Prenatal and perinatal risk factors for bipolar disorder

Bipolar disorder (BPD) is a severe mental disorder associated with considerable morbidity and mortality. Prenatal insults have been shown to be associated with later development of mental disorders and there is a growing interest in the potential role of prenatal and perinatal risk factors in the development of BPD. The aims of this thesis were to describe the overall study design of the Finnish Prenatal Study of Bipolar Disorders (FIPS-B) and demographic characteristics of the sample. Furthermore, it was aimed to examine the association of parental age, parental age difference, perinatal complications and maternal smoking during pregnancy with BPD. This thesis is based on FIPS-B, a nested case-control study using several nationwide registers. The cases included all people born in Finland between January 1st 1983 and December 31st 1998 and diagnosed with BPD according to the Finnish Hospital Discharge Register (FHDR) before December 31st 2008. Controls for this study were people who were without BPD, schizophrenia or diagnoses related to these disorders, identified from the Population Register Centre (PRC), and matched two-fold to the cases on sex, date of birth (+/- 30 days), and residence in Finland on the first day of diagnosis of the matched case. Conditional logistic regression models were used to examine the association between risk factors and BPD. This study included 1887 BPD cases and 3774 matched controls. The mean age at diagnosis was 19.3 years and females accounted for 68% of the cases. Mothers with the lowest educational level had the highest odds of having BPD in offspring. Being born in Eastern and Southern region of Finland increased the odds of having BPD later in life. A U-shaped distribution of odds ratio was observed between paternal age and BPD in the unadjusted analysis. Maternal age and parental age difference was not associated with BPD. Birth by planned caesarean section was associated with increased odd of BPD. Smoking during pregnancy was not associated with BPD in the adjusted analyses. Region of birth and maternal educational level were associated with BPD. Both young and old father’s age was associated with BPD. Most perinatal complications and maternal smoking during pregnancy were not associated with BPD. The findings of this thesis, considered together with previous literature, suggest that the pre- and perinatal risk factor profile varies among different psychiatric disorders.

Early relationship between very preterm infant and mother: The role of infant, maternal and dyadic factors

Pienipainoisen keskosen ja äidin varhainen suhde: Lapsen, äidin ja dyadisten muuttujien vaikutus Tämän tutkimuksen tavoitteena oli tutkia keskosvauvan ja äidin varhaista suhdetta. Tutkimuksessa selvitettiin myös vauvan itkukäyttäytymisen, vauvan sylissä olon ja äidin masentuneisuuden yhteyttä äidin ja keskosvauvan varhaiseen suhteeseen. Tutkimusryhmät koostuivat 32:sta (tutkimus I-II) ja 38:sta (tutkimus III-IV) keskosena syntyneestä vauvasta (syntymäpaino < 1501 g tai GI < 32 viikkoa) sekä 46:sta täysiaikaisena syntyneestä terveestä verrokkivauvasta. Lapsen ja äidin vuorovaikutusta arvioitiin 6 ja 12 kuukauden iässä (korjattu ikä) PCERAmenetelmällä. Äidin mielikuvia lapsestaan tutkittiin WMCI-haastattelulla, kun lapsi oli 12 kuukautta. Baby Day Diary -menetelmää käytettiin vauvan itkukäyttäytymisen ja sylissä olon keston mittaamisessa vauvan ollessa 5 kuukautta. Äidin masentuneisuutta arvioitiin EDPS-lomakkeella, kun lapsi oli 6 kuukautta. Tulokset osoittivat, että turvallisten kiintymyssuhdemielikuvien määrä tai vuorovaikutuksen laatu eivät keskosvauvan äideillä eronneet täysiaikaisina syntyneiden vauvojen äitien vastaavista. Ryhmien välillä ei löytynyt eroja myöskään dyadisen vuorovaikutuksen laadussa. Keskosena syntyneet lapset olivat kuitenkin vetäytyvämpiä ja heillä oli laadullisesti heikommat keskittymisen ja leikin taidot vuorovaikutustilanteessa 12 kuukauden iässä täysiaikaisina syntyneisiin lapsiin nähden. Lisäksi äidin masentuneisuus ja lapsen pitkittynyt itkuisuus olivat negatiivisessa yhteydessä vuorovaikutuksen laatuun keskosvauvojen ryhmässä. Vauvan itkukertojen määrän, sylissä olon keston sekä äidin ja vauvan vuorovaikutuksen laadun välillä löytyi positiivinen yhteys ainoastaan keskosena syntyneiden lasten ryhmässä. Tulostemme perusteelle toteamme, että lapsen ennenaikainen syntymä itsessään ei näytä muodostavan riskiä äidin vuorovaikutuksen laadulle tai turvalliselle kiintymyssuhteelle. Yhdessä muiden riskitekijöiden kanssa keskosuus kuitenkin altistaa vauvat ja heidän äitinsä varhaisen vuorovaikutuksen ongelmille. Lisäksi tuloksemme viittaavat siihen, että vauvan itku ja siitä seuraava sylissä olo toimivat suojaavana mekanismina pienipainoisen keskosen ja äidin varhaisessa suhteessa.

