Modern surgical treatment of otosclerosis

The modern unilateral surgical treatment of otosclerosis started in 1956. Simultaneous bilateral surgery has not been reported in stapes surgery and in case of bilateral otosclerosis ears are operated in two different sessions. Simultaneous surgery would give the patient the opportunity to gain advantages of bilateral hearing within one session, with less time spent in hospital and on sick leave. The mechanism for vestibular symptoms and the exact end organ affected after surgery is still unveiled. This thesis presents the results of experimental simultaneous bilateral stapes surgery, and vestibular symptoms and findings before and after unilateral stapes surgery. In addition, we explore reasons for outpatient failures in otosclerosis surgery. -- Study I examines the outcome of simultaneous bilateral surgery. Hearing was evaluated with standard pure tone and speech audiograms and vestibular apparatus with visual feedback posturography (VFP) during the one-year follow-up. Subjective symptoms and quality of life were assessed with questionnaires. In study II, reasons for outpatient failures in stapes surgery were explored. Forty-seven consecutive stapedotomies and stapedectomies performed by the same surgeon were included, and the effect of failures on hearing results were analysed. Vestibular symptoms and the end organ(s) affected after stapes surgery were investigated in studies III and IV. With video-oculography (VOG), nystagmus was measured preoperatively, and at one week, one month and 3 months postoperatively in the first phase (III). In the second phase (IV), recordings were obtained some hours postoperatively. The hearing results of the simultaneous bilateral surgery were comparable with unilateral surgeries reported. Recovery from the surgery was fast. Significant improvement in performance and quality of life was noted already month after operation in subjective evaluations. Based on these results, simultaneous bilateral surgery is a suitable approach in bilateral otosclerosis Significantly more outpatient failures occurred for medical reasons in the stapedectomy group (13%) than in the stapedotomy group (2%). Stapedotomy should be favoured if outpatient surgery is planned. However, unplanned admission did not worsen the prognosis. VOG measurements in study III did not show any specific type of nystagmus in patients having vestibular symptoms postoperatively. However, VOG measurements immediately after surgery (IV) revealed nystagmus consistent with a minor disturbance of the semicircular canals in 33% of the patients. Subjectively, half of the patients reported vestibular symptoms that were probably of diverse origin, and could have originated from both otolith and semicircular canal parts of the vestibular organ. Since vestibular symptoms and signs are mild, patients may be safely discharged some hours after stapes surgery.

Genistein and 17β-estradiol fatty acid esters in blood and adipose tissue and the structure-related antioxidant activity of estrogens on lipoproteins

Soy-derived phytoestrogen genistein and 17β-estradiol (E2), the principal endogenous estrogen in women, are also potent antioxidants protecting LDL and HDL lipoproteins against oxidation. This protection is enhanced by esterification with fatty acids, resulting in lipophilic molecules that accumulate in lipoproteins or fatty tissues. The aims were to investigate, whether genistein becomes esterified with fatty acids in human plasma accumulating in lipoproteins, and to develop a method for their quantitation; to study the antioxidant activity of different natural and synthetic estrogens in LDL and HDL; and to determine the E2 esters in visceral and subcutaneous fat in late pregnancy and in pre- and postmenopause. Human plasma was incubated with [3H]genistein and its esters were analyzed from lipoprotein fractions. Time-resolved fluoroimmunoassay (TR-FIA) was used to quantitate genistein esters in monkey plasma after subcutaneous and oral administration. The E2 esters in women s serum and adipose tissue were also quantitated using TR-FIA. The antioxidant activity of estrogen derivatives (n=43) on LDL and HDL was assessed by monitoring the copper induced formation of conjugated dienes. Human plasma was shown to produce lipoprotein-bound genistein fatty acid esters, providing a possible explanation for the previously reported increased oxidation resistance of LDL particles during intake of soybean phytoestrogens. Genistein esters were introduced into blood by subcutaneous administration. The antioxidant effect of estrogens on lipoproteins is highly structure-dependent. LDL and HDL were protected against oxidation by many unesterified, yet lipophilic derivatives. The strongest antioxidants had an unsubstituted A-ring phenolic hydroxyl group with one or two adjacent methoxy groups. E2 ester levels were high during late pregnancy. The median concentration of E2 esters in pregnancy serum was 0.42 nmol/l (n=13) and in pre- (n=8) and postmenopause (n=6) 0.07 and 0.06 nmol/l, respectively. In pregnancy visceral fat the concentration of E2 esters was 4.24 nmol/l and in pre- and postmenopause 0.82 and 0.74 nmol/l. The results from subcutaneous fat were similar. In serum and fat during pregnancy, E2 esters constituted about 0.5 and 10% of the free E2. In non-pregnant women most of the E2 in fat was esterified (the ester/free ratio 150 - 490%). In postmenopause, E2 levels in fat highly exceeded those in serum, the majority being esterified. The pathways for fatty acid esterification of steroid hormones are found in organisms ranging from invertebrates to vertebrates. The evolutionary preservation and relative abundance of E2 esters, especially in fat tissue, suggest a biological function, most likely in providing a readily available source of E2. The body s own estrogen reservoir could be used as a source of E2 by pharmacologically regulating the E2 esterification or hydrolysis.

