bluuebunny/crossref_metadata_2025 huggingface dataset:
Risk‐Benefit Value of Inhaled Glucocorticoids: A Pharmacokinetic/ Pharmacodynamic Perspective
Authors: Rohatagi Shashank , Appajosyula Sireesh , Derendorf Hartmut , Szefler Stanley , Nave Ruediger , Zech Karl , Banerji Donald
Published: December 2003

Inhaled glucocorticoids induce therapeutic and adverse systemic effects via the same types of receptors. Analysis of the pharmacokinetic/pharmacodynamic parameters of inhaled glucocorticoids generates a risk‐benefit value (RBV). Targeted efficacy with minimal adverse effects helps to quantify an appropriate RBV. High lung deposition/targeting, high receptor binding, longer pulmonary retention, and high lipid conjugation are among the pharmacokinetic parameters to be considered for improved efficacy of the compound. Low or negligible oral bioavailability, small particle size and inactive drug at the oropharynx, high plasma protein binding, rapid metabolism, high clearance, and lower systemic concentrations are associated with low risks for adverse effects. Inhaled glucocorticoid potency is enhanced by solution inhalers, which result in higher pulmonary deposition and minimize local adverse effects. These properties, among others, determine the efficacy and safety of inhaled glucocorticoids. Currently available inhaled glucocorticoids do not provide the complete pharmacokinetic/pharmacodynamic parameters to optimize RBV, leaving room for improvement in the development of future agents.
Human Liver Aldehyde Oxidase: Inhibition by 239 Drugs
Authors: Obach R. Scott , Huynh Phuong , Allen Mary C. , Beedham Christine
Published: December 2003

The authors tested 239 frequently used drugs and other compounds for their potential to inhibit the drug‐metabolizing enzyme, aldehyde oxidase, in human liver cytosol. A sensitive, moderate throughput HPLC‐MS assay was developed for 1‐phthalazinone, the aldehyde oxidase–catalyzed product of phthalazine oxidation. Inhibition of this activity was examined for the 239 drugs and other compounds of interest at a test concentration of 50 μM. Thirty‐six compounds exhibited greater than 80% inhibition and were further examined for measurement of IC50. The most potent inhibitor observed was the selective estrogen receptor modulator, raloxifene (IC50 = 2.9 nM), and tamoxifen, estradiol, and ethinyl estradiol were also potent inhibitors. Other classes of drugs that demonstrated inhibition of aldehyde oxidase included phenothiazines, tricyclic antidepressants, tricyclic atypical antipsychotic agents, and dihydropyridine calcium channel blockers, along with some other drugs, including loratadine, cyclobenzaprine, amodiaquine, maprotiline, ondansetron, propafenone, domperidone, quinacrine, ketoconazole, verapamil, tacrine, and salmeterol. These findings are discussed in context to potential drug interactions that could be observed between these agents and drugs for which aldehyde oxidase is involved in metabolism and warrant investigation of the possibility of clinical drug interactions mediated by inhibition of this enzyme.
The Pharmacokinetics of Nebulized Nanocrystal Budesonide Suspension in Healthy Volunteers
Authors: Kraft Walter K. , Steiger Barry , Beussink Don , Quiring John N. , Fitzgerald Nancy , Greenberg Howard E. , Waldman Scott A.
Published: December 2003

Nanocrystal budesonide (nanobudesonide) is a suspension for nebulization in patients with steroid‐responsive pulmonary diseases such as asthma. The pharmacokinetics and safety of the product were compared to those of Pulmicort Respules. Sixteen healthy volunteers were administered nanobudesonide 0.5 and 1.0 mg, Pulmicort Respules 0.5 mg, andplacebo in a four‐way, randomizedcrossover design. All nebulized formulations were well tolerated, with no evidence of bronchospasm. Nebulization times were significantly shorter for nanobudesonide compared to Pulmicort Respules. Because of a low oral bioavailability, plasma concentration of budesonide is a good marker of lung‐delivered dose. The pharmacokinetics of nanobudesonide 0.5 and 1.0 mg were approximately dose proportional with respect to Cmax, AUC(0‐t), and AUC(0‐∞). Nanobudesonide 0.5 mg and Pulmicort Respules 0.5 mg exhibited similar AUCs, suggesting a similar extent of pulmonary absorption. A higher Cmax was noted with nanobudesonide 0.5 mg, and the tmax was significantly different, suggesting a more rapid rate of drug delivery of nanobudesonide 0.5 mg than Pulmicort Respules. In conclusion, nebulized nanobudesonide 0.5 mg was safe in healthy volunteers, with a similar extent of absorption as Pulmicort Respules.
Genetic analysis of maximum cigarette-use phenotypes
Authors: Saccone Nancy L , Neuman Rosalind J , Saccone Scott F , Rice John P
Published: December 2003

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.
Genome-wide screen for heavy alcohol consumption
Authors: Wyszynski Diego F , Panhuysen Carolien I , Ma Qianli , Yip Agustin G , Wilcox Marsha , Erlich Porat , Farrer Lindsay A
Published: December 2003

Background

To find specific genes predisposing to heavy alcohol consumption (self-reported consumption of 24 grams or more of alcohol per day among men and 12 grams or more among women), we studied 330 families collected by the Framingham Heart Study made available to participants in the Genetic Analysis Workshop 13 (GAW13).

