Pharmacokinetics, efficacy, and safety of pravastatin in children : Studies in children with heterozygous familial hypercholesterolemia and in pediatric cardiac transplant recipients

Background. Hyperlipidemia is a common concern in patients with heterozygous familial hypercholesterolemia (HeFH) and in cardiac transplant recipients. In both groups, an elevated serum LDL cholesterol level accelerates the development of atherosclerotic vascular disease and increases the rates of cardiovascular morbidity and mortality. The purpose of this study is to assess the pharmacokinetics, efficacy, and safety of cholesterol-lowering pravastatin in children with HeFH and in pediatric cardiac transplant recipients receiving immunosuppressive medication. Patients and Methods. The pharmacokinetics of pravastatin was studied in 20 HeFH children and in 19 pediatric cardiac transplant recipients receiving triple immunosuppression. The patients ingested a single 10-mg dose of pravastatin, and plasma pravastatin concentrations were measured up to 10/24 hours. The efficacy and safety of pravastatin (maximum dose 10 to 60 mg/day and 10 mg/day) up to one to two years were studied in 30 patients with HeFH and in 19 cardiac transplant recipients, respectively. In a subgroup of 16 HeFH children, serum non-cholesterol sterol ratios (102 x mmol/mol of cholesterol), surrogate estimates of cholesterol absorption (cholestanol, campesterol, sitosterol), and synthesis (desmosterol and lathosterol) were studied at study baseline (on plant stanol esters) and during combination with pravastatin and plant stanol esters. In the transplant recipients, the lipoprotein levels and their mass compositions were analyzed before and after one year of pravastatin use, and then compared to values measured from 21 healthy pediatric controls. The transplant recipients were grouped into patients with transplant coronary artery disease (TxCAD) and patients without TxCAD, based on annual angiography evaluations before pravastatin. Results. In the cardiac transplant recipients, the mean area under the plasma concentration-time curve of pravastatin [AUC(0-10)], 264.1 * 192.4 ng.h/mL, was nearly ten-fold higher than in the HeFH children (26.6 * 17.0 ng.h/mL). By 2, 4, 6, 12 and 24 months of treatment, the LDL cholesterol levels in the HeFH children had respectively decreased by 25%, 26%, 29%, 33%, and 32%. In the HeFH group, pravastatin treatment increased the markers of cholesterol absorption and decreased those of synthesis. High ratios of cholestanol to cholesterol were associated with the poor cholesterol-lowering efficacy of pravastatin. In cardiac transplant recipients, pravastatin 10 mg/day lowered the LDL cholesterol by approximately 19%. Compared with the patients without TxCAD, patients with TxCAD had significantly lower HDL cholesterol concentrations and higher apoB-100/apoA-I ratios at baseline (1.0 ± 0.3 mmol/L vs. 1.4 ± 0.3 mmol/L, P = 0.031; and 0.7 ± 0.2 vs. 0.5 ± 0.1, P = 0.034) and after one year of pravastatin use (1.0 ± 0.3 mmol/L vs. 1.4 ± 0.3 mmol/L, P = 0.013; and 0.6 ± 0.2 vs. 0.4 ± 0.1, P = 0.005). Compared with healthy controls, the transplant recipients exhibited elevated serum triglycerides at baseline (median 1.3 [range 0.6-3.2] mmol/L vs. 0.7 [0.3-2.4] mmol/L, P=0.0002), which negatively correlated with their HDL cholesterol concentration (r = -0.523, P = 0.022). Recipients also exhibited higher apoB-100/apoA1 ratios (0.6 ± 0.2 vs. 0.4 ± 0.1, P = 0.005). In addition, elevated triglyceride levels were still observed after one year of pravastatin use (1.3 [0.5-3.5] mmol/L vs. 0.7 [0.3-2.4] mmol/L, P = 0.0004). Clinically significant elevations in alanine aminotransferase, creatine kinase, or creatinine ocurred in neither group. Conclusions. Immunosuppressive medication considerably increased the plasma pravastatin concentrations. In both patient groups, pravastatin treatment was moderately effective, safe, and well tolerated. In the HeFH group, high baseline cholesterol absorption seemed to predispose patients to insufficient cholesterol-lowering efficacy of pravastatin. In the cardiac transplant recipients, low HDL cholesterol and a high apoB-100/apoA-I ratio were associated with development of TxCAD. Even though pravastatin in the transplant recipients effectively lowered serum total and LDL cholesterol concentrations, it failed to normalize their elevated triglyceride levels and, in some patients, to prevent the progression of TxCAD.

