Complicated hereditary spastic paraplegia with thin corpus callosum: variation of phenotypic expression over time.
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Adaptor Proteins, Signal Transducing↗
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Asthma phenotypes according to the timing of smoking onset in young adults.
SETTING: Whether and how cigarette smoking influences asthma are still matters of debate. OBJECTIVE: To identify risk factors associated with asthma according to whether individuals began active smoking before or after asthma onset. DESIGN: A sample of 544 individuals was examined using the protocol of the European Community Respiratory Health Status, Phase 1. RESULTS: Current active smoking (43.6%) was associated with wheezing during the past year (15.2%, OR 3.7; 95% CI 1.7-8.4), but not with asthma (17.6%, OR 0.78; 95% CI 0.48-1.26). However, active smoking modulated risk factors for asthma. Asthma that developed before smoking and asthma without smoking were both significantly related to nasal allergy, parental asthma and atopy (as assessed by skin prick test positivity and increased total and specific IgE levels). Only a lower FEV1 level was significantly associated with asthma that initiated after beginning smoking. CONCLUSIONS: Our data put forward different phenotypes of asthma according to the timing of smoking onset and suggest that asthma either never accompanied by smoking or followed by smoking onset might be characterised by an allergic pattern. Longitudinal studies are warranted to further clarify the relationships among asthma phenotypes according to the sequence of disease onset and smoking.
Adult↗
Genetic analysis of maximum cigarette-use phenotypes.
BACKGROUND: Using the Framingham Heart Study data set provided for Genetic Analysis Workshop 13, we defined the cigarette-use phenotype M for smokers to be the maximum number of cigarettes-per-day (MAXCIG) reported over the longitudinal course of the study. Adjustments were made for the significant covariates of gender and year of birth, and sib-pair based linkage analysis was performed. RESULTS: The primary analyses, in which individuals with MAXCIG = 0 were considered to have missing phenotype, resulted in modest linkage evidence, with LOD scores over 1 on chromosomes 5, 9, 13, 14, and 22. CONCLUSIONS: While the results reported here do not indicate definitive evidence for linkage to specific chromosomal regions, future studies may find it useful to include direct assessments of maximum and quantitative cigarette use. In defining and analyzing quantitative or "maximum use" phenotypes, the choice of how to handle individuals with MAXCIG = 0, or alternatively, individuals who are substance-naive, is a crucial one for genetic studies of nicotine and other substance use. In this study, the linkage results vary greatly depending on whether or not these "unexposed" individuals are included in the analyses.
Adult Children↗
Association of apolipoprotein A phenotypes and oxidized low-density lipoprotein immune complexes in children.
BACKGROUND: Small apolipoprotein A (apo [A]) phenotypes and oxidized low-density lipoprotein immune complexes (oxLDL-ICs) are known to be associated with the development of atherosclerosis in adults. Presence of these factors in children and their relationships with other known cardiovascular risk factors have not been well documented. OBJECTIVE: To examine the relationship of oxLDL-ICs with apo(A) phenotypes and other known cardiovascular risk factors in children. DESIGN: A survey of asymptomatic 9- to 11-year-old children, randomly selected from a cohort of children stratified based on family history of premature coronary artery disease. SETTING: A preventive medicine research institute. PARTICIPANTS: Thirty-five children with or without a family history of premature coronary artery disease who are participating in a longitudinal cardiovascular health study. MAIN OUTCOME MEASURES: The influence of apo(A) phenotypes on plasma levels of oxLDL-ICs after controlling for lipid/lipoprotein levels, percentage of body fat, and physical fitness. RESULTS: Oxidized low-density lipoprotein immune complexes were significantly correlated with the levels of total cholesterol (r = 0.56, P< or =.05), low-density lipoprotein cholesterol (r = 0.64, P< or =.01), and low-density lipoprotein cholesterol/high-density lipoprotein cholesterol (r = 0.54, P<.05). Oxidized low-density lipoprotein immune complexes were also correlated with total cholesterol high-density lipoprotein cholesterol (r = 0.49, P< or =.06) and percentage of body fat (r = 0.48, P< or =.06). However, they achieved only a borderline level of statistical significance after adjustment for multiple comparisons. Multiple regression analysis demonstrated that small apo(A) phenotypes, levels of low-density lipoprotein cholesterol, and family history of premature coronary artery disease explained 54% of the variation of oxLDL-ICs using a parsimonious model (P = .001). CONCLUSIONS: Significant correlations exist between oxLDL-ICs and known cardiovascular risk factors in children. The association of oxLDL-ICs with the genetically controlled small apo(A) phenotype suggests that the genetic predisposition to immune complex formation may be an important determinant of future coronary artery disease.
