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  • Perälä, Nina (Helsingin yliopisto, 2011)
    Plexins (plxn) are receptors of semaphorins (sema), which were originally characterized as axon guidance cues. Semaphorin-plexin signalling has now been implicated in many other developmental and pathological processes. In this thesis, my first aim was to study the expression of plexins during mouse development. My second aim was to study the function of Plexin B2 in the development of the kidney. Thirdly, my objective was to elucidate the evolutionary conservation of Plexin B2 by investigating its sequence, expression and function in developing zebrafish. I show by in situ hybridisation that plexins are widely expressed also in the non-neuronal tissues during mouse development. Plxnb1 and Plxnb2, for example, are expressed also in the ureteric epithelium, developing glomeruli and undifferentiated metanephric mesenchyme of the developing kidney. Plexin B2-deficient (Plxnb2-/-) mice die before birth and have severe defects in the nervous system. I demonstrate that they develop morphologically normal but hypoplastic kidneys. The ureteric epithelium of Plxnb2-/- kidneys has fewer branches and a lower rate of proliferating cells. 10% of the embryos show unilateral double ureters and kidneys. The defect in the branching is intrinsic to the epithelium as the isolated ureteric epithelium grown in vitro fails to respond to Glial-cell-line-derived neurotrophic factor (Gdnf). We prove by co-immunoprecipitation that Plexin B2 interacts with the Gdnf-receptor Ret. Sema4C, the Plexin B2 ligand, increases branching of the ureteric epithelium in controls but not in Plxnb2-/- kidney explants. These results suggest that Sema4C-Plexin B2 signalling modulates ureteric branching in a positive manner, possibly through directly regulating the activation of Ret. I cloned the zebrafish orthologs of Plexin B2, Plexin B2a and B2b. The corresponding proteins contain the conserved domains the B-subfamily plexins. Especially the expression pattern of plxnb2b recapitulates many aspects of the expression pattern of Plxnb2 in mouse. Plxnb2a and plxnb2b are expressed, for example, in the pectoral fins and at the midbrain-hindbrain region during zebrafish development. The nearly complete knockdown of Plexin B2a alone or together with the 45% knockdown of Plexin B2b did not interfere with the normal development of the zebrafish. In conclusion, my thesis reveals that plexins are broadly expressed during mouse embryogenesis. It also shows that Sema4C-Plexin B2 signalling modulates the branching of the ureteric epithelium during kidney development, perhaps through a direct interaction with Ret. Finally, I show that the sequence and expression of Plexin B2a and B2b are conserved in zebrafish. Their knockdown does not, however, result in the exencephaly phenotype of Plxnb2-/- mice.
  • Rinta-Valkama, Johanna (Helsingin yliopisto, 2006)
    Type 1 diabetes is a disease where the insulin-producing beta cells of the pancreas are destroyed by an autoimmune mechanism. The incidence of type 1 diabetes, as well as the incidence of the diabetic kidney complication, diabetic nephropathy, are increasing worldwide. Nephrin is a crucial molecule for the filtration function of the kidney. It localises in the podocyte foot processes partially forming the interpodocyte final sieve of the filtration barrier, the slit diaphragm. The expression of nephrin is altered in diabetic nephropathy. Recently, nephrin was found from the beta cells of the pancreas as well, which makes this molecule interesting in the context of type 1 diabetes and especially in diabetic nephropathy. In this thesis work, the expression of other podocyte molecules in the beta cells of the pancreas, in addition to nephrin, were deciphered. It was also hypothesised that patients with type 1 diabetes may develop autoantibodies against novel beta cell molecules comparably to the formation of autoantibodies to GAD, IA-2 and insulin. The possible association of such novel autoantibodies with the pathogenesis of diabetic nephropathy was also assessed. Furthermore, expression of nephrin in lymphoid tissues has been suggested, and this issue was more thoroughly deciphered here. The expression of nephrin in the human lymphoid tissues, and a set of podocyte molecules in the human, mouse and rat pancreas at the gene and protein level were studied by polymerase chain reaction (PCR) -based methods and immunochemical methods. To detect autoantibodies to novel beta cell molecules, specific radioimmunoprecipitation assays were developed. These assays were used to screen a follow-up material of 66 patients with type 1 diabetes and a patient material of 150 diabetic patients with signs of diabetic nephropathy. Nephrin expression was detected in the lymphoid follicle germinal centres, specifically in the follicular dendritic cells. In addition to the previously reported expression of nephrin in the pancreas, expression of the podocyte molecules, densin, filtrin, FAT and alpha-actinin-4 were detected in the beta cells. Circulating antibodies to nephrin, densin and filtrin were discovered in a subset of patients with type 1 diabetes. However, no association of these autoantibodies with the pathogenesis of diabetic nephropathy was detected. In conclusion, the expression of five podocyte molecules in the beta cells of the pancreas suggests some molecular similarities between the two cell types. The novel autoantibodies against shared molecules of the kidney podocytes and the pancreatic beta cells appear to be part of the common autoimmune mechanism in patients with type 1 diabetes. No data suggested that the autoantibodies would be active participants of the kidney injury detected in diabetic nephropathy.
