Population projection for Namibia 2011-2020 - With an estimation of the impact of HIV/AIDS

This study presents a population projection for Namibia for years 2011–2020. In many countries of sub-Saharan Africa, including Namibia, the population growth is still continuing even though the fertility rates have declined. However, many of these countries suffer from a large HIV epidemic that is slowing down the population growth. In Namibia, the epidemic has been severe. Therefore, it is important to assess the effect of HIV/AIDS on the population of Namibia in the future. Demographic research on Namibia has not been very extensive, and data on population is not widely available. According to the studies made, fertility has been shown to be generally declining and mortality has been significantly increasing due to AIDS. Previous population projections predict population growth for Namibia in the near future, yet HIV/AIDS is affecting the future population developments. For the projection constructed in this study, data on population is taken from the two most recent censuses, from 1991 and 2001. Data on HIV is available from HIV Sentinel Surveys 1992–2008, which test pregnant women for HIV in antenatal clinics. Additional data are collected from different sources and recent studies. The projection is made with software (EPP and Spectrum) specially designed for developing countries with scarce data. The projection includes two main scenarios which have different assumptions concerning the development of the HIV epidemic. In addition, two hypothetical scenarios are made: the first considering the case where HIV epidemic would never have existed and the second considering the case where HIV treatment would never have existed. The results indicate population growth for Namibia. Population in the 2001 census was 1.83 million and is projected to result in 2.38/2.39 million in 2020 in the first two scenarios. Without HIV, population would be 2.61 million and without treatment 2.30 million in 2020. Urban population is growing faster than rural. Even though AIDS is increasing mortality, the past high fertility rates still keep young adult age groups quite large. The HIV epidemic shows to be slowing down, but it is still increasing the mortality of the working-aged population. The initiation of HIV treatment in 2004 in the public sector seems to have had an effect on many projected indicators, diminishing the impact of HIV on the population. For example, the rise of mortality is slowing down.

