<p>There is very little data on physical and psychological long-term outcome after severe burn injury. The aim of the present thesis was to improve current instruments for assessment of these issues, to assess long-term outcome in a cohort of patients with burn injuries, and to explore the contribution of the individual factors of personality and coping on perceived outcome.</p><p>Patients treated at the Burn Unit, Uppsala University Hospital, between 1980 and 1995 were included on a consecutive basis if they were 18 years of age or older at follow-up, had burn injuries of ten percent or more, or hospitalization times of seven days or more. A total of 350 patients fulfilled these inclusion criteria.</p><p>A factor analytic approach was used to derive a 40-item instrument called the Burn Specific Health Scale-Brief (BSHS-B), resulting in nine well-defined domains. Most burn patients reported a very good perceived outcome but a subgroup reported problems years after injury. On a group level most problems were related to Heat Sensitivity, Work and Body Image. The depth of injury, gender, marital status and living conditions were all related to outcome. Neurotic personality traits were related to perceived health, and were not confined only to psychological aspects of life but also included physical aspects. A 33-item burn-specific coping scale, the Coping with Burns Questionnaire (CBQ), with six clearly separated domains with acceptable internal consistencies was developed. Coping strategies were strongly related to outcome in the subgroup of patients reporting most problems in perceived health, and coping contributed more to psychosocial than physical health. Avoidant coping and Emotional support seeking had independent effects on outcome.</p><p>The observation that Neuroticism and Avoidant coping strategies are related to bad outcome after severe burn injury indicates that patients with such characteristics should be given special attention during rehabilitation.</p>

<p>Sweden has one of the highest incidences of osteoporotic fractures in the world. A more sedentary lifestyle is one of several proposed reasons for the increase in osteoporosis seen in the developed countries. The aim of this thesis was primarily to study the influence of muscle strength, and body composition, on bone mineral density, BMD, in young adults. The second aim was to evaluate the possible influence of estrogen on muscle strength in women.</p><p>A population-based study of 113 subjects (53 men and 60 women) aged 22-85 showed associations for premenopausal, but not postmenopausal women, between isometric quadriceps muscle strength and BMD in the total body, lumbar spine, and femoral neck. In men there was only an association between muscle strength and BMD in the total body. Another population-based study of 125 randomly selected young adults (64 women and 61 men) showed that total body BMD, TBMD, is influenced by isokinetic knee flexion and extension strength in women but not in men where body composition influenced TBMD. In 159 randomly selected young adult women (20-39 years) knee flexion and extension strength influenced not only TBMD but also total hip BMD, and heel BMD. However, lean body mass and body weight were better predictors for BMD at these skeletal sites. An extension of this study involving 335 women again demonstrated that lean body mass is the best predictor of BMD. This study also showed that Uppsala women aged 20-39 years have a BMD that is approximately 0.1-1.2 SD (2-12 %) above international/national references. In addition marked variations in BMD T-scores between various skeletal sites were noted. </p><p><i>In Conclusion: </i>The association between muscle strength and BMD is evident in women in their early twenties but with age lean body mass and body weight becomes better predictors for BMD. In men lean body mass and body composition but not muscle strength predicted BMD. Hormone replacement therapy does not influence muscle strength and there is no association between allelic variations in the estrogen receptor alpha and muscle strength in women.</p>

<p>In this thesis, occurrence of heterotopic ossification (HO) following total hip arthroplasty (THA) was studied. Preventive effects and complications with non-steroidal anti-inflammatory drugs (NSAIDs) were analyzed. Experimental investigations on bone formation were employed to gain insight to the mechanism of NSAIDs action on bone.</p><p>(I). Fifty-six patients with bilateral THAs were analyzed. We found a strong correlation between HO on the two sides. Incidence and grade of HO were higher in men than in women.</p><p>(II). Sixty-nine patients with bilateral THAs who had been treated with NSAIDs after one or both THAs were analyzed for HO. Widespread HO occurred in untreated THAs, but in none of the treated THAs.</p><p>(III). A consecutive series of THAs were analyzed for HO. No widespread HO occurred in patients treated with NSAIDs for 21 days. In contrast, widespread HO occurred in 23% of patients not treated.</p><p>(IV). A randomized, double-blind, prospective study on 144 patients was performed to determine the efficacy and minimum treatment time with Ibuprofen for prophylaxis of HO after THA. Treatment with Ibuprofen was effective for preventing HO and a treatment time of 8 days was sufficient.</p><p>(V). A ten-year follow-up examination was performed on the patients from study IV. Thirteen patients had been revised. All but one belonged to groups treated with Ibuprofen. However, the prosthetic survival time was not statistically different for patients treated with NSAIDs compared to the control group. Eighty-four more patients underwent radiographic examination10 years after THA. Nine loose prostheses were found. These were equally distributed between NSAIDs-treated and non-treated THAs. When combining complications (revisions and radiographic loosening) no significant effects could be verified.</p><p>(VI). Experimental induction of heterotopic new bone with demineralized allogeneic bone matrix (DABM) and with bone autografts, was used in rats to study effects of NSAIDs on new bone formation. Indomethacin inhibited net bone formation in DABMs and in orthotopic fractured bone. In contrast, a net mineral loss occurred in autografts, but neither mineral content nor ⁴⁵Ca incorporation was affected by Indomethacin treatment. The amount of bone formed per mg implanted DABM was linearly correlated to implant size.</p>

