Jeffrey L. Anderson, MD, FACC, FAHA, Chair 

Jonathan L. Halperin, MD, FACC, FAHA, Chair-Elect 

Alice K. Jacobs, MD, FACC, FAHA, Immediate Past Chair 2009–2011 [§§][1]

Sidney C. Smith, Jr, MD, FACC, FAHA, Past Chair 2006–2008 [§§][1]

Cynthia D. Adams, MSN, APRN-BC, FAHA[§§][1]

Nancy M

2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS guideline for the diagnosis and management of patients with stable ischemic heart disease: executive summary: a report of the American College of Cardiology Foundation/American Heart Association task force on practice guidelines, and the American College of Physicians, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons.

Warfarin is one of the most widely used anticoagulants in the world. Treatment is complicated by a large inter-individual variation in the dose needed to reach adequate levels of anticoagulation i.e. INR 2.0 – 3.0. The objective of this thesis was to evaluate which factors, mainly genetic but also non-genetic, that affect the response to warfarin in terms of required maintenance dose, efficacy and safety with special focus on warfarin dose prediction.Through candidate gene and genome-wide studies, we have shown that the genes CYP2C9 and VKORC1 are the major determinants of warfarin maintenance dose. By combining the SNPs CYP2C9 *2, CYP2C9 *3 and VKORC1 rs9923231 with the clinical factors age, height, weight, ethnicity, amiodarone and use of inducers (carbamazepine, phenytoin or rifampicin) into a prediction model (the IWPC model) we can explain 43 % to 51 % of the variation in warfarin maintenance dose. Patients requiring doses < 29 mg/week and doses ≥ 49 mg/week benefitted the most from pharmacogenetic dosing. Further, we have shown that the difference across ethnicities in percent variance explained by VKORC1 was largely accounted for by the allele frequency of rs9923231. Other novel genes affecting maintenance dose (NEDD4 and DDHD1), as well as the replicated CYP4F2 gene, have small effects on dose predictions and are not likely to be cost-effective, unless inexpensive genotyping is available.Three types of prediction models for warfarin dosing exist: maintenance dose models, loading dose models and dose revision models. The combination of these three models is currently being used in the warfarin treatment arm of the European Pharmacogenetics of Anticoagulant Therapy (EU-PACT) study. Other clinical trials aiming to prove the clinical validity and utility of pharmacogenetic dosing are also underway.The future of pharmacogenetic warfarin dosing relies on results from these ongoing studies, the availability of inexpensive genotyping and the cost-effectiveness of pharmacogenetic driven warfarin dosing compared with new oral anticoagulant drugs.

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Estimation of the warfarin dose with clinical and pharmacogenetic data

Background 
Neural stem cells are currently being investigated as potential therapies for neurodegenerative diseases, stroke, and trauma. However, concerns have been raised over the safety of this experimental therapeutic approach, including, for example, whether there is the potential for tumors to develop from transplanted stem cells.


Methods and Findings 
A boy with ataxia telangiectasia (AT) was treated with intracerebellar and intrathecal injection of human fetal neural stem cells. Four years after the first treatment he was diagnosed with a multifocal brain tumor. The biopsied tumor was diagnosed as a glioneuronal neoplasm. We compared the tumor cells and the patient's peripheral blood cells by fluorescent in situ hybridization using X and Y chromosome probes, by PCR for the amelogenin gene X- and Y-specific alleles, by MassArray for the ATM patient specific mutation and for several SNPs, by PCR for polymorphic microsatellites, and by human leukocyte antigen (HLA) typing. Molecular and cytogenetic studies showed that the tumor was of nonhost origin suggesting it was derived from the transplanted neural stem cells. Microsatellite and HLA analysis demonstrated that the tumor is derived from at least two donors.


Conclusions 
This is the first report of a human brain tumor complicating neural stem cell therapy. The findings here suggest that neuronal stem/progenitor cells may be involved in gliomagenesis and provide the first example of a donor-derived brain tumor. Further work is urgently needed to assess the safety of these therapies.

