<p>Only 12% of the patients died at home. When the period between diagnosis and death was less than one month, every patient died in an institution. Younger patients, married</p><p>patients, and those living within the 40 km radius of the hospital utilized more hospital days. The "length of terminal hospitalisation" and the "proportion of days at home/ total inclusion days" seemed to be feasible outcome varibles when evaluating a palliative support service. The hospital-based palliative support service in this study defrayed its own costs due to a median saving of 10 hospital days/patient, compared with matched historical controls.</p><p>A 19-item quality of life questionnaire (AQEL) was developed which evidenced good signs of reliability and validity. The item most closely correlated to global quality of life was the sense of meaningfulness. This was true for both patients and their spouses. Patients´ levels of pain and anxiety did not increase at the end of life. In this study we could not find convincing evidence for an additive analgesic effect of paracetamol in morphine therapy of pain in cancer patients.</p>

<p>Pancreatic endocrine tumors (PETs) occur sporadically or in the familial multiple endocrine neoplasia type 1 (MEN1) syndrome, whereas midgut carcinoids are nonfamilial, malignant endocrine tumors of the intestine. For these tumor entities morphological criteria are of limited use for prognostic prediction and selection of treatment. Genetic characterization may give additional information of clinical use and reveal pathways involved in tumor development.</p><p>Molecular genetic alterations in sporadic and MEN1-associated PETs and midgut carcinoids were studied with LOH and mutational analysis. In addition, immunohistochemistry was used to clarify gene expression. Detected genetic aberrations were correlated to the disease course of individual patients.</p><p>Somatic mutations of the<i> MEN1</i> gene at chromosome <i>11q13</i> were detected in 1/3 of sporadic PETs<i>. </i>Moreover, LOH was found in 70% of the lesions. All tumors with somatic <i>MEN1</i> mutations displayed loss of the remaining allele showing that the <i>MEN1</i> gene is involved in development of sporadic PETs.</p><p> Sporadic and MEN1 PETs were analyzed for LOH at <i>3p,</i> <i>11q13</i> and <i>18q</i>. A relation of LOH at <i>11q13</i> and <i>3p</i> to malignancy was found for the sporadic tumors. None of the benign tumors (all of them insulinomas) had allelic loss at <i>3p</i> or <i>11q13</i>, versus 92 % (p<0.01) of the malignant tumors (including malignant insulinomas). 1/4 of both sporadic and MEN1 lesions displayed LOH at <i>18q</i>, without altered <i>Smad4/DPC4</i>.</p><p>Genome-wide LOH screening of MEN1 PETs revealed multiple allelic deletions without general correlation to tumor size or malignancy. All tumors displayed LOH at the <i>MEN1 </i>locus, and 30% on chromosomes 3, 6, 8, 10, 18 and 21. Intratumoral heterogeneity was revealed, with chromosome 6 and 11 deletions in most tumor cells. Chromosome 6 deletions were mainly found in lesions from patients with malignant features. </p><p>A similar genome-wide LOH screening was performed on midgut carcinoids. Deletions at chromosome <i>18q</i> were found in 88% of the tumors indicating a potential tumor suppressor locus.</p>

Only 12% of the patients died at home. When the period between diagnosis and death was less than one month, every patient died in an institution. Younger patients, married patients, and those living within the 40 km radius of the hospital utilized more hospital days. The "length of terminal hospitalisation" and the "proportion of days at home/ total inclusion days" seemed to be feasible outcome varibles when evaluating a palliative support service. The hospital-based palliative support service in this study defrayed its own costs due to a median saving of 10 hospital days/patient, compared with matched historical controls. A 19-item quality of life questionnaire (AQEL) was developed which evidenced good signs of reliability and validity. The item most closely correlated to global quality of life was the sense of meaningfulness. This was true for both patients and their spouses. Patients´ levels of pain and anxiety did not increase at the end of life. In this study we could not find convincing evidence for an additive analgesic effect of paracetamol in morphine therapy of pain in cancer patients.