Probiotic interventions in infancy: Benefit and Safety Assessment of Extended Applications

Immaturity of the gut barrier system in the newborn has been seen to underlie a number of chronic diseases originating in infancy and manifesting later in life. The gut microbiota and breast milk provide the most important maturing signals for the gut-related immune system and reinforcement of the gut mucosal barrier function. Recently, the composition of the gut microbiota has been proposed to be instrumental in control of host body weight and metabolism as well as the inflammatory state characterizing overweight and obesity. On this basis, inflammatory Western lifestyle diseases, including overweight development, may represent a potential target for probiotic interventions beyond the well documented clinical applications. The purpose of the present undertaking was to study the efficacy and safety of perinatal probiotic intervention. The material comprised two ongoing, prospective, double-blind NAMI (Nutrition, Allergy, Mucosal immunology and Intestinal microbiota) probiotic interventions. In the mother-infant nutrition and probiotic study altogether 256 women were randomized at their first trimester of pregnancy into a dietary intervention and a control group. The intervention group received intensive dietary counselling provided by a nutritionist, and were further randomized at baseline, double-blind, to receive probiotics (Lactobacillus rhamnosus GG and Bifidobacterium lactis) or placebo. The intervention period extended from the first trimester of pregnancy to the end of exclusive breastfeeding. In the allergy prevention study altogether 159 women were randomized, double-blind, to receive probiotics (Lactobacillus rhamnosus GG) or placebo 4 weeks before expected delivery, the intervention extending for 6 months postnatally. Additionally, patient data on all premature infants with very low birth weight (VLBW) treated in the Department of Paediatrics, Turku University Hospital, during the years 1997 - 2008 were utilized. The perinatal probiotic intervention reduced the risk of gestational diabetes mellitus (GDM) in the mothers and perinatal dietary counselling reduced that of fetal overgrowth in GDM-affected pregnancies. Early gut microbiota modulation with probiotics modified the growth pattern of the child by restraining excessive weight gain during the first years of life. The colostrum adiponectin concentration was demonstrated to be dependent on maternal diet and nutritional status during pregnancy. It was also higher in the colostrum received by normal-weight compared to overweight children at the age of 10 years. The early perinatal probiotic intervention and the postnatal probiotic intervention in VLBW infants were shown to be safe. To conclude, the findings in this study provided clinical evidence supporting the involvement of the initial microbial and nutritional environment in metabolic programming of the child. The manipulation of early gut microbial communities with probiotics might offer an applicable strategy to impact individual energy homeostasis and thus to prevent excessive body-weight gain. The results add weight to the hypothesis that interventions aiming to prevent obesity and its metabolic consequences later in life should be initiated as early as during the perinatal period.

Role of Membrane Transporters, P-Glycoprotein and Mrp1, in The Placental Transfer of Drugs With Special Reference to Saquinavir and Quetiapine

