J Ahonen

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

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Publications (259)520.92 Total impact

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    J Ahonen, V Stefanovic, R Lassila
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    ABSTRACT: Management of post-partum haemorrhage (PPH) involves the treatment of uterine atony, evacuation of retained placenta or placental fragments, surgery due to uterine or birth canal trauma, balloon tamponade, effective volume replacement and transfusion therapy, and occasionally, selective arterial embolization. This article aims at introducing pregnancy- and haemorrhage-induced changes in coagulation and fibrinolysis and their relevant compensatory mechanisms, volume replacement therapy, optimal transfusion of blood products, and coagulation factor concentrates, and briefly cell salvage, management of uterine atony, surgical interventions, and selective arterial embolization. Special attention, respective management, and follow-up are required in women with bleeding disorders, such as von Willebrand disease, carriers of haemophilia A or B, and rare coagulation factor deficiencies. We also provide a proposal for practical instructions in the treatment of PPH.
    Acta Anaesthesiologica Scandinavica 11/2010; 54(10):1164-78. · 2.36 Impact Factor
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    ABSTRACT: The 5-HT(3) antagonists tropisetron and granisetron have been shown to block the analgesic effect of acetaminophen in healthy volunteers. To study the interaction between ondansetron and acetaminophen in women undergoing laparoscopic hysterectomy, we randomized 134 patients into three groups to receive acetaminophen-placebo (AP), acetaminophen-ondansetron (AO), or placebo-placebo (PP). One gram of intravenous acetaminophen or placebo was administered at the induction of anesthesia and every 6 h thereafter for 24 h, and 4 mg of ondansetron or placebo was administered at the end of surgery. Pain control was provided by patient-controlled analgesia (PCA)-oxycodone. Acetaminophen (as compared to placebo) in periodic doses starting at induction of anesthesia reduced the total dosage of oxycodone required over 0-24 h (P = 0.031), but ondansetron given at the end of the surgery had no impact on the analgesic effect of acetaminophen (P = 0.723). The Numeric Rating Scale (NRS) scores for pain were similar whether ondansetron or placebo was administered at the end of the surgery. Therefore, it may be concluded that in women undergoing laparoscopic hysterectomy, the administration of periodic doses of intravenous acetaminophen (as compared to placebo) starting at induction of anesthesia reduces the total dose requirement of oxycodone, and a concomitant dose of a 5-HT(3) antagonist such as ondansetron at the end of the surgery does not block the analgesic effect of acetaminophen.
    Clinical Pharmacology &#38 Therapeutics 03/2010; 87(6):672-8. · 6.85 Impact Factor
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    ABSTRACT: Multimodal pain management has been suggested to improve postoperative analgesia. In this study, we evaluated the quality of analgesia in women undergoing day-case gynaecological laparoscopic surgery, after premedication with pregabalin 75 mg (P75) or 150 mg (P150), compared with diazepam 5 mg (D5). All patients were given ibuprofen 800 mg orally. Altogether 90 consenting women were anaesthetized in a standardized fashion. Postoperative analgesia was provided by ibuprofen 800 mg twice a day with fentanyl i.v. on request in the recovery room (RR), and combination tablets with acetaminophen and codeine after the RR. The visual analogue scale (VAS) scores for pain and side-effects and the amounts of postoperative analgesics were recorded for 24 h after surgery. The areas under the curves (AUC) were calculated for the VAS scores for pain at rest, pain in motion, and pain at cough 1-8 and 1-24 h after surgery. The median AUC values for VAS scores for pain at rest (P=0.048) and in motion (P=0.046) 1-8 h after surgery were lower in the P150 group than that in the D5 group. The amounts of rescue analgesics or the degree of drowsiness did not differ in the three study groups. Analgesia was better after premedication with pregabalin 150 mg than after diazepam 5 mg, both with ibuprofen 800 mg, during the early recovery after day-case gynaecological laparoscopic surgery. Pregabalin 150 mg did not reduce the amount of postoperative analgesics required.
