bluuebunny/crossref_metadata_2025 huggingface dataset:
Charges dispersed over the permeation pathway determine the charge selectivity and conductance of a Cx32 chimeric hemichannel
Authors: Oh Seunghoon , Verselis Vytas K. , Bargiello Thaddeus A.
Published: March 2008

Previous studies have shown that charge substitutions in the amino terminus of a chimeric connexin, Cx32*43E1, which forms unapposed hemichannels in Xenopus oocytes, can result in a threefold difference in unitary conductance and alter the direction and amount of open channel current rectification. Here, we determine the charge selectivity of Cx32*43E1 unapposed hemichannels containing negative and/or positive charge substitutions at the 2nd, 5th and 8th positions in the N‐terminus. Unlike Cx32 intercellular channels, which are weakly anion selective, the Cx32*43E1 unapposed hemichannel is moderately cation selective. Cation selectivity is maximal when the extracellular surface of the channel is exposed to low ionic strength solutions implicating a region of negative charge in the first extracellular loop of Cx43 (Cx43E1) in influencing charge selectivity analogous to that reported. Negative charge substitutions at the 2nd, 5th and 8th positions in the intracellular N‐terminus substantially increase the unitary conductance and cation selectivity of the chimeric hemichannel. Positive charge substitutions at the 5th position decrease unitary conductance and produce a non‐selective channel while the presence of a positive charge at the 5th position and negative charge at the 2nd results in a channel with conductance similar to the parental channel but with greater preference for cations. We demonstrate that a cysteine substitution of the 8th residue in the N‐terminus can be modified by a methanthiosulphonate reagent (MTSEA‐biotin‐X) indicating that this residue lines the aqueous pore at the intracellular entrance of the channel. The results indicate that charge selectivity of the Cx32*43E1 hemichannel can be determined by the combined actions of charges dispersed over the permeation pathway rather than by a defined region that acts as a charge selectivity filter.
A technique for simultaneous measurement of Ca2+, FRET fluorescence and force in intact mouse small arteries
Authors: Wier W. Gil , Rizzo Mark A. , Raina Hema , Zacharia Joseph
Published: March 2008

FRET (Forster resonance energy transfer)‐based biosensor molecules are powerful tools to reveal specific molecular interactions in cells. Typically however, they are used in cultured cells that (inevitably) express different genes than their counterparts in intact organisms. In such cells it may be impossible to administer physiological stimuli and measure physiological outputs. Here, through the use of transgenic mice that express a FRET‐based myosin light chain kinase (MLCK) biosensor molecule, we report a technique for dynamically observing activation and regulation of MLCK within the smooth muscle cells of intact, functioning small arteries, together with measurement of arterial force production and intracellular [Ca2+].
Stretchable and Foldable Silicon Integrated Circuits
Authors: Kim Dae-Hyeong , Ahn Jong-Hyun , Choi Won Mook , Kim Hoon-Sik , Kim Tae-Ho , Song Jizhou , Huang Yonggang Y. , Liu Zhuangjian , Lu Chun , Rogers John A.
Published: March 2008

We have developed a simple approach to high-performance, stretchable, and foldable integrated circuits. The systems integrate inorganic electronic materials, including aligned arrays of nanoribbons of single crystalline silicon, with ultrathin plastic and elastomeric substrates. The designs combine multilayer neutral mechanical plane layouts and “wavy” structural configurations in silicon complementary logic gates, ring oscillators, and differential amplifiers. We performed three-dimensional analytical and computational modeling of the mechanics and the electronic behaviors of these integrated circuits. Collectively, the results represent routes to devices, such as personal health monitors and other biomedical devices, that require extreme mechanical deformations during installation/use and electronic properties approaching those of conventional systems built on brittle semiconductor wafers.
Long-term structural health monitoring of the Crowchild Trail Bridge
Authors: VanZwol Tim R. , Cheng J. J. Roger , Tadros Gamil
Published: March 2008

Steel-free deck design is a relatively new approach to bridge deck construction. Several steel-free deck bridges constructed in Canada exhibited satisfactory behaviour immediately after construction. However, the long-term health of many of these structures has not been investigated. Significant cracking has been observed in many of these structures after only a few years in service. Long-term structural health monitoring of these structures is key in determining their long-term performance and future adoption of this new technology. Structural health monitoring data were obtained from the steel-free deck of the Crowchild Trail Bridge during its first seven years in service. Field monitoring included ambient vibration tests, static and dynamic load tests, and deck crack mapping. Despite significant amounts of cracks in the concrete deck and barriers, the overall behaviour of the Crowchild Trail Bridge has remained satisfactory and consistent. Future steel-free deck designs should consider crack control to meet serviceability requirements.
Seismic retrofit of reinforced concrete circular columns using stainless steel wire mesh composite
Authors: Choi Jun-Hyeok
Published: March 2008

An experimental study on seismic retrofit of typical circular columns with lap splice details utilizing stainless steel wire mesh (SSWM) composites was conducted. One column without lap splices and two columns with different lap splice lengths were tested under “as-built” condition. Three columns retrofitted with SSWM were constructed and tested under reversed cyclic loading. Brittle failure was observed in the “as-built” model column due to the bond deterioration of the lap spliced longitudinal reinforcement. Retrofitted columns wrapped with SSWM composites in the potential plastic hinge region resulted in a stable hysteresis response with increased capacity and ductility. This study indicates that significant improvement in flexural strength and ductility can be achieved using this retrofitting method.
Asphalt modification with used lubricating oil
Authors: Villanueva Aaron , Ho Susanna , Zanzotto Ludo
Published: March 2008