<p>The aims of this project were to investigate the impact of perioperative myocardial damage on morbidity and mortality after coronary artery bypass grafting (CABG), to determine whether biochemical marker levels after CABG correlate to perioperative myocardial infarct size, and to assess the long-term morbidity after CABG, in particular to determine whether women do worse.</p><p>The studies were conducted in patients who had undergone isolated, primary CABG. The correlation of postoperative cardiac marker levels to early and late survival was evaluated in 4,911 consecutive patients; this showed that elevated cardiac markers implied a highly increased risk of both early cardiac death and late death. Hospital readmission for any cause and effect of gender on the readmission rate were analysed in 7,493 patients; it was found that the risk of readmission was higher in women than in men, because of greater co-morbidity and higher age. In the same patient cohort, it was clearly demonstrated that perioperative myocardial damage increased the risk of heart failure independently, and that late mortality was greatly increased in patients readmitted for heart failure. Finally, in a prospective, clinical trial, creatine kinase MB (CK-MB) and troponin I and T levels were found to correlate to infarction mass, as quantified by magnetic resonance imaging postoperatively. The findings strongly suggested that CK-MB above five times the upper normal limit was the result of perioperative myocardial infarction.</p><p>In conclusion, perioperative myocardial damage is an important adverse event with a highly negative effect on early and late survival after CABG, and also entails an increased risk of subsequent heart failure, which markedly impairs long-term survival. Gender differences may be explained by patient characteristics and risk factors and not by female sex per se. Increases in biochemical markers after CABG correspond to the amount of perioperatively infarcted myocardium. </p>

<p>Ischemic neuronal injury continues to be a major delimiting factor in achieving successful clinical outcomesafter resuscitation from cardiac arrest. In this thesis, a pig model of cardiopulmonary resuscitation (CPR) wasused to address the effects of different interventions on cerebral blood flow and oxygenation during CPR and theinitial postresuscitation period. A novel technique is presented to quantify the reperfusion oxidative injury.</p><p>Maximization of cerebral blood flow during CPR by open-chest cardiac compression, continuous aortic balloon occlusion, and intra-aortic administration of hypertonic saline-dextran (HSD) did not ameliorate thepostresuscitation hypoperfusion or improve the cerebral oxygen extraction ratio or tissue pH. These findings disaffirm earlier studies suggesting that conserving brain viability after global ischemia is mostly a question ofmaintaining high perfusion pressure.</p><p>Despite an increased cerebral perfusion pressure during CPR, intra-aortic administered epinephrineabove the aortic balloon occlusion did not further improve cerebral blood flow and oxygenation. This findingmay indicate adverse effects of epinephrine on cerebral vascular beds, possibly induced by a relatively highconcentration of epinephrine when administered above the site for aortic balloon occlusion.</p><p>The IV administration of equipotent doses of epinephrine or vasopressin during CPR resulted incomparable hemodynamic changes. The peak increase in cerebral cortical blood flow, however, was reachedapproximately 30 sec later by vasopressin. Furthermore, the second bolus of vasopressin during CPR did notaugment cerebral perfusion, whereas epinephrine did. Consequently, reports suggesting that vasopressin issuperior to epinephrine with respect to its effects on central hemodynamics and vital organ blood flow may bebiased by the pharmacodynamic differences between the drugs, depending on the time point at which blood flowmeasurements are performed.</p><p>In comparison with IV vasopressin, vasopressin administered above the aortic balloon occlusion resulted in a significant increase in cerebral perfusion pressure during CPR, but not after restoration of spontaneous circulation (ROSC). Cerebral cortical blood flow was, however, not improved <i>during</i> CPR, whereas a significant increase was recorded <i>after</i> ROSC. Relatively higher concentrations of vasopressin above the sitefor intra-aortic balloon occlusion may, therefore, predominantly induce cerebral cortical vasoconstriction duringCPR but induce vasodilatation after ROSC.</p><p>Assessment of oxidative stress or inflammation have been extremely difficult to attain. In our pig model of resuscitation, an association wasobserved between the duration of cardiac arrest and jugular bulb levels of 8-iso-PGF_2α, a major isoprostane and a novel index of oxidative injury. 8-iso-PGF_2α, and the prostaglandin 15-K-DH-PGF_2α, increased within 5 min after ROSC and remained so up to 2 h, indicating the interval of time during which cerebral reperfusion oxidative injury and inflammatory response may occur and are potentially preventable.</p>