The role of selected non-timber forest products for rural areas in Laos: Case studies in Ban Napo and Ban Kouay communities

Non-timber forest products (NTFPs) are one of the major income sources for the rural population of Laos. An exploratory study was conducted to determine the role of non-timber forest products for rural communities of the study area. The study was carried out in two villages viz. Ban Napo and Ban Kouay of Sangthong district between January and March 2010. A semi-structured questionnaire was used to gather data from the respondents. Twenty-five respondents from each village were chosen based on their involvement in NTFPs collection and marketing activities. Statistically significant NTFPs income differences were not found between the villages and age groups of the respondents, however, significant differences were found in the annual incomes between farms size of the respondents. This study also analyzed the value chain structure of the three (See khai’ ton, Bamboo mats and Incense sticks) important non-timber forest products and the interactions between the actors in the case study areas. Barriers to entry the market, governance and upgrading possibilities have been discussed for each of the value chains. Comparison of unit prices at different levels of the value chains indicated uneven income distribution in favour of the intermediaries, factories and foreign buyers. The lack of capital, marketing information and negotiation skills restricted the villagers to increase their income. However, all the respondents have shown their satisfaction with their income from NTFPs.

The Gendered Social Organisation of Defence: Two Ethnographic Case Studies in the Finnish Defence Forces

In Finland the organising of defence is undergoing vast restructuring. Recent legislation has redefined the central tasks of the Finnish Defence Forces. At the same time, international security cooperation, economic pressures and new administrative paradigms have steered the military towards new ways of organising. National defence is not just politics and principles; to a large extent it is also enacted in day-to-day life in organisations. The lens through which these realities of defence are analysed in this study is gender. How is the security sector – and national defence as part of it – organised in the changing security environment? What is the new division of labour between different societal actors in the face of security challenges? What happens ‘at work’ within the military and the defence sector more broadly? How does gender affect the way in which defence is organised and understood, and how do the changes in the organising of security affect gender relations? The thesis searches for answers to these questions in the context of two organisational settings in the male-dominated defence sector. The case study on a Finnish peacekeeping unit in the Balkans opens a critical view on men’s social practices and the everyday life of crisis management organisations. In the second case study, reorganising of provisioning in the Finnish Defence Forces turns out to be a complicated process where different power relations and social divisions intermingle. Tallberg’s extensive ethnographic fieldwork in the two focal organisations has produced a detailed set of data that lays the basis for critical analysis and policy development in terms of defence organising, cooperation around peace and security issues, and gender equality in organisations. Observations and results are provided for understanding social networks, militarisation, authority relations, care, public-private partnerships, personnel policies, career planning, and humour.

Taxonomy and phylogeny of white-rot polypores : case studies in Hymenochaetales and Polyporales (Basidiomycota)

