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  • Hirvonen, Johanna (Helsingin yliopisto, 2007)
    Although the principle of equal access to medically justified treatment has been promoted by official health policies in many Western health care systems, practices do not completely meet policy targets. Waiting times for elective surgery vary between patient groups and regions, and growing problems in the availability of services threaten equal access to treatment. Waiting times have come to the attention of decision-makers, and several policy initiatives have been introduced to ensure the availability of care within a reasonable time. In Finland, for example, the treatment guarantee came into force in 2005. However, no consensus exists on optimal waiting time for different patient groups. The purpose of this multi-centre randomized controlled trial was to analyse health-related quality of life, pain and physical function in total hip or knee replacement patients during the waiting time and to evaluate whether the waiting time is associated with patients health outcomes at admission. This study also assessed whether the length of waiting time is associated with social and health services utilization in patients awaiting total hip or knee replacement. In addition, patients health-related quality of life was compared with that of the general population. Consecutive patients with a need for a primary total hip or knee replacement due to osteoarthritis were placed on the waiting list between August 2002 and November 2003. Patients were randomly assigned to a short waiting time (maximum 3 months) or a non-fixed waiting time (waiting time not fixed in advance, instead the patient followed the hospitals routine practice). Patients health-related quality of life was measured upon being placed on the waiting list and again at hospital admission using the generic 15D instrument. Pain and physical function were evaluated using the self-report Harris Hip Score for hip patients and a scale modified from the Knee Society Clinical Rating System for knee patients. Utilization measures were the use of home health care, rehabilitation and social services, physician visits and inpatient care. Health and social services use was low in both waiting time groups. The most common services used while waiting were rehabilitation services and informal care, including unpaid care provided by relatives, neighbours and volunteers. Although patients suffered from clear restrictions in usual activities and physical functioning, they seemed primarily to lean on informal care and personal networks instead of professional care. While longer waiting time did not result in poorer health-related quality of life at admission and use of services during the waiting time was similar to that at the time of placement on the list, there is likely to be higher costs of waiting by people who wait longer simply because they are using services for a longer period. In economic terms, this would represent a negative impact of waiting. Only a few reports have been published of the health-related quality of life of patients awaiting total hip or knee replacement. These findings demonstrate that, in addition to physical dimensions of health, patients suffered from restrictions in psychological well-being such as depression, distress and reduced vitality. This raises the question of how to support patients who suffer from psychological distress during the waiting time and how to develop strategies to improve patients initiatives to reduce symptoms and the burden of waiting. Key words: waiting time, total hip replacement, total knee replacement, health-related quality of life, randomized controlled trial, outcome assessment, social service, utilization of health services
  • Stenberg, Jan-Henry (Helsingin yliopisto, 2014)
