Association between increased plasma ceramides and chronic kidney disease in patients with and without ischemic heart disease.

AIM: Plasma levels of certain ceramides are increased in patients with ischemic heart disease (IHD). Many risk factors for IHD are also risk factors for chronic kidney disease (CKD), but it is currently uncertain whether plasma ceramide levels are increased in patients with CKD. METHODS: We measured six previously identified high-risk plasma ceramide concentrations [Cer(d18:1/16:0), Cer(d18:1/18:0), Cer(d18:1/20:0), Cer(d18:1/22:0), Cer(d18:1/24:0) and Cer(d18:1/24:1)] in 415 middle-aged individuals who attended our clinical Cardiology and Diabetes services over a period of 9 months. RESULTS: A total of 97 patients had CKD (defined as e-GFRCKD-EPI<60ml/min/1.73m2 and/or urinary albumin-to-creatinine ratio≥30mg/g), 117 had established IHD and 242 had type 2 diabetes. Patients with CKD had significantly (P=0.005 or less) higher levels of plasma Cer(d18:1/16:0), Cer(d18:1/18:0), Cer(d18:1/20:0), Cer(d18:1/22:0), Cer(d18:1/24:0), and Cer(d18:1/24:1) compared to those without CKD. The presence of CKD remained significantly associated with higher levels of plasma ceramides (standardized beta coefficients ranging from 0.124 to 0.227, P<0.001) even after adjustment for body mass index, smoking, hypertension, diabetes, prior IHD, plasma LDL-cholesterol, hs-C-reactive protein levels and use of any lipid-lowering medications. Notably, more advanced stages of CKD and abnormal albuminuria were both associated (independently of each other) with increased levels of plasma ceramides. These results were consistent in all subgroups considered, including patients with and without established IHD or those with and without diabetes. CONCLUSION: Increased levels of plasma ceramides are associated with CKD independently of pre-existing IHD, diabetes and other established cardiovascular risk factors.

Associations between specific plasma ceramides and severity of coronary-artery stenosis assessed by coronary angiography.

AIM: Recent prospective studies have identified distinct plasma ceramides as strong predictors of major adverse cardiovascular events in patients with established or suspected coronary artery disease (CAD). Currently, it is uncertain whether higher levels of distinct plasma ceramides are associated with greater angiographic severity of coronary-artery stenoses in this patient population. METHODS: We measured six previously identified high-risk plasma ceramide species [Cer(d18:1/16:0), Cer(d18:1/18:0), Cer(d18:1/20:0), Cer(d18:1/22:0), Cer(d18:1/24:0) and Cer(d18:1/24:1)] in 167 consecutive patients with established or suspected CAD, who underwent urgent or elective coronary angiography. RESULTS: Approximately 77% of patients had a significant stenosis (≥50%) in one or more of the main coronary arteries, the majority of whom (∼60%) had a significant stenosis in the left anterior descending (LAD) artery. Of the six measured plasma ceramides, higher levels of plasma Cer(d18:1/20:0) (adjusted-odds ratio 1.39, 95%CI 1.0-1.99), Cer(d18:1/22:0) (adjusted-odds ratio 1.57, 95%CI 1.08-2.29) and Cer(d18:1/24:0) (adjusted-odds ratio 1.59, 95%CI 1.08-2.32) were significantly associated with the presence of LAD stenosis≥50%, after adjustment for age, sex, smoking, pre-existing CAD, hypertension, diabetes, dyslipidaemia, lipid-lowering therapy, estimated glomerular filtration rate and plasma C-reactive protein levels. Almost identical results were found even after excluding patients (n=15) with acute ST-elevation myocardial infarction. Similar results were also found when patients were categorized according to the Gensini severity score. CONCLUSION: Our cross-sectional study shows for the first time that higher levels of specific plasma ceramides are independently associated with a greater severity of coronary-artery stenoses in the LAD artery in patients who had suspected or established CAD.