Drug transporting membrane proteins are expressed in various human tissues and blood-tissue barriers, regulating the transfer of drugs, toxins and endogenous compounds into or out of the cells. Various in vitro and animal experiments suggest that P-glycoprotein (P-gp) forms a functional barrier between maternal and fetal blood circulation in the placenta thereby protecting the fetus from exposure to xenobiotics during pregnancy. The multidrug resistance-associated protein 1 (MRP1) is a relatively less studied transporter protein in the human placenta. The aim of this study series was to study the role of placental transporters, apical P-gp and basal MRP1, using saquinavir as a probe drug, and to study transfer of quetiapine and the role of P-gp in its transfer in the dually perfused human placenta/cotyledon. Furthermore, two ABCB1 (encoding P-gp) polymorphisms (c.3435C>T, p.Ile1145Ile and c.2677G>T/A, p.Ala893Ser/Thr) were studied to determine their impact on P-gp protein expression level and on the transfer of the study drugs. Also, the influence of the P-gp protein expression level on the transfer of the study drugs was addressed. Because P-gp and MRP1 are ATP-dependent drug-efflux pumps, it was studied whether exogenous ATP is needed for the function of ATP-dependent transporter in the present experimental model. The present results indicated that the addition of exogenous ATP was not necessary for transporter function in the perfused human placental cotyledon. Saquinavir and quetiapine were both found to cross the human placenta; transplacental transfer (TPTAUC %) for saquinavir was <0.5% and for quetiapine 3.7%. Pharmacologic blocking of P-gp led to disruption of the blood-placental barrier (BPB) and increased the placental transfer of P-gp substrate, saquinavir, into the fetal circulation by 6- to 8-fold. In reversed perfusions P-gp, MRP1 and possibly OATP2B1 had a negligible role in the fetal-to-maternal transfer of saquinavir. The TPTAUC % of saquinavir was about 100-fold greater from the fetal side to the maternal side compared with the maternal-to-fetal transfer. P-gp activity is not likely to modify the placental transfer of quetiapine. Higher P-gp protein expression levels were associated with the variant allele 3435T, but no correlation was found between the TPTAUC % of saquinavir and placental P-gp protein expression. The present results indicate that P-gp activity drastically affects the fetal exposure to saquinavir, and suggest that pharmacological blockade of the P-gp activity during pregnancy may pose an increased risk for adverse fetal outcome. The blockade of P-gp activity could be used in purpose to obtain higher drug concentration to the fetal side, for example, in prevention (to decrease virus transfer to fetal side) or in treating sick fetus.

Dental Health in Preschool and Schoolchildren in Relation to Dental Fear and Some Fear-Related Factors, and the Outcome of a Caries Prevention Program in Offspring of Fearful Mothers

Dental caries and dental fear and anxiety (DFA) are common interrelated problems but so far little is known about these problems in Estonia. The aim was to study dental health in relation to DFA, some fear-related factors, and to study the effect of a caries prevention program in children of fearful mothers. Dental health and DFA were assessed in two Estonian [2-4-year-olds (n=472) and 8-10-year-olds (n=344)], and the effect of some medical conditions on DFA in one Finnish child group [3-year-olds (n=148)]. 120 mother-child-pairs participated in the xylitol-based prevention program. Dental health was examined using the WHO or the ICDAS criteria and expressed as dmft/DMFT-indices. The modified children’s fear survey schedule dental subscale (MCFSS-DS) was used to assess DFA of schoolchildren, one single question to assess parental DFA, and the Corah’s dental anxiety scale (DAS) to assess DFA of mothers in the prevention study. Dentine caries was diagnosed in 42% of the 2-4-year-old and in 93% of the 8-10-year-old Estonian children. DFA of 8-10-year-olds (17%) was associated with experience of dental treatment, and maternal and paternal DFA. Dental apprehension at 9 years of age was associated with frequent exposure to invasive medical care. The xylitol-based prevention was successful irrespective of poor dental hygiene habits and maternal severe DFA. In conclusion, experience of operative dental treatment and DFA of Estonian children were closely associated. Invasive medical care and parental DFA were also linked to children’s DFA. Habitual use of xylitol by mothers was effective in preventing caries even in children of severely fearful mothers.

