecular mechanism of diseases has led to the discovery of drugs capable of increasing SMN protein level through activation of SMN2 gene. One of these drugs is the valproic acid (VPA), a histone deacetylase inhibitor. Methods: Twenty-two patients with type II and III SMA, aged between 2 and 18 years, were treated with VPA and were evaluated five times during a one-year period using the Manual Muscle Test (Medical Research Council scale-MRC), the Hammersmith Functional Motor Scale (HFMS), and the Barthel Index. Results: After 12 months of therapy, the patients did not gain muscle strength. The group of children with SMA type II presented a significant gain in HFMS scores during the treatment. This improvement was not observed in the group of type III patients. The analysis of the HFMS scores during the treatment period in the groups of patients younger and older than 6 years of age did not show any significant result. There was an improvement of the daily activities at the end of the VPA treatment period. Conclusion: Treatment of SMA patients with VPA may be a potential alternative to alleviate the progression of the disease.
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Introduction: The successful integration of stem cells in adult brain has become a central issue in modern neuroscience. In this study we sought to test the hypothesis that survival and neurodifferentiation of mesenchymal stem cells (MSCs) may be dependent upon microenvironmental conditions according to the site of implant in the brain. Methods: MSCs were isolated from adult rats and labeled with enhanced-green fluorescent protein (eGFP) lentivirus. A cell suspension was implanted stereotactically into the brain of 50 young rats, into one neurogenic area (hippocampus), and into another nonneurogenic area (striatum). Animals were sacrificed 6 or 12 weeks after surgery, and brains were stained for mature neuronal markers. Cells coexpressing NeuN (neuronal specific nuclear protein) and GFP (green fluorescent protein) were counted stereologically at both targets. Results: The isolated cell population was able to generate neurons positive for microtubule-associated protein 2 (MAP2), neuronal-specific nuclear protein (NeuN), and neurofilament 200 (NF200) in vitro. Electrophysiology confirmed expression of voltage-gated ionic channels. Once implanted into the hippocampus, cells survived for up to 12 weeks, migrated away from the graft, and gave rise to mature neurons able to synthesize neurotransmitters. By contrast, massive cell degeneration was seen in the striatum, with no significant migration. Induction of neuronal differentiation with increased cyclic adenosine monophosphate in the culture medium before implantation favored differentiation in vivo. Conclusions: Our data demonstrated that survival and differentiation of MSCs is strongly dependent upon a permissive microenvironment. Identification of the pro-neurogenic factors present in the hippocampus could subsequently allow for the integration of stem cells into nonpermissive areas of the central nervous system.
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Introduction: Work disability is a major consequence of rheumatoid arthritis (RA), associated not only with traditional disease activity variables, but also more significantly with demographic, functional, occupational, and societal variables. Recent reports suggest that the use of biologic agents offers potential for reduced work disability rates, but the conclusions are based on surrogate disease activity measures derived from studies primarily from Western countries. Methods: The Quantitative Standard Monitoring of Patients with RA (QUEST-RA) multinational database of 8,039 patients in 86 sites in 32 countries, 16 with high gross domestic product (GDP) (>24K US dollars (USD) per capita) and 16 low-GDP countries (<11K USD), was analyzed for work and disability status at onset and over the course of RA and clinical status of patients who continued working or had stopped working in high-GDP versus low-GDP countries according to all RA Core Data Set measures. Associations of work disability status with RA Core Data Set variables and indices were analyzed using descriptive statistics and regression analyses. Results: At the time of first symptoms, 86% of men (range 57%-100% among countries) and 64% (19%-87%) of women <65 years were working. More than one third (37%) of these patients reported subsequent work disability because of RA. Among 1,756 patients whose symptoms had begun during the 2000s, the probabilities of continuing to work were 80% (95% confidence interval (CI) 78%-82%) at 2 years and 68% (95% CI 65%-71%) at 5 years, with similar patterns in high-GDP and low-GDP countries. Patients who continued working versus stopped working had significantly better clinical status for all clinical status measures and patient self-report scores, with similar patterns in high-GDP and low-GDP countries. However, patients who had stopped working in high-GDP countries had better clinical status than patients who continued working in low-GDP countries. The most significant identifier of work disability in all subgroups was Health Assessment Questionnaire (HAQ) functional disability score. Conclusions: Work disability rates remain high among people with RA during this millennium. In low-GDP countries, people remain working with high levels of disability and disease activity. Cultural and economic differences between societies affect work disability as an outcome measure for RA.