  • Lahdenkari, Anne-Tiina (Helsingin yliopisto, 2005)
  • Hietala, Eeva-Maija (Helsingin yliopisto, 2004)
  • Avela, Kristiina (Helsingin yliopisto, 2000)
  • Joensuu, Tarja (Helsingin yliopisto, 2002)
  • Heikkilä, Jukka (Helsingin yliopisto, 2015)
    ABSTRACT Background. Posterior urethral valves (PUV) constitute the most common infravesical urinary obstruction in boys. PUV are often accompanied by severe consequences to the lower and upper urinary tract. They also represent a major urological cause for paediatric renal transplantations. Since no previous systemically analysed true long-term studies exist, early findings, treatment and their relations to late renal function are not clarified in many respects. Aims. The clinical characteristics and renal outcomes of PUV were assessed. Also evaluated were the risk factors for the progression to end-stage renal disease (ESRD). Patients and methods. All patients treated for PUV at Children s Hospital, University of Helsinki, from 1953 to 2003 were identified from the hospital database. Age and mode of presentation, structural abnormalities, treatment, follow-up data and outcome were registered. In addition, the Finnish Kidney Transplantation Registry and the Finnish Population Register were reviewed to identify those who had progression to dialysis or renal transplantation or had demised. Results. The diagnosis of PUV was made in 200 patients. The incidence of cryptorchidism was16-fold and the incidence of inguinal hernia 7-fold higher in PUV patients than in the normal population. Cryptorchidism and inguinal hernias was more common in patients with more severe PUV. The incidence of urinomas in PUV patients was 15% after onset of routine ultrasound. Of all 17 patients, 9 had perirenal urinoma, 6 urinary ascites and 2 urinothorax. Renal function was similar in PUV patients with and without urinoma. High voiding pressures were seen in infants around the ablation of the valves. No correlation between high voiding pressures and poor primary kidney function was observed. The voiding pressures were registered to decrease during the months following the release of the valvular obstruction. Vesicoureteral reflux (VUR) was observed in 127 PUV patients (64%). Bilateral VUR was present in 73 (37%) and unilateral VUR in 54 (27%). At presentation, refluxing patients had significantly higher serum creatinine values than patients without VUR. Reflux resolved spontaneously at a median of 1.28 years (range 0.04 to 15.16) after the release of the valvular obstruction. Of all patients, 44 (22.8%) had progression to ESRD at the evaluation, which occurred at a median age of 31 years (range 6 to 69); 30 (68%) had developed renal failure before the age of 17 years, and 14 (32%) as adults. In this study, the highest age at the onset of ESRD was 34 years. According to Kaplan-Meier analysis, the life-time risk of ESRD was 28.5% (SE 3.8%). Patients with higher creatinine values during the first postoperative year had progression to ESRD at an earlier age. Early age, poor renal function, pneumothorax and bilateral VUR at presentation and postoperative recurrent urinary tract infections (UTI) were risk factors for ESRD. Conclusions. Posterior urethral valves often lead to ESRD. Early presentation, poor primary renal function, pneumothorax perinatally as well as VUR bilaterally and recurrent postoperative UTIs carry a risk for renal function deterioration and ESRD. These risk factors should be recognized and proper management initiated, with follow-up extending through childhood to adulthood.
