Abstrakta


Vyšlo v časopise: Čes-slov Pediat 2013; 68 (6): 389-404.
Kategorie: Abstrakta

Vážení čtenáři,

dne 28. 6. 2013 v Hradci Králové proběhla 22. mezinárodní konference European Society of Pediatric Clinical Research. Této akce se zúčastňují postgraduální studenti oboru pediatrie se svými školiteli, aby si vyměnili zkušenosti a prezentovali průběžné výsledky své vědecké práce. Po Praze (2005) a Brně (2011) se konference potřetí vrátila do České republiky a byla uspořádána s laskavou podporou České pediatrické společnosti ČLS JEP a Lékařské fakulty v Hradci Králové, za což oběma institucím náleží upřímné poděkování.

Do místa konání se sjeli účastníci z pěti států (kromě tuzemských ještě ze Slovenska, Slovinska, Německa a Maďarska), kteří přednesli celkem 25 ústních sdělení. Jejich vystoupení pečlivě sledovali nejen ostatní posluchači, ale též hodnotící porota, v níž zasedli domácí (prof. J. Janda, prof. J. Lebl, prof. H. Hrstková, prof. M. Bayer) i zahraniční školitelé – prof. L. Kovács ze Slovenska, prof. N. Marčun Varda ze Slovinska a také prof. R. Urbanek z Německa, který byl zakladatelem a pořadatelem prvých ročníků těchto setkání.

Odborný program obohatil doc. F. Raiskup z Univerzitní nemocnice v Drážďanech svou vyzvanou přednáškou o nových léčebných postupech u korneálních ektazií.

Ve společenském programu nechyběl velmi působivý hudební zážitek (Jiřina Dvořáková Marešová – varhany) ani zajímavá přednáška z historie (P. Lazurko – bitva u Hradce Králové 1866) s názornými ukázkami výzbroje.

Budeme rádi, pokud tradice těchto setkání přetrvá i nadále a udrží si zájem doktorandů a jejich školitelů. Organizátory by v příštím roce měli být kolegové ze slovinského Mariboru.

Na následujících stránkách si Vám dovolujeme předložit abstrakta přednesených prací.

Za organizační výbor ES-PCR 2013

prof. MUDr. Milan Bayer, CSc.


Anti-IgE antibody therapy in severe asthma in adolescence

Bode S., Meinicke H., Heinzmann A., Müller C., Urbanek R.

Centre for Paediatrics and Adolescent Medicine, University Medical Centre Freiburg/Breisgau, Germany

Omalizumab is a recombinant humanized anti-IgE monoclonal antibody indicated as add-on therapy for severe asthma if inadequately controlled despite high doses of inhaled corticosteroids and beta-agonists. Three teenage patients (2 boys and 1 girl) with a persistent allergic asthma for several years were treated by monthly subcutaneous injections of omalizumab. All of them tolerated the treatment without any side effects and showed a distinct reduction of their asthmatic symptoms. Inhaled steroids and beta-agonists could be reduced or even paused. FEV1 improved and physical exercise/sports were well tolerated. Bronchial hyperreactivity tested by metacholin inhalation and tread mill exercise demonstrated a significant improvement as well. Associated food-triggered allergic symptoms were diminished or disappeared in two of the patients. Omalizumab can be considered in severe asthma in adolescence and can improve other allergic symptoms as well.

Renin release in ischemia/reperfusion kidney injury; gender differences

Csohány R., Prókai Á., Kosik A., Pap D., Balicza-Himer L., Vannay Á., Fekete A., Tulassay T., Szabó A.

Ist Department of Pediatrics, Semmelweis University, Budapest, Hungary

Ischemic/reperfusion (I/R) kidney injury is one of the most important risk factors for chronic allograft nephropathy. The course and severity of this injury differs in the two genders. Our studies focused on the role of renin in I/R kidney injury. The classical syntatizing localization of renin is the JGA contrariwise the collecting duct (CD) is a newly described localization of renin release. At both sites we have investigated in vivo the effect of I/R injury on renal renin system in male and female rats. Left renal pedicles of mature male and female Wistar rats were clamped for 50 minutes followed by 2, 8, 16, 24 and 48 hours of reperfusion, sham-operated rats served as controls. By histological analysis we described the structural changes affecting the whole kidney. We applied fluorescence-activated cell sorting (FACS) analysis for quantitative measurements and used multi-photon imaging to directly visualize the kidney in vivo. The histological analysis confirmed I/R injury. Applying FACS analysis we have detected decrease in both JGA and CD renin content in the first 8 hours of reperfusion however, following the 16th hour of reperfusion renin content increased in both localizations. These results were further supported by multi-photon microscopy, furthermore vasoconstriction was found in the kidney time- and gender dependently. In summary, our studies are the first ones which described renin response in I/R injury in the JGA and in the CD segment also. We could visualize the renin content in vivo even in CD and reveal that renin release is more explicit in males than in females.