<p>The purpose of this thesis was to develop novel ways to study tinnitus, to investigate the course of tinnitus, and to study the effects of cognitive-behaviour therapy on tinnitus related distress. Data from 377 tinnitus patients were collected.</p><p>A group of 216 patients completed audiological measures and were assessed in a structured interview. The Klockhoff and Lindblom's grading system was used and its inter-rater reliability assessed in a subsample showing a high degree of correspondence. A discriminant analysis showed that a substantial proportion of patients could be correctly classified into grade II or III, by measures of pitch, minimal masking level of tinnitus, avoidance of situations because of tinnitus, and tolerance in relation to onset.</p><p>Using tests developed in cognitive psychology, it was found that tinnitus patients had impaired performance. There was no evidence for an attentional bias towards tinnitus related words using a computerized emotional Stroop task, but masking sounds of an "on-and-off" character were more disruptive than constant masking when patients performed the digit-symbol test. It is suggested that tinnitus distress may be increased by the 'changing-state' character of the tinnitus signal, or alternatively by intermittent masking sounds.</p><p>In a case-study a patient received an i.v. injection of lidocaine while Positron Emission Tomograpy was conducted. The brain activity associated with tinnitus included the left primary, secondary and integrative auditory brain areas, as well as right paralimbic areas related to negative feelings. The precuneus (Brodmann area 7) might be a brain area involved in the aversiveness associated with tinnitus.</p><p>Using a tinnitus questionnaire as the dependent measure it was found that tinnitus maskability at admission predicted distress at follow-up for an average of five years following admission. Some improvement in tinnitus occurred over time, but this was more evident in patients who had received a cognitive-behavioural treatment program.</p><p>The effect of an Internet based cognitive-behavioural self-help treatment program for tinnitus was investigated showing a high dropout rate, but with positive results in that the treated patients improved.</p>

<p>Hip fractures are the most serious consequence of osteoporosis, and are one important cause of morbidity and mortality among the elderly. Prophylactic treatment for hip fractures are now available. Early detection of individuals with increased risk for hip fractures is therefor of great interest. A subset of non-institutionalised patients with a first hip fracture (cases;n=l18) and controls (n=263), aged 65-85 years, underwent dual X-ray absorptiometry (DXA) of the femoral neck, quantitative ultrasound (QUS) of the heel and phalanges and radiographic absorptiometry (RA) of the phalanges. The entire cohort was followed for approximately four years or to death. In women, DXA of the proximal femur and QUS of the heel showed a high predictive value for an incident first hip fracture, adjusted odds ratio (OR) 3.6 (95% confidence interval (CI) 2.4-5.5) and 3.4 (95%CI 2.2-5.0) respectively. The association was even stronger in men, but only for DXA of the proximal femu,r with an adjusted OR of4.8 (95%CI 2.3-9.9). Bone densitometry at non-weight-bearing sites, QUS and RA of the phalanges did not discriminate female cases from controls, but proved capable of separating male cases from controls. The risk of death was higher in cases than in controls, with a multivariate rate ratio (RR) of 3.4 (95%CI 1.7-7.0). There was no significant association between bone density and mortality. </p><p>Nursing home residents underwent QUS of the heel and phalanges. Almost all of the female residents and 51% of the male residents were, if the WHO-criterion for osteoporosis was applied, osteoporotic as assessed by heel and finger QUS. The QUS values were approximately 1.5 SD lower than expected for age and gender. </p><p>In this randomised controlled intervention study we evaluated the effect of external hip protectors in nursing home residents; 302 residents were allocated to wear such protectors and 442 were controls. External hip protectors were found to be effective in preventing hip fractures in nursing home residents, with an adjusted relative risk for hip fracture of 0.33 (CI 0.11 - 1.00). </p>

