T Seppälä

Helsinki University Central Hospital, Helsinki, Southern Finland Province, Finland

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Publications (169)425.3 Total impact

  • International journal of radiation oncology, biology, physics 09/2014; 90(1):S929-S930. · 4.59 Impact Factor
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    ABSTRACT: Introduction In Finland, a total of 98 glioma patients, 59 with malignant glioma recurrence after surgery and 39 who had undergone surgery for newly diagnosed glioblastoma, were treated with L-BPA-F-mediated BNCT in 1999 to 2011. Normal-brain-toblood (N/B) and tumor-to-blood (T/B) 10B concentration ratios of 1 and 3.5, respectively, were assumed in dose calculations. A correlation between the calculated tumor doses and survival was not found, suggesting an incorrect estimation of the dose. In this study, the T/B and tumor-to-normal-brain (T/N) ratios are estimated using a closed 3-compartment pharmacokinetic model based on the measured blood 10B concentrations. Patients and Methods Published average rate constants obtained from 8F-BPA-PET studies, and validated for a slow intravenous L-BPA-F infusion, were applied to predict the tumor and the normal brain 10B uptake based on the 3-compartment model and the measured blood 10B levels. Altogether 22 patients with recurrent glioma, treated within a clinical trial, were evaluated using their individual measured blood 10B concentration curves. The patients received a 290 to 450 mg/kg dose of L-BPA-F administered as a 2-hour intravenous infusion. Neutron irradiation was initiated 46 to 144 minutes after the end of infusion. The 10B concentrations of peripheral venous blood samples collected at 20-minute intervals were analyzed with inductively ICP-AES. The first blood sample was taken immediately before the initiation of the L-BPA F-infusion (the baseline sample), and the last one immediately after the completion of neutron irradiation. Results and conclusions According to the 3-compartment model, the T/B ratios reached their peaks of 2.3 to 3.1 at the time of the last blood sample taken after irradiation, consequently being lower during irradiation. The model predicts differing pharmacokinetics for the brain tissue and the blood, which results in distinct T/N and T/B concentration ratio curves. The highest T/N ratio of 1.9 to 2.0 was obtained at the end of the L-BPA-F infusion, and the ratio decreased thereafter gradually to 1.5 to 1.6. Instead of examining the T/N ratio, the ratio of tumor-to-combination of 1/3 blood + 2/3 the normal brain tissue T/(1/3B+2/3N) has been proposed to be examined, as the vascular endothelium may be the main target of BNCT damage. The highest T/(1/3B+2/3N) of 1.8 to 2.0 were observed 70 to 130 minutes after end of the L-BPA F-infusions, which was the time range within which all patients received neutron irradiation. The model suggests that the treated patients received a lower tumor dose than previously predicted due to considerably lower 10B levels in the tumor. The patient doses will be re-evaluated according to the 10B levels estimated here.
    16th International Congress on Neutron Capture Therapy, Helsinki; 06/2014
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    ABSTRACT: Purpose: To determine whether bones could be localized accurately by using MR images only in radiotherapy treatment planning. Furthermore, to measure absorbed dose in a material behind different parts of the bone, and to evaluate dose calculation error in a pseudo-CT image by assuming a single electron density for the bones. Methods: A dedicated phantom was constructed using fresh deer bones and gelatine. The accuracy of the bone edge location and the bone diameter in MR images were evaluated by comparing those in the images with the actual measures. The absorbed dose behind the bones was measured by a matrix detector at 6 and 15 MV. Thedose calculation error in the bulk density pseudo-CT image was quantified by comparing the calculation results with those obtained in a standard CT image by superposition and Monte Carlo algorithms (TPSs: Xio 4.60 and Monaco 3.00, Elekta CMS Software). Results: The examination of bone position revealed that the bones can be localized within a 1-mm-pixel-size in the MR images. The measured dose behind less than 2.5-cm-thick femur indicated that the absorbed dose behind the middle part of the bone is approximately one percentage unit (6 MV: 1.3%, 15 MV: 0.9%) smallerthan that of the physically narrower bone edge. The calculations illustrated that the bulk density pseudo-CT image used causes errors up to nearly 2% to the dose behind the middle part, but also, the edge of the femur. Conclusions: This research ascertains that the bone localization is not a restrictive issue for radiotherapy treatment planning by using MR imageonly. The work indicates also that the decrease in absorbed dose is not necessarily dependent on the diameter of the bone. Future research shouldinvestigate the generation of more complex pseudo-CT images and the dosecalculations by using these. Supported by Elekta.
