Physiological and biomechanical responses to walking underwater on a non-motorised treadmill: Effects of different exercise intensities and depths in middle-aged healthy women

Non-motorised underwater treadmills are commonly used in fitness activities. However, no studies have examined physiological and biomechanical responses of walking on non-motorised treadmills at different intensities and depths. Fifteen middle-aged healthy women underwent two underwater walking tests at two different depths, immersed either up to the xiphoid process (deep water) or the iliac crest (shallow water), at 100, 110, 120, 130 step-per-minute (spm). Oxygen consumption (VO2), heart rate (HR), blood lactate concentration, perceived exertion and step length were determined. Compared to deep water, walking in shallow water exhibited, at all intensities, significantly higher VO2 (+13.5%, on average) and HR (+8.1%, on average) responses. Water depth did not influence lactate concentration, whereas perceived exertion was higher in shallow compared to deep water, solely at 120 (+40%) and 130 (+39.4%) spm. Average step length was reduced as the intensity increased (from 100 to 130 spm), irrespective of water depth. Expressed as a percentage of maximum, average VO2 and HR were: 64–76% of peak VO2 and 71–90% of maximum HR, respectively at both water depths. Accordingly, this form of exercise can be included in the “vigorous” range of exercise intensity, at any of the step frequencies used in this study.

An empirical examination of the consequences of national pride: Analyses of survey and experimental data

National pride is both an important and understudied topic with respect to economic behaviour, hence this thesis investigates whether: 1) there is a "light" side of national pride through increased compliance, and a "dark" side linked to exclusion; 2) successful priming of national pride is linked to increased tax compliance; and 3) East German post-reunification outmigration is related to loyalty. The project comprises three related empirical studies, analysing evidence from a large, aggregated, international survey dataset; a tax compliance laboratory experiment combining psychological priming with measurement of heart rate variability; and data collected after the fall of the Berlin Wall (a situation approximating a natural experiment).

Work Stress and Early Atherosclerosis: Do Genetic Background and Pre-Employment Risk Factors Explain Conflicting Findings?

According to the models conceptualizing work stress, increased risk of health problems arise when high job demands co-occur with low job control (the demand-control model) or the efforts invested by the employee are disproportionately high compared to the rewards received (effort-reward imbalance model). This study examined the association between work stress and early atherosclerosis with particular attention to the role of pre-employment risk factors and genetic background in this association. The subjects were young healthy adults aged 24-39 who were participating in the 21-year follow-up of the ongoing prospective "Cardiovascular Risk in Young Finns" study in 2001-2002. Work stress was evaluated with questionnaires on demand-control model and on effort-reward model. Atherosclerosis was assessed with ultrasound of carotid artery intima-media thickness (IMT). In addition, risk for enhanced atherosclerotic process was assessed by measuring with heart rate variability and heart rate. Pre-employment risk factors, measured at age 12 to 18, included such as body mass index, blood lipids, family history of coronary heart disease, and parental socioeconomic position. Variants of the neuregulin-1 were determined using genomic DNA. The results showed that higher work stress was associated with higher IMT in men. This association was not attenuated by traditional risk factors of atherosclerosis and coronary heart disease or by pre-employment risk factors measured in adolescence. Neuregulin-1 gene moderated the association between work stress and IMT in men. A significant association between work stress and IMT was found only for the T/T genotype of the neuregulin-1 gene but not for other genotypes. Among women an association was found between higher work stress and lower heart rate variability, suggesting higher risk for developing atherosclerosis. These associations could not be explained by demographic characteristics or coronary risk factors. The present findings provide evidence for an association between work stress and atherosclerosis in relatively young population. This association seems to be modified by genetic influences but it does not appear to be confounded by pre-employment adolescent risk factors.

Chronic and acute stress in atherosclerosis : the role of endothelial function and arterial elasticity

Atherosclerosis is the main underlying pathology of coronary heart disease. Coronary heart disease is a serious health problem in Finland, and it is the leading cause of morbidity and mortality in industrialized countries. Psychological stress correlates with coronary heart disease events – myocardial infarction and sudden death, which are the most common clinical syndromes of atherosclerotic narrowing of arteries. The present series of studies examines the interaction between stress and endothelial function in relation to atherosclerosis. The study also aims to give new information on the mechanisms through which stress has its effect on atherosclerosis progression, focusing on possible relations between psychological stress and the functioning of the endothelium. Our project is based on data from one of the largest national epidemiological studies, the Cardiovascular Risk in Young Finns study, which has monitored the development of risk factors for coronary heart disease in 3596 young adults since 1980. The present study combines experimental stress research with epidemiology and uses an advanced method for examining atherosclerosis development in healthy subjects (intima-media thickness ultrasound measurement). The physiological parameters used were heart rate, respiratory sinus arrhythmia and pre-ejection period. Chronic stress was assessed by vital exhaustion. The ultrasound measurements that served as the indexes of preclinical atherosclerosis were carotid intima-media thickness, brachial flow-mediated dilatation and carotid artery compliance. The effects of cardiovascular risk factors found to be important were taken into account: serum cholesterols level, triglyceride level, serum insulin level and systolic and diastolic blood pressure. There were 69, 1596, 81 and 1721 participants in studies I-IV, respectively. The results showed that both chronic and acute stress may exert an effect on atherosclerosis in subjects with impaired endothelial responses. The findings are consistent with the idea that risk factors are more harmful if the endothelium is not working properly. Chronic stress was found to be a risk if it has resulted in ineffective cardiac stress reactivity or delayed recovery. Men were shown to be at increased risk for atherosclerotic progression in early life, which suggests men’s decreased stress coping ability in relation to stressful psychosocial coronary risk factors. Autonomic imbalance may be the common mechanism of the stress influence on atherosclerosis development. The results of the present study contain background information for the identification the first stages of atherosclerosis, and they may be useful for preventive medicine programs for young adults and could help to improve cardiovascular health in Finland as well as in other countries.

