747-4 Evaluation of Regurgitant Jets by Sound Intensity Using a Pulsatile Flow Model: Potential Contribution of Regurgitant Volume and Reynolds Number

Our goal in this study was to determine whether a new type of digital heart sound analysis method could give quantitative information about flow velocity and volume so as to allow a potentially lower-cost approach to followup studies of patients with stenotic or regurgitant valve lesions. To elucidate the relationships between hydrodynamic factors such as Reynolds number, flow velocity and flow volume and the sound characteristics of cardiac murmurs, we developed an in vitro pulsatile flow model with variable orifice size and shape (circular 0.11 cm2, 0.24 cm2, 1.77 cm2and 3.80 cm2; oval 0.24 cm2, with a ratio of major to minor axis=2; rectangular 0.24 cm2, ratio=4). Heart sounds were recorded with a new digital system (MCG) with real time spectral analysis and display and averaged over 15 “cardiac” cycles. Mean flow rate ranged from 0.6 l/min to 6 l/min. Actual instantaneous flow rate was measured using an ultrasonic flow meter for peak flow rates 1.6 l/min to 16.8 l/min. Reynolds number ranged from 6820 to 40050. For each orifice, there was an excellent relationship between total integrated sound energy (See figure: integration of intensity (I) and frequency (F) over time (T).) obtained by digital processing and Reynolds number, peak flow velocity and peak flow rate (r=0.89–0.97, 0.89–0.97, 0.93–D.99, P<0.001, respectively). The best relationship was obtained for the smallest orifice. Higher sound energies were detected for any given flow volume in asymmetrical orifices, probably due to higher turbulence. For all orifices combined, a correlation was found between peak frequency and peak velocity, but only total sound energywas correlated with peak flow rate (r=0.84, P<0.0t). Total integrated sound energy determined digitally is related to peak flow rate; peak velocity and Reynolds number parallel peak sound frequency

Testing the Children: Do Non-Genetic Health-Care Providers Differ in Their Decision to Advise Genetic Presymptomatic Testing on Minors? A Cross-Sectional Study in Five Countries in the European Union

BACKGROUND: Within Europe many guidelines exist regarding the genetic testing of minors. Predictive and presymptomatic genetic testing of minors is recommended for disorders for which medical intervention/preventive measures exist, and for which early detection improves future medical health. AIM: This study, which is part of the larger 5th EU-framework "genetic education" (GenEd) study, aimed to evaluate the self-reported responses of nongenetic health-care providers in five different EU countries (Germany, France, Sweden, the United Kingdom, and the Netherlands) when confronted with a parent requesting presymptomatic testing on a minor child for a treatable disease. METHODS: A cross-sectional study design using postal, structured scenario-based questionnaires that were sent to 8129 general practitioners (GPs) and pediatricians, between July 2004 and October 2004, addressing self-reported management of a genetic case for which early medical intervention during childhood is beneficial, involving a minor. RESULTS: Most practitioners agreed on testing the oldest child, aged 12 years (81.5% for GPs and 87.2% for pediatricians), and not testing the youngest child, aged 6 months (72.6% for GPs and 61.3% for pediatricians). After multivariate adjustment there were statistical differences between countries in recommending a genetic test for the child at the age of 8 years. Pediatricians in France (50%) and Germany (58%) would recommend a test, whereas in the United Kingdom (22%), Sweden (30%), and the Netherlands (32%) they would not. CONCLUSION: Even though presymptomatic genetic testing in minors is recommended for disorders for which medical intervention exists, EU physicians are uncertain at what age starting to do so in young children

Deficiency of knowledge of genetics and genetic tests among general practitioners, gynecologists, and pediatricians: A global problem