Perinatal mortality and maternal health in rural China

Background and context Since the economic reforms of 1978, China has been acclaimed as a remarkable economy, achieving 9% annual growth per head for more than 25 years. However, China's health sector has not fared well. The population health gains slowed down and health disparities increased. In the field of health and health care, significant progress in maternal care has been achieved. However, there still remain important disparities between the urban and rural areas and among the rural areas in terms of economic development. The excess female infant deaths and the rapidly increasing sex ratio at birth in the last decade aroused serious concerns among policy makers and scholars. Decentralization of the government administration and health sector reform impacts maternal care. Many studies using census data have been conducted to explore the determinants of a high sex ratio at birth, but no agreement has been so far reached on the possible contributing factors. No study using family planning system data has been conducted to explore perinatal mortality and sex ratio at birth and only few studies have examined the impact of the decentralization of government and health sector reforms on the provision and organization of maternal care in rural China. Objectives The general objective of this study was to investigate the state of perinatal health and maternal care and their determinants in rural China under the historic context of major socioeconomic reforms and the one child family planning policy. The specific objectives of the study included: 1) to study pregnancy outcomes and perinatal health and their correlates in a rural Chinese county; 2) to examine the issue of sex ratio at birth and its determinants in a rural Chinese county; 3) to explore the patterns of provision, utilization, and content of maternal care in a rural Chinese county; 4) to investigate the changes in the use of maternal care in China from 1991 to 2003. Materials and Methods This study is based on a project for evaluating the prenatal care programme in Dingyuan county in 1999-2003, Anhui province, China and a nationwide household health survey to describe the changes in maternal care utilization. The approaches used included a retrospective cohort study, cross sectional interview surveys, informant interviews, observations and the use of statistical data. The data sources included the following: 1) A cohort of pregnant women followed from pregnancy up to 7 days after birth in 20 townships in the study county, collecting information on pregnancy outcomes using family planning records; 2) A questionnaire interview survey given to women who gave birth between 2001 and 2003; 3) Various statistical and informant surveys data collected from the study county; 4) Three national household health interview survey data sets (1993-2003) were utilized, and reanalyzed to described the changes in maternity care utilization. Relative risks (RR) and their confidence intervals (CI) were calculated for comparison between parity, approval status, infant sex and township groups. The chi-square test was used to analyse the disparity of use of maternal care between and within urban and rural areas and its trend across the years in China. Logistic regression was used to analyse the factors associated with hospital delivery in rural areas. Results There were 3697 pregnancies in the study cohort, resulting in 3092 live births in a total population of 299463 in the 20 study townships during 1999-2000. The average age at pregnancy in the cohort was 25.9 years. Of the women, 61% were childless, 38% already had one child and 0.3% had two children before the current pregnancy. About 90% of approved pregnancies ended in a live birth while 73% of the unapproved ones were aborted. The perinatal mortality rate was 69 per thousand births. If the 30 induced abortions in which the gestational age was more than 28 weeks had been counted as perinatal deaths, the perinatal mortality rate would have been as high as 78 per thousand. The perinatal mortality rate was negatively associated with the wealth of the township. Approximately two thirds of the perinatal deaths occurred in the early neonatal period. Both the still birth rate and the early neonatal death rate increased with parity. The risk of a stillbirth in a second pregnancy was almost four times that for a first pregnancy, while the risk of early neonatal deaths doubled. The early neonatal mortality rate was twice as high for female as for male infants. The sex difference in the early neonatal mortality rate was mainly attributable to mortality in second births. The male early neonatal mortality rate was not affected by parity, while the female early neonatal mortality rate increased dramatically with parity: it was about six times higher for second births than for first births. About 82% early neonatal deaths happened within 24 hours after birth, and during that time, girls were almost three times more likely to die than boys. The death rate of females on the day of birth increased much more sharply with parity than that of males. The total sex ratio at birth of 3697 registered pregnancies was 152 males to 100 females, with 118 and 287 in first and second pregnancies, respectively. Among unapproved pregnancies, there were almost 5 live-born boys for each girl. Most prenatal and delivery care was to be taken care of in township hospitals. At the village level, there were small private clinics. There was no limitation period for the provision of prenatal and postnatal care by private practitioners. They were not permitted to provide delivery care by the county health bureau, but as some 12% of all births occurred either at home or at private clinics; some village health workers might have been involved. The county level hospitals served as the referral centers for the township hospitals in the county. However, there was no formal regulation or guideline on how the referral system should work. Whether or not a woman was referred to a higher level hospital depended on the individual midwife's professional judgment and on the clients' compliance. The county health bureau had little power over township hospitals, because township hospitals had in the decentralization process become directly accountable to the township government. In the township and county hospitals only 10-20% of the recurrent costs were funded by local government (the township hospital was funded by the township government and the county hospital was funded by the county government) and the hospitals collected user fees to balance their budgets. Also the staff salaries depended on fee incomes by the hospital. The hospitals could define the user charges themselves. Prenatal care consultations were however free in most township hospitals. None of the midwives made postnatal home visits, because of low profit of these services. The three national household health survey data showed that the proportion of women receiving their first prenatal visit within 12 weeks increased greatly from the early to middle 1990s in all areas except for large cities. The increase was much larger in the rural areas, reducing the urban-rural difference from more than 4 times to about 1.4 times. The proportion of women that received antenatal care visits meeting the Ministry of Health s standard (at least 5 times) in the rural areas increased sharply from 12% in 1991-1993 to 36% in 2001-2003. In rural areas, the proportion increase was much faster in less developed areas than in developed areas. The hospital delivery rate increased slightly from 90% to 94% in urban areas while the proportion increased from 27% to 69% in rural areas. The fastest change was found to be in type 4 rural areas, where the utilization even quadrupled. The overall difference between rural and urban areas was substantially narrowed over the period. Multiple logistic regression analysis shows that time periods, residency in rural or urban areas, income levels, age group, education levels, delivery history, occupation, health insurance and distance from the nearest health care facilities were significantly associated with hospital delivery rates. Conclusions 1. Perinatal mortality in this study was much higher than that for urban areas as well as any reported rate from specific studies in rural areas of China. Previous studies in which calculations of infant mortality were not based on epidemiological surveys have been shown to underestimate the rates by more than 50%. 2. Routine statistics collected by the Chinese family planning system proved to be a reliable data source for studying perinatal health, including still births, neonatal deaths, sex ratio at birth and among newborns. National Household Health Survey data proved to be a useful and reliable data source for studying population health and health services. Prior to this research there were few studies in these areas available to international audiences. 3.Though perinatal mortality rate was negatively associated with the level of township economic development, the excess female early neonatal mortality rate contributed much more to high perinatal mortality rate than economic factors. This was likely a result of the role of the family planning policy and the traditional preferences for sons, which leads to lethal neglect of female newborns and high perinatal mortality. 4. The selective abortions of female foetuses were likely to contribute most to the high sex ratio at birth. The underreporting of female births seemed to have played a secondary role. The higher early neonatal mortality rate in second-born as compared to first-born children, particularly in females, may indicate that neglect or poorer care of female newborn infants also contributes to the high sex ratio at birth or among newborns. Existing family planning policy proved not to effectively control the steadily increased birth sex ratio. 5. The rural-urban gap in service utilization was on average significantly narrowed in terms of maternal healthcare in China from 1991 to 2003. This demonstrates that significant achievements in reducing inequities can be made through a combination of socio-economic development and targeted investments in improving health services, including infrastructure, staff capacities, and subsidies to reduce the costs of service utilization for the poorest. However, the huge gap which persisted among cities of different size and within different types of rural areas indicated the need for further efforts to support the poorest areas. 6. Hospital delivery care in the study county was better accepted by women because most of women think delivery care was very important while prenatal and postnatal care were not. Hospital delivery care was more systematically provided and promoted than prenatal and postnatal care by township hospital in the study area. The reliance of hospital staff income on user fees gave the hospitals an incentive to put more emphasis on revenue generating activities such as delivery care instead of prenatal and postnatal care, since delivery care generated much profits than prenatal and postnatal care . Recommendations 1. It is essential for the central government to re-assess and modify existing family planning policies. In order to keep national sex balance, the existing practice of one couple one child in urban areas and at-least-one-son a couple in rural areas should be gradually changed to a two-children-a-couple policy throughout the country. The government should establish a favourable social security policy for couples, especially for rural couples who have only daughters, with particular emphasis on their pension and medical care insurance, combined with an educational campaign for equal rights for boys and girls in society. 2. There is currently no routine vital-statistics registration system in rural China. Using the findings of this study, the central government could set up a routine vital-statistics registration system using family planning routine work records, which could be used by policy makers and researchers. 3. It is possible for the central and provincial government to invest more in the less developed and poor rural areas to increase the access of pregnant women in these areas to maternal care services. Central government together with local government should gradually provide free maternal care including prenatal and postnatal as well as delivery care to the women in poor and less developed rural areas. 4. Future research could be done to explore if county and the township level health care sector and the family planning system could be merged to increase the effectiveness and efficiency of maternal and child care. 5. Future research could be done to explore the relative contribution of maternal care, economic development and family planning policy on perinatal and child health using prospective cohort studies and community based randomized trials. Key words: perinatal health, perinatal mortality, stillbirth, neonatal death, sex selective abortion, sex ratio at birth, family planning, son preference, maternal care, prenatal care, postnatal care, equity, China