The role of catechol-O-methyltransferase (COMT) and the effects of COMT inhibition in brain and in cardiovascular and renal pathophysiology

Catechol-O-methyltransferase (COMT) metabolizes catecholamines such as dopamine (DA), noradrenaline (NA) and adrenaline, which are vital neurotransmitters and hormones that play important roles in the regulation of physiological processes. COMT enzyme has a functional Val158Met polymorphism in humans, which affects the subjects COMT activity. Increasing evidence suggests that this functional polymorphism may play a role in the etiology of various diseases from schizophrenia to cancers. The aim of this project was to provide novel biochemical information on the physiological and especially pathophysiological roles of COMT enzyme as well as the effects of COMT inhibition in the brain and in the cardiovascular and renal system. To assess the roles of COMT and COMT inhibition in pathophysiology, we used four different study designs. The possible beneficial effects of COMT inhibition were studied in double-transgenic rats (dTGRs) harbouring human angiotensinogen and renin genes. Due to angiotensin II (Ang II) overexpression, these animals exhibit severe hypetension, cardiovascular and renal end-organ damage and mortality of approximately 25-40% at the age of 7-weeks. The dTGRs and their Sprague-Dawley controls tissue samples were assessed with light microscopy, immunohistochemistry, reverse transcriptase-polymerase chain reaction (RT-PCR) and high-pressure liquid chromatography (HPLC) to evaluate the tissue damages and the possible protective effects pharmacological intervention with COMT inhibitors. In a second study, the consequence of genetic and pharmacological COMT blockade in blood pressure regulation during normal and high-sodium was elucidated using COMT-deficient mice. The blood pressure and the heart rate were measured using direct radiotelemetric blood pressure surveillance. In a third study, the effects of acute and subchronic COMT inhibition during combined levodopa (L-DOPA) + dopa decarboxylase inhibitor treatment in homocysteine formation was evaluated. Finally, we assessed the COMT enzyme expression, activity and cellular localization in the CNS during inflammation-induced neurodegeneration using Western blotting, HPLC and various enzymatic assays. The effects of pharmacological COMT inhibition on neurodegeneration were also studied. The COMT inhibitor entacapone protected against the Ang II-induced perivascular inflammation, renal damage and cardiovascular mortality in dTGRs. COMT inhibitors reduced the albuminuria by 85% and prevented the cardiovascular mortality completely. Entacapone treatment was shown to ameliorate oxidative stress and inflammation. Furthermore, we established that the genetic and pharmacological COMT enzyme blockade protects against the blood pressure-elevating effects of high sodium intake in mice. These effects were mediated via enhanced renal dopaminergic tone and suggest an important role of COMT enzyme, especially in salt-sensitive hypertension. Entacapone also ameliorated the L-DOPA-induced hyperhomocysteinemia in rats. This is important, since decreased homocysteine levels may decrease the risk of cardiovascular diseases in Parkinson´s disease (PD) patients using L-DOPA. The Lipopolysaccharide (LPS)-induced inflammation and subsequent delayed dopaminergic neurodegeneration were accompanied by up-regulation of COMT expression and activity in microglial cells as well as in perivascular cells. Interestingly, similar perivascular up-regulation of COMT expression in inflamed renal tissue was previously noted in dTGRs. These results suggest that inflammation reactions may up-regulate COMT expression. Furthermore, this increased glial and perivascular COMT activity in the central nervous system (CNS) may decrease the bioavailability of L-DOPA and be related to the motor fluctuation noted during L-DOPA therapy in PD patients.

