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  • Tainio, Juuso (Helsingin yliopisto, 2015)
    Renal transplantation (RTx) has become an established treatment modality for end-stage renal disease in children. Along with the improvements in pre- and post-transplant care, the patient and graft outcomes have improved significantly during the past two decades. This attracts more attention to avoiding secondary complications and long-term side effects of the post-RTx immunosuppressive medication. Several risk factors cast a shadow over patients normal physical and mental development, but detailed reports on long-term outcome after pediatric RTx are scarce. This thesis was designed to investigate pubertal development and subsequent male fertility and semen quality with special emphasis on the effects of immunosuppressive medication on reproductive function. The study also aimed to analyze the prevalence of metabolic syndrome and its components in pediatric RTx patients and the association of these parameters with the long-term graft function. The onset of pubertal development occurred at the mean age of 12.7 years in boys with 22% considered delayed. In girls, however, no delayed development occurred, with the age at onset of puberty and menarche averaging 10.7 years and 12.5 years, respectively. Pubertal growth continued relatively long resulting in average final height of -1.7 height standard deviation score in boys and -1.2 in girls. The reproductive hormone levels were normal in a great majority of the patients. In young adult males who had received RTx in childhood, the free testosterone levels were lower and luteinizing hormone levels were higher in comparison with age-matched healthy controls. The RTx patients had also smaller testicular volumes and total sperm counts than the controls. Only a quarter of the RTx men who provided a semen sample had normospermia. Patients with a history of cyclophosphamide therapy had the worst outcome. Metabolic data were collected at several time points during a 13-year follow-up post-RTx. Hypertriglyceridemia associated with a worse kidney graft function at 1.5 and 5 years post-RTx, and it predicted the subsequent rate of kidney function decrease after 1.5 years post-RTx. Beyond the first postoperative year, other metabolic risk factors associated modestly with the long-term kidney graft function in pediatric RTx patients. The ambulatory BP monitoring data were retrospectively analyzed 5 to 10 years post-transplantation. The BP profiles were similar between renal, heart, and liver transplant groups. Hypertension was common especially at nighttime and the nocturnal BP dipping was often blunted. The use of antihypertensive medication did not notably change the ambulatory BP profile in RTx recipients. The BP variables correlated poorly with the metabolic parameters or kidney graft function.
  • Wedenoja, Satu (Helsingin yliopisto, 2007)
    The rare autosomal recessive disease congenital chloride diarrhea (CLD) is caused by mutations in the solute carrier family 26 member 3 (SLC26A3) gene on chromosome 7q22.3-31.1. SLC26A3 encodes for an apical epithelial chloride-bicarbonate exchanger, the intestinal loss of which leads to profuse chloride-rich diarrhea, and a tendency to hypochloremic and hypokalemic metabolic alkalosis. Although untreated CLD is usually lethal in early infancy, the development of salt substitution therapy with NaCl and KCl in the late 1960s made the disease treatable. While the salt substitution allows normal childhood growth and development in CLD, data on long-term outcome have remained unclarified. One of the world s highest incidences of CLD 1:30 000 to 1:40 000 occurs in Finland, and CLD is part of the Finnish disease heritage. We utilized a unique sample of Finnish patients to characterize the long-term outcome of CLD. Another purpose of this study was to search for novel manifestations of CLD based on the extraintestinal expression of the SLC26A3 gene. This study on a sample of 36 patients (ages 10-38) shows that the long-term outcome of treated CLD is favorable. In untreated or poorly treated cases, however, chronic contraction and metabolic imbalance may lead to renal injury and even to renal transplantation. Our results demonstrate a low-level expression of SLC26A3 in the human kidney. Although SLC26A3 may play a minor role in homeostasis, post-transplant recurrence of renal changes shows the unlikelihood of direct transporter modulation in the pathogenesis of CLD-related renal injury. Options to resolve the diarrheal symptoms of CLD have been limited. Unfortunately, our pilot trial indicated the inefficacy of oral butyrate as well. This study reveals novel manifestations of CLD. These include an increased risk for hyperuricemia, inguinal hernias, and probably for intestinal inflammation. The most notable finding of this study is CLD-associated male subfertility. This involves a low concentration of poorly motile spermatozoa with abnormal morphology, high seminal plasma chloride with a low pH, and a tendency to form spermatoceles. That SLC26A3 immunoexpression appeared at multiple sites of the male reproductive tract in part together with the main interacting proteins cystic fibrosis transmembrane conductance regulator (CFTR) and sodium-hydrogen exchanger 3 (NHE3) suggests novel sites for the cooperation of these proteins. As evidence of the cooperation, defects occurring in any of these transporters are associated with reduced male fertility. Together with a finding of high sweat chloride in CLD, this study provides novel data on extraintestinal actions of the SLC26A3 gene both in the male reproductive tract and in the sweat gland. These results provide the basis for future studies regarding the role of SLC26A3 in different tissues, especially in the male reproductive tract. Fortunately, normal spermatogenesis in CLD is likely to make artificial reproductive technologies to treat infertility and even make unassisted reproduction possible.