Elimination of axial venous reflux

Chronic venous disease (CVD), including uncomplicated varicose veins and chronic venous insufficiency, is one of the most common medical conditions in the Western world. The central feature of CVD is venous reflux, which may be primary, congenital, or result from an antecedent event, usually an acute deep venous thrombosis (DVT). When the history of DVT is clear, the clinical manifestations of secondary CVD are commonly referred to as the post-thrombotic syndrome. Regardless of the underlying etiology, the final pathway leading to symptoms is ambulatory venous hypertension. The spectrum of symptoms and signs of CVD ranges from minor cosmetic problems to venous ulceration, which results in considerable morbidity and increased medical costs. Aims of this study were to evaluate the outcome of superficial venous surgery performed with or without preoperative duplex evaluation and venous marking with hand-held doppler, to assess short-term outcome of ultrasound-guided foam sclerotherapy in patients with axial superficial venous incompetence, as well as to compare reflux patterns after catheter-directed and systemic thrombolysis of deep ileofemoral venous thrombosis, and to evaluate the long-term outcome of deep venous reconstructions for severe chronic venous insufficiency. The study consists of five separate retrospective projects and includes 315 patients. Of this, 133 patients had undergone superficial venous surgery 2 to 5 years earlier according to preoperative duplex examination and venous marking, or according to clinical evaluation alone, or to a written plan without venous marking. A total of 112 patients had undergone ultrasound-guided foam sclerotherapy 5.5 to 16.5 months before. In addition, 32 patients had received either catheter-directed or systemic thrombolysis for DVT 2 to 3 years earlier, and 38 patients had undergone deep venous reconstructions 2 to 7 years earlier. In the present studies, some venous reflux was present postoperatively irrespective of the method of evaluation or ablation of the reflux. It seemed, however, that preoperative examination with duplex ultrasound and marking of reflux sites before the operation by the operating surgeon improves the outcome of superficial venous surgery. Ultrasound-guided foam sclerotherapy is effective in elimination of venous reflux in selected cases in short-term follow-up. Catheter-directed thrombolysis for deep iliofemoral venous thrombosis reduces later reflux and most probably the development of post-thrombotic syndrome as well. The outcome of deep venous reconstructions, especially for post-thrombotic deep venous incompetence, is poor. Thus, prevention of valvular damage by active treatment of deep venous thrombosis is important.

The Pathobiology of the Saccular Cerebral Artery Aneurysm Rupture and Repair : A Clinicopathological and Experimental Approach