Results

Parametric and nonparametric methods of linkage analysis were used. No significant evidence of linkage was found; however, weak signals were identified in several chromosomal regions, including 1p22, 4q12, 4q25, and 11q24, which are in the vicinity of those reported in other similar studies.

Conclusion

Our study did not reveal significant evidence of linkage to heavy alcohol use; however, we found weak confirmation of studies carried out in other populations.
Analysis of gene × environment interactions in sibships using mixed models
Authors: Barnholtz-Sloan Jill S , Poisson Laila M , Coon Steven W , Chase Gary A , Rybicki Benjamin A
Published: December 2003

Background

Gene × environment models are widely used to assess genetic and environmental risks and their association with a phenotype of interest for many complex diseases. Mixed generalized linear models were used to assess gene × environment interactions with respect to systolic blood pressure on sibships adjusting for repeated measures and hierarchical nesting structures. A data set containing 410 sibships from the Framingham Heart Study offspring cohort (part of the Genetic Analysis Workshop 13 data) was used for all analyses. Three mixed gene × environment models, all adjusting for repeated measurement and varying levels of nesting, were compared for precision of estimates: 1) all sibships with adjustment for two levels of nesting (sibs within sibships and sibs within pedigrees), 2) all sibships with adjustment for one level of nesting (sibs within sibships), and 3) 100 data sets containing random draws of one sibship per extended pedigree adjusting for one level of nesting.

Results

The main effects were: gender, baseline age, body mass index (BMI), hypertensive treatment, cigarettes per day, grams of alcohol per day, and marker GATA48G07A. The interaction fixed effects were: baseline age by gender, baseline age by cigarettes per day, baseline age by hypertensive treatment, baseline age by BMI, hypertensive treatment by BMI, and baseline age by marker GATA48G07A. The estimates for all three nesting techniques were not widely discrepant, but precision of estimates and determination of significant effects did change with the change in adjustment for nesting.

Conclusion

Our results show the importance of the adjustment for all levels of hierarchical nesting of sibs in the presence of repeated measures.
Comparison of Haseman-Elston regression analyses using single, summary, and longitudinal measures of systolic blood pressure
Authors: Mirea Lucia , Bull Shelley B , Stafford James
Published: December 2003

To compare different strategies for linkage analyses of longitudinal quantitative trait measures, we applied the "revisited" Haseman-Elston (RHE) regression model (the cross product of centered sib-pair trait values is regressed on expected identical-by-descent allele sharing) to cross-sectional, summary, and repeated measurements of systolic blood pressure (SBP) values in replicate 34, randomly selected from the Genetic Analysis Workshop 13 simulated data. RHE linkage scans were performed without knowledge of the generating model using the following phenotypes derived from untreated SBP measurements: the first, the last, the mean, the ratio of the change between the first and last over time, and the estimated linear regression slope coefficient. Estimates of allele sharing in sibling pairs were obtained from the complete genotype data of Cohorts 1 and 2, but linkage analyses were restricted to the five visits of Cohort 2 siblings. Evidence for linkage was suggestive (p < 0.001) at markers neighboring SBP genes Gb35, Gs10, and Gs12, but weaker signals (p < 0.01) were obtained at markers mapping close to Gb34 and Gs11. Linkage to baseline genes Gb34 and Gb35 was best detected using the first SBP measurement, whereas linkage to slope genes Gs10-12 was best detected using the last or mean SBP value. At markers on chromosomes 13 and 21 displaying strongest linkage signals, marginal RHE-type models including repeated SBP measures were fit to test for overall and time-dependent genetic effects. These analyses assumed independent sib pairs and employed generalized estimating equations (GEE) with a first-order autoregressive working correlation structure to adjust for serial correlation present among repeated observations from the same sibling pair.
Linkage analysis of cross-sectional and longitudinally derived phenotypic measures to identify loci influencing blood pressure
Authors: Shephard Neil , Falcaro Milena , Zeggini Eleftheria , Chapman Philip , Hinks Anne , Barton Anne , Worthington Jane , Pickles Andrew , John Sally
Published: December 2003

Background

The design of appropriate strategies to analyze and interpret linkage results for complex human diseases constitutes a challenge. Parameters such as power, definition of phenotype, and replicability have to be taken into account in order to reach meaningful conclusions. Incorporating data on repeated phenotypic measures may increase the power to detect linkage but requires sophisticated analysis methods. Using the simulated Genetic Analysis Workshop 13 data set, we have estimated a variety of systolic blood pressure (SBP) phenotypic measures and examined their performance with respect to consistency among replicates and to true and false positive linkage signals.

