<p>The aims of this study were to document the levels of cobalamin, folate, methylmalonic acid (MMA) and total homocysteine (tHcy) in serum and their relations to symptoms, clinical findings, and other factors in order to improve the possibilities of detecting early deficiency of vitamin B12 or folate, and to study the effects of cobalamin and folic acid treatment over a three-year period.</p><p>The study population consisted of a 20% random sample of persons 70 years or older living in Älvkarleby in mid-Sweden. They were invited to a survey and 224 (88.4%) persons responded. Data were obtained by questionnaire, laboratory investigations and physical examination for the period 1993 – 1999.</p><p>In a multivariate analysis performed at baseline, serum MMA and tHcy were significantly and independently correlated to age, serum cobalamin, and creatinine levels, and tHcy also to sex and serum folate. Neither serum cobalamin, folate, MMA nor tHcy had any significant correlation to haemoglobin or mean red cell volume. Almost half of the study population had signs of low tissue levels of vitamin B12 or folate. Among those who took multivitamin preparations, the proportion was much lower, 25%.</p><p>Among traditional symptoms and clinical findings that have been linked to vitamin B12 or folate tissue deficiency, only changes in the tongue mucosa and mouth angle stomatitis were significantly associated with abnormal serum folate and tHcy levels. Traditional symptoms of vitamin deficiency may appear later in the course.</p><p>69 persons who had laboratory indications of early or overt tissue deficiency of vitamin B12 or folate and who had no ongoing vitamin treatment were given cobalamin for six months. Those whose MMA or tHcy levels did not normalise were given folic acid in addition to cobalamin. After further treatment for three months, all persons but one had normal levels. The laboratory effect still remained after three years of treatment. There was a tendency towards improvement of vibration sense, especially in the long nerve paths, and improvement of neurological symptoms and oral mucosa findings.</p><p><b>Conclusion:</b> A substantial proportion of elderly persons have laboratory signs of incipient tissue deficiency of vitamin B12 and folate. Treatment normalises lab parameters and some symptoms.</p>

<p>This dissertation has two parts. Firstly, satisfaction with life as a whole and with 10 life domains (using an instrument termed LiSat-11 with 6-graded scales) is described in a nationally representative sample aged 18-64 years (n: 2,533) and is related to some socio-demographic circumstances. Secondly, vocationally disabled people (n: 109) at an employability institute are prospectively followed in order to determine their life satisfaction and to identify early predictors of vocational rehabilitation outcome.</p><p><u>Main results</u>: Gender independently, 70 % of the national sample were satisfied with life as a whole (were happy). The ten domains formed a 4-factor pattern: ”Closeness, Health, Spare time, Provision”. Seven domains were sizeable predictors of overall life satisfaction. In a complex manner socio-demographics were predictive of (gross levels) all LiSat-11 items. Main predictors were perceived health, immigrant status and educational level. </p><p>Generally, the vocational rehabilitees had low LiSat-11 levels except for the closeness items. They had relatively poor background resources (low “sense of coherence“ level) for successful coping. Whereas a positive rehabilitation outcome was accompanied by increases in several LiSat-11 aspects, only satisfaction with the vocational situation was clearly responsive. Three early predictors of outcome were identified: belief in vocational return, educational level and sense of coherence. </p><p><u>In summary</u>: Besides providing reference values for the LiSat-11 instrument, this dissertation demonstrates that different socio-demographic factors influence different areas of concern (domains) in 18- to 64-year-old Swedes. In turn, satisfaction derived from different areas heavily influences level of overall life satisfaction. Moreover, the vocational rehabilitees generally seemed to be predisposed to being poor copers, possibly a major background of low levels of many LiSat-11 aspects. The identified set of predictors of the outcome of vocational rehabilitation emphasizes a need for focusing on psycho-social aspects within vocational rehabilitation.</p>