Adult↗
A longitudinal study of antigen expression in epithelial ovarian cancer.
The extent to which the antigenic phenotype of human epithelial ovarian cancer changes during the course of the disease is an issue that must be addressed in order to maximize the potential of antibody-directed imaging and therapy. We have obtained tumor specimens at two separate operations from ten patients with epithelial ovarian cancer and typed these specimens with a panel of 19 monoclonal antibodies to cell surface glycoprotein and carbohydrate antigens including blood group antigens. Antibodies with relatively high specificity for malignant cells as well as those detecting more widely distributed epithelial antigens were used in the study. Mean time between the two operations was 8.5 months. Five patients received intraperitoneal therapy during the interval between the two operations, including platinum-based regimens (four patients) and tumor necrosis factor (one patient). Four patients received intravenous platinum-based chemotherapy; one received no treatment. Frozen sections of specimens were stained with the antibodies by the indirect immunoperoxidase technique. Antigenic phenotypes were found to be unrelated to the patient's age, stage, tumor grade, histologic cell type, prior chemotherapy, and interval between operations. Most significantly, little difference was seen in antigenic expression between tumors obtained at the two operations for either the cell surface or blood group markers. Variations in the staining pattern were seen with antibody B72.3 and, to some extent, with the anti-blood group antibodies, which are known for producing heterogeneous staining. The antigenic phenotype of the tumor specimens in a given patient as determined immunohistochemically by our panel of antibodies showed only minor variation between operations, even under the selective pressures of chemotherapy and immunotherapy.
Adenocarcinoma↗
Effects of aerobic exercise and obesity phenotype on abdominal fat reduction in response to weight loss.
OBJECTIVE: To test the effects on abdominal fat reduction of adding aerobic exercise training to a diet program and obesity phenotype in response to weight loss. DESIGN: A prospective clinical trial with a 14-week weight-loss intervention design. SETTING AND PARTICIPANTS: In total, 209 overweight and obese women were assigned to four subgroups depending on type of treatment and the subject's obesity phenotype: diet alone (DA) with intra-abdominal fat (IF) obesity (> or =mean IF area), diet plus exercise (DE) with IF obesity, DA with abdominal subcutaneous fat (ASF) obesity (<mean IF area) and DE with ASF obesity. Abdominal fat areas were evaluated by CT scans, with values adjusted for selected variables. RESULTS: Values were adjusted for age, menopausal status and change in body weight and total fat mass. The IF reductions were significantly (P<0.0001) greater in subjects with IF obesity phenotype (-45.1 cm2) compared to the ASF obesity phenotype (-22.2 cm2). The ASF reductions were significantly (P<0.001) greater for subjects with ASF obesity (-74.5 cm2) compared to IF obesity (-55.5 cm2). For IF obesity, the IF reduction was significantly (P<0.01) greater in the DE group (-49.3 cm2) than in the DA group (-37.8 cm2). CONCLUSION: These results suggest that for individuals with IF obesity, the efficacy on reducing IF of adding aerobic exercise training to a diet-alone weight-reduction program is more prominent (-49.3 cm2/-37.8 cm2=1.3 times) compared with DA. Moreover, abdominal fat reduction was found to be modified by obesity phenotype in response to weight loss.