    Medical Physics 06/2012; 39(6):3664. · 2.91 Impact Factor
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    ABSTRACT: The abuse of anabolic androgenic steroids (AASs), such as nandrolone, is not only a problem in the world of sports but is associated with the polydrug use of non-athletes. Among other adverse effects, AAS abuse has been associated with long term or even persistent psychiatric problems. We have previously found that nandrolone decanoate treatment could produce prolonged changes in rats' brain reward circuits associated to drug dependence. The aim in this study was to evaluate whether AAS-induced neurochemical and behavioral changes are reversible. The increases in extracellular dopamine (DA) and serotonin (5-HT) concentration, as well as stereotyped behavior and locomotor activity (LMA) evoked by cocaine were attenuated by pretreatment with nandrolone. The recovery period, which was needed for the DA system to return back to the basic level, was fairly long compared to the dosing period of the steroid. In the 5-HT system, the time that system needed to return back to the basal level, was even longer than in the DA system. The attenuation was still seen though there were no detectable traces of nandrolone in the blood samples. Given that accumbal outflow of DA and 5-HT, as well as LMA and stereotyped behavior are all related to reward of stimulant drugs, this study suggests that nandrolone decanoate has significant, long-lasting but reversible effects on the rewarding properties of cocaine.
    Steroids 07/2011; 76(12):1310-6. · 2.80 Impact Factor
  • Oral Oncology 07/2011; 47. · 2.70 Impact Factor
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    ABSTRACT: In this paper, a phantom study was performed to evaluate the effect of an epithermal neutron beam irradiation on the cardiac pacemaker function. Severe malfunction occurred in the pacemakers after substantially lower dose from epithermal neutron irradiation than reported in the fast neutron or photon beams at the same dose rate level. In addition the pacemakers got activated, resulting in nuclides with half-lives from 25 min to 115 d. We suggest that BNCT should be administrated only after removal of the pacemaker from the vicinity of the tumor.
    Applied radiation and isotopes: including data, instrumentation and methods for use in agriculture, industry and medicine 04/2011; 69(12):1904-6. · 1.09 Impact Factor
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    ABSTRACT: Magnesium-walled argon gas flow ionization chamber (Mg(Ar)) is used for photon dose measurements in the epithermal neutron beam of FiR 1 reactor in Finland. In this study, the photon dose measurements were re-evaluated against calculations applying a new chamber calibration factor defined in water instead of in air. Also, effect of the build-up cap on the measurements was investigated. The new calibration factor provides improved agreement between measured and calculated photon dose. Use of the build-up cap does not affect the measured signal in water in neutron beam.
    Applied radiation and isotopes: including data, instrumentation and methods for use in agriculture, industry and medicine 03/2011; 69(12):1901-3. · 1.09 Impact Factor
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    ABSTRACT: Previously we have reported that sub-chronic administration of nandrolone modifies reward-related neurochemical effects of psychomotor stimulant drugs of abuse. The aim of the present study was to evaluate whether the ability of nandrolone (19-nortestosterone) to attenuate the effects of amphetamine depends on activation of androgen (AR) or estrogen receptors (ER). We used an in vivo microdialysis technique in fully conscious rats to monitor whether administration of the AR-antagonist flutamide (7x50 mg/kg) or the ER-antagonist clomiphene (7x20 mg/kg), attenuates nandrolone-induced modulation of dopaminergic and serotonergic effects of acute injections of amphetamine (1 mg/kg). Dopamine (DA), 5-hydroxytryptamine (5-HT) and their metabolites were measured from the samples using high performance liquid chromatography (HPLC). Blocking the androgen receptors with flutamide abolished the attenuating effect of nandrolone pre-treatment on amphetamine-induced elevation of extracellular DA concentration. Blocking the estrogen receptors with clomiphene did the same but to a lesser extent. In conclusion, the results of this study show that the ability of nandrolone to attenuate the effects of amphetamine depends on activation of androgen receptors or to a lesser extent, on estrogen receptors.