Pancreatic endocrine tumors (PETs) occur sporadically or in the familial multiple endocrine neoplasia type 1 (MEN1) syndrome, whereas midgut carcinoids are nonfamilial, malignant endocrine tumors of the intestine. For these tumor entities morphological criteria are of limited use for prognostic prediction and selection of treatment. Genetic characterization may give additional information of clinical use and reveal pathways involved in tumor development. Molecular genetic alterations in sporadic and MEN1-associated PETs and midgut carcinoids were studied with LOH and mutational analysis. In addition, immunohistochemistry was used to clarify gene expression. Detected genetic aberrations were correlated to the disease course of individual patients. Somatic mutations of the MEN1 gene at chromosome 11q13 were detected in 1/3 of sporadic PETs. Moreover, LOH was found in 70% of the lesions. All tumors with somatic MEN1 mutations displayed loss of the remaining allele showing that the MEN1 gene is involved in development of sporadic PETs. Sporadic and MEN1 PETs were analyzed for LOH at 3p, 11q13 and 18q. A relation of LOH at 11q13 and 3p to malignancy was found for the sporadic tumors. None of the benign tumors (all of them insulinomas) had allelic loss at 3p or 11q13, versus 92 % (p&lt;0.01) of the malignant tumors (including malignant insulinomas). 1/4 of both sporadic and MEN1 lesions displayed LOH at 18q, without altered Smad4/DPC4. Genome-wide LOH screening of MEN1 PETs revealed multiple allelic deletions without general correlation to tumor size or malignancy. All tumors displayed LOH at the MEN1 locus, and 30% on chromosomes 3, 6, 8, 10, 18 and 21. Intratumoral heterogeneity was revealed, with chromosome 6 and 11 deletions in most tumor cells. Chromosome 6 deletions were mainly found in lesions from patients with malignant features. A similar genome-wide LOH screening was performed on midgut carcinoids. Deletions at chromosome 18q were found in 88% of the tumors indicating a potential tumor suppressor locus.

Loosening of implants is a frequent complication in orthopaedic surgery. The aim of this thesis was to evaluate hydroxyapatite coating of pedicle screws with mechanical and histological methods and to correlate the results with the radiological findings. Hydroxyapatite (HA) coating of pedicle screws was investigated in experimental studies in sheep. Nine sheep were operated on with destabilising laminectomies at L2-L3 and L4-L5 and stabilised with pedicle screw instrumentations, where HA coated and uncoated screws were used in a randomised fashion. After both 6 and 12 weeks of implantation, the HA coated screws demonstrated a higher bone-to-implant contact and a higher amount of bone in the area close to the screw. The pull-out resistance, stiffness and total energy to failure was higher for the HA coated screws after 12 weeks of implantation. HA coating of pedicle screws was examined in two clinical studies. In the first series, the patients were stabilised with pedicle screw instrumentations, where HA coated screws were used in either the upper or lower instrumented level in a randomised fashion. After 10-22 months of implantation, the extraction torque was markedly higher for the HA coated screws. In the second series, instrumentations with uncoated, partly HA coated or fully HA coated screws were used. After 11-16 months implantation, the extraction torques were recorded. There were significant differences between all three groups, with the lowest extraction torques for the uncoated screws and the highest torques for the fully HA coated screws. The frequency of radiolucent zones surrounding the screws was higher for the uncoated screws than for the HA coated screws. Radiographs from both experimental and clinical studies were examined. Screws demonstrating radiolucent zones were compared to screws without zones with respect to pull-out resistance, extraction torque, bone-to-implant contact and amount of bone surrounding the screws. All these variables demonstrated higher values for the screws without radiolucent zones. The frequency of radiolucent zones surrounding uncoated screws in the clinical study was 53%. Conclusions: Radiolucent zones are good predictors of screw loosening. The frequency of radiolucent zones is higher than previously described. Hydroxyapatite coating improves the purchase of pedicle screws and reduces the frequency of screw loosening.