Metformin in gestational diabetes mellitus

METFORMIININ KÄYTTÖ RASKAUSDIABETEKSESSA Raskausdiabeteksella tarkoitetaan sokeriaineenvaihdunnan häiriötä, joka todetaan ensimmäisen kerran raskauden aikana. Hoidolla voidaan vähentää raskausdiabetekseen liittyviä äidin ja vastasyntyneen haittoja. Lääkitystä tarvitaan, jos ruokavaliohoidolla ei saavuteta hyvää sokeritasapainoa. Perinteisesti lääkityksenä on käytetty insuliinia, mutta metformii¬nin käyttöä insuliinin vaihtoehtona on ehdotettu. Metformiini läpäisee istukan, mutta sen läpäisymekanismi ei ole selvillä. Tämän tutkimuskokonaisuuden pääasiallisin tarkoitus oli verrata metformiinin tehokkuutta ja turvallisuutta insuliiniin raskausdiabeteksen hoidossa selvittämällä lääkkeen vaiku¬tusta äitiin ja vastasyntyneeseen. Lisäksi haluttiin tutkia, mitkä tekijät ennustavat insulii¬nin tarvetta metformiinin lisänä, jotta saavutettaisiin hyvä sokeritasapaino. Metformiinin annoksen vaikutus äitiin ja vastasyntyneeseen arvioitiin mittaamalla metformiinin pitoisuus äidistä, ja sikiön puolelta napanuoran veressä. Tässä tutkimuksessa selvitettiin myös aktiivisen kuljetusproteiinin (OCT) merkitystä metformiinin kulkeutumiseen istukan läpi perfusiomalla istukkaa ex vivo . Ex vivo istukkaperfuusiotutkimuksen tulokset viittasivat siihen, että OCT-kuljetusproteiinilla ei ollut todennäköisesti merkittävää osuutta metformiinin kulkeutumisessa istukan läpi. Metformiinin pitoisuusmittaukset synnytyksen yhteydessä osoittivat metformiinin siirtyvän sikiöön istukan läpi suuressa määrin (96 %) kertymättä kuitenkaan sikiön verenkiertoon. Metformiinin pitoisuudella ei ollut vaikutusta vastasyntyneen hyvinvointiin. Maksi¬maalisella metformiinin annostuksella ja korkealla metformiinipitoisuudella todettiin olevan suotuisa vaikutus äidin painon nousuun raskauden aikana. Insuliiniin verrattuna metformiini ei lisännyt äidin, sikiön tai vastasyntyneen haittatapahtumia, eikä sillä ollut vaikutusta synnytystapaan. Sokeritasapaino insuliini- ja metformiinilääkityksen aikana oli yhtäläinen arvioitaessa sitä HbA1c- ja fruktosamiinimittauksilla, mutta 21 % metformiinin käyttäjistä tarvitsi lisäksi insuliinia hyvän sokeritasapainon saavuttamiseksi. Tutkimuksesssa todettiin, että mitä iäkkäämpi äiti oli, mitä varhaisemmassa raskauden vaiheessa sokerirasitus oli tehty ja lääkitys aloitettu, ja mitä korkeammat HbA1c ja fruktosamiinipitoisuudet olivat, sitä suuremmalla todennäköisyydellä metformiinin lisänä tarvittiin insuliinia.

Pre- and postnatal nutrition – target for allergy risk reduction

A rapid increase in allergic diseases in Western societies has led to the conclusion that our modern lifestyle is a risk factor for immune dysregulation. Potential culprits and benefactors are searched among early dietary and microbial exposures, which may act to program later allergic disease. The aim of this thesis was to investigate the role of early maternal and child nutrition in reducing the risk of child allergy. The study population comprised of 256 mother – child pairs from families with a history of allergy participating in a randomized controlled dietary counseling and probiotic intervention (Lactobacillus rhamnosus GG and Bifidobacterium lactis Bb12) study from early pregnancy onwards. The dietary counseling aimed for a diet complying with dietary recommendations for pregnant and lactating women, with special attention to fat quality. Maternal dietary counseling was reflected in cord blood fatty acids suggesting better essential fatty acid status in infants in the counseling group. Dietary counseling with probiotics or placebo had no effect on child allergy risk, but associations between maternal diet during pregnancy and breastfeeding and child allergic outcomes were found in secondary analyses. During pregnancy, milk intake was related to decreased and cheese intake to increased risk of child atopic eczema. During breastfeeding, intake of vitamin C was related to increased risk of asthma and intake of egg was related to decreased risk of atopic eczema. The timing of introduction of complementary foods to infant’s diet was not associated with risk of atopic eczema, when adjusted with parental opinion of child allergic symptoms (i.e., potential reverse causality). In conclusion, the results demonstrate that infant fatty acid supply can be modified via maternal dietary changes. In addition, interesting associations of maternal diet with child allergy risk were discovered. However, no difference in the incidence of allergic diseases with dietary counseling was observed. This suggests that more potent dietary interventions might be necessitated to induce clinical risk reduction of allergy. Highrisk families can safely adhere to dietary recommendations for pregnant and lactating women, and the results support the current conception that no additional benefit is gained with delaying introduction of complementary feeding.

