bluuebunny/crossref_metadata_2025 huggingface dataset:
Exploring Medication Problems and Strategies for Future Medication Therapy Management in an Outpatient Psychiatric Center
Authors: Oji Valerie U. , Emanaha Ify , Oji Chinyere
Published: May 2007

Medication therapy management (MTM) for Medicare Part D beneficiaries offers new practice opportunities for pharmacists and insight in designing new modes of pharmaceutical care delivery for all patients. The authors' goal was to identify medication-related problems in an outpatient behavioral health care center, and other important considerations in designing a reimbursable, collaborative, pharmacist-coordinated MTM program. Nine months of medication use evaluation data obtained from medical record review, medication inventory audits, transcription records, patient, and staff were examined for variances from organizational standard of care. Of the 592 documented variances, a majority of them were in the areas of medication prescribing and transcription (508; 85%), patient self-administration (46; 8%), and dispensing (38; 6%). Medication-related problems were identified that could be addressed with pharmacist MTM. MTM design should include elements of pharmacotherapy effectiveness and program quality. Important considerations for reimbursement are the priorities of health care organizational stakeholders, promotion of the nondispensing role of pharmacists, capacity to integrate the workflow processes and billing codes of pharmacists and other health professionals, and newly emerging trends and service demands in health care. Although these experiences occurred in an outpatient psychiatric setting, they are generally applicable to future MTM program design.
Outcome of treatment in children with hypodiploid acute lymphoblastic leukemia
Authors: Nachman James B. , Heerema Nyla A. , Sather Harland , Camitta Bruce , Forestier Erik , Harrison Christine J. , Dastugue Nicole , Schrappe Martin , Pui Ching-Hon , Basso Giuseppe , Silverman Lewis B. , Janka-Schaub Gritta E.
Published: May 2007

One-hundred thirty-nine patients with acute lymphoblastic leukemia (ALL) and hypodiploidy (fewer than 45 chromosomes) were collected from 10 different national ALL study groups and single institutions. Patients were stratified by modal chromosome number into 4 groups: 24 to 29 (N = 46); 33 to 39 (N = 26); 40 to 43 (N = 13); and 44 (N = 54) chromosomes. Nine patients were Philadelphia chromosome (Ph) positive (4 cases: 44 chromosomes; 5 cases: 40-43 chromosomes) and were not considered further. Event-free survival (EFS) and overall survival (OS) of the remaining 130 patients were 38.5% ± 4.4% and 49.8% ± 4.2% at 8 years, respectively. There were no significant differences in outcome between patients with 24 to 29, 33 to 39, or 40 to 43 chromosomes. Compared with patients with fewer than 44 chromosomes, patients with 44 chromosomes had a significantly better EFS (P = .01; 8-year estimate, 52.2% vs 30.1%) and OS (P = .017; 69% vs 37.5%). For patients with 44 chromosomes, monosomy 7, the presence of a dicentric chromosome, or both predicted a worse EFS but similar OS. Doubling of the hypodiploid clone occurred in 32 patients (24-29 chromosomes [n = 25] and 33-39 chromosomes [n = 7]) and had no prognostic implication. Children and adolescents with ALL and hypodiploidy with fewer than 44 chromosomes have a poor outcome despite contemporary therapy.
Gene-expression profiling identifies distinct subclasses of core binding factor acute myeloid leukemia
Authors: Bullinger Lars , Rücker Frank G. , Kurz Stephan , Du Juan , Scholl Claudia , Sander Sandrine , Corbacioglu Andrea , Lottaz Claudio , Krauter Jürgen , Fröhling Stefan , Ganser Arnold , Schlenk Richard F. , Döhner Konstanze , Pollack Jonathan R. , Döhner Hartmut
Published: May 2007

Core binding factor (CBF) leukemias, characterized by either inv(16)/t(16;16) or t(8;21), constitute acute myeloid leukemia (AML) subgroups with favorable prognosis. However, there exists substantial biologic and clinical heterogeneity within these cytogenetic groups that is not fully reflected by the current classification system. To improve the molecular characterization we profiled gene expression in a large series (n = 93) of AML patients with CBF leukemia [(inv (16), n = 55; t(8;21), n = 38)]. By unsupervised hierarchical clustering we were able to define a subgroup of CBF cases (n = 35) characterized by shorter overall survival times (P = .03). While there was no obvious correlation with fusion gene transcript levels, FLT3 tyrosine kinase domain, KIT, and NRAS mutations, the newly defined inv(16)/t(8;21) subgroup was associated with elevated white blood cell counts and FLT3 internal tandem duplications (P = .011 and P = .026, respectively). Supervised analyses of gene expression suggested alternative cooperating pathways leading to transformation. In the “favorable” CBF leukemias, antiapoptotic mechanisms and deregulated mTOR signaling and, in the newly defined “unfavorable” subgroup, aberrant MAPK signaling and chemotherapy-resistance mechanisms might play a role. While the leukemogenic relevance of these signatures remains to be validated, their existence nevertheless supports a prognostically relevant biologic basis for the heterogeneity observed in CBF leukemia.
Mapping of possible prion protein self-interaction domains using peptide arrays
Authors: Rigter Alan , Langeveld Jan PM , Timmers-Parohi Drophatie , Jacobs Jorg G , Moonen Peter LJM , Bossers Alex
Published: May 2007