Backround and Purpose The often fatal (in 50-35%) subarachnoid hemorrhage (SAH) caused by saccular cerebral artery aneurysm (SCAA) rupture affects mainly the working aged population. The incidence of SAH is 10-11 / 100 000 in Western countries and twice as high in Finland and Japan. The estimated prevalence of SCAAs is around 2%. Many of those never rupture. Currently there are, however, no diagnostic methods to identify rupture-prone SCAAs from quiescent, (dormant) ones. Finding diagnostic markers for rupture-prone SCAAs is of primary importance since a SCAA rupture has such a sinister outcome, and all current treatment modalities are associated with morbidity and mortality. Also the therapies that prevent SCAA rupture need to be developed to as minimally invasive as possible. Although the clinical risk factors for SCAA rupture have been extensively studied and documented in large patient series, the cellular and molecular mechanisms how these risk factors lead to SCAA wall rupture remain incompletely known. Elucidation of the molecular and cellular pathobiology of the SCAA wall is needed in order to develop i) novel diagnostic tools that could identify rupture-prone SCAAs or patients at risk of SAH, and to ii) develop novel biological therapies that prevent SCAA wall rupture. Materials and Methods In this study, histological samples from unruptured and ruptured SCAAs and plasma samples from SCAA carriers were compared in order to identify structural changes, cell populations, growth factor receptors, or other molecular markers that would associate with SCAA wall rupture. In addition, experimental saccular aneurysm models and experimental models of mechanical vascular injury were used to study the cellular mechanisms of scar formation in the arterial wall, and the adaptation of the arterial wall to increased mechanical stress. Results and Interpretation Inflammation and degeneration of the SCAA wall, namely loss of mural cells and degradation of the wall matrix, were found to associate with rupture. Unruptured SCAA walls had structural resemblance with pads of myointimal hyperplasia or so called neointima that characterizes early atherosclerotic lesions, and is the repair and adaptation mechanism of the arterial wall after injury or increased mechanical stress. As in pads of myointimal hyperplasia elsewhere in the vasculature, oxidated LDL was found in the SCAA walls. Immunity against OxLDL was demonstrated in SAH patients with detection of circulating anti-oxidized LDL antibodies, which were significantly associated with the risk of rupture in patients with solitary SCAAs. Growth factor receptors associated with arterial wall remodeling and angiogenesis were more expressed in ruptured SCAA walls. In experimental saccular aneurysm models, capillary growth, arterial wall remodeling and neointima formation were found. The neointimal cells were shown to originate from the experimental aneurysm wall with minor contribution from the adjacent artery, and a negligible contribution of bone marrow-derived neointimal cells. Since loss of mural cells characterizes ruptured human SCAAs and likely impairs the adaptation and repair mechanism of ruptured or rupture-prone SCAAs, we investigated also the hypothesis that bone marrow-derived or circulating neointimal precursor cells could be used to enhance neointima formation and compensate the impaired repair capacity in ruptured SCAA walls. However, significant contribution of bone marrow cells or circulating mononuclear cells to neointima formation was not found.

Barrett's Esophagus and Associated Adenocarcinoma : studies on pathogenesis, clinical staging and cost-utility of cancer treatment

Esophageal and gastroesophageal junction (GEJ) adenocarcinoma is rapidly increasing disease with a pathophysiology connected to oxidative stress. Exact pre-treatment clinical staging is essential for optimal care of this lethal malignancy. The cost-effectiviness of treatment is increasingly important. We measured oxidative metabolism in the distal and proximal esophagus by myeloperoxidase activity (MPA), glutathione content (GSH), and superoxide dismutase (SOD) in 20 patients operated on with Nissen fundoplication and 9 controls during a 4-year follow-up. Further, we assessed the oxidative damage of DNA by 8-hydroxydeoxyguanosine (8-OHdG) in esophageal samples of subjects (13 Barrett s metaplasia, 6 Barrett s esophagus with high-grade dysplasia, 18 adenocarcinoma of the distal esophagus/GEJ, and 14 normal controls). We estimated the accuracy (42 patients) and preoperative prognostic value (55 patients) of PET compared with computed tomography (CT) and endoscopic ultrasound (EUS) in patients with adenocarcinoma of the esophagus/GEJ. Finally, we clarified the specialty-related costs and the utility of either radical (30 patients) or palliative (23 patients) treatment of esophageal/GEJ carcinoma by the 15 D health-related quality-of-life (HRQoL) questionnaire and the survival rate. The cost-utility of radical treatment of esophageal/GEJ carcinoma was investigated using a decision tree analysis model comparing radical, palliative, and hypothetical new treatment. We found elevated oxidative stress ( measured by MPA) and decreased antioxidant defense (measured by GSH) after antireflux surgery. This indicates that antireflux surgery is not a perfect solution for oxidative stress of the esophageal mucosa. Elevated oxidative stress in turn may partly explain why adenocarcinoma of the distal esophagus is found even after successful fundoplication. In GERD patients, proximal esophageal mucosal anti-oxidative defense seems to be defective before and even years after successful antireflux surgery. In addition, antireflux surgery apparently does not change the level of oxidative stress in the proximal esophagus, suggesting that defective mucosal anti-oxidative capacity plays a role in development of oxidative damage to the esophageal mucosa in GERD. In the malignant transformation of Barrett s esophagus an important component appears to be oxidative stress. DNA damage may be mediated by 8-OHdG, which we found to be increased in Barrett s epithelium and in high-grade dysplasia as well as in adenocarcinoma of the esophagus/GEJ compared with controls. The entire esophagus of Barrett s patients suffers from increased oxidative stress ( measured by 8-OhdG). PET is a useful tool in the staging and prognostication of adenocarcinoma of the esophagus/GEJ detecting organ metastases better than CT, although its accuracy in staging of paratumoral and distant lymph nodes is limited. Radical surgery for esophageal/GEJ carcinoma provides the greatest benefit in terms of survival, and its cost-utility appears to be the best of currently available treatments.

