Browsing by Subject "lastentaudit"

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  • Banerjee, Joanna (Helsingin yliopisto, 2020)
    Posterior reversible encephalopathy syndrome (PRES) and other central nervous system (CNS) toxicities not only complicate the treatment of acute lymphoblastic leukaemia (ALL) in children, but may lead to treatment modifications and long-term effects which increase morbidity and even mortality. Although recognition of these complications has improved in the last decades thanks to the increased availability of brain magnetic resonance imaging (MRI) in clinical practice, data on exact incidence rates, treatment strategies in different complications, and impact on outcomes are limited. Cranially irradiated leukaemia survivors are at risk of brain tumours, but the incidence rates of brain tumours after long latency periods need to be defined. In this thesis, the occurrence and spectrum of CNS symptoms, clinical characteristics and impact on prognosis and neurological outcome were determined during and after ALL therapy, as well as the significance for neurotoxicity of low dosing of folinic acid after high-dose methotrexate. In addition, the risk of secondary brain tumours in cranially irradiated leukaemia survivors after long latency periods was defined. For the first and second study, data were gathered on 643 children treated in Finland in accordance with the protocols of the Nordic Society of Paediatric Haematology and Oncology (NOPHO ALL 1992 and NOPHO ALL2000). The NOPHO leukaemia registry provided data on patient and treatment characteristics. Thorough reviews were performed of all medical records and the detailed data on CNS symptoms from all patients. In the first study, acute CNS symptoms occurred in 86 patients (13%) during the first two months of the treatment. PRES was the most common CNS complication. Cerebrovascular events occurred in 10 patients (1.6%), hypertensive encephalopathy in six (1.0%), and methotrexate-related stroke-like syndrome in one (0.2%). CNS symptoms due to systemic or unclear conditions, particularly sepsis, were important for differential diagnosis, and occurred in thirty-six (5.6%) children. No CNS symptom was characteristic for specific CNS complications and diagnosis in most cases required a combination of imaging, laboratory tests, and clinical judgement. CNS leukaemia was an independent risk factor for defined CNS complications in a multivariable logistic regression analysis. Defined CNS complications other than PRES were not associated with lower event-free or overall survival. Epilepsy was a common sequela. However, a majority of these sequelae occurred in patients with PRES. In the second study, a total of 29 (4.5%) patients developed PRES, almost exclusively during the induction treatment. All patients presented with seizures. Hyponatremia was a common finding in patients with PRES, and significant hypertension, constipation, and > 2 weeks of alkalinisation hydration was associated with PRES in a multivariable binary logistic regression analysis. PRES was associated with long-term neurological morbidity, as one third of the patients with PRES developed epilepsy. In addition, relapses were more common in PRES group and PRES was associated with lower overall survival. In the third study, data on high-dose methotrexate treatment were gathered from patients treated with NOPHO ALL2000 standard or intermediate risk protocols at Oulu and Kuopio University Hospitals. In over half (n = 181) of the 351 high-dose methotrexate courses, methotrexate clearance was fast, leading to low dosing of folinic acid. Despite low folinic acid previously having been suggested to associate with increased neurotoxicity, no neurotoxicity was seen in a cohort of forty-four patients. In the fourth study, all cranially irradiated adult leukaemia survivors (with a minimum of 10 years after end of therapy) from Oulu University Hospital were invited to a follow-up brain MRI, if not recently imaged due to neurologic symptoms. The cohort consisted of 60 patients; however, only 49 patients participated in the study. Of these leukaemia survivors, eleven (22%) developed a meningioma after an exceptionally long latency period, mean 25 years (range 14–34 years). The incidence of meningiomas continued to increase 20 years after the treatment, unlike that of gliomas, which typically develop with shorter latency periods. Four patients were symptomatic at the time of diagnosis, three had multiple meningiomas, and two had recurrent disease. Eight meningiomas were operated on, with a World Health Organization (WHO) I histology in seven patients and WHO II (atypical) in one patient. No other brain tumours were seen. In conclusion, the studies included in this thesis showed that CNS complications are common during and after ALL therapy. PRES in particular is a significant complication of the treatment associated with long-term morbidity (epilepsy) and poor prognosis. It was not clear whether the negative impact on outcome was due to PRES itself or a result of suboptimal therapy. The role of hyponatremia in the pathogenesis of PRES requires further studies. Although CNS complications can usually be cured, some are life-threatening. Accurate diagnostics of symptoms is crucial for proper treatment. In patients with fast clearance, a low dose of folinic acid after high-dose methotrexate was sufficient to prevent neurotoxicity. It was observed that meningiomas developed with a long latency, which is today a known feature of radiation-induced meningiomas.
