Conventional and novel cardiovascular risk factors in young Finns and their associations with structural and functional vascular changes of subclinical atherosclerosis. The Cardiovascular Risk in Young Finns Study

Background: Atherosclerosis begins in early life progressing from asymptomatic to symptomatic as we age. Although substantial progress has been made in identifying the determinants of atherosclerosis in middle to older age adults at increased cardiovascular risk, there is lack of data examining determinants and prediction of atherosclerosis in young adults. Aims: The current study was designed to investigate levels of cardiovascular risk factors in young adults, subclinical measures of atherosclerosis, and prediction of subclinical arterial changes with conventional risk factor measures and novel metabolic profiling of serum samples. Subjects and Methods: This thesis utilised data from the follow-ups performed in 2001 and 2007 in the Cardiovascular Risk in Young Finns study, a Finnish population-based prospective cohort study that examined 2,204 subjects who were aged 30-45 years in 2007. Subclinical atherosclerosis was studied using noninvasive ultrasound measurements of carotid intima-media thickness (IMT), carotid arterial distensibility (CDist) and brachial flow-mediated dilation (FMD). Measurements included conventional risk factors and metabolic profiling using highthroughput nuclear magnetic resonance (NMR) methods that provided data on 42 lipid markers and 16 circulating metabolites. Results: Trends in lipids were favourable between 2001 and 2007, whereas waist circumference, fasting glucose, and blood pressure levels increased. To study the stability of noninvasive ultrasound markers, 6-year tracking (the likelihood to maintain the original fractile over time) in 6 years was examined. IMT tracked more strongly than CDist and FMD. Cardiovascular risk scores (Framingham, SCORE, Finrisk, Reynolds and PROCAM) predicted subclinical atherosclerosis equally. Lipoprotein subclass testing did not improve the prediction of subclinical atherosclerosis over and above conventional risk factors. However, circulating metabolites improved risk stratification. Tyrosine and docosahexaenoic acid were found to be novel biomarkers of high IMT. Conclusions: Prediction of cardiovascular risk in young Finnish adults can be performed with any of the existing risk scores. The addition of metabonomics to risk stratification improves prediction of subclinical changes and enables more accurate targeting of prevention at an early stage.

Effect of bariatric surgery on adipose tissue distribution in severely obese patients

Background and aim: Bariatric surgery leads to sustain weight loss, improve metabolic and lipids profiles and ultimately leads to remission of type 2 diabetes (T2DM) in some obese individuals. The aim of the project is to evaluate the effect of bariatric on abdominal fat distribution in severely obese T2DM and non-T2DM obese patients. Study design and methods: A total of 23 morbidly obese subjects (mean ± SD body mass index 43.0 ± 3.6 kg/m2, age 46.5 ± 9.0 years) were recruited from the lager multicenter SLEEVEPASS studies (ClinicalTrials.gov/NCT00793143). 10 healthy age-matched non-obese individuals served as controls. The obese patients were studied before and 6 months after surgery. At baseline, there were 9 T2DMs and 14 non-diabetics. After surgery, there were 5 remitters and 4 nonremitters. Whole body magnetic resonance imaging including the abdominal regions was performed for the obese subjects before and 6 months after surgery and for the controls once. Abdominal fat were compartmentalized and analyzed. Results: At 6 months of follow-up, BMI in the obese decreased significantly (from 43 ± 4 to 33 ± 2 kg/m2, p < 0.001) with substantial improvement in whole body insulin sensitivity (from 12.2 ± 5.7 to 23.3 ± 8.1 µmol/kg/min, p < 0.001). Intraperitoneal fat mass decreased by 46% (from 3.4 ± 1.1 to 1.9± 1.0 kg, p < 0.001) more than the rest of the compartments. Abdominal visceral compartments in obese correlated with glycemic status independent of surgery. Pre-surgery posterior deep and intraperitoneal fat mass were better predictors of post-surgery glycemic status in obese. Remitters showed significant improvement in whole body insulin sensitivity (from 9.1 ± 2.1 to 20.9 ± 8.4 µmol/kg/min, p = 0.02), fasting glucose decreased significant only in nonremitters (from 7.1 ± 1.1 to 6.0 ± 0.8 mmol/l, p = 0.05) after surgery. There were no differences in extraperitoneal fat mass in remitters and superficial subcutaneous fat in non-remitters but all other compartments decreased significantly 6 months after the surgery Conclusion: Both deep subcutaneous and visceral fat are important contributors to glycemic status in obese subjects. Whereas visceral fat compartments are directly involved in T2DM, superficial subcutaneous may have offered protection against T2DM in obese subjects.