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Objectives: Adults with major depressive disorder (MDD) are reported to have reduced orbitofrontal cortex (OFC) volumes, which could be related to decreased neuronal density. We conducted a study on medication naive children with MDD to determine whether abnormalities of OFC are present early in the illness course. Methods: Twenty seven medication naive pediatric Diagnostic and Statistical Manual of Mental Disorders, 4(th) edition (DSM-IV) MDD patients (mean age +/- SD = 14.4 +/- 2.2 years; 10 males) and 26 healthy controls (mean age +/- SD = 14.4 +/- 2.4 years; 12 males) underwent a 1.5T magnetic resonance imaging (MRI) with 3D spoiled gradient recalled acquisition. The OFC volumes were compared using analysis of covariance with age, gender, and total brain volume as covariates. Results: There was no significant difference in either total OFC volume or total gray matter OFC volume between MDD patients and healthy controls. Exploratory analysis revealed that patients had unexpectedly larger total right lateral (F = 4.2, df = 1, 48, p = 0.05) and right lateral gray matter (F = 4.6, df = 1, 48, p = 0.04) OFC volumes compared to healthy controls, but this finding was not significant following statistical correction for multiple comparisons. No other OFC subregions showed a significant difference. Conclusions: The lack of OFC volume abnormalities in pediatric MDD patients suggests the abnormalities previously reported for adults may develop later in life as a result of neural cell loss.
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Background: Core promoters are cis-regulatory modules to which bind the basal transcriptional machinery and which participate in the regulation of transcription initiation. Although core promoters have not been extensively investigated through functional assays in a chromosomal context, the available data suggested that the response of a given core promoter might vary depending on the promoter context. Previous studies suggest that a (-57/+40) fragment constitutes the core promoter of the BhC4-1 gene which is located in DNA puff C4 of the sciarid fly Bradysia hygida. Here we tested this (-57/+40) fragment in distinct regulatory contexts in order to verify if promoter context affects its core promoter activity. Results: Consistent with the activity of a core promoter, we showed that in the absence of upstream regulatory sequences the (-57/+40) fragment drives low levels of reporter gene mRNA expression throughout development in transgenic Drosophila. By assaying the (-57/+40) fragment in two distinct regulatory contexts, either downstream of the previously characterized Fbp1 enhancer or downstream of the UAS element, we showed that the BhC4-1 core promoter drives regulated transcription in both the germline and in various tissues throughout development. Furthermore, the use of the BhC4-1 core promoter in a UAS construct significantly reduced salivary gland ectopic expression in third instar larvae, which was previously described to occur in the context of the GAL4/UAS system. Conclusions: Our results from functional analysis in transgenic Drosophila show that the BhC4-1 core promoter drives gene expression regardless of the promoter context that was assayed. New insights into the functioning of the GAL4/UAS system in Drosophila were obtained, indicating that the presence of the SV40 sequence in the 3' UTR of a UAS construct does not preclude expression in the germline. Furthermore, our analysis indicated that ectopic salivary gland expression in the GAL4/UAS system does not depend only on sequences present in the GAL4 construct, but can also be affected by the core promoter sequences in the UAS construct. In this context, we propose that the sciarid BhC4-1 core promoter constitutes a valuable core promoter which can be employed in functional assays in insects.