  • Porkholm, Mikaela (Unigrafia Oy, 2017)
    Although most children with cancer can be cured, every fifth patient still succumb from their disease. The need for new treatments and more refined diagnostic methods are thus understandable. Angiogenesis, the formation of new blood vessels, is an essential phenomenon in many malignancies. The first study in this thesis evaluated the role of two regulators of angiogenesis, vascular endothelial growth factor (VEGF) and angiopoietin-2 (Ang-2), during allogenic hematopoietic stem cell transplantation (HSCT) in 67 children. High levels of VEGF and Ang-2 in plasma samples collected after allogenic HSCT correlated with severe acute graft-versus-host disease (GVHD). High Ang-2 post-HSCT was associated with increased non-relapse mortality and, together with concomitantly high VEGF, correlated with inferior event-free survival. However, methodological challenges should prompt cautious interpretation of these results. The second study summarized results of the anti-angiogenic Angiocomb protocol in the treatment of pediatric diffuse intrinsic pontine gliomas (DIPGs). The survival of study patients (N = 41) did not differ from that of controls (N = 8), but the ability to attend school or daycare and walk was maintained for a longer time after the diagnosis in the study cohort. The Angiocomb protocol was generally well tolerated, with the most frequent adverse event being neutropenia. The third study explored the effect of the Extended Angiocomb protocol in a cohort of 17 heavily pre-treated children with high-risk or end-stage malignancies. Although a significant increase in Karnofsky-Lansky performance scores occurred in patients during therapy, the protocol was more toxic than anticipated. This underlines the importance of careful patient selection and close monitoring during metronomic therapy in heavily pre-treated patients. The fourth study analyzed genetic alterations by next-generation sequencing and protein expression and microvessel density (MVD) by immunohistochemistry in 26 DIPG tumor samples. 87% of the patients had mutations in H3-K27M, excluding two rarely encountered long-term survivors. One of the long-term survivors had an IDH1 mutation, an alteration formerly considered to be absent in DIPGs. Angiogenesis-related genes were altered in 40% of the patients, whereas MVD showed up to 6-fold variation. The clinical significance of these findings requires further studies in the future.
  • Pöllänen, Petra Maria (Helsingin yliopisto, 2020)
    Type 1 diabetes (T1D) is an immune-mediated endocrine disorder driven by progressive destruction of pancreatic insulin-producing beta cells. A presymptomatic period of highly variable duration precedes the onset of clinical T1D, during which autoantibodies to multiple beta-cell antigens are detected in the circulation. Thus far, the factors decisive for individual disease risk and the timing of disease onset have remained obscure. This thesis aimed at improving the early prediction of T1D by characterizing the genetic, immunological, and demographic factors associated with the progression rate to T1D and by describing the islet autoantibody dynamics during the first 15 years in human leukocyte antigen (HLA) -predisposed children. Newborn infants participating in the Finnish Type 1 Diabetes Prediction and Prevention (DIPP) study were screened for HLA genotypes predisposing to T1D from cord blood. Eligible infants were invited to clinical follow-up, including assessment of islet cell antibodies (ICA) and autoantibodies to insulin (IAA), glutamic acid decarboxylase (GADA), islet antigen-2 (IA-2A), and zinc transporter 8 (ZnT8A) as markers of islet autoimmunity. Multiple non-HLA single-nucleotide polymorphisms (SNPs) were analyzed for potential associations with the progression rate. In young children, IAA and ZnT8A emerged commonly as the first autoantibodies, but at preschool age, IA-2A- and especially GADA-initiated autoimmunity became common. Loss of IAA positivity indicated delayed progression from seroconversion to diagnosis compared with stable IAA positivity. Rapid progressors to T1D were characterized by positivity for multiple (≥2) autoantibodies, high autoantibody titers, especially ICA, IAA, and IA-2A at seroconversion, and the homozygous FUT2 secretor genotype and the high-risk HLA-DQB1*02/*03:02 genotype. Rapid progression occurred in both young (age <5 years) and prepubertal children (age >7 years). Depending on age, the immunological characteristics of rapid progressors were diverse. Slow progressors were distinguished from other progressors by immunological characteristics present at seroconversion, but no factors were explicitly predictive of slow progression. Season of birth differed between slow and other progressors. No differences emerged in the non-HLA SNP distributions between slow and other progressors. This study demonstrated that rapid progressors differ from slower progressors by factors present at seroconversion. The primary islet autoantibody is characteristic of age, suggesting that age and the stage of immunological maturation contribute substantially to the disease process. Triggers of aggressive islet autoimmunity may be heterogeneous. The labile state of islet autoantibodies affects the risk for T1D. The findings in this thesis improve the estimation of preclinical diabetes risk and the timing of disease onset, providing a clinically valuable framework for individualizing the efforts to delay or prevent T1D.