The viability of used lubricating oil as an asphalt modifier was studied, with the enhancement of the low-temperature grade as the specific goal. Used oil modification was found to improve the Superpave low-temperature performance grade (PG), but at the expense of the high-temperature PG grade. When evaluated according to the Superpave MP1 specification, the low-temperature grade of the modified asphalt was not significantly improved due to failure of the bending beam rheometer (BBR) test’s m value. When evaluated according to the Superpave MP1a specification, the modified asphalt overall PG grade temperature spread remained essentially constant, varying only by approximately two degrees. The asphalt took as much as 12% of oil and still had less than the maximum limit of 1.0% rolling thin film oven test (RTFOT) mass loss (emissions). However, the oil may possibly have a detrimental effect on the asphalt quality, such as reduced adhesiveness to the aggregates, leading to stripping and raveling. The field performance test should be checked before considering lubricating oil as a modifier.
Accumulation of frazil ice along a river bend
Authors: Sui Jueyi , Wang Jun , Balachandar Ram , Sun Zhaochu , Wang Desheng
Published: March 2008

This paper discusses the role of transverse currents on frazil ice accumulation along a river bend. To this end, field observations of a frazil ice jam along the ShiYaoBu bend reach of the Yellow River, in China, and a model study in the laboratory were carried out. Field measurements of flow velocities verified that there are two transverse circulations under an ice cover. The characteristics of frazil ice accumulation along a river bend have been discussed. The laboratory model study shows that the transverse accumulation of frazil ice depends not only on the hydraulic variables, such as Froude number, but also on the central angle of the river bend (inclined to the entrance cross section). Equations describing the transverse accumulation of frazil ice along a bend have been established. The dependency of the accumulation thickness in the longitudinal direction on the Froude number and ice discharge has been derived.
Improving road network databases by integrating a geographic information system and digital imagery
Authors: Abdalla M. , Easa Said M.
Published: March 2008

Road lighting information is an important record in road network databases. It has been frequently observed that such data are either missing or not updated due to the high data collection cost using traditional methods. This paper presents a new methodology for identifying and (or) resolving missing and conflicting road lighting data in road network databases. The methodology is based on: (i) integrating the single-line road network (SLRN) in a geographic information system format with a road network database and (ii) integrating the SLRN with a collision database. Missing and conflicting lighting data are resolved using a semi-automatic method for extracting streetlight pole information. The integrated system can also identify inconsistencies related to short segments and segments with mixed illumination characteristics. Inconsistencies in the traffic volume database were also examined and the effect of data inconsistency on safety performance functions was evaluated. The proposed methodology represents an inexpensive, efficient tool for improving the quality of road network databases and associated road safety analysis.
Proposals for limit states torsional strength design of wide-flange steel members
Authors: Ashkinadze Konstantin
Published: March 2008

This paper addresses the design of wide-flange steel members subjected to torsional forces as well as axial forces and moments about their strong and weak axes. The current Canadian steel design standard (CSA S16–01) gives no specific guidance on methodology with respect to torsional design. Codes of other countries (American, British, Australian) provide useful insight but are different in format from the Canadian standard and cannot be used directly in conjunction with it. Specialized second-order finite element programs have the capacity for torsional analysis, but are too complicated and costly to use in design practice. There is, therefore, a need for a practical design method that would allow engineers to account for the effects of torsion simply and accurately. This paper, written by a practicing design engineer, suggests a number of approaches that, subject to discussion and approval by experts in the field, could constitute the basis for design of steel members in torsion.
Ultra-high performance fibre reinforced concrete mix design in central Canada
Authors: Habel Katrin , Charron Jean-Philippe , Braike Shadi , Hooton R. Douglas , Gauvreau Paul , Massicotte Bruno
Published: March 2008

The mix design of ultra-high performance fibre reinforced concretes (UHPFRC) produced with locally available materials in Quebec and Ontario is presented. The procedure and results of the optimization of self-consolidating UHPFRC are discussed. The characterization of the retained mixes is presented with regards to strength, heat of hydration, shrinkage, chloride ion permeability, and freeze–thaw resistance. The results show that it is possible to produce self-consolidating UHPFRC with the targeted properties for use in precast products and in situ applications without requiring heat or pressure treatment during curing.
Dose-response effect of a β3-adrenergic receptor agonist, solabegron, on gastrointestinal transit, bowel function, and somatostatin levels in health
Authors: Grudell April B. M. , Camilleri Michael , Jensen Kim L. , Foxx-Orenstein Amy E. , Burton Duane D. , Ryks Michael D. , Baxter Kari L. , Cox Donna S. , Dukes George E. , Kelleher Dennis L. , Zinsmeister Alan R.
Published: March 2008