Results

The whole-genome scan conducted on a dichotomous hypertension phenotype indicated the involvement of few true loci with nominal significance and gave rise to a high rate of false positives. Analysis of a cross-sectional quantitative SBP measure performed better, although genome-wide significance was again not reached. Additional phenotypic measures were derived from the longitudinal data using random effects modelling for censored data with varying levels of covariate adjustment. These models provided evidence for significant linkage to most genes influencing SBP and produced few false positive results. Overall, replicability of results was poor for loci, representing weak effects.

Conclusion

Longitudinally derived phenotypes performed better than cross-sectional measures in linkage analyses. Bearing in mind the sample design and size of these data, linkage results that fail to replicate should not be dismissed; instead, different lines of evidence derived from complementary analysis methods should be combined to prioritize follow up.
Genome-wide linkage analysis using cross-sectional and longitudinal traits for body mass index in a subsample of the Framingham Heart Study
Authors: Li Xiaohui , Wang Dai , Yang Kai , Guo Xiuqing , Lin Ying-chao , Samayoa Carlos G , Yang Huiying
Published: December 2003

To evaluate linkage evidence for body mass index (BMI) using both cross-sectional and longitudinal data, we performed genome-wide multipoint linkage analyses on subjects who had complete data at four selected time points (initial, 8th, 12th, and 16th year following the initial visit) from the Framingham Heart Study. The cross-sectional measures included BMI at each of the four selected time points and the longitudinal measure was the within-subject mean of BMI at the above four time points.

Using the variance components method, we consistently observed the maximum LOD score out of the genome scan using BMI at each time point and the mean of BMI between 049xd2 and GATA71H05 on chromosome 16. The highest LOD score (3.0) was at time point 1, while the lowest (1.9) was at time point 4. We also observed other suggestive linkages on chromosome 6, 10, and 18 at time point 1 only.

The longitudinal measure we studied (mean of BMI) did not provide greater power to identify a positive linkage than some of the cross-sectional measures (e.g., time point 1). The changing of linkage evidence over time provided some insights on the variation of genetic effect on BMI with aging. There may be a QTL on chromosome 16 that contributes to BMI and this locus, and maybe others, is more likely to affect BMI during early adulthood.
Genome-wide scan on plasma triglyceride and high density lipoprotein cholesterol levels, accounting for the effects of correlated quantitative phenotypes
Authors: Lin Jing-Ping
Published: December 2003

Background

Plasma triglyceride and high density lipoprotein cholesterol levels are inversely correlated and both are genetically related. Two correlated traits may be influenced both by shared and unshared genes. The power to detect unshared trait-specific genes may be increased by incorporating correlated traits as covariates. The power to localize the shared genes may be improved by bivariate analysis. Univariate genome scans were carried out on triglyceride (high density lipoprotein cholesterol) with and without using high density lipoprotein cholesterol (triglyceride) as a covariate, and bivariate linkage analysis on triglyceride and high density lipoprotein cholesterol using the 330 Framingham pedigrees of the Genetic Analysis Workshop 13 data. The results of five genome scans were compared to determine the chromosomal regions which may harbor the genes influencing variation specific to triglycerides, specific to high density lipoprotein cholesterol, or the covariation of both triglyceride and high density lipoprotein cholesterol.

Results

The results of our five genome scans identified some chromosomal regions with possible quantitative trait loci (QTL) that may specifically influence one trait, such as the regions on chromosome 1 (at 1 cM near marker 280we5), on high density lipoprotein cholesterol, or control the covariation of both traits, such as the regions on chromosome 7 (at 169 cM near marker GATA30D09), chromosome 12 (at 3 cM near marker GATA4H03), chromosome 20 (at 49 cM near marker GATA29F06), chromosome 2 (at 146 cM near marker GATA8H05), and chromosome 6 (at 148 cM near marker GATA184A08) on triglyceride and high density lipoprotein cholesterol. The one on chromosome 6 had a LOD score of 3.1 with the bivariate linkage analysis.

Conclusion

There is strong evidence for a QTL on chromosome 6 near marker GATA184A08 appearing to influence the variation of high density lipoprotein cholesterol and triglycerides in the Framingham population.
Use of a random coefficient regression (RCR) model to estimate growth parameters
Authors: Corbett Jonathan , Kraja Aldi , Borecki Ingrid B , Province Michael A
Published: December 2003