Counselling on limited preoperative fasting in paediatric ambulatory tonsillectomy

Rajoitetun preoperatiivisen paaston ohjaus lasten päiväkirurgisessa nielurisaleikkauksessa Tutkimuksen tarkoituksena oli selvittää, onko sairaanhoitajan toteuttama, vanhempien interaktiivinen preoperatiivinen ohjaus lapsen rajoitettuun preoperatiiviseen paastoon ja aktiiviseen nesteyttämiseen turvallista, kuinka vanhemmat omaksuvat kyseistä tietoa ja edistääkö se turvallisesti lapsen postoperatiivista toipumista päiväkirurgisen nielurisaleikkauksen jälkeen. Aineisto koostui sadastakuudestatoista perheestä, joiden lapsi, iältään 4 – 10 vuotta, oli kutsuttu päiväkirurgiseen nielurisaleikkaukseen. Koeryhmä (n= 58) ohjattiin interaktiivisesti lapsen preoperatiiviseen paastoon ja aktiiviseen preoperatiiviseen nesteyttämiseen. Lapsen suositellut preoperatiiviset paastoajat olivat: 4t syömättä ja 2t juomatta. Leikkauspäivän aamuna vanhemmat rohkaisivat lapsia juomaan annokset kirkkaita nesteitä kahteen otteeseen; jälkimmäinen annos 2t ennen leikkausta. Kontrolliryhmä (n= 58) sai preoperatiivisen ohjauksen kirjallisena ilman interaktiivista ohjausta; paastoajat olivat samat kuin koeryhmässä: 4t syömättä ja 2t juomatta. Vanhempien tiedontasoa lapsen leikkaukseen liittyvästä paastosta mitattiin tietotestillä, joka sisälsi myös preoperatiivista tiedontarvetta ja ahdistusta mittaavan mittarin (The Amsterdam Preoperative Anxiety and Information scale, APAIS). Mittaukset suoritettiin ennen preoperatiivista ohjausta tai kirjallisten ohjeiden lähettämistä sekä lapsen leikkausta seuraavana päivänä. Lapsen leikkauksen jälkeen vanhemmat arvioivat myös heille välitetyn informaation tasoa. Lapsen postoperatiivista kipua, pahoinvointia, janoa ja nälkää lapset itse arvioivat VAS- asteikolla (10cm), ja vanhemmat ja sairaanhoitajat numeerisella 0 – 10 asteikolla. Mittaukset suoritettiin 2t, 4t, 8t, ja 24t lapsen leikkauksen jälkeen. Vanhemmat pitivät päiväkirjaa lapsen ravinnosta ja kipulääkityksestä. Aineisto analysoitiin sekä tilastollisesti että sisällön analyysilla. Vanhempien tiedontaso lapsen leikkauksen jälkeen oli molemmissa ryhmissä merkitsevästi parantunut, mutta kontrolliryhmän vanhempien ahdistus ei ollut helpottanut verrattuna heidän ahdistukseensa ennen lapsen leikkausta. Mitä korkeammat pisteet vanhemmat saivat tietotestistä lapsen leikkauksen jälkeen sitä vähemmän he tunsivat tiedontarvetta ja ahdistusta. Merkitsevästi alhaisemmat pisteet tietotestistä oli vanhemmilla, joilla oli alempi peruskoulutus. Kontrolliryhmän lapset paastosivat preoperatiivisesti merkitsevästi pitempään kuin koeryhmän lapset. Perioperatiivisesti lapset paastosivat kiinteästä ruuasta yhtä kauan, mutta nesteistä kontrolliryhmä merkitsevästi pitempään. Postoperatiivisen toipumisen alussa koeryhmän lapset olivat merkitsevästi kivuttomampia. Molemmissa ryhmissä lapset olivat kipeimpiä kahdeksan tuntia leikkauksesta ja pahoinvointisimpia neljä tuntia leikkauksesta. Ensimmäisen kahdeksan tunnin aikana leikkauksen jälkeen lapset eivät olleet janoisia tai nälkäisiä, mutta VAS- arvot koeryhmässä jäivät alhaisemmalle tasolle kuin kontrolliryhmässä 24 postoperatiivisen tunnin ajan. Leikkausta seuraavana aamuna kontrolliryhmän lapset olivat merkitsevästi janoisempia ja nälkäisempiä kuin interventioryhmän lapset. Sairaanhoitajan toteuttama vanhempien interaktiivinen preoperatiivinen ohjaus lapsen rajoitettuun preoperatiiviseen paastoon lisää vanhempien tiedontasoa ja vähentää preoperatiivista tiedontarvettaan ja ahdistusta, ja turvallisesti parantaa lapsen kokemusta leikkausprosessin ja postoperatiivisen toipumisen aikana nielurisaleikkauksen jälkeen. Kaikkien leikkaukseen tulevien lasten nesteyttäminen kaksi tuntia ennen päivän ensimmäistä leikkausta voi olla ratkaisu lasten kohtuuttomien perioperatiivisten paastoaikojen estämiseksi. Aina ei kuitenkaan ole mahdollisuuksia vanhempien henkilökohtaiseen kohtaamiseen, mikä haastaa hoitotieteellisen tutkimuksen kartoittamaan muita mahdollisuuksia vanhempien interaktiiviseen ohjaukseen.