The rs2516839 variation of USF1 gene is associated with 4-year mortality of nonagenarian women: The Vitality 90+ study.

Upstream transcription factor 1 (USF1) regulates the transcription of many genes related to cell and organism survival processes such as stress and immune response, regulation of cellular senesce, and carcinogenesis. In this study, our aim was to investigate the effect of USF1 single nucleotide variations (SNVs) on longevity in the Vitality 90+ study, a population-based study of nonagenarians (90 ±1 years of age) living in the area of Tampere municipality, Finland. Altogether 509 voluntary nonagenarians (115 males, 394 females) were genotyped using the 5'-nuclease assay for rs2774279G > A, rs2516839T > C, and rs2073658C > T SNVs. During the 4 years of follow-up, the total mortality rate was 64.2%. In the study, we found that the frequency of C-allele of rs2516839 among nonsurviving nonagenarians (52.5%) was higher than those who survived (41.2%; P = 0.0006, odds ratio = 1.575, 95% confidence interval [CI]: 1.215-2.041). Furthermore, carriage of this variation and its haplotypes had a significant gender by genotype interaction (P < 0.05) on mortality. Kaplan-Meier log-rank test during 4-years of follow-up showed significantly higher mortality rate in the case of CC genotype carriage than other genotype carriages in nonagenarian women (P < 0.0001). In addition, after adjusting for age in Cox regression analysis, cardiovascular disease, diabetes, infectious disease, dementia, and living place (nursing home or home), CC genotype of rs2516839T > C was found to be associated with shorter life expectancy in nonagenarian women (hazard ratio = 2.27; 95% CI, 1.34-3.85 P = 0.002). In conclusion, rs2516839 variation and related haplotypes of the USF1 gene are strongly related to all-cause mortality in Finnish nonagenarians, especially among women.

Synergistic Expression of Histone Deacetylase 9 and Matrix Metalloproteinase 12 in M4 Macrophages in Advanced Carotid Plaques.

OBJECTIVE/BACKGROUND: Expression patterns and association with cell specific gene expression signatures of the epigenetic regulator histone deacetylase 9 (HDAC9) and matrix metalloproteinase 12 (MMP12) in human plaque are not known. METHODS: This was a prospective cohort study. Genome wide expression analysis was performed in carotid, femoral, aortic plaques (n = 68) and left internal thoracic (LITA) controls (n = 28) and plaque histological severity assessed. Correlation and hierarchical cluster analysis was utilised. RESULTS: HDAC9 was associated with MMP12 expression in carotid plaques (r = .46, p = .012) and controls (r = -.44, p = .034). HDAC9 and MMP12 clustered with inflammatory macrophage markers but not with smooth muscle cell (SMC) rich markers. In plaques from all arterial sites, MMP12 but not HDAC9 showed positive correlation (p < .05) with M2 and M4 polarized macrophage markers, and negative correlation with SMC rich signatures. In the carotid plaques, all M4 macrophage markers associated with MMP12 and HDAC9. The negative association of MMP12 with SMC rich signatures was pronounced in the carotid plaques. Neither HDAC9 nor MMP12 associated consistently with plaque stabilisation or thrombosis related genes. Immunohistochemistry further supported the association between HDAC9 and MMP12 in atherosclerotic plaques. CONCLUSION: M4 macrophages are a possible source for HDAC9 and MMP12 expression in advanced human plaques.

Angiotensin-converting enzyme gene polymorphism and coronary reactivity in young men.

The purpose of the study was to examine whether the insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme (ACE) gene affects the vasodilatory properties of coronary arteries in healthy men. The ACE genotypes of 128 men (mean age 35 +/- 4 years) were determined and related to myocardial blood flow. The blood flow was measured by positron emission tomography at rest and during vasodilation caused by adenosine or dipyridamole infusion. The coronary flows and resistances at rest and during stimulation with adenosine or dipyridamole did not differ between the ACE genotypes. Furthermore, this polymorphism had no effect on coronary flow reserve corrected by a rate-pressure product. In conclusion, the ACE I/D polymorphism does not seem to affect myocardial reactivity--an early indicator of atherosclerosis--in healthy subjects.