We used a random coefficient regression (RCR) model to estimate growth parameters for the time series of observed serum glucose levels in the Replicate 1 of the Genetic Analysis Workshop 13 simulated data. For comparison, a two time-point interval was also selected and the slope between these two observations was calculated. This process yielded four phenotypes: the RCR growth phenotype, a two time-point slope phenotype, and Time 1 and Time 2 serum glucose level phenotypes. These four phenotypes were used for linkage analyses on simulated chromosomes 5, 7, 9, and 21, those chromosomes that contained loci affecting the growth course for serum glucose levels. The linkage analysis of the RCR-derived phenotype showed overwhelming evidence for linkage at one locus (LOD 65.78 on chromosome 5), while showing elevated but nonsignificant LOD scores for two other loci (LOD 1.25 on chromosome 7, LOD 1.10 on chromosome 9), and no evidence of linkage for the final locus. The two time-point slope phenotype showed evidence for linkage at one locus (LOD 4.16 on chromosome 5) but no evidence for linkage at any of the other loci. A parallel cross-sectional approach, using as input phenotypes the endpoints of the two-point slope phenotype, gave strong linkage results for the major locus on chromosome 5 (maximal LOD scores of 17.90 and 27.24 for Time 1 and Time 2, respectively) while showing elevated but nonsignificant linkage results on chromosome 7 (maximal LOD scores of 1.71 and 1.48) and no evidence for linkage at the two remaining loci. The RCR growth parameter showed more power to detect linkage to the major locus than either the cross-sectional or two-point slope approach, but the cross-sectional approach gave a higher maximal LOD score for one of the minor loci.
Exploring pleiotropy using principal components
Authors: Bensen Jeannette T , Lange Leslie A , Langefeld Carl D , Chang Bao-Li , Bleecker Eugene R , Meyers Deborah A , Xu Jianfeng
Published: December 2003

A standard multivariate principal components (PCs) method was utilized to identify clusters of variables that may be controlled by a common gene or genes (pleiotropy). Heritability estimates were obtained and linkage analyses performed on six individual traits (total cholesterol (Chol), high and low density lipoproteins, triglycerides (TG), body mass index (BMI), and systolic blood pressure (SBP)) and on each PC to compare our ability to identify major gene effects. Using the simulated data from Genetic Analysis Workshop 13 (Cohort 1 and 2 data for year 11), the quantitative traits were first adjusted for age, sex, and smoking (cigarettes per day). Adjusted variables were standardized and PCs calculated followed by orthogonal transformation (varimax rotation). Rotated PCs were then subjected to heritability and quantitative multipoint linkage analysis. The first three PCs explained 73% of the total phenotypic variance. Heritability estimates were above 0.60 for all three PCs. We performed linkage analyses on the PCs as well as the individual traits. The majority of pleiotropic and trait-specific genes were not identified. Standard PCs analysis methods did not facilitate the identification of pleiotropic genes affecting the six traits examined in the simulated data set. In addition, genes contributing 20% of the variance in traits with over 0.60 heritability estimates could not be identified in this simulated data set using traditional quantitative trait linkage analyses. Lack of identification of pleiotropic and trait-specific genes in some cases may reflect their low contribution to the traits/PCs examined or more importantly, characteristics of the sample group analyzed, and not simply a failure of the PC approach itself.
Pleiotropic effects on cardiovascular risk factors within and between the fourth and sixth decades of life: Implications for genotype × age interactions
Authors: Havill LM , Mahaney MC
Published: December 2003

We used an approach for detecting genotype × environment interactions to detect and characterize genotype × age interaction in longitudinal measures of three well known cardiovascular risk factors: total plasma cholesterol (TC), systolic blood pressure (SBP), and body weight (Wgt). Our objectives were to determine if the same gene or suite of genes influences quantitative variation in each of these phenotypes in the 4th and 6th decades of life, to assess the impact of additive gene effects in these two decades, and to evaluate the stability of pleiotropic relationships among these phenotypes. Using the Framingham Heart Study data, we constructed two cross-sectional samples comprising individuals on whom these phenotypes were measured at ages 30-39 years (Original Cohort: exam 1, Offspring Cohort: exam 2) and at ages 50-59 years (Original Cohort: exam 11, Offspring Cohort: exam 5). We also constructed a longitudinal sample from the cross-sectional sample members for whom measures on these traits were available at both ages (i.e., 4th and 6th decades of life). Patterns of pleiotropy, inferred from genetic correlations between traits, differ between the two age classes. Further, additive genetic variance in SBP during the 4th decade of life is attributable to a different gene or suite of genes than during the 6th. The magnitude of the effect increases for SBP. Variation in TC and Wgt appear to be influenced by the same gene or genes in both decades. The magnitude of the effect is stable for TC, but increases dramatically with age for Wgt.
Screening the genome to detect an association with hypertension
Authors: Atkinson Elizabeth J , Andrade Mariza de
Published: December 2003

We report tree-based association analysis as applied to the two Framingham cohorts and to the first replication of the simulated data obtained from the Genetic Analysis Workshop 13. For this analysis, familial association is ignored. The two endpoints examined are hypertension status at initial visit and time-to-hypertension, using a censored data approach. Although linkage association has previously been reported with hypertension, we found no association using the tree-based methodology.
A genome-wide scan using tree-based association analysis for candidate loci related to fasting plasma glucose levels
Authors: Chen Chien-Hsiun , Chang Chee Jen , Yang Wei-Shiung , Chen Chun-Liang , Fann Cathy SJ
Published: December 2003

Background

In the analysis of complex traits such as fasting plasma glucose levels, researchers often adjust the trait for some important covariates before assessing gene susceptibility, and may at times encounter confounding among the covariates and the susceptible genes. Previously, the tree-based method has been employed to accommodate the heterogeneity in complex traits. In this study, we performed a genome-wide screen on fasting glucose levels in the offspring generation of the Framingham Heart Study provided by the Genetic Analysis Workshop 13. We defined one quantitative trait and converted it to a dichotomous trait based on a predetermined cut-off value, and performed association analyses using regression and classification trees for the two traits, respectively. A marker was interpreted as positive if at least one of its alleles exhibited association in both analyses. Our purpose was to identify candidate genes susceptible to fasting glucose levels in the presence of other covariates. The covariates entered in the analysis including sex, body mass index, and lipids (total plasma cholesterol, high density lipoprotein cholesterol, and triglycerides) of the subjects, and those of their parents.

