Predictive models for mutations in mismatch repair genes: implication for genetic counseling in developing countries

Background: Lynch syndrome (LS) is the most common form of inherited predisposition to colorectal cancer (CRC), accounting for 2-5% of all CRC. LS is an autosomal dominant disease characterized by mutations in the mismatch repair genes mutL homolog 1 (MLH1), mutS homolog 2 (MSH2), postmeiotic segregation increased 1 (PMS1), post-meiotic segregation increased 2 (PMS2) and mutS homolog 6 (MSH6). Mutation risk prediction models can be incorporated into clinical practice, facilitating the decision-making process and identifying individuals for molecular investigation. This is extremely important in countries with limited economic resources. This study aims to evaluate sensitivity and specificity of five predictive models for germline mutations in repair genes in a sample of individuals with suspected Lynch syndrome. Methods: Blood samples from 88 patients were analyzed through sequencing MLH1, MSH2 and MSH6 genes. The probability of detecting a mutation was calculated using the PREMM, Barnetson, MMRpro, Wijnen and Myriad models. To evaluate the sensitivity and specificity of the models, receiver operating characteristic curves were constructed. Results: Of the 88 patients included in this analysis, 31 mutations were identified: 16 were found in the MSH2 gene, 15 in the MLH1 gene and no pathogenic mutations were identified in the MSH6 gene. It was observed that the AUC for the PREMM (0.846), Barnetson (0.850), MMRpro (0.821) and Wijnen (0.807) models did not present significant statistical difference. The Myriad model presented lower AUC (0.704) than the four other models evaluated. Considering thresholds of >= 5%, the models sensitivity varied between 1 (Myriad) and 0.87 (Wijnen) and specificity ranged from 0 (Myriad) to 0.38 (Barnetson). Conclusions: The Barnetson, PREMM, MMRpro and Wijnen models present similar AUC. The AUC of the Myriad model is statistically inferior to the four other models.

Physical activity counseling in primary health care in Brazil: a national study on prevalence and associated factors

Abstract Background The aim of this study was to determine the prevalence and correlates of physical activity counseling among physicians and nurses working in primary health care in Brazil. Methods A phone survey was carried out in 2011 with professionals working in primary health care in Brazil. The target sample consisted of 1,600 randomly selected primary care units covering all regions of the country. We successfully interviewed 529 professionals within the sampled units; 182 physicians and 347 nurses. The overall response rate was 49.6%. Multivariable logistic regression was used to estimate correlates of counseling in the whole sample and separately for physicians and nurses. Results The prevalence of regular physical activity counseling for at least six months was 68.9% (95% CI 64.9; 72.8) and was significantly higher among physicians compared to nurses (p < 0.05). Most professionals (93.2%) interviewed were unfamiliar with current physical activity recommendations for health. In the adjusted analysis, physical activity counseling was more frequent among those who report assessing patient’s physical activity (OR = 2.16; 95% CI 1.41; 3.29), those reporting that lack of time was not a barrier for counseling (OR = 0.62 95% CI 0.42-0.93), those who felt prepared to provide physical activity counseling (OR = 2.34; 95% CI 1.50-3.66), and those working at primary care units offering physical activity programs for patients (OR = 2.06; 95% CI 1.33-3.20). In the stratified analysis, only assessing patient’s physical activity was a significant correlate among physicians whereas assessing patient’s physical activity, feeling prepared to provide counseling and working in units with physical activity interventions were significant correlates among nurses. Conclusions Physicians and nurses deemed physical activity counseling of great importance in primary health care in Brazil. However, in order to increase the quality of counseling and the number of professionals engaging in this activity, these health teams require greater knowledge about physical activity (global recommendations for health) as well as training on the application of instruments for assessing physical activity. Moreover, sufficient time must be allowed during consultations for the counseling process, and physical activity promotion programs should be implemented within the primary health care units.