Background

The common event in transmissible spongiform encephalopathies (TSEs) or prion diseases is the conversion of host-encoded protease sensitive cellular prion protein (PrPC) into strain dependent isoforms of scrapie associated protease resistant isoform (PrPSc) of prion protein (PrP). These processes are determined by similarities as well as strain dependent variations in the PrP structure. Selective self-interaction between PrP molecules is the most probable basis for initiation of these processes, potentially influenced by chaperone molecules, however the mechanisms behind these processes are far from understood. We previously determined that polymorphisms do not affect initial PrPC to PrPSc binding but rather modulate a subsequent step in the conversion process. Determining possible sites of self-interaction could elucidate which amino acid(s) or amino acid sequences contribute to binding and further conversion into other isoforms. To this end, ovine – and bovine PrP peptide-arrays consisting of 15-mer overlapping peptides were probed with recombinant sheep PrPC fused to maltose binding protein (MBP-PrP).

Results

The peptide-arrays revealed two distinct high binding areas as well as some regions of lower affinity in PrPC resulting in total in 7 distinct amino acid sequences (AAs). The first high binding area comprises sheep-PrP peptides 43–102 (AA 43–116), including the N-terminal octarepeats. The second high binding area of sheep-PrP peptides 134–177 (AA 134–191), encompasses most of the scrapie susceptibility-associated polymorphisms in sheep. This concurs with previous studies showing that scrapie associated-polymorphisms do not modulate the initial binding of PrPC to PrPSc. Comparison of ovine – and bovine peptide-array binding patterns revealed that amino acid specific differences can influence the MBP-PrP binding pattern. PrP-specific antibodies were capable to completely block interaction between the peptide-array and MBP-PrP. MBP-PrP was also capable to specifically bind to PrP in a Western blot approach. The octarepeat region of PrP seems primarily important for this interaction because proteinase K pre-treatment of PrPSc completely abolished binding.

Conclusion

Binding of MBP-PrP to PrP-specific sequences indicate that several specific self-interactions between individual PrP molecules can occur and suggest that an array of interactions between PrPC-PrPC as well as PrPC-PrPSc may be possible, which ultimately lead to variations in species barrier and strain differences.
Non-coding sequence retrieval system for comparative genomic analysis of gene regulatory elements
Authors: Doh Sung Tae , Zhang Yunyu , Temple Matthew H , Cai Li
Published: May 2007

Background

Completion of the human genome sequence along with other species allows for greater understanding of the biochemical mechanisms and processes that govern healthy as well as diseased states. The large size of the genome sequences has made them difficult to study using traditional methods. There are many studies focusing on the protein coding sequences, however, not much is known about the function of non-coding regions of the genome. It has been demonstrated that parts of the non-coding region play a critical role as gene regulatory elements. Enhancers that regulate transcription processes have been found in intergenic regions. Furthermore, it is observed that regulatory elements found in non-coding regions are highly conserved across different species. However, the analysis of these regulatory elements is not as straightforward as it may first seem. The development of a centralized resource that allows for the quick and easy retrieval of non-coding sequences from multiple species and is capable of handing multi-gene queries is critical for the analysis of non-coding sequences. Here we describe the development of a web-based non-coding sequence retrieval system.

Results

This paper presents a Non-Coding Sequences Retrieval System (NCSRS). The NCSRS is a web-based bioinformatics tool that performs fast and convenient retrieval of non-coding and coding sequences from multiple species related to a specific gene or set of genes. This tool has compiled resources from multiple sources into one easy to use and convenient web based interface. With no software installation necessary, the user needs only internet access to use this tool.

Conclusion

The unique features of this tool will be very helpful for those studying gene regulatory elements that exist in non-coding regions. The web based application can be accessed on the internet at:http://cell.rutgers.edu/ncsrs/.
Evolutionary hierarchies of conserved blocks in 5'-noncoding sequences of dicot rbcS genes
Authors: Weeks Katie E , Chuzhanova Nadia A , Donnison Iain S , Scott Ian M
Published: May 2007

Background

Evolutionary processes in gene regulatory regions are major determinants of organismal evolution, but exceptionally challenging to study. We explored the possibilities of evolutionary analysis of phylogenetic footprints in 5'-noncoding sequences (NCS) from 27 ribulose-1,5-bisphosphate carboxylase small subunit (rbcS) genes, from three dicot families (Brassicaceae, Fabaceae and Solanaceae).

Results

Sequences of up to 400 bp encompassing proximal promoter and 5'-untranslated regions were analyzed. We conducted phylogenetic footprinting by several alternative methods: generalized Lempel-Ziv complexity (CLZ), multiple alignments with DIALIGN and ALIGN-M, and the MOTIF SAMPLER Gibbs sampling algorithm. These tools collectively defined 36 conserved blocks of mean length 12.8 bp. On average, 12.5 blocks were found in each 5'-NCS. The blocks occurred in arrays whose relative order was absolutely conserved, confirming the existence of 'conserved modular arrays' in promoters. Identities of half of the blocks confirmed pastrbcSresearch, including versions of the I-box, G-box, and GT-1 sites such as Box II. Over 90% of blocks overlapped DNase-protected regions in tomato 5'-NCS. Regions characterized by lowCLZin sliding-window analyses were also frequently associated with DNase-protection. Blocks could be assigned to evolutionary hierarchies based on taxonomic distribution and estimated age. Lineage divergence dates implied that 13 blocks found in all three plant families were of Cretaceous antiquity, while other family-specific blocks were much younger. Blocks were also dated by formation of multigene families, using genome and coding sequence information. Dendrograms of evolutionary relations of the 5'-NCS were produced by several methods, including: cluster analysis using pairwiseCLZvalues; evolutionary trees of DIALIGN sequence alignments; and cladistic analysis of conserved blocks.