Ambulatory arterial stiffness index in children after kidney transplantation

Dégi A.1, Kerti A.1, Cseprekál O.1,2, Kis É.1, Sallay P.1, Szabó A. J.1, Reusz G. S.1

11st Department of Pediatrics, Semmelweis University, Budapest, Hungary; 21st Department of Internal Medicine, Semmelweis University, Budapest, Hungary

Given the increase in cardiovascular (CV) morbidity after renal transplantation (RTx) and the scarcity of CV events in pediatrics, surrogate markers should be assessed to characterize CV damage in this population. Ambulatory arterial stiffness index (AASI) is a marker of arterial stiffness in adults, predicting cardio- and cerebrovascular morbidity.

Purpose: Our aim was to assess the determinants of AASI in RTx children (n=54, 15.5±3.5 y) and to examine its relationship to central pulse wave velocity (PWV).

Methods: AASI was calculated from 24-hour ambulatory blood pressure monitoring. PWV was determined by applanation tonometry, body composition by multifrequency bioimpedance measurement.

Results: Pulse pressure, nocturnal diastolic blood pressure fall and time on dialysis were the main predictors of AASI (p<0.01). Children with established hypertension (HT) (n=34) had increased AASI, extracellular body water and B-type natriuretic peptide (p<0.02). In contrast to AASI, PWV did not differ between HT and normotensive RTx patient groups. There was no correlation between AASI and PWV. PWV was increased in children who spent more than 1 year on dialysis prior to RTx. In conclusion, increased AASI in HT RTx children better characterizes the actual volume and pressure-dependent arterial rigidity rather than long term morphological changes of large arteries as reflected by PWV.

Investigation of the INS gene in the Czech families with diabetes

Dušátková L.1, Průhová Š.1, Dušátková P.1, Cinek O.1, Šumník Z.1, Koloušková S.1, Janštová V.2, Vosáhlo J.3, Lebl J.1

1Department of Pediatrics, 2nd Faculty of Medicine and University Hospital Motol, Prague, Czech Republic; 2Department of Pediatrics, University Hospital Ostrava, Ostrava, Czech Republic; 3Department of Children and Adolescents, Faculty Hospital Kralovske Vinohrady, Prague, Czech Republic

Purpose: Mutations in the insulin gene (INS) have been reported to cause different types of diabetes, such as neonatal diabetes, Maturity-Onset Diabetes of the Young, or autoantibody-negative Type 1 Diabetes (T1DM). Moreover, clinical phenotype could be variable within one family. Genetic screening of the INS gene is essential for precise diagnosis of the patients with diabetes.

Methods: We investigated the INS gene in the Czech families with diabetes in more than two generations. Genetic analysis was performed by direct sequencing.

Results: Mutations in the INS gene were found in three families. In the first family, the R55C was identified in three generations. Proband suffered from hyperglycemia since the age of 7 years, her mother was diagnosed with T1DM, and maternal grandmother had gestational diabetes. The R55C substitution is located between B-chain and C-peptide, the site for proteolytic processing of proinsulin to insulin. In the second family, three female patients with diabetes in three generations had mutation R46Q in the INS gene. The R46Q substitution at residue 22 of the B-chain disrupts a hydrogen bond with A-chain and leads to the destabilisation of the insulin molecule. Finally, mother and her daughter of the third family were diagnosed with diabetes at age 6 and 1 year, respectively. In both, mutation within the terminal intron c.188-31G>A was detected. It causes an ectopic splice site resulting in longer, abnormal transcript of insulin.

Conclusion: Identification of the INS mutations could clarify the etiology of diabetes and they may subsequently indicate prognosis and appropriate therapy.

The study was supported by a grant from the Czech Ministry of Health (NT 11402).

Recurrent mutations causing GCK-MODY and HNF4A-MODY: founder effect or mutation hot-spot?