Tutkimus käsittelee kääpien sukulaisuussuhteita. Käävät ovat kantasienten (Basidiomycota) muotoryhmä, joiden itiöemien alapinta muodostuu yhteensulautuneista pilleistä. Muotoryhmänä kääpiä voi verrata vaikka puihin siinä mielessä, että käävät kuten puutkaan eivät ole samankaltaisuudestaan huolimatta kaikki sukua toisilleen. DNA:n käyttö sukulaisuussuhteiden selvittämisessä on aloittanut mullistuksen kääpien luokittelussa. Aiemmin käytetty, itiöemien ominaisuuksiin perustunut luokittelu on osoittautunut keinotekoiseksi sukulaisuussuhteiden kannalta. Tutkimuksessani syvennyttiin useamman kääpäsuvun polveutumishistoriaan hyödyntäen DNA:ta ja perinteisiä menetelmiä. Tutkimuksen keskeisimmät tulokset liittyvät sitkokääpien sukuun (Antrodiella). Tämä noin 70 lajia sisältävä suku osoittautui rikkonaiseksi - sitkokääpiin luetut lajit kuuluvat kahteen sienilahkoon ja oikesti vähintään 13 sukuun. Tutkimuksessa löytyi kaksi Suomelle uutta sitkokääpää, leppikääpä (A. ichnusana) ja nipukkakääpä (A. leucoxantha). Uudet suvut kuvattiin Suomessa esiintyville sirppikääville (Sidera) ja talikääville (Obba). Uusi kääpäsuku ja -laji kuvattiin myös Indonesiasta (Sebipora aquosa). Valtaosa sitkokääpiin luetuista lajeista kuuluu orakarakoiden heimoon (Steccherinaceae), joka rajattiin tässä tutkimuksessa uudelleen. Heimoon kuuluvat mm. karakäävät (Junghuhnia) ja orakasmaiset orakarakat (Steccherinum). Sen sisällä selvitettiin kääpien ja orakkaiden sukulaisuussuhteita. Perinteisesti käävät ja orakkaat on viety eri sukuihin riippumatta niiden mikroskooppisesta samankaltaisuudesta. Tulosten valossa orakarakoiden heimossa käävät ja orakkaat pysyvät pääosin erillisissä suvuissa, mutta tästä on myös poikkeuksia (Antrodiella, Metuloidea ja Steccherinum). Lähes kaikki DNA:n perusteella määriteltävissä olevat suvut ovat tunnistettavissa itiöemien ominaisuuksiensa perusteella. Tulokset antavat eväitä kääpien luokitteluun laajemminkin osoittamalla, mitkä ominaisuudet ovat luokittelun kannalta merkityksellisiä. Tarkentunut tieto lajimäärästä ja lajien sukulaisuussuhteista hyödyttää ekologista tutkimusta sekä arvioita lajien uhanalaisuudesta. Tutkimuksen aikana luotua DNA-kirjastoa käytetään lajien tunnistamiseen. Tuloksia voidaan hyödyntää myös etsittäessä bioteknologisia sovelluksia käävistä, sillä sovellusten kannalta kiinnostavat ominaisuudet seuraavat usein sienten sukupuuta.

Quantification problems in the design of forest policy programs.

XVIII IUFRO World Congress, Ljubljana 1986.

Polarization studies in electromagnetic scattering by small Solar-system particles

In remote-sensing studies, particles that are comparable to the wavelength exhibit characteristic features in electromagnetic scattering, especially in the degree of linear polarization. These features vary with the physical properties of the particles, such as shape, size, refractive index, and orientation. In the thesis, the direct problem of computing the unknown scattered quantities using the known properties of the particles and the incident radiation is solved at both optical and radar spectral regions in a unique way. The internal electromagnetic fields of wavelength-scale particles are analyzed by using both novel and established methods to show how the internal fields are related to the scattered fields in the far zone. This is achieved by using the tools and methods that were developed specifically to reveal the internal field structure of particles and to study the mechanisms that relate the structure to the scattering characteristics of those particles. It is shown that, for spherical particles, the internal field is a combination of a forward propagating wave with the apparent wavelength determined by the refractive index of the particle, and a standing wave pattern with the apparent wavelength the same as for the incident wave. Due to the surface curvature and dielectric nature of the particle, the incident wave front undergoes a phase shift, and the resulting internal wave is focused mostly at the forward part of the particle similar to an optical lens. This focusing is also seen for irregular particles. It is concluded that, for both spherical and nonspherical particles, the interference at the far field between the partial waves that originate from these concentrated areas in the particle interior, is responsible for the specific polarization features that are common for wavelength-scale particles, such as negative values and local extrema in the degree of linear polarization, asymmetry of the phase function, and enhancement of intensity near the backscattering direction. The papers presented in this thesis solve the direct problem for particles with both simple and irregular shapes to demonstrate that these interference mechanisms are common for all dielectric wavelength-scale particles. Furthermore, it is shown that these mechanisms can be applied to both regolith particles in the optical wavelengths and hydrometeors at microwave frequencies. An advantage from this kind of study is that it does not matter whether the observation is active (e.g., polarimetric radar) or passive (e.g., optical telescope). In both cases, the internal field is computed for two mutually perpendicular incident polarizations, so that the polarization characteristics can then be analyzed according to the relation between these fields and the scattered far field.

