Browsing by Title

Sort by: Order: Results:

Now showing items 231-250 of 1683
  • Virtanen, Kaisa (Helsingin yliopisto, 2014)
    Traditionally, clavicle fractures and acromioclavicular (AC) joint dislocations have been treated nonoperatively. However, recent studies have shown that surgical treatment may diminish nonunion and sequels. Although articles discussing clavicle fractures and AC joint dislocations are abundant, the quality of evidence is still poor. To assess the various treatment modalities for clavicle fractures we performed an electronic database search of the literature from 1966 until the end of March 2011. The aim was to find potential high-quality comparative studies discussing acute clavicle fractures in adults. We conducted a randomized controlled trial comparing sling to plate fixation for completely displaced midshaft clavicle fractures to assess functional and radiological results after 1-year follow-up. Long-term results of surgery for acute and chronic AC joint dislocation were surveyed retrospectively. From electronic databases came 1072 abstracts discussing clavicle fractures. After exclusion, 230 reports remained, from which we assessed 13 for review. Midshaft fractures were discussed in 12 studies, lateral fractures in 1 study, but none concerned medial fractures. Evidence was mainly low or very low. Due to the lack of high-quality evidence, no conclusions can be drawn as to the best treatment for medial or lateral third fractures. Regarding midshaft fractures, it appears that after short-term follow-up, surgery leads to better function and less disability than does nonoperative treatment; benefits of surgery are small after 6 months; union is better secured with surgery; and nonoperative treatment usually leads to adequate function, pain relief, and union rates. Of the 60 randomized patients in our study, 28 came to an operative group, and 32 to a nonoperative group. At 1-year follow-up, we found no difference between these groups in function, in disability, or in pain. All fractures in the operative group healed. Nonoperative treatment was related to high nonunion rate (24%). Fracture displacement was associated with nonunion. After a mean 18-year follow-up, we found no difference in function or disability between the injured and uninjured shoulders in patients who had surgery for acute AC joint dislocation. Lateral clavicle osteolysis seemed to be related to constant AC joint dislocation. After a mean 4-year follow-up, patients who had undergone surgery for chronic AC joint dislocation with tendon grafts had moderately functional results. In almost half the patients, the AC joint remained unstable. Lateral clavicle osteolysis (56%) and tunnel widening (80%) were common. Thus, in chronic AC-joint dislocation, surgery may not necessarily restore shoulder function.
  • Wang, Shi-Xuan (Helsingin yliopisto, 2001)
  • Laine, Christine (Helsingin yliopisto, 2012)
    Osteoporosis is a common disease, which is caused by both genetic and environmental factors. Osteoporosis increases the risk of fragility fractures, reduces quality of life, and raises mortality rates in affected individuals. Despite years of extensive genetic research, only a few clinically significant underlying genes have been identified. These have been discovered by linkage analysis of families with extreme bone phenotypes. The numerous gene polymorphisms identified by genome-wide association studies have only modest effects on bone mineral density. This suggests that the osteoporosis phenotype seen in the general population is probably due to complex inheritance, i.e. caused by many interacting genetic factors. The aim of this investigation was to examine young patients and families with early-onset osteoporosis in order to better define their clinical phenotype and to clarify their genetic predisposition. A cohort of 27 children with juvenile osteoporosis and 60 family members were assessed at the Hospital for Sick Children, Toronto, Canada. The majority of assessed children had at least one parent with low bone mineral density implying a strong heredity of the disorder. Certain polymorphisms (Q89R, V667M, N740N and A1330V) in the gene encoding for low density lipoprotein receptor-related protein 5 (LRP5) were shown to be over-represented in this cohort. Patients with a clinical diagnosis of osteoporosis-pseudoglioma syndrome (OPPG), a rare disease caused by biallelic mutations in LRP5, were screened. Four new mutations affecting protein splicing along with the first functional data on a splice site mutation in LRP5 were presented. Finnish families with many individuals suffering from osteoporosis were also assessed. In a family with early-onset osteoporosis, 11 of 19 examined family members were found to be affected. The clinical characteristics include suboptimal bone accrual in adolescence, severe osteoporosis in adulthood, progressive compression fractures of the vertebrae, and proneness to peripheral fractures. Histomorphometric analyses from four affected individuals also indicated low-turnover bone metabolism. Two genomic regions (1p22.2-p21.1 and 11q22.1-q22.3), which may contain their disease-causing genetic variations, were identified by microsatellite linkage analysis. The exons in the putative linkage areas were sequenced by target enrichment and next-generation sequencing, and three heterozygous non-synonymous variations were found in the genes encoding for BCAR3 (p.F6Y), MMP10 (p.R53K), and DYNC2H1 (p.Q304L). These require further assessment to clarify their clinical significance. In another family, the rare syndrome of Calvarial Doughnut Lesions (CDL) was diagnosed in a young girl with osteoporosis and severe glaucoma. Her father and paternal grandmother were also affected. A thorough characterization of the clinical and bone histomorphometric features of the condition is provided here. A role for LRP5 has been excluded in the pathogenesis of CDL, given that no mutations were found in this gene to correspond with the clinical cases studied. This thesis provides new data regarding the clinical features and genetic background of bone weakness in children. The impact of these discovered genetic defects requires further elucidation in future studies.