Tacrolimus ointment for long-term treatment of atopic dermatitis

Atopic dermatitis (AD) or atopic eczema is characterised by a superficial skin inflammation with an overall Th2 cell dominance and impaired function of the epidermal barrier. Patients also are at an increased risk for asthma and allergic rhinitis. Treatment with tacrolimus ointment inhibits T cell activation and blocks the production of several inflammatory cytokines in the skin, without suppressing collagen synthesis. The aims of this thesis were to determine: (1) long-term efficacy, safety, and effects on cell-mediated immunity and serum IgE levels in patients with moderate-to-severe AD treated for 1 year with tacrolimus ointment or a corticosteroid regimen, (2) the 10-year outcome of eczema, respiratory symptoms, and serum IgE levels in AD patients initially treated long-term with tacrolimus ointment, and (3) pharmacokinetics and long-term safety and efficacy of 0.03% tacrolimus ointment in infants under age 2 with AD. Cell-mediated immunity, reflecting Th1 cell reactivity, was measured by recall antigens and was at baseline lower in patients with AD compared to healthy controls. Treatment with either 0.1% tacrolimus ointment or a corticosteroid regimen for one year enhanced recall antigen reactivity. Transepidermal water loss (TEWL), an indicator of skin barrier function, decreased at months 6 and 12 in both tacrolimus- and corticosteroid-treated patients; TEWL for the head and neck was significantly lower in tacrolimus-treated patients. Patients in the 10-year open follow-up study showed a decrease in affected body surface area from a baseline 19.0% to a 10-year 1.6% and those with bronchial hyper-responsiveness at baseline showed an increase in the provocative dose of inhaled histamine producing a 15% decrease in FEV1, indicating less hyper-responsiveness. Respiratory symptoms (asthma and rhinitis) reported by the patient decreased in those with active symptoms at baseline. A good treatment response after one year of tacrolimus treatment predicted a good treatment response throughout the 10-year follow-up and a decrease in total serum IgE levels at the 10-year follow-up visit. The 2-week pharmacokinetic and the long-term study with 0.03% tacrolimus ointment showed good and continuous improvement of AD in the infants. Tacrolimus blood levels were throughout the study low and treatment well tolerated. This thesis underlines the importance of effective long-term topical treatment of AD. When the active skin inflammation decreases, cell-mediated immunity of the skin improves and a secondary marker for Th2 cell reactivity, total serum IgE, decreases. Respiratory symptoms seem to improve when the eczema area decreases. All these effects can be attributed to improvement of skin barrier function. One potential method to prevent a progression from AD to asthma and allergic rhinitis may be avoidance of early sensitisation through the skin, so early treatment of AD in infants is crucial. Long-term treatment with 0.03% tacrolimus ointment was effective and safe in infants over age 3 months.

Invasive pneumococcal infections in Finland before routine use of conjugate vaccines : opportunities for prevention

Streptococcus pneumoniae is a leading cause of pneumonia, meningitis and bacteremia worldwide. The 23-valent pneumococcal polysaccharide vaccine (PPV23) is recommended for adults less than 65 years old with certain chronic medical conditions and for all elderly persons because of high rates of invasive pneumococcal infections (IPI) and increased risk of death. This study provides a comprehensive picture of the epidemiology of pneumococcal infections in Finland before the introduction of childhood pneumococcal conjugate vaccines, focusing on disease rates, risk factors, clinical outcome, and healthcare associated infections. This study was based on national, population-based laboratory surveillance for IPI. Information on all episodes of IPI was collected from the primary diagnostic laboratory. A case with IPI was defined as the isolation of S. pneumoniae from blood or cerebrospinal fluid during 1995-2002. Information on comorbidities and underlying conditions for IPI patients was obtained by linking the IPI surveillance database to other national, population-based health registries using each patient’s unique national identity code. In total, 4357 cases of IPI were identified. The overall annualized IPI incidence increased by 35% during the study period and was 10.6 per 100 000 population. The temporal increase in disease rates was associated with higher blood culturing rates over time. In working age adults, two-thirds of severe infections and one half of fatal cases occurred in persons with no recognized PPV23 indication. Persons with asthma were at increased risk for IPI and this new risk factor accounted for 5% of the overall disease burden. One tenth of pneumococcal bacteremias were healthcare-associated, and mortality among these patients was over twice as high as among patients with community-associated bacteremia. Most patients with nosocomial infections had underlying conditions for which PPV23 is recommended. The incidence of IPI in Finland has increased and the overall disease burden is higher than previously reported. The findings of this study underscore the urgent need for improved prevention efforts against pneumococcal infections in Finland through increased use of PPV23 in adult risk groups and introduction of childhood immunization with pneumococcal conjugate vaccine.