Physical activity, fitness, abdominal obesity, and cardiovascular risk factors in Finnish men and women : The National FINRISK 2002 Study

Physical inactivity, low cardiorespiratory fitness, and abdominal obesity are direct and mediating risk factors for cardiovascular disease (CVD). The results of recent studies suggest that individuals with higher levels of physical activity or cardiorespiratory fitness have lower CVD and all-cause mortality than those with lower activity or fitness levels regardless of their level of obesity. The interrelationships of physical activity, fitness, and abdominal obesity with cardiovascular risk factors have not been studied in detail. The aim of this study was to investigate the associations of different types of leisure time physical activity and aerobic fitness with cardiovascular risk factors in a large population of Finnish adults. In addition, a novel aerobic fitness test was implemented and the distribution of aerobic fitness was explored in men and women across age groups. The interrelationships of physical activity, aerobic fitness and abdominal obesity were examined in relation to cardiovascular risk factors. This study was part of the National FINRISK Study 2002, which monitors cardiovascular risk factors in a Finnish adult population. The sample comprised 13 437 men and women aged 25 to 74 years and was drawn from the Population Register as a stratified random sample according to 10-year age groups, gender and area. A separate physical activity study included 9179 subjects, of whom 5 980 participated (65%) in the study. At the study site, weight, height, waist and hip circumferences, and blood pressure were measured, a blood sample was drawn, and an aerobic fitness test was performed. The fitness test estimated maximal oxygen uptake (VO2max) and was based on a non-exercise method by using a heart rate monitor at rest. Waist-to-hip ratio (WHR) was calculated by dividing waist circumference with hip circumference and was used as a measure of abdominal obesity. Participants filled in a questionnaire on health behavior, a history of diseases, and current health status, and a detailed 12-month leisure time physical activity recall. Based on the recall data, relative energy expenditure was calculated using metabolic equivalents, and physical activity was divided into conditioning, non-conditioning, and commuting physical activity. Participants aged 45 to 74 years were later invited to take part in a 2-hour oral glucose tolerance test with fasting insulin and glucose measurements. Based on the oral glucose tolerance test, undiagnosed impaired glucose tolerance and type 2 diabetes were defined. The estimated aerobic fitness was lower among women and decreased with age. A higher estimated aerobic fitness and a lower WHR were independently associated with lower systolic and diastolic blood pressure, lower total cholesterol and triglyceride levels, and with higher high-density lipoprotein (HDL) cholesterol and HDL to total cholesterol ratio. The associations of the estimated aerobic fitness with diastolic blood pressure, triglycerides, and HDL to total cholesterol ratio were stronger in men with a higher WHR. High levels of conditioning and non-conditioning physical activity were associated with lower high-sensitivity C-reactive protein (CRP) levels. High levels of conditioning and overall physical activities were associated with lower insulin and glucose levels. The associations were stronger among women than men. A better self-rated physical fitness was associated with a higher estimated aerobic fitness, lower CRP levels, and lower insulin and glucose levels in men and women. In each WHR third, the risk of impaired glucose tolerance and type 2 diabetes was higher among physically inactive individuals who did not undertake at least 30 minutes of moderate-intensity physical activity on five days per week. These cross-sectional data show that higher levels of estimated aerobic fitness and regular leisure time physical activity are associated with a favorable cardiovascular risk factor profile and that these associations are present at all levels of abdominal obesity. Most of the associations followed a dose-response manner, suggesting that already low levels of physical activity or fitness are beneficial to health and that larger improvements in risk factor levels may be gained from higher activity and fitness levels. The present findings support the recommendation to engage regularly in leisure time physical activity, to pursue a high level of aerobic fitness, and to prevent abdominal obesity.

Validity of the OMNI rating of perceived exertion scale for children and adolescents with cerebral palsy

Aim This study evaluated the validity of the OMNI Walk/Run Rating of Perceived Exertion (OMNI-RPE) scores with heart rate and oxygen consumption (VO2) for children and adolescents with cerebral palsy (CP). Method Children and adolescents with CP, aged 6 to 18 years and Gross Motor Function Classification System (GMFCS) levels I to III completed a physical activity protocol with seven trials ranging in intensity from sedentary to moderate-to-vigorous. VO2 and heart rate were recorded during the physical activity trials using a portable indirect calorimeter and heart rate monitor. Participants reported OMNI-RPE scores for each trial. Concurrent validity was assessed by calculating the average within-subject correlation between OMNI-RPE ratings and the two physiological indices. Results For the correlational analyses, 48 participants (22 males, 26 females; age 12y 6mo, SD 3y 4mo) had valid bivariate data for VO2 and OMNI-RPE, while 40 participants (21 males, 19 females; age 12y 5mo, SD 2y 9mo) had valid bivariate data for heart rate and OMNI-RPE. VO2 (r=0.80; 95% CI 0.66–0.88) and heart rate (r=0.83; 95% CI 0.70–0.91) were moderately to highly correlated to OMNI-RPE scores. No difference was found for the correlation of physiological data and OMNI-RPE scores across the three GMFCS levels. The OMNI-RPE scores increased significantly in a dose-response manner (F6,258=116.1, p<0.001) as exercise intensity increased from sedentary to moderate-to-vigorous. Interpretation OMNI-RPE is a clinically feasible option to monitor exercise intensity in ambulatory children and adolescents with CP.

