Maternal serum screening: results disclosure, anxiety, and risk perception.

Although increased maternal anxiety following the disclosure of positive second-trimester maternal serum screen (MSS) results has been well documented, how this anxiety correlates with the method of results disclosure has not been well defined. This pilot study aimed to determine how abnormal second-trimester MSS results are disclosed, the level of anxiety experienced by women as a result of this disclosure, and the accuracy of their risk perception. Women referred for prenatal genetic counseling were asked to complete a questionnaire including demographics, standardized Spielberger State-Trait Anxiety Inventory, results disclosure information, and perceived risk. Of the 561 questionnaires distributed, 388 (69.2%) women chose to participate. Of the 136 participants referred for an abnormal MSS, 125 (91.9%) were aware of this indication and elected to complete the results disclosure portion of the questionnaire. The average anxiety level was not significantly different based on the method of results disclosure or who reported the results. We did not identify a definite cause for the anxiety experienced by women receiving abnormal MSS results; however, this study illustrates the need for further research to identify factors that contribute to the elevated anxiety experienced by these women.

Expanded newborn screening in Texas: a survey and educational module addressing the knowledge of pediatric residents.

PURPOSE: To assess the effectiveness of an educational module as a tool for improving the knowledge of pediatric residents about newborn screening and its expansion in Texas. METHODS: The study population consisted of 63 pediatric residents from the University of Texas at Houston, Baylor College of Medicine in Houston, and the University of Texas Medical Branch in Galveston. Residents were invited to participate in the study during daily scheduled didactic lectures in their respective residency programs. Questionnaires were distributed to the residents both before and after the presentation of an educational module about newborn screening in Texas to assess whether knowledge was gained from the presentation. RESULTS: Analysis of questionnaires from the full group of participants showed a substantial increase in knowledge about newborn screening in Texas after the presentation of the educational module. This included a 45.4% increase in knowledge about pre-expansion newborn screening conditions and a 308.4% increase in knowledge about expanded newborn screening conditions (P

Evidence for a novel x-linked modifier locus for leber hereditary optic neuropathy.

Leber Hereditary Optic Neuropathy (LHON) is a maternally inherited blinding disease caused by missense mutations in the mitochondrial DNA (mtDNA). However, incomplete penetrance and a predominance of male patients presenting with vision loss suggest that modifying factors play an important role in the development of the disease. Evidence from several studies suggests that both nuclear modifier genes and environmental factors may be necessary to trigger the optic neuropathy in individuals harboring an LHON-causing mtDNA mutation. Recently, an optic neuropathy susceptibility locus at Xp21-Xq21 has been reported. In this study, we performed X-chromosomal linkage analysis in a large Brazilian family harboring a homoplasmic G11778A mtDNA mutation on a haplogroup J background. We report the identification of a novel LHON susceptibility locus on chromosome Xq25-27.2, with multipoint non-parametric linkage scores of > 5.00 (P = 0.005) and a maximum two-point non-parametric linkage score of 10.12, (P = 0.003) for marker DXS984 (Xq27.1). These results suggest genetic heterogeneity for X-linked modifiers of LHON.

Genes in glucose metabolism and association with spina bifida.

The authors test single nucleotide polymorphisms (SNPs) in coding sequences of 12 candidate genes involved in glucose metabolism and obesity for associations with spina bifida. Genotyping was performed on 507 children with spina bifida and their parents plus anonymous control DNAs from Hispanic and Caucasian individuals. The transmission disequilibrium test was performed to test for genetic associations between transmission of alleles and spina bifida in the offspring (P < .05). A statistically significant association between Lys481 of HK1 (G allele), Arg109Lys of LEPR (G allele), and Pro196 of GLUT1 (A allele) was found ( P = .019, .039, and .040, respectively). Three SNPs on 3 genes involved with glucose metabolism and obesity may be associated with increased susceptibility to spina bifida.

Mortality in achondroplasia study: a 42-year follow-up.