A Critical Evaluation of the MARS Treatment in Finland

The Molecular Adsorbent Recirculating System (MARS) is an extracorporeal albumin dialysis device which is used in the treatment of liver failure patients. This treatment was first utilized in Finland in 2001, and since then, over 200 patients have been treated. The aim of this thesis was to evaluate the impact of the MARS treatment on patient outcome, the clinical and biochemical variables, as well as on the psychological and economic aspects of the treatment in Finland. This thesis encompasses 195 MARS-treated patients (including patients with acute liver failure (ALF), acute-on-chronic liver failure (AOCLF) and graft failure), and a historical control group of 46 ALF patients who did not undergo MARS. All patients received a similar standard medical therapy at the same intensive care unit. The baseline data (demographics, laboratory and clinical variables) and MARS treatment-related and health-related quality-of-life data were recorded before and after treatment. The direct medical costs were determined for a period of 3.5 years.Additionally, the outcome of patients (survival, native liver recovery and need for liver transplantation) and survival predicting factors were investigated. In the outcome analysis, for the MARS-treated ALF patients, their 6-month survival (75% vs. 61%, P=0.07) and their native liver recovery rate (49% vs. 17%, P<0.001) were higher, and their need for transplantations was lower (29% vs. 57%, P= 0.001) than for the historical controls. However, the etiological distribution of the ALF patients referred to our unit has changed considerably over the past decade and the percentage of patients with a more favorable prognosis has increased. The etiology of liver failure was the most important predictor of the outcome. Other survival predicting factors in ALF included hepatic encephalopathy, the coagulation factors and the liver enzyme levels prior to MARS treatment. In terms of prognosis, the MARS treatment of the cirrhotic AOCLF patient seems meaningful only when the patient is eligible for transplantation. The MARS treatment appears to halt the progression of encephalopathy and reduce the blood concentration of neuroactive amino acids, albumin-bound and water-soluble toxins. In general, the effects of the MARS treatment seem to stabilize the patients, thus allowing additional time either for the native liver to recover, or for the patients to endure the prolonged waiting for transplantation. Furthermore, for the ALF patients, the MARS treatment appeared to be less costly and more cost-efficient than the standard medical therapy alone. In conclusion, the MARS treatment appears to have a beneficial effect on the patient outcome in ALF and in those AOCLF patients who can be bridged to transplantation.

Atrial remodeling in atrial fibrillation : Epidemiological, clinical and magnetocardiographic aspects

Atrial fibrillation is the most common arrhythmia requiring treatment. This Thesis investigated atrial fibrillation (AF) with a specific emphasis on atrial remodeling which was analysed from epidemiological, clinical and magnetocardiographic (MCG) perspectives. In the first study we evaluated in real-life clinical practice a population-based cohort of AF patients referred for their first elective cardioversion (CV). 183 consecutive patients were included of whom in 153 (84%) sinus rhythm (SR) was restored. Only 39 (25%) of those maintained SR for one year. Shorter duration of AF and the use of sotalol were the only characteristics associated with better restoration and maintenance of SR. During the one-year follow-up 40% of the patients ended up in permanent AF. Female gender and older age were associated with the acceptance of permanent AF. The LIFE-trial was a prospective, randomised, double-blinded study that evaluated losartan and atenolol in patients with hypertension and left ventricular hypertrophy (LVH). Of the 8,851 patients with SR at baseline and without a history of AF 371 patients developed new-onset AF during the study. Patients with new-onset AF had an increased risk of cardiac events, stroke, and increased rate of hospitalisation for heart failure. Younger age, female gender, lower systolic blood pressure, lesser LVH in ECG and randomisation to losartan therapy were independently associated with lower frequency of new-onset AF. The impact of AF on morbidity and mortality was evaluated in a post-hoc analysis of the OPTIMAAL trial that compared losartan with captopril in patients with acute myocardial infarction (AMI) and evidence of LV dysfunction. Of the 5,477 randomised patients 655 had AF at baseline, and 345 patients developed new AF during the follow-up period, median 3.0 years. Older patients and patients with signs of more serious heart disease had and developed AF more often. Patients with AF at baseline had an increased risk of mortality (hazard ratio (HR) of 1.32) and stroke (HR 1.77). New-onset AF was associated with increased mortality (HR 1.82) and stroke (HR of 2.29). In the fourth study we assessed the reproducibility of our MCG method. This method was used in the fifth study where 26 patients with persistent AF had immediately after the CV longer P-wave duration and higher energy of the last portion of atrial signal (RMS40) in MCG, increased P-wave dispersion in SAECG and decreased pump function of the atria as well as enlarged atrial diameter in echocardiography compared to age- and disease-matched controls. After one month in SR, P-wave duration in MCG still remained longer and left atrial (LA) diameter greater compared to the controls, while the other measurements had returned to the same level as in the control group. In conclusion is not a rare condition in either general population or patients with hypertension or AMI, and it is associated with increased risk of morbidity and mortality. Therefore, atrial remodeling that increases the likelihood of AF and also seems to be relatively stable has to be identified and prevented. MCG was found to be an encouraging new method to study electrical atrial remodeling and reverse remodeling. RAAS-suppressing medications appear to be the most promising method to prevent atrial remodeling and AF.

