Extracellular superoxide dismutase accelerates endothelial recovery and inhibits in-stent restenosis in stented atherosclerotic Watanabe heritable hyperlipidemic rabbit aorta.

OBJECTIVES: This study examined whether local gene therapy with extracellular superoxide dismutase (EC-SOD) could inhibit in-stent restenosis in atherosclerotic Watanabe heritable hyperlipidemic rabbits. BACKGROUND: Stenting causes an acute increase in superoxide anion production and oxidative stress; EC-SOD is a major component of antioxidative defense in blood vessels and has powerful cardioprotective effects in ischemic myocardium. METHODS: Endothelial denudation and stenting were done in 36 adult (15 to 18 months old) rabbits. Catheter-mediated intramural delivery of clinical good manufacturing practice-grade adenoviruses encoding rabbit EC-SOD were done simultaneously with stenting. Control animals received adenovirus-encoding nuclear-targeted beta-galactosidase (AdLacZ). Circulating markers for oxidative stress (nonesterified 8-iso-prostaglandin F2 alpha) were measured. Analysis of 6-day, 28-day, and 90-day vessel histology, radical production, oxidation-specific epitopes, and expression studies were performed. RESULTS: The EC-SOD treatment reduced oxidant production in stented vessels compared with control vessels. Early systemic recovery of total SOD activity was observed in the treated rabbits. The EC-SOD significantly accelerated endothelial recovery (67.4% +/- 10.8% vs. 24.2.1% +/- 4.6% at 6 days, p < 0.05; 89.3% +/- 3.7% vs. 45.1% +/- 9.6% at 28 days, p < 0.05), and the beneficial effect involved increased proliferation of regenerating endothelium. The EC-SOD group showed a 61.3% lower (p < 0.05) neointimal formation at 28 days, with a similar, albeit nonsignificant trend at 90 days (1.20 +/- 0.32 mm2 vs. 1.88 +/- 0.24 mm2, p = 0.06). CONCLUSIONS: The results suggest a central pathogenetic role of oxidation sensitive signaling processes in endothelial recovery and developing in-stent restenosis in atherosclerotic vessels. Local therapy against oxidative stress represents a promising therapeutic strategy in stent-induced vascular injury.     

Coronary heart disease: from a disease of middle-aged men in the late 1970s to a disease of elderly women in the 2000s.

AIMS: To analyse secular changes in the prevalence of coronary heart disease (CHD) and to assess changes in the burden of CHD at population level. METHODS AND RESULTS: Data were used from two large cross-sectional health examination surveys representing the entire Finnish adult population in 1980 and 2000. In the 1978-80 survey, the sample covered 5101 individuals aged > or =45, of whom 88% participated. The 2000-2001 survey comprised 5310 individuals in the same age range. Participation rate in the health examination was 87%. Prevalence of CHD decreased in men and women under the age of 65 and increased among those aged > or =75. Prevalence of large Q-waves indicating previous myocardial infarction decreased in all male age groups and in women aged 65-74. The total estimated number of persons with CHD increased by 18% (95% CI=6-30) during the past 20 years in Finland. In 1980, the most dominant CHD group was men aged 45-64, whereas in 2000, women aged > or =75 comprised the largest CHD group. CONCLUSION: Although the prevalence of CHD has decreased among middle-aged persons, the number of CHD cases has increased during the past 20 years in Finland.     

Low serum HDL‐cholesterol levels are associated with long symptom duration in patients with major depressive disorder

Aims: The purpose of the present study was to examine whether the association between depression and the serum high‐density lipoprotein cholesterol (HDL‐C) is modified by symptom duration. Methods: Depressed patients (n = 88) and an age‐ and sex‐matched group of healthy general population controls (n = 88) underwent a Structured Clinical Interview for DSM‐IV (SCID), and depressed participants reported the duration of their symptoms. The serum levels of total cholesterol (TC), HDL‐C, low‐density lipoprotein cholesterol (LDL‐C), triglycerides (TG) and non‐HDL, and the ratios of LDL‐C/HDL and TC/HDL‐C were assessed. Results: Major depressive disorder (MDD) subjects with a long symptom duration (≥3 years) had lower levels of HDL‐C compared with healthy controls or MDD subjects with a symptom duration <3 years. The likelihood for long symptom duration doubled for each 0.5‐mmol/L decrease in HDL‐C levels in regression models adjusted for age, gender, marital status, overweight, symptom severity, alcohol consumption, smoking, physical exercise, medication use, and non‐HDL‐C (P < 0.05). Conclusions: These findings suggest that a low serum HDL‐C level, a risk factor for coronary heart disease, is specifically associated with long‐term depressive symptomatology.     

Small molecule designed to target metal binding site in the alpha2I domain inhibits integrin function

Integrin alpha2beta1 is a potential target molecule in drug development. We have established "design" criteria for molecules that bind to the "closed" conformation of alpha2I domain via Mg(2+) in MIDAS (metal ion dependent adhesion site) while simultaneously forming interactions with neighboring amino acid residues. Specific tetracyclic Streptomyces products belonging to the group of aromatic polyketides fulfill our criteria and inhibit alpha2beta1 integrin. All previously described inhibitors of alphaI domain integrins act in an allosteric manner.     