  • Riihimäki, Kirsi (Helsingin yliopisto, 2014)
    This study is the first naturalistic prospective long-term follow-up with a life-chart among primary care patients with depressive disorders. Patients with lifetime MDD spent 34% of follow-up time in MDEs, 24% in partial and only 42% in full remission. Nine in ten achieved at least partial and two-thirds full remission. Baseline severity of depression and substance use comorbidity predicted time spent in MDEs: a rise in Hamilton Rating Scale for Depression (HAMD) score of ten at baseline predicted 14 months and comorbid substance use disorder 25 months more time in MDEs. One-half of those who achieved partial remission and one-third of those who reached full remission were having at least one recurrence. The recurrences were predicted by personality disorders. The time from remission to recurrence was predicted by generalized anxiety disorder and somatoform disorder. One-tenth of patients attempted suicide one to three times. The incidence rate varied robustly depending on the level of depression, being 0 per 1000 patient-years during full remission, 5.8 during partial remission and 107 during MDEs. Functional and work ability were strongly associated with duration and severity of depression. Patients who belonged to the labour force spent one-third of the follow-up off work due to depression; two-thirds were granted sick leave, and one-tenth a disability pension due to depression. Longer duration of depression, comorbid disorders and having received social assistance predicted dropping out from work. A quarter of patients suffered from concurrent borderline personality disorder (BPD). Comorbid anxiety and substance use disorders were common among them. Concurrent BPD increased the severity and duration of depression, suicidal behaviour, unemployment and economic difficulties. This study revealed often slow and incomplete recovery and a common recurrent course, which needs to be taken into account when developing services. The use of measurement scales is warranted when planning and monitoring treatment. Comorbidity, concurrent substance use disorder, anxiety disorders, somatoform disorder and BPD all need to be taken into account in clinical practice guidelines. Duration of depression appears most decisive for suicide attempts among primary care patients with depression. Efforts should focus on the continuity of care.
  • Holma, Mikael (Helsingin yliopisto, 2010)
    Much of what we know regarding the long-term course and outcome of major depressive disorder (MDD) is based on studies of mostly inpatient tertiary level cohorts and samples predating the era of the current antidepressants and the use of maintenance therapies. In addition, there is a lack of studies investigating the comprehensive significance of comorbid axis I and II disorders on the outcome of MDD. The present study forms a part of the Vantaa Depression Study (VDS), a regionally representative prospective and naturalistic cohort study of 269 secondary-level care psychiatric out- and inpatients (aged 20-59) with a new episode of DSM-IV MDD, and followed-up up to five years (n=182) with a life-chart and semistructured interviews. The aim was to investigate the long-term outcome of MDD and risk factors for poor recovery, recurrences, suicidal attempts and diagnostic switch to bipolar disorder, and the association of a family history of different psychiatric disorders on the outcome. The effects of comorbid disorders together with various other predictors from different domains on the outcome were comprehensively investigated. According to this study, the long-term outcome of MDD appears to be more variable when its outcome is investigated among modern, community-treated, secondary-care outpatients compared to previous mostly inpatient studies. MDD was also highly recurrent in these settings, but the recurrent episodes seemed shorter, and the outcome was unlikely to be uniformly chronic. Higher severity of MDD predicted significantly the number of recurrences and longer time spent ill. In addition, longer episode duration, comorbid dysthymic disorder, cluster C personality disorders and social phobia predicted a worse outcome. The incidence rate of suicide attempts varied robustly de¬pending on the level of depression, being 21-fold during major depressive episodes (MDEs), and 4-fold during partial remission compared to periods of full remission. Although a history of previous attempts and poor social support also indicated risk, time spent depressed was the central factor determining overall long-term risk. Switch to bipolar disorder occurred mainly to type II, earlier to type I, and more gradually over time to type II. Higher severity of MDD, comorbid social phobia, obsessive compulsive disorder, and cluster B personality disorder features predicted the diagnostic switch. The majority of patients were also likely to have positive family histories not exclusively of mood, but also of other mental disorders. Having a positive family history of severe mental disorders was likely to be clinically associated with a significantly more adverse outcome.
  • Tiippana-Kinnunen, Tarja (Helsingin yliopisto, 2014)
    This 15-year follow-up focused on radiographic outcome, functional capacity, work disability and comorbidity in 86 patients (age 18-65 years), with early (≤ 12 months of disease duration) rheumatoid arthritis (RA) collected in 1986-1989 in Helsinki area and treated with early initiated DMARD therapy. The outcome was determined in relation to DMARD continuity, early disease activity, early radiographic remission (ERR) and baseline comorbidity. Of the 70 patients evaluated at 15-year examination, 50 (71%) needed continuous DMARD therapy (group A). In 20 patients (29%) DMARDs were discontinued due to clinical remission. Of these disease flared up and DMARDs were reintroduced in 9 patients (45%, group B) and 11 (55%) remained in remission (group C). The 15-year outcome was most favourable in group C: 64% of patients being in remission, according to American Collage of Rheumatology criteria, compared with 0% in B and 6% in A. Final functional capacity [mean Health Assessment Questionnaire (HAQ)] was 0.24 in C, 0.38 in B and 0.60 in A and radiographic outcome assessed with mean Larsen score (LS) 12, 25 and 54, respectively. As conclusion, patients whose DMARDs are discontinued due to remission, should be followed up closely for a flare-up of the disease. For those whose disease flares up, DMARDs should be reintroduced immediately. The 15-year LS of 69 patients determined in relation to ERR [an increase of LS ≤ 1 Larsen unit (LU) between two sequential sets of small joint radiographs during the first 2 years]. Mean 15-year LS of the small joints (14) and LS of the large joints (0.8) were lower in patients with sustained ERR (both year 1 and year 2), compared with 33 and 1.9 in patients with temporary ERR (either year 1 or year 2) or with 67 and 6.3 in patients with radiographic progression ≥ 2 LU during both first years. Considering these findings, radiographic remission should be a treatment goal in RA and early progression in small joints should be taken as a warning sign for later damage of large joints. Of 80 patients with adequate data, 20% had at least one comorbid condition at baseline and 60 % had comorbidities at the 15-year visit or at time od death, most commonly hypertension (30%), cardiovascular diseases (14%), malignancies (11%) or osteoporosis (11%). Elderly patients with baseline comorbidity showed higher disease activity both during first year of RA and at endpoint than younger patients without comorbidities. Of the 86 patients, 42 (49%) retired due to work disability (WD) during 15 years or before death, most of these due to RA. The Kaplan-Meier estimated cumulative RA-related WD was less frequent in patients with low disease activity during first 12 months (3% at year 5, 10% at year 10 and 22% at year 15) than in those with moderate or high disease activity (28%, 55% and 64%, respectively). The results of this study showed that most patients with RA need continuous DMARD treatment and emphasize the importance of targeting to clinical remission and to radiographic remission in early phase of the disease for the long-term outcome in RA.
