Risto Huupponen

In Vivo Detection of Vascular Adhesion Protein-1 in Experimental Inflammation

Vascular adhesion protein-1 (VAP-1) is an inflammation-inducible endothelial glycoprotein which mediates leukocyte-endothelial cell interactions. To study the pathogenetic significance of VAP-1 in inflammatory disorders, an in vivo immunodetection method was used to detect the regulation of luminally expressed VAP-1 in experimental skin and joint inflammation in the pig and dog. Moreover, VAP-1 was studied as a potential target to localize inflammation by radioimmunoscintigraphy. Up-regulation of VAP-1 in experimental dermatitis and arthritis could be visualized by specifically targeted immunoscintigraphy. Moreover, the translocation of VAP-1 to the functional position on the endothelial surface was only seen in inflamed tissues. These results suggest that VAP-1 is both an optimal candidate for anti-adhesive therapy and a potential target molecule for imaging inflammation.

Obesity, adipokines and asthma

Background:  The prevalence of asthma and obesity is increasing concomitantly, but many aspects of this link are unclear. Our objective was to examine whether obesity is associated with asthma in three time points of life, and whether immunomodulatory adipokines, leptin and adiponectin are linked to overweight‐associated asthma.

Human adipose tissue glucose uptake determined using [18F]-fluoro-deoxy-glucose ([18F]FDG) and PET in combination with microdialysis

Abstract.Aims/hypothesis: To determine the lumped constant (LC), which accounts for the differences in the transport and phosphorylation between [18F]-2-fluoro-2-deoxy-d-glucose ([18F]FDG) and glucose, for [18F]FDG in human adipose tissue. Methods: [18F]FDG-PET was combined with microdialysis. Seven non-obese (29 ± 2 years of age, BMI 24 ± 1 kg/m2) and seven obese (age 32 ± 2 years of age, BMI 31 ± 1 kg/m2) men were studied during euglycaemic hyperinsulinaemia (1 mU/kg · min–1 for 130 min). Abdominal adipose tissue [18F]FDG uptake (rGUFDG) and femoral muscle glucose uptake were measured using [18F]FDG-PET. Adipose tissue perfusion was measured using [15O]-labelled water and PET, and interstitial glucose concentration using microdialysis. Glucose uptake (by microdialysis, rGUMD) was calculated by multiplying glucose extraction by regional blood flow. The LC was determined as the ratio of rGUFDG to rGUMD. Results: Rates of adipose tissue glucose uptake (rGUMD) were 36 % higher in the non-obese than in the obese patients (11.8 ± 1.7 vs 7.6 ± 0.8 μmol/kg · min–1, p < 0.05, respectively) and a correlation between rGUMD and rGUFDG was found (r = 0.82, p < 0.01). The LC averaged 1.14 ± 0.11, being similar in the obese and the non-obese subjects (1.01 ± 0.15 vs 1.26 ± 0.15, respectively, NS). Muscle glucose uptake was fourfold to fivefold higher than adipose tissue glucose uptake in both groups. Conclusion/interpretation: [18F]FDG-PET seems a feasible tool to investigate adipose tissue glucose metabolism in human beings. Direct measurements with [18F]FDG-PET and microdialysis suggest a LC value of 1.14 for [18F]FDG in human adipose tissue during insulin stimulation and the LC does not appear to be altered in insulin resistance. Furthermore, the obese patients show insulin resistance in both adipose tissue and skeletal muscle. [Diabetologia (2001) 44: 2171–2179]

Effects of medication assessment as part of a comprehensive geriatric assessment on drug use over a 1-year period: a population-based intervention study.