Achondroplasia (ACH) is the most common dwarfing condition having a prevalence of 1/25,000 live births. An increase in overall mortality, age specific mortality up to age 34 years and heart disease-related mortality was first reported in a 1987 study of a large population of ACH individuals. Since this study, concern about premature death, particularly in young adults, has persisted in the ACH population. The present study was undertaken to follow-up the patterns of mortality in a more contemporaneous ACH population. The vital status of 718 ACH individuals from the original study and 75 new ACH individuals was determined through the search of two computerized mortality database. The results showed that the overall mortality and age-specific mortality at all ages remained significantly increased. Rates of death were similar across all 42 years of follow-up suggesting that higher death rates were still occurring in the contemporary ACH population. Accidental, neurological, and heart disease-related deaths were increased in adults. Heart disease-related mortality, between ages 25 and 35, was more than 10 times higher than the general population. Overall survival and the average life expectancy for this ACH population were decreased by 10 years. These results demonstrate that despite advances in the knowledge of the natural history of ACH and health care needs of this population, mortality remains significantly increased. The high rate of heart disease related deaths illustrates the need to identify risk factors in the ACH population and develop treatment interventions accordingly.

The impact of BRCA1 on spina bifida meningomyelocele lesions.

We examined the BRCA1 gene in 268 patients, and their parents, with a specific diagnosis of spina bifida meningomyelocele (SBMM). We genotyped two intragenic microsatellite markers (BRCA1 D17S1323, BRCA1 D17S1322) and 2 single nucleotide polymorphisms (A1186G, A4956G) in our patients. Transmission disequilibrium testing (TDT) showed significant association with A4956G, but not with A1186G. Extended TDT demonstrated over-transmission of the 17GT allele in BRCA1 D17S1323 and the 14GTT allele in BRCA1 D17S1322, and under-transmission of the 20GT allele in BRCA1 D17S1323 and the 16GTT allele in BRCA1 D17S1322. Our data included location of the rostral edge of the lesion. Individuals homozygous for the 17GT allele for BRCA1 D17S1323 were more likely to have SB lesions located caudally, while heterozygotes with the 17GT allele for BRCA1 D17S1323 had a more rostral lesion. Individuals heterozygous for the 16GTT allele of BRCA1 D17S1322 were more likely to have rostral lesions. We measured gene expression in CEPH members and demonstrated differential expression levels of BRCA1 associated with these polymorphisms. Integrating our data with HapMap findings showed that the polymorphic markers are associated with distinct haplotypes. We conclude that the BRCA1 gene is associated with SBMM and participates in the phenotypic variability seen in SBMM.

Pediatric and neonatal transport teams with and without a physician: a comparison of outcomes and interventions.

OBJECTIVE: To determine whether a transport team composed of advanced practice nurses could function as effectively as a physician-nurse team, as measured by patient outcome. DESIGN: Observational cohort study. SETTING: The interfacility transport team at a tertiary care children's hospital. PATIENTS AND OTHER PARTICIPANTS: Fourteen transport nurses and 539 patients. METHODS: A transport team was studied during a previously planned change in composition from a physician-nurse team to a nurse-nurse team. Data were recorded by transport nurses and by subsequent review of the medical record during two 4-month periods, 1 before and 1 after the team change. Pediatric risk of mortality scores (a marker for degree of illness) were assigned for the periods before, during, and after transport. Transport time intervals, demographic data, and patient outcomes were also recorded. Data were assessed using frequency tables for discrete variables, as well as mean and standard deviation for continuous variables. For identification of group differences, chi test was used. MAIN OUTCOME MEASURES: Mortality, transport-related morbidity, overall transport times and interval times, and outcome of procedures performed by transport nurses. RESULTS: Five hundred thirty-nine data sheets were received: 228 before (group 1) and 311 after (group 2) the team change. Physicians attended 128 (56.1%) group 1 transports and 15 (4.82%) group 2 transports. There were no significant differences in mean pediatric risk of mortality scores between group 1 and group 2 patients. Mortality was equivalent. Group 2 transport times were significantly shorter than group 1 times. Transport nurses performed 8 intubations; all were successful. CONCLUSIONS: Outcomes for the 2 types of teams were equivalent. Nonphysician teams responded more quickly and spent less time at the referring facility.