Dusatkova P.1, Pruhova S.1, Borowiec M.2, Gasperikova D.3, Klimes I.3, Lebl J.1, Mlynarski W.2, Cinek O.1

1Department of Paediatrics, 2nd Faculty of Medicine, Charles University in Prague and University Hospital Motol, Prague, Czech Republic; 2Department of Paediatrics, Oncology, Haematology and Diabetology, Medical University of Lodz, Lodz, Poland; 3DIABGENE and Diabetes Laboratory, Institute of Experimental Endocrinology, Slovak Academy of Sciences, Bratislava, Slovak Republic

Purpose: Most families with MODY (Maturity-Onset Diabetes of the Young) carry their private disease-causing mutation. However, we have identified high counts of unrelated families with several identical mutations in the genes for glucokinase (GCK) and hepatocyte nuclear factor 4-alpha (HNF4A) causing GCK-MODY and HNF4A-MODY, respectively. We investigated whether these recurrent mutations reflect a founder effect or were caused by a mutation hot-spot.

Methods: We genotyped 12-16 SNPs in 67 Czech, Polish, and Slovak families with GCK-MODY (29 with G318R mutation, 21 with E40K, and 17 with L315H), 10 Czech families with HNF4A-MODY (7 with R125Q mutation, 2 with R125P, 1 with R125W), and 94 unrelated controls. Haplotypes were inferred using the Haploview and Phase software, and the age of mutations estimated using the DMLE+ program.

Results: All tested mutations in the GCK gene were transmitted on conserved haplotypes stretching 9 to 1.4 Mb confirming their ancestral origin. The age of the respective mutations was estimated to be between 82 and 110 generations (95% credible set 65–151). On the other hand, we observed no definable haplotype around mutations R125Q/P/W in the HNF4A gene (Pearson’s r2≤0.04) indicating that these mutations originated by an independent events.

Conclusions: We demonstrate two mechanisms how recurrent mutations can appear in MODY patients: investigated GCK-MODY families arose from common, probably Slavic, ancestors. Contrariwise, prevalent occurrence of the R125Q/P/W mutations in families with HNF4A-MODY could be likely attributed to a mutation hot-spot, as no ancestral haplotype was detected.

Supported by a grant from the Czech Ministry of Health (NT11402).

Bone mineral density and body composition in pediatric patients with coeliac disease and inflammatory bowel disease

Ferant Ž.1, Kozar N.1, Dolinšek J.2, Šikić Pogačar M.1, Mičetić-Turk D.1

1Faculty of Medicine, University of Maribor, Slovenia; 2Gastroenterology Unit, Department of Paediatrics, University Clinical Centre Maribor, Slovenia

Purpose: Coeliac disease (CD) and inflammatory bowel disease (IBD) are frequently associated with reduced bone mineral density (BMD). In the present study we investigated BMD in pediatric patients with either CD or IBD in stable remission and compared them with their healthy peers. Furthermore, we investigated the applicability of bioimpedance analysis (BIA) as a diagnostic tool for lowered BMD.

Methods: Altogether, 104 children aged between 10 and 18 years (49 boys, 55 girls) were selected and followed-up. Lumbar and left hip BMD were measured using dual-energy X-ray absorptiometry (DXA), and results expressed as Z scores for a specific chronological age. CD and IBD were diagnosed previously in each test group and children/adolescents were treated accordingly. Additionally, levels of vitamin D were determined in all the groups including control. Percentage of body fat (BF %) and lean body mass (LBM) were measured using BIA method.

Results: BMD did not differ significantly between CD, IBD or control group. In CD and IBD group vitamin D levels were significantly lower than in the control group (p<0.01).

Conclusion: Results of the present study showed that pediatric patients with CD and IBD in a stable remission have good BMD. As vitamin D levels in both test groups were significantly lower than in the control, supplementation of vitamin D should be considered in order to prevent possible long term deteriorations of bone mineral mass. Our results showed that BIA is not a reliable method in determining lowered BMD.

Serum Adipokine levels during Infliximab therapy in pediatric Crohn’s disease

Frivolt K.1,2, Schwerd T.1, Schatz S. B.1, Freudenberg F.1, Prell C.1, Bufler P.1, Koletzko S.1

1Dr. v. Hauner Children’s Hospital, University Munich Medical Center, Munich, Germany; 22nd Department of Pediatrics, Comenius University Medical School, Bratislava, Slovak Republic

Purpose: Crohn’s disease (CD) is an inflammatory disorder of the intestine and the visceral adipose tissue, characterized by adipocyte hyperplasia and increased fat tissue concentrations of TNFα, leptin and adiponectin. In vitro TNFα suppresses the expression of leptin and the anti-inflammatory mediator adiponectin. We aimed to investigate the early effect of anti-TNFα therapy with infliximab (IFX) on serum adipokine levels in pediatric CD.