BackgroundHigh drug consumption among the elderly and inappropriate prescribing practices increase the risk of adverse drug effects in this population. This risk may be decreased by conducting, for example, a medication review alone or as part of a comprehensive geriatric assessment (CGA); however, little is known about the fate of the changes in medication made as a result of the CGA or medication review.ObjectiveTo study the performance of the CGA with regards to medication changes and to determine the persistence of these changes over a 1-year period.MethodsThis study was a population-based intervention study. A random sample of 1000 elderly (age ≥75 years) was randomized either to a CGA group or to a control group. Home-dwelling patients from these groups (n = 331 and n = 313 for intervention and control groups, respectively) were analysed in this study. Study nurses collected information on medication at study entry and 1 year later in both groups; in the intervention group, study physicians assessed, and changed when appropriate, the medication at study entry. The medication changes and their persistence over 1 year were then evaluated.ResultsMedication changes were more frequent in the intervention group than in the control group. Regular medication was changed during follow-up in 277 (83.7%) and in 228 (72.8%) [odds ratio (OR) 1.9; 95% CI 1.3, 2.8] patients in the intervention and control groups, respectively. In the intervention group, study physicians were responsible for 35.4% of all new prescriptions and for 15.6% of all drug terminations. Changes took place particularly in the prescription of CNS drugs. About 58% of the drugs initiated by study physicians were still in use 1 year later, and 25.5% of those terminated by study physicians had been reintroduced.ConclusionDrug intervention as part of a CGA can be used to rationalize the drug therapy of a patient. However, its effectiveness is subsequently partly counteracted by other physicians working in the healthcare system.

Long-Term Persistence with Statin Therapy: A Nationwide Register Study in Finland

BACKGROUND Preventive statin therapy is often recommended as lifelong treatment. OBJECTIVE The aim of this study was to analyze persistence with statin therapy over a decade of use and to identify factors associated with its discontinuation. METHODS Persistence with therapy among new users of statins in 1995 was followed up until December 31, 2005, in Finland using the nationwide drug reimbursement register. Cumulative persistence was analyzed using Kaplan-Meier analysis. A Cox regression model was applied to analyze associations of various baseline covariates with discontinuation. We further modeled the association of time-specific covariates by stratifying the duration of therapy in years and using a logistic regression in which those continuing therapy until the end of follow-up (persistent users) formed the reference group. Adherence, defined as the proportion of days covered by statins, stratified by the timing of discontinuation, was computed for the respective groups. RESULTS Of the 18,072 new statin users, 73.3% (n =13,254) were aged >54 years and 54.8% (n =9908) were men. Of this cohort, 43.9% (n = 7926) were using statins throughout and at the end of the tenth year. Sex was not associated with persistence at any point. In the Cox model, persons aged 45 to 74 years at initiation were more likely to continue statin use than younger or older age groups. Among those who still used statins after the fifth year of observation, the age difference was not observed in the logistic regression model. The use of 1, 2, 3, or > or =4 cardiovascular drugs before the initiation predicted continuation relative to no cardiovascular drug use (hazard ratio for discontinuation significantly <1.00 in all comparisons). Adherence was best (median 93.9%) among the persistent users. CONCLUSIONS The 10-year persistence with statin use in this general population was approximately 44%. Persons aged 45 to 74 years at initiation and those with at least 1 prescription for another cardiovascular medication were the most likely to continue statin therapy up to the fifth year.

Serum testosterone but not leptin predicts mortality in elderly men

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Risk of serious upper gastrointestinal events with concurrent use of NSAIDs and SSRIs: a case-control study in the general population

ObjectivesTo study the risk of serious upper gastrointestinal (GI) events associated with the concurrent use of selective serotonin re-uptake inhibitors (SSRIs) and different types of non-steroidal anti-inflammatory drugs (NSAIDs).MethodsThis was a nationwide, register-based matched case-control study on non-institutionalized residents of Finland during the period 2000–2004. Patient-cases with serious upper GI events (n = 9191) were drawn from the Hospital Discharge Register, and individually matched controls (n = 41,780) were drawn from the Population Register. Logistic regression was applied in the data analysis, and adjustments were made for various co-morbidities and the use of other drugs associated with the risk of serious upper GI event.ResultsThe adjusted odds ratio (AOR) of serious upper GI events for SSRI use compared to non-use of SSRIs or NSAIDs was 1.30 [95% confidence interval (95%CI: 1.13–1.50)], and the AOR for concurrent SSRI and NSAID use compared to the non-use of either drug was 4.19 (95%CI: 3.30–5.31). The AOR of upper GI events for the concurrent use of SSRIs with NSAIDs compared to patients using NSAIDs only was 1.57 (95%CI: 1.24–1.99). The respective AOR for traditional, non-selective NSAIDs was 1.77 (95%CI: 1.31–2.38), for semi-selective NSAIDs (nimesulide, nabumetone, meloxicam, and etodolac) 1.30 (95%CI: 0.76–2.24) and for COX-2 selective NSAIDs 1.33 (95%CI: 0.70–2.50).ConclusionsThe concurrent use of SSRIs and NSAIDs is associated with a moderate excess relative risk of a serious upper GI event when compared with NSAID use alone.