Improvement of myocardial blood flow by lipid-lowering therapy with pravastatin is modulated by apolipoprotein E genotype.

OBJECTIVE: Apolipoprotein E (apoE) polymorphism affects the risk of advanced coronary artery disease, but its role in early atherosclerosis remains unknown. We used positron emission tomography (PET) to study whether coronary reactivity or its response to pravastatin is related to the apoE genotype. MATERIAL AND METHODS: Samples from 44 mildly hypercholesterolaemic men (aged 35 +/- 4 years) of an earlier trial were re-analysed according to apoE genotype. Subjects were randomized to receive either 40 mg/day pravastatin or placebo for 6 months. To assess coronary reactivity, myocardial blood flow was measured by PET at rest and during adenosine infusion. PET studies and lipid analyses were done at baseline and after 6 months of therapy. RESULTS: There were no differences between apoE epsilon3/3 and epsilon4/3 genotypes in basal or adenosine-stimulated flow or in coronary flow reserve (CFR) at baseline. There was a significant apoE genotype-by-treatment group interaction regarding the change in adenosine-stimulated flow (ANCOVA; p = 0.018) and CFR (p = 0.020) at the end of the study. In the pravastatin group, the adenosine-stimulated flow increased by 32.5 % in subjects with epsilon3/3 (n = 9), but decreased non-significantly (-14.4 %) in subjects with epsilon4/3 (n = 9) (p = 0.0009). The corresponding changes in CFR were +17.8 % for epsilon3/3 and (-11.9 % for epsilon4/3 (p = 0.05). There were no significant changes from the baseline values in placebo recipients. After pravastatin treatment, both genotype groups showed a similar decrease in serum total and low-density lipoprotein cholesterol (p<0.0001 for both). CONCLUSIONS: Coronary function improves by 6 months of pravastatin in subjects with the apoE epsilon3/3 genotype, but not in those with the epsilon4/3.

Decreased skeletal muscle mitochondrial DNA in patients treated with high-dose simvastatin.

Statins are generally well tolerated, but can cause myopathy and have been associated with mitochondrial abnormalities. The aim of this study was to determine whether muscle mitochondrial DNA (mtDNA) levels are altered during statin therapy. We retrospectively quantified mtDNA in 86 skeletal muscle biopsy specimens collected as part of a previously published clinical trial of high-dose simvastatin or atorvastatin versus placebo.

High plasma levels of CD40 are associated with low coenzyme Q and vitamin E content of low-density lipoprotein in healthy men.

OBJECTIVE: There is a growing body of evidence to suggest that low-density lipoprotein (LDL) cholesterol, inflammation and oxidative stress are pivotal in the development of cardiovascular disease, but their interconnections are not well known. The objective of this study was to determine whether immunological activation, reflected by the plasma levels of soluble CD40 (sCD40), interleukin (IL)-1beta, tumor necrosis factor-alpha and IL-6 are associated with the antioxidant potential of LDL particles or with common lipid, immunological or thrombotic markers in 51 young healthy men. MATERIAL AND METHODS: We determined the coenzyme Q level from an oxidized LDL fraction, obtaining the concentration for ubiquinone, which indicates total coenzyme Q levels. RESULTS: The plasma level of sCD40 was negatively correlated with LDL ubiquinone (r=-0.45, p=0.001) and E vitamin (r=-0.37, p=0.008) and positively correlated with plasma concentration of plasminogen activator inhibitor-1 (PAI-1, r=0.52, p=0.002) and caspase-1 (r=0.40, p=0.004). No correlation was detected between sCD40 and plasma lipid or C-reactive protein concentrations. As sCD40 was strongly correlated with the content of LDL ubiquinone and vitamin E, their values were compared according to groups formed by sCD40 tertiles. Analysis of variance showed that there were significant differences in LDL ubiquinone (p<0.0001) and vitamin E (p=0.004) concentrations between sCD40 tertiles. CONCLUSIONS: The data indicate that increased activation of the CD40 system is related to low levels of LDL ubiquinone and vitamin E. This suggests that chronic or increased immunological activation may consume the antioxidant potential of LDL particles.