Assessing the effectiveness of High Intensity Interval Training (HIIT) for smoking cessation in women: HIIT to quit study protocol

Background: Smoking and physical inactivity are major risk factors for heart disease. Linking strategies that promote improvements in fitness and assist quitting smoking has potential to address both these risk factors simultaneously. The objective of this study is to compare the effects of two exercise interventions (high intensity interval training (HIIT) and lifestyle physical activity) on smoking cessation in female smokers. Method/design: This study will use a randomised controlled trial design. Participants: Women aged 18–55 years who smoke ≥ 5 cigarettes/day, and want to quit smoking. Intervention: all participants will receive usual care for quitting smoking. Group 1 - will complete two gym-based supervised HIIT sessions/week and one home-based HIIT session/week. At each training session participants will be asked to complete four 4-min (4 × 4 min) intervals at approximately 90 % of maximum heart rate interspersed with 3- min recovery periods. Group 2 - participants will receive a resource pack and pedometer, and will be asked to use the 10,000 steps log book to record steps and other physical activities. The aim will be to increase daily steps to 10,000 steps/day. Analysis will be intention to treat and measures will include smoking cessation, withdrawal and cravings, fitness, physical activity, and well-being. Discussion: The study builds on previous research suggesting that exercise intensity may influence the efficacy of exercise as a smoking cessation intervention. The hypothesis is that HIIT will improve fitness and assist women to quit smoking.

Tax compliance and psychic costs: Behavioral experimental evidence using a physiological marker

Although paying taxes is a key element of a well-functioning society, there is still limited understanding as to why people actually pay their taxes. Models emphasizing that taxpayers make strategic, financially motivated compliance decisions seemingly assume an overly restrictive view of human nature. Law abidance may be more accurately explained by social norms, a concept that has gained growing importance as research attempts to understand the tax compliance puzzle. This study analyzes the influence of psychic stress generated by the possibility of breaking social norms in the tax compliance context. We measure psychic stress using heart rate variability (HRV), which captures the psychobiological or neural equivalents of psychic stress that may arise from the contemplation of real or imagined actions, producing immediate physiologic discomfort. The results of our laboratory experiments provide empirical evidence of a positive correlation between psychic stress and tax compliance, thus underscoring the importance of moral sentiments for tax compliance. We also identify three distinct types of individuals who differ in their levels of psychic stress, tax morale, and tax compliance.

Placental abruption : Studies on incidence, risk factors and potential predictive biomarkers

Placental abruption, one of the most significant causes of perinatal mortality and maternal morbidity, occurs in 0.5-1% of pregnancies. Its etiology is unknown, but defective trophoblastic invasion of the spiral arteries and consequent poor vascularization may play a role. The aim of this study was to define the prepregnancy risk factors of placental abruption, to define the risk factors during the index pregnancy, and to describe the clinical presentation of placental abruption. We also wanted to find a biochemical marker for predicting placental abruption early in pregnancy. Among women delivering at the University Hospital of Helsinki in 1997-2001 (n=46,742), 198 women with placental abruption and 396 control women were identified. The overall incidence of placental abruption was 0.42%. The prepregnancy risk factors were smoking (OR 1.7; 95% CI 1.1, 2.7), uterine malformation (OR 8.1; 1.7, 40), previous cesarean section (OR 1.7; 1.1, 2.8), and history of placental abruption (OR 4.5; 1.1, 18). The risk factors during the index pregnancy were maternal (adjusted OR 1.8; 95% CI 1.1, 2.9) and paternal smoking (2.2; 1.3, 3.6), use of alcohol (2.2; 1.1, 4.4), placenta previa (5.7; 1.4, 23.1), preeclampsia (2.7; 1.3, 5.6) and chorioamnionitis (3.3; 1.0, 10.0). Vaginal bleeding (70%), abdominal pain (51%), bloody amniotic fluid (50%) and fetal heart rate abnormalities (69%) were the most common clinical manifestations of placental abruption. Retroplacental blood clot was seen by ultrasound in 15% of the cases. Neither bleeding nor pain was present in 19% of the cases. Overall, 59% went into preterm labor (OR 12.9; 95% CI 8.3, 19.8), and 91% were delivered by cesarean section (34.7; 20.0, 60.1). Of the newborns, 25% were growth restricted. The perinatal mortality rate was 9.2% (OR 10.1; 95% CI 3.4, 30.1). We then tested selected biochemical markers for prediction of placental abruption. The median of the maternal serum alpha-fetoprotein (MSAFP) multiples of median (MoM) (1.21) was significantly higher in the abruption group (n=57) than in the control group (n=108) (1.07) (p=0.004) at 15-16 gestational weeks. In multivariate analysis, elevated MSAFP remained as an independent risk factor for placental abruption, adjusting for parity ≥ 3, smoking, previous placental abruption, preeclampsia, bleeding in II or III trimester, and placenta previa. MSAFP ≥ 1.5 MoM had a sensitivity of 29% and a false positive rate of 10%. The levels of the maternal serum free beta human chorionic gonadotrophin MoM did not differ between the cases and the controls. None of the angiogenic factors (soluble endoglin, soluble fms-like tyrosine kinase 1, or placental growth factor) showed any difference between the cases (n=42) and the controls (n=50) in the second trimester. The levels of C-reactive protein (CRP) showed no difference between the cases (n=181) and the controls (n=261) (median 2.35 mg/l [interquartile range {IQR} 1.09-5.93] versus 2.28 mg/l [IQR 0.92-5.01], not significant) when tested in the first trimester (mean 10.4 gestational weeks). Chlamydia pneumoniae specific immunoglobulin G (IgG) and immunoglobulin A (IgA) as well as C. trachomatis specific IgG, IgA and chlamydial heat-shock protein 60 antibody rates were similar between the groups. In conclusion, although univariate analysis identified many prepregnancy risk factors for placental abruption, only smoking, uterine malformation, previous cesarean section and history of placental abruption remained significant by multivariate analysis. During the index pregnancy maternal alcohol consumption and smoking and smoking by the partner turned out to be the major independent risk factors for placental abruption. Smoking by both partners multiplied the risk. The liberal use of ultrasound examination contributed little to the management of women with placental abruption. Although second-trimester MSAFP levels were higher in women with subsequent placental abruption, clinical usefulness of this test is limited due to low sensitivity and high false positive rate. Similarly, angiogenic factors in early second trimester, or CRP levels, or chlamydial antibodies in the first trimester failed to predict placental abruption.