Conclusion

Dicot 5'-NCS contain conserved modular arrays of recurrent sequence blocks, which are coincident with functional elements. These blocks are amenable to evolutionary interpretation as hierarchies in which ancient, taxonomically widespread blocks can be distinguished from more recent, taxon-specific ones.
Gene function in early mouse embryonic stem cell differentiation
Authors: Sene Kagnew Hailesellasse , Porter Christopher J , Palidwor Gareth , Perez-Iratxeta Carolina , Muro Enrique M , Campbell Pearl A , Rudnicki Michael A , Andrade-Navarro Miguel A
Published: May 2007

Background

Little is known about the genes that drive embryonic stem cell differentiation. However, such knowledge is necessary if we are to exploit the therapeutic potential of stem cells. To uncover the genetic determinants of mouse embryonic stem cell (mESC) differentiation, we have generated and analyzed 11-point time-series of DNA microarray data for three biologically equivalent but genetically distinct mESC lines (R1, J1, and V6.5) undergoing undirected differentiation into embryoid bodies (EBs) over a period of two weeks.

Results

We identified the initial 12 hour period as reflecting the early stages of mESC differentiation and studied probe sets showing consistent changes of gene expression in that period. Gene function analysis indicated significant up-regulation of genes related to regulation of transcription and mRNA splicing, and down-regulation of genes related to intracellular signaling. Phylogenetic analysis indicated that the genes showing the largest expression changes were more likely to have originated in metazoans. The probe sets with the most consistent gene changes in the three cell lines represented 24 down-regulated and 12 up-regulated genes, all with closely related human homologues. Whereas some of these genes are known to be involved in embryonic developmental processes (e.g.Klf4, Otx2, Smn1, Socs3, Tagln, Tdgf1), our analysis points to others (such as transcription factorPhf21a, extracellular matrix relatedLama1andCyr61, or endoplasmic reticulum relatedSc4molandScd2) that have not been previously related to mESC function. The majority of identified functions were related to transcriptional regulation, intracellular signaling, and cytoskeleton. Genes involved in other cellular functions important in ESC differentiation such as chromatin remodeling and transmembrane receptors were not observed in this set.

Conclusion

Our analysis profiles for the first time gene expression at a very early stage of mESC differentiation, and identifies a functional and phylogenetic signature for the genes involved. The data generated constitute a valuable resource for further studies. All DNA microarray data used in this study are available in the StemBase database of stem cell gene expression data [1] and in the NCBI's GEO database.
Patient risk profiles and practice variation in nonadherence to antidepressants, antihypertensives and oral hypoglycemics
Authors: van Dijk Liset , Heerdink Eibert R , Somai Dinesh , van Dulmen Sandra , Sluijs Emmy M , de Ridder Denise T , Griens Anna MGF , Bensing Jozien M
Published: May 2007

Background

Many patients experience difficulties in following treatment recommendations. This study's objective is to identify nonadherence risk profiles regarding medication (antidepressants, antihypertensives, and oral hypoglycemics) from a combination of patients' socio-demographic characteristics, morbidity presented within general practice and medication characteristics. An additional objective is to explore differences in nonadherence among patients from different general practices.

Methods

Data were obtained by linkage of a Dutch general practice registration database to a dispensing registration database from the year 2001. Subjects included in the analyses were users of antidepressants (n = 4,877), antihypertensives (n = 14,219), or oral hypoglycemics (n = 2,428) and their GPs. Outcome variables were: 1) early dropout i.e., a maximum of two prescriptions and 2) refill nonadherence (in patients with 3+ prescriptions); refill adherence < 80% was considered as nonadherence. Multilevel modeling was used for analyses.

Results

Both early dropout and refill nonadherence were highest for antidepressants, followed by antihypertensives. Risk factors appeared medication specific and included: 1) non-western immigrants being more vulnerable for nonadherence to antihypertensives and antidepressants; 2) type of medication influencing nonadherence in both antihypertensives and antidepressants, 3) GP consultations contributing positively to adherence to antihypertensives and 4) somatic co-morbidity influencing adherence to antidepressants negatively. There was a considerable range between general practices in the proportion of patients who were nonadherent.

