| 51. |
- Jonsson, Andreas P., et al.
(författare)
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Minute quantities of misfolded mutant superoxide dismutase-1 cause amyotrophic lateral sclerosis
- 2004
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Ingår i: Brain. - : Oxford University Press. - 0006-8950 .- 1460-2156. ; 127:Pt 1, s. 73-88
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Tidskriftsartikel (refereegranskat)abstract
- Mutant forms of superoxide dismutase-1 (SOD1) cause amyotrophic lateral sclerosis (ALS) by an unknown noxious mechanism. Using an antibody against a novel epitope in the G127insTGGG mutation, mutant SOD1 was studied for the first time in spinal cord and brain of an ALS patient. The level was below 0.5% of the SOD1 level in controls. In corresponding transgenic mice the content of mutant SOD1 was also low, although it was enriched in spinal cord and brain compared with other tissues. In the mice the misfolded mutant SOD1 aggregated rapidly and 20% occurred in steady state as detergent-soluble protoaggregates. The misfolded SOD1 and the protoaggregates form, from birth until death, a potentially noxious burden that may induce the motor neuron injury. Detergent-resistant aggregates, as well as inclusions of mutant SOD1 in motor neurons and astrocytes, accumulated in spinal cord ventral horns of the patient and mice with terminal disease. The inclusions and aggregates may serve as terminal markers of long-term assault by misfolded SOD1 and protoaggregates.
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| 52. |
- Jonsson, Andreas P., et al.
(författare)
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Motor neuron disease in mice expressing the wild type-like D90A mutant superoxide dismutase-1
- 2006
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Ingår i: Journal of Neuropathology and Experimental Neurology. - : Oxford University Press (OUP). - 0022-3069 .- 1554-6578. ; 65:12, s. 1126-1136
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Tidskriftsartikel (refereegranskat)abstract
- Mutant human CuZn-superoxide dismutases (hSOD1s) cause amyotrophic lateral sclerosis (ALS). The most common mutation is the wild type-like D90A and to explore its properties, transgenic mice were generated and compared with mice expressing wild-type hSOD1. D90A hSOD1 was both in vivo in mice and in vitro under denaturing conditions nearly as stable as the wild-type human enzyme. It appeared less toxic than other tested mutants, but mice homozygous for the transgene insertion developed a fatal motor neuron disease. In these mice, the disease progression was slow and there were bladder disturbances similar to what is found in human ALS cases homozygous for the D90A mutation. The homozygous D90A mice accumulated detergent-resistant hSOD1 aggregates in spinal cords, and abundant hSOD1 inclusions and vacuoles were seen in the ventral horns. Mice expressing wild-type hSOD1 at a comparable rate showed similar pathologic changes but less and later. Hemizygous D90A mice showed even milder alterations. At 600 days, the wild-type hSOD1 transgenic mice had lost more ventral horn neurons than hemizygous D90A mice (38% vs 31% p < 0.01). Thus, wild-type hSOD1 shows a significant neurotoxicity in the spinal cord, that is less than equal but more than half as large as that of D90A mutant enzyme.
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| 53. |
- Karlsson, Fredrik, et al.
(författare)
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Interactions between a zwitterionic polythiophene derivative and oligonucleotides as resolved by fluorescence resonance energy transfer
- 2005
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Ingår i: Chemistry of Materials. - : American Chemical Society (ACS). - 0897-4756 .- 1520-5002. ; 17:16, s. 4204-4211
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Tidskriftsartikel (refereegranskat)abstract
- The interactions between a zwitterionic polythiophene derivative, POWT, and DNA oligonucleotides in solution have been studied by FRET (fluorescence resonance energy transfer). When POWT and ssDNA are bound alone in a complex, the distance between them is at its smallest. The distance increases when adding complementary DNA, but POWT is still mainly bound to the first DNA strand. We find that two POWT chains bind to one DNA strand, and the two POWT chains seem held together in pairs, unable to separate, as they can only bind to and quench half their own amount of labeled DNA. This POWT−POWT complex appears to dissociate at lower concentrations. ssDNA attached to POWT in a complex can also be substituted by other ssDNA in solution; this occurs to 50% when the free DNA is present in 10-fold concentration compared to the ssDNA bound to POWT. Titration studies at different concentrations show positive cooperativity in the binding of POWT and ssDNA into a complex. The hybridization of complementary DNA to the same complex involves no cooperativity. These observations indicate interesting possibilities for the use of POWT as a DNA sensor.
