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ObjectiveCognitive and motor impairments are the key clinical manifestations of cerebral small vessel disease (SVD), but their interrelations and combined effects on functional outcome have not been elucidated. We investigated the associations between cognitive and motor functions and their interactions and mediating effects on instrumental activities of daily living (IADL) and quality of life in older individuals with various degrees of white matter hyperintensities (WMH).MethodsParticipants of the Helsinki Small Vessel Disease Study (n=152) were assessed according to an extensive clinical, neuropsychological and MRI protocol. Cognitive composite scores for global cognition, processing speed, executive functions and memory were constructed from multiple tests within each domain. Physical examination included measures of gait speed, balance (single-leg-stance) and functional mobility (timed-up-and-go test). IADL was evaluated with a proxy-based Amsterdam IADL questionnaire and quality of life with a self-report EUROHIS-Qol index. Volumes of WMH and gray matter (GM) were obtained with automated segmentation. Sets of linear regression analyses were used to model the associations between motor and cognitive performances, WMH and GM volumes, and IADL and quality of life.ResultsDomain-specific cognitive and motor functions had strong interrelations with each other, and they were significantly associated with IADL, quality of life as well as WMH and GM volumes. A consistent pattern on significant interactions between cognitive and motor functions was found on IADL, but not on quality of life. In particular, low cognitive scores together with decline in the timed-up-and-go test and gait speed were strongly related to impaired IADL. The association of WMH volume with IADL was mediated by global cognition, whereas the association of GM volume with IADL was mediated by global cognition and timed up-and-go performance.ConclusionThe results highlight the complex interplay and synergism between motor and cognitive abilities on functional outcome in SVD. The combined effect of motor and cognitive disturbances on IADL is likely to be greater than the individual effects of each of the two impairments. WMH and brain atrophy contribute to disability through cognitive and motor impairment.

The Dali server (http://ekhidna2.biocenter.helsinki.fi/dali) is a network service for comparing protein structures in 3D. In favourable cases, comparing 3D structures may reveal biologically interesting similarities that are not detectable by comparing sequences. The Dali server has been running in various places for over 20 years and is used routinely by crystallographers on newly solved structures. The latest update of the server provides enhanced analytics for the study of sequence and structure conservation. The server performs three types of structure comparisons: (i) Protein Data Bank (PDB) search compares one query structure against those in the PDB and returns a list of similar structures; (ii) pairwise comparison compares one query structure against a list of structures specified by the user; and (iii) all against all structure comparison returns a structural similarity matrix, a dendrogram and a multidimensional scaling projection of a set of structures specified by the user. Structural superimpositions are visualized using the Java-free WebGL viewer PV. The structural alignment view is enhanced by sequence similarity searches against Uniprot. The combined structure-sequence alignment information is compressed to a stack of aligned sequence logos. In the stack, each structure is structurally aligned to the query protein and represented by a sequence logo.

OBJECTIVE Physical activity reduces high-sensitivity C-reactive protein (hs-CRP), cardiovascular disease (CVD), and total mortality in type 2 diabetic patients. However, it is not known whether the effects of physical activity on mortality depend on the levels of hs-CRP in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS We prospectively followed-up on 569 type 2 diabetic patients, aged 45–64 years, who were free of CVD at baseline. Participants were stratified according to the level of hs-CRP (3.0 mg/L) and the degree of physical activity (0–4 metabolic equivalent tasks [METs] or >4 METs). The Cox proportional hazards model was used to estimate the joint association between physical activity and hs-CRP levels and the risk of mortality. RESULTS During an 18-year follow-up, 356 patients died, 217 of whom died of CVD. Those who were physically more active had significantly reduced total, CVD and coronary heart disease (CHD) mortality among patients with elevated hs-CRP levels (>3 mg/L). These findings persisted in multivariable analyses. However, in patients with an hs-CRP level CONCLUSIONS Physical activity reduces total, CVD, and CHD mortality in type 2 diabetic patients with elevated hs-CRP levels. This suggests that the anti-inflammatory effect of physical activity may counteract increased CVD and CHD morbidity and mortality associated with high CRP levels.