Bariatric and Post-Bariatric Surgery: from Metabolic Surgery to Plastic Surgery Indications

Background: Controversy exists concerning indications and outcomes of major bariatric surgery procedures. Massive weight loss after bariatric surgery leads to excess skin with functional and aesthetic impairments. The aim of this study was to investigate the major bariatric surgery procedures and their outcomes in two specific subgroups of morbidly obese patients, ≥55-year-olds and the superobese. Further aims were to evaluate whether the preoperative weight loss correlates with laparoscopic gastric bypass complications. The prevalence and impact of excess skin and the desire for body contouring after bariatric surgery were also studied. Patients and Methods: Data from patients who underwent Laparoscopic Adjustable Gastric Banding (LAGB) and Laparoscopic Roux-en-Y Gastric Bypass (LRYGB) at Vaasa Central Hospital were collected and postoperative outcomes were evaluated according to the BMI, age and preoperative weight loss. Patients who had undergone bariatric surgery procedures were asked to complete a questionnaire to estimate any impairment due to redundant skin and to analyse each patient’s desire for body contouring by area. Results: No significant difference was found in operative time, hospital stay, or overall early postoperative morbidity between LAGB and LRYGB. Mean excess weight loss percents (EWL%) at 6 and 12 months after LRYGB were significantly higher. A significant difference was found in operative time favouring patients <55 years. Intraoperative complications were significantly more frequent in the group aged >55 years. No significant difference was detected in overall postoperative morbidity rates. A significant difference was found in operative time and hospital stay favouring all patients who lost weight preoperatively. Most patients reported problems with redundant skin, especially on the abdomen, upper arms and rear/buttocks, which impaired daily physical activity in half of them. Excess skin was significantly associated with female gender, weight loss and ΔBMI. Patients with a WL >20 kg, ΔBMI ≥10 kg/m2 and an EWL % > 50 showed a significantly surplus skin discomfort (p < 0.001). Most patients desired body contouring surgery, with high or very high desire for waist/abdomen (62.2%), upper arm (37.6%), chest/breast (28.3%), and rear/buttock (35.6%) contouring. Conclusions: LRYGB is effective and safe in superobese (BMI >50) and elderly (>55 years) patients. A preoperative weight loss >5% is recommended to improve the outcomes and reduce complications. A WL >20 kg, ΔBMI ≥10 kg/m2 and an EWL % > 50 are associated with a higher functional discomfort due to redundant skin and to a stronger desire for body contouring plastic surgery.

Safety and outcome of coronary interventions with special reference to anticoagulation and stent type

University of Turku, Faculty of Medicine, Department of Cardiology and Cardiovascular Medicine, Doctoral Programme of Clinical Investigation, Heart Center, Turku University Hospital, Turku, Finland Division of Internal Medicine, Department of Cardiology, Seinäjoki Central Hospital, Seinäjoki, Finland Heart Center, Satakunta Central Hospital, Pori, Finland Annales Universitatis Turkuensis Painosalama Oy, Turku, Finland 2015 Antithrombotic therapy during and after coronary procedures always entails the challenging establishment of a balance between bleeding and thrombotic complications. It has been generally recommended to patients on long-term warfarin therapy to discontinue warfarin a few days prior to elective coronary angiography or intervention to prevent bleeding complications. Bridging therapy with heparin is recommended for patients at an increased risk of thromboembolism who require the interruption of anticoagulation for elective surgery or an invasive procedure. In study I, consecutive patients on warfarin therapy referred for diagnostic coronary angiography were compared to control patients with a similar disease presentation without warfarin. The strategy of performing coronary angiography during uninterrupted therapeutic warfarin anticoagulation appeared to be a relatively safe alternative to bridging therapy, if the international normalized ratio level was not on a supratherapeutic level. In-stent restenosis remains an important reason for failure of long-term success after a percutaneous coronary intervention (PCI). Drug-eluting stents (DES) reduce the problem of restenosis inherent to bare metal stents (BMS). However, a longer delay in arterial healing may extend the risk of stent thrombosis (ST) far beyond 30 days after the DES implantation. Early discontinuation of antiplatelet therapy has been the most important predisposing factor for ST. In study II, patients on long-term oral anticoagulant (OAC) underwent DES or BMS stenting with a median of 3.5 years’follow-up. The selective use of DESs with a short triple therapy seemed to be safe in OAC patients, since late STs were rare even without long clopidogrel treatment. Major bleeding and cardiac events were common in this patient group irrespective of stent type. In order to help to predict the bleeding risk in patients on OAC, several different bleeding risk scorings have been developed. Risk scoring systems have also been used also in the setting of patients undergoing a PCI. In study III, the predictive value of an outpatient bleeding risk index (OBRI) to identify patients at high risk of bleeding was analysed. The bleeding risk seemed not to modify periprocedural or long-term treatment choices in patients on OAC after a percutaneous coronary intervention. Patients with a high OBRI often had major bleeding episodes, and the OBRI may be suitable for risk evaluation in this patient group. Optical coherence tomography (OCT) is a novel technology for imaging intravascular coronary arteries. OCT is a light-based imaging modality that enables a 12–18 µm tissue axial resolution to visualize plaques in the vessel, possible dissections and thrombi as well as, stent strut appositions and coverage, and to measure the vessel lumen and lesions. In study IV, 30 days after titanium-nitride-oxide (TITANOX)-coated stent implantation, the binary stent strut coverage was satisfactory and the prevalence of malapposed struts was low as evaluated by OCT. Long-term clinical events in patients treated with (TITANOX)-coated bio-active stents (BAS) and paclitaxel-eluting stents (PES) in routine clinical practice were examined in study V. At the 3-year follow-up, BAS resulted in better long-term outcome when compared with PES with an infrequent need for target vessel revascularization. Keywords: anticoagulation, restenosis, thrombosis, bleeding, optical coherence tomography, titanium