Results

Four out of seven positive regions in chromosomes 1, 2, 6, 11, 16, 18, and 19 from our analyses harbored or were very close to previously reported diabetes related genes or potential candidate genes.

Conclusion

This screen method that employed tree-based association showed promise for identifying candidate loci in the presence of covariates in genome scans for complex traits.
Use of tree-based models to identify subgroups and increase power to detect linkage to cardiovascular disease traits
Authors: Costello Tracy Jennifer , Swartz Michael David , Sabripour Mahyar , Gu Xiangjun , Sharma Rishika , Etzel Carol Jean
Published: December 2003

Background

Our goal was to identify subgroups of sib pairs from the Framingham Heart Study data set that provided higher evidence of linkage to particular candidate regions for cardiovascular disease traits. The focus of this method is not to claim identification of significant linkage to a particular locus but to show that tree models can be used to identify subgroups for use in selected sib-pair sampling schemes.

Results

We report results using a novel recursive partitioning procedure to identify subgroups of sib pairs with increased evidence of linkage to systolic blood pressure and other cardiovascular disease-related quantitative traits, using the Framingham Heart Study data set provided by the Genetic Analysis Workshop 13. This procedure uses a splitting rule based on Haseman-Elston regression that recursively partitions sib-pair data into homogeneous subgroups.

Conclusions

Using this procedure, we identified a subgroup definition for use as a selected sib-pair sampling scheme. Using the characteristics that define the subgroup with higher evidence for linkage, we have identified an area of focus for further study.
Mapping loci influencing blood pressure in the Framingham pedigrees using model-free LOD score analysis of a quantitative trait
Authors: Knight Jo , North Bernard V , Sham Pak C , Curtis David
Published: December 2003

This paper presents a method of performing model-free LOD-score based linkage analysis on quantitative traits. It is implemented in the QMFLINK program. The method is used to perform a genome screen on the Framingham Heart Study data. A number of markers that show some support for linkage in our study coincide substantially with those implicated in other linkage studies of hypertension.

Although the new method needs further testing on additional real and simulated data sets we can already say that it is straightforward to apply and may offer a useful complementary approach to previously available methods for the linkage analysis of quantitative traits.
Linkage analysis of adult height with parent-of-origin effects in the Framingham Heart Study
Authors: Mukhopadhyay Nandita , Weeks Daniel E
Published: December 2003

Current linkage analysis methods for quantitative traits do not usually incorporate imprinting effects. Here, we carried out genome-wide linkage analysis for loci influencing adult height in the Framingham Heart Study subjects using variance components while allowing for imprinting effects. We used a sex-averaged map for the 22 autosomes, while chromosomes 6, 14, 18, and 19 were also analyzed using sex-specific maps. We compared results from these four analyses: 1) non-imprinted with sex-averaged maps, 2) imprinted with sex-averaged maps, 3) non-imprinted with sex-specific maps, and 4) imprinted with sex-specific maps. We found four regions on three chromosomes (14q32, 18p11-q21, 18q21-22, and 19q13) with LOD scores above 2.0, with a maximum LOD score of 3.12, allowing for imprinting and sex-specific maps, at D18S1364 on 18q21. While we obtained significant evidence of imprinting effects in both the 18p11-q21 and 19q13 regions when using sex-averaged maps, there were no significant differences between the imprinted and non-imprinted LOD scores when we used sex-specific maps. Our results illustrate the importance of allowing for gender-specific effects in linkage analyses, whether these are in the form of gender-specific recombination frequencies, or in the form of imprinting effects.
Genome-wide linkage analysis of blood pressure under locus heterogeneity
Authors: Yang Xinqun , Wang Kai , Huang Jian , Vieland Veronica J
Published: December 2003

We describe a method for mapping quantitative trait loci that allows for locus heterogeneity. A genome-wide linkage analysis of blood pressure was performed using sib-pair data from the Framingham Heart Study. Evidence of linkage was found on four markers (GATA89G08, GATA23D06, GATA14E09, and 049xd2) at a significance level of 0.01. Two of them (GATA14E09 and 049xd2) seem to overlap with linkage signals reported previously, while the other two are not linked to any known signals.
Genome-wide linkage scan for genes affecting longitudinal trends in systolic blood pressure
Authors: Jacobs Kevin B , Gray-McGuire Courtney , Cartier Kevin C , Elston Robert C
Published: December 2003

