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. 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. In Conclusion: 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.

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. (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. (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. (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. (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. (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. (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.

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. 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. 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.

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. 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. 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. 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. 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. 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. 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.

Background and aims: Unrecognized intestinal mucosal ischemia in severely ill patients may trigger development of multiple organ failure. Such ischemia can be evaluated by intraluminal tonometry reflecting mucosal PCO2 and intramucosal pH (pHi). The aims were to develop an apparatus for continuous saline tonometry (CST), to analyse circulatory control mechanisms during intestinal hypoperfusion and to evaluate the effect of dopexamine on intestinal circulation. Methods: A modified standard tonometry catheter was integrated in a closed system with circulating saline. By measuring saline PCO2 in a measurement unit pHi could be calculated. This novel system was tested in vitro and in vivo. In a porcine study, CST was evaluated against standard saline tonometry, tissue oxygenation (PO2 TISSUE), jejunal mucosal perfusion (laser doppler flowmetry; LDF) and mesenteric net lactate flux during graded reductions of superior mesenteric arterial pressure (PSMA). Local control mechanisms for maintenance of intestinal oxygenation were analysed. Effects of dopexamine on the intestinal vascular bed were explored. Mucosal lactate production was assessed by microdialysis. Results: CST measured accurate PCO2 values and changes in pHi during restricted intestinal circulation and at reperfusion. Local control mechanisms were insufficient at a PSMA of 30 mmHg, pHi was reduced to 7.10 and intestinal net lactate production was demonstrated. Absence of anaerobic intestinal metabolism was verified at PSMA ≥ 50 mmHg, pHi ≥ 7.22 and a PCO2 gap ≤ 15.8 mmHg. Dopexamine induced negative regional metabolic effects at the lowest PSMA, as expressed by decreased PO2 TISSUE and pHi, increased PCO2 gap and intestinal net lactate production. Conclusions: CST reflected changes in pHi, induced by intestinal hypoperfusion and at reperfusion. Levels of PSMA, pHi and PCO2 gap as indicators of aerobic conditions were defined. Dopexamine induced a decrease of PO2 TISSUE and pHi as well as an increase in lactate flux at the lowest PSMA level.

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. 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. 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. 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. 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. Quality of life after complicated heart valve surgery resulted in reduced physical health but equal mental health compared to uncomplicated controls.

Bone formation and bone healing were studied in the mandible, tibia and skull bones in adult, healthy and estrogen deficient rabbits implanted with different bone substitutes. In the first study an evaluation of the differences in bone regeneration in and around solid (Alveograf *) and porous hydroxyapatite (Interpore 200*) was undertaken. The implant material was placed into experimentally made bone defects and in half of the defects hydroxyapatite was mixed with a fibrin sealant (Tisseel *). The material alone or mixed with Tisseel was also placed subperiostally in the mandible. The observation time was six month. No difference in bone regeneration was found between solid or porous hydroxyapatite granulas and the addition of Tisseel* did not seem to disturb the bone healing process. The implant material placed subperiostally did not induce bone formation nor did it provoke any bone resorption. The addition of Tisseel made the implant material much easier to handle and retain in the tissue during surgery. Bone healing around hydroxyapatite implants was also evaluated in the second study. Experimental cavities in the mandible and tibia were filled with hydroxyapatite in granules or blocks (Interpore 200*) but now with or without autolyzed, antigen-extracted, allogeneic bone (AAA). Also in this study Tisseel* was used to facilitate the handling of the material. All cavities implanted with AAA-bone, regardless of the combination with hydroxyapatite or Tisseel, demonstrated excessive bone formation resembling exostosis formation. Thus, hydroxyapatite, both as granules and blocks, can be successfully combined with AAA bone utilizing the bone inductive capacity of AAA bone. The same model was used to study the healing in ovariectomized animals in the third study. Bone cavities were implanted with or without AAA bone and left to heal. The results indicate that the osteoinductive capacity of AAA bone is in operation also in animals deprived of a normal estrogen production. The effect of using AAA bone prior to implant insertion was studied in paper four. The bone-implant contact was significant higher when AAA bone had been used. The implant stability did not seem to be affected. In paper five defects were made in skull and tibial bone in estrogen deficient animals. The deficiency of estrogen was confirmed through blood analysis, the decrease in the weight of uterus and bone mineral density. The whole body scanning with DEXA showed that the ovariectomized animals developed osteopenia. Various degree of bone formation was seen in the defects due to the influence of the bone inductive substance AAA bone. The studies indicate that a conductive material like hydroxyapatite in granules or blocks could be useful in oral reconstructive surgery. The combination with AAA bone enhanced the bone formation in calvarial and tibial bone in healthy and estrogen deficient animals. Tisseel* could be used to facilitate handling and retention of the material in the intended position during the healing process without negative effects.