Programming peculiarities in two cochlear implant users with superficial siderosis of the central nervous system

To report the audiological outcomes of cochlear implantation in two patients with severe to profound sensorineural hearing loss secondary to superficial siderosis of the CNS and discuss some programming peculiarities that were found in these cases. Retrospective review. Data concerning clinical presentation, diagnosis and audiological assessment pre- and post-implantation were collected of two patients with superficial siderosis of the CNS. Both patients showed good hearing thresholds but variable speech perception outcomes. One patient did not achieve open-set speech recognition, but the other achieved 70% speech recognition in quiet. Electrical compound action potentials could not be elicited in either patient. Map parameters showed the need for increased charge. Electrode impedances showed high longitudinal variability. The implants were fairly beneficial in restoring hearing and improving communication abilities although many reprogramming sessions have been required. The hurdle in programming was the need of frequent adjustments due to the physiologic variations in electrical discharges and neural conduction, besides the changes in the impedances. Patients diagnosed with superficial siderosis may achieve limited results in speech perception scores due to both cochlear and retrocochlear reasons. Careful counseling about the results must be given to the patients and their families before the cochlear implantation indication.

Assessing Pathogenicity for Novel Mutation/Sequence Variants: The Value of Healthy Older Individuals

Improvement in DNA technology is increasingly revealing unexpected/unknown mutations in healthy persons and generating anxiety due to their still unknown health consequences. We report a 44-year-old healthy father of a 10-year-old daughter with bilateral coloboma and hearing loss, but without muscle weakness, in whom a whole-genome CGH revealed a deletion of exons 38-44 in the dystrophin gene. This mutation was inherited from her asymptomatic father, who was further clinically and molecularly evaluated for prognosis and genetic counseling (GC). This deletion was never identified by us in 982 Duchenne/Becker patients. To assess whether the present case represents a rare case of non-penetrance, and aiming to obtain more information for prognosis and GC, we suggested that healthy older relatives submit their DNA for analysis, to which several complied. Mutation analysis revealed that his mother, brother, and 56-year-old maternal uncle also carry the 38-44 deletion, suggesting it an unlikely cause of muscle weakness. Genome sequencing will disclose mutations and variants whose health impact are still unknown, raising important problems in interpreting results, defining prognosis, and discussing GC. We suggest that, in addition to family history, keeping the DNA of older relatives could be very informative, in particular for those interested in having their genome sequenced.

Large-Scale Population Analysis Challenges the Current Criteria for the Molecular Diagnosis of Fascioscapulohumeral Muscular Dystrophy

Facioscapulohumeral muscular dystrophy (FSHD) is a common hereditary myopathy causally linked to reduced numbers (<= 8) of 3.3 kilobase D4Z4 tandem repeats at 4q35. However, because individuals carrying D4Z4-reduced alleles and no FSHD and patients with FSHD and no short allele have been observed, additional markers have been proposed to support an FSHD molecular diagnosis. In particular a reduction in the number of D4Z4 elements combined with the 4A(159/161/168)PAS haplotype (which provides the possibility of expressing DUX4) is currently used as the genetic signature uniquely associated with FSHD. Here, we analyzed these DNA elements in more than 800 Italian and Brazilian samples of normal individuals unrelated to any FSHD patients. We find that 3% of healthy subjects carry alleles with a reduced number (4-8) of D4Z4 repeats on chromosome 4q and that one-third of these alleles, 1.3%, occur in combination with the 4A161PAS haplotype. We also systematically characterized the 4q35 haplotype in 253 unrelated FSHD patients. We find that only 127 of them (50.1%) carry alleles with 1-8 D4Z4 repeats associated with 4A161PAS, whereas the remaining FSHD probands carry different haplotypes or alleles with a greater number of D4Z4 repeats. The present study shows that the current genetic signature of FSHD is a common polymorphism and that only half of FSHD probands carry this molecular signature. Our results suggest that the genetic basis of FSHD, which is remarkably heterogeneous, should be revisited, because this has important implications for genetic counseling and prenatal diagnosis of at-risk families.

