No association between the angiotensin-converting enzyme ID polymorphism and elite endurance athlete status.

Several studies have reported that the insertion (I) allele of the angiotensin-converting enzyme (ACE) I/deletion (D) polymorphism is associated with enhanced responsiveness to endurance training and is more common in endurance athletes than in sedentary controls. We tested the latter hypothesis in a cohort of 192 male endurance athletes with maximal oxygen uptake >/=75 ml. kg(-1). min(-1) and 189 sedentary male controls. The ACE ID polymorphism in intron 16 was typed with the three-primer polymerase chain reaction method. Both the genotype (P = 0.214) and allele (P = 0.095) frequencies were similar in the athletes and the controls. Further analyses in the athletes revealed no excess of the I allele among the athletes within the highest quartile (> 80 ml. kg(-1). min(-1)) or decile (>83 ml. kg(-1). min(-1)) of maximal oxygen uptake. These data from the GENATHLETE cohort do not support the hypothesis that the ACE ID polymorphism is associated with a higher cardiorespiratory endurance performance level.     

Effects of NR1H3 Genetic Variation on the Expression of Liver X Receptor α and the Progression of Alzheimer's Disease

Alzheimer''s disease (AD) has been postulated to involve defects in the clearance of amyloid-β (Aβ). Activation of liver X receptor α (LXRα) increases the expression of apolipoprotein E (ApoE) as well as cholesterol transporters ABCA1 and ABCG1, leading to augmented clearance of Aβ. We have previously shown that the C allele of rs7120118 in the NR1H3 gene encoding LXRα reduces the risk of AD. Here, we wanted to assess whether the rs7120118 variation affects the progression of AD and modulates the expression of NR1H3 and its downstream targets APOE, ABCA1 and ABCG1.We utilized tissue samples from the inferior temporal cortex of 87 subjects, which were subdivided according to Braak staging into mild, moderate and severe AD groups on the basis of AD-related neurofibrillary pathology. APOE ε4 allele increased soluble Aβ42 levels in the tissue samples in a dose-dependent manner, but did not affect the expression status of APOE. In contrast, the CC genotype of rs7120118 was underrepresented in the severe group, although this result did not reach statistical significance. Also, patients with the CC genotype of rs7120118 showed significantly decreased soluble Aβ42 levels as compared to the patients with TT genotype. Although the severity of AD did not affect NR1H3 expression, the mRNA levels of NR1H3 among the patients with CT genotype of rs7120118 were significantly increased as compared to the patients with TT genotype. These results suggest that genetic variation in NR1H3 modulates the expression of LXRα and the levels of soluble Aβ42.     

Immunohistochemical Characterization and Sensitivity to Human Adenovirus Serotypes 3, 5, and 11p of New Cell Lines Derived from Human Diffuse Grade II to IV Gliomas

BACKGROUND: Oncolytic adenoviruses show promise in targeting gliomas because they do not replicate in normal brain cells. However, clinical responses occur only in a subset of patients. One explanation could be the heterogenic expression level of virus receptors. Another contributing factor could be variable activity of tumor antiviral defenses in different glioma subtypes. METHODS: We established a collection of primary low-passage cell lines from different glioma subtypes (3 glioblastomas, 3 oligoastrocytomas, and 2 oligodendrogliomas) and assessed them for receptor expression and sensitivity to human adenovirus (HAd) serotypes 3, 5, and 11p. To gauge the impact of antiviral defenses, we also compared the infectivity of the oncolytic adenoviruses in interferon (IFN)-pretreated cells with IFN-sensitive Semliki Forest virus (SFV). RESULTS: Immunostaining revealed generally low expression of HAd5 receptor CAR in both primary tumors and derived cell lines. HAd11p receptor CD46 levels were maintained at moderate levels in both primary tumor samples and derived cell lines. HAd3 receptor DSG-2 was reduced in the cell lines compared to the tumors. Yet, at equal multiplicities of infection, the oncolytic potency of HAd5 in vitro in tumor-derived cells was comparable to HAd11p, whereas HAd3 lysed fewer cells than either of the other two HAd serotypes in 72 hours. IFN blocked replication of SFV, while HAds were rather unaffected. CONCLUSIONS: Adenovirus receptor levels on glioma-derived cell lines did not correlate with infection efficacy and may not be a relevant indicator of clinical oncolytic potency. Adenovirus receptor analysis should be preferentially performed on biopsies obtained perioperatively.     