    Schizophrenia is a severe, psychiatric illness with neurocognitive deficits as its major component, and affects about 1% of the world population. Improving impaired neurocognitive function is one of the pivotal treatment goals in this patient population. In the treatment of schizophrenia, only a partial treatment response is typically achieved with dopamine antagonists; i.e., antipsychotics . The antidepressant mirtazapine has a unique mechanism of action with, in theory, an ability to enhance neurocognition and provide added value to antipsychotic treatment. This study explored whether or not adjunctive mirtazapine has the potential to improve neurocognitive performance and alleviate clinical symptoms in patients with schizophrenia who demonstrated a suboptimal treatment response to first-generation antipsychotics (FGAs). This study was a neurocognitive arm of a single-center, randomized, add-on, double-blinded, placebo-controlled study, which was carried out in the Karelian Republic, Petrozavodsk, Russia. Patients with schizophrenia or a depressive type schizoaffective disorder, according to the Diagnostic and Statistical Manual of Mental and Behavioral Disorders 4th edition (DSM-IV) criteria, who received stable doses of FGA with inadequate treatment response were enrolled into the trial. Twenty patients were assigned to mirtazapine and 21 to placebo. After a one-week single-blind placebo run-in period, the participants were randomized to receive either 30 mg of mirtazapine or the placebo four times a day (QID) in a double-blind fashion for 6 weeks. Subsequently, those who were eligible to continue entered the following 6-week open-label phase, where they were treated with mirtazapine 30 mg QID. At study weeks 0, 6, and 12, a senior psychologist performed neuropsychological examinations to evaluate neurocognitive functioning. Verbal and visual memory, visuo-spatial and executive functions, verbal fluency and both general mental and psychomotor speeds were assessed by commonly used, validated neuropsychological tests for different neurocognitive domains. Clinical examinations were conducted at week 1 (screening), week 0 (baseline) and after 1, 2, 4, 6, 7, 8, 10, and 12 weeks of treatment. Within group and between group differences were analyzed on a Modified Intent-to Treat (MITT) basis with Last Observations Carried Forward (LOCF). After 6 weeks of treatment, 5/21 neurocognitive parameters (i.e. Wechsler Adult Intelligence Scale Revised (WAIS-R) Block Design, p=0.021; Wechsler Memory Scale (WMS) Logical Memory, p=0.044; WMS Logical Memory Delayed, p=0.044; Stroop Dots, p=0.044; Trail Making Test Part A (TMT-A), p=0.018) were improved with statistical significance in the mirtazapine group. In contrast, only 1 of the 21 parameters changed significantly (WMS Logical Memory, p=0.039) in the placebo group. Add-on 6-week mirtazapine treatment was superior when compared with placebo in the neuropsychological domains of visuo-spatial ability and general mental speed/attentional control (Block Design mirtazapine group vs. placebo and Stroop dots mirtazapine group vs. placebo, p=0.044 for both comparisons). The enhancing effect on the Block Design-measured visuo-spatial functioning was mediated through changes in positive, depressive symptoms and parkinsonism-like side effects, but not via changes in negative symptoms. Moreover, higher doses of FGAs, longer duration of illness and lower initial Block Design scores predicted this effect. During the 6 weeks extension phase, individuals who continued mirtazapine treatment and those who were switched from placebo to mirtazapine showed significant improvements on several neurocognitive tests. Those who switched from placebo to open label mirtazapine treatment achieved similar results in the 6 following weeks as the mirtazapine group during their first 6 weeks of mirtazapine treatment. From week 0 to week 12, the continuation group demonstrated improvements in 17/21 neurocognitive parameters, while the switch group improved in 8/21 of the measured parameters. Twelve weeks of mirtazapine treatment indicated an advantage over a shorter, 6-week mirtazapine treatment on Stroop Dots time (p=0.035) and Trail Making Test part B (TMT-B), and number of mistakes (p=0.043). During the 6-week open-label phase, significant improvements on several clinical parameters, which included the Positive and Negative Syndrome Scale (PANSS) total score, were observed. In the total population (i.e., pooled switch and continuation groups), the effect size was 0.94 (CI 95%=0.451.43) as determined by the PANSS total score. Conclusions. Adjunctive mirtazapine treatment might offer added value as a neurocognitive enhancer, and may augment the antipsychotic effect in FGA-treated schizophrenia patients with inadequate treatment response. The ability to generalize these results for a larger population may be limited by the small sample size of the present study.