Epidemiological and clinical characteristics of injuries among adolescents attended at an emergency service in the city of Ribeirao Preto, Sao Paulo

CONTEXT AND OBJECTIVE: Injuries are an important cause of morbidity during adolescence, but can be avoided through learning about some of their characteristics. This study aimed to identify the most frequent injuries among adolescents attended at an emergency service. DESIGN AND SETTING: Retrospective descriptive study on adolescents attended at the emergency service of the Teaching Health Center, Faculdade de Medicina de Ribeirao Preto (FMRP), between January 1, 2009, and September 30, 2009. METHODS: Age, sex, type of injury, site, day and time of occurrence, part of body involved, care received, whether the adolescent was accompanied at the time of injury and whether any type of counseling regarding injury prevention had been given were analyzed. RESULTS: Among 180 adolescents attended, 106 (58.8%) were boys and 74 (41.1%) were girls. Their ages were: 10 to 12 (66/36.6%), 12 to 14 (60/33.3%) and 14 to 16 years (54/30%). The injuries had occurred in public places (47.7%) and at home (21.1%). The main types were bruises (45.1%) and falls (39.2%), involving upper limbs (46.1%), lower limbs (31%) and head/neck (13.1%). The injuries occurred in the afternoon (44.4%) and morning (30%), on Mondays (17.7%) and Thursdays (16.6%). Radiological examinations were performed on 53.8%. At the time of injury, 76.1% of the adolescents were accompanied. Some type of counseling about injury prevention had been received by 39.4%. CONCLUSIONS: Although the injuries were of low severity, preventive attitudes need to be incorporated in order to reduce the risks and provide greater safety for adolescents.

Mutations, Clinical Findings and Survival Estimates in South American Patients with X-Linked Adrenoleukodystrophy

In this study, we analyzed the ABCD1 gene in X-linked adrenoleukodystrophy (X-ALD) patients and relatives from 38 unrelated families from South America, as well as phenotypic proportions, survival estimates, and the potential effect of geographical origin in clinical characteristics. Methods: X-ALD patients from Brazil, Argentina and Uruguay were invited to participate in molecular studies to determine their genetic status, characterize the mutations and improve the genetic counseling of their families. All samples were screened by SSCP analysis of PCR fragments, followed by automated DNA sequencing to establish the specific mutation in each family. Age at onset and at death, male phenotypes, genetic status of women, and the effect of family and of latitude of origin were also studied. Results: We identified thirty-six different mutations (twelve novel). This population had an important allelic heterogeneity, as only p. Arg518Gln was repeatedly found (three families). Four cases carried de novo mutations. Intra-familiar phenotype variability was observed in all families. Out of 87 affected males identified, 65% had the cerebral phenotype (CALD). The mean (95% CI) ages at onset and at death of the CALD were 10.9 (9.1-12.7) and 24.7 (19.8-29.6) years. No association was found between phenotypic manifestations and latitude of origin. One index-case was a girl with CALD who carried an ABCD1 mutation, and had completely skewed X inactivation. Conclusions: This study extends the spectrum of mutations in X-ALD, confirms the high rates of de novo mutations and the absence of common mutations, and suggests a possible high frequency of cerebral forms in our population.

Quality of life among Brazilian women living with HIV/AIDS

The purpose of the present study was to assess quality of life (QoL) in Brazilian women living with HIV/AIDS, according to the World Health Organization Quality of Life HIV-BREF (WHOQoL-HIV-BREF) domains. A quantitative-based, cross-sectional, analytical study was carried out in healthcare centers specialized in assisting people living with HIV/AIDS, located in a municipality of the state of Sao Paulo, Brazil. One hundred and six women of age 18 years or more, users of the public healthcare system, participated in the study. Socio-demographic and clinical variables were collected using a specific questionnaire. Quality of life related variables were collected by means of the WHOQoL-HIV-BREF instrument. As per the QoL domains, study results show that the Spirituality domain reached a standardized mean score of 65.7, followed by the Physical (64.7), Psychological (60.6), Social Relationships (59.5), Independence (58.6), and Environment (54.5) domains. Results of the multiple regression analysis indicate that the women's employment or retirement, income greater than the minimum wage, and higher educational level were associated with a higher standardized mean score of QoL. However, recent HIV/AIDS diagnosis and exposure to antiretroviral agents for a period shorter than two years were negatively associated with QoL. It is critical that public policies favor an all-embracing social inclusion of these women, thus promoting better social conditions. Counseling, clinical follow-up immediately after the infection diagnosis, and initiation of antiretroviral treatment are crucial moments in the lives of these individuals.