Cardiac positron emission tomography imaging with [11c]hydroxyephedrine, a specific tracer for sympathetic nerve endings, and its functional correlates in congestive heart failure

The integrative mechanisms of autonomic dysfunction in congestive heart failure (CHF) remain poorly understood. We sought to study cardiac retention of [11C]hydroxyephedrine (HED), a specific tracer for sympathetic presynaptic innervation, and its functional correlates in CHF. Thirty patients with mild to moderate heart failure underwent resting cardiac HED positron emission tomography imaging, spectrum analysis testing of systolic pressure and heart rate variability in the resting supine and 70 degrees head-up tilt positions, and testing of baroreflex sensitivity. Compared with control subjects, global myocardial HED retention index was reduced by 30% (p <0.01) in patients with CHF. The HED retention index did not correlate significantly with heart rate variability. However, it correlated with baroreflex sensitivity at rest (r = 0.43, p = 0.05) and with systolic pressure low-frequency (0.03 to 0.15 Hz) variability at head-up tilt (r = 0.76, p <0.01), as well as with low-frequency systolic pressure variability response from baseline to tilt (r = 0.75, p <0.01). We conclude that cardiac HED retention is reduced in patients with CHF. This correlates with blunted vascular sympathetic effector responses during posture-induced reflex activation and baroreflex control of heart rate, suggesting an interdependence between cardiac presynaptic innervation abnormalities and neural mechanisms important to blood pressure maintenance in CHF.

Hypothalamic neuropeptide expression after food restriction in Zucker rats: evidence of persistent neuropeptide Y gene activation.

The Obese Zucker rat is a model of genetic obesity characterized by hyperphagia, hyperinsulinemia and other endocrine abnormalities. In order to elucidate pathogenetic mechanisms contributing to disturbed feeding behavior in these animals, the effect of food restriction on three hypothalamic neuropeptides involved in the control of food intake was studied. Eighteen male obese and 18 lean Zucker rats were randomly divided into two groups: half of the animals were food-restricted for 2 weeks, while the other half served as controls and were fed ad libitum. The levels of preproneuropeptide Y (preproNPY), preprocorticotropin releasing factor (preproCRF) and preprosomatostatin (preproSOM) mRNAs were determined using in situ hybridization technique. In addition, plasma insulin and corticosterone concentrations were analyzed. Food restriction significantly increased the expression of preproNPY mRNA in the arcuate nucleus in both Zucker phenotypes, while the expressions of preproCRF mRNA in the paraventricular nucleus (PVN) and preproSOM mRNA in the periventricular nucleus (PeV) were not altered. The expression of preproNPY mRNA was significantly greater in control obese animals compared to control lean animals. Food restriction lowered plasma insulin levels, but did not change plasma corticosterone levels. It is concluded that food restriction specifically activates NPY gene transcription in the arcuate nucleus the response being similar in both Zucker phenotypes. The results suggest that orexigenic NPY plays a role in the adaptation to altered feeding status.

Cross-sectional associations between physical activity and selected coronary heart disease risk factors in young adults. The Cardiovascular Risk in Young Finns Study.

Abstract Objective. Physical activity (PA) may reduce the risk of coronary heart disease (CHD) by inducing beneficial changes in several risk factors. We studied the associations between PA and a range of risk markers of CHD in young adults. Methods and results. We measured serum lipoproteins, oxidized LDL, adipokines, inflammatory markers, metabolic markers, and arginine metabolites in 2,268 individuals (age 24–39 y). Participants were asked frequency, duration, and intensity of PA in leisure time. In addition, commuting to work was assessed. In both sexes, PA was inversely associated with waist circumference (all P < 0.0001). After controlling for sex, age, and waist circumference, PA was directly associated with HDL-cholesterol and apolipoprotein A1, and inversely with heart rate, smoking, oxidized LDL, apolipoprotein B, insulin, glucose, C-reactive protein, leptin, L-arginine, and phospholipase A2 activity (all P < 0.05). Conclusion. These population-based data are consistent with the idea that the beneficial effects of PA on CHD risk are mediated by favorable influences on several risk factors, as judged by independent relations to markers of lipoprotein metabolism, glucose metabolism, and inflammation. These associations reflect beneficial effects on cardiovascular health in both sexes and may offer mechanistic insights for the inverse association between PA and CHD.