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Donor-Derived Brain Tumor Following Neural Stem Cell Transplantation in an Ataxia Telangiectasia Patient

Theodore G. Ganiats, A. Michael Lincoff, Eric D. Peterson, George J. Philippides, Pierre D. Adams, Charles R. Bridges, Donald E. Casey, Jr, Steven M. Ettinger, Francis M. Fesmire, 2012 Writing Committee Members, Hani Jneid, Jeffrey L. Anderson, R. Scott Wright, Cynthia Foundation/American Heart Association Task Force on Practice Guidelines Cardiology and Replacing the 2011 Focused Update): A Report of the American College of ST-Elevation Myocardial Infarction (Updating the 2007 Guideline − Unstable Angina/Non 2012 ACCF/AHA Focused Update of the Guideline for the Management of Patients With

Accf/aha task force members

A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, and the American College of Physicians, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons Published by Elsevier Inc. http://dx.doi.org/10.1016/j.jacc.2012.07.013

/pdf/2012-accf-aha-acp-aats-pcna-scai-sts-guideline-for-the-3rcj2i2kf5.pdf

2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS Guideline for the Diagnosis and Management of Patients With Stable Ischemic Heart Disease

Purpose To assess the intraoperator repeatability and interoperator reproducibility of central corneal thickness measurements by the Pentacam Scheimpflug imaging system (Oculus) and the optical low-coherence reflectometer (OLCR) pachymeter (Haag-Streit) and to compare them with those of ultrasound (US) pachymetry. Setting Assaf Harofe Medical Center Ophthalmology Outpatient Clinic, Zerifin, Israel. Methods Repeatability was determined from 10 successive measurements in each of 4 healthy patients. Reproducibility for the Pentacam Scheimpflug system was determined from measurements by 2 operators in each of 24 patients; in these 24 patients, central corneal thickness measurements were compared between the Pentacam and US pachymetry. For the OLCR pachymeter, reproducibility was determined from measurements by 2 operators in each of 16 patients, in whom central corneal thickness was also measured with the Pentacam. Results Mean coefficient of repeatability was 0.84% for the Pentacam Scheimpflug system and 0.33% for the OLCR pachymeter. For the Pentacam, the coefficient of interoperator reproducibility was 1.10% and the 95% limits of agreement were −10.2 μm to +11.9 μm. Mean difference between Pentacam and US was 6.09 μm. For the OLCR pachymeter, the coefficient of interoperator reproducibility was 0.59% and the 95% limits of agreement were −5.4 μm to +7.0 μm. Mean difference between central corneal thickness values obtained with the OLCR pachymeter and Pentacam Scheimpflug system was 1.7 μm. Conclusions Objective, noncontact measurement of central corneal thickness with the Pentacam Scheimpflug system and OLCR pachymeter was convenient and yielded excellent intraoperator repeatability and interoperator reproducibility. Central corneal thickness values obtained with the Pentacam were similar to those obtained with both the OLCR pachymeter and an US pachymeter. Further research is needed to corroborate whether central corneal thickness measurements by the Pentacam and OLCR devices can be used interchangeably and are more clinically useful than US pachymetry.

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Central corneal thickness measurement with the Pentacam Scheimpflug system, optical low-coherence reflectometry pachymeter, and ultrasound pachymetry

A coding VKORC1 Asp36Tyr polymorphism predisposes to warfarin resistance

Several polymorphisms in the ApoA5 gene emerged as important candidate genes in triglyceride metabolism. The aim of this study was to determine the associations between ApoA5 polymorphisms, plasma triglyceride concentrations and the presence of cardiovascular disease (CVD) in three ethnic origins. Genotypes for 15 single nucleotide polymorphisms (SNPs) were determined in 659 older adults (mean age 71±7 years) who immigrated to Israel or whose ancestors originated from East Europe (Ashkenazi), North Africa, Asia (Sephardic) or Yemen (Yemenite). The minor alleles of the four common SNPs (rs662799, rs651821, rs2072560 and rs2266788) are associated with an increase of 27–38% in triglyceride concentration among Ashkenazi and Yemenite Jews compared with the major alleles, but not among those of Sephardic origin. Conversely, among the Sephardic group, the presence of the minor allele in SNP rs3135506 compared with the major allele was associated with an increase of 34% in triglyceride concentration. The four SNPs were in significant linkage disequilibrium (D′=0.96–0.99), resulting in three haplotypes H1, H2 and H3, representing 98–99% of the population. Haplotype H2 was significantly associated with triglyceride concentration among Ashkenazi and Yemenite but not among Sephardic Jews. Conversely, haplotype H3 was associated with triglyceride concentration in Sephardic but not in Ashkenazi and Yemenite Jews. Ashkenazi carriers of H2 haplotype had a CVD odds ratio of 2.19 (95% CI: 1.05–4.58) compared with H1 (the most frequent), after adjustment for all other risk factors. These results suggest that different SNPs in ApoA5 polymorphisms may be associated with triglyceride concentration and CVD in each of these ethnic origins.