    Pharmacology Biochemistry and Behavior 03/2010; 95(4):422-7. · 2.82 Impact Factor
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    ABSTRACT: The abuse of anabolic androgenic steroids (AASs) is not only a problem in the world of sports but is associated with the polydrug use of nonathletes. Investigations of the neurochemical effects of AAS have focused in part on the monoaminergic systems, involving, among other things, the development of dependence. We have previously shown that pretreatment with nandrolone decanoate attenuates dose-dependently the increase in extracellular dopamine (DA) concentration evoked by amphetamine and 3,4-methylenedioyxymethamphetamine in the nucleus accumbens (NAc). The aim of this study was to investigate whether the nandrolone pre-exposure modulates the acute neurochemical and behavioral effects of cocaine in rats and whether the effects are long lasting. DA, 5-hydroxytryptamine (5-HT), and their metabolites were measured from samples collected from the NAc by microdialysis. The behavior of the animals was recorded. The present study demonstrates that five injections of nandrolone (5 and 20 mg/kg) inhibited cocaine-evoked DA and 5-HT outflow in the NAc, locomotor activity (LMA), and stereotyped behavior in experimental animals, and that these effects are seen even after elimination of nandrolone from bloodstream. Given that accumbal outflow of DA and 5-HT, as well as LMA and stereotyped behavior, is related to gratification of stimulant drugs, this study suggests that nandrolone, at the doses tested, has a significant effect on the pleasurable properties of cocaine. Furthermore, because neurochemical and behavioral responses were still attenuated after a fairly long recovery period, it seems that nandrolone may induce long-lasting changes in the brains of rat.
    Psychopharmacology 02/2010; 209(3):271-81. · 4.06 Impact Factor
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    ABSTRACT: Alfa-Hydroxy-isocaproic acid (HICA) is an end product of leucine metabolism in human tissues such as muscle and connective tissue. According to the clinical and experimental studies, HICA can be considered as an anti-catabolic substance. The present study investigated the effects of HICA supplementation on body composition, delayed onset of muscle soreness (DOMS) and physical performance of athletes during a training period. Fifteen healthy male soccer players (age 22.1+/-3.9 yr) volunteered for the 4-week double-blind study during an intensive training period. The subjects in the group HICA (n = 8) received 583 mg of sodium salt of HICA (corresponding 500 mg of HICA) mixed with liquid three times a day for 4 weeks, and those in the group PLACEBO (n = 7) received 650 mg of maltodextrin mixed with liquid three times a day for the same period. According to a weekly training schedule, they practiced soccer 3 - 4 times a week, had strength training 1 - 2 times a week, and had one soccer game during the study. The subjects were required to keep diaries on training, nutrition, and symptoms of DOMS. Body composition was evaluated with a dual-energy X-ray absorptiometry (DXA) before and after the 4-week period. Muscle strength and running velocity were measured with field tests. As compared to placebo, the HICA supplementation increased significantly body weight (p < 0.005) and whole lean body mass (p < 0.05) while fat mass remained constant. The lean body mass of lower extremities increased by 400 g in HICA but decreased by 150 g in PLACEBO during the study. This difference between the groups was significant (p < 0.01). The HICA supplementation decreased the whole body DOMS symptoms in the 4(th )week of the treatment (p < 0.05) when compared to placebo. Muscle strength and running velocity did not differ between the groups. Already a 4-week HICA supplementation of 1.5 g a day leads to small increases in muscle mass during an intensive training period in soccer athletes.
    Journal of the International Society of Sports Nutrition 01/2010; 7:1. · 1.83 Impact Factor
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    ABSTRACT: Three treatment planning systems developed for clinical boron neutron capture therapy (BNCT) use are SERA developed by INL/Montana State University, NCTPlan developed by the Harvard-MIT and the CNEA group and JAEA computational dosimetry system (JCDS) developed by Japan Atomic Energy Agency (JAEA) in Japan. Previously, performance of the SERA and NCTPlan has been compared in various studies. In this preliminary study, the dose calculations performed with SERA and JCDS systems were compared in single brain cancer patient case with the FiR 1 epithermal neutron beam. A two-field brain cancer treatment plan was performed with the both codes. The dose components to normal brain, tumor and planning target volume (PTV) were calculated and compared in case of one radiation field and combined two fields. The depth dose distributions and the maximum doses in regions of interest were compared. Calculations with the treatment planning systems for the thermal neutron induced ((10)B and nitrogen) dose components and photon dose were in good agreement. Higher discrepancy in the fast neutron dose calculations was found. In case of combined two-field treatment plan, overall discrepancy of the maximum weighted dose was approximately 3% for normal brain and PTV and approximately 4% for tumor dose.