High oxidized LDL and elevated plasma homocysteine contribute to the early reduction of myocardial flow reserve in healthy adults.

BACKGROUND: Impairment of coronary blood flow reserve has been shown to be an early manifestation of atherosclerosis and coronary artery disease (CAD). We studied more closely the contribution of various risk factors on early deterioration of coronary function. MATERIALS AND METHODS: Fifty-one young, apparently healthy adults, with normal or mildly elevated serum cholesterol levels but without other major risk factors for CAD, such as diabetes or hypertension, underwent positron emission tomography (PET) studies. Coronary flow reserve (CFR) was measured using O15-water. In addition to the classical risk factors, the role of several new risk indicators, such as low-density lipoprotein (LDL) oxidation, infection (Chlamydia pneumoniae antibodies), and inflammation parameters (adhesion molecules, ICAM, VCAM, selectin, and C-reactive protein), homocysteine and body iron stores were investigated. RESULTS: Elevated lipid and lipoprotein levels were not associated with reduced coronary reactivity. However, high autoantibody titers against oxidized LDL (oxLDL) were associated with 21% lower CFR than low oxLDL (P < 0.05). Furthermore, high homocysteine levels predicted low CFR (P < 0.05). The other measured parameters, Chlamydia pneumoniae antibody levels, C-reactive protein and adhesion molecule concentrations did not associate with myocardial blood flow. In a stepwise regression model, oxLDL (P = 0.03), homocysteine (P = 0.04) and triglycerides (P = 0.018) were significant predictors of CFR. CONCLUSIONS: The present study suggests an important role for oxidized LDL and plasma homocysteine on early impairment of coronary reactivity in young adults.

Oestrogen receptor gene variation is a determinant of coronary reactivity in healthy young men.

BACKGROUND: Oxidised low-density lipoprotein (ox-LDL) is a determinant of impaired coronary function and oestrogens inhibit its formation probably throughout genetically-variable oestrogen receptor 1 (ESR1) in artery wall. We hypothesized that the ESR1 polymorphism might influence coronary function and reactivity as measured by positron emission tomography (PET), which allows the detection of coronary dysfunction before appearance of angiographic lesions. MATERIALS AND METHODS: Fifty-one healthy young men (aged 35 +/- 4 years), with normal or slightly-elevated serum cholesterol, underwent PET with intravenous adenosine. ESR1 PvuII genotypes P/P, P/p, and p/p in addition to the plasma autoantibody titre against ox-LDL, a marker of in vivo oxidation, were determined. RESULTS: The ESR1 genotype persisted as the only significant predictor of adenosine stimulated coronary flow (P = 0.035) after adjustment for other coronary risk factors. Subjects with P/P genotype had 33.4 and 41.8% lower adenosine-stimulated flow values than subjects with P/p and p/p genotypes (P = 0.030). Furthermore, plasma levels of ox-LDL titre were on average 59 and 77% higher in subjects with P/P genotype than in subjects with P/p or p/p genotypes (P = 0.049). CONCLUSIONS: These tentative findings from our pilot study provide evidence that genetic variation in ESR1 may modify coronary reactivity and LDL oxidation and reflect differences in the early pathogenesis of coronary dysfunction in these healthy young men.

Effect of lipid-lowering therapy with pravastatin on myocardial blood flow in young mildly hypercholesterolemic adults.