  • Pelttari, Hanna (Helsingin yliopisto, 2012)
    The goal of initial therapy in differentiated thyroid cancer (DTC) is to minimize disease related mortality and morbidity by surgically removing the primary tumour and all metastasized tumour tissue. A second goal is to minimize risk of recurrence and metastatic spread by facilitating post-operative radio-iodine ablation (RRA), permitting accurate long-term surveillance. Recurrences are relatively common even in patient population at low-risk for cancer-specific death, occurring in 10-40% of cases. The treatment and follow-up schemes have varied between centres and there is ongoing debate about appropriate methods for primary therapy and surveillance. With the increasing incidence of DTC, the need for new factors prognostic of disease recurrence is growing; most of the prognostic systems have been validated with cancer-specific death as outcome. We designed an observational retrospective study to assess the outcome of a large cohort of patients with low-risk thyroid carcinoma and with a uniform primary therapy. All patients belong to TNM stage I or II and were considered disease-free after initial therapy. We evaluated the safety and efficacy of a surveillance paradigm, comprising yearly thyroglobulin (TG) measurements on L-T4 therapy and neck ultrasonography (US) every second year, with an increase in TG to a detectable level being an indication for further investigations. We examined the health-related quality of life (HRQoL) of the patient cohort after long-term follow-up using a validated multidimensional method (15D®). We studied factors correlating with disease recurrence, including patient demographics, tumour characteristics and parameters with primary therapy, in 495 low-risk patients treated at Helsinki University Central Hospital over a 15-year period. Post-operative and post-ablative TG concentrations, age, tumour size, local infiltration and nodal metastasis at primary surgery, number of neck US, fine-needle aspiration biopsies (FNABs) and operations performed, presence of BRAF mutation in papillary tumour tissue, disease recurrences and cancer-specific deaths were evaluated. The majority of patients had total thyroidectomy and radio-active iodine remnant ablation as initial treatment. The median follow-up was 16 (range 10 24) years. Fifty-one patients (10.3%) experienced disease recurrence during follow-up. A combination of neck US and high TG revealed most recurrences. In multiple logistic regression analysis, post-ablative measurable TG concentrations (odds ratio (OR) 3.72, confidence interval (CI) 1.71 8.05, P = 0.0009) and presence of local infiltration on primary surgery (OR 2.66, CI 1.03 6.90, P = 0.04) were the only independent predictors of recurrence. BRAF V600E mutation is common (prevalence 67%) in this low-risk papillary thyroid cancer patient group but does not predict recurrence after long-term follow-up after initial treatment with total thyroidectomy (TTE) and RRA. HRQoL was preserved in DTC patients compared to a large age- and gender-standardized sample of the general Finnish population (n = 6001). After long-term follow-up, overall HRQoL is comparable with that of the general population. DTC patients demonstrate an age-related decline in HRQoL, similar to that seen in the population in general. We conclude that post-ablative TG concentration is a strong predictor of disease recurrence in DTC. Although longer follow-up is needed, monitoring low-risk differentiated thyroid carcinoma patients with neck US and TG measured on L-T4 appears safe and effective.The same principles have now been adapted also by many international centres.
  • Kosola, Silja (Helsingin yliopisto, 2013)
    Since survival rates after pediatric liver transplantation (LT) have improved, the focus of interest has shifted to gradually evolving histological changes, long-term complications, and quality of life. Histological changes and complications are closely associated with each other and the immunosuppressive medication used, and may in turn affect the LT recipient s perception of quality of life. This thesis investigates the survival and complication rates, usefulness of protocol liver biopsies and long-term histological status of the liver graft, and cholesterol metabolism profile after pediatric LT. The effect of immunosuppression on biopsy-proven changes and cholesterol metabolism is also evaluated. In the quality of life assessment, the effects of different complications are explored. The study population includes all 99 children less than 18 years who underwent LT in Finland between 1987 and 2007. Retrospective data on LT indications, surgical procedures, surgical and medical complications, immunosuppression, and annual follow-up visits were collected from patient records and the national LT registry. For 12 patients transplanted for hepatoblastoma (HB) or hepatocellular carcinoma (HCC), also relevant cancer treatment details were gathered. Cross-sectional data included liver biopsies of 54 LT recipients (82% of survivors), serum levels of noncholesterol sterols (surrogate markers of cholesterol metabolism) and fibroblast growth factor 21 (FGF21) in 49 LT recipients (74%), and health-related quality of life (HRQoL) assessment of 57 LT recipients (86%) at median 10-11 years posttransplant. Serum levels of noncholesterol sterols and FGF21 were compared to 93 controls matched for age and gender, and the HRQoL measurements to 141 randomly picked controls matched for age, gender, and place of residence. Of the 12 patients with liver malignancies, six had HB and six HCC. All patients received neoadjuvant chemotherapy, but no routine chemotherapy was administered after LT. Median time from diagnosis to LT was 7 (2-133) months. At LT, none of the patients had radiological evidence of extrahepatic disease. The overall survival rates at one, five, and ten years after LT were 100%, 80%, and 67%, respectively. Survival was similar between the tumor types, and two deaths occurred secondary to tumor recurrence, one of each type. Biopsies of 18 patients (33%) showed near-normal histology with minimal changes. Portal inflammation was present in 14 samples (26%), and was less frequent in patients whose immunosuppression included steroids (14% vs. 47%; p = 0.008). Fibrosis was found in 21 biopsies (39%), and fibrosis staging correlated negatively with serum prealbumin levels (r = -0.364, p = 0.007) and positively with portal inflammation (r = 0.350, p = 0.010) and periportal cytokeratin 7 staining (r = 0.529, p less than 0.001). Microvesicular steatosis was detected in 23 biopsies (43%; 5-80% of hepatocytes), and correlated with the patients body-mass-index (r = 0.458, p less than 0.001) but not with steroid use. The histological findings were mainly mild and led to treatment changes in ten patients (19%), while only one minor complication was encountered. Serum lipid levels were similar in LT recipients and controls. LT recipients, however, displayed increased whole-body synthesis and decreased absorption of cholesterol compared to controls (lathosterol to cholesterol ratio 129 ± 55 vs. 96 ± 41, respectively, p less