    BJA British Journal of Anaesthesia 07/2008; 100(6):834-40. · 4.24 Impact Factor
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    ABSTRACT: The restoration of functional connective tissue is a major goal of the wound healing process which is probably affected by matrix-modifying enzymes. To evaluate the spatial and temporal expression of matrix metalloproteinases (MMP) MMP-2 and MMP-9 and to study the regulation of MMP-2 in wound healing, subcutaneously implanted viscose cellulose sponges in rats were used to induce granulation tissue formation for up to 3 months. MMP-2 mRNA expression was seen throughout the experiment and it was highest after 2 months. MMP-9 gene expression was low between days 8–21 and increased after 4 weeks of granulation tissue formation. Membrane-type 1 MMP (MT1-MMP) mRNA was upregulated early and tissue inhibitor 2 of MMP (TIMP-2) mRNA later during wound healing. In in situ hybridization the expression of MMP-2 mRNA was seen mostly in fibroblast-like cells and MMP-9 mRNA in macrophage-like cells. MMP-9 immunoreactivity was detected in the polymorphonuclear leukocytes and macrophage-like cells on days 3–8. MMP-9 proteolytic activity was observed only on days 3–8. The active form of the MMP-2 increased up to day 14, whereafter it remained at a constant level, whereas latent MMP-2 did not show any apparent changes during the experimental period. We conclude that MMP-2 is important during the prolonged remodelling phase, whereas the gelatinolytic activity of MMP-9 was demonstrated only in early wound healing, and the MMP-9 gene is upregulated when the granulation tissue matures.
    Apmis 06/2008; 108(5):318 - 328. · 2.07 Impact Factor
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    K T Olkkola, J Ahonen
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    ABSTRACT: The actions of benzodiazepines are due to the potentiation of the neural inhibition that is mediated by gamma-aminobutyric acid (GABA). Practically all effects of the benzodiazepines result from their actions on the ionotropic GABA(A) receptors in the central nervous system. Benzodiazepines do not activate GABA(A) receptors directly but they require GABA. The main effects of benzodiazepines are sedation, hypnosis, decreased anxiety, anterograde amnesia, centrally mediated muscle relaxation and anti-convulsant activity. In addition to their action on the central nervous system, benzodiazepines have a dose-dependent ventilatory depressant effect and they also cause a modest reduction in arterial blood pressure and an increase in heart rate as a result of a decrease of systemic vascular resistance. The four benzodiazepines, widely used in clinical anaesthesia, are the agonists midazolam, diazepam and lorazepam and the antagonist flumazenil. Midazolam, diazepam and flumazenil are metabolized by cytochrome P450 (CYP) enzymes and by glucuronide conjugation whereas lorazepam directly undergoes glucuronide conjugation. CYP3A4 is important in the biotransformation of both midazolam and diazepam. CYP2C19 is important in the biotransformation of diazepam. Liver and renal dysfunction have only a minor effect on the pharmacokinetics of lorazepam but they slow down the elimination of the other benzodiazepines used in clinical anaesthesia. The duration of action of all benzodiazepines is strongly dependent on the duration of their administration. Based on clinical studies and computer simulations, midazolam has the shortest recovery profile followed by lorazepam and diazepam. Being metabolized by CYP enzymes, midazolam and diazepam have many clinically significant interactions with inhibitors and inducers of CYP3A4 and 2C19. In addition to pharmacokinetic interactions, benzodiazepines have synergistic interactions with other hypnotics and opioids. Midazolam, diazepam and lorazepam are widely used for sedation and to some extent also for induction and maintenance of anaesthesia. Flumazenil is very useful in reversing benzodiazepine-induced sedation as well as to diagnose or treat benzodiazepine overdose.
    Handbook of experimental pharmacology 02/2008;
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    J Ahonen, R Jokela, K Korttila
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    ABSTRACT: Empirical off-label use of recombinant activated factor VII (rFVIIa) has been reported to be effective in some cases of severe postpartum haemorrhage (PPH). Successful management of these patients has lead to more wide-spread use of rFVIIa in less severe cases without any evidence for the advantages of its administration. Until November 2006, we had administered rFVIIa to 38 parturients. Based on our initial experience with the first 12 patients, we prepared guidelines for the use of rFVIIa. During the existence of these guidelines, we made a retrospective comparison of the 26 women who received rFVIIa with another 22 women who were treated during the same time period without using rFVIIa. The total amount of blood loss was significantly higher (11.3 +/- 4.5 vs. 8.0 +/- 3.1 l), and the coagulation screen revealed significantly longer partial thromboplastin time (APTT) and prothrombin time (PT) values and significantly lower fibrinogen values in patients receiving rFVIIa. The need for red blood cells, platelets and fibrinogen concentrate was significantly higher in these women. Although the response was considered good in two-thirds of the women, several patients received rFVIIa with a poor or no response as a result of arterial bleeding. The decision to use rFVIIa resulted from a more profound haemorrhage. We did not gain any evidence to extend the use of rFVIIa into less severe cases of PPH. Furthermore, this policy would result in a profound increase in the overall costs of the treatment. Randomized placebo-controlled trials are urgently needed to optimize the use of rFVIIa in obstetric haemorrhage.