Conclusion

No clear risk profiles for nonadherence could be constructed. Characteristics that are correlated with nonadherence vary across different types of medication. Moreover, both patient and prescriber influence adherence. Especially non-western immigrants need more attention with regard to nonadherence, for example by better monitoring or communication. Since it is not clear which prescriber characteristics influence adherence levels of their patients, there is need for further research into the role of the prescriber.
Diagnosis and treatment of malaria in peripheral health facilities in Uganda: findings from an area of low transmission in south-western Uganda
Authors: Ndyomugyenyi Richard , Magnussen Pascal , Clarke Siân
Published: May 2007

Background

Early recognition of symptoms and signs perceived as malaria are important for effective case management, as few laboratories are available at peripheral health facilities. The validity and reliability of clinical signs and symptoms used by health workers to diagnose malaria were assessed in an area of low transmission in south-western Uganda.

Methods

The study had two components: 1) passive case detection where all patients attending the out patient clininc with a febrile illness were included and 2) a longitudinal active malaria case detection survey was conducted in selected villages. A malaria case was defined as any slide-confirmed parasitaemia in a person with an axillary temperature ≥ 37.5°C or a history of fever within the last 24 hrs and no signs suggestive of other diseases.

Results

Cases of malaria were significantly more likely to report joint pains, headache, vomiting and abdominal pains. However, due to the low prevalence of malaria, the predictive values of these individual signs alone, or in combination, were poor. Only 24.8% of 1627 patients had malaria according to case definition and > 75% of patients were unnecessarily treated for malaria and few slide negative cases received alternative treatment.

Conclusion

In low-transmission areas, more attention needs to be paid to differential diagnosis of febrile illnesses In view of suggested changes in anti-malarial drug policy, introducing costly artemisinin combination therapy accurate, rapid diagnostic tools are necessary to target treatment to people in need.
Some facts and thoughts: p73 as a tumor suppressor gene in the network of tumor suppressors
Authors: Boominathan Lakshmanane
Published: May 2007

The question of whether p73 is a tumor suppressor gene, is not yet answered with full confidence. The lack of spontaneous tumor formation in p73 null mice and infrequent p73 mutations seen in a variety of cancers analyzed would straightaway negate its role as a primary tumor suppressor gene. However, accumulating evidence suggest that p73 gene and its target genes are hypermethylated in the cancer of lymphoid origin. Here I discuss some facts and thoughts that support the idea that p73 could still be a tumor suppressor gene. The tumor suppressor network in which p73 appears to be a participant involves E2F1, JunB, INK4a/p16, ARF/p19, p57kip2 and BRCA1. Knock out of each gene in E2F-1-p73-JunB-p16INK4a network of tumor suppressor proteins result in lymphoma/leukemia formation. Further, I tried to explain why lymphomas are not seen in p73 null mice and why p73 gene is not prone to frequent mutation.
Tumor-specific T cells signal tumor destruction via the lymphotoxin β receptor
Authors: Winter Hauke , van den Engel Natasja K , Poehlein Christian H , Hatz Rudolf A , Fox Bernard A , Hu Hong-Ming
Published: May 2007

Background

Previously, we reported that adoptively transferred perforin k/o (PKO), and IFN-γ k/o (GKO), or perforin/IFN-γ double k/o (PKO/GKO) effector T cells mediated regression of B16BL6-D5 (D5) pulmonary metastases and showed that TNF receptor signaling played a critical role in mediating tumor regression. In this report we investigated the role of lymphotoxin-α (LT-α) as a potential effector molecules of tumor-specific effector T cells.

Methods

Effector T cells were generated from tumor vaccine-draining lymph node (TVDLN) of wt, GKO, LT-α deficient (LKO), or PKO/GKO mice and tested for their ability to mediate regression of D5 pulmonary metastases in the presence or absence of LT-βR-Fc fusion protein or anti-IFN-γ antibody. Chemokine production by D5 tumor cells was determined by ELISA, RT-PCR and Chemotaxis assays.

Results

Stimulated effector T cells from wt, GKO, or PKO/GKO mice expressed ligands for LT-β receptor (LT-βR). D5 tumor cells were found to constitutively express the LT-βR. Administration of LT-βR-Fc fusion protein completely abrogated the therapeutic efficacy of GKO or PKO/GKO but not wt effector T cells (p < 0.05). Consistent with this observation, therapeutic efficacy of effector T cells deficient in LT-α, was greatly reduced when IFN-γ production was neutralized. While recombinant LT-α1β2 did not induce apoptosis of D5 tumor cells in vitro, it induced secretion of chemokines by D5 that promoted migration of macrophages.

Conclusion

The contribution of LT-α expression by effector T cells to anti-tumor activity in vivo was not discernable when wt effector T cells were studied. However, the contribution of LT-β R signaling was identified for GKO or PKO/GKO effector T cells. Since LT-α does not directly induce killing of D5 tumor cells in vitro, but does stimulate D5 tumor cells to secrete chemokines, these data suggest a model where LT-α expression by tumor-specific effector T cells interacts via cross-linking of the LT-βR on tumor cells to induce secretion of chemokines that are chemotactic for macrophages. While the contribution of macrophages to tumor elimination in our system requires additional study, this model provides a possible explanation for the infiltration of inate effector cells that is seen coincident with tumor regression.
A focus reduction neutralization assay for hepatitis C virus neutralizing antibodies
Authors: Fournier Carole , Duverlie Gilles , François Catherine , Schnuriger Aurelie , Dedeurwaerder Sarah , Brochot Etienne , Capron Dominique , Wychowski Czeslaw , Thibault Vincent , Castelain Sandrine
Published: May 2007

Background/Aim

The role of humoral immunity in hepatitis C virus (HCV) infection is poorly understood. Nevertheless, there is increasing interest in characterizing the neutralizing antibodies in the serum of HCV-infected patients. Focus reduction assays have been widely used to evaluate neutralizing antibody responses against a range of non-cytopathic viruses. Based on the recent development of a HCV cell culture system using the genotype 2 JFH-1-strain, we developed a focus reduction assay for HCV-neutralizing antibodies.