  • Kotilainen, Hannele (Helsingin yliopisto, 2015)
    Introduction Non-tuberculous mycobacteria (NTM) are ubiquitous and they have become more common than M. tuberculosis (MTB). Most infections due to NTM are pulmonary and cutaneous, thereafter disseminated infections and lymphadenitis. Mycobacterium avium complex (MAC) is entailing for more than half of clinical cases. Chronic pulmonary patients and non-smoking healthy elderly females are the main risk groups for pulmonary NTM infections and others have been opportunistic NTM among in immunosuppressive patients and in families, rare genetic defects with disseminated NTM. Host defence role and immunological defects behind pulmonary NTM infections have not been found except a local defect in nitric oxide production and ciliary beat of airway epithelium. In present studies, the clinical symptoms and smoking as a risk factor for NTM infection and the prognostic value of The American Thoracic Society (ATS) criteria have been evaluated. Prognosis and clinical findings of patients infected with MAC has been compared to patients with other NTM infections. The clinical signs suggested immunological deficiency, therefore we investigated an association between deficiencies of complement components C4A or C4B and NTM and MTB patients in Finland. Study population. The studies I-II were based on 120 adult non-HIV patients with at least one NTM isolation retrospectively collected data in 1990 1998 followed at least four years. The patients were classified as smokers or never smokers and according to fulfilment of ATS 2007 criteria. In study III, 167 adult non-HIV patients with at least one positive NTM classified as MAC or other NTM and according to ATS 2007 criteria including patients from Studies I-II and IV with the median follow-up time 7.0 y. Study IV based on prospectively collected data and blood samples on HIV-negative 50 adult NTM and 31 MTB patients in the area of Helsinki University Central Hospital in 2004- 2009. The blood samples analyzed for C4A and C4B genotype. Controls were comprised of 149 healthy, unselected Finnish people. Results. Nearly half of patients with a NTM isolation had never smoked. Among non-smokers, 72 % were female, instead among smokers, only 30% were female. MAC comprised a majority of isolates among non-smokers compared to smokers (72% vs. 41%). Symptoms had started within a year of positive NTM isolation in 48% of patients. Smokers had higher risk of mortality than non-smokers but no difference was observed after adjusting for underlying diseases. The 2007 ATS criteria were fulfilled by half of patients. ATS positive cases were, more often, female with less fatal underlying diseases as compared to ATS-negative cases. No significant difference was seen in median survival time or symptoms between ATS-positive and -negative cases. ATS criteria fulfillment was a weak prognostic marker. MAC was isolated in 59% of overall 167 cases and MAC patients were significantly more often female (70 % vs. 34 %), and presented significantly fewer fatal underlying diseases than patients with other NTM (23 % vs. 47 %).The other NTM patients had suffered from symptoms less than a year as compared to MAC patients (54% vs. 34%). Pulmonary MAC patients had significantly lower risk of death and significantly longer survival time than other pulmonary NTM patients (13.0 years vs. 4.6 years). Serious underlying diseases and age were the significant predictors of mortality, female sex was a predictor of survival. Finnish NTM patients (72%) had significantly more frequent C4 deficiencies (C4A or C4B) as compared to unselected healthy controls (56%) and MTB (35%). C4 deficiencies were significantly common in female NTM patients (81%) as compared to female controls (55%). Conclusion. Risk factors for NTM infection were different for smokers and non-smokers. ATS 2007 criteria had a poor prognostic value in finding patients with risk of fatal outcome. Patients with MAC had a longer survival than patients with other NTM. Obviously symptom onset suggests a fairly rapid disease course. Complement C4 deficiency was found to be a plausible risk factor for NTM infection, especially among elderly female patients.
  • Rouhos, Annamari (Helsingin yliopisto, 2010)
    Measurement of fractional exhaled nitric oxide (FENO) has proven useful in assessment of patients with respiratory symptoms, especially in predicting steroid response. The objective of these studies was to clarify issues relevant for the clinical use of FENO. The influence of allergic sensitization per se on FENO in healthy asymptomatic subjects was studied, the association between airway inflammation and bronchial hyperresponsiveness (BHR) in steroid-naive subjects with symptoms suggesting asthma was examined, as well as the possible difference in this association between atopic and nonatopic subjects. Influence of smoking on FENO was compared between atopic and nonatopic steroid-naive asthmatics and healthy subjects. The short-term repeatability of FENO in COPD patients was examined in order to assess whether the degree of chronic obstruction influences the repeatability. For these purposes, we studied a random sample of 248 citizens of Helsinki, 227 army conscripts with current symptoms suggesting asthma, 19 COPD patients, and 39 healthy subjects. FENO measurement, spirometry and bronchodilatation test, structured interview. skin prick tests, and histamine and exercise challenges were performed. Among healthy subjects with no signs of airway diseases, median FENO was similar in skin prick test-positive and –negative subjects, and the upper normal limit of FENO was 30 ppb. In atopic and nonatopic subjects with symptoms suggesting asthma, FENO associated with severity of exercise- or histamine-induced BHR only in atopic patients. FENO in smokers with steroid-naive asthma was significantly higher than in healthy smokers and nonsmokers. Among atopic asthmatics, FENO was significantly lower in smokers than in nonsmokers, whereas no difference appeared among nonatopic asthmatics. The 24-h repeatability of FENO was equally good in COPD patients as in healthy subjects. These findings indicate that allergic sensitization per se does not influence FENO, supporting the view that elevated FENO indicates NO-producing airway inflammation, and that same reference range can be applied to both skin prick test-positive and -negative subjects. The significant correlation between FENO and degree of BHR only in atopic steroid-naive subjects with current asthmatic symptoms supports the view that pathogenesis of BHR in atopic asthma is strongly involved in NO-producing airway inflammation, whereas in development of BHR in nonatopic asthma other mechanisms may dominate. Attenuation of FENO only in atopic but not in nonatopic smokers with steroid-naive asthma may result from differences in mechanisms of FENO formation as well as in sensitivity of these mechanisms to smoking in atopic and nonatopic asthma. The results suggest, however, that in young adult smokers, FENO measurement may prove useful in assessment of airway inflammation. The short-term repeatability of FENO in COPD patients with moderate to very severe disease and in healthy subjects was equally good.