β3-Adrenoceptors(β3-AR) are expressed by cholinergic myenteric neurons and β3-AR agonists are effective in experimental models of diarrhea. Our aim was to explore the effects of a β3-AR agonist, solabegron, on gastrointestinal transit, safety, bowel function, plasma somatostatin, and solabegron pharmacokinetics (PK) following single and multiple doses. In a single-center, double-blind, parallel-group trial, 36 healthy volunteers were randomized to oral solabegron (50 or 200 mg twice daily) or placebo. Transit was measured by a validated method (99mTc-labeled egg meal and 111In charcoal delivered to the colon via delayed-release capsule). Stool frequency, form, and ease of passage were measured on a validated daily diary; plasma somatostatin by radioimmunoassay and plasma solabegron and its active metabolite by validated liquid chromatography-tandem mass spectroscopy analysis followed by PK analysis using noncompartmental methods. There were no overall or dose-related effects of solabegron on gastric, small bowel, or colonic transit, plasma somatostatin levels, stool frequency, form, or ease of passage in healthy volunteers. Solabegron and active metabolite exposures (area under the curve and maximum serum concentration) at both dose levels were consistent with PK at similar doses in previous phase I studies. We concluded that 7 days of the β3-AR agonist, solabegron, 50 or 200 mg twice daily, did not significantly alter gastrointestinal or colonic transit or bowel function. In this study, medication was generally well tolerated with few adverse events reported and no clinically significant changes in vital signs observed. Further studies on clinical efficacy, visceral sensitivity, and gastrointestinal transit are required in irritable bowel syndrome patients.
Selective expansion of the β-cell compartment in the pancreas of keratinocyte growth factor transgenic mice
Authors: Wagner Martin , Koschnick Stefan , Beilke Sven , Frey Melanie , Adler Guido , Schmid Roland M.
Published: March 2008

Epithelial-mesenchymal interactions are essential for growth, differentiation, and regeneration of exocrine and endocrine cells in the pancreas. The keratinocyte growth factor (KGF) is derived from mesenchyme and has been shown to promote epithelial cell differentiation and proliferation in a paracrine fashion. Here, we have examined the effect of ectopic expression of KGF on pancreatic differentiation and proliferation in transgenic mice by using the proximal elastase promoter. KGF transgenic mice were generated following standard procedures and analyzed by histology, morphometry, immunohistochemistry, Western blot analysis, and glucose tolerance testing. In KGF transgenic mice, the number of islets, the average size of islets, and the relation of endocrine to exocrine tissue are increased compared with littermate controls. An expansion of the β-cell population is responsible for the increase in the endocrine compartment. Ectopic expression of KGF results in proliferation of β-cells and pancreatic duct cells most likely through activation of the protein kinase B (PKB)/Akt signaling pathway. Glucose tolerance and insulin secretion are impaired in transgenic animals. These results provide evidence that ectopic expression of KGF in acinar cells promotes the expansion of the β-cell lineage in vivo through activation of the PKB/Akt pathway. Furthermore, the observed phenotype demonstrates that an increase in the β-cell compartment does not necessarily result in an improved glucose tolerance in vivo.
Tumor necrosis factor-α directly stimulates the overproduction of hepatic apolipoprotein B100-containing VLDL via impairment of hepatic insulin signaling
Authors: Qin Bolin , Anderson Richard A. , Adeli Khosrow
Published: March 2008

Insulin-resistant states are commonly associated with both increased circulating levels of tumor necrosis factor (TNF)-α and hepatic overproduction of very low density lipoproteins (VLDL). Here, we provide evidence that increased TNF-α can directly stimulate the hepatic assembly and secretion of apolipoprotein B (apoB) 100-containing VLDL1, using the Syrian golden hamster, an animal model that closely resembles humans in hepatic VLDL-apoB100 metabolism. In vivo TNF-α infusion for 4 h in chow-fed hamsters induced whole-body insulin resistance on the basis of euglycemic hyperinsulinemic clamp studies. Immunoprecipitation and immunoblotting analysis of livers from TNF-α-treated hamsters indicated decreased tyrosine phosphorylation of insulin receptor (IR)-β, IR substrate-1 (Tyr), Akt (Ser473), p38, ERK1/2, and JNK but increased serine phosphorylation of IRS-1 (Ser307) and Shc. TNF-α infusion also significantly increased hepatic production of total circulating apoB100 and VLDL-apoB100 in both fasting and postprandial (fat load) states. Ex vivo experiments, using cultured primary hepatocytes from hamsters, also showed TNF-α-induced VLDL-apoB100 oversecretion, an effect that was blocked by TNF receptor 2 antibody. Unexpectedly, TNF-α decreased the sterol regulatory element-binding protein-1c mass and mRNA levels but significantly increased microsomal triglyceride transfer protein mass and mRNA levels in primary hepatocytes. In summary, these data provide direct evidence that TNF-α induces whole-body insulin resistance and impairs hepatic insulin signaling accompanied by overproduction of apoB100-containing VLDL particles, an effect likely mediated via TNF receptor 2.
STAT-3 regulates surfactant phospholipid homeostasis in normal lung and during endotoxin-mediated lung injury
Authors: Ikegami Machiko , Falcone Angelica , Whitsett Jeffrey A.
Published: March 2008