Effects of mild physical exercise on serum lipoproteins and metabolites of arachidonic acid: a controlled randomised trial in middle aged men.

To study the effects of physical exercise on biochemical risk factors for ischaemic heart disease 31 healthy middle aged men undertook regular physical exercise for two months and 29 served as controls in a randomised trial. In the men taking regular exercise serum cholesterol concentrations increased 26% more in the high density lipoprotein subfraction two (HDL2) and decreased 31% more in the subfraction three (HDL3) and 9% more in the low density lipoprotein fraction than in the control group. A tendency towards increased plasma 6-keto-prostaglandin F1 alpha concentration and decreased serum thromboxane B2 concentration was found during the period of regular exercise, but prostaglandin E2 concentrations remained unchanged. The increase in plasma 6-keto-prostaglandin F1 alpha concentration was associated with an increase in serum HDL2 cholesterol concentration in the group taking regular exercise. Our data suggest that mild regular physical exercise favourably influences cholesterol distribution in serum lipoproteins in healthy middle aged men and may have beneficial effects on circulating metabolites of arachidonic acid.     

Effect of isometric strength training of mechanical, electrical, and metabolic aspects of muscle function

Monozygous twin pairs (two female and four male) were used in a strength training study so that one member of each pair served as training subject (TS) and the other members as nonexercising controls (CS). TS trained four times a week for 12 weeks with maximal isometric knee extensions of the right leg. The parameters studied included muscle strength, endurance time, electromyographic activity, and activities of several key enzymes in nonoxidative an oxidative muscle metabolism. The results disclosed that in addition to a 20% increase in isometric knee extension strength in the trained leg of TS, an average increase of 11% was observed in strength of TS untrained leg. CS did not demonstrate any change in muscle strength. Training also included an improvement in the maintenance of a static load of 60% of the pretraining maximum. Increase in the maximum integrated electromyographic activity (IEMG) of the rectus femoris muscle occurred concomitantly with the knee extension strength. Traning also caused reduction in the IEMG/tension ratio at submaximal loads indicating a more econimical usage of the rectus femoris muscles. Muscle biopsies taken from the vastus lateralis muscle showed that the enzyme activities of MDH, SDH, and HK were higher, and LDH and CPK lower in the trained leg as compared to the nontrained control leg of TS or to the values of the untrained member of the twin pair. It is concluded that isometric strength training as used in the present study can cause increased recruitment of the availabel motor unit pool, improved efficiency at submaximal loads, and surprisingly also enchancement of the oxidative metabolism in the muscle.     

Plasma lecithin:cholesterol acyltransferase and carotid intima-media thickness in European individuals at high cardiovascular risk

Lecithin:cholesterol acyltransferase (LCAT) is the enzyme responsible for cholesterol esterification in plasma. LCAT is a major factor in HDL remodeling and metabolism, and it has long been believed to play a critical role in macrophage reverse cholesterol transport (RCT). The effect of LCAT on human atherogenesis is still controversial. In the present study, the plasma LCAT concentration was measured in all subjects (n = 540) not on drug treatment at the time of enrollment in the multicenter, longitudinal, observational IMPROVE study. Mean and maximum intima-media thickness (IMT) of the whole carotid tree was measured by B-mode ultrasonography in all subjects. In the entire cohort, LCAT quartiles were not associated with carotid mean and maximum IMT (P for trend 0.95 and 0.18, respectively), also after adjustment for age, gender, HDL-cholesterol (HDL-C), and triglycerides. No association between carotid IMT and LCAT quartiles was observed in men (P=0.30 and P=0.99 for mean and maximum IMT, respectively), whereas carotid IMT increased with LCAT quartiles in women (P for trend 0.14 and 0.019 for mean and maximum IMT, respectively). The present findings support the concept that LCAT is not required for an efficient reverse cholesterol transport and that a low plasma LCAT concentration and activity is not associated with increased atherosclerosis.     