Adult↗
Epidemiology of chronic Pseudomonas aeruginosa infections in cystic fibrosis.
The epidemiology of chronic colonization of airways with Pseudomonas aeruginosa was monitored in 44 patients with cystic fibrosis (CF) by DraI/SpeI macrorestriction analyses of 489 isolates. Sequential P. aeruginosa isolates (144) that had been collected from 32 CF patients over < or = 2.5 years were investigated, and 12 patients were followed for 8 years after onset of colonization. Forty-eight different genotypes were uncovered from 481 typeable isolates. Ten genotypes were found in > 1 unrelated CF patient. The 6 most frequent clones were identified in 58% of isolates. Ten of the 12 patients monitored for 8 years were harboring their initially acquired P. aeruginosa clone at all times, with subtle shifts of fragment patterns indicating subclonal variation. During colonization, the bacteria gradually lost pyocin and phage typing responses, supporting the view that genotypically discordant P. aeruginosa strains develop a common phenotype.
Adolescent↗
Parathyroid hormone-(1-34) enhances aggrecan synthesis via an insulin-like growth factor-I pathway.
During endochondral bone formation, the growth plate chondrocytes proliferate, become hypertrophic, lose the cartilage phenotype, undergo mineralization, and provide a scaffold upon which subsequent longitudinal bone growth occurs. Parathyroid hormone (PTH), a calcium-regulating hormone, and parathyroid hormone-related peptide (PTHrP), which shares several properties with PTH, have profound effects on skeletal growth and new bone formation. In order to define further the mechanism by which PTH/PTHrP promotes the cartilage phenotype, chondrocytes isolated from the rib cages of developing rat embryos were evaluated for the biosynthesis of aggrecan. Cells treated with PTH-(1-34) for a 4-h period followed by a 20-h recovery period showed a significant increase in cartilage proteoglycan (aggrecan) synthesis in a dose-dependent manner. Only N-terminally intact PTH and PTHrP were effective in stimulating aggrecan synthesis. Addition of a neutralizing antibody to insulin-like growth factor-I (IGF-I) during PTH treatment resulted in the inhibition of PTH-stimulated aggrecan synthesis, whereas the addition of a neutralizing antibody to insulin-like growth factor-binding protein-2 (IGFBP-2) resulted in an increase in synthesis in both the control and PTH-treated cells. In addition, PTH treatment resulted in an increase in the mRNA for aggrecan, a reduction in IGFBP-3 mRNA, and no discernible changes in IGF-I mRNA levels, which was complemented by quantitative changes in IGFBP-3 and free IGF-I levels. The reciprocal relationship in the expression of aggrecan and IGFBP was further confirmed in chondrocytes from various gestational stages during normal development. Collectively, our results indicate that the effect of PTH may be mediated at least in part through the regulation of the IGF/IGFBP axis, by a decrease in the level of IGFBP-3, and an increase in free IGF-I levels. It is likely that the local increase in IGF-I may lead to an increase in cartilage type proteoglycan synthesis and maintenance of the cartilage phenotype. The consequence of the prolonged maintenance may be to halt mineralization while a new scaffolding is created.
Aggrecans↗
Incidence of erythromycin resistance in Streptococcus pyogenes: a 10-year study.
We studied the evolution of susceptibility of Streptococcus pyogenes isolated in our hospital from 1987 to 1996. Susceptibility to penicillin, ampicillin, cefotaxime, cefuroxime, imipenem, erythromycin, clindamycin, tetracycline, vancomycin, ciprofloxacin, rifampin, and chloramphenicol was determined by the National Committee for Clinical Laboratory Standards broth microdilution method. Differentiation of phenotypes of erythromycin-resistant strains was performed using the double-disc method. All isolates remained very susceptible in vitro to penicillin and all of the other beta-lactam agents tested. Between 1987 and 1995 the incidence of erythromycin resistant strains remained below 5%; the difference in the resistance rate between 1995 (2.6%) and 1996 (17.1%) was statistically significant. The macrolide resistance M phenotype was the most frequent. The isolation rates of tetracycline-resistant strains increased from 2.2% in 1987 to 11.2% in 1988. The marked increase in the incidence of erythromycin resistance observed in our area warrants periodic surveillance of antibiotic susceptibility of S. pyogenes isolates and emphasizes the need to control outpatient antibiotics. The preponderance of the M phenotype may have implications in the choice of antibiotic.