Mitä hyötyä tehohoidosta? : Tehohoitoa sisältäneiden hoitojaksojen vaikuttavuuden arviointi

Intensive care is to be provided to patients benefiting from it, in an ethical, efficient, effective and cost-effective manner. This implies a long-term qualitative and quantitative analysis of intensive care procedures and related resources. The study population consists of 2709 patients treated in the general intensive care unit (ICU) of Helsinki University Hospital. Study sectors investigate intensive care patients mortality, quality of life (QOL), Quality-Adjusted Life-Years (QALY units) and factors related to severity of illness, length of stay (LOS), patient s age, evaluation period as well as experiences and memories connected with the ICU episode. In addition, the study examines the qualities of two QOL measures, the RAND 36 Item Health Survey 1.0 (RAND-36) and the 5 Item EuroQol-5D (EQ-5D) and assesses the correlation of the test results. Patients treated in 1995 responded to the RAND-36 questionnaire in 1996. All patients, treated from 1995-2000, received a QOL questionnaires in 2001, when 1 7 years had lapsed from the intensive treatment. Response rate was 79.5 %. Main Results 1) Of the patients who died within the first year (n = 1047) 66 % died during the intensive care period or within the following month. The non-survivors were more aged than the surviving patients, had generally a higher than average APACHE II and SOFA score depicting the severity of illness, their ICU LOS was longer and hospital stay shorter than of the surviving patients (p < 0.001). Mortality of patients receiving conservative treatment was higher than of those receiving surgical treatment. Patients replying to the QOL survey in 2001 (n = 1099) had recovered well: 97 % of those lived at home. More than half considered their QOL as good or extremely good, 40 % as satisfactory and 7 % as bad. All QOL indexes of those of working-age were considerably lower (p < 0.001) than comparable figures of the age- and gender-adjusted Finnish population. The 5-year monitoring period made evident that mental recovery was slower than physical recovery. 2) The results of RAND-36 and EQ-5D correlated well (p < 0.01). The RAND-36 profile measure distinguished more clearly between the different categories of QOL and their levels. EQ-5D measured well the patient groups general QOL and the sum index was used to calculate QALY units. 3) QALY units were calculated by multiplying the time the patient survived after ICU stay or expected life-years by the EQ-5D sum index. Aging automatically lowers the number of QALY units. Patients under the age of 65 receiving conservative treatment benefited from treatment to a greater extent measured in QALY units than their peers receiving surgical treatment, but in the age group 65 and over patients with surgical treatment received higher QALY ratings than recipients of conservative treatment. 4) The intensive care experience and QOL ratings were connected. The QOL indices were statistically highest for those recipients with memories of intensive care as a positive experience, albeit their illness requiring intensive care treatment was less serious than average. No statistically significant differences were found in the QOL indices of those with negative memories, no memories or those who did not express the quality of their experiences.