  • Jaakkola, Susanna (Helsingin yliopisto, 2012)
    Large differences exist between countries in the context and use of postmenopausal hormone therapies. Differences also exist in genes, diet and lifestyle, which all affect the risk for cancers. I studied the effects of different estrogen-progestagen therapies (EPT) for the risk of endometrial and cervical cancer as well as uterine sarcoma in nationwide studies on postmenopausal Finnish women. A cohort of all Finnish women (> 50 years of age) who had used EPT for at least 6 months since 1994 was collected from the national Medical Reimbursement Register and followed for uterine cancers with the aid of the Finnish Cancer Registry. The risks were compared to those of the same age background population in the three cohort studies. The follow-up for the endometrial cohort study ended in 2006 and encountered a total of 1,364 endometrial cancer cases out of a total of 224,015 women with EPT. The follow-up was continued until the end of 2008 in the other cohort studies and accumulated 243,857 women with EPT of which 192 women showed cervical precancerous lesions, 97 women cervical cancers and 76 women uterine sarcomas (45 leiomyosarcomas, 24 stromal sarcomas and 7 other sarcomas). To control some of the various confounding factors and to assess, in addition to EPT, also the impact of tibolone, another study using a case-control study model was conducted. In total 7,261 women with endometrial cancer and 19,490 controls were compared in regard to the use of EPT or tibolone in 1995-2007. Hysterectomized women were excluded from the controls based on data from the Hospital Inpatient Register of the National Institute of Health and Welfare. Results were adjusted for parity, age at first delivery and hospital district, but not for body mass index, diabetes mellitus or socioeconomic status. In the cohort study, the incidence of endometrial cancer was increased among sequential EPT users after 5 years of use (standardized incidence ratio (SIR) 1.69; 95% confidence interval (CI) 1.43-1.96) when progestagen was added monthly and the risk doubled to 3.76 (2.90-4.79) when progestagen was added at 3-month intervals. In the case-control study, sequential EPT showed increased risk only after 10 years of use (odds ratio (OR) 1.38; 1.15-1.66) but long-cycle sequential EPT associated with increased risk after 5 years of use (1.63; 1.12-2.38). The use of tibolone showed no effect on endometrial cancer risk, but the number of cases (n = 19) was small. In contrast, the use of continuous combined EPT users was accompanied with a reduced risk for endometrial cancer from 3 years onwards (SIR 0.24; 0.06-0.60). Similar risk reductions for endometrial cancer were seen also in women using continuous combined EPT or an estradiol plus levonorgestrel releasing intrauterine system in the case-control study; the odds rations were 0.57 (0.37-0.88) and 0.16 (0.37-0.68), respectively. In the cohort study, endometrial cancers of women using monthly sequential EPT tended to be diagnosed more often in a localized stage than endometrial cancers in general. The most common oral progestagens as parts of EPT in Finland (norethisterone acetate, medroxyprogesterone acetate and dydrogesterone) showed no significant differences in the endometrial effects. Transdermal and oral routes of administration showed similar risks for monthly sequential EPT regimen including estradiol and norethisterone acetate. The incidence of cervical precancerous lesions in all EPT users did not differ from that in the background population, but the risk for squamous cell carcinoma was decreased (SIR 0.41; 0.28-0.58) and that of adenocarcinoma was increased (1.31; 1.01-1.67). When the use of EPT exceeded 5 years, the risk for squamous cell carcinoma showed a trend towards a further decrease 0.34 (0.16-0.65), and the risk of adenocarcinoma showed a trend towards an increase 1.83 (1.24-2.59). The risk for uterine sarcomas was not affected by the exposure to EPT for less than 5 years. Uses of EPT for 5-10 and 10+ years associated with an increased risk for uterine sarcomas (SIR 2.02; 1.36-2.91 and 3.01; 1.30-5.93); risks were highest for leiomyosarcoma. The mode of EPT did not affect these risks significantly. In conclusion, the use of postmenopausal EPT is one determinant for the occurrence of uterine cancers. Continuous combined regimens decrease and sequential regimens increase the risk for endometrial cancer; these data support earlier findings. The following new observations were made; oral and transdermal routes of administration or various types of progestagens do not modify these effects. A consistent decrease in the incidence of squamous cervical malignancies was seen in EPT users. In contrast, the incidence of cervical adenocarcinoma was increased. The risk for uterine sarcomas is increased if EPT has been used for longer times. These data are of importance for the potential users of EPT and for physicians prescribing such regimens.