Methods

The focus reduction assay was based on a standard microneutralization assay in which immunostained foci on tissue culture plates are counted. The neutralizing anti-HCV antibodies titers of purified serum immunoglobulin samples from seventy-seven individuals were determined using a 50% focus reduction neutralization assay. Each titer was determined as the log value of the reciprocal antibody dilution that reduced the number of viral foci by 50%. IgG antibodies were first purified from each serum in order to avoid the facilitating effect of HDL on HCV entry.

Results

The assay's cut-off using an ELISA and RNA HCV-negative samples was found to be 1.25 log, corresponding to a dilution of 1:18. The assay was compared with a commercial HCV ELISA and exhibited specificity and sensitivity values of 100% and 96.5%, respectively, and good reproducibility (with intra-assay and inter-assay coefficients of variation of 6.7% and 12.6%, respectively). The assay did not show any cross-reactivity with anti-HIV, anti-HBs or heterophile antibody-positive samples. The neutralizing antibodies titers were 2.13 log (1:134) for homologous samples from HCV genotype 2 infected patients harboring the same genotype as JFH-1 and 1.93 log (1:85) for heterologous samples from patients infected by genotypes other than type 2. These results confirm the presence of broadly cross-neutralizing antibodies already reported using the HCV pseudoparticles system.

Conclusion

This study presents a simple, specific and reproducible cell culture-based assay for determination of HCV-neutralizing antibodies in human sera. The assay should be an important tool for gauging the relationship between the neutralizing antibodies response and viral load kinetics in acutely or chronically infected patients and for investigating the possible eradication or prevention of HCV infection by neutralizing antibodies.
Chronic persistent cough in the community: a questionnaire survey
Authors: Everett Caroline F , Kastelik Jack A , Thompson Rachel H , Morice Alyn H
Published: May 2007

Background

Chronic cough is a common symptom which causes significant levels of morbidity. It is becoming increasingly well characterised by research taking place in specialist cough clinics, where successful treatment rates are high. However, there is a paucity of data regarding the symptom complex of chronic cough in the community. This report details the results of a postal questionnaire survey sent to individuals requesting further information on chronic cough.

Methods

856 chronic cough questionnaires were sent out to members of the public who requested an information sheet following a national UK radio broadcast. Information regarding demography, history of cough, previous treatment and physical, psychological and social effects of the cough was elicited.

Results

373 completed questionnaires were returned. Mean age was 65.3 years (SD 12.0, range 9–88 years). 73% were female and 2% current smokers. Median duration of cough was 6.5 years. 66% had no other coexisting respiratory diagnosis, whilst 24% reported asthma. Of those who responded, 91% had consulted a general practitioner regarding the cough and of them, 85% had been prescribed some sort of treatment. 61% had seen at least one hospital specialist. Commonly reported associated physical symptoms included breathlessness (55%), wheeze (37%), fatigue (72%) and disturbed sleep (70%). Incontinence occurred in 55% of women. Similarly, the majority reported psychological effects such as anger or frustration (83%), anxiety (69%) and depression (55%). 64% felt that the cough interfered with their social life.

Conclusion

Chronic cough causes a high level of morbidity in the community, which results in a correspondingly high rate of healthcare utilisation. Demography and symptomatology seems to be similar to that reported from specialist centres, but successful treatment of the cough was uncommon, despite a high number of medical consultations in both primary and secondary care. If understanding of this debilitating but eminently treatable condition is enhanced, management of chronic cough will improve and many patients will be helped.
Decline of nucleotide excision repair capacity in aging Caenorhabditis elegans
Authors: Meyer Joel N , Boyd Windy A , Azzam Gregory A , Haugen Astrid C , Freedman Jonathan H , Van Houten Bennett
Published: May 2007

Background

Caenorhabditis elegans is an important model for the study of DNA damage and repair related processes such as aging, neurodegeneration, and carcinogenesis. However, DNA repair is poorly characterized in this organism. We adapted a quantitative polymerase chain reaction assay to characterize repair of DNA damage induced by ultraviolet type C (UVC) radiation in C. elegans, and then tested whether DNA repair rates were affected by age in adults.

Results

UVC radiation induced lesions in young adult C. elegans, with a slope of 0.4 to 0.5 lesions per 10 kilobases of DNA per 100 J/m2, in both nuclear and mitochondrial targets. L1 and dauer larvae were more than fivefold more sensitive to lesion formation than were young adults. Nuclear repair kinetics in a well expressed nuclear gene were biphasic in nongravid adult nematodes: a faster, first order (half-life about 16 hours) phase lasting approximately 24 hours and resulting in removal of about 60% of the photoproducts was followed by a much slower phase. Repair in ten nuclear DNA regions was 15% and 50% higher in more actively transcribed regions in young and aging adults, respectively. Finally, repair was reduced by 30% to 50% in each of the ten nuclear regions in aging adults. However, this decrease in repair could not be explained by a reduction in expression of nucleotide excision repair genes, and we present a plausible mechanism, based on gene expression data, to account for this decrease.