Sulfuric acid - glucose separation using mixed-recycle steady state recycling chromatography

Batch chromatography is a widely used separation technique in a variety of fields meeting difficult separations. Several technologies for improving the performance of chromatography have been studied, including mixed-recycle steady state recycling (MR-SSR) chromatography. Design of MR-SSR has been commonly limited on 100 % purity constraint cases and empirical work. In this study a predictive design method was used to optimize feed pulse size and design a number of experimental MR-SSR separations for a solution of 20 % sulfuric acid and 100 g/L glucose. The design was under target product fraction purities of 98.7 % for H2SO4 and 95 % for glucose. The experiments indicate a maximum of 59 % increase in sulfuric acid productivity and 82 % increase for glucose when compared to corresponding batch separation. Eluent consumption was lowered by approximately 50 % using recycling chromatography. Within this study the target purities and yields set in design were not completely met, and further optimization of the process is deemed necessary.

On Glucose Metabolism in Patients with the m.3243A>G Mutation

Background: The m.3243A>G mutation in mitochondrial DNA is the most common cause for mitochondrial diabetes. In addition, unexpected deaths related to the m.3243A>G associate with encephalopathy and cardiomyopathy. Failing mitochondrial respiratory chain in neurons, myocytes and beta cells is considered to underlie the multiorgan manifestations of the m.3243A>G. Aims: The primary aim of the study was to characterize the organ-specific glucose metabolism in patients with m.3243A>G and secondly, to study patients with or without signs of diabetes, cardiomyopathy or encephalopathy. The insulin-stimulated glucose metabolism in brain, heart, skeletal muscle, adipose tissue and liver were measured with 2-deoxy-2-[18F]fluoro-α-D-glucose in 15 patients and 14 controls. Brain oxygen metabolism was assessed with [15O]oxygen and insulin secretion was modelled based on oral glucose tolerance test. Results: The glucose oxidation in brain was globally decreased in patients with or without clinical encephalopathy. The insulin-stimulated glucose influx to skeletal muscle and adipose tissue was decreased in patients with or without diabetes as the hepatic glucose metabolism was normal. Impaired beta cell function and myocardial glucose uptake were associated with the high m.3243A>G heteroplasmy. Conclusions: This cross-sectional study suggests that: 1) The ability of insulin to stimulate glucose metabolism in skeletal muscle and adipose tissue is weakened before the beta cell failure results in mitochondrial diabetes. 2) Glucose oxidation defect is detected in otherwise unaffected cerebral regions in patients with the m.3243A>G, thus it likely precedes the clinical encephalopathy. 3) Uneconomical glucose hypometabolism during hyperinsulinemia contributes to the cardiac vulnerability in patients with high m.3243A>G heteroplasmy