<p>The overall aim of this thesis was to study knowledge, attitudes and experience of emergency contraceptive pills among women and providers.</p><p>Both quantitative and qualitative methods were used. Focus-group interviews were conducted with teenage-girls (I) and with women who had purchased ECP without prescription (IV). Self-administered waiting-room questionnaires were administered to women presenting for induced abortion in three large hospitals (II, III), and after the deregulation of ECP, a postal questionnaire was sent to pharmacy staff and nurse-midwives in three counties in mid-Sweden (V). </p><p>Overall, women showed high basic awareness of ECP although specific knowledge such as the level of effectiveness, time-frames and how the method works was lacking. Approval of the method was high and most women were positive to use the method if they needed. Contradictory views as to whether ECP undermines contraceptive behavior were expressed. As many as 43% of women requesting induced abortion had a history of one or more previous abortions. Among the abortion applicants, one out of five, 22%, had previously used ECP and 3% had used it to prevent the current pregnancy. Media and friends were the two most common sources of information on ECP. Half of the women, 52%, were positive to having ECP prescription-free. Those women who had purchased ECP in a pharmacy without prescription, appreciated this possibility, and the major benefits expressed were time saving aspects. No severe side-effects were reported. The women's experiences of interaction with pharmacy staff were both positive and negative. The importance of up-to-date information about ECP and the OTC-availability from the health care providers was emphasized. Both pharmacy staff and nurse-midwives had positive attitudes towards ECP and the OTC availability. Of pharmacy staff, 38% reported that they referred women to nurse-midwives/gynecologists for further counseling and follow-ups. The need for increased communication and collaboration between pharmacies and local family planning clinics was reported by both study groups with suggestions of regular meetings for information and discussions.</p><p>The results suggest that ECP is still underused and that more factual information is needed before the method is becoming a known, accepted and integrated back-up method to the existing family planning repertoire. Longitudinal research to assess the long-term effects of ECP is needed. </p>

<p>Neuroblastoma is a childhood cancer that originates from neuroblasts in the peripheral nervous system. Neuroblastoma show considerable heterogeneity with respect to location, responsiveness to treatment and prognosis. Since current therapy involves drugs with risk of serious side effects in the growing child, there is a clinical need for more effective and less toxic treatment strategies.</p><p>Angiogenesis, the formation of new blood vessels, is critical for tumor progression. Specific inhibition of tumor-induced angiogenesis should restrict growth of most solid tumors and thereby provide a new treatment strategy. The aim of this study was to investigate the effects of angiogenic inhibition in experimental neuroblastoma in mice.</p><p>We found that experimental neuroblastomas expressed the perhaps most potent angiogenic growth factor, VEGF-A, and that plasma VEGF-A levels correlated with tumor size. SU5416, a novel antagonist of VEGFR-1 and 2, reduced angiogenesis and tumor growth in our model. We also investigated the properties of SU11657, a new, orally available, synthetic small molecule multi-targeted tyrosine kinase inhibitor. SU11657, at a well-tolerated dose, was more potent than SU5416 in reducing tumor growth rate and angiogenesis, even in MYCN-amplified tumors. Chemotherapeutics can also inhibit angiogenesis, when administrated daily in a non-toxic dose. CHS 828, a new chemotherapeutic, given orally, alone induced complete neuroblastoma regression in 44 % of the animals. Furthermore, the bisphosphonate zoledronic acid, developed to reduce bone resorption, showed anti-tumor activity in our model. Zoledronic acid was more potent than the angiogenic inhibitor TNP-470. Thus bisphosphonates may have other beneficial properties in patients with cancer apart from preventing bone resorption.</p><p>In conclusion, SU5416, SU11657, CHS 828, and zoledronic acid represent new drugs with potent anti-tumor effects. Angiogenic inhibition as single therapy or in combination with chemotherapeutics may be beneficial in the treatment of rapidly growing and highly vascularized solid tumors of childhood such as neuroblastoma.</p>

<p>Neural stem cells are the precursors of neurons, astrocytes and oligodendrocytes. During neural development, the division of stem cells takes place close to the lumen of the neural tube, after which they migrate to their final positions within the central nervous system (CNS). Soluble factors, including growth factors, regulate neural stem cell proliferation, survival, migration and differentiation towards specific cell lineages. </p><p>This thesis describes the function of platelet-derived growth factor (PDGF) and stem cell factor (SCF) in neural stem cell regulation. PDGF was previously suggested to stimulate neuronal differentiation, but the mechanisms were not defined. This study shows that PDGF is a mitogen and a survival factor that expands a pool of immature cells from neural stem cells. The PDGF-treated cells can be stained by neuronal markers, but need further stimuli to continue their maturation. They can become either neurons or glia depending on the secondary instructive cues. Moreover, neural stem cells produce PDGF. Inhibition of this endogenous PDGF negatively affects the cell number in stem cell cultures. We find that SCF stimulates migration and supports the survival of neural stem cells, but that it has no effect on their proliferation or differentiation into neurons and glia. Intracellular signaling downstream from the receptors for PDGF and SCF includes activation of extracellular signal-regulated kinase (ERK). This investigation shows that active ERK is not needed for the differentiation of stem cells into neurons, at least not during early stages.</p><p>Neural stem cells have a future potential in the treatment of CNS disorders. To be able to use neural stem cells clinically we need to understand how their proliferation, differentiation, survival and migration are controlled. The results presented in this thesis increase our knowledge of how neural stem cells are regulated by growth factors.</p>