Conclusion

Repair of UVC-induced DNA damage in C. elegans is similar kinetically and genetically to repair in humans. Furthermore, this important repair process slows significantly in aging C. elegans, the first whole organism in which this question has been addressed.
Preparation of Cyclohexene-d10 by H/D-Exchange Reaction
Authors: Ishibashi Kenichi , Matsubara Seijiro
Published: May 2007

Preparation of fully deuterium-labeled cyclohexene by H/D-exchange reaction was performed efficiently in the presence of ruthenium catalyst under irradiation of microwaves. The reaction proceeds via a repetition of hydroruthenation and β-elimination.
Resolving the Genetic and Environmental Sources of the Correlation Between Height and Intelligence: A Study of Nearly 2600 Norwegian Male Twin Pairs
Authors: Sundet Jon Martin , Tambs Kristian , Harris Jennifer R. , Magnus Per , Torjussen Tore M.
Published: May 2007

The main aim of this paper was to resolve the correlation between intelligence test scores and standing height into genetic and environmental components. Data on 1181 identical and 1412 fraternal twin pairs (all males) were retrieved by matching files from the Norwegian Army with twin registries. The data were analyzed by means of a structural equation model comprising latent genetic, shared environmental and nonshared environmental factors and correlations between them. A major part of the height–intelligence correlation was due to correlated shared environments (59% of the phenotypic height–intelligence correlation), but statistically significant effects of correlated genes and nonshared environments were also found (respectively 35% and 6% of the phenotypic correlation).
Genetic and Environmental Influences on Temperament in the First Year of Life: The Puerto Rico Infant Twin Study (PRINTS)
Authors: Silberg Judy L. , San Miguel Vivian Febo , Murrelle E. Lenn , Prom Elizabeth , Bates John E. , Canino Glorisa , Egger Helen , Eaves Lindon J.
Published: May 2007

Three dimensions of temperament — difficult temperament, unadaptablility and unsociability — were assessed in the first year of life by maternal interview in twins born in Puerto Rico during 2001 and 2002. Eight hundred and sixty-five eligible mothers (80%) were traced and interviewed. Model- fitting results showed that additive genetic factors and the individual specific environment contributed to variation in all three dimensions. In addition, the pattern of variances and correlations suggested that sibling contrast effects influence ratings of difficult temperament. Moderate effects of the shared environment contributed to ratings of adaptability and sociability. There was a significant genetic correlation between difficult temperament and unadaptability. Genetic and environmental effects do not differ significantly between boys and girls. The study is the first population-based study of Puerto Rican twins and one of few to attempt the assessment of behavior in the first year. Preliminary results for difficult temperament and sociability were consistent with those in other populations and ages. In contrast, a significant effect of the shared environment on the temperamental trait of unadaptability has not been reported previously.
A Comparison of DNA Pools Constructed Following Whole Genome Amplification for Two-Stage SNP Genotyping Designs
Authors: Zhao Zhen Zhen , Nyholt Dale R. , James Michael R. , Mayne Renee , Treloar Susan A. , Montgomery Grant W.
Published: May 2007

Genotyping in DNA pools reduces the cost and the time required to complete large genotyping projects. The aim of the present study was to evaluate pooling as part of a strategy for fine mapping in regions of significant linkage. Thirty-nine single nucleotide polymorphisms (SNPs) were analyzed in two genomic DNA pools of 384 individuals each and results compared with data after typing all individuals used in the pools. There were no significant differences using data from either 2 or 8 heterozygous individuals to correct frequency estimates for unequal allelic amplification. After correction, the mean difference between estimates from the genomic pool and individual allele frequencies was .033. A major limitation of the use of DNA pools is the time and effort required to carefully adjust the concentration of each individual DNA sample before mixing aliquots. Pools were also constructed by combining DNA after Multiple Displacement Amplification (MDA). The MDA pools gave similar results to pools constructed after careful DNA quantitation (mean difference from individual genotyping .040) and MDA provides a rapid method to generate pools suitable for some applications. Pools provide a rapid and cost-effective screen to eliminate SNPs that are not polymorphic in a test population and can detect minor allele frequencies as low as 1% in the pooled samples. With current levels of accuracy, pooling is best suited to an initial screen in the SNP validation process that can provide high-throughput comparisons between cases and controls to priori- tize SNPs for subsequent individual genotyping.
Evaluating Whole Genome Amplification via Multiply-Primed Rolling Circle Amplification for SNP Genotyping of Samples With Low DNA Yield
Authors: Silander Kaisa , Komulainen Kati , Ellonen Pekka , Jussila Minttu , Alanne Mervi , Levander Minna , Tainola Päivi , Kuulasmaa Kari , Salomaa Veikko , Perola Markus , Peltonen Leena , Saarela Janna
Published: May 2007