  • Helve, Otto (Helsingin yliopisto, 2008)
    The aim of the present thesis was to study the role of the epithelial sodium channel (ENaC) in clearance of fetal lung fluid in the newborn infant by measurement of airway epithelial expression of ENaC, of nasal transepithelial potential difference (N-PD), and of lung compliance (LC). In addition, the effect of postnatal dexamethasone on airway epithelial ENaC expression was measured in preterm infants with bronchopulmonary dysplasia (BPD). The patient population was formed of selected term newborn infants born in the Department of Obstetrics (Studies II-IV) and selected preterm newborn infants treated in the neonatal intensive care unit of the Hospital for Children and Adolescents (Studies I and IV) of the Helsinki University Central Hospital in Finland. A small population of preterm infants suffering from BPD was included in Study I. Studies I, III, and IV included airway epithelial measurement of ENaC and in Studies II and III, measurement of N-PD and LC. In Study I, ENaC expression analyses were performed in the Research Institute of the Hospital for Sick Children in Toronto, Ontario, Canada. In the following studies, analyses were performed in the Scientific Laboratory of the Hospital for Children and Adolescents. N-PD and LC measurements were performed at bedside in these hospitals. In term newborn infants, the percentage of amiloride-sensitive N-PD, a surrogate for ENaC activity, measured during the first 4 postnatal hours correlates positively with LC measured 1 to 2 days postnatally. Preterm infants with BPD had, after a therapeutic dose of dexamethasone, higher airway epithelial ENaC expression than before treatment. These patients were subsequently weaned from mechanical ventilation, probably as a result of the clearance of extra fluid from the alveolar spaces. In addition, we found that in preterm infants ENaC expression increases with gestational age (GA). In preterm infants, ENaC expression in the airway epithelium was lower than in term newborn infants. During the early postnatal period in those born both preterm and term airway epithelial βENaC expression decreased significantly. Term newborn infants delivered vaginally had a significantly smaller airway epithelial expression of αENaC after the first postnatal day than did those delivered by cesarean section. The functional studies showed no difference in N-PD between infants delivered vaginally and by cesarean section. We therefore conclude that the low airway epithelial expression of ENaC in the preterm infant and the correlation of N-PD with LC in the term infant indicate a role for ENaC in the pathogenesis of perinatal pulmonary adaptation and neonatal respiratory distress. Because dexamethasone raised ENaC expression in preterm infants with BPD, and infants were subsequently weaned from ventilator therapy, we suggest that studies on the treatment of respiratory distress in the preterm infant should include the induction of ENaC activity.
  • Seikku, Paula (Helsingin yliopisto, 2008)
    Pediatric renal transplantation (TX) has evolved greatly during the past few decades, and today TX is considered the standard care for children with end-stage renal disease. In Finland, 191 children had received renal transplants by October 2007, and 42% of them have already reached adulthood. Improvements in treatment of end-stage renal disease, surgical techniques, intensive care medicine, and in immunosuppressive therapy have paved the way to the current highly successful outcomes of pediatric transplantation. In children, the transplanted graft should last for decades, and normal growth and development should be guaranteed. These objectives set considerable requirements in optimizing and fine-tuning the post-operative therapy. Careful optimization of immunosuppressive therapy is crucial in protecting the graft against rejection, but also in protecting the patient against adverse effects of the medication. In the present study, the results of a retrospective investigation into individualized dosing of immunosuppresive medication, based on pharmacokinetic profiles, therapeutic drug monitoring, graft function and histology studies, and glucocorticoid biological activity determinations, are reported. Subgroups of a total of 178 patients, who received renal transplants in 1988 2006 were included in the study. The mean age at TX was 6.5 years, and approximately 26% of the patients were <2 years of age. The most common diagnosis leading to renal TX was congenital nephrosis of the Finnish type (NPHS1). Pediatric patients in Finland receive standard triple immunosuppression consisting of cyclosporine A (CsA), methylprednisolone (MP) and azathioprine (AZA) after renal TX. Optimal dosing of these agents is important to prevent rejections and preserve graft function in one hand, and to avoid the potentially serious adverse effects on the other hand. CsA has a narrow therapeutic window and individually variable pharmacokinetics. Therapeutic monitoring of CsA is, therefore, mandatory. Traditionally, CsA monitoring has been based on pre-dose trough levels (C0), but recent pharmacokinetic and clinical studies have revealed that the immunosuppressive effect may be related to diurnal CsA