/pdf/different-effects-of-apolipoprotein-a5-snps-and-haplotypes-2vx4g45r3u.pdf

Different effects of apolipoprotein A5 SNPs and haplotypes on triglyceride concentration in three ethnic origins

BACKGROUND The physical activity questionnaire is typically chosen for population studies because it is practical and does not interfere with the behavior of the surveyed individual. This instrument can be adapted for the particular studied population, and in terms of accuracy it is both reliable and valid. AIM To develop a valid and appropriate measure to assess physical fitness according to the level of physical activity throughout the day, and to estimate the relation between a subjective questionnaire measurement evaluating physical activity, to predicted VO2max, as an objective measure of physical fitness. METHODS Three hundred healthy subjects, 150 men and 150 women, aged 25-65 years old participated in this study. All subjects were routinely examined in the Sheba Medical Center Executive Screening Survey. They were asked to complete a self-administered questionnaire and report on the level of physical activity at work, the level of sports activity and the level of leisure time non-sport activity. The index calculated from the questionnaire was compared to the result from a sub-maximal exercise test, which they performed in The Executive Screening Survey, to composite a valid questionnaire to estimate physical fitness. RESULTS A high and statistically significant correlation (r = 0.64, P < 0.01) was found between the indexes of physical activity calculated from the questionnaire to the predicted VO2max, measured from the sub-maximal exercise test. The reliability of the questionnaire was examined by test-retest and a high and statistically significant correlation (r = 0.89, P < 0.01) was found between the first and the proceeding one month administration of the questionnaire. The final modal to predict VO2max included a total index of physical activity, gender, BMI, age and resting heart rate. Overall this model predicted 58% of the VO2max. CONCLUSIONS The self-administered questionnaire developed in this study has high construct validity and a significant correlation to predicted VO2max, with high sensitivity in both sexes and among active and non-active subjects. It is therefore an appropriate tool to be used in epidemiological studies.

[Development of a Hebrew questionnaire to be used in epidemiological studies to assess physical fitness--validation against sub maximal stress test and predicted VO2max].

Epidemiological study and laboratory evidence show that physical activity protects against the development and progression of chronic diseases. The physiological and biomechanical principles of the assessment of physical activity are ambiguous, energy expenditure calculations are complex, and numerous difficulties can be encountered in developing simple field techniques for assessing habitual activity. The greatest obstacle to validating field methods of assessing habitual physical activity or energy expenditure in humans has been the lack of adequate comparison criteria for the technique. Physical activity can be described as having four dimensions: duration (minutes/hours), frequency (time per week/per month), intensity (rate of energy expenditure) and circumstances or purpose of the activity. Methodology incorporating questionnaires/interviews are relatively inexpensive, and at present are the only methods feasible for large population studies. Specific activities can be identified in conjunction with frequency and duration. The procedure does not influence subjects' activities to the extent that can occur with observation or diary keeping. The limitations of questionnaires/interviews are the actual definitions and interpretations of the term "physical activity", despite the attempts of interviewers to provide a clear definition. Subjects do not necessarily recall their activities accurately; they may tend to overestimate time or intensity. A self-administered questionnaire must be suited to respondents' ages and education levels. Detailed questionnaires/interviews place a considerable burden on subjects.

Gie Ken-Dror

Papers

Central corneal thickness measurement with the Pentacam Scheimpflug system, optical low-coherence reflectometry pachymeter, and ultrasound pachymetry

A coding VKORC1 Asp36Tyr polymorphism predisposes to warfarin resistance

Different effects of apolipoprotein A5 SNPs and haplotypes on triglyceride concentration in three ethnic origins

[Development of a Hebrew questionnaire to be used in epidemiological studies to assess physical fitness--validation against sub maximal stress test and predicted VO2max].

Measurement and assessment of habitual physical activity in epidemiological studies