than 0.001; campesterol to cholesterol ratio 233 ± 91 vs. 316 ± 107, respectively, p less than 0.001). Low-dose methylprednisolone and azathioprine were negatively associated with the lathosterol/sitosterol ratio (r = -0.492, p less than 0.001 and r = -0.383, p = 0.007, respectively) reflecting a favorable effect on cholesterol metabolism. FGF21 levels were higher in LT recipients than in controls (248 pg/mL vs. 77 pg/mL, p less than 0.001). Under school-aged LT recipients and controls had similar HRQoL, and 54% of LT recipients aged over 7 scored within the controls normal range on all HRQoL domains. Biliary complications, reoperations, and obesity were independently associated with decreased HRQoL (p less than 0.05 for all). For those LT recipients already attending adult health care, physical functioning and general health yielded reduced scores (p less than 0.05). Still 64% of adults considered their health excellent. Sexual health was similar to controls although LT recipients may experience problems with their orgasm strength (p = 0.050). In conclusion, continued use of low-dose steroids seems to be associated with milder changes of both liver graft histology and cholesterol metabolism. Normal HRQoL and sexual health are achievable in long-term survivors of pediatric LT.
  • Sistonen, Saara (2010)
    Esophageal atresia (EA), a common congenital anomaly comprising interrupted esophagus with or without a tracheoesophageal fistula (TEF), affects one in 2840 newborns. Over half have associated anomalies. After EA repair in infancy, gastroesophageal reflux (GER) and esophageal dysmotility and respiratory problems are common. As there exist no previous population-based long-term follow-up-studies on EA, its long-term sequelae are unclear. The aims of this study were to assess the cancer incidence (I), esophageal morbidity and function (II), respiratory morbidity (III), and the spinal defects (IV) in adults with repaired EA. All patients treated for EA at the Hospital for Children and Adolescents, University of Helsinki, from 1947 to 1985 were identified, and those alive with their native esophagus were contacted, and the first hundred who replied made up the study group. The patients were interviewed, they filled in symptom questionnaires, and they underwent esophageal endoscopy and manometry, pulmonary function tests, and a full orthopedic evaluation was performed with radiographs of the spine. The questionnaire was also sent by mail to adults with repaired EA not attending the clinical study, and to 287 general population-derived controls matched for age, gender, and municipality of residence. Incidence of cancer among the study population was evaluated from the population-based countrywide cancer registry. 169 (72%) adults with repaired EA replied; 101 (42%) (58 male) participated in the clinical studies at a median age of 36 years (range, 22-56). Symptomatic GER occurred in 34% and dysphagia in 85% of the patients and in 8% and 2% of the controls (P<0.001 for both). The main endoscopic findings included hiatal hernia (28%), Barrett´s esophagus (11%), esophagitis (8%), and stenotic anastomosis (8%). Histology revealed esophagitis in 25 individuals, and epithelial metaplasia in another 21. At immunohistochemistry, CDX2-positive columnar epithelial metaplasia was present in all 21 individuals, and 6 of these also demonstrated goblet cells and MUC2 positivity. In all histological groups, GER and dysphagia were equally common (P=ns). Esophageal manometry demonstrated non-propagating peristalsis in most of the patients, and low ineffective pressure of the distal esophageal body in all. The changes were significantly worse in those with epithelial metaplasia (P≤0.022). Anastomotic complications (OR 8.6-24, 95%CI 1.7-260, P=0.011-0.008), age (OR 20, 95%CI 1.3-310, P=0.034), low distal esophageal body pressure (OR 2.6, 95%CI 0.7-10, P=0.002), and defective esophageal peristalsis (OR 2.2, 95%CI 0.4-11, P=0.014) all predicted development of epithelial metaplasia. Despite the high incidence of esophageal metaplasia, none of the EA patients had suffered esophageal cancer, according to the Finnish Cancer Registry. Although three had had cancer (SIR, 1.0; 95% CI, 0.20-2.8). The overall cancer incidence among adults with repaired EA did not differ from that of the general Finnish population. Current respiratory symptoms occurred in 11% of the patients and 2% of the controls (P<0.001). Of the patients, 16%, and 6% of the controls had doctor-diagnosed asthma (P<0.001). A total of 56% and 70% of the patients and 20% and 50% of the controls had a history of pneumonia and of bronchitis (P<0.001 for both). Respiratory-related impaired quality of life was observable in 11% of the patients in contrast to 6% of the controls (P<0.001). PFT revealed obstruction in 21 of the patients, restriction in 21, and both in 36. A total of 41 had bronchial hyper-responsiveness (BHR) in HCT, and 15 others had an asthma-like response. Thoracotomy-induced rib fusion (OR 3.4, 95%CI 1.3-8.7, P=0.01) and GER-associated epithelial metaplasia in adulthood (OR 3.0, 95%CI 1.0-8.9, P=0.05) were the most significant risk factors for restrictive ventilatory defect. Vertebral anomalies were evident in 45 patients, predominating in the cervical spine in 38. The most significant risk factor for the occurrence of vertebral anomalies was any additional anomaly (OR 27, 95%C I8-100). Scoliosis (over 10 degrees) was observable in 56 patients, over 20 degrees in 11, and over 45 degrees in one. In the EA patients, risk for scoliosis over 10 degrees was 13-fold (OR 13, 95%CI 8.3-21) and over 20 degrees, 38-fold (OR 38, 95%CI 14-106) when compared to that of the general population. Thoracotomy-induced rib fusion (OR 3.6, 95%CI 0.7-19) and other associated anomalies (OR 2.1, 95%CI 0.9-2.9) were the strongest predictive factors for scoliosis. Significant esophageal morbidity associated with EA extends into adulthood. No association existed between the esophageal symptoms and histological findings. Surgical complications, increasing age, and impaired esophageal motility predicted development of epithelial metaplasia after repair of EA. According to our data, the risk for esophageal cancer is less than 500-fold that of the general population. However, the overall cancer incidence among adults with repaired EA did not differ from that of the general population. Adults with repaired EA have had significantly more respiratory symptoms and infections, as well as more asthma, and allergies than does the general population. Thoracotomy-induced rib fusion and GER-associated columnar epithelial metaplasia were the most significant risk factors for the restrictive ventilatory defect that occurred in over half the patients. Over half the patients with repaired EA are likely to develop scoliosis. Risk for scoliosis is 13-fold after repair of EA in relation to that of the general population. Nearly half the patients had vertebral anomalies. Most of these deformities were diagnosed neither in infancy nor during growth. The natural history of spinal deformities seems, however, rather benign, with spinal surgery rarely indicated.