Variable expressivity of osteogenesis imperfecta in a Brazilian family due to p.G1079S mutation in the COL1A1 gene

Osteogenesis imperfecta (OI) is a Mendelian disease with genetic heterogeneity characterized by bone fragility, recurrent fractures, blue sclerae, and short stature, caused mostly by mutations in COL1A1 or COL1A2 genes, which encode the pro-alpha 1(I) and pro-alpha 2(I) chains of type I collagen, respectively. A Brazilian family that showed variable expression of autosomal dominant OI was identified and characterized. Scanning for mutations was carried out using SSCP and DNA sequence analysis. The missense mutation c.3235G>A was identified within exon 45 of the COL1A1 gene in a 16-year-old girl diagnosed as having OI type I; it resulted in substitution of a glycine residue (G) by a serine (S) at codon 1079 (p.G1079S). The proband's mother had the disease signs, but without bone fractures, as did five of nine uncles and aunts of the patient. All of them carried the mutation, which was excluded in four healthy brothers of the patient's mother. This is the first description in a Brazilian family with OI showing variable expression; only one among seven carriers for the c.3235G>A mutation developed bone fractures, the most striking clinical feature of this disease. This finding has a significant implication for prenatal diagnosis in OI disease.

Cytogenomic characterization of an unexpected 17.6 Mb 9p deletion associated to a 14.8 Mb 20p duplication in a dysmorphic patient with multiple congenital anomalies presenting a normal G-banding karyotype

We describe a female patient with developmental delay, dysmorphic features and multiple congenital anomalies who presented a normal G-banded karyotype at the 550-band resolution. Array and multiplex-ligation probe amplification (MLPA) techniques identified an unexpected large unbalanced genomic aberration: a 17.6 Mb deletion of 9p associated to a 14.8 Mb duplication of 20p. The deleted 9p genes, especially CER1 and FREM1, seem to be more relevant to the phenotype than the duplicated 20p genes. This study also shows the relevance of using molecular techniques to make an accurate diagnosis in patients with dysmorphic features and multiple anomalies suggestive of chromosome aberration, even if on G-banding their karyotype appears to be normal. Fluorescence in situ hybridization (FISH) was necessary to identify a masked balanced translocation in the patient's mother, indicating the importance of associating cytogenetic and molecular techniques in clinical genetics, given the implications for patient management and genetic counseling. (C) 2012 Elsevier B.V. All rights reserved.

Women's knowledge of health effects of oral contraceptives in five Brazilian cities

Background: Although acceptability of combined oral contraceptives (COCs) is widespread, patients are often unaware of the noncontraceptive benefits. Study Design: An opinion survey through telephone interview was conducted to evaluate the knowledge of 500 Brazilian women 15-45 years of age who were current users or had recently used COCs. Data were obtained on their knowledge of adverse events, the effects of COCs on health- and menstrual-related symptoms, noncontraceptive benefits and aspects related to sexual response. Results: Most of the women interviewed learned about the pill from doctors or the Internet. Other than the pill, the best-known contraceptive methods were the condom and intrauterine device. The majority of women believe that COCs do not change the risk of gynecological cancers. Most believed that they had no significant effect on sexual response. Conclusions: COCs users in Brazil lack precise information on aspects related to general health, particularly menstrual-related symptoms and noncontraceptive health benefits. (C) 2012 Elsevier Inc. All rights reserved.

Penetrance rate estimation in autosomal dominant conditions

Accurate estimates of the penetrance rate of autosomal dominant conditions are important, among other issues, for optimizing recurrence risks in genetic counseling. The present work on penetrance rate estimation from pedigree data considers the following situations: 1) estimation of the penetrance rate K (brief review of the method); 2) construction of exact credible intervals for K estimates; 3) specificity and heterogeneity issues; 4) penetrance rate estimates obtained through molecular testing of families; 5) lack of information about the phenotype of the pedigree generator; 6) genealogies containing grouped parent-offspring information; 7) ascertainment issues responsible for the inflation of K estimates.