  • Vainio, Petri J. (Helsingin yliopisto, 2000)
  • Pilvi, Taru (Helsingin yliopisto, 2008)
    Diet high in dairy products is inversely associated with body mass index, risk of metabolic syndrome and prevalence of type 2 diabetes in several populations. Also a number of intervention studies support the role of increased dairy intake in the prevention and treatment of obesity. Dairy calcium has been suggested to account for the effect of dairy on body weight, but it has been repeatedly shown that the effect of dairy is superior to the effect of supplemental calcium. Dairy proteins are postulated to either enhance the effect of calcium or have an independent effect on body weight, but studies in the area are scarce. The aim of this study was to evaluate the potential of dairy proteins and calcium in the prevention and treatment of diet-induced obesity in C57Bl/6J mice. The effect of dairy proteins and calcium on the liver and adipose tissue was also investigated in order to characterise the potential mechanisms explaining the reduction of risk for metabolic syndrome and type 2 diabetes. A high-calcium diet (1.8%) in combination with dietary whey protein inhibited body weight and fat gain and accelerated body weight and fat loss in high-fat-fed C57Bl/6J mice during long-term studies of 14 to 21 weeks. α-lactalbumin, one of the major whey proteins, was the most effective whey protein fraction showing significantly accelerated weight and fat loss during energy restriction and reduced the amount of visceral fat gain during ad libitum feeding after weight loss. The microarray data suggest sensitisation of insulin signalling in the adipose tissue as a result of a calcium-rich whey protein diet. Lipidomic analysis revealed that weight loss on whey protein-based high-calcium diet was characterised by significant decreases in diabetogenic diacylglycerols and lipotoxic ceramide species. The calcium supplementation led to a small, but statistically significant decrease in fat absorption independent of the protein source of the diet. This augments, but does not fully explain the effects of the studied diets on body weight. A whey protein-containing high-calcium diet had a protective effect against a high-fat diet-induced decline of β3 adrenergic receptor expression in adipose tissue. In addition, a high-calcium diet with whey protein increased the adipose tissue leptin expression which is decreased in this obesity-prone mouse strain. These changes are likely to contribute to the inhibition of weight gain. The potential sensitisation of insulin signalling in adipose tissue together with the less lipotoxic and diabetogenic hepatic lipid profile suggest a novel mechanistic link to explain why increased dairy intake is associated with a lower prevalence of metabolic syndrome and type 2 diabetes in epidemiological studies. Taken together, the intake of a high-calcium diet with dairy proteins has a body weight lowering effect in high-fat-fed C57Bl/6J mice. High-calcium diets containing whey protein prevent weight gain and enhance weight loss, α-lactalbumin being the most effective whey protein fraction. Whey proteins and calcium have also beneficial effects on hepatic lipid profile and adipose tissue gene expression, which suggest a novel mechanistic link to explain the epidemiological findings on dairy intake and metabolic syndrome. The clinical relevance of these findings and the precise mechanisms of action remain an intriguing field of future research.
  • Penttinen, Heidi (2013)
    The main goal of the thesis was to investigate the effects of a 12-month supervised exercise intervention on breast cancer patients' QoL shortly after adjuvant treatment. The secondary aims were to assess the physical and psychological well-being of patients immediately after adjuvant treatment of the largest breast cancer survivor population intervention study (BREX) to date and the patients' willingness to participate in such a long intervention. In addition, the work aimed to further clarify the results of the intervention by analyzing the QoL changes of participants of the exercise study compared to those of normal follow-up patients. Patients: Of the 573 randomized patients (aged 35 to 68 years), 500 were included in the final analyses of the effects of exercise intervention: 263 in the exercise group and 237 in the control group. A total of 73 patients were excluded from the final analyses for various reasons: not meeting the inclusion criteria (36), declined for personal reasons (20), breast cancer recurrence (14), and new malignancy during the intervention (3). All 537 patients who met the inclusion criteria after the baseline visit and investigations were included in the baseline analysis. Patients of the additional study consisted of two separate patient groups: 237 control patients of the BREX study and 108 similar breast cancer patients (who met the same inclusion criteria and were treated according to the same guidelines as the patients in exercise study) participating in a follow-up study which did not contain any intervention. Methods: The EORTC QLQ-C30 and BR-23 questionnaires were used to evaluate QoL, FACIT-F for fatigue, and the Finnish modified version of Beck s 13-item depression scale (BDI). Physical fitness was assessed by a 2-km walking test and figure-8 running test, and physical activity (PA) by metabolic equivalent (MET) hours per week (MET-h/wk) based on data collected by a prospective two-week physical activity diary. Results: Of the eligible patients 78.3% participated in the study. At baseline, the global QoL of the study patients was lower than in the general population; 26% of them were rated as depressed, 20% as fatigued, and 82% suffered from menopausal symptoms, which seemed to impair QoL. Most scores from the EORTC QLQ-C30 improved significantly within both the exercise and control groups during 12 months, with no significant differences between groups. Participation in the exercise intervention study per se seemed not to