  • Hirvonen-Kari, Mirja (Helsingin yliopisto, 2013)
    Recent decades have witnessed a large and rapid expansion of medical imaging technologies with the development of digital imaging, computed tomography (CT), intervention radiology (IR), magnetic resonance imaging (MRI) and positron emission tomography (PET). The average effective dose per capita in Finland, received from X-ray examinations and interventional radiology has risen within reasonable levels, but the proportional CT scan dose sustained by the population out of the total population dose has increased and is currently over 50% from the total population dose in medicine. These technical developments and an increase in diagnostic examinations have raised concerns regarding the quality and safety of imaging practices. Organizations using medical imaging modalities should have a documented quality assurance (QA) program, as well as methods to justify the use of new radiological procedures ensuring the safe operation and adequate quality of clinical images and the imaging process. According to decree 423/2000 departments using ionizing radiation should be audited in all essential aspects at intervals not exceeding five years. Clinical audits should be arranged to expediently complement the self-assessment of activities. Reports of the two clinical audit periods were evaluated at 14 diagnostic radiation departments in the Hospital District of Southwest Finland (I). Recommendations given during the first clinical audit period were largely implemented by the second run. Auditing appeared to positively affect radiological imaging quality in our study. The use of ionizing radiation always requires a safety license and on-site inspections. The Radiation and Nuclear Safety Authority (STUK) is Finland s regulatory body controlling safety aspects of radiation utilization, and ensuring that safety guidelines defined by the Radiation Act are followed. The contents of the clinical audits and regulatory inspections of radiological procedures were examined and overlaps were searched for in 20 radiological imaging departments in the Hospital District of Helsinki and Uusimaa (HUS) (II). Radiation safety organizations, examination and personal dosimeter usage guidelines, patient doses, the quality control of equipments and self-assessments were evaluated by both the clinical auditors and the inspectors. Clinical audits and regulatory inspections have partly addressed similar topics. The personal equivalent doses of 267 radiation employees were monitored using personal dosimeters at the HUS Helsinki Medical Imaging Center (III). A personal dosimeter was worn by a total of 116 radiologists and 151 radiographers. Exposure monitoring results exceeding the registration threshold were observed in the personal dosimeters of 59 radiologists and 14 radiographers during a five-year period. Only 10 angiography radiologists recorded doses above 10 mSv during the five-year period. Individual exposure monitoring is justified for radiologists working in interventional procedures. Report quality was examined at the HUS Helsinki Medical Imaging Center. An experienced chest radiologist re-reported 293 chest radiograph examinations in accordance with the original request and without identifying patients (IV). Two experienced radiologists compared the content of the initial and re-reported reports. Three referring physicians evaluated the usefulness of the reports. Radiologists mostly addressed the questions posed by referring physicians, but separate conclusions were seldom included. Significantly shorter reports were initially prepared by general radiologists (29 words on average) than by the chest radiologist (93 words on average) in her re-reported reports. Inter-observer agreement between the two radiologists revealed that identical opinions of the findings was low (0.31), due to unstructured reports containing differing quantities of information. Referring physicians considered the reports clear and intelligible.
  • Merras-Salmio, Laura (Helsingin yliopisto, 2014)
    Background: Cow s milk protein allergy (CMPA) is often suspected in infants and young children with non-specific gastrointestinal symptoms. The pathomechanisms behind the different presentations of gastrointestinally manifesting CMPA (GI-CMPA) remain unproven. Diagnosing GI-CMPA is difficult, with the gold standard of diagnosis being the double-blind, placebo-controlled food challenge (DBPCFC). However, the protocols reported in the literature are often not feasible in clinical practice. The occurrence of CMPA in Finland is 2%, and GI symptoms are reported in 20-25%. The aim of this study is to provide a detailed clinical picture of GI-CMPA and to examine various clinical, and until recently, mainly research-based laboratory tests in order to investigate new diagnostic approaches to GI-CMPA. Little is known about the psychosocial maladjustments in patients and families suffering from GI-CMPA. Therefore, this study aims to characterise mother child interactions and other associated psychological factors in patients suspected of GI-CMPA. Results: This study prospectively recruited 57 patients with GI symptoms suspected of CMPA to undergo a DBPCFC for cow s milk. The proportion of positive DBPCFCs was only 32% (18/57), and the only symptom associated with the diagnosis of CMPA was loose stools. Vomiting or regurgitation occurred in similar frequencies among the CMPA-negative and CMPA-positive patients. Excessive crying/fussing was the most common symptom among the CMPA-negative patients, reported frequently during the placebo challenges. None of the patients suspected of GI-CMPA had detectable CMP-specific IgE. Faecal calprotectin was slightly higher among the challenge-positive patients both while on a cow s milk-free diet and after CMP provocation. The CM protein-specific blood IgG, IgG4 and IgA levels were found to be significantly low among both CMPA-positive and CMPA-negative patients while on a CMP-free diet compared to those of the control patients (without allergic or atopic diseases) who consumed cow s milk normally. Feeding-related symptoms and problems occurred frequently. Regarding the mother-child interaction substudy, the patients (n=24) frequently demonstrated problematic mother child emotional interactions, especially the CMPA-negative patients (n=17). This interaction pattern was less severe but identical to the pattern found in infants with diagnosed feeding disorders. Based on the questionnaires on child behavioural characteristics, children with GI symptoms suspected of CMPA were often perceived by their mothers as being demanding and difficult, regardless of the CMPA diagnosis. Taken together, these findings suggest that the dyadic psychological attributes may augment the infant s symptoms or the reporting of them and may even cause feeding-related problems resulting in food refusal and feeding-related symptoms leading to suspicion of CMPA. Conclusions: Gastrointestinal symptoms suspected of cow s milk allergy are seldom confirmed when using the DBPCFC. Placebo symptoms occur frequently, the most typical being excessive crying and regurgitation. There may be CMP independent low-grade gut mucosal inflammation present in patients with positive provocation tests. Cow s milk free diet in study infants lead to low levels of CMP specific antibodies raising concern over the safety of prolonged exclusion diets. Mother-child interaction may be problematic in patients with unconfirmed GI-CMPA, and the mothers often perceive the young children with suspicion of GI-CMPA as difficult and demanding. This psychological profile should be taken into consideration when managing patients with suspicion of GI-CMPA.