The pathogenetic mechanisms of organ-specific autoimmune diseases remain obscured by the complexity of the genetic and environmental factors participating in the breakdown of tolerance. A unique opportunity to study the pathogenesis of human autoimmunity is provided by autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), a rare inherited autoimmune disease caused by mutations in Autoimmune Regulator (AIRE) gene. Loss of AIRE function disrupts the deletion of autoreactive T cells and impairs the suppressive function of regulatory T (Treg) cells. Here we show by multiparameter flow cytometry that in healthy controls the peripheral naive Treg cell subset forms a slowly dividing, persistent reservoir of recent thymic emigrants (RTEs). In APECED patients the RTE Treg cells show accelerated turnover and shift to the activated pool and the RTE reservoir is depleted. Moreover, the activated Treg cell population in the patients expresses significantly less Forkhead box protein P3 (FOXP3) than in the healthy controls, consistent with the impairment of peripheral activation. Our results indicate that in addition to their thymic effects, loss-of-function mutations in AIRE disrupt the peripheral homeostasis and activation of Treg cells. This may synergize with failed negative selection to cause APECED.

Modification of alpha-biphenylsulfonamidocarboxylic acids led to potent and selective MMP-13 inhibitors. Compound 16 showed 100% oral bioavailability in rats and demonstrated50% inhibition of bovine cartilage degradation at 10 ng/mL.

Summary Coronary artery disease (CAD) is the cause of death of many patients with type 2 diabetes (T2D). Type 2 diabetes intensifies the risk associated with cardiovascular events, especially coronary heart disease. Major risk factors for CAD in patients with T2D are dyslipidaemia (high low-density lipoprotein cholesterol, low high-density lipoprotein cholesterol, high total triglycerides), elevated blood pressure, smoking, hyperglycaemia, and insulin resistance. Treating these conditions (dyslipidaemia, elevated blood pressure, and hyperglycaemia) as single cardiovascular risk factors is beneficial, but multifactorial intervention may be more clinically beneficial in preventing cardiovascular complications or secondary cardiovascular events.

We have modeled the silicon melt flow and temperature as well as the applied and induced magnetic fields in a large-scale, cylindrically symmetric Czochralski crystal growth system. The validity of a cylindrically symmetric model is evaluated by comparing melt flow simulations to previously published three-dimensional simulations and experimental measurements in identical setups. The applied magnetic field, due to a given external magnet configuration and its current distribution, is first solved. Subsequently, the coupled magnetohydrodynamical system, i.e., the Navier–Stokes, heat and induction equations, is solved in the melt region. The mathematical model is discretized by the finite element method. The numerical methods used are explained in this article. The applied external magnetic fields we have considered are time-independent and axisymmetric. The magnetohydrodynamical problem is time-dependent, and the velocity and the induced magnetic field have azimuthal components. The velocity distributions and temperature time series for various cusp-type fields are compared. It is found that a magnetic field of the order of 25 mT strongly damps the temperature oscillations in the melt outside about half the crucible radius. A higher field of about 100 mT stabilizes the flow in most of the melt.

