Mucopolysaccharidosis type II: identification of 30 novel mutations among Latin American patients.

In this study, 103 unrelated South-American patients with mucopolysaccharidosis type II (MPS II) were investigated aiming at the identification of iduronate-2-sulfatase (IDS) disease causing mutations and the possibility of some insights on the genotype-phenotype correlation The strategy used for genotyping involved the identification of the previously reported inversion/disruption of the IDS gene by PCR and screening for other mutations by PCR/SSCP. The exons with altered mobility on SSCP were sequenced, as well as all the exons of patients with no SSCP alteration. By using this strategy, we were able to find the pathogenic mutation in all patients. Alterations such as inversion/disruption and partial/total deletions of the IDS gene were found in 20/103 (19%) patients. Small insertions/deletions/indels (<22 bp) and point mutations were identified in 83/103 (88%) patients, including 30 novel mutations; except for a higher frequency of small duplications in relation to small deletions, the frequencies of major and minor alterations found in our sample are in accordance with those described in the literature.

[Validity and reliability of DASH questionnaire in women who suffer from lymphedema as a side effect of a breast cancer treatment]. / Validez y fiabilidad del cuestionario DASH en mujeres con linfedema secundario a tratamiento de cáncer de mama.

INTRODUCTION: DASH questionnaire was designed to assess upper limb function in musculoskeletal pathologies. The aim of this manuscript is to study the reliability and validity of this questionnaire, to determine if is adequate to use in women with lymphedema due to breast cancer treatment. METHODS: Prospective study in 65 women with lymphedema due to breast cancer treatment was done, in which the reliability of DASH score with internal consistency (Cronbach's alpha) and test-retest reproducibility 15 days' interval (interclass correlation coefficient) and validity by correlation with SF-36v2 and FACT-B+4 (r or Kendall's τ b) scores was investigated. RESULTS: The internal consistency and the test-retest were Cronbach's alpha 0.969 and interclass correlation coefficient 0.861, respectively. There was correlation between the DASH score with the SF-36v2 score, mainly in the areas of physical function, body pain and physical role (r 0.800, 0.738, and 0.682, respectively; p<0.001), and lowest with the emotional and social wellbeing. The DASH score had correlation with FACT-B+4 (0.836; p<0.001) and the subscales the upper limb score (r=0.816; p<0.001), and there was no correlation with the social/familiar subscale (r=0.193; p=0.216). CONCLUSION: The DASH questionnaire is a reliable and valid tool to assess upper limb functionality in Spanish women with breast cancer related lymphedema.

Improving echographic monitoring of hemodynamics in critically ill patients: Validation of right cardiac output measurements through the modified subcostal window.

OBJECTIVE: We aimed to assess the usefulness of using the right ventricle outflow tract (RVOT) velocity-time integral (VTI) for echocardiographic monitoring of cardiac output compared to the gold standard, the VTI along the left ventricle outflow tract (LVOT). DESIGN: Prospective observational study. SETTING: A tertiary intensive care unit. PATIENTS: 100 consecutive patients. INTERVENTIONS: echocardiographic monitoring in critically ill patients. MAIN VARIABLES OF INTEREST: We used intraclass correlation coefficients (ICC) to compare echocardiographic measurements of LVOT VTI through apical window with RVOT VTI through the parasternal and modified subcostal windows and to assess interobserver reproducibility. Preplanned post hoc analyses compared the ICC between ventilated and nonventilated patients. RESULTS: At the time of echocardiography, 44 (44%) patients were mechanically ventilated and 28 (28%) were receiving vasoactive drugs. Good-quality measurements were obtained through the parasternal short-axis and/or apical views in 81 (81%) patients and in 100 (100%) patients through the subcostal window. Consistency with LVOT VTI was moderate for RVOT VTI measured from the modified subcostal view (ICC 0.727; 95%CI: 0.62-0.808) and for RVOT VTI measured from the transthoracic view (0.715; 95%CI: 0.59-0.807). CONCLUSIONS: Measurements of RVOT VTI are moderately consistent with measurements of LVOT VTI. Adding the modified subcostal window allows monitoring RVOT VTI in all the patients of this selected cohort, even those under mechanical ventilation.