  • Terevnikov, Viacheslav (Helsingin yliopisto, 2013)
    Although a number of add-on treatment strategies have been studied to improve the outcome of antipsychotic-treated chronic schizophrenia, none of them have thus far proved to be conclusively effective. Mirtazapine, an antidepressant with a unique receptor profile, improves the clinical effect of first generation antipsychotics (FGAs), in terms of negative and extrapyramidal symptoms (EPS) in some published studies, when used in conjunction with FGAs. The present study aimed to explore the efficacy of adjunctive mirtazapine on the symptoms of schizophrenia in patients with an insufficient response to different FGA monotherapies at adequate stable dosages. Thirtynine patients who met the DSM-IV-TR criteria for schizophrenia or schizoaffective disorder depressive type, and who were at least moderately ill (as measured by the Clinical Global Impression Scale) despite their FGA treatment, received add-on mirtazapine 30 mg/day (n=20) or placebo (n=19) in a 6-week double-blind randomized controlled trial (RCT). Thirtyseven completers of the double-blind phase were treated in an open-label design with mirtazapine 30 mg/day during an additional 6 weeks. Dosages of current antipsychotics remained unchanged. The Positive and Negative Syndrome Scale (PANSS) total score (primary outcome), as well as secondary outcomes, which included PANSS subscales, Simpson-Angus Scale for Extrapyramidal Side-effects (SAS) and Calgary Depression Scale for Schizophrenia (CDSS) were measured prospectively. Patients underwent a physical examination (weight, vital signs) and a range of laboratory measures that included fasting glucose and total cholesterol. Within group and between group differences were compared on the Modified Intent-to-Treat basis with Last Observations Carried Forward. Correlation analyses and regression analyses were used to measure relationships between clinical and metabolic parameters. In the within group analyses, mirtazapine add-on treatment led to a statistically significant improvement of all measured clinical parameters during the double-blind phase. Improvement in PANSS total scores was as large as 12.5% (p less than 0.001), whereas the improvement in PANSS positive symptoms was 17.2% (p less than 0.001) while the improvement in PANSS negative symptoms was 12.0% (p less than 0.001). SAS scores improved by 9.8% (p=0.017) and CDSS scores improved by 52% (p=0.003). The latter change exhibited a direct correlation with several subscales of PANSS. In the mirtazapine group, the effect size was 1.00 (95%CI 0.34-1.67) on the primary outcome parameter. The between-group difference favoured mirtazapine on PANSS total scores (p=0.004), PANSS positive subscale (p=0.001) and PANSS negative subscale (p=0.001). No significant differences were found in other parameters. Mirtazapine treatment led to an increase in body weight and cholesterol levels, and the latter change was associated with a clinical improvement on all PANSS subscales, where an increase in total cholesterol by 1 mmol/L predicted a reduction on the PANSS total score by 7 points [r=0.85, p=0.001]. 8 During the open-label phase, patients who switched to mirtazapine demonstrated an improvement in PANSS (effect size 0.94 on PANSS total scores), CDSS and SAS scores in a manner similar to their mirtazapine-treated counterparts in the double-blind phase. The incidence of adverse events did not differ between mirtazapine and placebo. These findings indicate that add-on mirtazapine to current FGA treatment is significantly more efficacious in the reduction of positive, negative and depressive symptoms than a placebo add-on. This is the first RCT report of a statistically significant additive antipsychotic effect from an adjunctive antidepressant. Mirtazapine induced changes in body weight and lipid metabolism were similar to those seem with the most effective antipsychotics, and this metabolic effect may even contribute to its clinical efficacy. The main limitation of the study was its small sample size. Thus, larger and longer follow up trials are undoubtedly needed to confirm these results. Further research should also consider combinations of mirtazapine with second generation antipsychotics, and especially comparisons with clozapine.