exposure and blood CsA concentration 0-4 hours after dosing. The two-hour post-dose concentration (C2) has proved a reliable surrogate marker of CsA exposure. Individual starting doses of CsA were analyzed in 65 patients. A recommended dose based on a pre-TX pharmacokinetic study was calculated for each patient by the pre-TX protocol. The predicted dose was clearly higher in the youngest children than in the older ones (22.9±10.4 and 10.5±5.1 mg/kg/d in patients <2 and >8 years of age, respectively). The actually administered oral doses of CsA were collected for three weeks after TX and compared to the pharmacokinetically predicted dose. After the TX, dosing of CsA was adjusted according to clinical parameters and blood CsA trough concentration. The pharmacokinetically predicted dose and patient age were the two significant parameters explaining post-TX doses of CsA. Accordingly, young children received significantly higher oral doses of CsA than the older ones. The correlation to the actually administered doses after TX was best in those patients, who had a predicted dose clearly higher or lower (> ±25%) than the average in their age-group. Due to the great individual variation in pharmacokinetics standardized dosing of CsA (based on body mass or surface area) may not be adequate. Pre-Tx profiles are helpful in determining suitable initial CsA doses. CsA monitoring based on trough and C2 concentrations was analyzed in 47 patients, who received renal transplants in 2001 2006. C0, C2 and experienced acute rejections were collected during the post-TX hospitalization, and also three months after TX when the first protocol core biopsy was obtained. The patients who remained rejection free had slightly higher C2 concentrations, especially very early after TX. However, after the first two weeks also the trough level was higher in the rejection-free patients than in those with acute rejections. Three months after TX the trough level was higher in patients with normal histology than in those with rejection changes in the routine biopsy. Monitoring of both the trough level and C2 may thus be warranted to guarantee sufficient peak concentration and baseline immunosuppression on one hand and to avoid over-exposure on the other hand. Controlling of rejection in the early months after transplantation is crucial as it may contribute to the development of long-term allograft nephropathy. Recently, it has become evident that immunoactivation fulfilling the histological criteria of acute rejection is possible in a well functioning graft with no clinical sings or laboratory perturbations. The influence of treatment of subclinical rejection, diagnosed in 3-month protocol biopsy, to graft function and histology 18 months after TX was analyzed in 22 patients and compared to 35 historical control patients. The incidence of subclinical rejection at three months was 43%, and the patients received a standard rejection treatment (a course of increased MP) and/or increased baseline immunosuppression, depending on the severity of rejection and graft function. Glomerular filtration rate (GFR) at 18 months was significantly better in the patients who were screened and treated for subclinical rejection in comparison to the historical patients (86.7±22.5 vs. 67.9±31.9 ml/min/1.73m2, respectively). The improvement was most remarkable in the youngest (<2 years) age group (94.1±11.0 vs. 67.9±26.8 ml/min/1.73m2). Histological findings of chronic allograft nephropathy were also more common in the historical patients in the 18-month protocol biopsy. All pediatric renal TX patients receive MP as a part of the baseline immunosuppression. Although the maintenance dose of MP is very low in the majority of the patients, the well-known steroid-related adverse affects are not uncommon. It has been shown in a previous study in Finnish pediatric TX patients that steroid exposure, measured as area under concentration-time curve (AUC), rather than the dose correlates with the adverse effects. In the present study, MP AUC was measured in sixteen stable maintenance patients, and a correlation with excess weight gain during 12 months after TX as well as with height deficit was found. A novel bioassay measuring the activation of glucocorticoid receptor dependent transcription cascade was also employed to assess the biological effect of MP. Glucocorticoid bioactivity was found to be related to the adverse effects, although the relationship was not as apparent as that with serum MP concentration. The findings in this study support individualized monitoring and adjustment of immunosuppression based on pharmacokinetics, graft function and histology. Pharmacokinetic profiles are helpful in estimating drug exposure and thus identifying the patients who might be at risk for excessive or insufficient immunosuppression. Individualized doses and monitoring of blood concentrations should definitely be employed with CsA, but possibly also with steroids. As an alternative to complete steroid withdrawal, individualized dosing based on drug exposure monitoring might help in avoiding the adverse effects. Early screening and treatment of subclinical immunoactivation is beneficial as it improves the prospects of good long-term graft function.