    Applied radiation and isotopes: including data, instrumentation and methods for use in agriculture, industry and medicine 04/2009; 67(7-8 Suppl):S126-9. · 1.09 Impact Factor
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    ABSTRACT: The meaningful sharing and combining of clinical results from different centers in the world performing boron neutron capture therapy (BNCT) requires improved precision in dose specification between programs. To this end absorbed dose normalizations were performed for the European clinical centers at the Joint Research Centre of the European Commission, Petten (The Netherlands), Nuclear Research Institute, Rez (Czech Republic), VTT, Espoo (Finland), and Studsvik, Nyköping (Sweden). Each European group prepared a treatment plan calculation that was bench-marked against Massachusetts Institute of Technology (MIT) dosimetry performed in a large, water-filled phantom to uniformly evaluate dose specifications with an estimated precision of +/-2%-3%. These normalizations were compared with those derived from an earlier exchange between Brookhaven National Laboratory (BNL) and MIT in the USA. Neglecting the uncertainties related to biological weighting factors, large variations between calculated and measured dose are apparent that depend upon the 10B uptake in tissue. Assuming a boron concentration of 15 microg g(-1) in normal tissue, differences in the evaluated maximum dose to brain for the same nominal specification of 10 Gy(w) at the different facilities range between 7.6 and 13.2 Gy(w) in the trials using boronophenylalanine (BPA) as the boron delivery compound and between 8.9 and 11.1 Gy(w) in the two boron sulfhydryl (BSH) studies. Most notably, the value for the same specified dose of 10 Gy(w) determined at the different participating centers using BPA is significantly higher than at BNL by 32% (MIT), 43% (VTT), 49% (JRC), and 74% (Studsvik). Conversion of dose specification is now possible between all active participants and should be incorporated into future multi-center patient analyses.
    Medical Physics 01/2009; 35(12):5419-25. · 2.91 Impact Factor
  • Medicine and Science in Sports and Exercise - MED SCI SPORT EXERCISE. 01/2009; 41.
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    ABSTRACT: The dopamine D(2)/D(3) receptor ligand [(11)C]FLB 457 and PET enable quantification of low-density extrastriatal D(2)/D(3) receptors, but it is uncertain whether [(11)C]FLB 457 can be used for measuring extrastriatal dopamine release. We studied the effects of d-amphetamine (0.3 mg/kg i.v.) on extrastriatal [(11)C]FLB 457 binding potential (BP(ND)) in a randomized, double-blind, placebo-controlled study including 24 healthy volunteers. The effects of d-amphetamine on [(11)C]FLB 457 BP(ND) and distribution volume (V(T)) in the frontal cortex were not different from those of placebo. Small decreases in [(11)C]FLB 457 BP(ND) were observed only in the posterior cingulate and hippocampus. The regional changes in [(11)C]FLB 457 BP(ND) did not correlate with d-amphetamine-induced changes in subjective ratings of euphoria. This placebo-controlled study showed that d-amphetamine does not induce marked changes in measures of extrastriatal dopamine D(2)/D(3) receptor binding. Our results indicate that [(11)C]FLB 457 PET is not a useful method for measuring extrastriatal dopamine release in humans.