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Objective: To reevaluate the responses of thyrotropin-releasing hormone ( TRH) stimulation test in baseline condition as well as after the administration of graded supraphysiological doses of liothyronine ( L- T-3) in normal subjects. Design: To assess various parameters related to the hypothalamic-pituitary axis and peripheral tissue responses to L- T-3 in 22 normal individuals ( median age: 30.5 years). Subjects were submitted to an intravenous TRH test at baseline condition and also to the oral administration of sequential and graded doses of L- T-3 ( 50, 100, and 200 mu g/day), each given over 3 days, at an outpatient clinic. Blood samples were obtained for thyrotropin (TSH) and prolactin (PRL) at basal and then 15, 30, and 60 minutes after the TRH injection. Effects of L- T3 administration on cholesterol, creatine kinase, retinol, ferritin, and sex hormone-binding globulin ( SHBG) were also measured at basal and after the oral administration of L- T-3. Main outcome: TRH administration resulted in an increase of 4-to 14-fold rise in serum TSH ( 8.3 +/- 2.5-fold), and in a slight rise in serum PRL concentrations ( 3.8 +/- 1.5-fold). Administration of graded doses of triiodothyronine ( T-3) resulted in a dose-dependent suppression of TSH and PRL. Basal thyroxine- binding globulin (TBG) and cholesterol levels decreased, and ferritin and SHBG increased after L- T-3 administration, while creatine kinase and retinol did not change throughout the study. There was a positive correlation between basal TSH and TSH peak response to TRH at basal condition and after each sequential L- T-3 doses. On the other hand, TSH peak response to the TRH test did not predict cholesterol, TBG, ferritin, or SHBG values. Conclusion: Using the current methods on hormone and biochemical analysis, we standardized the response of many parameters to TRH stimulation test after sequential and graded T-3 suppression test in normal subjects. Our data suggest that the evaluation of the responses of the hypothalamus-pituitary axis to TRH test as well as the impact of L- T-3 on peripheral tissues were not modified by the current methods.
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AIM: To evaluate the effects of meal size and three segmentations on intragastric distribution of the meal and gastric motility, by scintigraphy. METHODS: Twelve healthy volunteers were randomly assessed, twice, by scintigraphy. The test meal consisted of 60 or 180 mL of yogurt labeled with 64 MBq (99m)Tc-tin colloid. Anterior and posterior dynamic frames were simultaneously acquired for 18 min and all data were analyzed in MatLab. Three proximal-distal segmentations using regions of interest were adopted for both meals. RESULTS: Intragastric distribution of the meal between the proximal and distal compartments was strongly influenced by the way in which the stomach was divided, showing greater proximal retention after the 180 mL. An important finding was that both dominant frequencies (1 and 3 cpm) were simultaneously recorded in the proximal and distal stomach; however, the power ratio of those dominant frequencies varied in agreement with the segmentation adopted and was independent of the meal size. CONCLUSION: It was possible to simultaneously evaluate the static intragastric distribution and phasic contractility from the same recording using our scintigraphic approach. (C) 2010 Baishideng. All rights reserved.
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Background: Cerebral palsy (CP) patients have motor limitations that can affect functionality and abilities for activities of daily living (ADL). Health related quality of life and health status instruments validated to be applied to these patients do not directly approach the concepts of functionality or ADL. The Child Health Assessment Questionnaire (CHAQ) seems to be a good instrument to approach this dimension, but it was never used for CP patients. The purpose of the study was to verify the psychometric properties of CHAQ applied to children and adolescents with CP. Methods: Parents or guardians of children and adolescents with CP, aged 5 to 18 years, answered the CHAQ. A healthy group of 314 children and adolescents was recruited during the validation of the CHAQ Brazilian-version. Data quality, reliability and validity were studied. The motor function was evaluated by the Gross Motor Function Measure (GMFM). Results: Ninety-six parents/guardians answered the questionnaire. The age of the patients ranged from 5 to 17.9 years (average: 9.3). The rate of missing data was low(< 9.3%). The floor effect was observed in two domains, being higher only in the visual analogue scales (<= 35.5%). The ceiling effect was significant in all domains and particularly high in patients with quadriplegia (81.8 to 90.9%) and extrapyramidal (45.4 to 91.0%). The Cronbach alpha coefficient ranged from 0.85 to 0.95. The validity was appropriate: for the discriminant validity the correlation of the disability index with the visual analogue scales was not significant; for the convergent validity CHAQ disability index had a strong correlation with the GMFM (0.77); for the divergent validity there was no correlation between GMFM and the pain and overall evaluation scales; for the criterion validity GMFM as well as CHAQ detected differences in the scores among the clinical type of CP (p < 0.01); for the construct validity, the patients' disability index score (mean: 2.16; SD: 0.72) was higher than the healthy group ( mean: 0.12; SD: 0.23)(p < 0.01). Conclusion: CHAQ reliability and validity were adequate to this population. However, further studies are necessary to verify the influence of the ceiling effect on the responsiveness of the instrument.