Methods: Serum concentrations of leptin, adiponectin and resistin were measured with ELISAs before the 1st, 2nd and 4th IFX infusion (week 0, 2 and 14). Results of 18 CD patients were compared with 15 weight/BMI matched healthy controls (HC).

Results: IFX treated patients included 10 males (median age 14.9 years, range 12.2–17.5). Baseline resistin levels were higher in patients compared to HC (median 14.7 ng/ml, range 5.1–50.5) vs 7.3 ng/ml (0.5–14.5) (p<0.001), and decreased with IFX (p<0.01). In girls leptin levels increased after 2 weeks from 9.5 ng/ml (7.6–30.1) to 16.0 ng/ml (7.9–35.2) (p<0.05), while boys showed a trend from 2.0 ng/ml (0.6–12.9) to 2.8 ng/ml (1.7–8.6). Adiponectin peaked 2 weeks after 1st IFX infusion from 7.8 µg/ml (4.6–11.9) to 9.2 µg/ml (4.1–20.7), (p<0.01) and thereafter fell to 6.5 µg/ml (3.0–12.7), (p<0.05 vs baseline vs HC; p<0.001 vs 2 weeks).

Conclusions: TNFα blockade by IFX effectively reduced disease activity and inflammatory markers including resistin in CD and led to an early increase of adiponectin. Leptin parallels weight gain. We speculate that successful induction therapy with IFX is partially mediated by the anti-inflammatory properties of released adiponectin.

The project was supported by Collegium Talentum and Ministry of Education of the Slovak Republic #VEGA 1/1267/12.

Microalbuminuria in hypertensive children and adolescents

Golob Jančič S., Marčun Varda N.

University Medical Centre Maribor, Department of Paediatrics, Maribor, Slovenia

Purpose: Microalbuminuria in adults has been found to be an early marker of cardiovascular as well as renal disease. In children, however, limited data of its importance and prevalence are available, including hypertensive children. The purpose of our study was to investigate the role of microalbuminuria in hypertensive children and adolescents.

Methods: 100 healthy children and 117 children and adolescents with essential hypertension have been prospectively included in the study. One random morning urine sample was obtained from each patient for microalbuminuria measurement by immunoturbidimetry and for creatinine determination using standard technique. In microalbuminuria positive children and adolescents with hypertension control sample was obtained after 6-months. In addition, the prevalence in healthy children was compared with that determined in 842 children with different nephrologic diseases.

Results: The prevalence of microalbuminuria in hypertensive and healthy children and adolescents was found to be 8.5% and 6.0%, respectively. There was no statistically significant difference in microalbuminuria between hypertensive and healthy group (χ2=0.51, p=0.47). In 9 out of 10 children and adolescents with hypertension a persistent microalbuminuria after 6 months of follow-up was determined. We also found no statistically significant difference in microalbuminuria between healthy children and children with different nephrologic diseases (χ2=3.29, p=0.07).

Conclusions: Our study found no significant difference in microalbuminuria between children with hypertension, different nephrologic diseases and healthy population. However, its short-time persistent elevation was found in most hypertensives. Larger prospective studies with follow-up are needed to finaly determine its role in paediatric patients.

Renin-angiotensin-aldosterone system blockers in diabetic nephropathy: the role of epithelial to mesenchymal transition

Hodrea J.1,2, Kőszegi S.1, Lénárt L.1, Hosszú Á.1, Gellai R.1, Bánki N. F.3, Wagner L.4, Szkibinszkij E.1, Vannay Á.2, Tulassay T.2,3, Fekete A.1,3

1“Momentum” Diabetes Research Group and 2Research Group for Paediatrics and Nephrology, Hungarian Academy of Sciences and Semmelweis University; 31st Dep. of Pediatrics; 4Dep. of Transplant Surgery; Semmelweis University, Budapest, Hungary

Purpose: In diabetic nephropathy the activated renin-angiotensin-aldosterone system (RAAS) induces epithelial to mesenchymal transition (EMT). Here we investigated the alterations of α smooth muscle actin (αSMA) and platelet-derived growth factor (PDGF) – the key markers of EMT – In diabetes and after RAAS blockade.

Methods: Streptozotocin-diabetic male Wistar rats were treated either with enalapril, ramipril, losartan, spironolactone or eplerenone for 2 weeks. Proximal tubular cells were cultured under normal or high glucose condition. Mannitol was used as osmotic control. Mesangial matrix expansion and tubulointerstitial fibrosis were analyzed on kidney sections. The protein level and the renal localization of αSMA and PDGF were also examined.