The amount of available DNA is often a limiting factor in pursuing genetic analyses of large-scale population cohorts. An association between higher DNA yield from blood and several phenotypes associated with inflammatory states has recently been demonstrated, suggesting that exclusion of samples with very low DNA yield may lead to biased results in statistical analyses. Whole genome amplification (WGA) could present a solution to the DNA concentration-dependent sample selection. The aim was to thoroughly assess WGA for samples with low DNA yield, using the multiply-primed rolling circle amplification method. Fifty-nine samples were selected with the lowest DNA yield (less than 7.5µg) among 799 samples obtained for one population cohort. The genotypes obtained from two replicate WGA samples and the original genomic DNA were compared by typing 24 single nucleotide polymorphisms (SNPs). Multiple genotype discrepancies were identified for 13 of the 59 samples. The largest portion of discrepancies was due to allele dropout in heterozygous genotypes in WGA samples. Pooling the WGA DNA replicates prior to genotyping markedly improved genotyping reproducibility for the samples, with only 7 discrepancies identified in 4 samples. The nature of discrepancies was mostly homozygote genotypes in the genomic DNA and heterozygote genotypes in the WGA sample, suggesting possible allele dropout in the genomic DNA sample due to very low amounts of DNA template. Thus, WGA is applicable for low DNA yield samples, especially if using pooled WGA samples. A higher rate of genotyping errors requires that increased attention be paid to genotyping quality control, and caution when interpreting results.
Estimation of Prevalence of DSM-IV and Latent Class-Defined ADHD Subtypes in a Population-Based Sample of Child and Adolescent Twins
Authors: Neuman Rosalind J. , Sitdhiraksa Nantawat , Reich Wendy , Ji Ted H.-C. , Joyner Cynthia A. , Sun Ling-Wei , Todd Richard D.
Published: May 2007

The goal of this study is to determine the prevalence and age of onset of Diagnostic and Statistical Manual of Mental Disorders (4th ed.; DSMIV; American Psychiatric Association, 1994) and latent class-derived attention deficit/hyperactivity disorder (ADHD) subtypes in a population-based twin sample of boys and girls. Missouri birth records identified families with a twin pair 7 to 18 years of age. Telephone screening interviews for ADHD symptoms were completed for 5007 families. Diagnostic assessments were administered to 564 families with at least one twin meeting screening criteria, plus 183 control families. Prevalence and age of onset for both ADHD nosologies were calculated by sex and zygosity from parent report data. The prevalence of any DSM-IV ADHD was 6.2% overall, 7.4% in boys and 3.9% in girls. The inattentive subtype was most common in boys; the combined subtype was most common in girls. The mean age of onset of symptoms in children with any DSM-IV ADHD was 3.5 years, with no significant differences between boys and girls. Prevalences of latent class defined ADHD subtypes also varied by sex with the severe inattentive and combined classes more common in boys than girls. The age of onset of symptoms did not differ between boys and girls but were higher than in the DSM-IV subtypes. Findings in this twin sample showed that clinically significant ADHD, defined by either DSM-IV or latent class criterion, has an early age of onset and is more common in boys than girls. As clinical samples are most commonly composed of male combined subtypes, the inattentive subtype of both sexes in the general population is an under- treated segment of the general population.
Telomere Length Among the Elderly and Oldest-Old
Authors: Bischoff Claus , Graakjaer Jesper , Petersen Hans Christian , Jeune Bernard , Bohr Vilhelm A. , Koelvraa Steen , Christensen Kaare
Published: May 2007

Human chromosomes terminate in a number of repeats of the sequence TTAGGG. At birth, each chromosome end is equipped with approximately 15 kb of telomere sequence, but this sequence is shortened during each cell division. In cell cultures telomere shortening is associated with senescence, a phenomenon that has also been observed in normal adult tissues, indicating that telomere loss is associated with organismal ageing. Previous work has established that the rate of telomere loss in humans is age dependent, and recent work shows a sex-specific difference in telomere length and shortening in individuals over the age span of 20 to 75 years. Here, terminal restriction fragment lengths on DNA purified from whole blood were measured to examine the mean telomere length in a cross-sectional cohort of 816 Danish individuals of age 73 to 101 years. In this age group, females show a linear correlation between telomere length and age, whereas the pattern tends to be nonlinear (quadratic in age) for males. This difference in telomere length dynamics between the 2 sexes may be caused by several different mechanisms, including differences in selection by mortality, differences in leukocyte population or different telomerase expression pattern.
Comorbidity Between ADHD and Symptoms of Bipolar Disorder in a Community Sample of Children and Adolescents
Authors: Reich Wendy , Neuman Rosalind J. , Volk Heather E. , Joyner Cynthia A. , Todd Richard D.
Published: May 2007