Effects of opioids on ventilation and hemodynamics

Opioids are most commonly used for treatment of severe pain. However, the fear of respiratory depression has restricted the use of opioids. Depending on the monitoring system used, different modes of opioid respiratory effects have been noted in previous studies. All opioids also cause alterations in hemodynamics at least to some extent. The main goal of this series of investigations was to elucidate the native ventilatory and hemodynamic effects of different opioids. Studies I-IV each involved 8 healthy male volunteers. Study V involved 13 patients with lower or upper extremity traumas. The opioids studied were morphine, oxycodone, pethidine, fentanyl, alfentanil, tramadol and ketamine. The respiratory parameters used in this study were breathing pattern measured with respiratory inductive plethysmography, gas exchange measured with indirect calorimetry, blood gas analysis and pulse oximetry. Hemodynamics was measured with arterial blood pressure, heart rate and oxygen consumption. Plasma catecholamine and histamine concentrations were also determined. All opioids studied caused an alteration in respiratory function. Respiratory rate, alveolar ventilation and minute ventilation decreased, while tidal volume increased in most situations. Breathing pattern was also significantly affected after opioid administration. The respiratory depression caused by oxycodone was deeper than the one caused by same dose of morphine. An equianalgesic dose of tramadol caused markedly smaller respiratory depression compared to pethidine. The potency ratio for respiratory depression of fentanyl and alfentanil is similar to analgesic potency ratio studied elsewhere. Racemic ketamine attenuated the respiratory depression caused by fentanyl, if measured with minute ventilation. However, this effect was counteracted by increased oxygen consumption. Supplemental oxygen did not offer any benefits, nor did it cause any atelectasis when given to opioid treated trauma patients. Morphine caused a transient hemodynamic stimulation, which was accompanied by an increase in oxygen consumption. Oxycodone, alfentanil, fentanyl, tramadol and pethidine infusions had minimal effects on hemodynamics. Plasma catecholamine concentrations were increased after high dose opioid administration. Plasma histamine concentrations were not elevated after morphine nor oxycodone administration. Respiratory depression is a side effect noted with all opioids. The profile of this phenomenon is quite similar with different opioid-receptor agonists. The hemodynamic effects of opioids may vary depending on the opioid used, morphine causing a slight hemodynamic stimulation. However, all opioids studied could be considered hemodynamically stable.

Therapeutic hypothermia after cardiac arrest : Studies on neurological and cardiological outcome and prediction of outcome in hypothermia-treated patients resuscitated from out-of-hospital cardiac arrest