Antarctic ice shelf melting and its impact on the global sea ice-ocean system

Earth s ice shelves are mainly located in Antarctica. They cover about 44% of the Antarctic coastline and are a salient feature of the continent. Antarctic ice shelf melting (AISM) removes heat from and inputs freshwater into the adjacent Southern Ocean. Although playing an important role in the global climate, AISM is one of the most important components currently absent in the IPCC climate model. In this study, AISM is introduced into a global sea ice-ocean climate model ORCA2-LIM, following the approach of Beckmann and Goosse (2003; BG03) for the thermodynamic interaction between the ice shelf and ocean. This forms the model ORCA2-LIM-ISP (ISP: ice shelf parameterization), in which not only all the major Antarctic ice shelves but also a number of minor ice shelves are included. Using these two models, ORCA2-LIM and ORCA2-LIM-ISP, the impact of addition of AISM and increasing AISM have been investigated. Using the ORCA2-LIM model, numerical experiments are performed to investigate the sensitivity of the polar sea ice cover and the Antarctic Circumpolar Current (ACC) transport through Drake Passage (DP) to the variations of three sea ice parameters, namely the thickness of newly formed ice in leads (h0), the compressive strength of ice (P*), and the turning angle in the oceanic boundary layer beneath sea ice (θ). It is found that the magnitudes of h0 and P* have little impact on the seasonal sea ice extent, but lead to large changes in the seasonal sea ice volume. The variation in turning angle has little impact on the sea ice extent and volume in the Arctic but tends to reduce them in the Antarctica when ignored. The magnitude of P* has the least impact on the DP transport, while the other two parameters have much larger influences. Numerical results from ORCA2-LIM and ORCA2-LIM-ISP are analyzed to investigate how the inclusion of AISM affects the representation of the Southern Ocean hydrography. Comparisons with data from the World Ocean Circulation Experiment (WOCE) show that the addition of AISM significantly improves the simulated hydrography. It not only warms and freshens the originally too cold and too saline bottom water (AABW), but also warms and enriches the salinity of the originally too cold and too fresh warm deep water (WDW). Addition of AISM also improves the simulated stratification. The close agreement between the simulation with AISM and the observations suggests that the applied parameterization is an adequate way to include the effect of AISM in a global sea ice-ocean climate model. We also investigate the models capability to represent the sea ice-ocean system in the North Atlantic Ocean and the Arctic regions. Our study shows both models (with and without AISM) can successfully reproduce the main features of the sea ice-ocean system. However, both tend to overestimate the ice flux through the Nares Strait, produce a lower temperature and salinity in the Hudson Bay, Baffin Bay and Davis Strait, and miss the deep convection in the Labrador Sea. These deficiencies are mainly attributed to the artificial enlargement of the Nares Strait in the model. In this study, the impact of increasing AISM on the global sea ice-ocean system is thoroughly investigated. This provides a first idea regarding changes induced by increasing AISM. It is shown that the impact of increasing AISM is global and most significant in the Southern Ocean. There, increasing AISM tends to freshen the surface water, to warm the intermediate and deep waters, and to freshen and warm the bottom water. In addition, increasing AISM also leads to changes in the mixed layer depths (MLD) in the deep convection sites in the Southern Ocean, deepening in the Antarctic continental shelf while shoaling in the ACC region. Furthermore, increasing AISM influences the current system in the Southern Ocean. It tends to weaken the ACC, and strengthen the Antarctic coastal current (ACoC) as well as the Weddell Gyre and the Ross Gyre. In addition to the ocean system, increasing AISM also has a notable impact on the Antarctic sea ice cover. Due to the cooling of seawater, sea ice concentration and thickness generally become higher. In austral winter, noticeable increases in sea ice concentration mainly take place near the ice edge. In regards with sea ice thickness, large increases are mainly found along the coast of the Weddell Sea, the Bellingshausen and Amundsen Seas, and the Ross Sea. The overall thickening of sea ice leads to a larger volume of sea ice in Antarctica. In the North Atlantic, increasing AISM leads to remarkable changes in temperature, salinity and density. The water generally becomes warmer, more saline and denser. The most significant warming occurs in the subsurface layer. In contrast, the maximum salinity increase is found at the surface. In addition, the MLD becomes larger along the Greenland-Scotland-Iceland ridge. Global teleconnections due to AISM are studied. The AISM signal is transported with the surface current: the additional freshwater from AISM tends to enhance the northward spreading of the surface water. As a result, more warm and saline water is transported from the tropical region to the North Atlantic Ocean, resulting in warming and salt enrichment there. It would take about 30 40 years to establish a systematic noticeable change in temperature, salinity and MLD in the North Atlantic Ocean according to this study. The changes in hydrography due to increasing AISM are compared with observations. Consistency suggests that increasing AISM is highly likely a major contributor to the recent observed changes in the Southern Ocean. In addition, the AISM might contribute to the salinity contrast between the North Atlantic and North Pacific, which is important for the global thermohaline circulation.