  • Arajärvi, Ritva (Helsingin yliopisto, 2006)
    This study is part of the joint project "The Genetic Epidemiology and Molecular Genetics of schizophrenia in Finland" between the Departments of Mental Health and Alcohol Research, and Molecular Medicine at the National Public Health Institute. In the study, we utilized three nationwide health care registers: 1) the Hospital Discharge Register, 2) the Free Medication Register, and 3) the Disability Pension Register, plus the National Population Register, in order to identify all patients with schizophrenia born from 1940 to 1976 (N=33,731) in Finland, and their first degree-relatives. 658 patients with at least one parent born in a homogeneous isolate in northeastern Finland were identified, as well as 4904 familial schizophrenia patients with at least two affected siblings from the whole country. The comparison group was derived from the Health 2000 Study. We collected case records and reassessed the register diagnosis. Were contacted the isolate patients and a random sample of patients from the whole country to make diagnostic clinical interviews and to assess the negative and positive symptoms and signs of schizophrenia. In addition to these patients, we interviewed siblings who were initially healthy according to the Hospital Discharge Register. Of those with a register diagnosis of schizophrenia, schizoaffective or schizophreniform disorder, 69% received a record-based consensus diagnosis and 63% an interview-based diagnosis of schizophrenia. Patients with schizophrenia having first-degree relatives with psychotic disorder had more severe affective flattening and alogia than those who were the only affected individuals in their family. The novel findings were: 1) The prevalence of schizophrenia in the isolate was relatively high based on register (1.5%), case record (0.9-1.3%), and interview (0.7-1.2%) data. 2) Isolate patients, regardless of their familial loading for schizophrenia, had less delusions and hallucinations than the whole country familial patients, which may be related to the genetic homogeneity in the isolate. This phenotype encourages the use of endophenotypes in genetic analyses instead of diagnoses alone. 3) The absence of register diagnosis does not confirm that siblings are healthy, because 7.7% of siblings had psychotic symptoms already before the register diagnoses were identified in 1991. For genetic research, the register diagnosis should therefore be reassessed using either a structured interview or a best- estimate case note consensus diagnosis. Structured clinical interview methods need be considered also in clinical practice.
  • Förster, Johannes G (Helsingin yliopisto, 2008)
    Continuous epidural analgesia (CEA) and continuous spinal postoperative analgesia (CSPA) provided by a mixture of local anaesthetic and opioid are widely used for postoperative pain relief. E.g., with the introduction of so-called microcatheters, CSPA found its way particularly in orthopaedic surgery. These techniques, however, may be associated with dose-dependent side-effects as hypotension, weakness in the legs, and nausea and vomiting. At times, they may fail to offer sufficient analgesia, e.g., because of a misplaced catheter. The correct position of an epidural catheter might be confirmed by the supposedly easy and reliable epidural stimulation test (EST). The aims of this thesis were to determine a) whether the efficacy, tolerability, and reliability of CEA might be improved by adding the α2-adrenergic agonists adrenaline and clonidine to CEA, and by the repeated use of EST during CEA; and, b) the feasibility of CSPA given through a microcatheter after vascular surgery. Studies I IV were double-blinded, randomized, and controlled trials; Study V was of a diagnostic, prospective nature. Patients underwent arterial bypass surgery of the legs (I, n=50; IV, n=46), total knee arthroplasty (II, n=70; III, n=72), and abdominal surgery or thoracotomy (V, n=30). Postoperative lumbar CEA consisted of regular mixtures of ropivacaine and fentanyl either without or with adrenaline (2 µg/ml (I) and 4 µg/ml (II)) and clonidine (2 µg/ml (III)). CSPA (IV) was given through a microcatheter (28G) and contained either ropivacaine (max. 2 mg/h) or a mixture of ropivacaine (max. 1 mg/h) and morphine (max. 8 µg/h). Epidural catheter tip position (V) was evaluated both by EST at the moment of catheter placement and several times during CEA, and by epidurography as reference diagnostic test. CEA and CSPA were administered for 24 or 48 h. Study parameters included pain scores assessed with a visual analogue scale, requirements of rescue pain medication, vital signs, and side-effects. Adrenaline (I and II) had no beneficial influence as regards the efficacy or tolerability of CEA. The total amounts of epidurally-infused drugs were even increased in the adrenaline group in Study II (p=0.02, RM ANOVA). Clonidine (III) augmented pain relief with lowered amounts of epidurally infused drugs (p=0.01, RM ANOVA) and reduced need for rescue oxycodone given i.m. (p=0.027, MW-U; median difference 3 mg (95% CI 0 7 mg)). Clonidine did not contribute to sedation and its influence on haemodynamics was minimal. CSPA (IV) provided satisfactory pain relief with only limited blockade of the legs (no inter-group differences). EST (V) was often related to technical problems and difficulties of interpretation, e.g., it failed to identify the four patients whose catheters were outside the spinal canal already at the time of catheter placement. As adjuvants to lumbar CEA, clonidine only slightly improved pain relief, while adrenaline did not provide any benefit. The role of EST applied at the time of epidural catheter placement or repeatedly during CEA remains open. The microcatheter CSPA technique appeared effective and reliable, but needs to be compared to routine CEA after peripheral arterial bypass surgery.