  • Tuomikoski, Pauliina (Helsingin yliopisto, 2010)
    Vasomotor hot flushes are complained of by approximately 75% of postmenopausal women, but their frequency and severity show great individual variation. Hot flushes have been present in women attending observational studies showing cardiovascular benefit associated with hormone therapy use, whereas they have been absent or very mild in randomized hormone therapy trials showing cardiovascular harm. Therefore, if hot flushes are a factor connected with vascular health, they could perhaps be one explanation for the divergence of cardiovascular data in observational versus randomized studies. For the present study 150 healthy, recently postmenopausal women showing a large variation in hot flushes were studied in regard to cardiovascular health by way of pulse wave analysis, ambulatory blood pressure and several biochemical vascular markers. In addition, the possible impact of hot flushes on outcomes of hormone therapy was studied. This study shows that women with severe hot flushes exhibit a greater vasodilatory reactivity as assessed by pulse wave analysis than do women without vasomotor symptoms. This can be seen as a hot flush-related vascular benefit. Although severe night-time hot flushes seem to be accompanied by transient increases in blood pressure and heart rate, the diurnal blood pressure and heart rate profiles show no significant differences between women without and with mild, moderate or severe hot flushes. The levels of vascular markers, such as lipids, lipoproteins, C-reactive protein and sex hormone-binding globulin show no association with hot flush status. In the 6-month hormone therapy trial the women were classified as having either tolerable or intolerable hot flushes. These groups were treated in a randomized order with transdermal estradiol gel, oral estradiol alone or in combination with medroxyprogesterone acetate, or with placebo. In women with only tolerable hot flushes, oral estradiol leads to a reduced vasodilatory response and increases in 24-hour and daytime blood pressures as compared to women with intolerable hot flushes receiving the same therapy. No such effects were observed with the other treatment regimes or in women with intolerable hot flushes. The responses of vascular biomarkers to hormone therapy are unaffected by hot flush status. In conclusion, hot flush status contributes to cardiovascular health before and during hormone therapy. Severe hot flushes are associated with an increased vasodilatory, and thus, a beneficial vascular status. Oral estradiol leads to vasoconstrictive changes and increases in blood pressure, and thus to possible vascular harm, but only in women whose hot flushes are so mild that they would probably not lead to the initiation of hormone therapy in clinical practice. Healthy, recently postmenopausal women with moderate to severe hot flushes should be given the opportunity to use hormone therapy alleviate hot flushes, and if estrogen is prescribed for indications other than for the control of hot flushes, transdermal route of administration should be favored.