    European Journal of Nuclear Medicine 12/2008; 36(3):475-83. · 4.53 Impact Factor
  • Sanna Kurling, Aino Kankaanpää, Timo Seppälä
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    ABSTRACT: Misuse of anabolic-androgenic steroids (AASs) is increasing, and appears to have much in common with the use of substances known to induce drug dependence. Moreover, persons who abuse AASs also tend to abuse other psychotropic drugs such as amphetamine or 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy"). The aim of this study was to investigate whether nandrolone (5 x 5 or 5 x 20 mg/kg) pre-exposure modulates the acute neurochemical and behavioral effects of amphetamine (1mg/kg) and MDMA (5 mg/kg) in rats. Dopamine (DA), 5-hydroxytryptamine (5-HT) and their metabolites were measured from samples collected from the nucleus accumbens (NAc) by in vivo microdialysis. The behavior of the animals was recorded on videotapes, from which it was later rated. Our results demonstrate that sub-chronic treatments with supraphysiological doses of nandrolone attenuate dose-dependently the increase in extracellular DA concentration evoked by amphetamine or MDMA. The lower dose of nandrolone attenuated MDMA-induced increase in 5-HT-levels, while the higher dose potentiated it. Analysis of the behavioral data suggests that effects of the amphetamine and MDMA are dose-dependently attenuated by AAS-treatment, paralleling DA results. In conclusion, the results of this study show that AAS-pre-treatment is able to modulate the reward-related neurochemical and behavioral effects of amphetamine and MDMA.
    Behavioural Brain Research 06/2008; 189(1):191-201. · 3.33 Impact Factor
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    ABSTRACT: To investigate the effects of a rapid weight reduction program under authentic pre-competition conditions, eighteen elite wrestlers were studied with dual-energy X-ray absorptiometry (DXA) before and after two to three weeks' weight reduction regimens. In order to establish the degree of dehydration and hormonal status, blood samples were collected to obtain blood chemistry, electrolytes and endocrinological parameters after both DXA measurements. The mean weight loss was 8.2 +/- 2.3 % and it was constituted by the mean reductions of fat mass of 16 +/- 6.9 % (p < or = 0.001) and lean body mass of 7.9 +/- 2.5 %. The rapid weight reduction caused significant dehydration which was noticed as increased blood hemoglobin (7.8 +/- 5.9 %, p < or = 0.001), hematocrit (11.3 +/- 6.8 %, p < or = 0.001), and serum creatinine (35 +/- 23 %, p < or = 0.001). There was a significant decrease in serum testosterone (63 +/- 33 %, p < or = 0.001) and luteinizing hormone (54 +/- 47 %, p < or = 0.001) concentrations. A reduced body weight correlated with decreased serum testosterone concentration (r = 0.53, p < or = 0.024). Serum sex hormone binding globulin concentration increased significantly (40 +/- 21 %, p < or = 0.001). The results suggest that even short-term weight reduction may have marked effects on body composition, blood chemistry and hormonal parameters. It may constitute a possible health risk at least in a growing adolescent athlete.
    International Journal of Sports Medicine 05/2008; 29(11):872-7. · 2.27 Impact Factor
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    ABSTRACT: 1-Benzylpiperazine (also known as 'Legal X', 'Legal E', or 'A2') is a psychoactive compound increasingly encountered on the clandestine market. Previous experimental data suggest that the compound possesses addictive properties. In the present study, we used the conditioned place preference method in the rat to test whether 1-benzylpiperazine possesses rewarding properties. Furthermore, the mechanisms of the 1-benzylpiperazine reward were investigated using selected dopamine and serotonin receptor antagonists. 1-Benzylpiperazine (1.25, 5, and 20 mg/kg) induced dose-dependently place preference. This place preference was attenuated by the antagonists SCH23390 (0.2 mg/kg; dopamine D1-like receptors) and MDL72222 (1.0 mg/kg; serotonin3 receptors), but not by raclopride (0.8 mg/kg; dopamine D2-like receptors) or ketanserin (2 mg/kg; preferentially serotonin2 receptors). Our results show that 1-benzylpiperazine possesses rewarding properties in the rat, which suggests the compound to be susceptible to human abuse. The brain dopaminergic and serotonergic systems appear to be involved in the 1-benzylpiperazine reward.
    Basic &amp Clinical Pharmacology &amp Toxicology 05/2006; 98(4):346-50. · 2.12 Impact Factor
  • Duodecim; lääketieteellinen aikakauskirja 02/2006; 122(19):2352-3.