Only one genome scan to date has attempted to make use of the longitudinal data available in the Framingham Heart Study, and this attempt yielded evidence of linkage to a gene for mean systolic blood pressure. We show how the additional information available in these longitudinal data can be utilized to examine linkages for not only mean systolic blood pressure (SBP), but also for its trend with age and its variability. Prior to linkage analysis, individuals treated for hypertension were adjusted to account for right-censoring of SBP. Regressions on age were fitted to obtain orthogonal measures of slope, curvature, and residual variance of SBP that were then used as dependent variables in the model-free linkage program SIBPAL. We included mean age, gender, and cohort as covariates in the analysis. To improve power, sibling pairs were weighted for informativity using weights derived from both the marker and trait. The most significant results from our analyses were found on chromosomes 12, 15, and 17 for mean SBP, and chromosome 20 for both SBP slope and curvature.
Longitudinal familial analysis of blood pressure involving parametric (co)variance functions
Authors: Soler Julia MP , Blangero John
Published: December 2003

Background

For analyzing longitudinal familial data we adopted a log-linear form to incorporate heterogeneity in genetic variance components over the time, and additionally a serial correlation term in the genetic effects at different levels of ages. Due to the availability of multiple measures on the same individual, we permitted environmental correlations that may change across time.

Results

Systolic blood pressure from family members from the first and second cohort was used in the current analysis. Measures of subjects receiving hypertension treatment were set as censored values and they were corrected. An initial check of the variance and covariance functions proposed for analyzing longitudinal familial data, using empirical semi-variogram plots, indicated that the observed trait dispersion pattern follows the assumptions adopted.

Conclusion

The corrections for censored phenotypes based on ordinary linear models may be an appropriate simple model to correct the data, ensuring that the original variability in the data was retained. In addition, empirical semi-variogram plots are useful for diagnosis of the (co)variance model adopted.
Genome-wide linkage analysis of the tracking of systolic blood pressure using a mixed model
Authors: Wang Tao , Zhu Guohua , Keen Kevin J
Published: December 2003

Background

Elevated blood pressure in middle age is a major risk factor for subsequent cardiovascular complications. An important longitudinal characteristic of blood pressure is the "tracking phenomenon". Tracking is defined as the persistence of the rank of a person's blood pressure level in a group over a long period of time. In this analysis, we used the Framingham data to investigate whether there are some genes responsible for this phenomenon.

Results

Both two-point and multipoint linkage analyses were applied to family members with complete data only and to all family data with missing values imputed by a Gaussian model. The results of two-point linkage analysis indicated that two loci for linkage with the intercept were on chromosomes 10 and 13, and two loci for linkage with both slope and intercept were on chromosomes 1 and 3. Multipoint linkage analysis indicated only one region, 200–240 cM on chromosome 1, to be linked with both intercept and slope. For the intercept of SBP, the highest LOD (4.43) was found at 214 cM when missing data were imputed, and the highest LOD (2.81) was at 231 cM for the complete case data. For the slope of SBP, the highest multipoint LODs were 3.63 at 227 cM and 2.02 at 234 cM for the complete case data and imputation data, respectively.

Conclusion

One or more genes in the range of 200–240 cM on chromosome 1 may be related to the tracking phenomenon of SBP.
A QTL genome scan of the metabolic syndrome and its component traits
Authors: McQueen Matthew B , Bertram Lars , Rimm Eric B , Blacker Deborah , Santangelo Susan L
Published: December 2003

Background

Because high blood pressure, altered lipid levels, obesity, and diabetes so frequently occur together, they are sometimes collectively referred to as the metabolic syndrome. While there have been many studies of each metabolic syndrome trait separately, few studies have attempted to analyze them combined, i.e., as one composite variable, in quantitative trait linkage or association analysis. We used genotype and phenotype data from the Framingham Heart Study to perform a full-genome scan for quantitative trait loci underlying the metabolic syndrome.

Results

Heritability estimates for all of the covariate-adjusted and age- and gender-standardized individual traits, and the composite metabolic syndrome trait, were all fairly high (0.39–0.62), and the composite trait was among the highest at 0.61. The composite trait yielded no regions with suggestive linkage by Lander and Kruglyak's criteria, although there were several noteworthy regions for individual traits, some of which were also observed for the composite variable.

Conclusion

Despite its high heritability, the composite metabolic syndrome trait variable did not increase the power to detect or localize linkage peaks in this sample. However, this strategy and related methods of combining correlated individual traits deserve further investigation, particularly in settings with complex causal pathways.
Application of the Italian version of the Intensive Care Unit Memory tool in the clinical setting
Authors: Capuzzo Maurizia , Valpondi Vanna , Cingolani Emiliano , De Luca Serena , Gianstefani Giovanna , Grassi Luigi , Alvisi Raffaele
Published: December 2003

Introduction

The aims of the present study were to assess patients' memories of their stay in the intensive care unit (ICU) over time, using the Italian version of the ICU Memory (ICUM) tool, and to examine the relationship between memory and duration of ICU stay and infection.