  • Keltanen, Terhi (Helsingin yliopisto, 2015)
    Postmortem (PM) biochemistry is utilized in cause of death (CoD) investigations. The challenges in PM biochemistry are caused mainly by the PM changes. Analytes may be degraded or denatured leading to methodological difficulties. In addition, the re-distribution may cause falsely elevated values when compared to clinical samples. Analytes may also be consumed or produced by microbial metabolism. The sample matrix is often different from that in clinical biochemistry and the reference levels need be obtained through research. The actual death process and agonal period can also lead to unique changes in the analyte concentrations. Despite these challenges, with a sufficient number of samples and adequate research it is possible to optimize biochemical methods for PM samples and obtain reference values for certain conditions. The biochemical results can provide supporting information in cases where the death is caused or associated with metabolic disturbances for instance in diabetes mellitus (DM) or alcohol abuse. Hyperglycemia and ketoacidosis in diabetes can be fatal if not treated. The macroscopical, histological and toxicological findings in autopsy may be scarce or even absent. Determination of vitreous humor (VH) glucose and ketone bodies are very informative in these cases. As ketoacidosis can be present also after heavy alcohol use, the determination of glycemic status prior to death is essential in distinguishing between these two conditions. Glycated hemoglobin (HbA1c) provides information on the glycemic balance in previous weeks. In our studies, we have assessed the results, methods and interpretation provided by analysis of glucose, lactate, ketone bodies, HbA1c and C-reactive protein (CRP) in PM samples. Optimization has been performed in routine casework according to our findings providing more accurate information to the medico-legal pathologists in their CoD investigation work. In addition, our results have provided some insights into the pathology of severe diabetic emergencies as well as to ketoacidosis due to alcohol. According to our results, we recommend that in DM and alcohol abuse related deaths VH glucose, total ketone bodies or beta-hydroxy butyrate and blood HbA1c should always be analyzed. Lactate levels may provide additional information, when the results are interpreted considering the PM interval (PMI). These analyses are recommended also in cases where no suspicion of metabolic disturbances exists, but the findings in autopsy are scarce. The collaboration between the medico-legal pathologists and the laboratory is very important for the development and understanding of PM biochemistry and to include novel analyses to support the CoD investigation. The CoD determination is very important not only on the individual level, but also nationally, since Finnish Statistics collects the CoD data, which can be than further utilized in recommendations concerning health and primary prevention.
  • Koski, Antti (Helsingin yliopisto, 2010)
    The risk is obvious for soft tissue complications after operative treatment of the Achilles tendon, calcaneal bone or after ankle arthroplasty. Such complications after malleolar fractures are, however, seldom seen. The reason behind these complications is that the soft tissue in this region is tight and does not allow much tension to the wound area after surgery. Furthermore the area of operation may be damaged by swelling after the injury, or can be affected by peripheral vascular disease. While complications in this area are unavoidable, they can be diminished. This study attempts to highlight the possible predisposing factors leading to complications in these operations and on the other hand, to determine the solutions to solve soft tissue problems in this region. The study consists of five papers. The first article is a reprint on the soft tissue reconstruction of 25 patients after their complicated Achilles tendon surgeries were analysed. The second study reviews a series of 126 patients after having undergone an operative treatment of calcaneal bone fractures and analyses the complications and possible reasons behind them. The third part analyses a series of corrections of 35 soft tissue complications after calcaneal fracture operations. The fourth part reviews a series of 7 patients who had undergone complicated ankle arthroplasties. The last article presents a series of post operative lateral defects of the ankle treated with a less frequently used distally based peroneus brevis muscle flap and analyses the results. What can be conducted from these studies is that in general, the results after the correction of even severe soft tissue complications in the ankle region are good. For the small defects around the Achilles tendon, the local flaps are useful, but the larger defects are best treated with a free flap. We found that a long delay from trauma to surgery and a long operating time were predisposing factors that lead to soft tissue complications after operatively treated calcaneal bone fractures. The more severe the injury, the greater the risk for wound complication. Surprisingly, the long-term results after infected calcaneal osteosyntheses were acceptable and the calcaneal bone seems to tolerate chronic infections very well if the soft tissue is reconstructed successfully. Behind the complicated ankle arthroplasties, unexpectedly high number of cases experiencing arteriosclerosis of the lower extremity was found. These complications lead to ankle fusion but can be solved with a free flap if the vascularity is intact or can be reconstructed. For this reason a vascular examination of the lower extremity arteries of the patients going to ankle arthroplasty is strongly recommended. Moreover postoperative lateral malleolar wound infections which typically create lateral ankle defects can successfully be treated with a peroneus brevis muscle flap covered with a free skin graft.