Functional expression and subcellular localization of the Cl- cotransporters KCC2 and NKCC1 in rodent hippocampal and neocortical neurons

The work presented here has focused on the role of cation-chloride cotransporters (CCCs) in (1) the regulation of intracellular chloride concentration within postsynaptic neurons and (2) on the consequent effects on the actions of the neurotransmitter gamma-aminobutyric acid (GABA) mediated by GABAA receptors (GABAARs) during development and in pathophysiological conditions such as epilepsy. In addition, (3) we found that a member of the CCC family, the K-Cl cotransporter isoform 2 (KCC2), has a structural role in the development of dendritic spines during the differentiation of pyramidal neurons. Despite the large number of publications dedicated to regulation of intracellular Cl-, our understanding of the underlying mechanisms is not complete. Experiments on GABA actions under resting steady-state have shown that the effect of GABA shifts from depolarizing to hyperpolarizing during maturation of cortical neurons. However, it remains unclear, whether conclusions from these steady-state measurements can be extrapolated to the highly dynamic situation within an intact and active neuronal network. Indeed, GABAergic signaling in active neuronal networks results in a continuous Cl- load, which must be constantly removed by efficient Cl- extrusion mechanisms. Therefore, it seems plausible to suggest that key parameters are the efficacy and subcellular distribution of Cl- transporters rather than the polarity of steady-state GABA actions. A further related question is: what are the mechanisms of Cl- regulation and homeostasis during pathophysiological conditions such as epilepsy in adults and neonates? Here I present results that were obtained by means of a newly developed method of measurements of the efficacy of a K-Cl cotransport. In Study I, the developmental profile of KCC2 functionality during development was analyzed both in dissociated neuronal cultures and in acute hippocampal slices. A novel method of photolysis of caged GABA in combination with Cl- loading to the somata was used in this study to assess the extrusion efficacy of KCC2. We demonstrated that these two preparations exhibit a different temporal profile of functional KCC2 upregulation. In Study II, we reported an observation of highly distorted dendritic spines in neurons cultured from KCC2-/- embryos. During their development in the culture dish, KCC2-lacking neurons failed to develop mature, mushroom-shaped dendritic spines but instead maintained an immature phenotype of long, branching and extremely motile protrusions. It was shown that the role of KCC2 in spine maturation is not based on its transport activity, but is mediated by interactions with cytoskeletal proteins. Another important player in Cl- regulation, NKCC1 and its role in the induction and maintenance of native Cl- gradients between the axon initial segment (AIS) and soma was the subject of Study III. There we demonstrated that this transporter mediates accumulation of Cl- in the axon initial segment of neocortical and hippocampal principal neurons. The results suggest that the reversal potential of the GABAA response triggered by distinct populations of interneurons show large subcellular variations. Finally, a novel mechanism of fast post-translational upregulation of the membrane-inserted, functionally active KCC2 pool during in-vivo neonatal seizures and epileptiform-like activity in vitro was identified and characterized in Study IV. The seizure-induced KCC2 upregulation may act as an intrinsic antiepileptogenic mechanism.

Change detection and controlling forest information using multi-temporal Landsat TM imagery.

A method was developed for relative radiometric calibration of single multitemporal Landsat TM image, several multitemporal images covering each others, and several multitemporal images covering different geographic locations. The radiometricly calibrated difference images were used for detecting rapid changes on forest stands. The nonparametric Kernel method was applied for change detection. The accuracy of the change detection was estimated by inspecting the image analysis results in field. The change classification was applied for controlling the quality of the continuously updated forest stand information. The aim was to ensure that all the manmade changes and any forest damages were correctly updated including the attribute and stand delineation information. The image analysis results were compared with the registered treatments and the stand information base. The stands with discrepancies between these two information sources were recommended to be field inspected.