  • Heiskanen, Ilkka (Helsingin yliopisto, 2000)
  • Demir, And (Helsingin yliopisto, 2015)
    This study was undertaken to assess the feasibility of non-invasive sampling and assay of urinary gonadotropins for clinical evaluation of pubertal development. In the first study, the concentrations of LH and FSH in concurrent serum and first-morning-voided (FMV) urine samples of 820 children (486 boys and 334 girls, age 0-17 years) were determined with time-resolved immunofluorometric assay (IFMA). The detection limit of IFMA was 0.018 IU/L for FSH, 0.015 IU/L for LH and 0.012 IU/L for LHspec. It was possible to measure the low prepubertal LH and FSH concentrations reliably in these samples due to the high sensitivity and low detection limits of IFMA. The correlation between serum and urinary gonadotropin values was high (r=0.751; p < 0.001 for FSH and r=0.720; p < 0.001 for LH), and the urinary and serum concentrations were close to each other. Correcting urinary gonadotropin concentrations on the basis of urinary density or creatinine did not improve the correlation. Age-related changes in urinary LH and FSH (U-LH and U-FSH) were examined. The concentrations of U-LH and U-FSH decreased from birth until the child was a few months old, after which the upper range of the U-LH levels of girls remained stable at below 0.5 IU/L until age 9 years and of boys below 1.0 IU/L until age 11 years. The upper range of the U-FSH levels of girls remained below 3.0 IU/L until age 10 years and of boys below the same concentration until age 12 years. The median U-LH concentration during the prepubertal period was about 0.06 for girls and 0.07 for boys. For the boys, this figure rose 10-fold by age 11, 40-fold by age 12 and 50-fold by age 13-14. The overall increase in the median U-LH concentrations was 75-fold from 5 to 15 years and 35-fold from Tanner stage G1 to G5. The corresponding figures for girls were 30-fold by age 11, 70-fold by age 12 and 90-fold by age 14; the overall increase in median U-LH concentrations was 90-fold from 5 to 15 years and 40-fold from Tanner stage B1 to B5 times. These finding indicate that the U-LH concentrations of FMV samples obtained from clinically prepubertal children reflect pubertal levels. The age-related changes in U-FSH concentrations were similar for boys and girls; the only difference was that the levels were generally higher for girls, in particular between ages 2 8 years. U-FSH reached a 5-fold level compared to prepubertal levels by the end of the puberty in both sexes. FMV U-LH, U-FSH and their ratios correlated well with the corresponding basal and GnRH-stimulated serum concentrations (P < 0.001). Receiver operating characteristic (ROC) curve analyses of urinary and serum LH and FSH concentrations showed that FMV U-LH and U-LH/U-FSH performed equally well as the GnRH test for differentiating early puberty (Tanner 2) from prepuberty (Tanner 1) [area under the curve (AUC) 0.768-0.890 vs. 0.712-0.858]. FMV U-LH and U-LH/U-FSH performed equally well as basal S-LH for predicting a pubertal GnRH test result (AUCs 0.90 0.93). Among the tests studied, only FMV U-LH differentiated the transitions from Tanner stage 1 to 2 and Tanner stage 2 to 3 (p < 0.001 for boys and p-0.003 for girls). Again, this corroborates that FMV U-LH is the most reliable tool for evaluation of pubertal development. Therefore, FMV urinary LH determinations, which are non-invasive and, at most, minimally stressful for the child patient, can be used for preliminary diagnostic evaluation of pubertal development. It reduces the need for S-LH determinations and the GnRH stimulation tests, both invasive procedures.
  • Holmberg, Ville (Helsingin yliopisto, 2004)
  • Siira, Lotta (Helsingin yliopisto, 2014)
    Streptococcus pneumoniae, or the pneumococcus, is a bacterium of the human nasopharyngeal normal flora that also causes non-invasive respiratory tract infections, and serious infections, such as pneumonia, septicaemia, and meningitis. Globally, the rise in pneumococcal antimicrobial resistance over the past few decades is a worrying trend. The bacterium is covered by a polysaccharide capsule and over 90 different kinds of pneumococcal capsules can be recognised by serotyping. The most important serotypes are included in the available polysaccharide and conjugate vaccines. The 10-valent conjugate vaccine has been part of the Finnish national vaccination programme since September 2010. In this study, the serotype and genotype clonality of the invasive pneumococcal population in Finland was studied in relation to antimicrobial resistance. All invasive pneumococci (n=7,765) isolated in Finland during 2002-2011 and a subset of non-invasive multidrug-resistant isolates (n=12) from 2008 were serotyped and studied for antimicrobial susceptibility. The penicillin-resistant isolates were genotyped by multi locus sequence typing (MLST) and pilus-encoding virulence genes were detected by PCR. A sequential multiplex PCR assay for deducting the serotypes of pneumococci was set up tailored to the serotype distribution of invasive isolates recovered in Finland. Serotype 14 was the predominant serotype every year of the study, representing 17.5% of all the invasive isolates. The proportion of invasive isolates non-susceptible to penicillin or erythromycin was high, and it increased over the study period, reaching 22% and 26% for penicillin and erythromycin, respectively, in 2011. The proportion of non-susceptible isolates was particularly high among isolates from children and within serotype 14. Among the genotyped isolates, international resistant clones such as PMEN3 Spain9VST156 and PMEN14 Taiwan19FST236 dominated. However, novel genotypes were also found, which illustrates the continuous recombination of pneumococci. This study showed that in Finland multidrug-resistant serotype 19A pneumococci appeared among the non-invasive isolates prior to large-scale vaccination. In many countries, the clone has emerged following vaccination. Pilus-encoding gene carriage, which may serve as a competitive advantage for the bacterium by facilitating adherence to the epithelium, was frequent among the penicillin- and multidrug-resistant isolates. In the future, a vaccine targeting the pilus proteins might successfully help to control these clones. The serotyping scheme, which was set up, is useful in surveillance, as knowledge of the serotype distribution of the invasive pneumococci is essential for vaccine development and monitoring of the vaccination programme.