Lewy bodies and dystrophic neurites have been considered a common substrate for dementia, but they are also frequently found in the normal elderly population. The primary component of this pathology involves alpha-synuclein. The main objective of the present study was to estimate the prevalence of alpha-synuclein pathology in aged population, and to assess its relative significance in relation to dementia. The study also investigated whether differences could be detected in alpha-synuclein pathology in relation to age, gender or concomitant Alzheimer's pathology. Furthermore, the influence of sampling strategies was analysed. Alpha-synuclein pathology was assessed using immunohistochemistry in well-characterized post-mortem material. The investigation included patients from a longitudinal study of dementia of Alzheimer's type (n = 103, 85% demented), subjects from a prospective longitudinal clinical study of ageing (n = 69, 29% demented), a cohort of consecutive clinical post-mortem cases collected for 1 year (n = 262, 12% demented), a sample of forensic post-mortem cases collected for 6 months (n = 121, 15% demented) and a sample of Brain Bank material (n = 234, 26% demented). Overall, alpha-synuclein pathology was found in 14% of all 774 subjects over 40 years of age, and this percentage varied from 8% to 27% according to sampling strategies. These results indicate that the prevalence of alpha-synuclein pathology clearly depends on the selection of material. Furthermore alpha-synuclein pathology was found in 23% of clinically demented patients and in 11% of non-demented subjects. The load of alpha-synuclein pathology was significantly greater in the demented patients versus non-demented subjects indicating that alpha-synuclein pathology is indeed of importance in the pathogenesis of dementia.

We investigated serum concentrations of lipoprotein subclass particles and their lipid components determined by proton nuclear magnetic resonance spectroscopy in a population-based study.A total of 9399 Finnish men were included in the study: 3034 men with normal fasting glucose and normal glucose tolerance; 4345 with isolated impaired fasting glucose (IFG); 312 with isolated impaired glucose tolerance (IGT); 1058 with both IFG and IGT; and 650 with newly diagnosed type 2 diabetes (New DM). Lipoprotein subclasses included chylomicrons (CM) and largest VLDL particles, other VLDL particles (five subclasses), intermediate-density lipoprotein (IDL), LDL (three subclasses) and HDL (four subclasses). The phospholipid, triglyceride (TG), cholesterol, free cholesterol and cholesterol ester levels of the lipoprotein particles were measured.Abnormal glucose tolerance (especially IGT and New DM) was significantly associated with increased concentrations of VLDL subclass particles and their components (with the exception of very small VLDL particles). After further adjustment for total TGs and HDL cholesterol, increased lipid concentrations in the CM/largest VLDL particles and in most of the other VLDL particles remained significant in individuals with isolated IGT, IFG+IGT and New DM. There was a consistent trend towards a decrease in large and an increase in small HDL particle concentrations in individuals with hyperglycaemia even after adjustment for serum total TGs and HDL cholesterol.Abnormal glucose tolerance modifies the concentrations of lipoprotein subclass particles and their lipid components in the circulation and is also related to compositional changes in these particles.

The objective of this study was to examine the associations between indices of liver insulin resistance (IR) and whole-body insulin sensitivity and different cardiovascular disease (CVD) risk factors.A total of 8750 nondiabetic men (age 57.2 ± 7.1 years, body mass index 26.8 ± 3.8 kg m(-2) ) were included in this study from the population-based cross-sectional Metabolic Syndrome In Men (METSIM) cohort. Liver IR index and Matsuda insulin sensitivity index (ISI) were used as markers of liver IR and whole-body insulin sensitivity, respectively. Pearson correlation analysis was performed to examine the associations between these indices and various CVD risk factors.Total cholesterol (r = -0.088 vs. r = 0.020; P0.0019), high-sensitivity C-reactive protein (CRP) (r = 0.284 vs. r = -0.219; P0.0019) and total triglycerides (r = 0.507 vs. r = -0.477; P0.05) were more highly correlated with liver IR index than with Matsuda ISI. By contrast, Matsuda ISI was nominally more highly correlated with systolic and diastolic blood pressure (r = -0.234 and r = -0.275 vs. r = 0.202 and r = 0.239, respectively) compared to liver IR index. Furthermore, the variance explained by liver IR index was larger than that explained by Matsuda ISI for the majority of CVD risk factors measured.Liver IR index correlated more strongly than Matsuda ISI with levels of total cholesterol, CRP and triglycerides. Therefore, liver IR might be a significant indicator of CVD risk amongst men.