[Impact of mammographic breast density on computer-assisted detection (CAD) in a breast imaging department]. / Impacto de la densidad mamaria mamográfica en el funcionamiento de un sistema de detección asistido por ordenador en una unidad de patología mamaria.

OBJECTIVE: To evaluate whether breast density influences the sensitivity of a computer-assisted detection (CAD) system for the detection of breast cancer. MATERIAL AND METHODS: We prospectively studied 8750 digital mammograms with an associated CAD system. We used BI-RADS criteria to classify breast density. We calculated the overall sensitivity of the radiologist and of the CAD system, as well as the sensitivity for each projection and type of finding in relation to the mammographic density of the breast. Finally, we analyzed the interval carcinomas. We used SPSS 11 for all statistical analyses. RESULTS: The overall sensitivity of the CAD system was 88.5% (95% CI: 83.2-92.7%), and the overall sensitivity of the radiologist was 93.5% (95% CI: 84.4%-95.5%). The sensitivity of the craniocaudal view was 81.6% (95% CI: 76.5-90.7%) vs 76.5% (95% CI: 69.3-89.3%) for the mediolateral oblique view. The sensitivity for microcalcifications was 98.6% (95% CI: 96.5-99.7%), and the sensitivity for masses 83.4% (95% CI: 81.2-91.7%). We detected discrepancies smaller than 20% both for microcalcifications present in the four types of densities and for masses with densities 1 and 2. In masses with density 3 the discrepancy was 20.8% and in those with density 4 it was 55%. The CAD system failed to mark only 9.1% (9/94) of the cancers presenting as masses. Half of the interval carcinomas were found in type 4 density and 75% manifested as masses, asymmetries, and distortions. The CAD system had marked 35.7% of the carcinomas. CONCLUSIONS: The craniocaudal view was more sensitive, although this difference was not statistically significant. The sensitivity of CAD was high for microcalcifications in all four density types; however, CAD's sensitivity for masses was low in density types 3 and 4. The CAD system only failed to mark 9.1% of the cancers presenting as masses but was not sensitive for the other two radiological findings included in this marking. Half of the interval carcinomas occurred in type 4 densities and 35.7% had been marked by the CAD system.

Clinical and biochemical studies in mucopolysaccharidosis type II carriers.

The aim of the study was to characterize clinically and biochemically mucopolysaccharidosis type II (MPS II) heterozygotes. Fifty-two women at risk to be a carrier, with a mean age of 34.1 years (range 16-57 years), were evaluated through pedigree analysis, medical history, physical examination, measurement of iduronate sulfatase (IDS) activities in plasma and in leukocytes, quantification of glycosaminoglycans (GAGs) in urine, and analysis of the IDS gene. Eligibility criteria for the study also included being 16 years of age or older and being enrolled in a genetic counselling programme. The pedigree and DNA analyses allowed the identification of 40/52 carriers and 12/52 non-carriers. All women evaluated were clinically healthy, and their levels of urinary GAGs were within normal limits. Median plasma and leukocyte IDS activities found among carriers were significantly lower than the values found for non-carriers; there was, however, an overlap between carriers' and non-carriers' values. Our data suggests that MPS II carriers show lower plasma and leukocyte IDS activities but that this reduction is generally associated neither with changes in levels of urinary GAGs nor with the occurrence of clinical manifestations.

[Effect of Helicobacter pylori eradication on patients with functional dyspepsia]. / Efecto del tratamiento erradicador para Helicobacter pylori en pacientes con dispepsia funcional.