Anti-Bacterial Agents↗
Apolipoprotein(a) phenotype-associated decrease in lipoprotein(a) plasma concentrations after renal transplantation.
High lipoprotein(a) [Lp(a)] plasma concentrations are an independent risk factor for atherosclerosis. In the general population, Lp(a) levels are primarily determined by allelic variation at the apolipoprotein(a) [apo(a)] gene locus. Apo(a) isoforms of various sizes are associated with different Lp(a) concentrations. Patients with end-stage renal disease (ESRD) have elevated plasma concentrations of Lp(a), which are not explained by the size variation at the apo(a) gene locus. To further investigate the origin of the elevated Lp(a) plasma concentrations, we examined Lp(a) concentrations and apo(a) phenotypes in 154 ESRD patients undergoing renal transplantation. In a prospective longitudinal study we observed a rapid normalization of Lp(a) levels from an average concentration of 25.9 +/- 28.7 mg/dL before to 17.9 +/- 25.5 mg/dL 3 weeks after renal transplantation (P < .0001). Only patients with high-molecular-weight phenotypes had a significant decrease in Lp(a) plasma concentrations. This study demonstrates the nongenetic origin of elevated Lp(a) concentrations in ESRD patients, which is obviously caused by the disease. It further confirms a phenotype-associated elevation of Lp(a) concentrations in ESRD.
Adolescent↗
Cystic fibrosis mutations and genotype-pulmonary phenotype analysis.
BACKGROUND: Although there are more than 1000 mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, most of them are uncommon and only limited information exists regarding genotype-pulmonary phenotype relationships. METHODS: We determined and classified the CFTR mutations using denaturing high-performance liquid chromatography and developed new, quantitative methods to categorize pulmonary phenotypes. RESULTS: Two novel alleles were discovered, namely G1047R and 1525-2A-->G, which were accompanied by F508del and G551D mutations, respectively. Assessment of numerous options revealed that CF pulmonary phenotype categorization in children cannot be accomplished with clinical or pulmonary function data but is facilitated by longitudinal quantitative chest radiology. It was most useful to categorize pulmonary disease status by evaluating the typical pattern of abnormalities in patients homozygous for the F508del mutation, and then compare patients with minor mutations to this typical CF pulmonary phenotype. By this method, both patients with novel mutations have pulmonary phenotypes typical of F508del homozygotes. However, patients with class IV mutations (e.g., R347P) or with pancreatic sufficiency showed serial chest radiographs that were atypically mild. CONCLUSIONS: Longitudinal quantitative chest radiography provides a new strategy for CF pulmonary phenotype categorization that should be useful for genotype-phenotype delineation in individual patients and in both epidemiologic studies and clinical trials involving groups of children with CF.
Child↗
Use of latent profile analysis to identify eating disorder phenotypes in an adult Australian twin cohort.