Biological mechanisms behind clozapine-induced agranulocytosis

Clozapine is the most effective drug in treating therapy-resistant schizophrenia and may even be superior to all other antipsychotics. However, its use is limited by a high incidence (approximately 0.8%) of a severe hematological side effect, agranulocytosis. The exact molecular mechanism(s) of clozapine-induced agranulocytosis is still unknown. We investigated the mechanisms behind responsiveness to clozapine therapy and the risk of developing agranulocytosis by performing an HLA (human leukocyte antigens) association study in patients with schizophrenia. The first group comprised patients defined by responsiveness to first-generation antipsychotics (FGAs) (n= 19). The second group was defined by a lack of response to FGAs but responsiveness to clozapine (n=19). The third group of patients had a history of clozapine-induced granulocytopenia or agranulocytosis (n=26). Finnish healthy blood donors served as controls (n= 120). We found a significantly increased frequency of HLA-A1 among patients who were refractory to FGAs but responsive to clozapine. We also found that the frequency of HLA-A1 was low in patients with clozapine-induced neutropenia or agranulocytosis. These results suggest that HLA-A1 may predict a good therapeutic outcome and a low risk of agranulocytosis and therefore HLA typing may aid in the selection of patients for clozapine therapy. Furthermore, in a subgroup of schizophrenia, HLA-A1 may be in linkage disequilibrium with some vulnerability genes in the MHC (major histocompatibility complex) region on chromosome 6. These genes could be involved in antipsychotic drug response and clozapine-induced agranulocytosis. In addition, we investigated the effect of clozapine on gene expression in granulocytes by performing a microarray analysis on blood leukocytes of 8 schizophrenic patients who had started clozapine therapy for the first time. We identified an altered expression in 4 genes implicated in the maturation or apoptosis of granulocytes: MPO (myeloperoxidase precursor), MNDA (myeloid cell nuclear differentiation antigen), FLT3LG (Fms-related tyrosine kinase 3 ligand) and ITGAL (antigen CD11A, lymphocyte function-associated antigen 1). The altered expression of these genes following clozapine administration may suggest their involvement in clozapine-induced agranulocytosis. Finally, we investigated whether or not normal human bone marrow mesenchymal stromal cells (MSC) are sensitive to clozapine. We treated cultures of human MSCs and human skin fibroblasts with 10 µM of unmodified clozapine and with clozapine bioactivated by oxidation. We found that, independent of bioactivation, clozapine was cytotoxic to MSCs in primary culture, whereas clozapine at the same concentration stimulated the growth of human fibroblasts. This suggests that direct cytotoxicity to MSCs is one possible mechanism by which clozapine induces agranulocytosis.

Total Hip and Knee Arthoplasty for Osteoarthritis : Factors Related to the Early Outcome of Surgery

Some perioperative clinical factors related to the primary cemented arthroplasty operation for osteoarthritis of the hip or knee joint are studied and discussed in this thesis. In a randomized, double-blind study, 39 patients were divided into two groups: one receiving tranexamic acid and the other not receiving it. Tranexamic acid was given in a dose of 10 mg/kg before the operation and twice thereafter, at 8-hour intervals. Total blood loss was smaller in the tranexamic acid group than in the control group. No thromboembolic complications were noticed. In a prospective, randomized study, 58 patients with hip arthroplasty and 39 patients with knee arthroplasty were divided into groups with postoperative closed-suction drainage and without drainage. There was no difference in healing of the wounds, postoperative blood transfusions, complications or range of motion. As a result of this study, the use of drains is no longer recommended. In a randomised study the effectiveness of a femoral nerve block (25 patients) was compared with other methods of pain control (24 patients) on the first postoperative day after total knee arthroplasty. The femoral block consisted of a single injection administered at patients´ bedside during the surgeon´s hospital rounds. Femoral block patients reported less pain and required half of the amount of oxycodone. Additional femoral block or continued epidural analgesia was required more frequently by the control group patients. Pain management with femoral blocks resulted in less work for nursing staff. In a retrospective study of 422 total hip and knee arthroplasty cases the C-reactive protein levels and clinical course were examined. After hip and knee arthroplasty the maximal C-reactive protein values are seen on the second and third postoperative days, after which the level decreases rapidly. There is no difference between patients with cemented or uncemented prostheses. Major postoperative complications may cause a further increase in C-reactive protein levels at one and two weeks. In-hospital and outpatient postoperative control radiographs of 200 hip and knee arthroplasties were reviewed retrospectively. If postoperative radiographs are of good quality, there seems to be no need for early repetitive radiographs. The quality and safety of follow-up is not compromised by limiting follow-up radiographs to those with clinical indications. Exposure of the patients and the staff to radiation is reduced. Reading of the radiographs by only the treating orthopaedic surgeon is enough. These factors may seem separate from each other, but linking them together may help the treating orthopaedic surgeon to adequate patient care strategy. Notable savings can be achieved.

