| 1. |
- Djoussé, L, et al.
(författare)
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Interaction of normal and expanded CAG repeat sizes influences age at onset of Huntington disease.
- 2003
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Ingår i: American Journal of Medical Genetics. Part A. - : Wiley. - 1552-4825 .- 1552-4833. ; 119A:3, s. 279-82
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Tidskriftsartikel (refereegranskat)abstract
- Huntington disease (HD) is a neurodegenerative disorder caused by the abnormal expansion of CAG repeats in the HD gene on chromosome 4p16.3. Past studies have shown that the size of expanded CAG repeat is inversely associated with age at onset (AO) of HD. It is not known whether the normal Huntington allele size influences the relation between the expanded repeat and AO of HD. Data collected from two independent cohorts were used to test the hypothesis that the unexpanded CAG repeat interacts with the expanded CAG repeat to influence AO of HD. In the New England Huntington Disease Center Without Walls (NEHD) cohort of 221 HD affected persons and in the HD-MAPS cohort of 533 HD affected persons, we found evidence supporting an interaction between the expanded and unexpanded CAG repeat sizes which influences AO of HD (P = 0.08 and 0.07, respectively). The association was statistically significant when both cohorts were combined (P = 0.012). The estimated heritability of the AO residual was 0.56 after adjustment for normal and expanded repeats and their interaction. An analysis of tertiles of repeats sizes revealed that the effect of the normal allele is seen among persons with large HD repeat sizes (47-83). These findings suggest that an increase in the size of the normal repeat may mitigate the expression of the disease among HD affected persons with large expanded CAG repeats.
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| 2. |
- Djoussé, Luc, et al.
(författare)
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Evidence for a modifier of onset age in Huntington disease linked to the HD gene in 4p16.
- 2004
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Ingår i: Neurogenetics. - : Springer Science and Business Media LLC. - 1364-6745 .- 1364-6753. ; 5:2, s. 109-14
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Tidskriftsartikel (refereegranskat)abstract
- Huntington disease (HD) is a neurodegenerative disorder caused by the abnormal expansion of CAG repeats in the HD gene on chromosome 4p16.3. A recent genome scan for genetic modifiers of age at onset of motor symptoms (AO) in HD suggests that one modifier may reside in the region close to the HD gene itself. We used data from 535 HD participants of the New England Huntington cohort and the HD MAPS cohort to assess whether AO was influenced by any of the three markers in the 4p16 region: MSX1 (Drosophila homeo box homologue 1, formerly known as homeo box 7, HOX7), Delta2642 (within the HD coding sequence), and BJ56 ( D4S127). Suggestive evidence for an association was seen between MSX1 alleles and AO, after adjustment for normal CAG repeat, expanded repeat, and their product term (model P value 0.079). Of the variance of AO that was not accounted for by HD and normal CAG repeats, 0.8% could be attributed to the MSX1 genotype. Individuals with MSX1 genotype 3/3 tended to have younger AO. No association was found between Delta2642 (P=0.44) and BJ56 (P=0.73) and AO. This study supports previous studies suggesting that there may be a significant genetic modifier for AO in HD in the 4p16 region. Furthermore, the modifier may be present on both HD and normal chromosomes bearing the 3 allele of the MSX1 marker.
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| 3. |
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| 4. |
- Li, Jian-Liang, et al.
(författare)
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A genome scan for modifiers of age at onset in Huntington disease : The HD MAPS study.
- 2003
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Ingår i: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297 .- 1537-6605. ; 73:3, s. 682-7
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Tidskriftsartikel (refereegranskat)abstract
- Huntington disease (HD) is caused by the expansion of a CAG repeat within the coding region of a novel gene on 4p16.3. Although the variation in age at onset is partly explained by the size of the expanded repeat, the unexplained variation in age at onset is strongly heritable (h2=0.56), which suggests that other genes modify the age at onset of HD. To identify these modifier loci, we performed a 10-cM density genomewide scan in 629 affected sibling pairs (295 pedigrees and 695 individuals), using ages at onset adjusted for the expanded and normal CAG repeat sizes. Because all those studied were HD affected, estimates of allele sharing identical by descent at and around the HD locus were adjusted by a positionally weighted method to correct for the increased allele sharing at 4p. Suggestive evidence for linkage was found at 4p16 (LOD=1.93), 6p21-23 (LOD=2.29), and 6q24-26 (LOD=2.28), which may be useful for investigation of genes that modify age at onset of HD.
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| 5. |
- Myers, T. M., et al.