The outcome of the successfully resuscitated patient is mainly determined by the extent of hypoxic-ischemic cerebral injury, and hypothermia has multiple mechanisms of action in mitigating such injury. The present study was undertaken from 1997 to 2001 in Helsinki as a part of the European multicenter study Hypothermia after cardiac arrest (HACA) to test the neuroprotective effect of therapeutic hypothermia in patients resuscitated from out-of-hospital ventricular fibrillation (VF) cardiac arrest (CA). The aim of this substudy was to examine the neurological and cardiological outcome of these patients, and especially to study and develop methods for prediction of outcome in the hypothermia-treated patients. A total of 275 patients were randomized to the HACA trial in Europe. In Helsinki, 70 patients were enrolled in the study according to the inclusion criteria. Those randomized to hypothermia were actively cooled externally to a core temperature 33 ± 1ºC for 24 hours with a cooling device. Serum markers of ischemic neuronal injury, NSE and S-100B, were sampled at 24, 36, and 48 hours after CA. Somatosensory and brain stem auditory evoked potentials (SEPs and BAEPs) were recorded 24 to 28 hours after CA; 24-hour ambulatory electrocardiography recordings were performed three times during the first two weeks and arrhythmias and heart rate variability (HRV) were analyzed from the tapes. The clinical outcome was assessed 3 and 6 months after CA. Neuropsychological examinations were performed on the conscious survivors 3 months after the CA. Quantitative electroencephalography (Q-EEG) and auditory P300 event-related potentials were studied at the same time-point. Therapeutic hypothermia of 33ºC for 24 hours led to an increased chance of good neurological outcome and survival after out-of-hospital VF CA. In the HACA study, 55% of hypothermia-treated patients and 39% of normothermia-treated patients reached a good neurological outcome (p=0.009) at 6 months after CA. Use of therapeutic hypothermia was not associated with any increase in clinically significant arrhythmias. The levels of serum NSE, but not the levels of S-100B, were lower in hypothermia- than in normothermia-treated patients. A decrease in NSE values between 24 and 48 hours was associated with good outcome at 6 months after CA. Decreasing levels of serum NSE but not of S-100B over time may indicate selective attenuation of delayed neuronal death by therapeutic hypothermia, and the time-course of serum NSE between 24 and 48 hours after CA may help in clinical decision-making. In SEP recordings bilaterally absent N20 responses predicted permanent coma with a specificity of 100% in both treatment arms. Recording of BAEPs provided no additional benefit in outcome prediction. Preserved 24- to 48-hour HRV may be a predictor of favorable outcome in CA patients treated with hypothermia. At 3 months after CA, no differences appeared in any cognitive functions between the two groups: 67% of patients in the hypothermia and 44% patients in the normothermia group were cognitively intact or had only very mild impairment. No significant differences emerged in any of the Q-EEG parameters between the two groups. The amplitude of P300 potential was significantly higher in the hypothermia-treated group. These results give further support to the use of therapeutic hypothermia in patients with sudden out-of-hospital CA.

Measurements of adequacy of anesthesia and level of consciousness during surgery and intensive care