The most important goal in the treatment of patients with diabetes is to lower the risk of long-term diabetes complications. Hyperglycaemia is the most important risk factor for microvascular complications in diabetes, but, in addition to hyperglycaemia, several other risk factors, particularly dyslipidaemia, elevated blood pressure and smoking, also determine the risk of macrovascular complications. In this review, we present evidence from longitudinal population-based studies that hyperglycaemia is an important risk factor for long-term complications of diabetes and discuss the results from clinical trials of the effects of the treatment of hyperglycaemia on the prevention of long-term micro- and macrovascular complications in type 1 and type 2 diabetes. An HbA(1c) target of7.0% for the treatment of diabetes is generally accepted on the basis of evidence from several trials, whereas a target of6.5% may be reasonable for patients with a short duration of type 2 diabetes and without extensive atherosclerosis.

The ability to sense molecular tension is crucial for a wide array of cellular processes, including the detection of auditory stimuli, control of cell shape, and internalization and transport of membranes. We show that myosin I, a motor protein that has been implicated in powering key steps in these processes, dramatically alters its motile properties in response to tension. We measured the displacement generated by single myosin I molecules, and we determined the actin-attachment kinetics with varying tensions using an optical trap. The rate of myosin I detachment from actin decreases >75-fold under tension of 2 piconewtons or less, resulting in myosin I transitioning from a low (0.9) duty-ratio motor. This impressive tension sensitivity supports a role for myosin I as a molecular force sensor.

There has been no previous study to determine the severity and extent of coronary artery disease (CAD) in subjects with no diagnosis or symptoms of CAD at the time of the angiography.Fifty-three subjects, who were siblings of patients with early onset CAD, underwent coronary angiography. Indices to describe per-patient characteristics of CAD were calculated, based on computer-aided quantitative coronary angiography. Clinical and laboratory characteristics were correlated to the angiographic parameters.Serum total homocysteine (rho = 0.29, P0.05) and creatinine (rho = 0.47, P = 0.001) levels were related to the global atheroma burden index. The median of the atheroma burden index was two times higher in the top homocysteine quartile compared to the lowest quartile. The overall atheroma burden index correlated significantly with the fasting blood glucose level in all subjects. Diabetes, especially when albuminuria was present, was a powerful risk factor. In a multivariate analysis, only age and sex were independent predictors of atheroma burden.Serum homocysteine and creatinine concentrations, and diabetes with albuminuria were found to be markers of the severity and extent of CAD in subjects of high-risk families without symptoms of CAD.

How cardiac autonomic nervous control is related to the severity of essential hypertension in patients receiving long-term antihypertensive therapy is not well known. The aim of this study was to examine heart rate variability (HRV), a non-invasive measure of cardiac autonomic function, in patients with long-term and medically treated mild and severe essential hypertension and healthy control subjects, and to assess the clinical determinants of HRV in these patients. Thirty-four patients with severe essential hypertension (SEHT) and 29 with mild essential hypertension (MEHT) as well as healthy age- and sex-matched control subjects were studied. HRV was assessed from 10 min ECG-recordings during paced (0.2 Hz) breathing at rest and expressed as time and frequency domain measures. In the SEHT group time (SDNN, RMSSD) and frequency domain measures (total power, low-frequency (LF) power and high-frequency (HF) power of HRV in absolute units, and LF and HF power of HRV in normalized units) of HRV were significantly lower when compared with those of the control group. The MEHT and control groups did not differ from each other with respect to time or frequency domain measures of HRV. Comparison between the hypertensive groups showed that SDNN, total power, LF power and HF power were lower in the SEHT group compared with the MEHT group (P0.05 for all). Among hypertensive patients RR-interval, age, gender, systolic finger blood pressure and diastolic office blood pressure as well as 24-h blood pressure were significant determinants of HRV. In conclusion, we found that the severity of chronic essential hypertension seems to be related to the severity of impairment of cardiac autonomic control.