Genotype/phenotype correlation in 325 individuals referred for a diagnosis of tuberous sclerosis complex in the United States.

Tuberous sclerosis complex is an autosomal dominant neurocutaneous disorder marked by hamartoma growth in multiple organ systems. We performed mutational analyses on 325 individuals with definite tuberous sclerosis complex diagnostic status. We identified mutations in 72% (199/257) of de novo and 77% (53/68) of familial cases, with 17% of mutations in the TSC1 gene and 50% in the TSC2 gene. There were 4% unclassified variants and 29% with no mutation identified. Genotype/phenotype analyses of all observed tuberous sclerosis complex findings in probands were performed, including several clinical features not analyzed in two previous large studies. We showed that patients with TSC2 mutations have significantly more hypomelanotic macules and learning disability in contrast to those with TSC1 mutations, findings not noted in previous studies. We also observed results consistent with two similar studies suggesting that individuals with mutations in TSC2 have more severe symptoms. On performing meta-analyses of our data and the other two largest studies in the literature, we found significant correlations for several features that individual studies did not have sufficient power to conclude. Male patients showed more frequent neurologic and eye symptoms, renal cysts, and ungual fibromas. Correlating genotypes with phenotypes should facilitate the disease management of tuberous sclerosis complex.

Improvements in systemic metabolism, anthropometrics, and left ventricular geometry 3 months after bariatric surgery.

BACKGROUND: Several lines of evidence have suggested a link between obesity and heart failure, including chronic inflammation, increased sympathetic tone, and insulin resistance. The goal of this study was to evaluate the changes in systemic metabolism, anthropometrics, and left ventricular (LV) contraction, as well as geometry, in clinically severe obese women after bariatric surgery. METHODS: Enrollment was offered consecutively to 22 women with clinically severe obesity. Participants underwent abdominal magnetic resonance imaging to quantify the visceral adipose tissue (VAT) area and tissue Doppler imaging echocardiography to measure the LV contractile function. Fasting blood chemistries were drawn to measure inflammatory markers and to calculate insulin sensitivity. All tests were performed before surgery and 3 months postoperatively. RESULTS: Three months after surgery, a significant increase in insulin sensitivity (mean change +/- SEM 34.0 +/- 10.4, P < .0001) was present. The VAT area had significantly decreased (-66.1 +/- 17.8 cm2, P = .002) and was associated with decreases in body mass index, serum glucose concentrations, and high-sensitivity C-reactive protein levels (r = .61 and P = .005, r = .48 and P = .033, and r = .53 and P = .016, respectively). The LV mass decreased significantly (-3.8 +/- 1.7 g/m(2.7), P = .037), and this decrease was associated with a decrease in glucose concentration (r = .46, P = .041). The LV systolic and diastolic contractile function were normal at baseline, and no change occurred after surgery. CONCLUSION: The early phase of weight loss after bariatric surgery produces favorable changes in LV geometry, and these are associated with normalization in the glucose metabolism.

The role of MMP-2 and MMP-9 polymorphisms in sporadic intracranial aneurysms.

OBJECT: Matrix metalloproteinases (MMPs) are a family of endopeptidases that mediate vascular remodeling by degrading extracellular matrix components, such as collagen and elastin. On the basis of accumulating evidence that implicates increased MMP-2 (gelatinase A) and MMP-9 (gelatinase B) amounts and activity in the pathogenesis of aneurysms, the authors investigated the genetic association between polymorphisms in MMP-2 and MMP-9 and sporadic intracranial aneurysms. METHODS: Eight polymorphisms located in MMP-2 and MMP-9 were genotyped, and the association of these variations with disease was assessed in a Caucasian population consisting of 125 patients with intracranial aneurysms and 234 ethnically matched healthy volunteers. Polymorphisms in the MMP-2 gene and the haplotypes generated from these polymorphisms were not associated with the occurrence of intracranial aneurysms. However, a polymorphism located in the 3' untranslated region of MMP-9 showed a significant association with disease in the study population, with individuals carrying the TT genotype at increased risk for developing intracranial aneurysms (odds ratio 1.91, p = 0.005). Haplotypes containing the T allele of this polymorphism also showed a comparable association with disease. Similar results were obtained in an analysis of these polymorphisms in a subgroup of patients who presented with ruptured aneurysms. CONCLUSIONS: The study findings support a role for MMP-9, but not MMP-2, in the pathogenesis of intracranial aneurysms.