Ruismallasuute vähägluteenisessa kauraleivonnassa

Tutkielman kirjallisuuskatsauksessa tarkasteltiin kauran leivontateknologisia ominaisuuksia, entsyymiaktiivista leivontaa ja ruismaltaan hyödyntämistä vähägluteenisessa leivonnassa. Kokeellisessa osiossa tutkittiin ruismallashapantaikinasta valmistetun uutteen vaikutusta kaurataikinan viskositeettiin ja kauraleivän ominaisuuksiin. Työn tarkoituksena oli kehittää maultaan ja rakenteeltaan onnistunut rukiinmakuinen kauraleipä. Ruismaltaan entsyymien annettiin pilkkoa keliaakikolle haitallisia rukiin prolamiineja hapantaikinaprosessissa. Hapantaikinasta erotettiin uute sentrifugoimalla. Leivontakokeisiin käytettiin entsyymiaktiivista ja kuumentamalla inaktivoitua uutetta. Uutteella korvattiin taikinavettä 15, 25 ja 30 % (taikinan painosta). Leivonta toteutettiin miniatyyrikoossa, vuokaleivontana 20 g:n taikinapaloja käyttäen. Taikinoiden viskositeetti mitattiin tarkoituksena seurata beetaglukaanin hydrolyysiä. Rukiin makua mitattiin koulutetun raadin avulla. Happaman uutteen lisäys laski taikinan pH-arvoa noin 5,8:sta noin 4,4:ään. Entsyymiaktiivisen uutteen lisäys laski taikinan viskositeettia ja inaktivoitu uute puolestaan kasvatti sitä. Leipien sisus tiivistyi, jolloin mitatut sisuksen kovuudet kasvoivat uutteen lisäyksen myötä. Uutelisäys paransi leipien makua ja aromia. Uutteen vaikutuksesta leipien huokoset olivat pienempiä ja ne jakaantuivat tasaisemmin leipämatriisiin. Jos uutetta käytettiin inaktivoituna, leipien murenevuus kasvoi. Tutkimuksessa kehitetyn teknologian avulla oli mahdollista valmistaa hyvänlaatuinen, rukiinmakuinen kauraleipä myös ilman että uutteen entsyymit inaktivoitiin keittämällä. Tähän vaikutti ilmeisesti taikinan alhainen pH, joka inhiboi alfa-amylaasia, ja kauratärkkelyksen korkea liisteröitymislämpötila, jolloin entsyymien inaktivoituminen paiston aikana tapahtui ennen kuin tärkkelys tuli alttiiksi liialliselle pilkkoutumiselle. Tämä mahdollistaa uutteen käytön osana leivontaprosessia ilman inaktivointia. Hapantaikinafermentaatio osana gluteenitonta leivontaa havaittiin toimivaksi yhdistelmäksi, sillä se paransi leivän väriä, makua ja rakennetta. Myös leivän homeeton aika parani jo vähäisenkin uutelisäyksen vaikutuksesta. Näyttää siltä, että tämän teknologian avulla on mahdollista tuoda esille pitkään kaivattua rukiin makua vähägluteenisten kauraleipien valikoimassa. Laskennallisesti ja aiempiin tuloksiin tukeutuen, voitiin päätellä, että leivän prolamiinipitoisuudessa on mahdollista päästä tasolle 63,5 mg/kg, mutta jatkokehityksen avulla päästäisiin luultavasti vielä parempiin tuloksiin.

Changing Paradigms in Biblical Criticism : 2 Kings 22:1 23:30 in the Flux of Discourses

The subject and methodology of biblical scholarship has expanded immense-ly during the last few decades. The traditional text-, literary-, source- and form-critical approaches, labeled historical-critical scholarship , have faced the challenge of social sciences. Various new literary, synchronic readings, sometimes characterized with the vague term postmodernism, have in turn challenged historicalcritical, and social-scientific approaches. Widened limits and diverging methodologies have caused a sense of crisis in biblical criticism. This metatheoretical thesis attempts to bridge the gap between philosophical discussion about the basis of biblical criticism and practical academic biblical scholarship. The study attempts to trace those epistemological changes that have produced the wealth of methods and results within biblical criticism. The account of the cult reform of King Josiah of Judah as reported in 2 Kings 22:1 23:30 serves as the case study because of its importance for critical study of the Hebrew Bible. Various scholarly approaches embracing 2 Kings 22:1 23:30 are experimentally arranged around four methodological positions: text, author, reader, and context. The heuristic model is a tentative application of Oliver Jahraus s model of four paradigms in literary theory. The study argues for six theses: 1) Our knowledge of the world is con-structed, fallible and theory-laden. 2) Methodological plurality is the neces-sary result of changes in epistemology and culture in general. 3) Oliver Jahraus s four methodological positions in regard to literature are also an applicable model within biblical criticism to comprehend the methodological plurality embracing the study of the Hebrew Bible. 4) Underlying the methodological discourse embracing biblical criticism is the epistemological ten-sion between the natural sciences and the humanities. 5) Biblical scholars should reconsider and analyze in detail concepts such as author and editor to overcome the dichotomy between the Göttingen and Cross schools. 6) To say something about the historicity of 2 Kings 22:1 23:30 one must bring together disparate elements from various disciplines and, finally, admit that though it may be possible to draw some permanent results, our conclusions often remain provisional.