OBJECTIVE: This study evaluated Helicobacter pylori eradication therapy in terms of symptomatic response in patients with functional dyspepsia. On the other hand, we analyzed the importance of histologic findings as a predictor of treatment response. In particular, we studied whether antral gastritis (which is associated with peptic ulcer) may predict a greater symptomatic response to Helicobacter pylori eradication in functional dyspepsia. PATIENTS AND METHODS: This prospective, randomized, single-center trial included 48 patients with functional dyspepsia and Helicobacter pylori infection (27 women and 21 men, mean age 37 +/- 13.5 years). Twenty-seven patients received a 10-day course of rabeprazole, amoxicillin, and clarithromycin (eradication group), followed by 20 mg of rabeprazole for 3 months. Twenty-one patients received 20 mg of rabeprazole for 3 months (control group). Patients were followed up over a 1-year period. All patients completed the Dyspepsia-Related Health Scale Questionnaire, which studies four dimensions: pain intensity, pain disability, non-pain symptoms, and satisfaction with dyspepsia-related health. RESULTS: There was significant symptomatic improvement (p < 0.002) after 6 and 12 months, which was similar with both treatments. In the multivariate analyses, eradication therapy and less severe symptoms before treatment were the only independent factors. The symptomatic response to Helicobacter pylori eradication after 6 months was significantly greater as compared to control therapy (p = 0.01) in patients with antral gastritis and in the non-pain symptoms dimension of the questionnaire. CONCLUSIONS: Both treatments proved to be clinically beneficial in patients with functional dyspepsia. We observed a tendency to greater symptomatic benefit with Helicobacter pylori eradication therapy when compared to control treatment in patients with functional dyspepsia and in a population with a high prevalence of this infection. There is a tendency to symptomatic benefit with Helicobacter pylori eradication therapy in patients with antral gastritis.

Autosomal dominant osteosclerosis type Stanescu: the third family.

We describe a family with Stanescu osteosclerosis. The propositus and his mother were short and had cortical sclerosis of the long bones, deficient facial sinus development, cranial bone malformations, and normal intelligence. To the best of our knowledge, only two such families have been described previously. The autosomal dominant pattern of inheritance of this skeletal dysplasia is reinforced, as there are many other reportedly affected relatives, including the maternal grandfather, uncles, and aunts of the propositus. The findings of wormian bones and calcification of the falx, not previously described, may be added to the phenotype.

Premature ovarian failure and FMR1 premutation co-segregation in a large Brazilian family.

Fragile X syndrome is the most common form of inherited mental retardation in men. The molecular mechanism underlying the disease is an amplification of a polymorphic trinucleotide repeat (CGG)n located at 5' end of FMR1 which promotes transcriptional silencing of the gene. Four different classes of alleles could be distinguished in the population based on the size of the repeat, however only large amplifications over 200 CGG are associated with the disease. In the past decade several authors have associated premutated alleles, which harbor expansions from 61 to 200 repeats, with the occurrence of premature ovarian failure (POF). In this work we describe a large Brazilian family in which a POF/premutated woman has transmitted to five out of seven daughters a FMR1 premutated allele. From these five women with premutations, three have experienced premature ovarian failure. Our data clearly indicate a co-segregation pattern of inheritance between POF and fragile X premutation.

[Fragile X syndrome confirmed by molecular analysis: a case-control study with pre and post-puberal patients]. / Síndrome do X frágil: estudo caso-controle envolvendo pacientes pré e pós-puberais com diagnóstico confirmado por análise molecular.

The fragile X syndrome (FRAXA) is the most common cause of inherited mental retardation. However, it has been frequently underdiagnosed in pediatric population. The characterization of the most significant pre and post-puberal clinical features observed among patients that are positive for the FMR-1 mutation, is useful as a screening tool for ordering the DNA test. Therefore, a screening program for FRAXA has been conducted in a sample of 104 mentally retarded individuals (92 males and 12 females), comprehending familial history and physical examination in order to determine the clinical characteristics. The molecular test for the disease was performed in all individuals. Seventeen patients (14 males) were positive for the FMR-1 mutation. Familial mental retardation and poor eye contact were the most common clinical findings with statistical significance (p<0.05) in FRAXA pre and post-puberal patients. The post-puberal patients presented, as opposed to the control group, large ears, broad forehead and macroorchidism.

Huntington disease: DNA analysis in Brazilian population.

Huntington disease (HD) is associated with expansions of a CAG trinucleotide repeat in the HD gene. Accurate measurement of a specific CAG repeat sequence in the HD gene in 92 Brazilian controls without HD, 44 Brazilian subjects with clinical findings suggestive of HD and 40 individuals from 6 putative HD families, showed a range from 7 to 33 repeats in normal subjects and 39 to 88 repeats in affected subjects. A trend between early age at onset of first symptoms and increasing number of repeats was seen. Major increase of repeat size through paternal inheritance than through maternal inheritance was observed. Data generated from this study may have significant implications for the etiology, knowledge of the incidence, diagnosis, prognosis, genetic counseling and treatment of HD Brazilian patients.