Pitfalls in the Treatment of Persons with Dementia

Pitfalls in the treatment of persons with dementia Persons with dementia require high-quality health care, rehabilitation and sufficient social services to support their autonomy and to postpone permanent institutionalization. This study sought to investigate possible pitfalls in the care of patients with dementia: hip fracture rehabilitation, use of inappropriate or antipsychotic medication, social and medicolegal services offered to dementia caregiving families. Three different Finnish samples were used from years 1999-2005, mean age 78 to 86 years. After hip fracture operation, the weight-bearing restriction especially in group of patients with dementia, was associated with a longer rehabilitation period (73.5 days vs. 45.5 days, p=0.03) and the inability to learn to walk after six weeks (p<0.001). Almost half (44%) of the pre-surgery home-dwellers with dementia in our sample required permanent hospitalization after hip fracture. Potentially inappropriate medication was used among 36.2% of nursing home and hospital patients. The most common PIDs in Finland were temazepam over 15 mg/day, oxybutynin, and dipyridamole. However, PID use failed to predict mortality or the use of health services. Nearly half (48.4%) of the nursing home and hospital patients with dementia used antipsychotic medication. The two-year mortality did not differ among the users of conventional or atypical antipsychotics or the non-users (45.3% vs.32.1% vs.49.6%, p=0.195). The mean number of hospital admissions was highest among non-users (p=0.029). A high number of medications (HR 1.12, p<0.001) and the use of physical restraints (HR 1.72, p=0.034) predicted higher mortality at two years, while the use of atypical antipsychotics (HR 0.49, p=0.047) showed a protective effect, if any. The services most often offered to caregiving families of persons with Alzheimer s disease (AD) included financial support from the community (36%), technical devices (33%), physiotherapy (32%), and respite care in nursing homes (31%). Those services most often needed included physiotherapy for the spouse with dementia (56%), financial support (50%), house cleaning (41%), and home respite (40%). Only a third of the caregivers were satisfied with these services, and 69% felt unable to influence the range of services offered. The use of legal guardians was quite rare (only 4.3%), while the use of financial powers of attorney was 37.8%. Almost half (47.9%) of the couples expressed an unmet need for discussion with their doctor about medico-legal issues, while only 9.9% stated that their doctor had informed them of such matters. Although we already have many practical methods to develop the medical and social care of persons with AD, these patients and their families require better planning and tailoring of such services. In this way, society could offer these elderly persons better quality of life while economizing on its financial resources. This study was supported by Social Insurance Institution of Finland and part of it made in cooperation with the The Central Union of the Welfare for the Aged, Finland.

Comparison and integration of MEG and fMRI

MEG directly measures the neuronal events and has greater temporal resolution than fMRI, which has limited temporal resolution mainly due to the larger timescale of the hemodynamic response. On the other hand fMRI has advantages in spatial resolution, while the localization results with MEG can be ambiguous due to the non-uniqueness of the electromagnetic inverse problem. Thus, these methods could provide complementary information and could be used to create both spatially and temporally accurate models of brain function. We investigated the degree of overlap, revealed by the two imaging methods, in areas involved in sensory or motor processing in healthy subjects and neurosurgical patients. Furthermore, we used the spatial information from fMRI to construct a spatiotemporal model of the MEG data in order to investigate the sensorimotor system and to create a spatiotemporal model of its function. We compared the localization results from the MEG and fMRI with invasive electrophysiological cortical mapping. We used a recently introduced method, contextual clustering, for hypothesis testing of fMRI data and assessed the the effect of neighbourhood information use on the reproducibility of fMRI results. Using MEG, we identified the ipsilateral primary sensorimotor cortex (SMI) as a novel source area contributing to the somatosensory evoked fields (SEF) to median nerve stimulation. Using combined MEG and fMRI measurements we found that two separate areas in the lateral fissure may be the generators for the SEF responses from the secondary somatosensory cortex region. The two imaging methods indicated activation in corresponding locations. By using complementary information from MEG and fMRI we established a spatiotemporal model of somatosensory cortical processing. This spatiotemporal model of cerebral activity was in good agreement with results from several studies using invasive electrophysiological measurements and with anatomical studies in monkey and man concerning the connections between somatosensory areas. In neurosurgical patients, the MEG dipole model turned out to be more reliable than fMRI in the identification of the central sulcus. This was due to prominent activation in non-primary areas in fMRI, which in some cases led to erroneous or ambiguous localization of the central sulcus.