The adequacy of anesthesia has been studied since the introduction of balanced general anesthesia. Commercial monitors based on electroencephalographic (EEG) signal analysis have been available for monitoring the hypnotic component of anesthesia from the beginning of the 1990s. Monitors measuring the depth of anesthesia assess the cortical function of the brain, and have gained acceptance during surgical anesthesia with most of the anesthetic agents used. However, due to frequent artifacts, they are considered unsuitable for monitoring consciousness in intensive care patients. The assessment of analgesia is one of the cornerstones of general anesthesia. Prolonged surgical stress may lead to increased morbidity and delayed postoperative recovery. However, no validated monitoring method is currently available for evaluating analgesia during general anesthesia. Awareness during anesthesia is caused by an inadequate level of hypnosis. This rare but severe complication of general anesthesia may lead to marked emotional stress and possibly posttraumatic stress disorder. In the present series of studies, the incidence of awareness and recall during outpatient anesthesia was evaluated and compared with that of in inpatient anesthesia. A total of 1500 outpatients and 2343 inpatients underwent a structured interview. Clear intraoperative recollections were rare the incidence being 0.07% in outpatients and 0.13% in inpatients. No significant differences emerged between outpatients and inpatients. However, significantly smaller doses of sevoflurane were administered to outpatients with awareness than those without recollections (p<0.05). EEG artifacts in 16 brain-dead organ donors were evaluated during organ harvest surgery in a prospective, open, nonselective study. The source of the frontotemporal biosignals in brain-dead subjects was studied, and the resistance of bispectral index (BIS) and Entropy to the signal artifacts was compared. The hypothesis was that in brain-dead subjects, most of the biosignals recorded from the forehead would consist of artifacts. The original EEG was recorded and State Entropy (SE), Response Entropy (RE), and BIS were calculated and monitored during solid organ harvest. SE differed from zero (inactive EEG) in 28%, RE in 29%, and BIS in 68% of the total recording time (p<0.0001 for all). The median values during the operation were SE 0.0, RE 0.0, and BIS 3.0. In four of the 16 organ donors, EEG was not inactive, and unphysiologically distributed, nonreactive rhythmic theta activity was present in the original EEG signal. After the results from subjects with persistent residual EEG activity were excluded, SE, RE, and BIS differed from zero in 17%, 18%, and 62% of the recorded time, respectively (p<0.0001 for all). Due to various artifacts, the highest readings in all indices were recorded without neuromuscular blockade. The main sources of artifacts were electrocauterization, electromyography (EMG), 50-Hz artifact, handling of the donor, ballistocardiography, and electrocardiography. In a prospective, randomized study of 26 patients, the ability of Surgical Stress Index (SSI) to differentiate patients with two clinically different analgesic levels during shoulder surgery was evaluated. SSI values were lower in patients with an interscalene brachial plexus block than in patients without an additional plexus block. In all patients, anesthesia was maintained with desflurane, the concentration of which was targeted to maintain SE at 50. Increased blood pressure or heart rate (HR), movement, and coughing were considered signs of intraoperative nociception and treated with alfentanil. Photoplethysmographic waveforms were collected from the contralateral arm to the operated side, and SSI was calculated offline. Two minutes after skin incision, SSI was not increased in the brachial plexus block group and was lower (38 ± 13) than in the control group (58 ± 13, p<0.005). Among the controls, one minute prior to alfentanil administration, SSI value was higher than during periods of adequate antinociception, 59 ± 11 vs. 39 ± 12 (p<0.01). The total cumulative need for alfentanil was higher in controls (2.7 ± 1.2 mg) than in the brachial plexus block group (1.6 ± 0.5 mg, p=0.008). Tetanic stimulation to the ulnar region of the hand increased SSI significantly only among patients with a brachial plexus block not covering the site of stimulation. Prognostic value of EEG-derived indices was evaluated and compared with Transcranial Doppler Ultrasonography (TCD), serum neuron-specific enolase (NSE) and S-100B after cardiac arrest. Thirty patients resuscitated from out-of-hospital arrest and treated with induced mild hypothermia for 24 h were included. Original EEG signal was recorded, and burst suppression ratio (BSR), RE, SE, and wavelet subband entropy (WSE) were calculated. Neurological outcome during the six-month period after arrest was assessed with the Glasgow-Pittsburgh Cerebral Performance Categories (CPC). Twenty patients had a CPC of 1-2, one patient had a CPC of 3, and nine patients died (CPC 5). BSR, RE, and SE differed between good (CPC 1-2) and poor (CPC 3-5) outcome groups (p=0.011, p=0.011, p=0.008, respectively) during the first 24 h after arrest. WSE was borderline higher in the good outcome group between 24 and 48 h after arrest (p=0.050). All patients with status epilepticus died, and their WSE values were lower (p=0.022). S-100B was lower in the good outcome group upon arrival at the intensive care unit (p=0.010). After hypothermia treatment, NSE and S-100B values were lower (p=0.002 for both) in the good outcome group. The pulsatile index was also lower in the good outcome group (p=0.004). In conclusion, the incidence of awareness in outpatient anesthesia did not differ from that in inpatient anesthesia. Outpatients are not at increased risk for intraoperative awareness relative to inpatients undergoing general anesthesia. SE, RE, and BIS showed non-zero values that normally indicate cortical neuronal function, but were in these subjects mostly due to artifacts after clinical brain death diagnosis. Entropy was more resistant to artifacts than BIS. During general anesthesia and surgery, SSI values were lower in patients with interscalene brachial plexus block covering the sites of nociceptive stimuli. In detecting nociceptive stimuli, SSI performed better than HR, blood pressure, or RE. BSR, RE, and SE differed between the good and poor neurological outcome groups during the first 24 h after cardiac arrest, and they may be an aid in differentiating patients with good neurological outcomes from those with poor outcomes after out-of-hospital cardiac arrest.

The effects of entacapone on cardiorespiratory, autonomic, and clinical responses in L-dopa-treated patients with Parkinson's disease