Results: Each RAAS blocker ameliorated the diabetes induced renal fibrosis. The increased levels of αSMA and PDGF in the diabetic kidney were lowered by all RAAS inhibitors. In tubular cells high glucose elevated the PDGF level and this increase was prevented by the RAAS blockers. Mannose had no effect. In controls αSMA was localized only around the vessels, while in diabetic kidneys intraepithelial and glomerular signals were detected. Tubulointerstitial PDGF staining was more intensive in diabetic rats than in controls. This effect was neutralized by each RAAS inhibitor.

Conclusions: Inhibition of EMT, which is a key feature of diabetes induced renal fibrosis could serve as a new therapeutic target of RAAS blockers. The changes in EMT are likely to be due to hyperglycemia than to glucose induced hyperosmolarity.

Pre-term newborns and bone metabolism

Kanioková Veselá P., Kaniok R.

Charles University in Prague, Faculty of Medicine in Hradec Králové, Czech Republic

Purpose: The main purpose of this study was to monitor markers of bone mineral metabolism and its connection with serum level of leptin during first two years of live.

Methods: This study is prospective. Into study were included pre-term newborns borned between 34 and 36+6 weeks of gestation.

Results and conclusion: Into this study were included 63 pre-term nerwborns. The children were devided into groups according to weeks of gestation, trophic and other ananmnestic data (medication during pregnancy, mothers smoking etc.). It was investigated level of 25 OH D, osteocalcin, Ca (iCa),P and leptin in cord blood and later in serum of patients each 6 months. In the age of two years was investigated the bone mineral density. In the presentation will be analysed groups of patients according to anamnestic data, mineral levels and possibilities of prediction of bone mineral status during growth spurt (during first two years).

End-stage renal disease in Slovak children: Roma are at risk

Kolvek G., Podracka L.

Ist Department of Paediatrics, Safarik University, Kosice, Slovak Republic

Purpose: Ethnic differences in the occurence of end-stage renal disease (ESRD) are reported on various populations, but the evidence on Roma fully lacks. The aim of this study was to explore the relative risk (RR) of ESRD for Roma children who constitute a major minority in Slovakia.

Methods: Ethnicity was assessed in all children (aged 0–14 y; n=44) who underwent renal replacement therapy (RRT) in Slovakia during the years 2005–2009. Rates of ESRD among Roma and non-Roma based on RRT data were calculated as well as the RR of Roma for ESRD. The latter was repeated after standardization for differences in age of both populations.

Results: Roma represented 25.0% (n=11) of all RRT patients. The average prevalence rate of RRT in majority population was 22.6 per million age-related population (pmarp) while in Roma the prevalence rate was significantly higher (38.1 pmarp). The RR of ESRD for Roma was 1.56, compared to the majority population. After age-standardization the RR for Roma was 1.72. Congenital anomalies (36.4%) and hereditary nephritides (27.3%) were the most common reasons of ESRD in Roma. Hereditary nephritides were significantly more common in Roma (p=0.015).

Conclusions: This study shows that the risk for ESRD is significantly higher for Roma than for non-Roma. A genetic propensity of Roma to ESRD might partially explain the higher risk. Another significant factors may add to this higher risk too, particularly consanguinity as well as different attitude towards own health.

Grant’s support: VEGA 1/0715/1.

Mineral bone density correlates with t-TG levels in pediatric patients with celiac disease

Kozar N.1, Ferant Ž.1, Dolinšek J.2, Šikić Pogačar M.1, Mičetić-Turk D.1

1Faculty of Medicine, University of Maribor, Slovenia; 2Gastroenterology Unit, Department of Paediatrics, University Clinical Centre, Maribor, Slovenia

Purpose: Chronic inflammation and malabsorption in celiac disease (CD) can cause bone metabolism alterations and bone mineral loss. Low BMD (bone mineral density) is a risk factor for osteoporosis and bone fracture, not only in later years, but also in childhood and adolescence. The aim of the present study was to determine the extent, to which anti-tissue transglutaminase (t-TG) antibody levels may correlate to bone mineral density (BMD) in children and adolescents with celiac disease.

Methods: The study included 41 pediatric patients with CD (23 girls, 18 boys), between 10 and 18 years of age and control group of 37 healthy subjects (19 boys, 18 girls). All patients declared to be on a strict gluten free diet (GFD) for the period of at least 6 months prior to the study. t-TG was measured in all the patients. Lumbar and left hip BMD were measured using dual-energy X-ray absorptiometry (Hologic Explorer QDR). Results are expressed as Z scores for a particular chronological age.