Patients and method

Adult patients consecutively admitted to a four-bed ICU of a university hospital, whose stay in the ICU was at least 3 days, were prospectively studied. The ICUM tool was administered twice: face to face 1 week after ICU discharge to 93 patients (successfully in 87); and by phone after 3 months to 67 patients. Stability of memories over time was analyzed using Kappa statistics.

Results

Delusional memories appeared to be the most persistent recollections over time (minimum κ value = 0.68), followed by feelings (κ value > 0.7 in three out of six memories) and factual memories (κ value > 0.7 in three out of 11 memories). The patients without a clear memory of their stay in the ICU reported a greater number of delusional memories than did those with a clear memory. Of patients without infection 35% had one or two delusional memories, and 60% of patients with infection had one to four delusional memories (P = 0.029).

Conclusion

The ICUM tool is of value in a setting and language different from those in which it was created and used. Delusional memories are the most stable recollections, and are frequently associated both with lack of clear memory of ICU experience and with presence of infection during ICU stay.
Psychiatric aspects of the assessment and treatment of sex offenders
Authors: Gordon Harvey , Grubin Don
Published: December 2003

Training in general and forensic psychiatry in the assessment and treatment of sex offenders is in need of considerable improvement. Although most sex offenders are not mentally ill, many are subject to substance misuse, abnormal personality traits, personality disorder, learning disability or dysphoric mood, and in some organic factors will be involved. Comprehensive assessment of sex offenders includes a full history and mental state evaluation, obtaining a collateral history from other sources, observation, psychometric testing, and psychophysiological methods of assessment, including penile plethysmography. Trials of the use of the polygraph are also under way. The treatment of sex offenders, especially those with paraphilias, may include medication with selective serotonin reuptake inhibitors or anti-libidinal agents. Ethical considerations can be problematic, but a balance can often be found between the welfare of the offender and the safety of the public.
Lone mothers' experience of physical and sexual violence: association with psychiatric disorders
Authors: Butterworth Peter
Published: December 2003

Background

Violence against women is increasingly recognised as an important issue in both research and social policy.

Aims

To assess the lifetime experience of physical and sexual violence among lone and partnered mothers and the association with psychiatric disorders.

Method

Analysis of the Australian National Survey of Mental Health and Wellbeing. The representative sample included 2232 women with children who completed the Composite International Diagnostic Interview, a scale of psychological distress and sociodemographic measures.

Results

Lone mothers were more likely to have psychiatric disorders (odds ratios between 2.4 and 3.4) and have experienced physical and sexual violence (odds ratios between 31 and 41) than partnered mothers. The measures of physical and sexual violence were better predictors of psychiatric disorders than either lone parent status or the sociodemographic measures.

Conclusions

Experience of physical and sexual violence accounted for much of the greater prevalence of psychiatric disorders among lone compared with partnered mothers.
Antidepressant-related deaths and antidepressant prescriptions in England and Wales, 1998–2000
Authors: Cheeta Survjit , Schifano Fabrizio , Oyefeso Adenekan , Webb Lucy , Ghodse A. Hamid
Published: December 2003

Background

Deaths from antidepressants continue to account for a substantial proportion of drug-related deaths.

Aims

To investigate the relative toxicity of the major classes of antidepressant drugs, with the specific objective of assessing this in relation to the cause of death; and to analyse the deaths where there were multiple mentions of antidepressant drugs or other psychoactive drugs with antidepressants.

Method

Mortality data were collected from the National Programme of Substance Abuse Deaths, and antidepressant prescription data were collected.

Results

Most deaths from antidepressant drugs were suicides (80%). Tricyclic antidepressants (TCAs) accounted for more drug mentions than did other antidepressant drugs (12 per million prescriptions). Selective serotonin reuptake inhibitors (SSRIs) were associated with a significantly lower risk of toxicity, but 93% of deaths from SSRIs occurred in combination with other drugs, especially TCAs (24.5%). In ‘combination’ deaths patients were significantly more likely to have had a history of drug misuse.

Conclusions

The efficacy and safety of augmentation therapy with TCAs in SSRI-resistant patients should be monitored carefully, and patients prescribed antidepressants should be screened for drug use/misuse.
Heterogeneity of outcomes in schizophrenia
Authors: Ruggeri Mirella , Lasalvia Antonio , Tansella Michele , Bonetto Chiara , Abate Maria , Thornicroft Graham , Allevi Liliana , Ognibene Paola
Published: December 2003

Background

Care for people with schizophrenia should address a wide range of outcomes, including professional and consumer perspectives.

Aims

To measure changes in psychopathology functioning, needs for care and quality of life; to develop predictive models for each outcome domain; and to assess the frequency of ‘good'and ‘poor’ outcomes, as defined in a series of different definitions that use combinations of the four domains measured.

Method

Three-year follow-up of a 1-year-treated prevalence cohort of 107 patients with an ICD–10 diagnosis of schizophrenia attending the South Verona community-based mental health service.

Results

Mean symptom severity and some types of needs for care worsen, but quality of life shows no change. Functioning shows a non-significant trend to deteriorate. Between 32% and 42% of the variance in the four key outcomes was explained by our model. Different definitions of good'and ‘poor’ outcome included 0–31% of patients, depending on the definition used.