Acute lung injury associated with surfactant deficiency remains a major cause of pulmonary morbidity and mortality. Since signal transducer and activator of transcription-3 (STAT-3) plays an important role in protecting respiratory epithelial cells during injury, we hypothesized that STAT-3 may regulate gene expression in type II cells that mediate surfactant phospholipid synthesis. Conditional deletion of Stat-3 in respiratory epithelial cells in the lung of transgenic mice ( Stat-3Δ/Δmice) decreased surfactant phospholipid synthesis and secretion. Deletion of Stat-3 was associated with decreased expression of Akt2, Srebf-1, and other genes expressed in type II cells that may influence surfactant phospholipid synthesis ( Glut-1, Slc34a2, Gpam, Acox2, and Cds2). Stat-3Δ/Δmice were more susceptible to intratracheal lipopolysaccharide (LPS). Saturated phosphatidylcholine and surfactant protein B levels were significantly decreased in bronchoalveolar lavage fluid from LPS-treated Stat-3Δ/Δmice. Alveolar capillary leak, proinflammatory cytokine expression, and perturbations of lung mechanics caused by LPS were exacerbated after deletion of STAT-3. STAT-3 plays a critical role in the regulation of surfactant lipid synthesis in the normal lung and during lung injury caused by LPS.
Escherichia coli Nissle 1917 Facilitates Tumor Detection by Positron Emission Tomography and Optical Imaging
Authors: Brader Peter , Stritzker Jochen , Riedl Christopher C. , Zanzonico Pat , Cai Shangde , Burnazi Eva M. , Ghani E.Rashid , Hricak Hedvig , Szalay Aladar A. , Fong Yuman , Blasberg Ronald
Published: March 2008

Purpose: Bacteria-based tumor-targeted therapy is a modality of growing interest in anticancer strategies. Imaging bacteria specifically targeting and replicating within tumors using radiotracer techniques and optical imaging can provide confirmation of successful colonization of malignant tissue.

Experimental Design: The uptake of radiolabeled pyrimidine nucleoside analogues and [18F]FDG by Escherichia coli Nissle 1917 (EcN) was assessed both in vitro and in vivo. The targeting of EcN to 4T1 breast tumors was monitored by positron emission tomography (PET) and optical imaging. The accumulation of radiotracer in the tumors was correlated with the number of bacteria. Optical imaging based on bioluminescence was done using EcN bacteria that encode luciferase genes under the control of an l-arabinose–inducible PBAD promoter system.

Results: We showed that EcN can be detected using radiolabeled pyrimidine nucleoside analogues, [18F]FDG and PET. Importantly, this imaging paradigm does not require transformation of the bacterium with a reporter gene. Imaging with [18F]FDG provided lower contrast than [18F]FEAU due to high FDG accumulation in control (nontreated) tumors and surrounding tissues. A linear correlation was shown between the number of viable bacteria in tumors and the accumulation of [18F]FEAU, but not [18F]FDG. The presence of EcN was also confirmed by bioluminescence imaging.

Conclusion: EcN can be imaged by PET, based on the expression of endogenous E. coli thymidine kinase, and this imaging paradigm could be translated to patient studies for the detection of solid tumors. Bioluminescence imaging provides a low-cost alternative to PET imaging in small animals.
Endometrial Glandular Dysplasia with Frequent p53 Gene Mutation: A Genetic Evidence Supporting Its Precancer Nature for Endometrial Serous Carcinoma
Authors: Jia Lin , Liu Yongjuan , Yi Xiaofang , Miron Alexander , Crum Christopher P. , Kong Beihua , Zheng Wenxin
Published: March 2008

Purpose: Endometrial glandular dysplasia (EmGD) has been recently proposed to be a putative precursor to endometrial serous carcinoma (ESC). The purpose of this study is to determine if EmGD is genetically linked to ESC and if it can be used for early detection.

Experimental Design: The tumor suppressor p53 gene was sequenced from serial samples of benign and neoplastic endometria with serous differentiation. The study group contained 15 neoplastic uteri and the control group had 12 age-matched benign uteri. A total of 139 informative samples were obtained, including 55 resting endometrium, 37 EmGD, 25 serous endometrial intraepithelial carcinoma (EIC), and 22 ESC. At least one representative section from each uterus was used for p53 immunohistochemical staining to correlate p53 overexpression with gene mutation status.

Results: The mutations of p53 were detected in 0%, 43%, 72%, and 96% in resting endometrium, EmGD, serous EIC, and ESC, respectively. More than 50% of the neoplastic uteri showed at least one identical p53 gene mutant among lesions of EmGD, serous EIC, and/or ESC. The majority of lesions showed overexpression of p53 protein, which was significantly correlated with p53 gene mutation (P < 0.01).

Conclusions: This genetic evidence strongly supports that EmGD represents the precancer of ESC or serous EIC. Mutation of p53 gene is probably one of the most important factors to initiate the endometrial serous carcinogenesis. Correct identification of EmGD will provide us an opportunity of early diagnosis and a potentially effective therapeutic modality to control ESC.
Thalassaemia and Glucose-6-Phosphate Dehydrogenase Screening in 13- to 14-Year-Old Students of the Sardinian Population: Preliminary Findings
Authors: Cao A. , Congiu R. , Sollaino M.C. , Desogus M.F. , Demartis F.R. , Loi D. , Cau M. , Galanello R.
Published: March 2008

Objectives: In this paper we describe the outline and results of a 7-year screening programme for thalassaemias and glucose-6-phosphate dehydrogenase (G6PD) deficiency in 13- to 14-year-old students from the Sardinian population. Method: This programme had several steps: formal education on thalassaemia, request of informed consent by parents, blood testing and genetic counselling. Results:Out of 63,285 subjects tested, 6,521 (10.3%) were heterozygotes for β-thalassaemia, 16,175 (25.6%) for α-thalassaemia and 101 were carriers of a haemoglobin variant. One thousand four hundred and twenty (16.4%) males were hemizygotes for G6PD deficiency and 1,893 (20.6%) females were heterozygotes. Conclusion: The uptake of the programme was remarkably high and homogeneous across the island, indicating and confirming a great interest of the Sardinian population in any initiative directed at the prevention of homozygous β-thalassaemia.
Alpha-Thalassaemia in Association with Beta-Thalassaemia Patients in Malaysia: A Study on the Co-Inheritance of Both Disorders
Authors: Wee Y.C. , Tan K.L. , Kuldip K. , Tai K.S. , George E. , Tan P.C. , Chia P. , Subramaniam R. , Yap S.F. , Tan J.A.M.A.
Published: March 2008