  • Palmu, Sauli (Helsingin yliopisto, 2013)
    Every fourth injured child seeking medical aid has sustained a fracture. Tibial fracture (annual incidence in less than 17 year old citizens in Finland is 1/1000) is the third most common fracture in children and femoral fracture (0.3/1000) among the most common pediatric injuries leading to hospitalization. Long-term treatment result of these fractures is not well known and there are no studies of treatment injuries in this pediatric patient population. Altogether 94 tibial and 74 femoral fractures were treated under anesthesia in Aurora Hospital, Helsinki between 1980-89. All but 5 of the tibial fractures were manipulated under anesthesia and casted. A remanipulation was performed in 41 patients. Femoral fractures were treated with skeletal traction in 62 patients, with internal fixation in 8 patients and by cast-immobilization 4 patients. A patients assessment form and an invitation to participate in a clinical and radiological examination at a mean follow-up of more than 20 years (16-32) was sent to all 168 patients. Six of the 58 tibial fracture patients that responded reported pain as their only memory of treatment. Results of tibial fracture treatment were satisfactory with few exceptions: functionally significant axial malalignment, limb length discrepancies nor arthritis was not found excluding four patients with >20° rotational deformity of the tibia. On the contrary 21/52 of the femoral fracture patients examined had angular malalignment of the femur exceeding 10°. Ten patients walked with a limp and leg-length discrepancy of more than 15 mm was measured in 8 patients. Knee arthritis had developed in 6/15 patients who were older than 10 years at the time of the injury. There was a positive correlation between angular deformity and knee arthritis. Treatment injuries were evaluated using patient compensation data from the Finnish Patient Insurance Centre (PIC): 50 claims involving tibial fracture treatment, 30 involving femoral fracture treatment were filed during the study period between 1997-2004. Compensation was granted in 35/50 claims after tibial fracture treatment and in 16/30 after femoral fracture treatment. The most common reasons for compensations in tibial fractures were missed diagnosis and inappropriate casting technique and delay in treatment, unnecessary or inappropriate treatment in femoral fractures. Most of the treatment injuries were regarded in retrospect as avoidable. Satisfactory long-term results in pediatric tibial fractures treated with closed manipulation and cast-immobilization can be expected. Many children require remanipulation to maintain satisfactory alignment, however. Over 10 year old patients with femoral malunion run a high risk of early knee arthritis. Most treatment injuries in pediatric tibial and femoral fractures can be avoided by accurate primary diagnostics, correct casting techniques and appropriate surgery.
  • Kirjavainen , Mikko (Helsingin yliopisto, 2010)
    Background: Brachial plexus birth palsy (BPBP) most often occurs as a result of foetal-maternal disproportion. The C5 and C6 nerve roots of the brachial plexus are most frequently affected. In contrast, roots from the C7 to Th1 that result in total injury together with C5 and C6 injury, are affected in fewer than half of the patients. BPBP was first described by Smellie in 1764. Erb published his classical description of the injury in 1874 and his name became linked with the paralysis that is associated with upper root injury. Since then, early results of brachial plexus surgery have been reasonably well documented. However, from a clinical point of view not all primary results are maintained and there is also a need for later follow-up results. In addition most of the studies that are published emanate from highly specialized clinics and no nation wide epidemiological reports are available. One of the plexus injuries is the avulsion type, in which the nerve root or roots are ruptured at the neural cord. It has been speculated whether this might cause injury to the whole neural system or whether shoulder asymmetry and upper limb inequality results in postural deformities of the spine. Alternatively, avulsion could manifest as other signs and symptoms of the whole musculoskeletal system. In addition, there is no available information covering activities of daily living after obstetric brachial plexus surgery. Patients and methods: This was a population-based cross-sectional study on all patients who had undergone brachial plexus surgery with at least 5 years of follow-up. An incidence of 3.05/1000 for BPBP was obtained from the registers for this study period. A total of 1706 BPBP patients needing hospital treatment out of 1 717 057 newborns were registered in Finland between 1971 and 1997 inclusive. Of these BPBP patients, 124 (7.3%) underwent brachial plexus surgery at a mean age of 2.8 months (range: 0.4―13.2 months). Surgery was most often performed by direct neuroraphy after neuroma resection (53%). Depending on the phase of the study, 105 to 112 patients (85-90%) participated in a clinical and radiological follow-up assessment. The mean follow up time exceeded 13 years (range: 5.0―31.5 years). Functional status of the upper extremity was evaluated using Mallet, Gilbert and Raimondi scales. Isometric strength of the upper limb, sensation of the hand and stereognosis were evaluated for both the affected and unaffected sides then the differences and their ratios were calculated and recorded. In addition to the upper extremity, assessment of the spine and lower extremities were performed. Activities of daily living (ADL), participation in normal physical activities, and the use of physiotherapy and occupational therapy were recorded in a questionnaire. Results: The unaffected limb functioned as the dominant hand in all, except four patients. The mean length of the affected upper limb was 6 cm (range: 1-13.5 cm) shorter in 106 (95%) patients. Shoulder function was recorded as a mean Mallet score