    Acta Anaesthesiologica Scandinavica 09/2007; 51(7):929-36. · 2.36 Impact Factor
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    ABSTRACT: In a search for information to improve decision making on red blood cell (RBC) transfusion, we examined the impact of RBC transfusion on the length of hospital stay for delivery in moderately anaemic women (haemoglobin, 7-10 g/dl). This was a retrospective, observational study covering 2 years (2002 and 2003), and included major blood-transfusing hospitals from four university and five central hospital districts managing 67.5% of Finnish in-hospital deliveries. The impact of the transfusion of 1-2 RBC units vs. no transfusion on the length of hospital stay was evaluated for three different haemoglobin levels: 7-7.9, 8-8.9 and 9-10 g/dl. Of the 1954 moderately anaemic mothers in hospital for delivery, 13.3% were transfused with RBC. The mean length of hospital stay was 5.2 days vs. the average Finnish hospital delivery stay of 3.5 days. No differences in stay were found between patients with comparable anaemia transfused with 1-2 RBC units or none (at the three haemoglobin levels: P= 0.50, P= 0.07 and P= 0.54, respectively). The final haemoglobin value was higher (P < 0.001) in transfused patients. The duration of admission for delivery in moderately anaemic parturients was longer than the average length of hospital stay in Finnish parturients. However, 1-2 RBC units had no impact on the length of stay, suggesting that unnecessary RBCs are transfused after delivery. Thus, transfusion practices in obstetrics are not always optimal.
    Acta Anaesthesiologica Scandinavica 06/2007; 51(5):565-9. · 2.36 Impact Factor
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    J Ahonen, R Jokela, K Uutela, M Huiku
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    ABSTRACT: Monitoring of analgesia remains a challenge during general anaesthesia. The surgical stress index (SSI) is derived from the photoplethysmographic waveform amplitude and the heart beat-to-beat interval. We evaluated the ability of SSI to measure surgical stress in patients undergoing gynaecological laparoscopy. Our hypothesis was that while keeping State Entropy (SE) at a predetermined level, SSI would be higher in patients receiving a beta-blocking agent (esmolol) than in those receiving an opioid (remifentanil) during laparoscopy. Thirty women undergoing gynaecological laparoscopy were assigned randomly to receive esmolol (n = 15) or remifentanil (n = 15). Anaesthesia was induced with propofol and fentanyl and maintained with desflurane and nitrous oxide 50% in oxygen to keep SE at 50(5). The infusion of esmolol or remifentanil was started before laparoscopy and adjusted to keep the systolic blood pressure at -20 to +10% from the preoperative value. During the fentanyl phase, before surgery, both groups behaved similarly, with an increase in SSI after intubation. In the patients receiving esmolol, the SSI reacted to the initial incision (P < 0.05), and remained high after trocar insertion (P < 0.05). In patients receiving remifentanil, it did not react to the initial incision, but increased after trocar insertion (P < 0.05), and it remained lower both after incision (P < 0.05) and after trocar insertion (P < 0.05). SSI was higher in patients receiving esmolol. The index seems to reflect the level of surgical stress and may help guide the use of opioids during general anaesthesia.