Association of plasma free fatty acids and left ventricular diastolic function in patients with clinically severe obesity.

BACKGROUND: Obesity is an important contributor to many cardiovascular risk factors and has been associated with abnormalities in cardiac contractile function. Causes of impaired contractile function are not fully understood and may include an oversupply of substrates. OBJECTIVE: We tested the hypothesis that metabolic dysregulation may adversely influence cardiac function. Specifically, we examined the effects of plasma free fatty acids and insulin sensitivity on left ventricular function in patients with clinically severe obesity. DESIGN: We measured metabolic and cardiac variables in 64 obese patients [body mass index (BMI; in kg/m(2)) > 35], including 2-D complete echocardiogram with M-mode and tissue Doppler imaging, anthropometric measurements, and analysis of blood chemistries. RESULTS: The median (25th and 75th percentile) age and BMI were 46 y (36, 53 y) and 51.5 (42.5, 56.5), respectively. The prevalence of diabetes, hypertension, and insulin resistance were 38%, 53%, and 90%, respectively. Plasma free fatty acid (FFA) concentrations were elevated in the cohort. No association was observed between insulin sensitivity or anthropometric measurements and left ventricular contractile function. However, FFA concentration was independently associated with diastolic function (r = -0.33, P = 0.01), and 40% of the cohort showed age-adjusted diastolic impairment as measured by tissue Doppler imaging. CONCLUSION: The negative association between FFA and diastolic function, in the setting of insulin resistance, suggests that excess FFA may exert a lipotoxic effect on the heart.

Does having children extend life span? A genealogical study of parity and longevity in the Amish.

BACKGROUND: The relationship between parity and life span is uncertain, with evidence of both positive and negative relationships being reported previously. We evaluated this issue by using genealogical data from an Old Order Amish community in Lancaster, Pennsylvania, a population characterized by large nuclear families, homogeneous lifestyle, and extensive genealogical records. METHODS: The analysis was restricted to the set of 2,015 individuals who had children, were born between 1749 and 1912, and survived until at least age 50 years. Pedigree structures and birth and death dates were extracted from Amish genealogies, and the relationship between parity and longevity was examined using a variance component framework. RESULTS: Life span of fathers increased in linear fashion with increasing number of children (0.23 years per additional child; p =.01), while life span of mothers increased linearly up to 14 children (0.32 years per additional child; p =.004) but decreased with each additional child beyond 14 (p =.0004). Among women, but not men, a later age at last birth was associated with longer life span (p =.001). Adjusting for age at last birth obliterated the correlation between maternal life span and number of children, except among mothers with ultrahigh (>14 children) parity. CONCLUSIONS: We conclude that high parity among men and later menopause among women may be markers for increased life span. Understanding the biological and/or social factors mediating these relationships may provide insights into mechanisms underlying successful aging.

Inflammatory gene polymorphisms influence risk of postoperative morbidity after lung resection.