Molecular studies on LIM-domain protein CRP1

Various intrinsic and external factors are constantly attacking the cells causing damage to DNA and to other cellular structures. Cells in turn have evolved with different kinds of mechanisms to protect against the attacks and to repair the damage. Ultraviolet radiation (UVR) is one of the major environmental genotoxic carcinogens that causes inflammation, mutations, immunosuppression, accelerated aging of the skin and skin cancers. Epidermis is the outermost layer of the skin consisting mostly of keratinocytes, whose primary function is to protect the skin against e.g. UV radiation. LIM domain proteins are a group of proteins involved in regulation of cell growth, damage signalling, cell fate determination and signal transduction. Despite their two zinc fingers, LIM domains do not bind to DNA, but rather mediate protein-protein interactions and function as modular protein binding interfaces. We initially identified CSRP1 as UVR-regulated transcript by using expression profiling. Here we have further studied the regulation and function of CRP1, a representative of cysteine rich protein- family consisting of two LIM domains. We find that CRP1 is increased by UVR in primary human keratinocytes and in normal human skin fibroblasts. Ectopic expression of CRP1 protected the cells against UVR and provided a survival advantage, whereas silencing of CRP1 rendered the cells more photosensitive. Actinic keratosis is a premalignant lesion of skin caused by excess exposure to sunlight and sunburn, which may lead to formation of squamous cell carcinoma. The expression of CRP1 was increased in basal keratinocytes of Actinic keratosis patient specimens suggesting that CRP1 may be increased by constant exposure to UVR and may provide survival advantage for the cells also in vivo. In squamous cell carcinoma, CRP1 was only expressed in the fibroblasts surrounding the tumour. Moreover, we found that ectopic expression of CRP1 suppresses cell proliferation. Transforming growth factor beta (TGFbeta) is a multifunctional cytokine that regulates several functions in cell including growth, apoptosis and differentiation, and plays important roles in pathological disorders like cancer and fibrosis. We found that TGFbeta-signalling pathway regulates CRP1 at protein, but not at transcriptional level. The increase was mediated both through Smad and non-Smad signalling pathways involving MAPK/p38. Furthermore, we found that TGFbeta-mediated increase in CRP1 was associated with myofibroblast differentiation, and that CRP1 was significantly more expressed in idiopathic pulmonary fibrosis as compared to normal lung specimens. Since cell contractility is a distinct feature of myofibroblasts, and CRP1 is associated with actin cytoskeleton, we studied the role of CRP1 in cell contractility. CRP1 was found to localize to stress fibres that mediate contractility and to mediate myofibroblast contraction. These studies identify CRP1 as a stress responsive and cytokine regulated cytoskeletal protein that participates in pathological processes involved in fibrotic diseases and cancer.

Mechanism-based inhibition of CYP2C8 by gemfibrozil in humans : characterisation of time and dose relationships

Drug-drug interactions may cause serious, even fatal clinical consequences. Therefore, it is important to examine the interaction potential of new chemical entities early in drug development. Mechanism-based inhibition is a pharmacokinetic interaction type, which causes irreversible loss of enzyme activity and can therefore lead to unusually profound and long-lasting consequences. The in vitro in vivo extrapolation (IVIVE) of drug-drug interactions caused by mechanism-based inhibition is challenging. Consequently, many of these interactions have remained unrecognised for many years. The concomitant use of the fibrate-class lipid-lowering agent gemfibrozil increases the concentrations of some drugs and their effects markedly. Even fatal cases of rhabdomyolysis occurred in patients administering gemfibrozil and cerivastatin concomitantly. One of the main mechanisms behind this effect is the mechanism-based inhibition of the cytochrome P450 (CYP) 2C8 enzyme by a glucuronide metabolite of gemfibrozil leading to increased cerivastatin concentrations. Although the clinical use of gemfibrozil has clearly decreased during recent years, gemfibrozil is still needed in some special cases. To enable safe use of gemfibrozil concomitantly with other drugs, information concerning the time and dose relationships of CYP2C8 inhibition by gemfibrozil should be known. This work was carried out as four in vivo clinical drug-drug interaction studies to examine the time and dose relationships of the mechanism-based inhibitory effect of gemfibrozil on CYP2C8. The oral antidiabetic drug repaglinide was used as a probe drug for measuring CYP2C8 activity in healthy volunteers. In this work, mechanism-based inhibition of the CYP2C8 enzyme by gemfibrozil was found to occur rapidly in humans. The inhibitory effect developed to its maximum already when repaglinide was given 1-3 h after gemfibrozil intake. In addition, the inhibition was shown to abate slowly. A full recovery of CYP2C8 activity, as measured by repaglinide metabolism, was achieved 96 h after cessation of gemfibrozil treatment. The dose-dependency of the mechanism-based inhibition of CYP2C8 by gemfibrozil was shown for the first time in this work. CYP2C8 activity was halved by a single 30 mg dose of gemfibrozil or by twice daily administration of less than 30 mg of gemfibrozil. Furthermore, CYP2C8 activity was decreased over 90% by a single dose of 900 mg gemfibrozil or twice daily dosing of approximately 100 mg gemfibrozil. In addition, with the application of physiological models to the data obtained in the dose-dependency studies, the major role of mechanism-based inhibition of CYP2C8 in the interaction between gemfibrozil and repaglinide was confirmed. The results of this work enhance the proper use of gemfibrozil and the safety of patients. The information related to time-dependency of CYP2C8 inhibition by gemfibrozil may also give new insights in order to improve the IVIVE of the drug-drug interactions of new chemical entities. The information obtained by this work may be utilised also in the design of clinical drug-drug interaction studies in the future.