  • Eloranta, Katja (Helsingin yliopisto, 2021)
    Hepatoblastoma (HB) is the most common pediatric liver malignancy with an annual incidence of 1.8 cases per million children. Most cases are sporadic, although certain genetic disorders such as Beckwith-Wiedemann syndrome and familial adenomatous polyposis are associated with increased risk of HB. Developmental pathways, such as WNT/β-catenin and Hedgehog signaling, are often aberrantly activated in HB cells. The overall mutation burden in HB is generally low, but the CTNNB1 gene encoding β-catenin is altered in over 60% of cases. Surgical resection of tumor is a mainstay of HB treatment, generally supported by pre- and post-operative chemotherapy. The survival rate of HB is over 80% if tumor is confined to liver but decreases dramatically when there is extrahepatic involvement, so new treatment options are needed. In this thesis we examined two key factors, GATA4 and neuropilin-2, in the pathobiology of HB. Additionally, we conducted in vitro experiments investigating the potential of chloroquine as a novel HB therapy. Transcription factor GATA4 is crucial for early liver development. We observed that most HB patient samples and cell lines express high levels of GATA4. Moreover, GATA4 expression was associated with mesenchymal-like and motile phenotype in HB cells. Neuropilins (NRP) are multifunctional receptors involved both in physiological and pathological processes. We noted high NRP1 and NRP2 expression in HB patient samples and six HB cell models. Utilizing siRNA transfection, we observed decreased viability and motility in NRP2 knockdown cells compared to cells with intact gene expression suggesting that NRP2 promotes aggressive behavior in HB cells. Chloroquine is a traditional anti-malarial which has demonstrated potential in cancer management. We observed a drastic decrease in HB spheroid viability after chloroquine treatment. Chloroquine treatment also modified the metabolic profile of HB cells with a remarkable decrease in NAD+ and aspartate concentrations. Additionally, we noticed significant decrease in PARP1/2 expression suggesting that chloroquine may have effect on DNA repair system in HB cells. In summary, this thesis shed new light on the molecular mechanisms of HB pathogenesis. In the future, these findings may be utilized in development of novel treatment approaches and diagnostics to improve survival and life quality of HB patients.
  • Helin, Noora (Helsingin yliopisto, 2021)
    Background: Small children often experience gastrointestinal (GI) symptoms such as regurgitation or abdominal pain. These are usually benign, functional symptoms. In infants, spilling or vomiting can also be suspected to be a symptom of food allergy. In children of developed countries, the most common organic disease in the upper GI tract is gastroesophageal reflux disease (GERD), which refers to troublesome symptoms caused by reflux and related complications such as esophagitis. Upper endoscopy has traditionally been used to verify or exclude esophagitis in patients with symptoms suggestive of GERD, or to exclude other diseases such as eosinophilic esophagitis. Distinguishing children with functional symptoms from those in whom symptoms are associated with disease is often challenging, although guidelines to facilitate differential diagnosis are available. Good availability of endoscopy and lack of data on the long-term prognosis of common upper GI symptoms may have increased the number of upper endoscopies in young children. However, clinical experience suggests that upper endoscopies performed on young patients with non-acute, non-specific symptoms seldom provide clinically relevant data.   Aim: This study aimed to evaluate the diagnostic role of upper endoscopy in children younger than 7 years presenting with non-acute, non-specific GI symptoms. The aim was also to estimate school-age outcomes of symptoms suggestive of GERD or cow’s milk protein allergy with GI symptoms (GI-CMPA) in early childhood.  Patients and methods: The first substudy included children who had undergone primary upper endoscopy at Helsinki University Children’s Hospital in 2006-2016. At an age younger than 7 years, these children had presented with non-specific, non-acute symptoms (n=1850). Patients with acute symptoms, a known disease, or a foreign body for which endoscopy was performed, and congenital malformations of the head, neck and respiratory tract or GI tract, as well as patients with antibody-positive suspected celiac disease were excluded from the study. The remaining patients’ records (n=666) were retrospectively searched for data on the symptoms leading to upper endoscopy, the use of anti-acid medication at the time of endoscopy, the endoscopy results, and the impact of the results on the follow-up or treatment plans.  