BACKGROUND: Polymorphisms in genes encoding proteins involved in the inflammatory response may lead to a differential response to a noxious stimulus. We hypothesized that proinflammatory alleles at candidate loci would predispose patients undergoing lung resection to cardiopulmonary complications with a presumed inflammatory cause. METHODS: We determined the genotypes at six candidate loci in 155 patients who underwent 160 lung resection operations at our center. We correlated these results with data from our clinical database, constructed a model predicting the risk of postoperative complications, and assessed its adequacy using receiver operating characteristic curve methodology. RESULTS: Preexisting cardiovascular disease (p < 0.001), primary lung cancer (p = 0.009), extent of lung resection (p = 0.042), interleukin 6 genotype (p = 0.017), and tumor necrosis factor genotype (p = 0.005) were significantly associated with complications. The odds ratio for complications for rare allele homozygosity was 3.9 (95% confidence interval, 1.4 to 10.4) for interleukin 6 and 15.3 (95% confidence interval, 1.7 to 131.4) for tumor necrosis factor. In multivariate analysis we found that cardiovascular disease (p < 0.001; odds ratio, 4.0 [95% confidence interval, 1.9 to 8.6]), interleukin 6 genotype (p = 0.027; odds ratio, 1.8 [95% confidence interval, 1.1 to 3.1]), and tumor necrosis factor genotype (p = 0.011; odds ratio, 2.5 [95% confidence interval, 1.2 to 5.1]) were independently predictive of complications, with an area under the receiver operating characteristic curve for the entire model of 0.765. CONCLUSIONS: Carriage of specific alleles, and homozygosity in particular, at loci within the interleukin 6 and tumor necrosis factor genes appears to contribute to the risk of experiencing an adverse event after lung resection.

Characterization of an aquaporin-2 water channel gene mutation causing partial nephrogenic diabetes insipidus in a Mexican family: evidence of increased frequency of the mutation in the town of origin.

A Mexican family with partial congenital nephrogenic diabetes insipidus (NDI) that resulted from a mutation in the aquaporin-2 water channel (AQP2) was characterized, and the source of this rare mutation was traced to the family's town of origin in Mexico. Affected individuals with profound polyuria and polydipsia were homozygous for an autosomal recessive missense V168M mutation in the AQP2 gene. Expression in oocytes revealed that, although retained in the endoplasmic reticulum (ER) to a great extent, a considerable amount of the partially functional AQP2-V168M was expressed at the plasma membrane, and that its ER retention was less than AQP2-T126M, a functional mutant in severe recessive NDI. None of the affected AQP2-V168M individuals had neurologic deficits, which also suggested a milder form of the disease. The homozygous individuals reported subjective improvement in polyuria and polydipsia with the use of dDAVP (1-desamino-8-D-arginine-vasopressin). When clinically tested, infusion of dDAVP at variable doses produced a partial increase in the urinary osmolality in homozygous individuals and decreased their water intake. Heterozygotes were unaffected when compared with controls. Samples were obtained from the population of the Mexican town of origin of the family; 30% of the population was heterozygous for the V168M AQP2 mutation and 1% was homozygous for the mutation. The high frequency of this rare mutation in the town provides evidence for an important health care problem in the village with consequences for future generations.

Genetic susceptibility to enteroaggregative Escherichia coli diarrhea: polymorphism in the interleukin-8 promotor region.

Enteroaggregative Escherichia coli (EAEC) infection can be identified in 26% of travelers with diarrhea and is associated with fecal interleukin (IL)-8 production. We hypothesized that single-nucleotide polymorphisms (SNPs) in the IL-8 gene are associated with EAEC-related symptoms. Fecal IL-8 production and IL-8 SNPs at 5 loci were identified in 69 US students who remained in Mexico for 5 weeks; 23 subjects had EAEC-associated diarrhea, 7 were asymptomatic EAEC carriers, 22 had nonspecific diarrhea, and 17 were asymptomatic without an enteropathogen. The chances of having EAEC-associated diarrhea were significantly increased among those with the AA genotype at the -251 position (odds ratio [OR], 208.51; 95% confidence interval [CI], 28.5-1525.36) and among those with AT genotype (OR, 14.3; 95% CI, 1.98-105.74), compared with those with the TT genotype at the -251 position. Among subjects with EAEC-associated diarrhea, the AA genotype at the -251 position produced greater concentrations of fecal IL-8 than those with the AT or TT genotype (P=.0053). In the present study, the AA genotype at the -251 position was associated with the occurrence of EAEC-associated diarrhea and increased levels of fecal IL-8.

Expression of a 65 kDa oncofetal protein in human prostatic carcinoma.