Purpose: The objective of this study was to assess knowledge of genetics and awareness of genetic tests among Dutch general practitioners (GPs), gynecologists (GYNs), and pediatricians (PEDs), as well as factors influencing their knowledge and awareness. Methods: An anonymous questionnaire inquiry was used, validated with a sample of 52 clinical geneticists (CGs). The study was carried out in primary care (general practice) and secondary care (general and university hospitals) in The Netherlands. A random sample of 200 GPs, 300 GYNs, and 265 PEDs received a questionnaire. In addition, all registered CGs (58) received a questionnaire for validation. In total, 122 GPs, 187 GYNs, 164 PEDs, and 52 CGs returned a completed questionnaire. The main outcome measures were differences in knowledge scores between physicians working in different disciplines and factors influencing these scores. Results: Knowledge scores of GPs (mean 64% correct answers, 61%-66% [95% confidence interval]), GYNs (mean 75% correct answers, 73%-76% [95% confidence interval]), and PEDs (mean 81% correct answers, 79%-82% [95% confidence interval]) were lower than those in the CG validation group (mean 95% correct answers, 94%-96% [95% confidence interval]). The 5th percentile of GPs, GYNs, and PEDs was at approximately 40%, 52% and 62% correct answers, respectively. There was a specific lack of knowledge about DNA testing. In addition to specialty, important factors positively associated with the knowledge scores of nongeneticists are more recent graduation, having taken an elective course in genetics, and providing genetic counseling in their own practice. Conclusion: The overall knowledge levels of genetics in many nongeneticist health care providers show clear deficiencies. This is in line with reports from other countries, showing that these deficiencies are a global problem

Preconceptional cystic fibrosis carrier screening: Opinions of general practitioners, gynecologists, and pediatricians in The Netherlands

Knowledge of the opinions of physicians with regard to preconceptional cystic fibrosis (CF) carrier screening and the possible factors that are associated with their opinions is important for the implementation of such a screening program. Data were obtained from a study in which genetic knowledge, opinions with regard to genetic testing and related skills were investigated. A questionnaire, developed and used by American researchers, was adapted to the Dutch health care situation, and sent to randomly selected general practitioners (GPs) (n = 200), gynecologists (GYNs) (n = 300), and pediatricians (PEDs) (n = 265). In this part of the study, their opinions with regard to genetic preconceptional CF carrier screening in different situations were assessed. The response rate for the GPs, GYNs, and PEDs was 64%, 69%, and 72%, respectively. In total, 63% of the GPs, 69% of the GYNs and 72% of the PEDs supported preconceptional CF carrier testing if a couple requested a test. Sixteen percent, 19% and 25%, respectively, were in favor of actively offering a test with 95% test sensitivity to all couples who were planning a pregnancy. A positive opinion on preconceptional CF carrier screening was associated with the following variables: "considering the test sensitivity as less important" (GPs, GYNs), "high perceived risk of having a child with CF" (GYNs), "providing genetic counselling in their own practice" (PEDs) and "reassurance when both partners test negative" (PEDs). Physicians are sympathetic toward preconceptional CF carrier screening if the couples themselves request a test. Physicians had reservations about routinely offering a CF carrier test

A Mutation in C2orf64 Causes Impaired Cytochrome c Oxidase Assembly and Mitochondrial Cardiomyopathy

The assembly of mitochondrial respiratory chain complex IV (cytochrome c oxidase) involves the coordinated action of several assembly chaperones. In Saccharomyces cerevisiae, at least 30 different assembly chaperones have been identified. To date, pathogenic mutations leading to a mitochondrial disorder have been identified in only seven of the corresponding human genes. One of the genes for which the relevance to human pathology is unknown is C2orf64, an ortholog of the S. cerevisiae gene PET191. This gene has previously been shown to be a complex IV assembly factor in yeast, although its exact role is still unknown. Previous research in a large cohort of complex IV deficient patients did not support an etiological role of C2orf64 in complex IV deficiency. In this report, a homozygous mutation in C2orf64 is described in two siblings affected by fatal neonatal cardiomyopathy. Pathogenicity of the mutation is supported by the results of a complementation experiment, showing that complex IV activity can be fully restored by retroviral transduction of wild-type C2orf64 in patient-derived fibroblasts. Detailed analysis of complex IV assembly intermediates in patient fibroblasts by 2D-BN PAGE revealed the accumulation of a small assembly intermediate containing subunit COX1 but not the COX2, COX4, or COX5b subunits, indicating that C2orf64 is involved in an early step of the complex IV assembly process. The results of this study demonstrate that C2orf64 is essential for human complex IV assembly and that C2orf64 mutational analysis should be considered for complex IV deficient patients, in particular those with hypertrophic cardiomyopathy

Growth charts for Marfan syndrome in the Netherlands and analysis of genotype-phenotype relationships