  • Hannula, Johanna (Helsingin yliopisto, 2000)
  • Mattila, Eero (Helsingin yliopisto, 2013)
    Background and aims. Standard treatment of recurrent Clostridium difficileinfection (CDI) with antibiotics leads to recurrences in up to 50% of patients.In recent years the incidence and mortality of Clostridium difficile (C.difficile)enteritis have increased. Nevertheless, C.difficile has rarely been isolated in extraintestinal infections. The aims of the study were to investigate efficacy of rifaximin, metronidazole, fecal microbiota transplantation (FMT) and Clostridium difficile immune whey (CDIW) in the treatment of recurrent CDI and to characterize clinical feature and risk factors for extra-intestinal CDI. Subjects and methods. Study I was a prospective, randomized, double-blind study designed to compare CDIW with metronidazole for treatment of laboratory confirmed,mild to moderate episodes of recurrent CDI. CDIW was manufactured by immunization of cows in their gestation period with inactivated C. difficile vaccine.The resulting colostrum was processed, immunoglubulins were concentrated and the end product containing high titres of C. difficile immunoglobulin was used as CDIW. 20 patients received metronidazole at a dosage of 400 mg t.i.d. and 18 patients CDIW 200 ml t.i.d. Study II was a retrospective review of 70 patients with recurrent CDI who had undergone fecal transplantation. FMT was performed at colonoscopy by infusing fresh donor feces into cecum. Before transplantation, the patients had whole-bowel lavage with polyethylene glycol solution. Study III was a retrospective study of 32 patients who were treated with rifaximin for recurrent CDI. In Study IV extra-intestinal CDIs were searched for in an electronic database of all C. difficile positive isolates found during a 10-year period. The medical records were reviewed retrospectively. Disease severity and co-morbidities of the patients were evaluated using Horn disease severity and Charlson co-morbidity indexes. Results. In Study I, 10 weeks after the beginning of treatment, sustained responses were observed in 11 (55%) of 20 patients receiving metronidazole and 10(56%) of 18 patients treated with CDIW. In Study II, 12 weeks after FMT, 66 (94%)of 70 patients had a favourable response. In Study III, 12 weeks after rifaximin treatment 17 (53%) of 30 patients had no relapse. In Study IV extra-intestinal CDI was found in 31 patients who comprised 0.17% of all CDIs. One-year mortalityrate was 36% and it correlated with the severity of underlying diseases Conclusions. CDIW was as effective as metronidazole in the prevention of CDI recurrences and it was well tolerated. FMT through colonoscopy seems to be an effective treatment also for recurrent CDI caused by the virulent C difficile 027 strain. The MIC value of rifampin seemed to predict the response to rifaximin treatment. Extra-intestinal CDIs occur mainly in hospitalized patients with significant comorbidities.Extra-intestinal CDIs in the abdominal area may result either from intestinal perforation after infection or after intestinal surgery. C. difficile may reach distant sites via bacteremia. Mortality in extra-intestinal CDIs is associated with the severity of underlying diseases
  • Liebkind, Ron (Helsingfors universitet, 2008)
    The regeneration capacity of the adult mammalian central nervous system (CNS) is limited. Following an insult to the CNS, many environmental factors inhibiting or stimulating neuronal regrowth are activated. Several molecules including laminin have stimulating effects on CNS regeneration. Laminins are essential molecular constituents of all basement membranes of the body. In the CNS, laminins are involved in developmental events, such as neuronal migration and axon guidance, while in the adult CNS they participate in the formation and maintenance of the blood-brain-barrier (BBB) and are involved in trauma reactions of the CNS. Laminin-1 is a large glycoprotein and is composed from three disulfide-bonded subunits, α1, β1, and the γ1 chain. Many neurons express γ1 laminin in the mammalian adult brain; it is critical for hippocampal neuronal survival and is expressed by glial cells after CNS injury. The KDI peptide is derived from γ1 laminin as a neurotrophic peptide. In this thesis study, we analyzed the role of γ1 laminin and its KDI peptide in different settings of CNS injury. An experimental cell culture model mimicking a damaged CNS environment showed that the KDI peptide has a stimulating effect on neuronal survival and neurite outgrowth. We analyzed neurons from human embryonic spinal cord, retina, and neocortex, leading to findings that both neuronal survival and neurite outgrowth were stimulated by the soluble KDI peptide in all of these tissues. A stereotaxic injection of kainic acid into rat hippocampus was done for testing the possible protective effect of the KDI peptide. A preceding injection of the KDI peptide protected both hippocampal and neocortical areas of excitotoxic brain damage caused by kainic acid. Kainic acid alone caused serious tissue damage to the hippocampal and neocortical injection sites. The KDI peptide showed inhibition of glutamate excitotoxicity by inhibiting kainate, AMPA, and NMDA subclasses of glutamate receptors in patch clamp recordings. Neurons were cultured from human embryonic neocortex and from HEK 293 cells expressing recombinant glutamate subunits. These studies indicate that the KDI peptide of γ1 laminin enhances neuronal survival and protects against glutamate excitotoxicity at least partially through inhibition of various glutamate receptors. Following middle cerebral artery occlusion leading to focal brain ischemia in rats, various laminins were mapped both spatially and temporally. Laminin-1 was increased in basement membranes and scar-forming extracellular matrix; γ1 laminin was in-duced earlier than other laminins and expressed by reactive astrocytes. Similarly, the KDI peptide of γ1 laminin was expressed by reactive astrocytes surrounding the ischemic region but detected along major neuronal pathways as well. The different patterns of laminin expression suggest involvement of different laminins in different functions in the pathophysiology of experimental brain ischemia. In general, these studies present novel data on the expression of laminins in the healthy and damaged brain, demonstrate protective effects of the KDI tripeptide of γ1 laminin in cell cultures and in vivo in the brain, and give clues as to the mechanisms of KDI peptide neuroprotection.