Molecular patterns behind immunological and metabolic alterations in lysinuric protein intolerance

Lysinuric protein intolerance (LPI) is a recessively inherited disorder characterised by reduced plasma and increased urinary levels of cationic amino acids (CAAs), protein malnutrition, growth failure and hyperlipidemia. Some patients develop severe immunological, renal and pulmonary complications. All Finnish patients share the same LPIFin mutation in the SLC7A7 gene that encodes CAA transporter y+LAT1. The aim of this study was to examine molecular factors contributing to the various symptoms, systemic metabolic and lipid profiles, and innate immune responses in LPI. The transcriptomes, metabolomes and lipidomes were analysed in whole-blood cells and plasma using RNA microarrays and gas or liquid chromatography-mass spectrometry techniques, respectively. Toll-like receptor (TLR) signalling in monocyte-derived macrophages exposed to pathogens was scrutinised using qRT-PCR and the Luminex technology. Altered levels of transcripts participating in amino acid transport, immune responses, apoptosis and pathways of hepatic and renal metabolism were identified in the LPI whole-blood cells. The patients had increased non-essential amino acid, triacylglycerol and fatty acid levels, and decreased plasma levels of phosphatidylcholines and practically all essential amino acids. In addition, elevated plasma levels of eight metabolites, long-chain triacylglycerols, two chemoattractant chemokines and nitric oxide correlated with the reduced glomerular function in the patients with kidney disease. Accordingly, it can be hypothesised that the patients have increased autophagy, inflammation, oxidative stress and apoptosis, leading to hepatic steatosis, uremic toxicity and altered intestinal microbe metabolism. Furthermore, the LPI macrophages showed disruption in the TLR2/1, TLR4 and TLR9 pathways, suggesting innate immune dysfunctions with an excessive response to bacterial infections but a deficient viral DNA response.

Ventricular rate during acute atrial fibrillation and outcome of electrical cardioversion: The FinCV Study

The impact of ventricular rate (VR) on the outcome of electrical cardioversion (ECV) of acute atrial fibrillation (AF) is currently unknown. We aimed to determine the effect of VR during acute AF on the success of ECV, recurrence of AF and occurrence of post-cardioversion complications in 30 days follow-up. All ECVs performed in patients with acute atrial fibrillation lasting <48 hours in 2 Finnish university hospitals during 2003-2010 and 1 central hospital during 2010 were retrospectively identified. A total of 6,624 ECVs were performed in 2,821 consecutive patients. VR≤60 BPM was defined low and VR≥160 BPM high. The median VR before ECV was 109 BPM. The success rate of ECV was 94.2%. Bradycardia occurred in 62 (0.9%) and thromboembolic complications in 39 (0.6%) ECVs. Low VR was observed before 75 (1.1%) ECVs and male sex was its only independent predictor. High VR was observed in 165 (2.5%) ECVs. The independent predictors of high VR were younger age, <12 h episode duration, no previous history of AF and alcohol abuse. Low or high VR were not related to the success of ECV, incidence of thromboembolic or bradycardic complications, or recurrence of AF, although VR was significantly (p<0.001) lower in the patients in whom AF recurred. In conclusion, ECV of acute AF is an effective procedure and VR during AF does not affect its efficacy, the maintenance of sinus rhythm or the incidence of bradycardic, thromboembolic or other complications during 30 days follow-up after ECV. Low VR is predominately observed in male patients, while high VR was a feature related to a shorter history of AF and high alcohol-intake.