In the second substudy, children who had undergone primary upper endoscopy due to suspicion of GERD (n=254) were further investigated by evaluating the effect of predisposing conditions to GER on endoscopy findings. Also, the current well-being and anti-acid medication use of children in whom the primary upper endoscopy had resulted in normal findings (n=199) was assessed using the Patient Data Repository and Prescription Service. Of these patients, those whose native language is Finnish (n=175) were invited to an electronic follow-up survey on current symptoms, medications, and GI health-related quality of life (QoL).  The third substudy investigated children who had in early childhood undergone a double-blind, placebo-controlled food challenge due to suspicion of GI-CMPA (n=57). The suspicion of GI-CMPA had not been confirmed in the majority (68%) of these patients. Mothers of both challenge-positive and challenge-negative children were invited to respond to an electronic follow-up questionnaire on children's current GI symptoms, diet, and QoL.    Results: In the majority (81%) of the 666 children who had undergone primary upper endoscopy to investigate non-acute, non-specific symptoms, the endoscopy results were completely normal. Especially in infants, the findings were minor. The most common symptoms leading to endoscopy were related to gastroesophageal reflux, and the most common cause of endoscopy was suspicion of GERD. None in the cohort had erosive esophagitis. The most common histological finding was mild to moderate histological esophagitis (9%). The number of histological findings increased significantly with age. The use of acid blocker medication at the time of endoscopy did not significantly affect the histological findings. There were no unsuspected celiac disease cases, and the number of histologically confirmed eosinophilic esophagitis in this group was low (0.3%). In children diagnosed with inflammatory bowel disease using concomitant colonoscopy, upper endoscopy findings (most often mild gastritis) did not require active treatment. Regardless of the original cause of the primary upper endoscopy, the results affected treatment or follow-up plans in less than 10% of the patients. In children with suspicion of GERD, the upper endoscopy findings were normal in 83%. Vomiting was the most common symptom associated with suspicion of GERD, but none of the symptoms leading to the endoscopy predicted positive findings. Some of the children (39%) had also undergone 24-hour pH- monitoring, but increased esophageal acid reflux did not predict positive endoscopy findings. Thirty-one patients had undergone more than one upper endoscopy. In these patients, the histological degree of changes in the esophageal biopsies remained unchanged or became less severe. Based on medical records, after a median of eight years of follow-up, the otherwise healthy children had seldom reported reflux-related complaints. However, 4% of children with initially normal primary upper endoscopy findings were currently using long-term acid blocker medication, with most of them having underlying conditions predisposing them to GER. Of the 175 Finnish-speaking families who were invited to the follow-up survey, 51 parents (29%) completed the questionnaire on their child’s current reflux symptoms and use of anti-acid medications. Current daily or weekly occurring reflux-related complaints were parentally reported by 24% of survey responders. The use of anti-acid medications was uncommon, but many parents described their child to use a restricted diet. The GI health-related QoL was reported as good by both parents and children older than 8 years of age who responded to the survey. Of the children who had previously undergone a double-blind, placebo-controlled food challenge for symptoms suggestive of GI-CMPA, all had a normal diet after an average of five follow-up years, and mothers reported their children's quality of life as good. After the food challenge, two challenge-negative children with on-going GI symptoms had also undergone an upper endoscopy with normal results.   Conclusions: Based on this study, the diagnostic role of upper endoscopy is minimal in young children presenting with non-specific, non-acute symptoms. There were only a few positive findings in the endoscopy, most non-specific, and the findings rarely led to changes in the child's treatment or follow-up plan. In children who had undergone more than one upper endoscopy, the histological changes either remained unchanged or became less severe. The suspicion of symptom-based diseases in early childhood was not associated with long-term morbidity at school age. Also, the early childhood symptoms leading to suspicion of GERD were not associated with long-term use of acid blocker medications at school age, especially if the child did not have underlying diseases predisposing to GERD. Moreover, no subsequent dietary restrictions occurred in children investigated due to an early childhood suspicion of GI-CMPA.  It is essential to educate clinicians referring children to upper endoscopy about the rarity of diagnostic findings in association with non-acute, non-specific GI symptoms in young children. Also, centers performing pediatric upper endoscopies should ensure that their endoscopy indications are in line with the scientifically approved data, reserving the endoscopy for those who most benefit from it.