Increased γ-Secretase Activity in Idiopathic Normal Pressure Hydrocephalus Patients with β-Amyloid Pathology

The potential similarity between the brain pathology of idiopathic normal pressure hydrocephalus (iNPH) and Alzheimer disease (AD) is intriguing and thus further studies focusing on the underlying molecular mechanisms may offer valuable information for differential diagnostics and the development of treatments for iNPH. Here, we investigated β- and γ-secretase activities in relation to amyloid-β (Aβ) pathology in the brain tissue samples collected from iNPH and AD patients. β- and γ-secretase activities were measured from the frontal cortical biopsies of 26 patients with suspected iNPH as well as post-mortem tissue samples from the inferior temporal cortex of 74 AD patients and eight subjects without neurofibrillary pathology. In iNPH samples with detectable Aβ plaques, γ-secretase activity was significantly increased (∼1.6-fold) when compared to iNPH samples without Aβ plaques (p = 0.009). In the AD samples, statistically significant differences in the γ-secretase activity were not observed with respect to disease severity (mild, moderate and severe AD according to neurofibrillary pathology). Conversely, β-secretase activity was unaltered in iNPH samples with or without Aβ plaques, while it was significantly increased in relation to disease severity in the AD patients. These results show for the first time increased γ-secretase but not β-secretase activity in the biopsy samples from the frontal cortex of iNPH patients with AD-like Aβ pathology. Conversely, the opposite was observed in these secretase activities in AD patients with respect to neurofibrillary pathology. Despite the resemblances in the Aβ pathology, iNPH and AD patients appear to have marked differences in the cellular mechanisms responsible for the production of Aβ.     

Positive and negative life changes and LDL cholesterol.

Epidemiological studies have revealed that stressful changes in social environment increase the risk of cardiovascular mortality. In this study, the influence of major negative and positive life changes on serum cholesterol was examined in middle-aged men to determine a possible biochemical link between life changes and cardiovascular mortality. The results showed no influence of negative life changes on serum cholesterols. However, positive life changes significantly predicted a reduction in total and LDL (low-density lipoprotein) cholesterol levels after adjustment for the baseline cardiovascular health status, baseline cholesterol level, diet, body mass index, waist-to-hip ratio and cardiorespiratory fitness. The odds ratio for lowering LDL cholesterol was 5.2 in the men reporting positive events compared with those reporting none. The findings suggest a predictive value of positive life changes for atherogenic lipid profile in middle-aged men.     

Regular physical exercise, heart rate variability and turbulence in a 6-year randomized controlled trial in middle-aged men: the DNASCO study

HRV and HRT are independent predictors of cardiovascular mortality. Aging reduces HRV, but results from the physical exercise trials are controversial. The primary aim was to study changes in heart rate variability (HRV) and heart rate turbulence (HRT) in a six-year controlled randomized trial at regular low to moderate intensity physical exercise. One hundred forty men aged 53--63 years were randomized in to an exercise or a control groups. The participants underwent a maximal bicycle ergometer exercise test with respiratory gas analyses annually for six years. At baseline and after intervention, 24-h ambulatory ECG registrations were performed to assess HRV (n=100). HRT was determined among subjects with single ventricular premature complexes (VPC) (n=73). In the exercise group, ventilatory aerobic threshold (VAT) increased by 16% indicating enhanced submaximal cardiorespiratory fitness. No significant differences were found in any of the HRV or HRT parameters between the groups. However, the observed increase in VAT correlated significantly with the improvement in HRV parameters. The change in turbulence slope (TS) correlated with the changes in most HRV variables and the change in turbulence onset (TO) correlated with the changes in three frequency domain parameters. Our results suggest that in addition to improvement in submaximal cardiorespiratory fitness, regular low to moderate intensity physical exercise seems to have beneficial effects also on cardiac autonomic nervous function, a clinically relevant predictor of cardiovascular morbidity and mortality.