Pain measurement and management in elderly patients : Clinical studies in long term hospital care and after cardiac surgery

The proportion of patients over 75 years of age, receiving all different types of healthcare, is constantly increasing. The elderly undergo surgery and anaesthetic procedures more often than middle-aged patients. Poor pain management in the elderly is still an issue. Although the elderly consumes the greatest proportion of prescribed medicines in Western Europe, most clinical pharmacological studies have been performed in healthy volunteers or middle-aged patients. The aim of this study was to investigate pain measurement and management in cognitively impaired patients in long term hospital care and in cognitively normal elderly patients after cardiac surgery. This thesis incorporated 366 patients, including 86 home-dwelling or hospitalized elderly with chronic pain and 280 patients undergoing cardiac surgery with acute pain. The mean age of patients was 77 (SD ± 8) years and approximately 8400 pain measurements were performed with four pain scales: Verbal Rating Scale (VRS), the Visual Analogue Scale (VAS), the Red Wedge Scale (RWS), and the Facial Pain Scale (FPS). Cognitive function, depression, functional ability in daily life, postoperative sedation and postoperative confusion were assessed with MMSE, GDS, Barthel Index, RASS, and CAM-ICU, respectively. The effects and plasma concentrations of fentanyl and oxycodone were measured in elderly (≥ 75 years) and middle-aged patients (≤ 60 years) and the opioid-sparing effect of pregabalin was studied after cardiac surgery. The VRS pain scores after movement correlated with the Barthel Index. The VRS was most successful in the groups of demented patients (MMSE 17-23, 11-16 and ≤ 10) and in elderly patients on the first day after cardiac surgery. The elderly had a higher plasma concentration of fentanyl at the end of surgery than younger patients. The plasma concentrations of oxycodone were comparable between the groups. Pain intensity on the VRS was lower and the sedation scores were higher in the elderly. Total oxycodone consumption during five postoperative days was reduced by 48% and the CAM-ICU scores were higher on the first postoperative day in the pregabalin group. The incidence of postoperative pain during movement was lower in the pregabalin group three months after surgery. This investigation demonstrates that chronic pain did not seem to impair daily activities in home-dwelling Finnish elderly. The VRS appeared to be applicable for elderly patients with clear cognitive dysfunction (MMSE ≤17) and it was the most feasible pain scale for the early postoperative period after cardiac surgery. After cardiac surgery, plasma concentrations of fentanyl in elderly were elevated, although oxycodone concentrations were at similar level compared to middle-aged patients. The elderly had less pain and were more sedated after doses of oxycodone. Therefore, particular attention must be given to individual dosing of the opioids in elderly surgical patients, who often need a smaller amount for adequate analgesia than middle-aged patients. The administration of pregabalin reduced postoperative oxycodone consumption after cardiac surgery. Pregabalin-treated patients had less confusion, and additionally to less postoperative pain on the first postoperative day and during movement at three months post-surgery. Pregabalin might be a new alternative as analgesic for acute postoperative and chronic pain management in the elderly. Its clinical role and safety remains to be verified in large-scale randomized and controlled studies. In the future, many clinical trials in the older category of patients will be needed to facilitate improvements in health care methods.