  • Laatio, Jenni (Helsingin yliopisto, 2018)
    Tutkielmassa tarkastellaan palovammojen hoitoa lapsilla. Tavoitteena oli tehdä katsaus tämän hetkisistä hoitokäytännöistä lasten palovammojen hoidossa. Aluksi tehtiin yleinen kirjallisuuskatsaus. Tämän jälkeen systemaattinen kirjallisuuskatsaus, analyysi ja tiivistys tärkeimmistä hoitomenetelmistä. Katsauksessa analysoitiin 34:ä tutkimusta, jotka käsittelivät nestehoitoa, inhalaatiovammoja, infektiosuojausta, kivunhallintaa, hypermetaboliaa sekä palovammahaavojen hoitoa. Palovammat jaetaan syvyyden mukaan pinnallisesta punoituksesta koko kudoksen läpi menevään vammaan. Ensimmäisen ja toisen asteen vammat re-epitelisoituvat asianmukaisella hoidolla, mutta kolmannen ja neljännen asteen vammat tarvitsevat ihosiirteen. Potilaan nesteytyksen määrä riippuu palovamman laajuudesta. Inhalaatiovamma voi syntyä, jos potilas on ollut suljetussa tilassa altistuessaan palovammalle. Palovamma aiheuttaa elimistöön katabolian. Tämän normalisoimiseksi käytetään hypermetaboliaa rajoittavia lääkkeitä. Haavojen hoito mahdollisimman kivuttomasti on yksi tärkeimmistä tavoitteista lapsipotilaiden kohdalla traumatisoitumisen ehkäisemiseksi. Palovammojen komplikaationa voi syntyä monielinvaurio. Nesteytys palovamman jälkeen aloitetaan varhain. Palovamman lopullinen laajuusarvio on tärkeä, jotta vältyttäisiin yli- tai alinesteytyksen aiheuttamilta komplikaatioilta. Antibioottiprofylaksian käyttöä ilman infektion merkkejä ei ole todettu tarpeelliseksi. Kipua lapsilla hoidetaan tehokkaasti morfiinilla tai fentanyylillä, joko tasavälein annosteltuna tai havainnoidun tarpeen mukaisesti. Hypermetabolian hoidossa propranololilla aikaansaatu syketason lasku vähentää elimistön lepoenergian kulutusta ja kataboliaa. Oksandrololilla on saatu aikaan jopa anabolisia vaikutuksia. Pamidronaatilla on pystytty säilyttämään rangan mineraalisisältö. Laajat palovammat aiheuttavat hyperglykemiaa. Insuliinilla on saatu suotuisa vaste lepoenergian kulutukseen sitä pienentämällä. Haavojen hoidossa parhaat tulokset kivun ja re-epitelisaation osalta on saatu Mepilex Ag:llä, Aquacelilla, DuoDermilla ja Transcytella.
  • Helenius, Mikko (Helsingin yliopisto, 2015)
    Irreversible vascular remodeling has a central role in a variety of pathophysiological conditions including pulmonary arterial hypertension (PAH). Hypoxia and inflammation are prominent features in PAH, along with hyperplasia and hypertrophy of vessel wall layers. Although, endothelial cell (EC) dysfunction is thought to drive the multiple forms of vascular remodeling, the origins of this phenomenon are poorly understood. Extracellular ATP and its metabolites are important regulators of vascular tone, permeability, and homeostasis. Yet little is known about their role in pathological vascular remodeling. By using chronic hypoxia and PAH animal models as well as human PAH patient samples, this study was undertaken to evaluate the catalytic activities and expression levels of nucleoside triphosphate diphosphohydrolase-1 (NTPDase1, otherwise known as CD39) and other purine-converting ectoenzymes with a primary focus on vascular EC. For this purpose we employed thin-layer chromatographic enzyme assays with 3H-labelled nucleotide substrates, in combination with various immunoassays and qPCR. In addition we have developed a highly sensitive assay for simultaneous sensing of extracellular ATP and its metabolites and also a novel method for measuring CD39 activity in modeled to in vivo conditions. In functional assays, cells or animals were stimulated through purine signaling pathways and proliferation, apoptosis, permeability, and DNA damage were assayed. Our results clearly demonstrated that the activity of CD39 was downregulated in chronic hypoxia, monocrotaline induced animal models of PAH and in human PAH patients. Attenuated enzyme activities could create a niche in the vasculature where ATP levels were increased and adenosine levels were decreased. Even a small increase in ATP concentration was enough to induce an apoptosis-resistant, hyper-proliferative, and DNA-damageresistant phenotype in ECs of pulmonary origin. The observed effects were at least partly dependent on P2Y11 receptor activation. In addition, we found that low ATP concentrations could induce pulmonary smooth muscle cell proliferation and migration. Interestingly, we found that small apelin peptide could directly restore the downregulated CD39 activity. This study implies that purinergic signaling, ATP mediated cell activation in particular, plays a truly significant role in pathological vascular remodeling, and that it could be used as a therapeutic target. Moreover, purinergic signaling pathways could be used before vascular injury to precondition EC against irradiation or chemotherapy induced DNA damage.