Insulin resistance in the most common familial dyslipidemia, familial combined hyperlipidemia (FCHL), could be due to variations in the hormone sensitive lipase (HSL) gene.The coding region of the HSL gene was screened with the single strand conformation polymorphism analysis in probands of 27 FCHL families with 228 members. In addition, the C-60G promoter substitution of the HSL gene was determined by the restriction fragment length polymorphism analysis in these subjects.No variants in the coding region of the HSL gene were found and the allele frequencies of the C-60G promoter substitution and the silent variant (G3138A) in the 3' untranslated region did not differ between 110 control subjects and 27 probands with FCHL. However, in control women the C-60G substitution was associated with high body mass index [30.6 +/- 0.9 kg m(-2) (mean +/- SD) in subjects with the C/G genotype and 24.8 +/- 4.6 in subjects with the C/C genotype, P = 0.012], and in control men with high rates of insulin-stimulated whole body glucose uptake (70.1 +/- 14.7 vs. 56.7 +/- 14.2 micromol kg(-1) min(-1), P = 0.014). In 228 FCHL family members this substitution was associated with high low-density lipoprotein cholesterol levels in men (4.51 +/- 1.12 vs. 5.17 +/- 1.28 mmol L(-1), P = 0.049), but not in women.The HSL gene is not a major gene for FCHL. However, the - 60G allele of this gene may affect body weight, insulin sensitivity and serum cholesterol levels.

We have recently demonstrated that subjects having Pro7 in the signal peptide ofneuropeptide Y (NPY) have higher serum cholesterol and apolipoprotein B levels than individuals with wild-type (Leu7Leu7) signal peptide sequence. We investigated the association of Leu7Pro polymorphism with common carotid intima media thickness (IMT) assessed by ultrasonograph in patients with type 2 diabetes (n = 81; 41 men and 40 women; mean age, 67.1 yr) and nondiabetic subjects (n = 105; 48 men and 57 women; mean age, 65.5 yr) and genotyped for the Leu7Pro polymorphism in prepro-NPY. The frequency of Pro7 in prepro-NPY was 9.9% (8 of 81) in diabetic patients and 14.3% (15 of 105) in control subjects (P = 0.360). The mean common carotid IMT was 1.04 +/- 0.02 mm in nondiabetic subjects without the Leu7Pro polymorphism and 1.14 +/- 0.04 mm in nondiabetic subjects with in (P = 0.156) and 1:18 +/- 0.03 and 1.58 +/- 0.21mm in diabetic patients without and with the Leu7Pro polymorphism (P = 0.004), respectively. In the analysis of covariance of the entire group, the mean common carotid IMT was independently associated with the Leu7Pro polymorphism (F = 5.165; P = 0.024) after adjustment for known risk factors. Thus, the presence of the Pro7 substitution in the prepro-NPY associates with increased carotid atherosclerosis.

AIMS/HYPOTHESIS; The aim of the Diabetes Prevention Study is to assess the efficacy of an intensive diet-exercise programme in preventing or delaying Type II (non-insulin-dependent) diabetes mellitus in subjects with impaired glucose tolerance, to evaluate the effects of the intervention programme on cardiovascular risk factors and to assess the determinants for the progression to diabetes in persons with impaired glucose tolerance.A total of 523 overweight subjects with impaired glucose tolerance ascertained by two oral glucose tolerance tests were randomised to either a control or intervention group. The control subjects received general information at the start of the trial about the lifestyle changes necessary to prevent diabetes and about annual follow-up visits. The intervention subjects had seven sessions with a nutritionist during the first year and a visit every 3 months thereafter aimed at reducing weight, the intake of saturated fat and increasing the intake of dietary fibre. Intervention subjects were also guided individually to increase their physical activity.During the first year, weight loss in the first 212 study subjects was 4.7 +/- 5.5 vs 0.9 +/- 4.1 kg in the intervention and control group, respectively (p0.001). The plasma glucose concentrations (fasting: 5.9 +/- 0.7 vs 6.4 +/- 0.8 mmol/l, p0.001; and 2-h 7.8 +/- 1.8 vs 8.5 +/- 2.3 mmol/l, p0.05) were significantly lower in the intervention group after the first year of intervention. Favourable changes were also found in blood pressure, serum lipids and anthropometric indices in the intervention group.The interim results show the efficacy and feasibility of the lifestyle intervention programme.