To optimize care for children with Marfan syndrome (MFS) in the Netherlands, Dutch MFS growth charts were constructed. Additionally, we aimed to investigate the effect of FBN1 variant type (haploinsufficiency [HI]/dominant negative [DN]) on growth, and compare MFS-related height increase across populations. Height and weight data of individuals with MFS aged 0–21 years were retrospectively collected. Generalized Additive Models for Location, Scale and Shape (GAMLSS) was used for growth chart modeling. To investigate genotype–phenotype relationships, FBN1 variant type was included as an independent variable in height-for-age and BMI-for-age models. MFS-related height increase was compared with that of previous MFS growth studies from the United States, Korea, and France. Height and weight data of 389 individuals with MFS were included (210 males). Height-for-age, BMI-for-age, and weight-for-height charts reflected the tall and slender MFS habitus throughout childhood. Mean increase in height of individuals with MFS compared with the general Dutch population was significantly lower than in the other three MFS populations compared to their reference populations. FBN1-HI variants were associated with taller height in both sexes, and decreased BMI in females (p-values <0.05). This Dutch MFS growth study broadens the notion that genetic background and MFS variant type (HI/DN) influence tall and slender stature in MFS

Growth charts for Marfan syndrome in the Netherlands and analysis of genotype–phenotype relationships

To optimize care for children with Marfan syndrome (MFS) in the Netherlands, Dutch MFS growth charts were constructed. Additionally, we aimed to investigate the effect of FBN1 variant type (haploinsufficiency [HI]/dominant negative [DN]) on growth, and compare MFS-related height increase across populations. Height and weight data of individuals with MFS aged 0–21 years were retrospectively collected. Generalized Additive Models for Location, Scale and Shape (GAMLSS) was used for growth chart modeling. To investigate genotype–phenotype relationships, FBN1 variant type was included as an independent variable in height-for-age and BMI-for-age models. MFS-related height increase was compared with that of previous MFS growth studies from the United States, Korea, and France. Height and weight data of 389 individuals with MFS were included (210 males). Height-for-age, BMI-for-age, and weight-for-height charts reflected the tall and slender MFS habitus throughout childhood. Mean increase in height of individuals with MFS compared with the general Dutch population was significantly lower than in the other three MFS populations compared to their reference populations. FBN1-HI variants were associated with taller height in both sexes, and decreased BMI in females (p-values <0.05). This Dutch MFS growth study broadens the notion that genetic background and MFS variant type (HI/DN) influence tall and slender stature in MFS

Heritable connective tissue disorders in childhood : increased fatigue, pain, disability and decreased general health

Heritable Connective Tissue Disorders (HCTD) show an overlap in the physical features that can evolve in childhood. It is unclear to what extent children with HCTD experience burden of disease. This study aims to quantify fatigue, pain, disability and general health with standardized validated questionnaires. Methods. This observational, multicenter study included 107 children, aged 4-18 years, with Marfan syndrome (MFS), 58%; Loeys-Dietz syndrome (LDS), 7%; Ehlers-Danlos syndromes (EDS), 8%; and hypermobile Ehlers-Danlos syndrome (hEDS), 27%. The assessments included PROMIS Fatigue Parent-Proxy and Pediatric self-report, pain and general health Visual-Analogue-Scales (VAS) and a Childhood Health Assessment Questionnaire (CHAQ). Results. Compared to normative data, the total HCTD-group showed significantly higher parent-rated fatigue T-scores (M = 53 (SD = 12), p = 0.004, d = 0.3), pain VAS scores (M = 2.8 (SD = 3.1), p < 0.001, d = 1.27), general health VAS scores (M = 2.5 (SD = 1.8), p < 0.001, d = 2.04) and CHAQ disability index scores (M = 0.9 (SD = 0.7), p < 0.001, d = 1.23). HCTD-subgroups showed similar results. The most adverse sequels were reported in children with hEDS, whereas the least were reported in those with MFS. Disability showed significant relationships with fatigue (p < 0.001, r(s) = 0.68), pain (p < 0.001, r(s) = 0.64) and general health (p < 0.001, r(s) = 0.59). Conclusions. Compared to normative data, children and adolescents with HCTD reported increased fatigue, pain, disability and decreased general health, with most differences translating into very large-sized effects. This new knowledge calls for systematic monitoring with standardized validated questionnaires, physical assessments and tailored interventions in clinical care