CONTEXT: The relationships among the different eating disorders that exist in the community are poorly understood, especially for residual disorders in which bingeing or purging occurs in the absence of other behaviors. OBJECTIVE: To examine a community sample for the number of mutually exclusive weight and eating profiles. DESIGN: Data regarding lifetime eating disorder symptoms and weight range were submitted to a latent profile analysis. Profiles were compared regarding personality, current eating and weight, retrospectively reported life events, and lifetime depressive psychopathology. SETTING: Longitudinal study among female twins from the Australian Twin Registry in whom eating was assessed by a telephone interview. PARTICIPANTS: A community sample of 1002 twins (individuals) who had participated in earlier waves of data collection. MAIN OUTCOME MEASURES: Number and clinical character of latent profiles. RESULTS: The best fit was a 5-profile solution with women who were (1) of normal weight with few lifetime eating disorders (4.3%), (2) overweight (10.6% had a lifetime eating disorder), (3) underweight and generally had no eating disorders except for 5.3% who had restricting anorexia nervosa, (4) of low to normal weight (89.0% had a lifetime eating disorder), and (5) obese (37.0% had a lifetime eating disorder). Each profile contained more than 1 type of lifetime eating disorder except for the third profile. Women in the first and third profiles had the best functioning, with women in the fourth and fifth profiles having similarly poorer functioning. The women in the fourth group had a symptom profile distinctive from the other 4 groups in terms of severity; they were also more likely to have had lifetime major depression and suicidality. CONCLUSION: Lifetime weight ranges and the severity of eating disorder symptoms affected clustering more than the type of eating disorder symptom.
Adult↗
[The Delta locus in Drosophila virilis: alleles, wing phenotypes and genetic interactions].
A considerable number of Delta (D1) alleles resulting from spontaneous mutation or induced by following X-ray irradiation have been isolated on the basis of the dominant phenotype consisting of disrupted wing venation and associated with heterozygosity for different D1 alleles. The L2 "delta" forming at the wing margin is the most characteristic fully penetrant phenotype of D1-heterozygous adults. The structure disruption of all other longitudinal (L3-L5) and cross (C1 and C2) veins including formation of "deltas" and other additional vein material, have been characterized as the irregular bilaterally asymmetrical nondirectional fluctuations of D1 phenotype expression. The phenotypic interactions between Delta and two D1 phenotype enhancer mutations, L2 fork and gap L2, have been found. Possible participation of Delta, one of the elements of Notch signaling system, in the structure formation is discussed.
Alleles↗
Tyrosine kinase inhibition produces specific alterations in axon guidance in the grasshopper embryo.
Tyrosine kinase signaling pathways are essential for process outgrowth and guidance during nervous system development. We have examined the roles of tyrosine kinase activity in programming growth cone guidance decisions in an intact nervous system in which neurons can be individually identified. We applied the tyrosine kinase inhibitors herbimycin A and genistein to whole 40% grasshopper embryos placed in medium, or injected the inhibitors into intact grasshopper eggs. Both inhibitors caused interneuronal axons that normally would grow along the longitudinal connectives to instead leave the central nervous system (CNS) within the segmental nerve root and grow out toward the body wall muscles. In addition, herbimycin A produced pathfinding errors in which many longitudinal axons crossed the CNS midline. To study how this drug affected guidance decisions made by individual growth cones, we dye-filled the pCC interneuron, which normally extends an axon anteriorly along the ipsilateral longitudinal connective. In the presence of herbimycin A, the pCC growth cone was redirected across the anterior commissure. These phenotypes suggest that tyrosine kinase inhibition blocks a signaling mechanism that repels the growth cones of longitudinal connective neurons and prevents them from crossing the midline.
Animals↗
Genetic principles and methods in high-risk studies of schizophrenia.
Recent advances in genetic epidemiology present excellent opportunities for future high-risk studies of schizophrenia. Improved methods are now available for specifying the natural boundaries of the schizophrenia spectrum and evaluating the mode of inheritance of schizophrenia and its biosocial risk factors. Path-analytic techniques permit the derivation of multifactor indices of both biological and social antecedents of schizophrenia. Powerful advances have been made in segregation analysis of pedigree data and in the power of linkage tests with DNA markers to confirm the presence of putative major loci that influence susceptibility to complex phenotypes like schizophrenia. The yield of information from high-risk samples is greatly increased when both longitudinal and pedigree analyses are combined.
Genetic Markers↗
Assortative mating by body height and BMI: Finnish twins and their spouses.