Type 2 diabetes is associated with an increased risk for cardiovascular disease. In recent years, prospective studies have indicated that, in addition to conventional risk factors, glycaemic control of diabetes predicts cardiovascular disease in both middle-aged and elderly patients with Type 2 diabetes. However, there are no consistent data from different studies to indicate that postprandial glucose is a better predictor for cardiovascular risk than fasting glucose level. Although no clinical trials are available to show that improving glycaemic control prevents cardiovascular mortality and morbidity, recent studies imply that hyperglycaemia in patients with Type 2 diabetes should be treated more intensively than recommended by current guidelines

High plasma homocysteine level has been associated with increased risk for coronary heart disease (CHD) events in nondiabetic individuals, especially in those with previously diagnosed CHD. In persons with type 2 diabetes mellitus, the association between homocysteine level and cardiovascular disease may be stronger than that in nondiabetic individuals, but no large prospective studies have examined the relationship between homocysteine level and CHD mortality in persons with type 2 diabetes.To investigate whether moderately elevated plasma homocysteine levels are independently related to increased incidence of fatal and nonfatal CHD events in persons with type 2 diabetes.Prospective study.Finnish sample of patients with type 2 diabetes.462 men and 368 women who were 45 to 64 years of age at baseline.Coronary heart disease mortality and incidence of nonfatal myocardial infarction during the 7-year follow-up.Participants with plasma homocysteine levels of 15 micromol/L or more at baseline had a higher risk for CHD death than those with plasma homocysteine levels less than 15 micromol/L (26.1% and 13.5%, respectively; P = 0.005). The risks for all CHD events were 36.2% and 22.6%, respectively (P = 0.011). In Cox regression analyses, elevated plasma homocysteine level was significantly associated with CHD mortality (P0.001) and all CHD events (P = 0.002) even after adjustment for confounding variables, including creatinine clearance. In participants without myocardial infarction at baseline, moderate hyperhomocysteinemia was also associated with CHD mortality and all CHD events in univariate (P0.001 and P = 0.006, respectively) and multivariate Cox regression analyses (P0.001 and P = 0.004, respectively).In this large cohort of patients with type 2 diabetes, plasma homocysteine level was a strong and independent risk factor for CHD events.

The findings in six patients admitted to hospital 0.5-4.5 h after the ingestion of an overdose of 2.4-8 g sotalol are described. In addition to bradycardia and hypotension, all patients had a considerably prolonged corrected Q-T interval, up to 172 +/- 8% of normal. Severe ventricular tachyarrhythmias occurred in five of the six patients, the risk was greatest up to 20 h after the ingestion of sotalol. The long Q-T interval returned to normal over 3 to 4 days, which is consistent with the long half-life of sotalol. In addition to its beta-blocking action, sotalol has marked electrophysiological properties of a Class III antiarrhythmic drugs, which are likely to be able to account for its observed effects. Special attention should be paid to the risk of severe ventricular arrhythmias in sotalol intoxications.

Five hundred men and 500 women, aged 40 or over, with rheumatoid arthritis, together with a control population matched for age and sex, were observed over 10 years. During that time 352 patients with rheumatoid arthritis (208 men, 144 women) and 221 controls (148 men, 73 women) died. The overall mortality was significantly higher (p less than 0.0001) in both men and women with rheumatoid arthritis than in the controls. Infections and cardiovascular and renal diseases (especially amyloidosis) appeared to be the main causes of death in rheumatoid arthritis.