The prevalence and frequency of comorbidity of possible bipolar disorder was examined with attention-deficit hyperactivity disorder (ADHD) in a nonreferred population of twins. Children and adolescents aged 7 to 18 years with a history of manic symptoms were identified from a population-based twin sample obtained from state birth records (n = 1610). The sample was enriched for ADHD; however, there was also a random control sample (n = 466), which allowed a look at the population prevalence of the disorder. Juveniles with threshold or below threshold manic episodes were further assessed for comorbidity with Diagnostic and Statistical Manual of Mental Disorders (4th ed.; DSM-IV; American Psychiatric Association, 1994) and population-defined ADHD subtypes (from latent class analysis) using Fisher's exact test. Nine juveniles who exhibited DSM-IV manic (n = 1), hypomanic (n = 2) or below threshold episodes (n = 6) were identified. The population prevalence of broadly defined mania in the random sample was 0.2%. The possible manic episodes showed significant comorbidity with population-defined severe combined and talkative ADHD subtypes. It can be concluded that there is a significant association of bipolar symptoms with two population-defined subtypes of ADHD. Episodes of possible bipolar disorders as defined by DSM-IV are uncommon in this nonreferred sample. Children and adolescents with ADHD appear to be only modestly at increased risk for bipolar disorders.
Genetic Contributions to Subtypes of Aggression
Authors: Ligthart Lannie , Bartels Meike , Hoekstra Rosa A. , Hudziak James J. , Boomsma Dorret I.
Published: May 2007

Boys and girls may display different styles of aggression. The aim of this study was to identify subtypes of aggression within the Child Behavior Checklist (CBCL) aggression scale, and determine their characteristics for both sexes. Maternal CBCL ratings of 7449 7-year-old twin pairs were analyzed using principal components analyses to identify sub- types of aggression, and structural equation modeling to carry out genetic analyses. Two aggression subtypes were identified: relational and direct aggression. The correlation between these subtypes was .58 for boys and .47 for girls. Boys had higher mean scores for both subtypes of aggression, but sex differences were largest for direct aggression. For relational aggression, 66% of the variance was due to additive genetic influences, 16% to shared environment and 18% to nonshared environment. For direct aggression, additive genetic effects accounted for 53% of the variance in males and 60% in females, shared environment explained 23% of the variance in males and 13% in females, and nonshared environmental effects explained 24% of the variance in males and 27% in females. Covariance between the aggression subtypes was mostly accounted for by additive genetic (55% for boys, 58% for girls) and shared environmental influences (33% for boys, 30% for girls). Direct and relational aggression were both influenced by one underlying set of shared environmental factors, but only partly by the same genes (the genetic correlation was .54 for boys and .43 for girls). These findings may have implications for how aggressive behavior should be assessed in boys and girls.
Limitations of DSM-IV Operationalizations of Alcohol Abuse and Dependence in a Sample of Australian Twins
Authors: Lynskey Michael T. , Nelson Elliot C. , Neuman Rosalind J. , Bucholz Kathleen K. , Madden Pamela A. F. , Knopik Valerie S. , Slutske Wendy , Whitfield John B. , Martin Nicholas G. , Heath Andrew C.
Published: May 2007

Alcohol abuse and dependence are among the most common psychiatric conditions identified in epidemiological surveys of the general population. The aim of this article is to examine the psychometric properties of Diagnostic and Statistical Manual of Mental Disorders, (4th ed.; DSM-IV; American Psychiatric Association, 1994) criteria for alcohol abuse and dependence using latent class analysis (LCA). Six thousand two hundred and sixty-five young Australian twins (median age 30 years) were interviewed by telephone between 1996 and 2000 using a modified version of the Semi-Structured Assessment for the Genetics of Alcoholism (SSAGA). DSM-IV symptoms of alcohol abuse and dependence were collected by structured diagnostic interview and analyzed using methods of LCA. LCA revealed a 4-class solution for women that classified individuals according to the severity of their alcohol- related problems: no/few problems (66.5%), heavy drinking (23.9%), moderate dependence (7.6%) and severe dependence (2.0%). Among men the preferred solution included 5 classes corresponding to no/few problems (46.4%), heavy drinking (34.3%), moderate dependence (12.2%), severe dependence (3.0%) and abuse (4.0%). Evidence of a male-specific class of alcohol-related problems corresponding to abuse partially supports the DSM conceptualization of alcohol use disorders but suggests that this conceptualization — and measurement — may need to be refined for women. Identification of a male- specific abuse class also has important implications for interventions and treatment as these individuals experienced significant alcohol-related problems and comprised approximately 21% of all men classified with an alcohol use disorder.
Multivariate Genetic Analysis of Academic Skills of the Queensland Core Skills Test and IQ Highlight the Importance of Geneticg
Authors: Wainwright Mark A. , Wright Margaret J. , Luciano Michelle , Geffen Gina M. , Martin Nicholas G.
Published: May 2007

This study examined the genetic and environmental relationships among 5 academic achievement skills of a standardized test of academic achievement, the Queensland Core Skills Test (QCST; Queensland Studies Authority, 2003a). QCST participants included 182 monozygotic pairs and 208 dizygotic pairs (mean 17 years ± 0.4 standard deviation). IQ data were included in the analysis to correct for ascertainment bias. A genetic general factor explained virtually all genetic variance in the component academic skills scores, and accounted for 32% to 73% of their phenotypic variances. It also explained 56% and 42% of variation in Verbal IQ and Performance IQ respectively, suggesting that this factor is genetic g. Modest specific genetic effects were evident for achievement in mathematical problem solving and written expression. A single common factor adequately explained common environmental effects, which were also modest, and possibly due to assortative mating. The results suggest that general academic ability, derived from genetic influences and to a lesser extent common environmental influences, is the primary source of variation in component skills of the QCST.