<p>Physicians are supposed to act as sick-listing experts and they possess a role as gate-keepers to the social insurance system. Earlier studies have demonstrated variation between physicians and physician categories regarding sick-listing practice. In addition to the patient's disease and its severity, a number of other factors may be expected to influence sick-listing practice. Most earlier studies have focused on the patient's disease and his or her work place as cause for sickness absence.</p><p>The aims of this study were to analyse variation of sick-listing practice between physician categories and the influence of physician characteristics on sick-listing practice, the influence of structure, organisation and remuneration of health care on physician sick-listing practice, the influence of local structural factors in the community, and the influence of a legislative change on physician sick-listing practice.</p><p>The study was conducted as a cross-sectional epidemiological study of 57563 doctors’ certificates for sickness absence, received by 28 local social insurance offices in eight Swedish counties, during four months in 1995 and two months in 1996.</p><p>Patient age, sex, and diagnostic group, issuing physician category, presence of a hospital in the municipality, municipality population size and county were all significantly and independently correlated to number of net days of sick-listing. Physician characteristics, such as age, sex and degree of specialisation were all associated with number of net days of sick-listing. Physicians working in general practice issued significantly shorter periods of sick-listing than the other physician categories. Reimbursement of general practice and participation in financial co-operation with social insurance were significantly correlated to length of sickness episode issued by general practitioners. A legislative change performed during the study period was associated with small effects in sick-listing practice.</p><p>In conclusion, a number of factors other than disease and disease severity and other patient and physician linked factors were found to influence the variation of sick-listing practice. It appears that the closer the influencing factor was to the place were the decision was taken, i.e., the patient-physician consultation, the higher the impact on the decision appeared to be.</p>

<p>The present work is analyzing the general biomechanical aspects of fixation techniques in the upper and lower cervical spine along with clinical implications.</p><p>The in vitro biomechanical properties of five different posterior atlanto-axial fixation techniques are compared. They provided for either a one, two or three-point fixation between atlas and axes. A new device, the C1 claw was biomechanically tested, which allow for fixation without the need for a structural bone graft. The three-point reconstructions indicated superior biomechanical properties compared to all others.</p><p>The new C1 claw device was clinically evaluated in a series of 26 patients treated with a posterior C1-C2 fusion. There were no clinical or radiological failures in the series, Twenty-one patients out of twenty-three with any length of follow up either showed a solidly healed fusion or a healed fracture. </p><p>Distractive flexion (DF) injuries in the lower cervical spine treated with anterior plate alone were analyzed with respect to healing rate and complications in a consecutive series of 36 patients. Results indicated that DF injury stage 1 and 2 according to Allen and Ferguson healed without complication, whereas DF injuries stage 3 had a high frequency of failure, needing an additional posterior fixation. </p><p>The in vitro biomechanical properties of four different fixation techniques for a distractive flexion injury stage 3 were analyzed. The result indicated that anterior plate alone for fixation of a DF injury stage 3 is insufficient supporting the clinical finding in the previous study.</p><p>Adjacent level motion was analyzed following a one segment fusion in the lower cervical spine. Motion was found to increase in adjacent levels possibly contributing to accelerated degeneration.</p>