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    ABSTRACT: 4-Methylaminorex is a potential psychostimulant drug of abuse that exists as four stereoisomers: cis-4R,5S, cis-4S,5R, trans-4S,5S, and trans-4R,5R. The racemic mixture of the cis-isomers has been encountered in illicit samples, but previous animal studies suggest that also the trans-isomers could have similar stimulant-like properties. We tested whether the stereoisomers possess rewarding properties and compared their potency using the conditioned place preference method in rats. Furthermore, the involvement of the brain dopaminergic system in the 4-methylaminorex reward was tested with the dopamine D1- and D2-receptor antagonists SCH 23390 and raclopride administered systemically, or with the neurotoxin 6-hydroxydopamine injected into the nucleus accumbens. All the four isomers induced place preference, with no apparent differences in their potency. SCH 23990 and raclopride attenuated 4-methylaminorex-induced increase in place preference, and 6-hydroxydopamine also tended to be efficacious. These findings indicate that all the four stereoisomers of 4-methylaminorex possess rewarding properties and thus abuse potential; the trans-isomers are at least as potent as the cis-isomers. Furthermore, the brain dopaminergic system appears to be involved in the 4-methylaminorex-reward.
    Pharmacology Biochemistry and Behavior 09/2005; 81(4):715-24. · 2.82 Impact Factor
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    ABSTRACT: Ibuprofen is a nonsteroidal anti-inflammatory drug which has both peripheral and central analgesic effects. Ibuprofen has been shown to be an effective antipyretic and postoperative analgesic drug both in adults and children with few side effects. Pharmacokinetics of rectal ibuprofen has not been studied, although suppositories are frequently used for perioperative pain control in children. There were four study groups: full-term infants aged 1-7 weeks (n = 9), infants aged 8-25 weeks (n = 8), and infants aged 26-52 weeks (n = 7). Adult patients were 20-40 years old (n = 7). Ibuprofen suppository 20 mg.kg(-1) was administered after induction of anesthesia. Blood samples were collected from 20 min to 10 h after dosing and pharmacokinetic analysis of ibuprofen enantiomers were done. Both ibuprofen enantiomers were detectable in blood in 20 min. Total ibuprofen plasma concentrations >10 mg.l(-1) were seen from 40 min to 8 h. Values for T(max) of ibuprofen enantiomers and total ibuprofen were higher in the adult group than any of the infant groups (P < 0.05). In addition, values for physiological (standardized) t(1/2) of (R)-(-)- and (S)-(+)-ibuprofen were higher in infants aged 1-7 weeks than the adults (P < 0.05). None of the other pharmacokinetic variables, C(max), AUC, chronological t(1/2) or AUC ratio differed between the groups. A single dose of ibuprofen suppository 20 mg.kg(-1) after induction of anesthesia guarantees analgesic plasma concentrations during the early postoperative period. Except for the delayed absorption of ibuprofen in adults and higher physiological t(1/2) in infants aged 1-7 weeks, no major pharmacokinetic differences were observed between study groups.
    Pediatric Anesthesia 08/2005; 15(7):566-73. · 2.44 Impact Factor

Publication Stats

3k Citations
425.30 Total Impact Points

Institutions

  • 2011
    • Helsinki University Central Hospital
      • Department of Oncology
      Helsinki, Southern Finland Province, Finland
  • 2010–2011
    • National Institute for Health and Welfare, Finland
      • Department of Alcohol, Drugs and Addiction
      Helsinki, Province of Southern Finland, Finland
    • University of Jyväskylä
      • Department of Biology of Physical Activity
      Jyväskylä, Western Finland, Finland
  • 1974–2011
    • University of Helsinki
      • • Department of Physics
      • • Department of Physical Sciences
      • • Department of Mental Health and Alcohol Research
      • • Institute of Biomedicine
      • • Division of Pharmacology and Toxicology
      • • Department of Pharmacology
      Helsinki, Province of Southern Finland, Finland
  • 1987–2008
    • National Public Health Institute
      Helsinki, Southern Finland Province, Finland
  • 1998–2005
    • University of Turku
      • Department of Anaesthesiology, Intensive Care, Emergency Care and Pain Medicine
      Turku, Province of Western Finland, Finland
  • 1991–1995
    • University of Tampere
      • • Department of Anaesthesia
      • • Department of Biomedical Sciences
      Tampere, Western Finland, Finland