    BJA British Journal of Anaesthesia 04/2007; 98(4):456-61. · 4.24 Impact Factor
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    ABSTRACT: Controlled-release (CR) oxycodone provides an option for the prevention of postoperative pain. We designed this randomized double-blinded placebo controlled study to evaluate the control of pain after premedication with CR oxycodone 15 mg in addition to ibuprofen 800 mg orally in day-case gynaecological laparoscopic surgery. Sixty consenting patients were anaesthetized in a standardized fashion. Postoperative analgesia was provided by ibuprofen 800 mg twice a day in combination with fentanyl i.v. in the recovery room and normal-release (NR) oxycodone orally after the recovery room. The visual analogue scale (VAS) scores for pain and side-effects, and the amounts of postoperative analgesics were recorded for 24 h after discharge from the hospital. After a statistical analysis of the original study, we extended the study to investigate another 10 patients, who received CR oxycodone 15 mg orally in an open-labelled fashion 60 min before surgery. The plasma concentrations of oxycodone were measured from samples drawn before and 2, 4, 6 and 8 h after premedication. The amounts of fentanyl [100 microg (0-330) in the CR oxycodone group; 125 microg (0-330) in the placebo group], NR oxycodone, or the VAS scores for pain during the first 24 h after the discharge from the hospital did not differ after the premedication with CR oxycodone or placebo. In the extension study group, the peak plasma concentration (C(max)) of oxycodone was 10.0 (4.6-14.7) ng ml(-1), indicating possibly a sub-therapeutic level. Oral premedication with CR oxycodone did not improve management of postoperative pain after day-case gynaecological laparoscopic surgery.
    BJA British Journal of Anaesthesia 03/2007; 98(2):255-60. · 4.24 Impact Factor
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    ABSTRACT: Monitoring of analgesia remains a challenge during general anaesthesia. Activation of Response Entropy (RE) to painful stimuli has been suggested to be a sign of inadequate analgesia. We evaluated the ability of RE to be more sensitive than State Entropy (SE) in measuring nociception in patients undergoing gynaecological laparoscopy. Our hypothesis was that while keeping SE at a predetermined level, RE would be higher in patients receiving a beta-blocking agent (esmolol) instead of an opioid (remifentanil) during a propofol/nitrous oxide anaesthesia. Fifty-one women aged between 22-53 years were randomly assigned to receive esmolol (n=25) or remifentanil (n=26). SE was kept at 50+/-5. RE and SE were recorded at an interval of 30 s to 2 min and the areas under the RE and SE value-time curves (AUCRE and AUCSE) were calculated during the time of intubation and start of surgery as well as during the entire anaesthesia. The difference between RE and SE recordings in both groups was determined by subtracting the AUCSE from the corresponding AUCRE. Movements of the patients were recorded. No significant differences were detected in any of the several AUC values between the groups. The difference between RE and SE recordings was similar in both groups. Every patient in the esmolol group moved some time during the procedure interfering with surgery while no one in the remifentanil group moved. In patients undergoing gynaecological laparoscopic day-case surgery, RE seems not to be more sensitive than SE in guiding the use of opioids during general anaesthesia.
    Acta Anaesthesiologica Scandinavica 02/2006; 50(1):32-9. · 2.36 Impact Factor
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    BJA British Journal of Anaesthesia 11/2005; 95(4):558; author reply 558. · 4.24 Impact Factor
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    ABSTRACT: Recent studies have suggested that cytochrome P-450 isoenzyme 1A2 has an important role in lidocaine biotransformation. We have studied the effect of a cytochrome P-450 1A2 inhibitor, ciprofloxacin, on the pharmacokinetics of lidocaine. In a randomized, double-blinded, cross-over study, nine healthy volunteers ingested for 2.5 days 500 mg oral ciprofloxacin or placebo twice daily. On day 3, they received a single dose of 1.5 mg kg[-1] lidocaine intravenously over 60 min. Plasma concentrations of lidocaine, 3-hydroxylidocaine and monoethylglycinexylidide were determined for 11 h after the start of the lidocaine infusion. Ciprofloxacin increased the mean peak concentration and area under plasma concentration-time curve of lidocaine by 12% (range [-6] to+46%; P<0.05) and 26% (8--59%; P 0.01), respectively. The mean plasma clearance of lidocaine was decreased by ciprofloxacin by 22% (7--38%; P<0.01). Ciprofloxacin decreased the area under the plasma concentration-time curve of monoethylglycinexylidide by 21% (P<0.01) and that of 3-hydroxylidocaine by 14% (P< 0.01). The plasma decay of intravenously administered lidocaine is modestly delayed by concomitantly administered ciprofloxacin. Ciprofloxacin may increase the systemic toxicity of lidocaine.