<p>The blood vessels of the pancreatic islets are of crucial importance for oxygen and metabolite supply as well as dispersal of secreted hormones. In addition to this, endothelial cells have an important role in the revascularization process after islet transplantation. Previous studies have reported signs of poor engraftment of transplanted islets, presumably due to impaired revascularization. The aims of this thesis were to investigate the revascularization process of transplanted islets and to examine the role of islet endothelial cells. In this context, the lectin Bandeiraea simplicifolia was found to stain endothelium of both endogenous and transplanted pancreatic islets. By using this lectin we investigated the vascular density of both endogenous and islets transplanted syngeneically beneath the renal capsule, into the spleen or intraportally into the liver of normoglycemic C57BL/6 mice. One month post-transplantation, a time point when the grafts are assumed to be completely revascularized, the vascular density was decreased at all three implantation sites when compared to endogenous islets. Furthermore, most of the blood vessels were located in the graft connective tissue stroma. Similar results were obtained when islet transplant vascular density was determined six months post-transplantation and in cured diabetic animals after one month. In order to evaluate the function of intraportally transplanted islets, we developed a method to retrieve such islets. We treated the implantation organ (liver) first enzymatically (collagenase) and then mechanically, thereafter we could re-isolate the transplanted islets for further in vitro studies. The retrieved islets had a decreased insulin relase, insulin content and glucose oxidation rate when compared to non-transplanted control islets. To understand the role of islet endothelium in the revascularization of transplanted islets we performed angiogenesis GEArray studies on islet endothelial cells, from non-cultured, cultured and transplanted islets. We found that the islet endothelium expressed mRNA for both inhibitors and inducers of angiogenesis, and that this expression differed with time. The functional consequences of this remain to be determined. In summary, the results presented above provide a useful platform for future studies of the morphology and function of islet endothelial cells, especially with a view for elucidating changes induced by islet transplantation.</p>

<p>Cardiopulmonary bypass (CPB) is associated with inflammatory response and activation of coagulation. Heparin coating of the CPB circuit is shown to improve the biocompatibility of the surface. The biological effects of a new heparin surface, the Corline Heparin Surface (CHS), prepared according to a new principle, have been studied. </p><p>The CHS used during coronary artery bypass grafting with CPB in sixty patients prevented adhesion of cells to the extracorporeal device. The activation of inflammation, coagulation, and fibrinolysis was significantly reduced by the use of CHS. Both a reduced and an increased dose of systemic heparin in combination with the heparin-coated surface resulted in more activation of inflammation and coagulation. </p><p>Photoelectron spectroscopy studies of the molecular structure of the CHS demonstrated that a single layer of the heparin surface, equivalent to what was used in the <i>in vivo</i> studies, did not completely cover the substrate surface. Additional layer of immobilized heparin has resulted in a complete coverage. We examined the biological effects, i.e. activation of inflammation and coagulation, by CHS in one and two layers in an <i>in vitro</i>-study. The data from this study clearly demonstrated that a uniform surface coating of the CHS results in only minor activation of coagulation, inflammation and cell activation. </p><p>Monocytes do not normally express tissue factor (TF), initiator of the coagulation <i>in vivo</i>, but can be induced upon adhesion to artificial surfaces. TF is receptor for coagulation factor VIIa (FVIIa) and binding subsequently leads to formation of thrombin. Other biological effects beyond coagulation, as inflammation and angiogenesis, has recently been associated with the formation of TF·FVIIa. The TF∙FVIIa signal transduction induced an increased sensitivity to PDGF-BB-stimulated migration and an increased production of IL-8 and TNF-α in monocytes. These could be important mechanisms for continued recruitment of cells to sites of inflammation. </p>

<p>In the field of transplantation, the increasing deficit of human donors have lead to an interest in animals as an alternative source of organs and tissues. </p><p>Different <i>in vitro </i>systems and rodent models of xenotransplantation were used to examine the most significant barriers that have to be overcome, before isolated islets of Langerhans from pigs can be used as a cure for insulin-dependent diabetes mellitus in humans.</p><p>In clinical transplantation, islets are infused into the liver through the portal vein. During this procedure the islets are susceptible to harmful innate reactions triggered in blood. Adenoviral vectors generating transgenic expression of human complement regulatory proteins were evaluated in pig islets and shown to confer protection against acute complement-mediated damage. </p><p>Transplanted islets escaping this immediate destruction will be targets of a cellular immune response. Using a new mouse model of islet xenograft rejection, it was demonstrated that macrophages, effector cells in the rejection, were part of an MHC-restricted xenospecific immune response mediated by T cells. In a strain of knockout mice it was further shown that this process can proceed in the absence of an important signalling system, mediated by Toll-like receptors, between cells in innate and adaptive immunity. These findings illustrate some of the mechanistic differences compared to cellular islet allograft rejection which partly explain why immunosuppressive drugs used in clinical allotransplantation is not sufficient for preventing xenograft rejection. </p><p>Porcine endogenous retroviruses (PERV) remain a safety concern in xenotransplantation. Characterization of PERV in pig islets indicated that virus expression is low <i>in vitro </i>but increases during the immediate time period following transplantation. This suggests that antiviral therapies administered at the time of transplantation could be used for preventing the risk of PERV transmission after xenotransplantation.</p>