Results: Bone mineral density in children and adolescents with CD, who are consuming a strict GFD, was not significantly lower according to the local reference values (lumbar Z=-0.2 and left hip Z=-0.4). When compared with the control group, their BMD was slightly higher (lumbar Z=-0.3 and left hip Z=-0.8). Even though all the patients declared to be on a strict gluten free diet, only 58 % of them had negative values of t-TG. Interestingly, we found a significant negative correlation between BMD and t-TG levels within the serologically negative CD patients, where higher levels of t-TG were associated with lower BMD (R=-0.5, p=0.032).

Conclusion: A strict gluten-free diet is of great importance in patients with CD. It reduces the risk of long-term complications such as osteoporosis in this group of patients. Our results indicate that even in patients, who are consuming a strict GFD and are considered serologically negative (t-TG levels below 100 U/ml) their BMD can be affected according to the levels of t-TG which relates to the strictness of the diet. It is therefore strongly recommended that all CD patients comply with gluten free diet as strictly as possible.

Next-generation sequencing in the study of virome: looking for the „diabetogenic“ virus

Kramná L., Cinek O., Holková K.

Department of Paediatrics, 2nd Faculty of Medicine, Charles University in Prague and University Hospital Motol, Prague, Czech Republic

Purpose: Type 1 diabetes is a polygenic multifactorial disease with rapidly increasing incidence. Enteroviruses are often mentioned as the environmental triggers of this disease, but significance for this differs in published studies. It is suggested that „diabetogenicity“ depends on the specific type of virus. The aim of our project is reveal the potentially diabetogenic virus using the next-generation sequencing.

Methods: In the present pilot study children’s stool samples obtained from pre-diabetic cohort MIDIA were used for virome sequencing. Sample processing consisted of filtration and high speed centrifugation to enrich the viral particles. Subsequently, we performed viral RNA extraction, reverse transcription and second strand synthesis using random primers with tags. Fragments of cDNA flanked with tags were amplified using PCR and the products were used for the library preparation according to the Roche/454/GS Junior protocol. The gaps in the enterovirus genome were filled with the Sanger sequencing.

Results: So far three sequencing runs were carried out. From the last run we obtained 106254 sequences. We tested 12 samples there and after de novo assembly we obtained 741 contigs, 22 of them belonged to enterovirus. By now 19 samples were examined and in 13 of them serotype was determined from the next generation sequencing data only.

Conclusion: The next generation sequencing can be used efficiently in studies of virome. Further analyses using reference genome comparison, phylogenetic and the functional analyses at base and amino acid level should lead us to the unique and potentially “diabetogenic” part of the genome.

Supported by Ministry of Health, CZ, NT11465; Ministry of Health, CZ, 00064203.

Mucosal healing in pediatric patients with Crohn´s disease

Melek J., Pozler O.†

Department of Pediatrics of University Hospital, Hradec Kralove, Czech Republic

Over the past few years, mucosal healing in patients with Crohn´s disease has become a discussed issue. Mucosal healing has emerged as a perspective goal in clinical trials in patients with Crohn´s disease. The main point of the study is to determine the percentage of children and adolescents that achieved mucosal healing in interval 12-36 months from beginning of the therapy. The secondary output is the effect of the chosen treatment on mucosal healing.

Methods: Retrospective (2004-2012) a prospective (2013–2014) observation of newly-diagnosed Crohn´s disease pediatric patients (approximately N=50) of Dept. of Pediatrics of The University Hospital Hradec Kralove in years 2004–2014. We assess two groups of parameters (at the time of the diagnosis vs. examination in the interval of 12–36 months after diagnosis). In both examinations we studied these parameters: 1. PCDAI (Pediatric Crohn´s Disease Activity Index), 2. Colonoscopy, 3. Mucosal healing. Mucosal healing is defined as a complete endoscopic disappearence of all mucosal ulcerations in terminal ileum and large bowel, in this case we signed „mucosal healing yes“. In the other cases the result was signed „mucosal healing not“. The patients were devided into two groups depending on the therapy.

  1. azathioprine + corticosteroids ± 5-ASA (N=30)
  2. infliximab + azathioprine + corticosteroids ± 5-ASA (N=20)

Short-term blood pressure regulation and its association with angiotensin‑converting enzyme insertion/deletion polymorphism

Novák J., Závodná E., Nováková Z.