of 3 (range: 2―4) which was moderate. Both elbow function and hand function were good. The mean Gilbert elbow scale value was 3 (range: -1―5) and the mean Raimondi hand scale was 4 (range:1―5). One-third of the patients experienced pain in the affected limb including all those patients (n=9) who had clavicular non-union resulting from surgery. A total of 61 patients (57%) had an active shoulder external rotation of less than 0° and an active elbow extension deficiency was noted in 82 patients (77%) giving a mean of 26° (range: 5°―80°). In all, expect two patients, shoulder external rotation strength at a mean ratio 35% (range: 0―83%) and in all patients elbow flexion strength at a mean ratio of 41% (range: 0―79%) were impaired compared to the unaffected side. According to radiographs, incongruence of the glenohumeral joint was noted in 15 (16%) patients, whereas incongruence of the radiohumeral joint was found in 20 (21%) patients. Fine sensation was normal for 34/49 (69%) patients with C5-6 injury, for 15/31 (48%) with C5-7 and for only 8/25 (32%) of patients with total injury. Loss of protective sensation or absent sensation was noted in some palmar areas of the hand for 12/105 patients (11%). Normal stereognosis was recorded for 88/105 patients (84%). No significant inequalities in leg length were found and the incidence of structural scoliosis (1.7%) did not differ from that of the reference population. Nearly half of the patients (43%) had asynchronous motion of the upper limbs during gait, which was associated with impaired upper limb function. Data obtained from the completed questionnaires indicated that two thirds (63%) of the patients were satisfied with the functional outcome of the affected hand although one third of all patients needed help with ADL. Only a few patients were unable to participate in physical activities such as: bicycling, cross-country skiing or swimming. However, 71% of the patients reported problems related to the affected upper limb, such as muscle weakness and/or joint stiffness during the aforementioned activities. Incongruity of the radiohumeral joints, extent of the injury, avulsion type injury, age less than three months of age at the time of plexus surgery and inexperience of the surgeon was related to poor results as determined by multivariate analyses. Conclusions: Most of the patients had persistent sequelae, especially of shoulder function. Almost all measurements for the total injury group were poorer compared with those of the C5-6 type injury group. Most of the patients had asymmetry of the shoulder region and a shorter affected upper limb, which is a probable reason for having an abnormal gait. However, BPBP did not have an effect on normal growth of the lower extremities or the spine. Although, participation in physical activities was similar to that of the normal population, two-thirds of the patients reported problems. One-third of the patients needed help with ADL. During the period covered by this study, 7.3% BPBP of patients that needed hospital treatment had a brachial plexus operation, which amounts to fewer than 10 operations per year in Finland. It seems that better results of obstetric plexus surgery and more careful follow-up including opportunities for late reconstructive procedures will be expected, if the treatment is solely concentrated on by a few specialised teams.
  • Heikkinen, Marja (Helsingin yliopisto, 2008)
    The aim of the study was to evaluate long-term results of operative treatment for Hirschsprung's disease(HD) and internal anal sphincter achalasia. Fecal continence and quality of life were evaluated by a questionnaire in 100 adult patients who had undergone surgery for HD, during 1950-75. Fecal continence was evaluated using a numerical scoring described by Holschneider. Fifty-four of the 100 patients underwent clinical examination, rigid sigmoidoscopy and manometric evaluation. In anorectal manometry basal resting pressure(BRP)and maximal squeeze pressure(MSP) were measured and voluntary sphincter force(VSF) was calculated by subtracting the BRP from MSP. The results of operative treatment for adult HD were compared with the results of the patients operated in childhood. In adult HD the symptoms are such mild that the patients attain adolescence or even adulthood. The patients with HD and cartilage-hair-hypoplasia were specifically evaluated. The outcome of the patients with internal anal sphincter achalasia operated on by myectomy was evaluated by a questionnaire and continence was evaluated using a numerical scoring described by Holschneider. Of the 100 patients operated on for HD 38 patients had completely normal bowel habits. A normal or good continence score was found in 91 our of 100 patients. Nine patients had fair continence. One of the patients with fair continence had Down's syndrome and two were mentally retarded for other reasons. Only one patient suffered from constipation. In anorectal manometry the difference in BRP between patients with normal and good continence was statistically significant, whereas the difference between good and fair continence groups was not statistically significant. The differences on MSP and VSF between patient groups with different continence outcome were not statistically significant. The differences between patient groups and normal controls were statistically significant in BRP and MSP. In VSF there was not statistically significant difference between the patients and the normal controls. The VSF reflects the working power of the muscles including external sphincter, levator ani and gluteal muscles. The patients operated at adult age had as good continence as patients operated in childhood. The patients with HD and cartilage-hair-hypoplasia had much more morbidity and mortality than non-cartilage-hair-hypoplasia HD patients. The mortality was as high as 38%. In patients with internal anal sphincter achalasia the constipation was cured or alleviated by myectomy whereas a significant number suffered from soiling-related social problems.