<p>A more global analysis of the outcome of heart valve surgery is desirable to reflect the actual benefit for the patient. This thesis focuses on the preoperative assessment of the patient, and the outcome after surgery with regard to operative mortality, long-term survival, valve-related complications, and quality of life. </p><p>Magnetic resonance imaging and echocardiography were comparable in assessing severe mitral regurgitation, but did not agree in measuring regurgitant fraction. Natriuretic peptides correlated well to regurgitant fraction on magnetic resonance imaging and to PISA and vena contracta on echocardiography. </p><p>The risk of death, myocardial injury and postoperative heart failure after valve surgery has decreased over the last decade whereas the proportion older patients has increased. </p><p>Survival is reduced after mitral valve replacement in patients with severe symptoms whereas patients with less symptoms have excellent survival. Older patients are more often severly symptomatic at the time of mitral valve surgery. </p><p>Event-free survival is superior in patients with a mechanical prosthesis, but not influenced by valve type in older patients. A mechanical prosthesis is associated with a higher risk of bleeding < 5 years from surgery, especially in older patients; and a bioprosthesis is associated with a higher risk of thromboembolism > 5 years from surgery. Ageing with a mechanical prosthesis implied an increased risk for an adverse event, this was not true for bioprostheses. </p><p>Quality of life after complicated heart valve surgery resulted in reduced physical health but equal mental health compared to uncomplicated controls.</p>

<p>In hyperparathyroidism (HPT) raised serum concentrations of ionized calcium is caused by increased secretion of parathyroid hormone (PTH) by parathyroid tumors. Active vitamin D, 1α,25-dihydroxyvitamin D₃, is known to suppress PTH secretion and to reduce proliferation of parathyroid tumor cells.</p><p>The aim of this thesis was to examine expression of vitamin D hydroxylating enzymes, regulating the activation and inactivation of vitamin D and to study effects of vitamin D analogues, in parathyroid tumors and breast cancer.</p><p>The vitamin D activating enzyme, CYP27B1/25-hydroxyvitamin D₃ 1α-hydroxylase (1α-hydroxylase) and the vitamin D inactivating enzyme CYP24A1/25-hydroxyvitamin D₃ 24-hydroxylase (24-hydroxylase) were expressed in parathyroid tumors and breast cancer. </p><p>The parathyroid tumors had raised expression levels of 1α-hydroxylase and reduced levels of 24-hydroxylase in comparison to normal parathyroid glands, indicating ability for endogenous activation of vitamin D. The expression of 1α-hydroxylase may be of therapeutic advantage for local activation of non-1α-hydroxylated vitamin D analogues in tumor cells, thereby reducing unwanted hypercalcemic effects. </p><p>Three of five selected low calcemic vitamin D analogues had as efficient PTH suppressing effect, in bovine parathyroid cells, as three vitamin D analogues used clinically for treatment of secondary HPT.</p><p>The non-1α-hydroxylated vitamin D analogue EB1285 showed antiproliferative and PTH suppressive effects as well as transcriptional activity in parathyroid and breast tumor cells, respectively.</p><p>Ketoconazole, an inhibitor of vitamin D hydroxylating enzymes, suppressed PTH secretion and potentiated the effect of vitamin D analogues. Combined treatment with vitamin D analogues and specific 24-hydroxylase inhibitors may be important for future therapy. </p>

<p>In two prospective, clinical studies the stability of implants and prosthetic constructions were evaluated after three years of loading. In the first study, the implant and the bridge stability of 39 patients with 1-stage bone grafts, were compared to a reference-group of 37 patients who did not need bone grafts. In the second study, 40 patients were randomised to have either 1-stage sinus inlay bloc grafts or 2-stage sinus inlay particulated grafts. </p><p>Implant success in Paper 1, was 75.3% in the study group and 93.1% in the reference group. In Paper 2 implant survival in the 1-stage group was 77.7% and 86.5% in the 2-stage group. Bruxism and post-operative complications, such as unexpected pain, dehiscence and infection were found to be associated with the later loss of implants. </p><p>The volumes of onlay block and inlay particulated bone grafts, after 6 months as evaluated by computed tomography showed the decrease of 49.5% and 47% respectively, although there was a wide range in both groups. </p><p>Using of cutting torque measurements during the placement of implants in grafted and non-grafted jaw bone, showed a significant inverse correlation to the commonly used clinical estimation of jaw bone quality, acc. to Lekholm & Zarb. Significantly lower torque values were recorded in grafted regions when compared to non-grafted. </p><p>It was shown that autogenous bone grafts and implants to the edentulous maxilla, after early high failure rates, showed stable and predictable results after three years. Bruxism was found to be significantly associated with implant failures and initially reduced biomechanical properties was seen in the grafted bone. </p>