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| 54. |
- Khalili, Payam, et al.
(författare)
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Smoking as a modifier of the systolic blood pressure-induced risk of cardiovascular events and mortality : a population-based prospective study of middle-aged men
- 2002
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Ingår i: Journal of Hypertension. - : Ovid Technologies (Wolters Kluwer Health). - 0263-6352 .- 1473-5598. ; 20:9, s. 1759-1764
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Tidskriftsartikel (refereegranskat)abstract
- Objective To examine to what degree smoking habits modulate the relationship between systolic blood pressure (SBP) and risk for cardiovascular morbidity (first event) and mortality in middle-aged men. Design and methods In all, 22 444 middle-aged men were recruited from a population-based screening study (mean attendance rate 71%). Risk factor intervention was offered to about 20% of participants. Subjects were followed in local and national registers for cardiovascular morbidity and mortality during more than 17 years of follow-up. Lifestyle variables were investigated at baseline, including smoking habits. Event rates were calculated in relation to quintiles (Q1-Q5) of baseline SBP in untreated subjects, subdivided into categories of smoking habits, but also for 915 previously known, treated hypertensive (tHT) patients at baseline. Results We found an increasing incidence of first cardiovascular event (CE) with increasing SBP levels, ranging from 63.5 CE/10 000 person-years (Q1) to 62.3, 70.5,82.3 and 115.1 CE/10 000 person-years (Q2-Q5). The corresponding figure in tHTs; was 153 CE/10 000 person-years. If further subdivided into smokers/ex-smokers/non-smokers, the relative risks (RR) of smokers were 1.9 [95% confidence interval (Cl): 1.5-2.4], 2.1 (1.8-2.5), 2.3 (1.8-2.9), 1.8 (1.5-2.1), and 1.7 (1.5-2.0) compared to present non-smokers, in relation to SBP (Q1-Q5). In tHTs; the RR was 1.4 (1.1-1.8). Cardiovascular mortality rates differed in relation to SBP and smoking habits, from 40.3 (present non-smokers) and 70.7 (smokers) deaths/10 000 person-years in Q1, to 54.2 and 134.0 deaths/10 000 person-years in Q5. In tHTs the corresponding figures were 81.6 and 149.4 deaths/10 000 person-years, respectively. No difference in risk was found for never-smokers compared to ex-smokers in relation to SBP. The risk in moderate/heavy smokers (> 10 cigarettes/day) compared to other smokers (less than or equal to 10 cigarettes/day) was significantly (P < 0.005) increased only in Q5. Conclusion Increasing systolic blood pressure levels in middle-aged men is associated with an increasing risk of future cardiovascular events and mortality, an association modified by smoking habits. Patients with treated hypertension in the 1970-1980s were also at an increased risk in spite of healthcare efforts. This calls for a more comprehensive multiple risk factor approach for the management and reduction of cardiovascular risk in these patients. (C) 2002 Lippincott Williams Wilkins.
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| 55. |
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| 56. |
- Kozakova, Michaela, et al.
(författare)
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Habitual Physical Activity and Vascular Aging in a Young to Middle-Age Population at Low Cardiovascular Risk.
- 2007
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Ingår i: Stroke: a journal of cerebral circulation. - 1524-4628. ; 38:9, s. 2549-2555
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Tidskriftsartikel (refereegranskat)abstract
- Background and Purpose - Regular endurance exercise has been shown to reduce the age-related increase in arterial stiffness that is thought to contribute to cardiovascular risk. The aim of this study was to evaluate the influence of age and habitual physical activity on carotid artery wall thickness and stiffness in a population of young to middle-age subjects at low cardiovascular risk. Methods - The study population consisted of 432 healthy subjects (166 men; mean +/- SD age, 43 +/- 8 years; range, 30 to 60 years) free of carotid atherosclerosis and with low coronary heart disease risk, as determined by the Framingham prediction score sheet. All subjects underwent B-mode ultrasonography of the extracranial carotid arteries and physical activity assessment by actigraph, an accelerometer capable of monitoring the intensity and duration of body movements. The intima-media thickness of the common carotid artery was measured on ultrasound images, along with systodiastolic changes in luminal diameter, and indices of carotid stiffness were calculated. Results - Intima-media thickness and carotid stiffness increased with age in both men and women (r = 0.24 to 0.52, P<0.001). The magnitude of objectively assessed daily physical activity was negatively related to indices of carotid stiffness (r from -0.20 to -0.25, P<0.001) but not to intima-media thickness. In multivariate regression analyses that included several cardiovascular risk factors such as obesity, blood pressure, plasma lipids, and smoking habits, age and physical activity were independently related to carotid stiffness. Conclusions - This study provides cross-sectional evidence that habitual physical activity is inversely related to the age-dependent increase in carotid wall stiffness in a young to middle-age population at low risk.