The concentration of a novel 65 kDa oncofetal protein, p65, was measured in the sera of patients with prostatic malignancies using an enzyme-linked immunosorbent assay. The prostate cancer sera were positive for p65 in 40 out of 59 cases (68%), while only 7 of 79 normal sera (9%) and 12 of 61 sera from patients with benign diseases (20%) were positive. The detection system had an overall sensitivity of 68% and a specificity of 86%. Elevated p65 levels correlated positively with the pathologic stages of the prostate cancer. Using this marker in concert with PSA may increase our ability to evaluate treatment response and aid in early detection of prostate cancer.

Sample size for biomarker studies: more subjects or more measurements per subject?

PURPOSE: In molecular epidemiologic studies, optimizing the use of available biological specimens while minimizing the cost is always a challenge. This is particularly true in pilot studies, which often have limited funding and involve small numbers of biological samples too small for assessment of recently developed biomarkers. METHODS: In this study we examined several statistical approaches for determining how many experimental subjects to use in a biomarker study and how many repeated measurements to make on each sample, given specific funding considerations and the correlated nature of the repeated measurements. RESULTS: A molecular epidemiology study of DNA repair and aging in basal cell carcinoma was used to illustrate the application of the statistical methods proposed. CONCLUSIONS: Our methods extend traditional designs on biomarker studies with repeated measurements to including funding constraints.

Using simultaneous equation modeling for defining complex phenotypes.

BACKGROUND: Interactions between multiple biological phenotypes are difficult to model. Simultaneous equation modelling (SEM), as used in econometric modelling, may prove an effective tool for this problem. Generalized linear models were used to derive the structural equations defining the interactions between cholesterol, glucose, triglycerides and high-density lipoprotein cholesterol (HDL-C). These structural equations were then applied, using SEM, to Cohort 2 data (replicates 1-100) to estimate the phenotypic structure underlying the simulation. The goal was to determine if this empiric method of deriving structural equations for use in SEM was able to recover the simulation model better than generalized linear models. RESULTS: First, the underlying structural equations were estimated using generalized linear model techniques, which found strong a relationship between glucose, triglycerides and HDL-C. Using these structural equations, I used SEM to evaluate these relationships jointly. I found that a combination of the empiric structural equations and the SEM method was better at recovering the underlying simulated relationship between biologic measures than generalized linear modelling. CONCLUSION: The empiric SEM procedure presented here estimated different relationships between dependent variables than generalized linear modelling. The SEM procedure using empirically developed structural equations was able to recover the underlying simulation relationship partially and thus holds promise as a technique for complex phenotype analysis. Robust methods for determining the structural equations must be developed for application of SEM to population data.

Bleomycin hydrolase and a genetic locus within the MHC affect risk for pulmonary fibrosis in mice.

Susceptibility to pulmonary fibrosis following environmental insults or cytotoxic cancer therapies has a genetic component. In mouse strains differing in susceptibility to bleomycin-induced lung fibrosis, we show highly significant linkage to only two loci. The first locus on chromosome 17 in the major histocompatibility complex (MHC), LOD = 17.4, named Blmpf1, is highly significant in both males and females, and accounts for approximately 20% of the phenotypic variance. We confirmed the presence of Blmpf1 in MHC congenic mice and narrowed the region to 2.7 cM in a reduced MHC congenic strain. The second locus on chromosome 11, LOD = 5.6, named Blmpf2, is significant in males only. A model including an interaction between Blmpf1 and Blmpf2 best fit the data in males. We confirmed Blmpf2 in a chromosome substitution strain, C57BL/6J-11(C3H), and found that its presence reduces the severity of fibrosis. Functional studies of bleomycin hydrolase activity indicate that this enzyme modulates bleomycin-induced pulmonary fibrosis, suggesting that it may be a candidate gene for Blmpf2. The data suggest sex-specific models of susceptibility to bleomycin-induced lung fibrosis, with an interaction between Blmpf2 and Blmpf1 for the more susceptible males and Blmpf1 as the major locus in females. A putative mechanism for the interaction between the two loci in males is that bleomycin hydrolase functions as an MHC class I epitope-processing protease.