Background/Aims: Individuals with double heterozygosity for α- and β-thalassaemia and heterozygous β-thalassaemia show a similar haematological picture. Co-inheritance of α- and β-thalassaemia in both partners may result in pregnancies with either Hb Bart’s hydrops foetalis or β-thalassaemia major, or pregnancies with both disorders. Methods: The co-inheritance of α-thalassaemia in 322 β-thalassaemia carriers in Malaysia was studied. Results: The frequency of α-thalassaemia in the β-thalassaemia carriers was 12.7% (41/322), with a carrier frequency of 7.8% for the SEA deletion, 3.7% for the -α3.7 deletion, 0.9% for Hb Constant Spring and 0.3% for the -α4.2 deletion. Conclusion: Double heterozygosity for α- and β-thalassaemia was confirmed in 5 out of the 41 couples and the risk of the fatal condition Hb Bart’s hydrops foetalis was confirmed in two of these couples. Detection of the Southeast Asian (SEA) deletion in the Malaysian Malays in this study confirms that Hb Bart’s hydrops foetalis can occur in this ethnic group. Results of this study have provided new information on the frequency and different types of α-thalassaemia (--SEA, -α3.7 and -α4.2 deletions, Hb Constant Spring) in Malaysian β-thalassaemia carriers.
Cytochrome P450 Enzyme Polymorphism Frequency in Indigenous and Native American Populations: A Systematic Review
Authors: Jaja Cheedy , Burke Wylie , Thummel Ken , Edwards Karen , Veenstra David L.
Published: March 2008

Objective: The purpose of our study was to evaluate the evidence on the prevalence of cytochrome P450 enzyme polymorphisms as potential genetic factors influencing drug efficacy and safety in the indigenous populations of the American hemispheres. Methods: We conducted a systematic review of studies published between 1985 and 2006 using the Pubmed database. Results: We identified only 10 original research studies on CYP2A6, CYP2D6, CYP2C9, CYP2C19 and CYP2E1 in 13 indigenous American populations. Interethnic differences in the frequency of CYP450 genetic variants existed both among the examined indigenous populations and in comparison with African, Asian and European populations. Conclusions: There are surprisingly few data on CYP450 enzyme polymorphisms in indigenous American populations, and it is difficult to draw any clear inferences about how these populations might be expected to respond to drugs in relation to other racial or ethnic groups. This lack of information could create a barrier to the use of pharmacogenetic testing in these populations. Collaborative partnerships between indigenous communities and researchers are needed to avail the clinical benefits of CYP450 enzyme polymorphism testing to indigenous populations.
Genetic Heterogeneity in a Susceptible Region for Essential Hypertension among Demographically Different Local Populations in Japan
Authors: Kumada Maki , Lkhagvasuren Munkhtulga , Utsumi Nanami , Omi Toshinori , Gotoh Takaya , Kamesaki Toyomi , Okuda Hiroshi , Kajii Eiji , Iwamoto Sadahiko
Published: March 2008

Objective: The aim of the study was to investigate genetic heterogeneity among local Japanese populations. Methods: We performed a single nucleotide polymorphism (SNP) study of four demographically distinct local populations (population 1: a large city; population 2: isolated islands; populations 3 and 4: rural areas). Seventy SNPs in a region spanning 5 Mb of chromosome 17 known to be a candidate region for essential hypertension were genotyped and linkage disequilibrium analyses were performed. Results: Statistical analyses of SNP allele frequencies and haplotype distribution showed significant divergence among the populations, mostly between population 2 and the other populations. Pairwise D′ declined with increasing population size, and smaller populations retained a high linkage disequilibrium. Conclusion: Population 2 is likely to have a different ancestry from the majority of the Japanese population, whereas the heterogeneity among the other populations may result from differences in population size or geographic background.
Educational Needs in Genetic Medicine: Primary Care Perspectives
Authors: Trinidad Susan B. , Fryer-Edwards Kelly , Crest Anthony , Kyler Penny , Lloyd-Puryear Michele A. , Burke Wylie
Published: March 2008

Background/Aims: This study was performed to identify primary care physicians’ (PCPs) attitudes toward genetic medicine and their perceived needs for education in this area. Methods: Semistructured telephone interviews with 24 PCPs in the northwestern United States. Results: PCPs are interested in learning more about who should receive genetic testing and what tests are available. Training in counseling and risk communication is desired, as are ‘just-in-time’ resources to guide clinical decisions. Conclusions: PCPs are eager to learn about genetic medicine; however, their priorities may differ in emphasis from those put forward by genetics experts. Future educational efforts would do well to build on PCPs’ prior knowledge base, highlight the clinical relevance of genetic medicine to primary care practice, and emphasize ‘red flags’: cues to alert PCPs to a potential genetic contribution.
Women’s Motives for Not Participating in Preconception Counseling: Qualitative Study
Authors: Hosli E.J. , Elsinga J. , Buitendijk S.E. , Assendelft W.J.J. , van der Pal-de Bruin K.M.
Published: March 2008