Serum low-density lipoprotein cholesterol concentration is an important regulator of vascular reactivity. This double-blinded study examined the effect of lipid-lowering therapy on myocardial vasodilatory function in young hypercholesterolemic but otherwise healthy men. Fifty-one men (age 35 +/- 4 years) with mild hypercholesterolemia (total cholesterol, 5.6 +/- 0.8 mM ) were randomly assigned to receive pravastatin, 40 mg/day, or placebo for 6 months. Myocardial blood flow was measured at rest and during adenosine-induced hyperemia using positron emission tomography and oxygen-15-labeled water at baseline and after treatment. Pravastatin lowered low-density-lipoprotein cholesterol by 33% from 3.77 +/- 0.76 mM (p < 0.001), whereas placebo had no effect. At baseline, resting and adenosine-induced flow values were 0.85 +/- 0.27 and 3.61 +/- 1.00 ml/min per gram in the pravastatin group and 0.83 +/- 0.18 and 3.17 +/- 0.69 ml/min per gram in the placebo group. Despite significant low-density-lipoprotein cholesterol lowering, resting and adenosine-stimulated blood flow values remained similar at follow-up: 0.86 +/- 0.23 and 3.79 +/- 1.31 vs. 0.78 +/- 0.20 and 3.20 +/- 0.86 ml/min per gram, in the pravastatin and placebo groups, respectively. An improvement in adenosine-induced flow after pravastatin, but not after placebo, was seen only in a subgroup of subjects (n = 15) with relatively low adenosine flow (<4.0 ml/min per gram) at baseline. Six months of cholesterol-lowering therapy with statin treatment has no overall significant effect on coronary vasodilator capacity in healthy subjects with mildly elevated cholesterol levels. A controlled study is needed to further test whether improvement in coronary function is obtained in subjects with initially reduced hyperemic flow response.

Paraoxonase gene polymorphisms and coronary reactivity in young healthy men.

This study examined the relationships between paraoxonase genotypes, coronary artery reactivity, and indices of low-density lipoprotein oxidation in healthy men. Impairment in coronary flow reserve, as assessed by positron emission tomography, is associated with lipoprotein oxidation, which is affected by high-density lipoprotein bound enzyme, paraoxonase. Paraoxonase has two common polymorphisms (M/L55 and R/Q192) that change the activity of the enzyme. Forty-nine healthy men (mean age 35 +/- 4 years) were divided by paraoxonase genotype into low (Q192/Q192, or M55/M55, M55/L55) and high-active (R192/Q192, R192/R192, or L55/L55) groups and related to the myocardial blood flow, to the susceptibility of low-density lipoprotein to oxidation, and the autoantibody titer against oxidized low-density lipoprotein. The blood flow was measured by positron emission tomography at rest and during adenosine infusion. The low-active Q192/Q192 genotype was associated with higher resting blood flow corrected for rate-pressure product compared to the high-active R192/R192 and R192/Q192 genotypes (P=0.011). The blood flow stimulated by adenosine was not significantly different in the low- and high-active genotype groups. Paraoxonase genotypes had no effect on low-density lipoprotein susceptibility to oxidation or autoantibody formation against oxidized low-density lipoprotein. Genotypes of paraoxonase may not clearly contribute to the early changes in coronary reactivity. Coronary vasomotor tone at rest appears to be modulated by paraoxonase R/Q192 polymorphism through mechanism(s) unrelated to low-density lipoprotein oxidation.

Hepatic lipase gene variation is related to coronary reactivity in healthy young men.