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| 57. |
- Leosdottir, Margrét, et al.
(författare)
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Cardiovascular event risk in relation to dietary fat intake in middle-aged individuals: data from The Malmo Diet and Cancer Study
- 2007
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Ingår i: European Journal of Cardiovascular Prevention & Rehabilitation. - 1741-8275. ; 14:5, s. 701-706
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND AND DESIGN: The hypothesis that diets rich in total and saturated fat and poor in unsaturated fats increase the risk for cardiovascular disease is still vividly debated. The aim of this study was to examine whether total fat, saturated fat, or unsaturated fat intakes are independent risk factors for cardiovascular events in a large population-based cohort. METHODS: 28 098 middle-aged individuals (61% women) participated in the Malmo Diet and Cancer Study between 1991 and 1996. In this analysis, individuals with an earlier history of cardiovascular disease were excluded. With adjustments made for confounding by age and various anthropometric, social, dietary, and life-style factors, hazard ratios (HR) were estimated for individuals categorized by quartiles of fat intake [HR (95% confidence interval, CI), Cox's regression model]. RESULTS: No trend towards higher cardiovascular event risk for women or men with higher total or saturated fat intakes, was observed. Total fat: HR (95% CI) for fourth quartile was 0.98 (0.77-1.25) for women, 1.02 (0.84-1.23) for men; saturated fat: 0.98 (0.71-1.33) for women and 1.05 (0.83-1.34) for men. Inverse associations between unsaturated fat intake and cardiovascular event risk were not observed. CONCLUSIONS: In relation to risks of cardiovascular events, our results do not suggest any benefit from a limited total or saturated fat intake, nor from relatively high intake of unsaturated fat.
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| 58. |
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| 59. |
- Lindskog, Bengt I., et al.
(författare)
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Medicinsk terminologi
- 2004
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Bok (övrigt vetenskapligt/konstnärligt)
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| 60. |
- Lyssenko, Valeriya, et al.
(författare)
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Clinical risk factors, DNA variants, and the development of type 2 diabetes.
- 2008
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Ingår i: New England Journal of Medicine. - 0028-4793. ; 359:21, s. 2220-2232
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Type 2 diabetes mellitus is thought to develop from an interaction between environmental and genetic factors. We examined whether clinical or genetic factors or both could predict progression to diabetes in two prospective cohorts. METHODS: We genotyped 16 single-nucleotide polymorphisms (SNPs) and examined clinical factors in 16,061 Swedish and 2770 Finnish subjects. Type 2 diabetes developed in 2201 (11.7%) of these subjects during a median follow-up period of 23.5 years. We also studied the effect of genetic variants on changes in insulin secretion and action over time. RESULTS: Strong predictors of diabetes were a family history of the disease, an increased body-mass index, elevated liver-enzyme levels, current smoking status, and reduced measures of insulin secretion and action. Variants in 11 genes (TCF7L2, PPARG, FTO, KCNJ11, NOTCH2, WFS1, CDKAL1, IGF2BP2, SLC30A8, JAZF1, and HHEX) were significantly associated with the risk of type 2 diabetes independently of clinical risk factors; variants in 8 of these genes were associated with impaired beta-cell function. The addition of specific genetic information to clinical factors slightly improved the prediction of future diabetes, with a slight increase in the area under the receiver-operating-characteristic curve from 0.74 to 0.75; however, the magnitude of the increase was significant (P=1.0x10(-4)). The discriminative power of genetic risk factors improved with an increasing duration of follow-up, whereas that of clinical risk factors decreased. CONCLUSIONS: As compared with clinical risk factors alone, common genetic variants associated with the risk of diabetes had a small effect on the ability to predict the future development of type 2 diabetes. The value of genetic factors increased with an increasing duration of follow-up.
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