improve the QoL of breast cancer survivors. At baseline, 62% of the walking test results were below the population average. Physical performance in walking tests correlated significantly to MET hours and to previous leisure-time physical activity. The amount of physical activity increased from baseline over a 12-month period in both groups; there were no significant differences between the groups. Neuromuscular performance improved significantly in the training group during 12 months. No significant effect of intervention was observed on cardiorespiratory fitness. However, the walk time improved significantly in both groups during the intervention. Already at baseline, PA improved QoL. After the 12-month follow-up there was a linear relationship between increased PA and improved QoL, irrespective of the intervention. There was a significant linear trend between higher physical activity and improved QoL and recovery from fatigue. No significant relationship was detected between physical activity and depression or between physical performance (figure-8 running or 2-km walking test) and QoL, fatigue or depression. Conclusions: Recruiting patients to the study succeeded excellently. With the exception of age limit and musculoskeletal disorders, the study population represents the general Finnish breast cancer population. At baseline, the QoL of the patients was impaired and the physical performance poor compared with the general population; in particular, depression and fatigue were related to impaired QoL. The study did not find evidence to support the superiority of the 12-month supervised vigorous aerobic exercise and home training over the control arm in improving physical activity and QoL of the patients. In contrast, both groups improved equally during the follow-up duration. Spontaneous recovery of QoL seems to be the most likely explanation for the observed results, at least when the intervention is timed to the rehabilitation period. Future exercise intervention studies targeting improvement of QoL should identify groups of patients that could benefit the most from an intervention and tailor the interventions to their specific needs.
  • Xiang, Xiaoqiang (Helsingin yliopisto, 2011)
    Bile acids are important steroid-derived molecules essential for fat absorption in the small intestine. They are produced in the liver and secreted into the bile. Bile acids are transported by bile flow to the small intestine, where they aid the digestion of lipids. Most bile acids are reabsorbed in the small intestine and return to the liver through the portal vein. The whole recycling process is referred to as the enterohepatic circulation, during which only a small amount of bile acids are removed from the body via faeces. The enterohepatic circulation of bile acids involves the delicate coordination of a number of bile acid transporters expressed in the liver and the small intestine. Organic anion transporting polypeptide 1B1 (OATP1B1), encoded by the solute carrier organic anion transporter family, member 1B1 (SLCO1B1) gene, mediates the sodium independent hepatocellular uptake of bile acids. Two common SNPs in the SLCO1B1 gene are well known to affect the transport activity of OATP1B1. Moreover, bile acid synthesis is an important elimination route for cholesterol. Cholesterol 7α-hydroxylase (CYP7A1) is the rate-limiting enzyme of bile acid production. The aim of this thesis was to investigate the effects of SLCO1B1 polymorphism on the fasting plasma levels of individual endogenous bile acids and a bile acid synthesis marker, and the pharmacokinetics of exogenously administered ursodeoxycholic acid (UDCA). Furthermore, the effects of CYP7A1 genetic polymorphism and gender on the fasting plasma concentrations of individual endogenous bile acids and the bile acid synthesis marker were evaluated. Firstly, a high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method for the determination of bile acids was developed (Study I). A retrospective study examined the effects of SLCO1B1 genetic polymorphism on the fasting plasma concentrations of individual bile acids and a bile acid synthesis marker in 65 healthy subjects (Study II). In another retrospective study with 143 healthy individuals, the effects of CYP7A1 genetic polymorphism and gender as well as SLCO1B1 polymorphism on the fasting plasma levels of individual bile acids and the bile acid synthesis marker were investigated (Study III). The effects of SLCO1B1 polymorphism on the pharmacokinetics of exogenously administered UDCA were evaluated in a prospective genotype panel study including 27 healthy volunteers (Study IV). A robust, sensitive and simple HPLC-MS/MS method was developed for the simultaneous determination of 16 individual bile acids in human plasma. The method validation parameters for all the analytes met the requirements of the FDA (Food and Drug Administration) bioanalytical guidelines. This HPLC-MS/MS method was applied in Studies II-IV. In Study II, the fasting plasma concentrations of several bile acids and the bile acid synthesis marker seemed to be affected by SLCO1B1 genetic polymorphism, but these findings were not replicated in Study III with a larger sample size. Moreover, SLCO1B1 polymorphism had no effect on the pharmacokinetic parameters of exogenously administered UDCA. Furthermore, no consistent association was observed between CYP7A1 genetic polymorphism and the fasting plasma concentrations of individual bile acids or the bile acid synthesis marker. In contrast, gender had a major effect on the fasting plasma concentrations of several bile acids and also total bile acids. In conclusion, gender, but not SLCO1B1 or CYP7A1 polymorphisms, has a major effect on the fasting plasma concentrations of individual bile acids. Moreover, the common genetic polymorphism of CYP7A1 is unlikely to influence the activity of CYP7A1 under normal physiological conditions. OATP1B1 does not play an important role in the in vivo disposition of exogenously administered UDCA.