BACKGROUND: Impaired coronary flow reserve (CFR) can be used to indicate vascular dysfunction before the appearance of angiographic lesions. The hepatic lipase (HL) gene has a functional promoter polymorphism at position C-480T, which affects transcription and leads to high activity (C/C) and low activity (C/T, T/T) genotypes. These genotypes modulate HL activity, but their role in coronary artery disease is controversial and the effect on coronary function has not been studied. We investigated whether HL genotypes are associated with coronary artery function in healthy young men. MATERIALS AND METHODS: We studied 49 healthy, mildly hypercholesterolemic men (aged 35 +/- 4 years). Myocardial blood flow was measured at rest and during adenosine induced hyperaemia with positron emission tomography using [15O] H2O. HL genotype was determined by PCR and Nla III enzyme digestion. RESULTS: Resting myocardial blood flow was not statistically different in subjects with high and low activity HL genotypes. However, CFR (the ratio of adenosine flow to resting flow) was 24% higher (4.62 +/- 1.52 vs. 3.73 +/- 1.08 mL g-1 min-1, P = 0.024) in men with the high activity genotype (n = 26) than in those with low activity (n = 23). In multivariate analysis, the HL genotype remained a significant predictor of CFR (P = 0.038) after adjusting for age, body mass index, serum lipids and smoking. CONCLUSIONS: The findings of our preliminary study suggest that the C-480T polymorphism of the HL gene may modify coronary reactivity and reflect differences in the early pathogenesis of coronary dysfunction in these healthy young men. If the association between HL polymorphism and impaired CFR is also present in subjects with other dyslipoproteinemias, the HL polymorphism could be a new risk factor for cardiovascular disease.

Pharmacokinetics of intravenous N-acetylcysteine in pre-term new-born infants.

BACKGROUND: Reactive oxygen species have been considered to play a role in several clinical complications in pre-term infants. The aim of this study was to determine the pharmacokinetics of intravenous N-acetylcysteine in pre-term neonates. This information is needed to evaluate the use of N-acetylcysteine as an antioxidant in this patient group. METHODS: N-acetylcysteine was infused intravenously in ten patients (gestational age 24.9-31.0 weeks, weight 500-1384 g) for 24 h (3.4-4.6 mg/kg/h), starting 2.0-11.2 h from birth (study I) and in six patients (gestational age 25.9-29.7 weeks, weight 520-1335 g) for 6 days (0.3-1.3 mg/kg/h), starting at the age of 24 h (study II). Arterial plasma N-acetylcysteine and cyst(e)ine concentrations were determined from timed samples taken during (study I and II) and after (study I) the N-acetylcysteine infusion. RESULTS: In study I, the mean elimination half-life of N-acetylcysteine was 11 h (range 7.8-15.2 h). The mean plasma clearance of N-acetylcysteine was 37 ml/kg/h (range 13-62 ml/kg/h) and the mean volume of distribution was 573 ml/kg (range 167-1010 ml/kg). The plasma clearance and volume of distribution correlated with weight (r = 0.81, P < 0.01, and r = 0.78, P < 0.01, respectively) and with gestational age (r = 0.71, P < 0.05, and r = 0.64, P < 0.05, respectively). In study II, the steady-state concentration of N-acetylcysteine was reached in 2-3 days in five of six patients during a constant infusion. CONCLUSIONS: The pharmacokinetics of N-acetylcysteine in pre-term infants depend markedly on weight and gestational age. The elimination of N-acetylcysteine is much slower in pre-term new-borns than in adults.

Low-density lipoprotein-independent effects of statins.

Statins have pleiotropic properties that complement their cholesterol-lowering effects. These properties may partly account for their established benefit in the prevention of coronary artery disease beyond the reduction of LDL-cholesterol levels. The most widely recognized properties are reviewed here. They include: (i) nitric oxide-mediated improvement of endothelial dysfunction and upregulation of endothelin-1 expression; (ii) antioxidant effects; (iii) anti-inflammatory properties; (iv) inhibition of cell proliferation with anticarcinogenic actions in animals; (v) stabilization of atherosclerotic plaques; (vi) anticoagulant effects; and (vii) inhibition of graft rejection after heart and kidney transplantation. As advances are made in our knowledge, new properties are steadily being uncovered. Pleiotropic effects are currently being given consideration when instituting combination therapy for patients at high cardiovascular risk. Some pleiotropic effects are negative, and may account for occasional untoward drug interactions. For many of these new properties, the clinical relevance has not been established. The challenge for the future will be to design and carry out appropriate clinical trials to establish their relative importance in the prevention of coronary artery disease.