  • Raulio, Susanna (Helsingin yliopisto, 2011)
    Work has a central role in the lives of big share of adult Finns and meals they eat during the workday comprise an important factor in their nutrition, health, and well-being. On workdays, lunch is mainly eaten at worksite canteens or, especially among women, as a packed meal in the workplace s break room. No national-level data is available on the nutritional quality of the meals served by canteens, although the Finnish Institute of Occupational Health laid out the first nutrition recommendations for worksite canteens in 1971. The aim of this study was to examine the contribution of various socio-demographic, socioeconomic, and work-related factors to the lunch eating patterns of Finnish employees during the working day and how lunch eating patterns influence dietary intake. Four different population-based cross-sectional datasets were used in this thesis. Three of the datasets were collected by the National Institute for Health and Welfare (Health Behaviour and Health among the Finnish Adult Population survey from 1979 to 2001, n=24746, and 2005 to 2007, n=5585, the National Findiet 2002 Study, n=261), and one of them by the Finnish Institute of Occupational Health (Work and Health in Finland survey from 1997, 2000, and 2003, n=6369). The Health Behaviour and Health among the Finnish Adult Population survey and the Work and Health in Finland survey are nationally representative studies that are conducted repeatedly. Survey information was collected by self-administered questionnaires, dietary recalls, and telephone interviews. The frequency of worksite canteen use has been quite stable for over two decades in Finland. A small decreasing trend can be seen in all socioeconomic groups. During the whole period studied, those with more years of education ate at worksite canteens more often than the others. The size of the workplace was the most important work-related determinant associated with the use of a worksite canteen. At small workplaces, other work-related determinants, like occupation, physical strain at work, and job control, were also associated with canteen use, whereas at bigger workplaces the associations were almost nonexistent. The major social determinants of worksite canteen availability were the education and occupational status of employees and the only work-related determinant was the size of the workplace. A worksite canteen was more commonly available to employees at larger workplaces and to those with the higher education and the higher occupational status. Even when the canteen was equally available to all employees, its use was nevertheless determined by occupational class and the place of residence, especially among female employees. Those with higher occupational status and those living in the Helsinki capital area ate in canteens more frequently than the others. Employees who ate at a worksite canteen consumed more vegetables and vegetable and fish dishes at lunch than did those who ate packed lunches. Also, the daily consumption of vegetables and the proportion of the daily users of vegetables were higher among those male employees who ate at a canteen. In conclusion, life possibilities, i.e. the availability of a canteen, education, occupational status, and work-related factors, played an important role in the choice of where to eat lunch among Finnish employees. The most basic prerequisite for eating in a canteen was availability, but there were also a number of underlying social determinants. Occupational status and the place of residence were the major structural factors behind individuals choices in their lunch eating patterns. To ensure the nutrition, health, and well-being of employees, employers should provide them with the option to have good quality meals during working hours. The availability of worksite canteens should be especially supported in lower socioeconomic groups. In addition, employees should be encouraged to have lunch at a worksite canteen when one is available by removing structural barriers to its use.
  • Harve, Heini (Helsingin yliopisto, 2009)
    Sudden cardiac arrest (CA) is one of the leading causes of death in Europe. It has been estimated that about 40 % of CA victims have ventricular fibrillation (VF) at the time of the first heart rhythm analysis. The treatment for VF is immediate cardiopulmonary resuscitation (CPR) and rapid defibrillation. The automated external defibrillator (AED) and the concept of public access defibrillation (PAD) may be a key to shortening defibrillation delays. Recent studies have shown that PAD programs are associated with high survival rates from VF when devices have been placed in certain risk sites and used by trained laypersons. Today many public places are equipped with AEDs. The purpose of this study was to find new ways of utilizing layperson defibrillation and promote the concept of public access defibrillation (PAD). The study explored the use of AEDs by non-medical first responders in Finland and cabin crew on board a commercial aircraft. A simulated study was performed to explore the role of dispatcher assistance in layperson CPR and defibrillation. A 15-year follow-up study of 59 one-year survivors after successful out-of-hospital resuscitation was performed to evaluate the long-term quality of life of the CA patients. Although there are many AEDs in use by non-medical first responders in Finland, the results of the study showed that there are large variations between individual first response units. This is considered to be caused by the lack of national standards and regulations that would define a full integration of first-responder programmes into the Emergency Medical Services system. The goal of rapid defibrillation in five minutes after the onset of CA is difficult to achieve in Finland due to sparse population and long distances. Local PAD programs may shorten the defibrillation delays. Dispatcher assistance in defibrillation by a layperson not trained to use an AED seems feasible and does not compromise the performance of CPR. In a simulated study, the quality of mouth-to-mouth ventilation performed by laypersons was found to be better after CPR training compared with performance with dispatcher assistance before training. Training was not found to have an influence on the quality of compressions or defibrillation compared with dispatcher assistance of untrained laypersons. The target groups for CPR and defibrillation training need further evaluation. The placements of the AEDs in public areas should be known by the emergency response center and the location should be marked with an international sign. The finding that once a good neurological outcome after CA is achieved, it can be maintained for more than 10 years, encourages further efforts to improve the survival of CA patients.