Aims: Information about risk factors and preventive measures given before conception is estimated to prevent 15–35% of adverse pregnancy outcomes. We aimed to identify women’s motives for not responding to an invitation for preconception counseling (PCC) from their general practitioner. Methods: A purposive sample of 11 women who did not respond to an invitation for PCC and who became pregnant within 1 year was interviewed. Results: Three key themes influencing nonresponse emerged from the data: perceived knowledge, perceived lack of risk and a misunderstanding of the aim of PCC. Conclusion: For successful future implementation of PCC, a more tailored approach may be necessary for certain (groups of) women, addressing the reasons why women do not consider themselves part of the target group for PCC.
Participant Characteristics That Influence Consent for Genetic Research in a Population-Based Survey: The Baltimore Epidemiologic Catchment Area Follow-Up
Authors: Mezuk Briana , Eaton William W. , Zandi Peter
Published: March 2008

Background: The purpose of this study is to investigate the sociodemographic and health characteristics associated with the willingness to donate a DNA sample, and consent to testing and long-term storage of that sample, among participants in a longitudinal community-based survey. Sample: Eighty-three percent of the 1,071 participants interviewed in 2004/5 agreed to donate a biological specimen (blood or buccal). Results: Age was consistently inversely associated with the willingness to allow genetic testing (OR 0.97; p < 0.05), but was unrelated to the willingness to donate or allow storage.There was no association between race and the consent to donate a specimen, but Blacks were less likely to consent to DNA storage for future research as compared with members of other racial groups (OR 0.50; p < 0.01). Four conditions were listed on the consent form as relevant to the genes targeted for assay. Participants with a family history of 1 or more of these conditions were more likely to donate than those without (OR 1.68; p < 0.01). Participants with a personal history of 1 of the 4 conditions listed were not more or less likely to donate, allow testing or allow storage than respondents without such a history. Conclusions: Sociodemographic characteristics were unrelated to the willingness to donate a biological sample. Age, but not race, sex or education, was related to consent to genetic testing. Race, but not age, sex or education, was related to consent to storage. A family history of health conditions listed as relevant to the assays being requested was related to the willingness to donate. Factors that affect the willingness to donate a biological sample in an epidemiologic study are not the same as those associated with the willingness to allow genetic testing or storage of that sample for unspecified future research.
Review and Evaluation of Methods Correcting for Population Stratification with a Focus on Underlying Statistical Principles
Authors: Tiwari Hemant K. , Barnholtz-Sloan Jill , Wineinger Nathan , Padilla Miguel A. , Vaughan Laura K. , Allison David B.
Published: March 2008

When two or more populations have been separated by geographic or cultural boundaries for many generations, drift, spontaneous mutations, differential selection pressures and other factors may lead to allele frequency differences among populations. If these ‘parental’ populations subsequently come together and begin inter-mating, disequilibrium among linked markers may span a greater genetic distance than it typically does among populations under panmixia [see glossary]. This extended disequilibrium can make association studies highly effective and more economical than disequilibrium mapping in panmictic populations since less marker loci are needed to detect regions of the genome that harbor phenotype-influencing loci. However, under some circumstances, this process of intermating (as well as other processes) can produce disequilibrium between pairs of unlinked loci and thus create the possibility of confounding or spurious associations due to this population stratification. Accordingly, researchers are advised to employ valid statistical tests for linkage disequilibrium mapping allowing conduct of genetic association studies that control for such confounding. Many recent papers have addressed this need. We provide a comprehensive review of advances made in recent years in correcting for population stratification and then evaluate and synthesize these methods based on statistical principles such as (1) randomization, (2) conditioning on sufficient statistics, and (3) identifying whether the method is based on testing the genotype-phenotype covariance (conditional upon familial information) and/or testing departures of the marginal distribution from the expected genotypic frequencies.
Likelihood-Based Association Analysis for Nuclear Families and Unrelated Subjects with Missing Genotype Data
Authors: Dudbridge Frank
Published: March 2008

Missing data occur in genetic association studies for several reasons including missing family members and uncertain haplotype phase. Maximum likelihood is a commonly used approach to accommodate missing data, but it can be difficult to apply to family-based association studies, because of possible loss of robustness to confounding by population stratification. Here a novel likelihood for nuclear families is proposed, in which distinct sets of association parameters are used to model the parental genotypes and the offspring genotypes. This approach is robust to population structure when the data are complete, and has only minor loss of robustness when there are missing data. It also allows a novel conditioning step that gives valid analysis for multiple offspring in the presence of linkage. Unrelated subjects are included by regarding them as the children of two missing parents. Simulations and theory indicate similar operating characteristics to TRANSMIT, but with no bias with missing data in the presence of linkage. In comparison with FBAT and PCPH, the proposed model is slightly less robust to population structure but has greater power to detect strong effects. In comparison to APL and MITDT, the model is more robust to stratification and can accommodate sibships of any size. The methods are implemented for binary and continuous traits in software, UNPHASED, available from the author.
The Future Is Now – Will the Real Disease Gene Please Stand Up?
Authors: Martin E.R. , Schmidt M.A.
Published: March 2008