Carotid Surgery : A posse ad esse non valet consequentia

According to a large body of evidence, carotid endarterectomy (CEA) can prevent strokes, provided that appropriate inclusion criteria and high-quality perioperative treatment methods are utilised with low complication rates. From the patient s perspective, it is of paramount importance that the operation is as safe and effective as possible. From the community s point of view, it is important that CEA provision prevents as many strokes as possible. In order to define the stroke preventing potential of CEA in different communities, a comparison between eight European countries and Australia was performed including 53 077 carotid interventions. A more detailed evaluation was performed in Finland, the United Kingdom and Egypt. It could be estimated that many potentially preventable strokes occur due to insufficient diagnostics and CEA provision. The number of CEAs should be at least doubled in the Helsinki region. The theoretical power of CEA provision in stroke prevention varied significantly between the countries. Delay from symptom to surgery has been identified as one of the most important factors influencing the effectiveness of CEA. In 2008 only 11% of CEAs in Helsinki university central hospital (HUCH) were performed within the recommended14 days. Registered data of 673 CEAs in HUCH during 2000-2005 was analyzed. There was no systematic error that would have changed the outcome analysis. However it is important that registers are audited regularly and cross matching of different registries is possible. A previously unpublished method of combining medial mandibulotomy, neck incision and carotid artery interposition was carried out as a collaboration of maxillofacial, ear, nose and throat and vascular surgeons. Five patients were operated on with a technique that was feasible and possible to perform with little morbidity, but due to the significant risks involved, this technique should be reserved for carefully selected cases. In stroke prevention, organisational decisions seem far more important than details in interventional procedures when CEA is performed with low complication rates, as was the case in the present study. A TIA clinic approach with close co-operation between the on-call vascular surgeons, neurologists and radiologists should be available at all centres treating these patients. Patients should have a direct and fast admission to the hospital performing CEA.

Naudanlihan jalostusketjun hiilijalanjälki Suomessa

Kirjallisuustutkimuksen tavoitteena oli perehtyä kasvihuoneilmiön taustoihin ja kartoittaa aiempia tutkimuksia naudan- ja muiden lihatuotteiden kasvihuonekaasupäästöistä. Lisäksi kirjallisuustutkimuksessa perehdyttiin aiemmissa tutkimuksissa elintarvikkeiden hiilijalanjäljen laskemisessa sovellettuun elinkaarianalyysiin ISO 14040-standardin mukaisesti. Kokeellisen osion tavoitteena oli määrittää naudanlihan hiilijalanjälki Suomessa maatilan portilta kuluttajan ruokapöytään. Tavoitteena oli myös ymmärtää jalostusketjun päästöjen merkitys verrattuna koko naudanlihan tuotantoketjuun ja määrittää jalostusketjun vaiheiden merkitys ketjussa. Työn toiminnallisena yksikkönä toimi kilo naudanlihaa. Työ toteutettiin perehtymällä yksityiskohtaisesti yhteen naudanlihan jalostusketjuun Suomessa. Päästöt laskettiin todellisten yhteistyöyritykseltä saatujen prosessitietojen perusteella. Tiedot kerättiin tiedonkeruulomakkeella vierailemalla yhteistyöyrityksen kahdessa tuotantolaitoksessa ja täydentämällä tietoja haastatteluilla. Naudanlihan jalostusketjun päästöt olivat 1240 g CO2-ekv/lihakilo. Eniten päästöjä tuottivat jalostusvaihe (310 g CO2-ekv/lihakilo), teurastus (280 g CO2-ekv/lihakilo) ja lihatuotteiden kuljetus kuluttajalle (210 g CO2-ekv/lihakilo). Koko naudanlihan tuotantoketjusta jalostusketjun päästöt muodostivat alle 4 %, sillä syntymästä maatilan portille syntyviksi päästöiksi laskettiin kirjallisuuden perusteella yli 30 000 g CO2-ekv/lihakilo. Jatkossa naudanlihan hiilijalanjälkeä voitaisiin pääasiassa pienentää kehittämällä prosessia maatilan portille asti. Tämän työn tulokset olivat hyvin samansuuruiset verrattuna aiempaan tutkimukseen broilerin jalostusketjun päästöistä Suomessa (Katajajuuri ym. 2008). Tämä vastasi ennakko-odotuksia, sillä jalostusketjujen vaiheissa ei ollut merkittäviä eroja. Aiempia tutkimuksia naudanlihan jalostusketjun päästöistä ei ollut saatavilla.

Determination of intestinal permeability in healthy horses using the contrast medium iohexol