  • Mikkola, Kaija (Helsingin yliopisto, 2007)
    The project consisted of two long-term follow-up studies of preterm children addressing the question whether intrauterine growth restriction affects the outcome. Assessment at 5 years of age of 203 children with a birth weight less than 1000 g born in Finland in 1996-1997 showed that 9% of the children had cognitive impairment, 14% cerebral palsy, and 4% needed a hearing aid. The intelligence quotient was lower (p<0.05) than the reference value. Thus, 20% exhibited major, 19% minor disabilities, and 61% had no functional abnormalities. Being small for gestational age (SGA) was associated with sub-optimal growth later. In children born before 27 gestational weeks, the SGA had more neuropsychological disabilities than those appropriate for gestational age (AGA). In another cohort with birth weight less than 1500 g assessed at 5 years of age, echocardiography showed a thickened interventricular septum and a decreased left ventricular end-diastolic diameter in both SGA and AGA born children. They also had a higher systolic blood pressure than the reference. Laser-Doppler flowmetry showed different endothelium-dependent and -independent vasodilation responses in the AGA children compared to those of the controls. SGA was not associated with cardio-vascular abnormalities. Auditory event-related potentials (AERPs) were recorded using an oddball paradigm with frequency deviants (standard tone 500 Hz and deviant 750-Hz with 10% probability). At term, the P350 was smaller in SGA and AGA infants than in controls. At 12 months, the automatic change detection peak (mismatch negativity, MMN) was observed in the controls. However, the pre-term infants had a difference positivity that correlated with their neurodevelopment scores. At 5 years of age, the P1-deflection, which reflects primary auditory processing, was smaller, and the MMN larger in the preterm than in the control children. Even with a challenging paradigm or a distraction paradigm, P1 was smaller in the preterm than in the control children. The SGA and AGA children showed similar AERP responses. Prematurity is a major risk factor for abnormal brain development. Preterm children showed signs of cardiovascular abnormality suggesting that prematurity per se may carry a risk for later morbidity. The small positive amplitudes in AERPs suggest persisting altered auditory processing in the preterm in-fants.
  • Morales-Munoz, Isabel; Kantojärvi, Katri; Uhre, Veli-Matti; Saarenpää-Heikkilä, Outi; Kylliäinen, Anneli; Pölkki, Pirjo; Himanen, Sari-Leena; Karlsson, Linnea; Karlsson, Hasse; Paavonen, E. Juulia; Paunio, Tiina (2021)
    Purpose: No previous research has examined the impact of the genetic background of diurnal preference on children´s sleep. Here, we examined the effects of genetic risk score for the liability of diurnal preference on sleep development in early childhood in two population-based cohorts from Finland. Participants and methods: The primary sample (CHILD-SLEEP, CS) comprised 1420 infants (695 girls), and the replication sample (FinnBrain, FB; 962 girls) 2063 infants. Parent-reported sleep duration, sleep-onset latency and bedtime were assessed at three, eight, 18 and 24 months in CS, and at six, 12 and 24 months in FB. Actigraphy-based sleep latency and efficiency were measured in CS in 365 infants at eight months (168 girls), and in 197 infants at 24 months (82 girls). Mean standard scores for each sleep domain were calculated in both samples. Polygenic risk scores (PRS) were used to quantitate the genetic risk for eveningness (PRSBestFit) and morningness (PRS10kBest). Results: PRSBestFit associated with longer sleep-onset latency and later bedtime, and PRS10kBest related to shorter sleep-onset latency in CS. The link between genetic risk for diurnal preference and sleep-onset latency was replicated in FB, and meta-analysis resulted in associations (P<0.0005) with both PRS-values (PRSBestFit: Z=3.55; and PRS10kBest: Z=-3.68). Finally, PRSBestFit was related to actigraphy-based lower sleep efficiency and longer sleep latency at eight months. Conclusion: Genetic liability to diurnal preference for eveningness relates to longer sleep-onset during the first two years of life, and to objectively measured lowered sleep efficiency. These findings enhance our understanding on the biological factors affecting sleep development, and contribute to clarify the physiological sleep architecture in early childhood.