The transmission/disequilibrium test (TDT) [Spielman et al.: Am J Hum Genet 1993;52:506–516] has been postulated as the future of gene mapping for complex diseases, provided one is able to genotype a dense enough map of markers across the genome. Risch and Merikangas [Science 1996;273:1516–1517] suggested a million-marker screen in affected sibpair (ASP) families, demonstrating that the TDT is a more powerful test of linkage than traditional linkage tests based on allele-sharing when there is also association between marker and disease alleles. While the future of genotyping has arrived, successes in family-based association studies have been modest. This is often attributed to excessive false positives in candidate gene studies. This problem is only exacerbated by the increasing numbers of whole genome association (WGA) screens. When applied in ASPs, the TDT statistic, which assumes transmissions to siblings are independent, is not expected to have a constant variance in the presence of variable linkage. This results in generally more extreme statistics, hence will further aggravate the problem of having a large number of positive results to sort through. So an important question is how many positive TDT results will show up on a chromosome containing a disease gene due only to linkage, and will they obfuscate the true disease gene location. To answer this question we combined theory and computer simulations. These studies show that in ASPs the normal version of the TDT statistic has a mean of 0 and a variance of 1 in unlinked regions, but has a variance larger than 1 in linked regions. In contrast, the pedigree disequilibrium test (PDT) statistic adjusts for correlation between siblings due to linkage and maintains a constant variance of 1 at unassociated markers irrespective of linkage. The TDT statistic is generally larger than the PDT statistic across linked regions. This is true for unassociated as well as associated markers. To compare the two tests we ranked both statistics at the disease locus, or an associated marker, among statistics at all other markers. The TDT did better job than PDT placing the score of the associated marker near the top. Though, strictly speaking, the TDT in ASPs should be interpreted as a test of linkage and not a test of association, there is a good chance that if a marker stands out, the marker is associated as well as linked. In conclusion, our results suggest that TDT is an effective screening tool for WGA studies, especially in multiplex families.
Depression and Heart Disease: Therapeutic Implications
Authors: Somberg Trudie C. , Arora Rohit R.
Published: March 2008

The consequences of depression and coronary artery disease (CAD) were reviewed in the literature. The comorbidity of depression and CAD results in an increased cardiovascular mortality. We reviewed possible explanations for this increased morbidity, which include: toxicity of tricyclic antidepressants that can cause cardiac arrhythmias, abnormalities in platelet function leading to increased platelet aggregation due to abnormalities in serotonin in the platelet (an abnormality that possibly causes depression in the central nervous system), diffuse atherosclerosis causing central nervous system abnormalities including depression (vascular depression), as well as the possibility that depressed patients are less compliant with their medications and physician-directed health recommendations. Recent reports of selective serotonin reuptake inhibitors (SSRIs) causing a reduced cardiovascular mortality may be related to serotonin platelet abnormalities in depressed patients that are effectively treated by SSRIs (SADHART and ENRICHD trial). It is possible that these trials reveal a mechanism of depression that also effects platelet function and can be improved with SSRI therapy, suggesting a preferential therapeutic pathway for the treatment of depressed patients with CAD.
Efficacy of a Home-Based Exercise Program for Orthotopic Heart Transplant Recipients
Authors: Wu Ying-Tai , Chien Chen-Lin , Chou Nai-Kuan , Wang Shoei-Shen , Lai Jin-Shin , Wu Yen-Wen
Published: March 2008

Background:A hospital-based cardiac rehabilitation program can significantly improve the cardiopulmonary endurance and quality of life (QOL) in patients after orthotopic heart transplantation (OHT). Home-based programs for these patients have advantages of low cost and high accessibility, but little is known about their efficacy. This prospective study was designed to evaluate the effect of an 8-week home-based exercise program on muscular strength and endurance of lower limbs, aerobic capacity and QOL in OHT recipients. Methods:Thirty-seven OHT recipients were randomized into exercise (n = 14) or control (n = 23) groups. Exercise group subjects were to exercise at least 3 times a week for 8 weeks. Each subject was evaluated by Cybex testing of right quadriceps strength and endurance, 1-min sit-to-stand test, a symptom-limited maximal exercise test and QOL assessment before and after 8 weeks. Results: Subjects in the exercise group improved significantly in sit-to-stand test, fatigue index of the right quadriceps, maximal workload achieved and physical domain of QOL compared to controls after 8 weeks, regardless of older age and lower value for sit-to-stand test at baseline. Conclusions: OHT recipients can significantly improve their muscular endurance, sit-to-stand test scores and QOL after a medically directed home-based exercise program.
Gastrointestinal Emergencies in Cardiac Surgery
Authors: Vassiliou Ioannis , Papadakis Emmanouel , Arkadopoulos Nikolaos , Theodoraki Kassiani , Marinis Athanasios , Theodosopoulos Theodosios , Palatianos George , Smyrniotis Vassilios
Published: March 2008