Assortative mating by body height and weight is well established in various populations, but its causal mechanisms remain poorly understood. We analyzed the effect of phenotypic assortment and social homogamy on spousal correlations for body height and body mass index (BMI, kg/m(2)). Our data derived from a questionnaire administered to the adult Finnish Twin Cohort in 1990 (response rate 77%) yielding results from 922 monozygotic and 1697 dizygotic adult twin pairs who reported information about their body height and weight and that of their spouses. Assortative mating was evident for body height and BMI. For body height, the effects of social homogamy (0.24 in men and 0.29 in women) and phenotypic assortment (0.27 and 0.28, respectively) were about the same. For BMI, the effect of social homogamy was stronger (0.31 in men and 0.28 in women) than the effect of phenotypic assortment (0.13 in both men and women). When assortative mating was taken into account, shared environmental factors had no effect on phenotypic variation in body height or BMI. Our results show that assortative mating needs to be considered in population genetic studies of body height and weight.
Aged↗
Correlations of alcohol consumption with related covariates and heritability estimates in older adult males over a 14- to 18-year period: the NHLBI Twin Study.
Consistent maximum-likelihood heritability estimates of consumption of alcoholic beverages were observed at three separate times during a 14- to 18-year period in adult twin males initially aged 42-56 years in 1969-1973. Log transformation of the average number of drinks/week of the returnees to all three examinations was examined relative to potential covariates representing both antecedents of drinking alcohol and consequences of alcohol consumption. Significant relationships were noted for 38 of the covariates at one or more of the separate examinations, including positive correlations with smoking, coffee consumption, high-density lipoprotein cholesterol, mean corpuscular volume, systolic blood pressure, uric acid and behavioral measures, and negative correlations with blood urea nitrogen, red blood cell count, tea consumption, and tricep skinfolds. Analysis of the average alcohol consumption adjusted for nine independent covariates selected from multiple stepwise regression resulted in a modest decline in maximum-likelihood heritability estimates compared with unadjusted data, but little difference from heritability estimates obtained when abstainers from alcohol (no alcoholic beverages consumed at all three examinations) were excluded. The most striking effect of omitting abstainers from alcohol was the decline in the intraclass correlations in dizygotic twins. Bivariate analyses of alcohol and individual covariates revealed the phenotypic correlation between alcohol consumption and a measure of hostility was primarily environmental, that for high-density lipoprotein, smoking and coffee drinking with alcohol was primarily genetic, and the phenotypic correlation between alcohol consumption and mean corpuscular volume had both significant genetic and environmental correlations.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
[Wheezing in infants and toddlers: new insights].
Wheezing in infants and toddlers is a common symptom, and these patients are difficult to approach--both diagnostically and therapeutically. Congenital conditions causing wheezing disorders should not be missed and--not all wheezy bronchitis is or will become asthma. Results from longitudinal studies indicate that the term "asthma" includes different phenotypes: so-called transient early wheezing, non atopic wheezing and atopic wheezing (asthma). Transient early wheezing is generally accepted to define recurrent wheezing in non-atopic babies or toddlers and tends to disappear by the age of 3. The primary risk factor is reduced pulmonary function since birth. The most common cause for non-atopic wheezing is viral infection, most frequently caused by respiratory syncytial virus. Infection with respiratory syncytial virus is a risk factor for ongoing wheeze during childhood but resolves in most children by the age of 13. Asthma can start at any age and is determined by a more chronic condition, provoked by a number of triggers in addition to viruses, frequently associated with a family history of atopy, early allergic sensitization and concomitant atopic dermatitis. Only asthma seems to be a progressive disease; and there is evidence from long-term studies that if anti-inflammatory interventions are started late, it might be too late to alter the natural course of the disease with its decline in pulmonary function. On the other hand, there is no evidence that small children with non-atopic wheezy bronchitis would benefit from long-term therapy with anti-inflammatory treatment; in this group a therapeutic trial with bronchodilators is sufficient. The diagnostic and therapeutic challenges of diagnosing asthma in this age group are considerable and require a comprehensive approach.
Adolescent↗