[Down Syndrome--a clinical, cytogenetic and epidemiologic analysis of 165 patients]. / Síndrome de Down--análise clínica, citogenética e epidemiológica de 165 casos.

A clinical follow up of 165 Down Syndrome (DS) patients in an outpatient clinic programme at the Centro de Genética Médica (IFF - FIOCRUZ) was undertaken retrospectively. Clinical and laboratorial investigations were performed, such as cytogenetics and hematological analysis, thyroid hormones survey, abdominal ultrasound and cervical column X Rays. The clinical diagnosis of Down Syndrome was mostly performed during the first year of life, and 70% of all patients were under 4 years of age, being predominantly males. Trisomy 21 derived from non disjunction was found in 85% of the patients. The most common congenital malformation was cardiopathy (37.5%) and among all the clinical complications, repeated pneumonia could be evidenced in 30% of the patients, mainly during the first year of life. Leukopenia was observed in 14% of the patients and abdominal ultrasound scans allowed the early detection of biliary stones in 4.3% of the patients examined, a significative finding in the paediatric population. A prospective clinical programme aiming to anticipate the detection of clinical complications on at risk DS populations will fulfill its objectives and may act as a reducing factor in the infantile mortality rate.

[Predictive capacity of 3 methods for estimating the maintenance dose of digoxin in elderly patients]. / Capacidad predictiva de tres métodos de cálculo de la dosis de mantenimiento de digoxina en ancianos.

PURPOSE: To evaluate three methods for digoxin dose adjustment in aged patients. METHODS: We determined the plasma digoxin levels that would be attained in 47 consecutive old patients with doses adjusted to the creatinin clearance (Clc) by means of three mathematical functions. RESULTS: Age: 79.1 +/- 6.1 years of age; Clc: 0.77 +/- 0.24 mL/kg of lean body weight and minute. Once the dose has been fitted to the digoxin pharmacokinetic parameters described in the bibliography, the drug levels would oscillate between 0.8 and 2.0 ng/mL in 85.1% of the patients, with a 95% confidence interval (95% CI) from 72.3% to 92.6%; in 0.0% of the patients the levels would be greater than 2 ng/mL (95% IC: 0.0% to 7.6%). The precision and the bias would be 0.40 ng/mL (95% IC: 0.33 to 0.46 ng/mL) and--0.08 ng/m (95% IC: -0.19 to 0.04 ng/mL), respectively. The drug level would not be associated with the Clc (coefficient of Clc in the regression line: -0.0003; P > 0.9). The results would be worse with the others two mathematical functions. CONCLUSION: The first of the above adjustment methods would lead to good results if digoxin has not been prescriped in order to control the cardiac frequency in the setting of auricular fibrillation.

[Best result of digoxin dosing in the aged by taking into account that both the elimination as well as the volume of distribution of the drug decrease when the kidney function deteriorates]. / Mejor resultado del ajuste de la dosis de digoxina en ancianos si se tiene en cuenta que tanto la eliminación como el volumen de distribución del fármaco disminuyen cuando se reduce la función renal.

PURPOSE: To evaluate three methods for digoxin dose adjustment in aged patients. METHODS: We determined the plasma digoxin levels that would be attained in 87 old patients with doses adjusted to the kidney function by means of three separate procedures. RESULTS: Age: 79.0 "6.3 years of age; creatinin clearance (Clc): 0.70" 0.23 ml/Kg of lean body weight and minute. Only the methods that adjust both the digoxin clearance and the volume of distribution to the Clc achieve the independence between the digoxinemia and the kidney function. The best of them, by calculating the elimination constant (K) and the volume of distribution (V) as linear functions of the Clc, so that K ranges between 0.173 and 0.462 days-1 and V between 4 and 10 l/Kg of lean body weight when the Clc varies from 0 to 110 ml/minute, achieve digoxinemia figures between 0.8 y 2.0 ng/ml and above 2.0 ng/ml in the 81.6% and 0.0% of the patients (95% confidence intervals (95% CI): 72.2% to 88.4 and 0.0% to 4.6%), respectively; with a precision and a bias of 0.43 and -0.06 ng/ml (95% CI: 0.38 to 0.48 and -0.16 to 0.03 ng/ml), respectively. CONCLUSION: The described method would lead to good results if digoxin has not been prescribed in order to control the cardiac frequency in the setting of auricular fibrilation.