Department of Physiology, Faculty of Medicine, Masaryk University, Brno, Czech Republic

Purpose: Renin-angiotensin-aldosteron system is the most important system dealing with long-term blood pressure (BP) regulation. Angiotensin-converting enzyme (ACE) is one of the enzymes within this system and insertion-deletion (ID) polymorphism was identified inside its gene. The connection between long-term and short-term BP regulation and its genetic background is still not well established. Our study focuses on the effect of the ACE ID polymorphism on short-term BP regulation.

Methods: 308 healthy individuals (148 men; age19–24 years) were enrolled in the study. Parameters of short-term BP variability were determined using Penaz method (e.g. standard deviation of diastolic blood pressure, DBPSD [mmHg], and pulse pressure, PP [mmHg]) and spectral analysis, e.g. normalized systolic BP in arbitral units (nSBP [a.u.]). Polymorphisms were identified using allele-specific PCR.

Results: There was no statistically significant difference in genotype frequencies and Hardy-Weinberg equilibrium (II=24% vs. ID=48% vs. DD=28%, χ2=0.0015; p=0.97). No differences in parameters of short-term BP variability were found comparing distinct genotypes, however when dominant models for each allele were used, statistically significant differences in nSBP (Mann-Whitney: II/ID vs. DD; 0.0495±0.0291 vs. 0.0569±0.0309 [a.u.]; p=0.033) and DBPSD (M-W: DD/ID vs. II; 2.97±0.8478 vs. 2.77±0.8409 [mmHg]; p=0.048) were observed. In subgroup of women, there was a statistically significant difference in PP (M-W: DD/ID vs. II; 51.08±10.84 vs. 46.30±8.53 [mmHg]; p=0.0175).

Conclusion: ACE I/D polymorphism affects mostly the parameters of diastolic blood pressure variability.

Supported by MUNI/A/0951/2012.

Role of interleukin-24 (IL-24) in the pathogenesis of inflammatory bowel disease (IBD)

Ónody A.1, Pap D.1, Sziksz E.1,2, Himer L.1,2, Szebeni B.1,2, Bernáth M.1, Jávorszky E.1, Veres-Székely A.1, Kovács K.1, Molnár K.1, Ruszinkó V.3, Veres G.1, Arató A.1, Tulassay T.1,2, Vannay Á.1,2

11st Department of Pediatrics, Semmelweis University, Budapest, Hungary; 2Research Group for Pediatrics and Nephrology, Semmelweis University and Hungarian Academy of Sciences, Budapest, Hungary; 3Petz Aladár Teaching Hospital, Győr, Hungary

Purposes: The occurrence of inflammatory bowel disease (IBD) is increasing worldwide, yet the reasons remain unknown. Interleukin (IL)-24, a new member of IL-10 cytokin family was shown to be involved in the regulation of inflammation and tissue regeneration, however its role in IBD is not clarified. Therefore we aimed to investigate its effect on the pathomechanism of IBD.

Methods: Colonic biopsy samples were collected from children with Crohn’s disease (CD) (n=12), ulcerative colitis (UC) (n=12) and controls (n=12). The mRNA expression and localization of IL-24 and its receptor (IL-20RB), as well as platelet-derived growth factor (PDGF-BB), tumor growth factor (TGF-ß) were determined using real-time RT-PCR and immunofluorescent staining, respectively. HT-29 colonic epithelial cells were treated with recombinant IL-24, ERK1/2 and JNK1/2 specific inhibitors. Phosphorylation of ERK1/2, JNK1/2 and the amount of TGF-ß, PDGF-BB were analyzed by flow cytometry.

Results: The mRNA expression of IL-24, PDGF-BB, and TGF-β was significantly elevated in the colonic mucosa of children with IBD compared to controls (p<0.05). IL-24 and IL-20RB were detected in colonic epithelial cells and subepithelial fibroblasts in children with IBD. Increased ERK1/2 and JNK1/2 phosphorilation and elevated level of PDGF-BB and TGF-β were observed in HT-29 cells following IL-24 treatment. After administration of ERK1/2 and JNK1/2 inhibitors number of PDGF-BB and TGF-β positive cells decreased.

Conclusion: Elevated level of IL-24 and its effect on PDGF-BB and TGF-β may refer to its potential role during fibrotic processes in IBD mediated by ERK1/2 and JNK1/2 signaling pathways.

Evaluation of systolic and diastolic function in young patients after anthracycline therapy

Pekař M.1, Petrová A.1, Balcárková P.2, Nováková Z.1

1Department of Physiology, Faculty of Medicine, Masaryk University, Brno, Czech Republic; 2First Department of Internal Medicine– Cardioangiology, St. Anne´s Faculty Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic

Purpose: Evaluation of systolic and diastolic heart function by non-invasive echocardiography for patients after anthracycline therapy.