Acute changes in muscle activation and leg extension performance after different running exercises in elite long distance runners

This study investigated acute changes in muscle activation and muscular power performance after three different running exercises in elite long-distance runners. Twenty-two nationally and internationally ranked long-distance runners performed first an incremental treadmill running test until exhaustion (MR) and then 40 min continuous (TR) and intermittent (2 min run/2 min rest) (IR) running exercises at an intensity of 80 and 100% of the velocity associated with VO_2max, respectively. Muscle activation and muscular power performance tests (counter-movement jumps, CMJ, and a set of ten maximal half squats from the static starting position with an extra load of 35% of the subjects,′ one repetition maximum) were performed before and immediately after the runs. The average mechanical power (P) of the half squats was calculated and the root mean square electromyogram (EMGrms) from the vastus lateralis, vastus medialis, gastrocnemius and biceps femoris muscles was recorded simultaneously during the half squat performances. The results showed an acute exercise–induced increase in P (ANOVA time effect, P=0.000) together with a reduction in EMGrms of the knee extensor muscles (ANOVA time effect, P=0.000). However, mechanical P expressed as a relative change within the set decreased after MR. In TR the improvement in P correlated positively with the maximal running performance of the runners (P<0.05), while in IR it correlated negatively (P<0.05). Jumping performance was significantly enhanced after each run (P<0.001, for all) and the improvement correlated negatively with the maximal sprinting speed and maximal jumping height of the runners (P<0.01, for all). It is concluded that in elite long distance runners an intensive prolonged running exercise reduces the surface EMG of the knee extensor muscles, and may lead to a different coordination strategy in leg extension exercises performed into the vertical direction. After continuous type of running the power improvement correlates positively with maximal endurance running capacity, whereas after intermittent type of running it correlates negatively.     

Serum anti-inflammatory markers in general population subjects with elevated depressive symptoms

Anti-inflammatory substances have previously been suggested to show compensatory elevations in depressed individuals with pronounced inflammatory changes. In order to further clarify these observations, we examined depression-related alterations in the serum levels of anti-inflammatory markers interleukin (IL)-1 receptor antagonist (RA) and IL-10 and the pro-inflammatory marker IL-6 in 416 general population participants. Depression was evaluated with the Beck Depression Inventory (BDI). Participants with elevated depressive symptoms (BDI > 14, n = 44) had increased levels of IL-1 RA and IL-6. No changes were observed in their IL-10 levels. In multivariate modeling with adjustments for age, gender, obesity, regular smoking, alcohol use, metabolic syndrome, physical exercise, sleep disturbance, and the use of non-steroidal anti-inflammatory drugs, a high level of IL-1 RA was associated with an increased likelihood of belonging to the group with elevated depressive symptoms (OR for each 1 SD increase in the serum level of IL-1 RA: 2.17, 95% CI 1.35–3.48, p = 0.001). The significance of IL-6 alterations did not persist in the same model. The pronounced secretion of anti-inflammatory marker IL-1 RA may reflect the presence of compensatory mechanisms during a depression-related inflammatory state.     

Midbrain binding of [123I]nor-beta-CIT in atypical depression

BACKGROUND: Altered serotonin (SERT) and dopamine transporter (DAT) densities have been recorded in major depression. Atypical depression (ATD) has been suggested to be connected to decreased serotonergic transmission, but no studies have been published on the association between brain serotonin transporter density and ATD. METHODS: PATIENTS with depression (n=29) were divided into three groups according to DSM-IV criteria: atypically depressed, melancholic patients, and "undifferentiated" patients. Depressive symptoms were evaluated with the 29-item Hamilton Depression Rating Scale (HAM-D-29). Single photon emission computed tomography (SPECT) with [(123)I]nor-beta-CIT was used to evaluate serotonin transporter density (SERT) in the midbrain and dopamine transporter density (DAT) in the striatum of patients and healthy controls (n=18). RESULTS: All subgroups except those with undifferentiated depression had lower SERT densities compared to controls. No significant differences were found in the densities between the subgroups. Atypical scores of HAM-D-29 were associated with SERT densities in the midbrain (beta=-0.40, t=-2.3, p=0.03), even after adjustment for age, gender and HAM-D-21 scores (beta=-0.39, t=-2.32, p=0.03). CONCLUSIONS: The association between atypical scores of HAM-D-29 and midbrain SERT densities suggests a relationship between serotonergic dysfunction and ATD.     

Changes in midbrain serotonin transporter availability in atypically depressed subjects after one year of psychotherapy

BACKGROUND: Psychotherapy is an effective treatment method for depression, but no differences in the psychotherapy response have been found between the subtypes of depression. The effect of psychotherapy on neurotransmitter transporter functions has never been recorded in depressed subjects. METHODS: Depressive outpatients (N=19) received psychodynamic psychotherapy for 12 months. All subjects fulfilled the DSM-IV criteria for depression, and 8 were classified as having atypical depression. The severity of depression was assessed with the 29-item Hamilton Depression Rating Scale (HAM-D-29). Midbrain serotonin transporter (SERT) and striatum dopamine transporter (DAT) densities were recorded using single photon emission computed tomography (SPECT) brain imaging with the [123I]nor-beta-CIT radioligand before and after psychotherapy. RESULTS: Midbrain SERT density significantly increased during psychotherapy in atypicals but not in nonatypicals. There were no changes in the levels of DAT. CONCLUSIONS: The psychotherapy-related SERT elevation of atypically depressed subjects may be due to some unknown adaptive mechanisms inducing an increase in either the levels of SERT or serotonergic nerve terminals and therefore enhancing serotonergic activity and improving mood.