Modification of neuromagnetic cortical signals by thalamic infarctions.

Auditory evoked responses and spontaneous cortical activity were recorded with a whole-scalp 122-channel neuromagnetometer from 7 patients, who had small thalamic infarctions in the region of the left anterior tuberothalamic artery and associated memory defects. In contrast to healthy control subjects, with dominant rhythmic activity at 10.6 +/- 0.6 Hz in the parieto-occipital region, the spectral maximum in the patients was at 8.9 +/- 0.4 Hz. Abnormal acceleration of rhythmic activity was also observed bilaterally in rolandic areas. Our findings imply that lesions of non-specific thalamic nuclei may disturb human brain rhythms in widespread cortical areas. 'Mismatch responses' to deviant tones (1.1 kHz) among standards (1.0 kHz), suggested to reflect sensory auditory memory in healthy subjects, were absent in 2 patients, markedly decreased in 3, and normal in 2, implying that pathways passing through the anteromedial thalamus contribute to modulation of these responses. We conclude that local unilateral lesions in the anteromedial thalamus may cause extensive, bilateral alterations in the brain's electric activity.

The effect of simvastatin treatment on natural antioxidants in low-density lipoproteins and high-energy phosphates and ubiquinone in skeletal muscle.

It has been hypothesized that treating hypercholesterolemic patients with statins will lead not only to a reduction in cholesterol, but also to inhibited synthesis of other compounds which derive from the synthetic pathway of cholesterol. In theory, this could further lead to ubiquinone deficiency in muscle cell mitochondria, disturbing normal cellular respiration and causing adverse effects such as rhabdomyolysis. Furthermore, ubiquinone is one of the lipophilic antioxidants in low-density lipoprotein (LDL), and therefore it has also been hypothesized that statin treatment will reduce the antioxidant capacity of LDL. We investigated the effect of 6 months of simvastatin treatment (20 mg/day) on skeletal muscle concentrations of high-energy phosphates and ubiquinone by performing biopsies in 19 hypercholesterolemic patients. Parallel assays were performed in untreated control subjects. The muscle high-energy phosphate and ubiquinone concentrations assayed after simvastatin treatment were similar to those observed at baseline and did not differ from the values obtained in control subjects at the beginning and end of follow-up. These results do not support the hypothesis of diminished isoprenoid synthesis or energy generation in muscle cells during simvastatin treatment. Furthermore, the results of analysis of antioxidant concentrations in LDL before and after simvastatin treatment indicate that the antioxidant capacity of LDL is maintained in simvastatin-treated patients.

Behavioral assessment of patients treated with alpha-interferon.

To document behavioral effects of interferon (IFN) with daily consecutive assessments we developed an easily administered procedure for bedside testing. It included assessment of mental control and affective behavior, and a self-assessment questionnaire. The method was evaluated in 9 lung cancer patients before and during the treatment with alpha-IFN and the results were supplemented with those obtained by a neuropsychological test battery of one of the patients. The latter tests covered memory, visuoperceptual, visuoconstructional, speech, language, intellectual and psychomotor functions, reading, writing, and calculation. The bedside method was capable of revealing the essential effects of IFN on human behavior, i.e. irritability, slowing of behavior, dyscoordination, and motor perseveration. Consequently, the bedside testing method is recommended for frequently repeated clinical assessments of aberrant behavior of patients treated with IFN, while neuropsychological test batteries serve better for testing situations requiring more detailed and quantified data of localization value.

Dementia-like, largely reversible syndrome after cranial irradiation and prolonged interferon treatment.

An elderly man with small cell lung cancer developed a largely reversible, dementia-like syndrome after cranial irradiation and prolonged treatment with interferon (IFN). The development of the symptoms started 2 months after cranial irradiation following more than 2 years of IFN treatment. The behavioral impairment did not suggest any specific brain localization. The dementia-like behaviour may be due to a combined effect of irradiation and IFN.