  • Schramko, Alexey (Helsingin yliopisto, 2010)
    Background: Patients may need massive volume-replacement therapy after cardiac surgery because of large fluid transfer perioperatively, and the use of cardiopulmonary bypass. Hemodynamic stability is better maintained with colloids than crystalloids but colloids have more adverse effects such as coagulation disturbances and impairment of renal function than do crystalloids. The present study examined the effects of modern hydroxyethyl starch (HES) and gelatin solutions on blood coagulation and hemodynamics. The mechanism by which colloids disturb blood coagulation was investigated by thromboelastometry (TEM) after cardiac surgery and in vitro by use of experimental hemodilution. Materials and methods: Ninety patients scheduled for elective primary cardiac surgery (Studies I, II, IV, V), and twelve healthy volunteers (Study III) were included in this study. After admission to the cardiac surgical intensive care unit (ICU), patients were randomized to receive different doses of HES 130/0.4, HES 200/0.5, or 4% albumin solutions. Ringer’s acetate or albumin solutions served as controls. Coagulation was assessed by TEM, and hemodynamic measurements were based on thermodilutionally measured cardiac index (CI). Results: HES and gelatin solutions impaired whole blood coagulation similarly as measured by TEM even at a small dose of 7 mL/kg. These solutions reduced clot strength and prolonged clot formation time. These effects were more pronounced with increasing doses of colloids. Neither albumin nor Ringer’s acetate solution disturbed blood coagulation significantly. Coagulation disturbances after infusion of HES or gelatin solutions were clinically slight, and postoperative blood loss was comparable with that of Ringer’s acetate or albumin solutions. Both single and multiple doses of all the colloids increased CI postoperatively, and this effect was dose-dependent. Ringer’s acetate had no effect on CI. At a small dose (7 mL/kg), the effect of gelatin on CI was comparable with that of Ringer’s acetate and significantly less than that of HES 130/0.4 (Study V). However, when the dose was increased to 14 and 21 mL/kg, the hemodynamic effect of gelatin rose and became comparable with that of HES 130/0.4. Conclusions: After cardiac surgery, HES and gelatin solutions impaired clot strength in a dose-dependent manner. The potential mechanisms were interaction with fibrinogen and fibrin formation, resulting in decreased clot strength, and hemodilution. Although the use of HES and gelatin inhibited coagulation, postoperative bleeding on the first postoperative morning in all the study groups was similar. A single dose of HES solutions improved CI postoperatively more than did gelatin, albumin, or Ringer’s acetate. However, when administered in a repeated fashion, (cumulative dose of 14 mL/kg or more), no differences were evident between HES 130/0.4 and gelatin.
  • Mero-Matikainen, Niina (Helsingin yliopisto, 1999)
  • Melkas, Susanna (Helsingin yliopisto, 2011)
    The aim of the present study was to investigate the influence of different manifestations of cerebral SVD on poststroke survival and ischemic stroke recurrence in long-term follow-up. The core imaging features of small-vessel disease (SVD) are confluent and extensive white matter changes (WMC) and lacunar infarcts. These are associated with minor motor deficits but a major negative influence on cognition, mood, and functioning in daily life, resulting from small-vessel lesions in the fronto-subcortical brain network. These sub-studies were conducted as part of the Helsinki Stroke Aging Memory (SAM) study. The SAM cohort consisted of 486 consecutive patients aged 55 to 85 years who were admitted to Helsinki University Central Hospital with acute ischemic stroke. The study included comprehensive clinical, neuropsychological, psychiatric and radiological assessment three months poststroke. The patients were followed up up for 12 years using extensive national registers. The effect of different manifestations of cerebral SVD on poststroke survival and stroke recurrence was analyzed controlling for factors such as age, education, and cardiovascular risk factors. Poststroke dementia and cognitive impairment relate to poor long-term survival. In particular, deficits in executive functions as well as visuospatial and constructional abilities predict poor outcome. The predictive value of cognitive deficits is further underlined by the finding that depression-executive dysfunction syndrome (DES), but not depression in itself, is associated with poor poststroke survival. Delirium is not independently associated with increased risk for long-term poststroke mortality, although it is associated with poststroke dementia. Furthermore, acute index stroke attributable to SVD is associated with poorer long-term survival and a higher risk for cardiac death than other stroke subtypes. Severe WMC, a surrogate of SVD, is independently related to an increased risk of stroke recurrence at five years. In summary, cognitive poststroke outcomes reflecting changes in the executive network brain, and the presence of cerebral SVD are important determinants of poststroke mortality and ischemic stroke recurrence, regardless of whether SVD is the cause of the index stroke or a condition concurrent to some other etiology.