Objectives: The aim of this study is to retrospectively analyze risk factors, diagnosis and management of gastrointestinal (GI) complications following cardiac operations. Methods: Patients who developed GI complications after a cardiac operation were studied. Anesthesia protocols, techniques of cardiac surgery, potential risk factors, complications and medical and surgical interventions were reviewed and analyzed. Results: Out of 3,724 consecutive patients undergoing heart operations during an 8-year period, 33 patients developed GI complications. Eleven patients developed ischemic colitis, 8 cholecystitis, 6 GI bleeding, 4 liver failures, 3 pancreatitis and 1 esophageal hernia. Patients with GI complications had a lower mean ejection fraction compared to patients not developing these complications (45.1 vs. 49.7%, p < 0.01). Also, patients undergoing an urgent cardiac operation were significantly more likely (3.49 times more likely) to develop GI complications postoperatively. Of the 33 affected patients, 18 were treated conservatively and 15 underwent an emergency exploratory laparotomy. Overall mortality was 12% (4 patients). Conclusions: Intestinal ischemia and cholecystitis appear to be the most frequent GI complications associated with cardiac surgery. Risk factors include a low ejection fraction and an urgent cardiac operation. Early recognition and treatment of these complications may reduce mortality.
Ischemia Induced by Transesophageal Atrial Pacing Stress Echocardiography Predicts Long-Term Mortality
Authors: Anselmi Maurizio , Pilati Mara , Golia Giorgio , Agostoni Pierfrancesco , Quintarelli Silvia , Rossetti Lucia , Vassanelli Corrado
Published: March 2008

Objectives: It was the aim of this study to investigate the long-term value of transesophageal atrial pacing in predicting death in patients with known or suspected coronary artery disease. Background: Exercise, dobutamine and dipyridamole stress echocardiography are all effective in predicting cardiac death. Transesophageal atrial pacing stress echocardiography (TAPSE) is a safe alternative to pharmacologic tests, but no information is available on prognosis with TAPSE. Methods: One thousand and ten TAPSE were performed in 975 consecutive patients. TAPSE was feasible in 970 tests (96%); after exclusion of the 35 patients with more than 1 TAPSE and those 42 lost at follow-up (mean 4.5 ± 3.7 years, median 6 years), the final population consisted of 857 patients (675 males, 58 ± 9 years old). The Cox model was used to analyze the association of clinical, resting and TAPSE variables with cardiac death. Results: TAPSE was abnormal in 281 (32%) patients. There were 46 cardiac-related deaths (5%), 25 among the 281 patients with an abnormal test (8.9%) and 21 among the 576 patients with a normal test (3.6%). The predictors of cardiac death were age, previous revascularization, resting wall motion score index and its variation during TAPSE. Abnormal TAPSE significantly increases the value of models predicting cardiac death. Moreover, cardiac mortality increased progressively with the extent of the induced ischemia. Conclusions: TAPSE is a useful tool in predicting death in patients with known or suspected coronary artery disease and might be considered an alternative to pharmacologic stressors.
Differential Index: A Simple Time Domain Heart Rate Variability Analysis with Prognostic Implications in Stable Angina Pectoris
Authors: Björkander Inge , Forslund Lennart , Kahan Thomas , Ericson Mats , Held Claes , Rehnqvist Nina , Hjemdahl Paul
Published: March 2008

Objectives: To examine the usefulness of time domain heart rate variability (HRV) measurements by a simple graphical method, the differential index (DI), in prognostic assessments of patients with chronic stable angina pectoris. Methods: HRV measurements in the time domain by DI were compared to conventional measurements of standard deviation of all normal-to-normal intervals (SDNN), percent of differences between adjacent normal RR intervals >50 ms (PNN50) and square root of the mean of the sum of squares of differences between adjacent normal RR intervals (RMSSD) from 24-hour ambulatory electrocardiographic recordings in 678 patients in the Angina Prognosis Study in Stockholm. The patients received double-blind treatment with metoprolol or verapamil. Main outcome measures were cardiovascular death or non-fatal myocardial infarction during follow-up (median 40 months). Results: Patients suffering cardiovascular death (n = 30) had lower DI, SDNN and PNN50 (all p < 0.001). In a multivariate Cox model, DI below median independently predicted cardiovascular death (p = 0.002), as did SDNN (p = 0.016) and PNN50 (p = 0.030), but not RMSSD (p = 0.10). The separation of survival curves was most pronounced and specificity was slightly better with DI. DI and PNN50 increased with metoprolol but not verapamil treatment. Short-term treatment effects were not related to prognosis. Conclusions: Low time domain HRV carries independent prognostic information regarding cardiovascular death in stable angina pectoris. The simple DI method provided equally good or better prognostic information than conventional, more laborious HRV methods.
Impact of Telemedical Care and Monitoring on Morbidity in Mild to Moderate Chronic Heart Failure
Authors: Morguet Andreas J. , Kühnelt Paul , Kallel Antje , Jaster Markus , Schultheiss Heinz-Peter
Published: March 2008

Objective: We investigated in a pilot study whether telemedicine is beneficial in mild to moderate chronic heart failure. Methods: A total of 128 patients with an ejection fraction ≤60% and NYHA class II or III chronic heart failure were evaluated. Thirty-two patients were enrolled prospectively in a staged telemedical service program. Ninety-six controls were matched 3:1 to each telemedicine patient. Results: Median follow-up was 307 days (range 104–459). All-cause hospitalization duration [317 vs. 693 days/100 patient years; relative risk (RR) 0.46; 95% confidence interval (CI) 0.37–0.58; p < 0.0001) and rate (38 vs. 77/100 patient years; RR 0.49; 95% CI 0.25–0.95; p = 0.034) as well as cardiac hospitalization duration (49 vs. 379 days/100 patient years; RR 0.13; 95% CI 0.08–0.23; p < 0.0001] were significantly lower, cardiac hospitalization rate (11 vs. 35/100 patient years; RR 0.31; 95% CI 0.11–1.02; p = 0.058) tended to be lower in the telemedicine compared with the control group. Conclusion: These preliminary data suggest that telemedical care and monitoring may reduce morbidity in patients with NYHA class II and III chronic heart failure.