(författare)
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Hemodynamic Evaluation of the Jarvik 2000 Heart During Heart Failure
- 2001
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Ingår i: ASAIO journal (1992). - : Wolters Kluwer. - 1058-2916 .- 1538-943X. ; 46:2, s. 167-
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Tidskriftsartikel (refereegranskat)abstract
- The Jarvik 2000 Heart is an axial flow left ventricular assist system designed for long-term circulatory support. Purpose: To assess the level of hemodynamic support provided by the Jarvik 2000 in an animal model, with acute, severe heart failure. Methods: Heart failure (HF) was induced in 5 calves by progressively ligating the LAD coronary artery. A continuous infusion of esmolol hydrochloride was given to maintain the stability of HF. Compared to normal baseline values, during heart failure CI decreased by 33% (p < 0.02), LAP increased by 16% (p < 0.03), and BP decreased by 28% (p < 0.13). Once stable HF was established, the pump was turned on, and hemodynamic measurements were obtained at pump speed settings that ranged from 8,000 to 12,000 rpm. Results: Selected, mean hemodynamic values are presented in the table, CI, LAP, and BP improved significantly (p < 0.05) at pump speeds >9000 rpm. Pulse pressure (PP) narrowed by 64% (p < 0.009), and the PAP remained unchanged.Image ToolsBlood flow in the femoral artery increased but was not statistically significant. Other hemodynamic parameters such as HR, SVR, PVR, and CVP did not change significantly. Conclusions: The Jarvik 2000 Heart can provide a level of cardiac output support that normalizes the CI and LAP, while maintaining some arterial pressure pulsatility during HF. Systemic perfusion is increased while the left heart is unloaded.
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| 6. |
- Piepoli, MF, et al.
(författare)
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Exercise training meta-analysis of trials in patients with chronic heart failure (ExTraMATCH)
- 2004
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Ingår i: BMJ: British Medical Journal. - 1756-1833. ; 328:7433, s. 189-192
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Tidskriftsartikel (refereegranskat)abstract
- Objective To determine the effect of exercise training on survival in patients with heart failure due to left ventricular systolic dysfunction. Design Collaborative meta-analysis. Inclusion criteria Randomised parallel group controlled trials of exercise training, for at least eight weeks with individual patient data on survival for at least three months. Studies reviewed Nine datasets, totalling 801 patients: 395 received exercise training and 406 were controls. Main outcome measure Death from all causes. Results During a mean (SD) follow up of 705 (729) days there were 88 (22%) deaths in the exercise arm and 105 (26%) in the control arm. Exercise training significantly reduced mortality (hazard ratio 0.65, 95% confidence interval, 0.46 to 0.92; log rank chi(2) = 5.9; P = 0.015). The secondary end point of death or admission to hospital was also reduced (0.72, 0.56 to 0.93; log rank chi(2) = 6.4; P = 0.011). No statistically significant subgroup specific treatment effect was observed. Conclusion Meta-analysis of randomised trials to date gives no evidence that properly supervised medical training programmes for patients with heart failure might be dangerous, and indeed there is clear evidence of an overall reduction in mortality. Further research should focus on optimising exercise programmes and identifying appropriate patient groups to target.
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| 7. |
- Krook, A, et al.
(författare)
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Characterization of signal transduction and glucose transport in skeletal muscle from type 2 diabetic patients
- 2000
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Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 49:2, s. 284-292
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Tidskriftsartikel (refereegranskat)abstract
- We characterized metabolic and mitogenic signaling pathways in isolated skeletal muscle from well-matched type 2 diabetic and control subjects. Time course studies of the insulin receptor, insulin receptor substrate (IRS)-1/2, and phosphatidylinositol (PI) 3-kinase revealed that signal transduction through this pathway was engaged between 4 and 40 min. Insulin-stimulated (0.6-60 nmol/l) tyrosine phosphorylation of the insulin receptor beta-subunit, mitogen-activated protein (MAP) kinase phosphorylation, and glycogen synthase activity were not altered in type 2 diabetic subjects. In contrast, insulin-stimulated tyrosine phosphorylation of IRS-1 and anti-phosphotyrosine-associated PI 3-kinase activity were reduced 40-55% in type 2 diabetic subjects at high insulin concentrations (2.4 and 60 nmol/l, respectively). Impaired glucose transport activity was noted at all insulin concentrations (0.6-60 nmol/l). Aberrant protein expression cannot account for these insulin-signaling defects because expression of insulin receptor, IRS-1, IRS-2, MAP kinase, or glycogen synthase was similar between type 2 diabetic and control subjects. In skeletal muscle from type 2 diabetic subjects, IRS-1 phosphorylation, PI 3-kinase activity, and glucose transport activity were impaired, whereas insulin receptor tyrosine phosphorylation, MAP kinase phosphorylation, and glycogen synthase activity were normal. Impaired insulin signal transduction in skeletal muscle from type 2 diabetic patients may partly account for reduced insulin-stimulated glucose transport; however, additional defects are likely to play a role.
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