Tämä lisensiaatin tutkielma koostuu kolmesta osasta; kirjallisuuskatsauksesta, kokeellisesta osasta ja liitteistä. Iohexol on ionisoitumaton, trijodattu ja vesiliukoinen röntgenvarjoaine. Iohexolia on hyödynnetty lääketieteessä useita vuosia. Iohexolia on käytetty muun muassa angio- ja myelografiassa, lisäksi iohexolia on hyödynnetty arvioitaessa munuaiskerästen suodattumisnopeutta sekä suoliston läpäisevyyden muutoksia. Hevosen tulehduksellisessa suolistosairaudessa (Inflammatory bowel disease, IBD) suoliston rakenne ja sen läpäisevyys muuttuu; tyypillistä on tulehdussolujen kertyminen suoliston seinämään ja myös sidekudosmuodostusta saattaa esiintyä. Suolisto muutoksia saatetaan havaita sekä ohut- että paksusuolessa. IBD aiheuttaa hevoselle laihtumista, johtuen ravintoaineiden puutteellisesta imeytymisestä ja proteiinien menetyksestä suoleen suoliston häiriötilan yhteydessä. Tällä hetkellä IBD:n diagnostiikka perustuu tyypillisiin oireisiin, kliiniseen tutkimukseen, verinäytteisiin, glukoosin imeytymistestiin ja peräsuolesta otettuun koepalaan. IBD:n diagnostiikka on kuitenkin erittäin haastavaa ja tutkimusmenetelmiin liittyy lukuisia ongelmia, jotka vähentävät niiden luotettavuutta IBD:n diagnostiikassa. Tutkimuksemme tarkoituksena on kehittää hevosen IBD:n diagnostiikkaa entistä helpompaan, luotettavampaan ja turvallisempaan suuntaan. Tämän alustavan tutkimuksen tavoitteet olivat: (1) tutkia voidaanko iohexol havaita hevosen seerumissa oraalisen annostelun jälkeen ja (2) muodostaa iohexolin pitoisuuskuvaaja ajan funktiona terveillä hevosilla. Materiaalimme koostui kymmenestä terveestä hevosesta, joilla ei ollut havaittu laihtumista tai ripulia. Ennen iohexolin annostelua hevosille suoritettiin kliininen tutkimus ja verinäytteet otettiin maha-suolikanavan sairauden poissulkemiseksi. Hevosille suoritettiin myös mahalaukun tähystys. 16 tunnin paaston jälkeen 1 ml/kg Iohexolia annosteltiin 10 % -liuoksena nenämahaletkulla suoraan mahaan ja verinäytteet otettiin 0, 30, 60, 120, 180, 240, 300 ja 360 minuuttia annostelun jälkeen. Iohexolin pitoisuus määritettiin käyttämällä korkean erotuskyvyn nestekromatografiaa. Iohexolin pitoisuuksista tietyillä ajanhetkillä muodostettiin kuvaaja. Hevosilla ei havaittu maha-suolikanavan sairauksia. Kaikki hevoset olivat hyvässä kuntoluokassa ja mahalaukun tähystyksessä ei havaittu merkittäviä muutoksia. Verinäytteiden tulokset olivat viiterajoissa. Kaikki hevoset sietivät iohexolia hyvin ja haittavaikutuksia ei havaittu. Iohexol oli havaittavissa seerumissa 60 minuutin kuluttua annostelusta. Kuvaajassa voitiin havaita kaksi huippua. Statistiset menetelmät tukivat löydöksiä. Iohexol testi oli yksinkertainen suorittaa ja siihen ei liittynyt haittavaikutuksia. Annos 1ml/kg oli havaittavissa seerumissa. Iohexolin pitoisuuskuvaaja muodosti kaksi huippua, ja tämänkaltainen ilmiö on kuvattu kirjallisuudessa aikaisemmin useiden lääkkeiden tapauksessa. Hevosella ilmiö liittyy todennäköisesti maha-suolikanavan rakenteellisiin ja fysiologisiin eroavaisuuksiin ja lisätutkimuksia ilmiön varmistamiseksi tarvitaan. Iohexol näyttää olevan potentiaalinen merkkiaine suoliston läpäisevyyden arviointiin ja lisätutkimuksia IBD:tä sairastavien hevosten seerumin iohexolin pitoisuuksista verrattuna terveiden hevosten seerumin iohexolin pitoisuuksiin on suunnitteilla.

Koti keskellä kaupunkia : Keskusta lapsiperheen asuinalueena, esimerkkeinä Tukholma ja Helsinki

Families with children have traditionally moved to suburbs. In the last 20 years a modest counter process has however been recognized. Families with an urban lifestyle stay in the city centres. This study looks at the phenomenon through two cases, Stockholm and Helsinki. In the first case it has already been observed that the city centre has grown in popularity among families with children. Therefore it serves as a basis for the study and as well as a point of comparison. Stockholm’s city centre is expanding as new neighbourhoods have been built and are being planned. In the city centre of Helsinki the building of two large neighbourhoods for 30 000 inhabitants will start in a few years. The first aim of the study is to look closer at what has really happened in the city centre of Stockholm, why families choose to live there with their children and how the City of Stockholm has reacted to the change. The main sources of information are secondary sources, statistics and interviews with planners, politicians and experts in the field. The main object is to look at the situation in the city centre of Helsinki. Can a preference for urban residential environments be observed in Helsinki? What are the reasons for a family to choose the city centre as a living place? How does the everyday life of a family in the city centre appear? How are these families taken into account in the planning of the city? The main sources of information here are statistics, interviews with dwellers in the neighbourhood Kruununhaka and interviews with planners. In Stockholm the birth rate has grown constantly during the 2000s and is highest in the city centre. Some of the families still move elsewhere, but many of them do not. One of the most important reasons for living in the city centre is short working distances which give working parents more time with their children. Another reason is a preference of an urban, active lifestyle. Families prefer to live close to everything, childcare, schools, shops and entertainments. The popularity of the city centre among families with children has taken politicians and planners by surprise. Helsinki has not experienced a baby boom like Stockholm. However the negative changes in the birth rate have been more modest in the central areas than in the suburbs. Statistics show, that many families move away from the city centre as the children grow. Families who stay in the city centre especially appreciate closeness to public and private services and good public transportation which means that they are not dependent on using the car. Further they find that the city centre has a tolerant climate and is a safe and beautiful place to live in. The families enjoy the social life of the neighbourhood and feel that it makes a good climate to raise children in. However they are concerned with traffic safety and the lack of stimulus in the playgrounds of the neighbourhood parks. Two large neighbourhoods with homes for about 30 000 inhabitants are now planned in the former Port Districts in the city centre of Helsinki. The other one, Jätkäsaari has been planned to become an attractive alternative for families with children. Traffic safety has been one of the main objects for the planning. The other, Kalasatama, has been planned to attract all groups in society.