  • Toivonen, Päivi (Helsingin yliopisto, 2011)
    Uveal melanoma (UM) is the most common primary ocular malignancy in adults. In Finland, approximately 50 new cases are diagnosed yearly. Up to 50% of UM metastasize, mostly to the liver, although other organs are also affected. Despite improvements in the management of the primary tumour, the survival rates of patients with metastatic UM are poor. Until the 1970s, UMs were treated by enucleation i.e. removal of the eye. Currently, UM is usually treated by brachytherapy, which is known to influence tumour cells and blood vessels. UMs enucleated both primarily and secondarily after brachytherapy contain tumour-infiltrating macrophages, and a high number of macrophages in primary UM is associated with a shorter survival and a higher microvascular density (MVD) within the tumour tissue. The latter is independently associated with a shorter time to metastatic death. Macrophages have several diverse roles depending on their response to variable signals from the surrounding microenvironment. They function as scavengers, as producers of angiogenic and growth factors as well as proteases, which modulate extracellular matrix. Thus, tumour invasiveness and the risk for metastasis increase with increasing macrophage density. The aim of this study was to evaluate the effects of regression and progression of UM on macrophage numbers and microcirculation factors. Tumour regression is induced by primary brachytherapy, and tumour progression is evidenced by the development of metastases. Understanding the biological behaviour of UMs in the both states may help us in finding new treatment modalities against this disease. To achieve these aims case-control analyses of irradiated UMs and primarily-enucleated eyes (34 matched pairs) were performed. UMs were stained immunohistochemically to detect macrophages, extravascular matrix (EVM) loops and networks, and MVD. Following brachytherapy, a lower MVD was observed. The average number of macrophages remained unchanged. Considering that irradiated melanomas may still contain proliferating tumour cells, a clinically-relevant consequence of my study would be the reassurance that the risk for metastasis is likely to be reduced, given that the low MVD in untreated UMs indicates a favourable prognosis. The effect of progression on macrophages was studied in a paired analysis of primarily-enucleated UM and their corresponding hepatic metastases (48 pairs). A cross-sectional histopathological analysis of these pairs was carried out by staining both specimens in a similar way to the first study. MVD was greater in hepatic metastases than in corresponding primary tumours, and the survival of the patient tended to be shorter if hepatic metastases had a higher MVD. Hepatic metastases had also more dendritic macrophages than the primary UMs. Thus, the progression to metastasis seems to alter the inflammatory status within the tumour. Furthermore, determining MVD of biopsied hepatic metastases may serve as a supplementary tool in estimating the prognosis of patients with metastatic uveal melanoma. After irradiation, the majority of treated eyes have been clinically observed to have pigmented episcleral deposits. A noncomparative clinical case series of 211 irradiated UM eyes were studied by recording the number and location of pigmented episcleral deposits during follow-up visits after brachytherapy. For the first time, the study described pigmented episcleral deposits, which are found in the most UM eyes after brachytherapy, and proved them to consist of macrophages full with engulfed melanin particles. This knowledge may save patients from unnecessary enucleation, because episcleral pigmented deposits might be mistaken for extrascleral tumour growth. The presence of pigmented macrophage-related episcleral deposits was associated with plaque size and isotope rather than with tumour size, suggesting that, in addition to tumour regression, radiation atrophy of retinal pigment epithelium and choroid contributes to the formation of the deposits. In the paired (the same 34 pairs as in the first study) cross-sectional study of irradiated and non-irradiated UMs, clinically-visible episcleral deposits and migrating macrophages in other extratumoral tissues were studied histopathologically. Resident macrophages were present in extratumoral tissues in eyes with both irradiated and non-irradiated UM. Irradiation increased both the number of CD68+ macrophages in the sclera beneath the tumour and the number of clinically-observed episcleral macrophages aggregates. Brachytherapy seemed to alter the route of migration of macrophages: after irradiation, macrophages migrated preferentially through the sclera while in non-irradiated UMs they seemed to migrate more along the choroid. In order to understand the influence of these routes on tumour progression and regression in the future, labelling and tracking of activated macrophages in vivo is required.
  • Pöyhiä, Tiina (Helsingin yliopisto, 2011)
    Brachial plexus birth injury (BPBI) is caused by stretching, tearing or avulsion of the C5-C8 or Th1 nerve roots during delivery. Foetal-maternal disproportion is the main reason for BPBI. The goal of this study was to find out the incidence of posterior subluxation of the humeral head during first year of life in BPBI and optimal timing of the ultrasonographic screening of the glenohumeral joint. The glenohumeral congruity and posterior subluxation of the humeral head associated to muscle atrophy were assessed and surgical treatment of the shoulder girdle as well as muscle changes in elbow flexion contracture were evaluated. The prospective, population based part of the study included all neonates born in Helsinki area during years 2003-2006. Patients with BPBI sent to the Hospital for Children and Adolescents because of decreased external rotation, internal rotation contracture or deformation of the glenohumeral joint as well as patients with elbow flexion contracture were also included in this prospective study. The incidence of BPBI was calculated to be 3.1/1000 newborns in Helsinki area. About 80% of the patients with BPBI recover totally during the follow-up within the first year of life. Permanent plexus injury at the age of one year was noted in 20% of the patients (0.64/1000 newborns). Muscle imbalance resulted in sonographically detected posterior subluxation in one third of the patients with permanent BPBI. If muscle imbalance and posterior subluxation are left untreated bony deformities will develop. All patients with internal rotation contracture of the glenohumeral joint presented muscle atrophy of the rotator cuff muscles. Especially subscapular and infraspinous muscles were affected. A correlation was found particularly between greatest thickness of subscapular muscle and subluxation of the humeral head, degree of glenoid retroversion, as well as amount of internal rotation contracture. Supinator muscle atrophy was evident among all the studied patients with elbow flexion contracture. Brachial muscle pathology seemed to be an important factor for elbow flexion contracture in BPBI. Residual dysfunction of the upper extremity may require operative treatment such as tendon lengthening, tendon transfers, relocation of the humeral head or osteotomy of the humerus. Relocation of the humeral head improved the glenohumeral congruency among patients under 5 years of age. Functional improvement without remodeling of the glenohumeral joint was achieved by other reconstructive procedures. In conclusion: Shoulder screening by US should be done to all patients with permanent BPBI at the age of 3 and 6 months. Especially atrophy of the subscapular muscle correlates with glenohumeral deformity and posterior subluxation of the humeral head, which has not been reported in previous studies. Permanent muscle changes are the main reason for diminished range of motion of the elbow and forearm. Relocation of the humeral head, when needed, should be performed under the age of 5 years.