Conclusions

The 3-year outcome for schizophrenia depends on the domain of outcome used, whether staff or patient ratings are used and the stringency of the definitions used for good and poor outcome.
Effects of antipsychotics on fat deposition and changes in leptin and insulin levels
Authors: Zhang Zhi-Jun , Yao Zhi-Jian , Liu Wen , Fang Qun , Reynolds Gavin P.
Published: December 2003

Background

Weight gain is a common consequence of antipsychotic drug treatment and can lead to further morbidity.

Aims

To assess the effects of antipsychotic drug therapy on abdominal fat deposition, on insulin and leptin secretion, and on circulating glucose and lipids.

Method

Abdominal body fat was determined by magnetic resonance imaging in a group of previously untreated patients with schizophrenia, before and after 10 weeks'antipsychotic drug treatment. Body mass and blood concentrations of glucose, insulin, leptin and lipids were also measured.

Results

Significant increases in both subcutaneous and intra-abdominal fat were identified after antipsychotic drug treatment. A three-fold increase in leptin secretion as well as significant increases in levels of circulating lipids and non-fasting glucose were also identified.

Conclusions

Patients first receiving antipsychotic drugs experience substantial deposition of both subcutaneous and intra-abdominal fat, reflecting a loss of the normal inhibitory control of leptin on body mass. Along with fat deposition, the increase in levels of fasting lipids and in non-fasting glucose may provide early signs of drug-induced progression towards the metabolic syndrome.
The Child Attention-Deficit Hyperactivity Disorder Teacher Telephone Interview (CHATTI): reliability and validity
Authors: Holmes Jane , Lawson Deborah , Langley Kate , Fitzpatrick Helen , Trumper Anne , Pay Helen , Harrington Richard , Thapar Anita
Published: December 2003

Background

The ICD – 10 and DSM – IV diagnostic criteria for hyperkinetic disorder and attention-deficit hyperactivity disorder (ADHD) require symptoms or impairment in two or more settings. Thus, information on children's symptoms in school is usually required. This paper presents the Child ADHD Teacher Telephone Interview (CHATTI), an instrument aimed at systematically obtaining this information.

Aims

To examine the stability, test–retest reliability and criterion validity of the CHATTI for children referred with a suspected diagnosis of ADHD.

Method

Data were obtained from 79 teachers, of whom 36 were interviewed on two occasions.

Results

Overall, the CHATTI shows good stability test–retest reliability and criterion validity for symptom scores. Test–retest reliability for some individual items was low. Reliability for the operationalised criteria of ‘pervasiveness' (i.e. symptoms at school and home) and ‘school impairment’ was excellent (κ=1).

Conclusions

The CHATTI appears to be a promising tool for assessing ADHD symptoms in a school setting and could be useful in clinical as well as research settings.
Runx2deficiency in chondrocytes causes adipogenic changes in vitro
Authors: Enomoto Hirayuki , Furuichi Tatsuya , Zanma Akira , Yamana Kei , Yoshida Carolina , Sumitani Satoru , Yamamoto Hiroyasu , Enomoto-Iwamoto Motomi , Iwamoto Masahiro , Komori Toshihisa
Published: December 2003

Runx2 (runt-related transcription factor 2) is an important transcription factor for chondrocyte differentiation as well as for osteoblast differentiation. To investigate the function of Runx2 in chondrocytes, we isolated chondrocytes from the rib cartilage of Runx2-deficient (Runx2–/–) mice and examined the effect of Runx2 deficiency on chondrocyte function and behavior in culture for up to 12 days. At the beginning of the culture, Runx2–/– chondrocytes actively proliferated, had a polygonal shape and expressed type II collagen; these are all characteristics of chondrocytes. However, they gradually accumulated lipid droplets that stained with oil red O and resembled adipocytes. Northern blot analysis revealed that the expression of adipocyte-related differentiation marker genes including PPARγ (peroxisome proliferator-activated receptor γ), aP2 and Glut4 increased over time in culture, whereas expression of type II collagen decreased. Furthermore, the expression of Pref-1, an important inhibitory gene of adipogenesis, was remarkably decreased. Adenoviral introduction of Runx2 or treatment with transforming growth factor-β, retinoic acid, interleukin-1β, basic fibroblast growth factor, platelet-derived growth factor or parathyroid hormone inhibited the adipogenic changes in Runx2–/– chondrocytes. Runx2 and transforming growth factor-β synergistically upregulated interleukin-11 expression, and the addition of interleukin-11 to the culture medium reduced adipogenesis in Runx2–/– chondrocytes. These findings indicate that depletion of Runx2 resulted in the loss of the differentiated phenotype in chondrocytes and induced adipogenic differentiation in vitro, and show that Runx2 plays important roles in maintaining the chondrocyte phenotype and in inhibiting adipogenesis. Our findings suggest that these Runx2-dependent functions are mediated, at least in part, by interleukin-11.