Starting Insulin Treatment in Type 2 Diabetes

Type 2 diabetes is a disorder of glucose metabolism characterized by chronic hyperglycemia. Initially type 2 diabetes is characterized by insulin resistance and impaired function of beta cells, leading progressively to insulin deficiency. Type 2 diabetes is treated with diet and other lifestyle changes, and with medication modulating e.g. insulin resistance, liver glucose production and insulin secretion. Injectable insulin is added to the treatment when lifestyle changes and other medication are insufficient to maintain adequate control of hyperglycemia. The aim of the treatment is to remove the symptoms of diabetes and to prevent late complications of diabetes. Insulin was traditionally started at hospital wards, but from the early 1990’s also in outpatient care. The first substudy of this thesis examined retrospectively initiation practices and how successfully insulin treatment was introduced in 1990 – 1996 in Southwestern Finland. This study aimed also at identifying the best methods of controlling plasma glucose. It showed that in the 1990’s the incidence of insulin treatment increased and was initiated more often in outpatient care than previously. The use of combination treatment also increased, first with sulfonylureas and later with metformin as the oral drug. In combination therapy the insulin dose was smaller than with insulin monotherapy. HbA1c improved similarly in middle-aged and older age groups. Weight increase associated with insulin initiation was smaller when combined with oral agents. A prospective insulin initiation study (1994 – 1998) tested the hypothesis that hyperglycemia (fasting and postprandial hyperglycemia) may affect the outcome of insulin initiation. The type of hyperglycemia was determined by the relation of fasting plasma glucose to HbA1c. Treatment was initiated with insulin Lente or human NPH insulin. In patients treated with insulin monotherapy twice daily the decline in HbA1c was markedly greater for postprandial than fasting hyperglycemia patients suggesting that hyperglycemia type has significance in the selection of the insulin regimen. Another insulin initiation study showed that patients with fasting hyperglycemia starting on insulin (2004-2005) were significantly more prone to overweight than patients with postprandial hyperglycemia. Irrespective of the insulin preparation (insulin NPH or insulin glargine), patients with fasting hyperglycemia had a greater weight increase compared to patients with postprandial hyperglycemia. Special attention should be paid to prevention of weight increase in these patients.

Effects of Obesity and Weight Loss Following Bariatric Surgery on Brain Function, Structural Integrity and Metabolism

Obesity is one of the key challenges to health care system worldwide and its prevalence is estimated to rise to pandemic proportions. Numerous adverse health effects follow with increasing body weight, including increased risk of hypertension, diabetes, hypercholesterolemia, musculoskeletal pain and cancer. Current evidence suggests that obesity is associated with altered cerebral reward circuit functioning and decreased inhibitory control over appetitive food cues. Furthermore, obesity causes adverse shifts in metabolism and loss of structural integrity within the brain. Prior cross-sectional studies do not allow delineating which of these cerebral changes are recoverable after weight loss. We compared morbidly obese subjects with healthy controls to unravel brain changes associated with obesity. Bariatric surgery was used as an intervention to study which cerebral changes are recoverable after weight loss. In Study I we employed functional magnetic resonance imaging (fMRI) to detect the brain basis of volitional appetite control and its alterations in obesity. In Studies II-III we used diffusion tensor imaging (DTI) and voxel-based morphometry (VBM) to quantify the effects of obesity and the effects of weight loss on structural integrity of the brain. In study IV we used positron emission tomography (PET) with [18F]-FDG in fasting state and during euglycemic hyperinsulinemia to quantify effects of obesity and weight loss on brain glucose uptake. The fMRI experiment revealed that a fronto-parietal network is involved in volitional appetite control. Obese subjects had lower medial frontal and dorsal striatal brain activity during cognitive appetite control and increased functional connectivity within the appetite control circuit. Obese subjects had initially lower grey matter and white matter densities than healthy controls in VBM analysis and loss of integrity in white matter tracts as measured by DTI. They also had initially elevated glucose metabolism under insulin stimulation but not in fasting state. After the weight loss following bariatric surgery, obese individuals’ brain volumes recovered and the insulin-induced increase in glucose metabolism was attenuated. In conclusion, obesity is associated with altered brain function, coupled with loss of structural integrity and elevated glucose metabolism, which are likely signs of adverse health effects to the brain. These changes are reversed by weight loss after bariatric surgery, implicating that weight loss has a causal role on these adverse cerebral changes. Altogether these findings suggest that weight loss also promotes brain health.Key words: brain, obesity, bariatric surgery, appetite control, structural magnetic resonance