    European Journal of Anaesthesiology 10/2005; 22(10):795-9. · 2.79 Impact Factor
  • European Journal of Anaesthesiology 09/2005; 22(10):795 - 799. · 2.79 Impact Factor
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    ABSTRACT: The temporal activity and gene expression of matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinase (TIMP) were investigated in a rat model of chronic allograft nephropathy. Gelatinolytic activity of MMP-2 and -9 were demonstrated by zymography, and MMP-2,-9 and TIMP-3 mRNA by in situ hybridization. The generation of fibrosis was determined as total collagen content/DNA. Significantly more latent and active MMP-2, as well as latent MMP-9, were seen in allografts than in autografts. Intense MMP-2 mRNA expression was demonstrated in the allografts during the first 20 days after transplantation, located mainly in the interstitium of the kidney. In addition, some tubular cells expressed MMP-2 mRNA. After day 20, MMP-2 gene expression was faint. MMP-9 mRNA expression in allografts was located mainly in the glomerulus. TIMP-3 mRNA expression was downregulated in allografts. MMP-2, MMP-9 and TIMP-3 seem to play a critical role in the development of fibrosis in the renal allograft.
    Transplant International 06/2005; 18(5):506-12. · 3.16 Impact Factor
  • J Ahonen, R Jokela
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    ABSTRACT: The treatment of life-threatening post-partum haemorrhage (PPH) still remains challenging, and hysterectomy may be required to control the bleeding. We present 12 cases of severe PPH treated with recombinant factor VIIa (rFVIIa). We briefly describe the causes of the haemorrhage and the medical and surgical interventions before rVIIa administration. In 11 women there was a partial or good response to rFVIIa administration, while in one there was no response. In the four women undergoing a subsequent selective arterial embolization, the bleeding was significantly reduced although not completely stopped. From our experience with these 12 cases, and from previously reported cases, the use of rFVIIa may be of benefit in life-threatening PPH. However, treatment with rFVIIa, in addition to standard surgical and medical interventions, may not be definitive in every patient and a selective arterial embolization may be needed.
    BJA British Journal of Anaesthesia 06/2005; 94(5):592-5. · 4.24 Impact Factor
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    ABSTRACT: The effect of cardiopulmonary bypass (CPB) on the level of anaesthetic depth has not been studied previously in a randomized way. We assessed the effect of CPB on the propofol needed to maintain a fixed bispectral index score, and on the recovery from anaesthesia in 22 patients undergoing coronary artery bypass graft surgery with CPB (on-pump) compared with 18 patients operated on without CPB (off-pump). Anaesthesia was induced and maintained with propofol and alfentanil. Throughout the procedure, the infusion rate of propofol was adjusted to keep the BIS value at 40 +/- 5. With the off-pump technique, the duration of surgery and anaesthetic administration were significantly greater. The need for propofol in proportion to time was exactly the same in both groups. During anaesthesia and the first 3 h thereafter, the BIS recordings were similar in both groups. No differences were detected in the time to awakening or tracheal extubation. CPB does not affect propofol requirements or immediate postoperative recovery compared with the off-pump technique.
    BJA British Journal of Anaesthesia 02/2004; 92(1):137-9. · 4.24 Impact Factor
  • J Ahonen, M Salmenperä
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    ABSTRACT: Despite remarkable progress in surgical, cardiopulmonary bypass and anaesthetic techniques during the last three decades, brain damage remains an important complication of adult cardiac surgery. Effective brain protection strategies are already implemented today, but ongoing research is needed to meet the challenges faced in operating on increasingly old and disabled patients. The incidence of brain injury may be reduced by modifying the surgical procedure according to carotid duplex scanning and epiaortic echocardiography, by using techniques to reduce microembolization during cardiopulmonary bypass and by optimizing patient temperature during and after surgery. Increased knowledge will aid in choosing the best procedure or combination of procedures in each case to ensure that risks do not outweigh benefits.