  • Palojärvi, Anniina (Helsingin yliopisto, 2014)
    A complex interaction prevails between coagulation and inflammation. The coagulation system is adapted to thrombotic challenges during and after birth, leading to specific features in the coagulation system of the newborn. Inflammation and intra-alveolar fibrin formation characterize respiratory distress syndrome (RDS). Tissue factor (TF) is a link between inflammation and coagulation pathways. In the very low birth weight (VLBW) infant, birth and intensive care present major immunological challenges, and the developmental immaturity of the immune system adds to the risks of intensive care. A protective response to a strong inflammatory stimulus downregulates the antigen-presenting molecules (Human leukocyte antigen (HLA)-DR) on monocytes. If severe, however, the response may lead to immunodepression or immunoparalysis, which in adults is associated with increased morbidity and death. Antenatal betamethasone treatment for mothers at risk for premature delivery effectively reduces neonatal morbidity and mortality. This thesis evaluates the bidirectional interaction between inflammation and coagulation and combines the findings in VLBW infants with clinical morbidity. Patients were 56 VLBW infants, with a gestational age (GA) of less than 32 weeks and a birth weight of less than 1500 g. A control population comprised 25 healthy infants with a GA of more than 34 weeks. VLBW infants showed low monocyte HLA-DR expression. On day 3, 45% of infants presented with immunodepression. VLBW infants showed high plasma TF in circulation, but which did not lead to coagulation. In VLBW infants, tissue factor pathway inhibitor (TFPI) was the main anticoagulant in the first days; on day 3, however, the TF surge exceeded the TFPI capacity, leaving the VLBW infant with a pool of plasma TF. In VLBW infants, antenatal betamethasone associated with immunodepression and suppressed both proinflammatory IL-6 and anti-inflammatory IL-10. VLBW infants are postnatally in a state of immunodepression, which associated with RDS, low GA, and subsequent infections. Immunodepression may represent a link between low GA and risk for infections. TF is expressed in the lungs of a VLBW infant and leaks into circulation. TFPI could not control the TF surge on day 3. Plasma TF does not lead to thrombin formation, thereby making it available for inflammatory pathways (e.g. protease-activated receptors (PARs)). VLBW infants showed an inflammatory profile similar to adult sepsis or acute respiratory distress syndrome, with additional VLBW-specific features: a lower net anti-inflammatory cytokine effect without TF-induced activation of coagulation. Antenatal betamethasone (BM) was associated in a time-dependent manner to immunodepression, those infants with BM less than 24 hours before birth showing the deepest nadir in HLA-DR expression.
  • Pietola, Laura (Helsingin yliopisto, 2012)
    Hearing loss is the most common sensory deficit in humans. Genetic defects play a major part among patients with sensorineural hearing loss. Usher syndrome (USH) is an autosomal recessive disorder defined by bilateral sensorineural hearing loss and a visual impairment phenotypically similar to retinitis pigmentosa (RP). USH is divided into three main clinical types (USH1, USH2 and USH3), based on the severity and progression of the hearing impairment, the presence or absence of vestibular dysfunction, and the age of onset of RP. The most common form of Usher syndrome in Finland is USH3, which comprises 40% of all USH cases. USH3 is caused by mutations in the clarin 1 (CLRN1) gene. To date, treatment methods for sensorineural hearing loss are limited to rehabilitation with traditional hearing aids or cochlear implantation. An ideal cure would be targeted, long-term or permanent, and should cause as little damage as possible to the inner ear structure. Our studies focused on cochlear gene therapy and Usher syndrome type 3 (USH3). Finnish USH3 patients answered three questionnaires which evaluated their quality of life after cochlear implantation. We also collected data of these patients audiological tests and speech discrimination tests from their patient records. We developed an in vitro model suitable for cochlear gene transfer studies from a detached mouse round window membrane (RWM) and also tested the suitability of adeno-associated virus vectors and lentivirus vectors for cochlear gene therapy applications in cell lines and in the mouse cochlea. Cochlear implantation is beneficial for USH3 patients and improves their quality of life. The detached mouse RWM model is suitable for inner ear gene transfer studies in vitro. Manipulation of the RWM with AgNO3, trichloracetic acid or histamine-glycerol did not increase the permeability of the membrane. Lentivirus vectors are safe and can be used in gene transfer into the perilymph. Silencing of p53 protein may decrease apoptosis in the kanamycin-damaged mouse cochlea. AAV-delivered clarin-1 ribozyme may induce apoptosis in cochlear hair cells and cells of the stria vascularis. Apoptosis could explain the progressive nature of USH3.