Sugar intake is correlated with adiposity and obesity indicators and sedentary lifestyle in Brazilian individuals with morbid obesity

Obesity is a chronic disease characterized by increased accumulation of body fat. We evaluated the socioeconomic aspects, body composition, risk of metabolic complications associated with obesity, eating habits and lifestyle in both women and men adults and elderly with body mass index (BMI) 40 kg/m(2). Among the subjects studied, 79% (n = 32) are female, 5% (n = 2) smokers, 39% (n = 16) use alcohol and only 24% (n = 10) are practitioners of physical exercise. The higher food intake was breads, followed by rice. The daily intake of fruits and vegetables is low. Positive correlation between consumption of sugar and BMI and abdominal circumference (AC) was observed. In summary, was found that morbidly obese patients that looking for nutritional counseling presents increased body fat, poor eating habits and sedentary lifestyle.

Wide Clinical Variability in Cat Eye Syndrome Patients: Four Non-Related Patients and Three Patients from the Same Family

A small supernumerary marker chromosome (sSMC) derived from chromosome 22 is a relatively common cytogenetic finding. This sSMC typically results in tetrasomy for a chromosomal region that spans the chromosome 22p arm and the proximal 2 Mb of 22q11.21. Using classical cytogenetics, fluorescence in situ hybridization, multiplex ligation-dependent probe amplification, and array techniques, 7 patients with sSMCs derived from chromosome 22 were studied: 4 non-related and 3 from the same family (mother, daughter, and son). The sSMCs in all patients were dicentric and bisatellited chromosomes with breakpoints in the chromosome 22 low-copy repeat A region, resulting in cat eye syndrome (CES) due to chromosome 22 partial tetrasomy 22pter -> q11.2 including the cat eye chromosome region. Although all subjects presented the same chromosomal abnormality, they showed a wide range of phenotypic differences, even in the 3 patients from the same family. There are no previous reports of CES occurring within 3 patients in the same family. Thus, the clinical and follow-up data presented here contribute to a better delineation of the phenotypes and outcomes of CES patients and will be useful for genetic counseling. Copyright (C) 2012 S. Karger AG, Basel

Living Invisible: HTLV-1-Infected Persons and the Lack of Care in Public Health

Introduction: Human T-cell lymphotropic virus type 1 (HTLV-1) infection is intractable and endemic in many countries. Although a few individuals have severe symptoms, most patients remain asymptomatic throughout their lives and their infections may be unknown to many health professionals. HTLV-1 can be considered a neglected public health problem and there are not many studies specifically on patients' needs and emotional experiences. Objective: To better understand how women and men living with HTLV-1 experience the disease and what issues exist in their healthcare processes. Methods: A qualitative study using participant observation and life story interview methods was conducted with 13 symptomatic and asymptomatic patients, at the outpatient clinic of the Emilio Ribas Infectious Diseases Institute, in Sao Paulo, Brazil. Results and Discussion: The interviewees stated that HTLV-1 is a largely unknown infection to society and health professionals. Counseling is rare, but when it occurs, focuses on the low probability of developing HTLV-1 related diseases without adequately addressing the risk of infection transmission or reproductive decisions. The diagnosis of HTLV-1 can remain a stigmatized secret as patients deny their situations. As a consequence, the disease remains invisible and there are potentially negative implications for patient self-care and the identification of infected relatives. This perception seems to be shared by some health professionals who do not appear to understand the importance of preventing new infections. Conclusions: Patients and medical staff referred that the main focus was the illness risk, but not the identification of infected relatives to prevent new infections. This biomedical model of care makes prevention difficult, contributes to the lack of care in public health for HTLV-1, and further perpetuates the infection among populations. Thus, HTLV-1 patients experience an "invisibility" of their complex demands and feel that their rights as citizens are ignored.