    Acta Anaesthesiologica Scandinavica 02/2004; 48(1):4-19. · 2.36 Impact Factor
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    ABSTRACT: To study the inflammatory reaction and myocardial metabolism in off-pump and on-pump coronary artery bypass patients. Fifty coronary artery bypass patients were randomized to off-pump or on-pump operations. Myocardial biopsies were taken to determine myocardial metabolism and inflammation (glutathione (GSH), superoxide dismutase (SOD) and myeloperoxidase (MP)) and plasma samples for indicators of oxidative stress (conjugated dienes (s-BDC), oxidative products of proteins (s-ox-Prot) and low-density lipoprotein (LDL)-total peroxyl radical trapping antioxidant potential (s-TRAP)). s-ox-Prot 10 min was 2.11 +/- 0.75 vs 2.69 +/- 0.60 (p = 0.014), s-TRAP 5 min was 861 +/- 180 vs 969 +/- 192 (p = 0.032) and s-TRAP 10 min 857 +/- 176 vs 985 +/- 166 (p = 0.011), GSH 10 min 0.55 +/- 0.19 vs 0.72 +/- 1.16 (p = 0.007) (off-pump vs on-pump). The monobasic (MB) fraction of the creatinine kinase 24 h after the operation was significantly lower in the off-pump group, 20.5 +/- 24.2 vs 61.8 +/- 84.6 (p = 0.023). GSH levels from the biopsies were increased in the perfusion group early in the reperfusion time showing that myocardial tissue was well protected and recovered more rapidly after cross-clamping than after the occlusion of the coronary arteries. However, release of creatinine kinase was lower in the off-pump group showing that cardiopulmonary bypass has more deleterious effects later after the operation.
    Scandinavian Cardiovascular Journal 10/2003; 37(4):211-5. · 0.82 Impact Factor
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    ABSTRACT: Connective tissue growth factor (CTGF) is a polypeptide implicated in the extracellular matrix synthesis. Previous studies have provided evidence that angiotensin II (Ang II) promotes collagen synthesis and regulates collagen degradation. We investigated whether or not CTGF mediates the profibrotic effects of Ang II in the heart and kidneys and the role of calcineurin-dependent pathways in CTGF gene regulation. In transgenic rats harboring human renin and angiotensinogen genes, Ang II induced an age-dependent increase in myocardial CTGF expression, which was 3.5-fold greater compared to normotensive Sprague Dawley (SD) rats. CTGF overexpression correlated closely with the Ang II-induced rise in blood pressure. CTGF mRNA and protein were located predominantly in areas with leukocyte infiltration, myocardial, and vascular lesions and co-localized with TGFbeta(1), collagen I, and collagen III mRNA expressions. Ang II induced CTGF mRNA and protein to a lesser extent in the kidneys, predominantly in glomeruli, arterioles, and in the interstitium with ample inflammation. However, no expression was found in the right ventricle or pulmonary arteries. Blockade of calcineurin activity by cyclosporine A completely normalized Ang II-induced CTGF overexpression in heart and kidney, suppressed the inflammatory response, and mitigated Ang II-induced cell proliferation and apoptosis. In contrast, blockade of mTOR (target of rapamycin) pathway by everolimus, further increased the expression of CTGF even though everolimus ameliorated cell proliferation and T-cell-mediated inflammation. Our findings provide evidence that CTGF mediates Ang II-induced fibrosis in the heart and kidneys via blood pressure and calcineurin-dependent pathways.
    American Journal Of Pathology 08/2003; 163(1):355-66. · 4.60 Impact Factor
  • Transplantation Proceedings 04/2003; 35(2):803. · 0.95 Impact Factor

Publication Stats

3k Citations
520.92 Total Impact Points


  • 1979–2010
    • Helsinki University Central Hospital
      • • Department of Surgery
      • • Division of Nephrology
      • • Surgical Hospital
      Helsinki, Southern Finland Province, Finland
  • 2008
    • Turku University Hospital
      Turku, Province of Western Finland, Finland
    • University of Turku
      • Department of Medical Biochemistry and Genetics
      Turku, Western Finland, Finland
    • Hospital District for Helsinki and Uusimaa
      Helsinki, Southern Finland Province, Finland
  • 1982–2008
    • University of Helsinki
      • • Department of Anaesthesia
      • • Institute of Biomedicine
      • • Clinical Pharmacology
      • • Division of Pharmacology and Toxicology
      • • IV Department of Surgery
      • • Transplantation Laboratory
      • • Fourth Department of Medicine
      Helsinki, Southern Finland Province, Finland
  • 1992
    • Finnish Red Cross
      Helsinki, Southern Finland Province, Finland
  • 1988
    • Lund University
      • Department of Surgery
      Lund, Skane, Sweden