<p>Bone formation and bone healing were studied in the mandible, tibia and skull bones in adult, healthy and estrogen deficient rabbits implanted with different bone substitutes. </p><p>In the first study an evaluation of the differences in bone regeneration in and around solid (Alveograf *) and porous hydroxyapatite (Interpore 200*) was undertaken. The implant material was placed into experimentally made bone defects and in half of the defects hydroxyapatite was mixed with a fibrin sealant (Tisseel *). The material alone or mixed with Tisseel was also placed subperiostally in the mandible. The observation time was six month. No difference in bone regeneration was found between solid or porous hydroxyapatite granulas and the addition of Tisseel* did not seem to disturb the bone healing process. The implant material placed subperiostally did not induce bone formation nor did it provoke any bone resorption. The addition of Tisseel made the implant material much easier to handle and retain in the tissue during surgery.</p><p>Bone healing around hydroxyapatite implants was also evaluated in the second study. Experimental cavities in the mandible and tibia were filled with hydroxyapatite in granules or blocks (Interpore 200*) but now with or without autolyzed, antigen-extracted, allogeneic bone (AAA). Also in this study Tisseel* was used to facilitate the handling of the material. All cavities implanted with AAA-bone, regardless of the combination with hydroxyapatite or Tisseel, demonstrated excessive bone formation resembling exostosis formation. Thus, hydroxyapatite, both as granules and blocks, can be successfully combined with AAA bone utilizing the bone inductive capacity of AAA bone.</p><p>The same model was used to study the healing in ovariectomized animals in the third study. Bone cavities were implanted with or without AAA bone and left to heal. The results indicate that the osteoinductive capacity of AAA bone is in operation also in animals deprived of a normal estrogen production.</p><p>The effect of using AAA bone prior to implant insertion was studied in paper four. The bone-implant contact was significant higher when AAA bone had been used. The implant stability did not seem to be affected.</p><p>In paper five defects were made in skull and tibial bone in estrogen deficient animals. The deficiency of estrogen was confirmed through blood analysis, the decrease in the weight of uterus and bone mineral density. The whole body scanning with DEXA showed that the ovariectomized animals developed osteopenia. Various degree of bone formation was seen in the defects due to the influence of the bone inductive substance AAA bone. </p><p>The studies indicate that a conductive material like hydroxyapatite in granules or blocks could be useful in oral reconstructive surgery. The combination with AAA bone enhanced the bone formation in calvarial and tibial bone in healthy and estrogen deficient animals. Tisseel* could be used to facilitate handling and retention of the material in the intended position during the healing process without negative effects. </p>

<p>The aim was to study pathophysiological mechanisms and risk factors for developing atrial fibrillation (AF) after coronary artery bypass grafting (CABG), and the effect of thoracic epidural anaesthesia (TEA).</p><p>The study comprised 141 patients undergoing CABG, including 45 patients randomised for TEA intra- and postoperatively. All patients underwent 24-hour Holter monitoring pre- and postoperatively for the analysis of arrhythmias and heart rate variability (HRV). Catecholamines and neuropeptides (reflecting sympathetic and parasympathetic activity), atrial peptides and echocardiographically assessed atrial arias were obtained pre- and postoperatively.</p><p>Logistic regression analysis identified body mass index (BMI), maximum supraventricular beats (SPB) per minute, and total amount of cardioplegia as independent predictors of postoperative AF. Patients developing AF showed limited diurnal variation of HRV preoperatively. All HRV parameters decreased significantly in all patients postoperatively. The significant postoperative increase in atrial areas and atrial peptides did not differ between patients developing AF and those who did not. TEA had no effect on the incidence of postoperative AF, but resulted in lower heart rate, less increase in adrenaline levels, and decreased neuropeptide levels (reflecting sympathetic and parasympathetic activity). AF was initiated by an SPB in 72.4% of non-TEA and 100% of TEA treated patients, whereas changes in heart rate only, before onset, were seen in 17.2% non-TEA patients.</p><p>The observed risk factors, SPB and cardioplegia, may both induce electrophysiological changes known to increase the susceptibility to AF. The observed postoperative atrial dilatation and autonomic imbalance, indicated by HRV and neuropeptide levels, may further favour the development of AF. The observation that a majority of postoperative AF was initiated by a premature atrial contraction supports our hypothesis that latent atrial foci may be a major trigger mechanism of postoperative AF.</p>

<p>Live donor nephrectomy (LDN) is a unique surgical challenge where surgery is performed on healthy individuals. It is of great importance to keep the morbidity of donors as low as possible, as well as harvesting a kidney in optimal condition. Lowering morbidity is the motive for introducing the endoscopic technique in LDN. Oliguria and impaired kidney function can, however, be seen during pneumoperitoneum and endoscopic LDN have been criticized for not yet being proven safe enough.</p><p>The aims of this study were to investigate the changes in renal function during elevated intraabdominal pressure (IAP) in donors and rats and to evaluate donor morbidity and safety of the new endoscopic techniques compared to the open LDN.</p><p>In two studies, a rat model was used. It was found that elevation of IAP diminished glomerular filtration rate (GFR). Cardiac output (CO) and renal blood flow decreased as well. Elevation of IAP activates the renin system and aldosterone was increased. Acute angiotensin II receptor 1 blockade (candesartan) treatment lowered blood pressure significantly and impaired renal function during elevated IAP. Volume expansion prior to, and during, pneumoperitoneum reduces the deleterious effects on renal function.</p><p>Three studies on kidney live donors show that traditional laparoscopic surgery (TLS) takes longer time to perform than open LDN. Hand-assistance facilitates the operation and increases the safety margin as well as shortens the operation by 27% compared to TLS. Evaluation of a hand-assisted retroperitoneoscopy (HARS), performed for the first time ever in Uppsala 2001, show that the operation is short and safe, the donors experience little pain and the renal function is favourable compared to open surgery, TLS and hand-assisted transperitoneal laparoscopic approaches.</p><p>In conclusion, the results indicate that elevated IAP decreases GFR due to decreased CO and activation of the RAAS, which can be avoided with adequate hydration. Endoscopy can be facilitated if hand-assistance is applied and in particular hand-assisted retroperitoneoscopic nephrectomy shows advantages for the donor.</p>