A large amount of non-protein nitrogen, in the form of urea and ammonium, is present in human breastmilk; however its physiological role in the infant is as yet not fully understood. It has been hypothesized that an insufficient enteric metabolism of urea could play a role in the sudden infant death syndrome (SIDS). This thesis was undertaken to study the enteric metabolism of non- protein nitrogen in healthy infants, in comparison with those who had succumbed to SIDS. Aerobic and anaerobic faecal microflora, were studied in healthy infants from birth to 6 months of age. They were found to appear in faeces within 3 days of birth and were present throughout the first 6 months of life. The effect of nitrate, nitrite and nitric oxide on faecal urease activity was investigated and found to be inhibitory in action. The sigmoid faecal urease activity and sigmoid faecal urea content of SIDS infants were compared to those of control infants; significantly lower sigmoid faecal urease activity and greater sigmoid faecal urea content were found in the SIDS infants. The total number of SIDS cases occurring in Sweden during the period 1990 through 1996 was analysed regarding geographical and seasonal distribution, in relation to the nitrate concentration in drinking water and changes in the groundwater level. The northernmost parts of the country had its highest incidence when the rest of the country had its lowest incidence, and the occurrence of individual deaths was associated with the recharge of groundwater, which is known to increase its nitrate content. The effect of ingested ammonium on carbon dioxide production was determined in healthy infants using the doubly labelled water technique. No change in carbon dioxide production was observed. An insufficient enteric metabolism of urea in infants and peak or greatly varying nitrate concentrations in drinking water are associated with the occurrence of SIDS. Ingested ammonium supplements in the given doses did not influence carbon dioxide production in healthy infants.

The primary aim of this thesis was to modify saphenous vein (SV) harvesting technique and evaluate its clinical importance. A new "no touch" (NT) technique of SV preparation was developed where the vein is harvested with a pedicle of surrounding tissue, which protects the vein from spasm therefore obviating the need for distension. Firstly, a prospective randomised study in 156 patients who underwent coronary artery bypass grafting was done to compare this new "no touch" technique to two others, the conventional (C) and the intermediate (I) techniques. A morphological study of the endothelium showed an endothelial integrity of 97% in NT vessels while about half of endothelial surface of veins harvested by the other two techniques was devoid of endothelium. At angiographic follow up, the patency for NT was 95.4%, 88.9% for grafts in group C and 86.2% for grafts in group I. A statistically significant difference in patency rate was found between the NT group and group C (p=0.025) and the poorest result was observed in group I. Secondly, the immunohistochemistry assessment using CD31-antibody confirmed a better-preserved endothelium for NT vessels. Putative NOS was identified by NADPH-diaphorase histochemistry and autoradiographic localization of [3H] L-nitroarginine (NOARG) binding. NADPH staining was almost continuous on the luminal aspect and was also present in the intact adventitia of NT vessels, which was markedly reduced in conventionally harvested veins. Autoradiographic analysis of specific NOARG binding showed greater binding in the no-touch vessels, confirming the histochemistry results. All three NOS isoforms were identified in the media of SV grafts. In NT, NOS I was abundant in adventitial nerves; NOS II was found in adventitial vasa vasorum and NOS III was associated with endothelial cells lining both the vessel lumen and microvessels within the adventitia. In conclusion, this study demonstrated that the endothelial integrity and NOS activity are better maintained when using the no-touch technique for vein graft harvesting. The vasorelaxant and thromboresistent activities of NO may be responsible for the reduced venospasm and improved early patency rates observed. Furthermore, the mechanical properties provided by the cushion of surrounding tissue in grafts harvested by NT technique may contribute to the observed high patency rate.

Familial primary hyperparathyroidism (HPT) is a rare disorder that is treated surgically and mostly occurs in association with tumor-susceptibility syndromes, like multiple endocrine neoplasia and the hyperparathyroidism-jaw tumor syndrome. Familial hypercalciuric hypercalcemia (FHH) is another cause of hereditary hypercalcemia that generally is considered to require no treatment and is genetically and pathophysiologically distinct from HPT. Inactivating mutations in the calcium receptor gene cause FHH, whereas the down-regulated expression of the CaR in HPT never has been coupled to CaR gene mutations. Family screening revealed a hitherto unknown familial condition with characteristics of both FHH and HPT. The hypercalcemia was mapped to a point mutation in the intracellular domain of the CaR gene that was coupled to relative calcium resistance of the PTH release by transient expression in HEK 294 cells. Unusually radical excision of parathyroid glands was required to normalise the hypercalcemia. The mildly enlarged parathyroid glands displayed hyperplasia with nodular components. Frequent allelic loss on especially 12q was found and contrasts to findings in HPT. Allelic loss was also seen in loci typical for primary HPT like 1p, 6q and 15q, but not 11q13. Quantitative mRNA analysis showed that the glands had mild increase in a proliferation index (PCNA/GAPDH mRNA ratio) and mild reduction in genes important to parathyroid cell function, like CaR, PTH, VDR and LRP2. A previously unrecognized variant of hypercalcemia is explored that could be one explanation for persistent hypercalcemia after apparently typical routine operations for HPT. It also raises the issue of possibilities to treat FHH with parathyroidectomy provided it is radical enough.