Epidemiology of Cytochrome P450-mediated Drug-Drug Interactions

Drug-drug interactions (DDIs) comprise an important cause of adverse drug reactions leading to excess hospitalizations. Drug metabolism is catalyzed by 75% by cytochrome P450 (CYP) enzymes and thus they are often involved in pharmacokinetic DDIs. In general, DDIs are studied in randomized controlled clinical trials in selected study populations. The overall aim of the present studies was to perform observational pharmacoepidemiological surveys on CYP-mediated DDIs in diseases important at the population level. The prevalence of co-administrations of four prodrugs (losartan, codeine, tramadol, and clopidogrel), three sulphonylureas (glibenclamide, glimepiride, and glipizide), or two statins (lovastatin and simvastatin) with well established agents altering CYP activity, as well as of statins with fibrates, was studied in Finland utilizing data from a university hospital medication database (inpatients) and the National Prescription Register of the Social Insurance Institution of Finland, Kela (outpatients). Clinical consequences of potential DDIs were estimated by reviewing laboratory data, and information from hospital care and cause-of-death registers. Concomitant use of study substrates with interacting medication was detected in up to one fifth of patients in both hospital and community settings. Potential CYP3A4 interactions in statin users did not manifest in clear adverse laboratory values but pharmacodynamic DDIs between statins and fibrates predisposed patients to muscular toxicity. Sulphonylurea DDIs with CYP2C9 inhibitors increased the risk of hypoglycaemia. CYP3A4 inhibitor use with clopidogrel was not associated with significant changes in mortality but non-fatal thrombosis and haemorrhage complications were seen less often in this group. Concomitant administration of atorvastatin with clopidogrel moderately attenuated the antithrombotic effect by clopidogrel. The overall mortality was increased in CYP3A4 inducer and clopidogrel co-users. Atorvastatin used concomitantly with prodrug clopidogrel seems to be beneficial in terms of total and LDL cholesterol concentrations, and overall mortality compared with clopidogrel use without interacting medication. In conclusion, CYP-mediated DDIs are a common and often unrecognized consequence of irrational drug prescribing.

Percutaneous Coronary Intervention in Patients with Atrial Fibrillation: A Study of Factors Affecting Outcome, with a Special Emphasis on Periprocedural Antithrombotic Treatment

Antithrombotic treatment of patients with atrial fibrillation (AF) undergoing percutaneous coronary intervention (PCI) is a delicate balancing between the risk of thromboembolism and the risk of bleeding. The purpose of this dissertation was to analyze current antithrombotic treatment strategies at the periprocedural stage and report outcomes in-hospital and at 1-month follow-up, and to evaluate the effect of renal impairment and predictive values of various bleeding scores on 1-year outcome after PCI in patients with AF. The first article was based on retrospective data from 7 Finnish hospitals between 2002–2006 (n=377), while the others were based on a prospective 17-center European register (AFCAS) gathered between 2008–2010 (n=963). The main findings in patients with AF undergoing PCI were: The use of glycoprotein IIb/IIIa inhibitors during PCI was associated with a four- to five-fold increase in the risk of major bleeding (I). Uninterrupted warfarin treatment did not increase perioperative complications and seemed to decrease bleeding complications compared to heparin bridging (II). Already mild renal impairment (eGFR 60–90mL/min) was associated with a 2.3-fold risk of all-cause mortality during the 12 months following PCI (III). Major adverse cardiac events occurred in 4.5% and bleeding complications in 7.1% of patients in the AFCAS register by 1-month follow-up (IV). In a study of patients in AFCAS register, all currently used bleeding risk scores were poor predictors of bleeding complications by 1-year follow-up (V). The findings will help improve treatment strategies for this fragile patient population with a high risk of bleeding and thrombotic complications.