  • Heikkilä, Outi (Helsingin yliopisto, 2010)
    The metabolic syndrome and type 1 diabetes are associated with brain alterations such as cognitive decline brain infarctions, atrophy, and white matter lesions. Despite the importance of these alterations, their pathomechanism is still poorly understood. This study was conducted to investigate brain glucose and metabolites in healthy individuals with an increased cardiovascular risk and in patients with type 1 diabetes in order to discover more information on the nature of the known brain alterations. We studied 43 20- to 45-year-old men. Study I compared two groups of non-diabetic men, one with an accumulation of cardiovascular risk factors and another without. Studies II to IV compared men with type 1 diabetes (duration of diabetes 6.7 ± 5.2 years, no microvascular complications) with non-diabetic men. Brain glucose, N-acetylaspartate (NAA), total creatine (tCr), choline, and myo-inositol (mI) were quantified with proton magnetic resonance spectroscopy in three cerebral regions: frontal cortex, frontal white matter, thalamus, and in cerebellar white matter. Data collection was performed for all participants during fasting glycemia and in a subgroup (Studies III and IV), also during a hyperglycemic clamp that increased plasma glucose concentration by 12 mmol/l. In non-diabetic men, the brain glucose concentration correlated linearly with plasma glucose concentration. The cardiovascular risk group (Study I) had a 13% higher plasma glucose concentration than the control group, but no difference in thalamic glucose content. The risk group thus had lower thalamic glucose content than expected. They also had 17% increased tCr (marker of oxidative metabolism). In the control group, tCr correlated with thalamic glucose content, but in the risk group, tCr correlated instead with fasting plasma glucose and 2-h plasma glucose concentration in the oral glucose tolerance test. Risk factors of the metabolic syndrome, most importantly insulin resistance, may thus influence brain metabolism. During fasting glycemia (Study II), regional variation in the cerebral glucose levels appeared in the non-diabetic subjects but not in those with diabetes. In diabetic patients, excess glucose had accumulated predominantly in the white matter where the metabolite alterations were also the most pronounced. Compared to the controls values, the white matter NAA (marker of neuronal metabolism) was 6% lower and mI (glia cell marker) 20% higher. Hyperglycemia is therefore a potent risk factor for diabetic brain disease and the metabolic brain alterations may appear even before any peripheral microvascular complications are detectable. During acute hyperglycemia (Study III), the increase in cerebral glucose content in the patients with type 1 diabetes was, dependent on brain region, between 1.1 and 2.0 mmol/l. An every-day hyperglycemic episode in a diabetic patient may therefore as much as double brain glucose concentration. While chronic hyperglycemia had led to accumulation of glucose in the white matter, acute hyperglycemia burdened predominantly the gray matter. Acute hyperglycemia also revealed that chronic fluctuation in blood glucose may be associated with alterations in glucose uptake or in metabolism in the thalamus. The cerebellar white matter appeared very differently from the cerebral (Study IV). In the non-diabetic men it contained twice as much glucose as the cerebrum. Diabetes had altered neither its glucose content nor the brain metabolites. The cerebellum seems therefore more resistant to the effects of hyperglycemia than is the cerebrum.
  • Mildh, Leena (Helsingin yliopisto, 2007)
    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.