The laparoscopic way of performing general surgical procedures was introduced all over the Western world in a few years around 1990. No previous scientific studies of the safety of this new way of performing general surgery had been undertaken. In an animal study, it was shown that carbon dioxide pneumoperitoneum (CO2PP) causes an increase in inferior caval vein (ICV) pressure, although there were no effects on the ICV blood flow. There were gradual increases in systemic, pulmonary and ICV vascular resistance, which remained after exsufflation. These effects on vascular resistance could not be reproduced in a second animal study, presumably due to a different form of anesthesia. In this study, there was only indirect evidence of CO2 PP decreasing urine output. No increase in vasopressin, which is commonly seen during CO2 PP, was found, indicating that vasopressin may play a role in the decreased urine output during CO2 PP but that there must be other contributing factors as well. Only brief effects on the renal arterial blood flow were seen.Renal venous pressure increased to that of the ICV. A literature review indicated that thromboembolic complications do occur after laparoscopic cholecystectomy (LC). The relative frequencies indicated an underreporting of deep vein thrombosis (DVT) in relation to pulmonary embolism (PE). In a clinical study, activation of the coagulation after LC was demonstrated. There were differences between the groups receiving dextran and low molecular weight heparin as prophylaxis. A further clinical study showed the incidence of DVT, as demonstrated by phlebography, to be 2.0 % (95 % confidence interval 0-6.0 %) 7-11 days after LC, even though thromboembolism prophylaxis was given in shorter courses than those scientifically proven to be effective against DVT. D-dimer values increased at the first postoperative day and even further at the time of phlebography, suggesting that the effects of LC on coagulation and/or fibrinolysis may be of longer duration than previously known.

During a three-year period (1989-91), all patients living in the county of Uppsala, Sweden, with a radiographically verified fracture of the clavicle were prospectively, consecutively followed (n=245). The epidemiological study (I) was restricted to the two first years with 187 fractures in185 patients. The short term study (II) with 6 months follow-up included 222 patients. The long term study (III) with 10 years follow-up included 208 patients. The malunion study (IV) included eight patients and the nonunion study (V) 24 patients all of whom were consecutively operated between 1988-2000. Displacement, especially with no bony contact in the initial radiographs, was a statistically significant risk factor for sequelae. Comminute fractures, especially if including transversally placed fragments, were associated with a significantly increased risk of remaining symptoms. An increasing number of fragments was also associated with an increased risk of sequelae. Patients with remainig symptoms after 6 months were on average older at the time of injury as compared to patients without remaining symptoms. Advancing age was also a significant risk factor for sequelae – specifically pain at rest – still after 10 years. There was no difference between gender with respect to the risk of sequelae, except for nonunion. Fracture location did not predict outcome, except for more cosmetic defects (middle part). Shortening defined as overlapping at the fracture site was a significant risk factor for cosmetic defects after 10 years. Patients who experience pain at rest and/or cosmetic defects more than twelve weeks after the fracture have a higher risk for sequelae. The radiographic examination should always consist of two projections: the AP (0°) view and the 45° tilted view. Transversally placed fragments are not seen in the 0° view. Removal of excessive callus in patients with persistent symptoms even several years after the fracture showed a good outcome. One does not have to stabilize the clavicle when excising the hypertrophic callus. Symptomatic clavicular nonunions should be treated with surgery. Reconstruction plate combined with cancellous bone gives a faster and more reliable healing rate than external fixation.