Rest tremor, rigidity, and slowness of movements-considered to be mainly due to markedly reduced levels of dopamine (DA) in the basal ganglia-are characteristic motor symptoms of Parkinson's disease (PD). Although there is yet no cure for this illness, several drugs can alleviate the motor symptoms. Among these symptomatic therapies, L-dopa is the most effective. As a precursor to DA, it is able to replace the loss of DA in the basal ganglia. In the long run L-dopa has, however, disadvantages. Motor response complications, such as shortening of the duration of drug effect ("wearing-off"), develop in many patients. In addition, extensive peripheral metabolism of L-dopa by aromatic amino acid decarboxylase and catechol-O-methyltransferase (COMT) results in its short half-life, low bioavailability, and reduced efficacy. Entacapone, a nitrocatechol-structured compound, is a highly selective, reversible, and orally active inhibitor of COMT. It increases the bioavailability of L-dopa by reducing its peripheral elimination rate. Entacapone extends the duration of clinical response to each L-dopa dose in PD patients with wearing-off fluctuations. COMT is important in the metabolism of catecholamines. Its inhibition could, therefore, theoretically lead to adverse cardiovascular reactions, especially in circumstances of enhanced sympathetic activity (physical exercise). PD patients may be particularly vulnerable to such effects due to high prevalence of cardiovascular autonomic dysfunction, and the common use of monoamine oxidase B inhibitor selegiline, another drug with effects on catecholamine metabolism. Both entacapone and selegiline enhance L-dopa's clinical effect. Their co-administration may therefore lead to pharmacodynamic interactions, either beneficial (improved L-dopa efficacy) or harmful (increased dyskinesia). We investigated the effects of repeated dosing (3-5 daily doses for 1-2 weeks) of entacapone 200 mg administered either with or without selegiline (10 mg once daily), on several safety and efficacy parameters in 39 L-dopa-treated patients with mild to moderate PD in three double-blind placebo-controlled, crossover studies. In the first two, the cardiovascular, clinical, and biochemical responses were assessed repeatedly for 6 hours after drug intake, first with L-dopa only (control), and then after a 2 weeks on study drugs (entacapone vs. entacapone plus selegiline in one; entacapone vs. selegiline vs. entacapone plus selegiline in the other). The third study included cardiovascular reflex and spiroergometric exercise testing, first after overnight L-dopa withdrawal (control), and then after 1 week on entacapone plus selegiline as adjuncts to L-dopa. Ambulatory ECG was recorded in two of the studies. Blood pressure, heart rate, ECG, cardiovascular autonomic function, cardiorespiratory exercise responses, and the resting/exercise levels of circulating catecholamines remained unaffected by entacapone, irrespective of selegiline. Entacapone significantly enhanced both L-dopa bioavailability and its clinical response, the latter being more pronounced with the co-administration of selegiline. Dyskinesias were also increased during simultaneous use of both entacapone and selegiline as L-dopa adjuncts. Entacapone had no effect on either work capacity or work efficiency. The drug was well tolerated, both with and without selegiline. Conclusions: the use of entacapone-either alone or combined with selegiline-seems to be hemodynamically safe in L-dopa-treated PD patients, also during maximal physical effort. This is in line with the safety experience from larger phase III studies. Entacapone had no effect on cardiovascular autonomic function. Concomitant administration of entacapone and selegiline may enhance L-dopa's clinical efficacy but may also lead to increased dyskinesia.

Ion channel gene variants predisposing to severe human ventricular arrhythmias

Congenital long QT syndrome (LQTS) with an estimated prevalence of 1:2000-1:10 000 manifests with prolonged QT interval on electrocardiogram and risk for ventricular arrhythmias and sudden death. Several ion channel genes and hundreds of mutations in these genes have been identified to underlie the disorder. In Finland, four LQTS founder mutations of potassium channel genes account for up to 40-70% of genetic spectrum of LQTS. Acquired LQTS has similar clinical manifestations, but often arises from usage of QT-prolonging medication or electrolyte disturbances. A prolonged QT interval is associated with increased morbidity and mortality not only in clinical LQTS but also in patients with ischemic heart disease and in the general population. The principal aim of this study was to estimate the actual prevalence of LQTS founder mutations in Finland and to calculate their effect on QT interval in the Finnish background population. Using a large population-based sample of over 6000 Finnish individuals from the Health 2000 Survey, we identified LQTS founder mutations KCNQ1 G589D (n=8), KCNQ1 IVS7-2A>G (n=1), KCNH2 L552S (n=2), and KCNH2 R176W (n=16) in 27 study participants. This resulted in a weighted prevalence estimate of 0.4% for LQTS in Finland. Using a linear regression model, the founder mutations resulted in a 22- to 50-ms prolongation of the age-, sex-, and heart rate-adjusted QT interval. Collectively, these data suggest that one of 250 individuals in Finland may be genetically predisposed to ventricular arrhythmias arising from the four LQTS founder mutations. A KCNE1 D85N minor allele with a frequency of 1.4% was associated with a 10-ms prolongation in adjusted QT interval and could thus identify individuals at increased risk of ventricular arrhythmias at the population level. In addition, the previously reported associations of KCNH2 K897T, KCNH2 rs3807375, and NOS1AP rs2880058 with QT interval duration were confirmed in the present study. In a separate study, LQTS founder mutations were identified in a subgroup of acquired LQTS, providing further evidence that congenital LQTS gene mutations may underlie acquired LQTS. Catecholaminergic polymorphic ventricular tachycardia (CPVT) is characterized by exercise-induced ventricular arrhythmias in a structurally normal heart and results from defects in the cardiac Ca2+ signaling proteins, mainly ryanodine receptor type 2 (RyR2). In a patient population of typical CPVT, RyR2 mutations were identifiable in 25% (4/16) of patients, implying that noncoding variants or other genes are involved in CPVT pathogenesis. A 1.1 kb RyR2 exon 3 deletion was identified in two patients independently, suggesting that this region may provide a new target for RyR2-related molecular genetic studies. Two novel RyR2 mutations showing a gain-of-function defect in vitro were identified in three victims of sudden cardiac death. Extended pedigree analyses revealed some surviving mutation carriers with mild structural abnormalities of the heart and resting ventricular arrhythmias suggesting that not all RyR2 mutations lead to a typical CPVT phenotype, underscoring the relevance of tailored risk stratification of a RyR2 mutation carrier.