Methods: We examined 48 patients (group A, age: 18.4±6.9 years, time after end of therapy 10±5.2 years, cumulative dose of anthracycline 227.1±55.3 mg/m2) and 87 healthy controls (group K, age: 17.6±3.4 years). Standard echocardiography was used to study systolic heart function parameters (e.g.: ejection fraction EF, stroke volume SV, left ventricle ejection time ET, maximal speed of mitral lateral annulus movement in systole latS) and diastolic heart function (e.g.: maximal value of mitral inflow velocities – in early diastole: E wave, during atrial contraction: A wave). We used Mann-Whitney test for statistical analysis.

Results: We found statistically significant changes in heart function parameters in the group of post-anthracycline patients A versus K (A vs. K, p<0.05: left atrium diameter LA 29.5±4.2 vs. 31±4.1 mm; left ventricle outflow tract LVOT 17.6±2 vs. 18.5±2.1 mm; SV 61.2±20.7 vs. 65.6±14.7 ml; cardiac output CO 4.7±1.4 vs. 4.3±1.3 l/min; cardiac index CI 2.9±0.8 vs. 2.5±0.6 l/min/m2; ET 283.2±24.8 vs. 293.6±24 ms; latS 11.5±2.1 vs. 12.3±2.3 m/s; maximal speed of annulus movement in early diastole – mitral sepE´ 13.4±1.8 vs. 14.1±2.1 m/s and latE´tri 15.1±3.6 vs. 16.4±3.5 m/s; latA´tri 11.7±8.3 vs. 11.3±19.1 m/s). In statistical tests the subgroup of female patients showed more differences.

Conclusion: The results show that 10 years after antitumour therapy there are detectable changes in the subclinical level of some parameters of systolic and diastolic heart function in group of patients.

Supported by MUNI/A/0951/2012.

The prevalence of ZnT8 autoantibodies in Czech children at the onset of type 1 diabetes mellitus and dynamic changes of serum ZnT8 autoantibody concentrations over time

Petruzelkova L.1, Ananieva-Jordanova R.2, Vcelakova J.1, Vesely Z.1, Stechova K.1, Lebl J.1, Dusatkova P.1, Sumnik Z.1, Coles R.2, Powell M.2, Furmaniak J.2, Rees Smith B.2, Kolouskova S.1

1Department of Paediatrics, University Hospital Motol and 2nd Faculty of Medicine, Charles University in Prague, Prague, Czech Republic; 2FIRS Laboratories RSR Ltd, Parc Ty Glas, Llanishen, Cardiff, UK

Aims: The prevalence of autoantibodies to zinc transporter 8 (ZnT8) in Czech children at the onset of type 1 diabetes mellitus (T1D) and dynamic changes in ZnT8Ab concentrations during a follow up were studied. The value of ZnT8Ab measurement for diagnosis of T1D was assessed.

Methods: Serum samples from 227 children with newly diagnosed T1D and from 101 control children without diabetes were used in the study. A total of 171 samples from 116 diabetic patients were analysed in a follow up study at (median) 1 year, 3 years, 5 years and 10 years after T1D onset. ZnT8Ab were measured using a bridging ELISA while antibodies to GADAb, to IA-2Ab and to IAA were measured by radioimmunoassays.

Results: ZnT8Ab were detected in 163/227 (72%) of children at T1D onset and in 1/101 (1%) of control children. 16/227 (7%) T1D patients were antibody negative based on three antibodies (GADAb, IA-2Ab and IAA) which reduced to 10/227 (4.4%) (p<0.03) after addition of ZnT8Ab measurements. The ZnT8Ab concentrations significantly decreased over time after T1D onset and we observed seroconversion from positive to negative levels in some patients.

Conclusions: ZnT8Ab ELISA showed 72% disease sensitivity at T1D onset with 99% specificity for T1D at onset. The prevalence of ZnT8Ab in Czech children at T1D onset was similar to the prevalence reported for other populations. Combined measurement of GADAb, IA-2Ab, IAA and ZnT8Ab showed 96% diagnostic sensitivity for T1D compared to 93% sensitivity for combined GADAb, IA-2Ab and IAA.

Pulse wave, augmentation index, and intima-media thickness of carotid arteries after antitumour treatment with anthracyclines in childhood

Rohanová M.1, Kothaj D.2, Budinskaya K.2, Nováková Z.2, Hrstková H.3

1Department of Paediatrics, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic; 2Department of Physiology, Faculty of Medicine, Masaryk University, Brno, Czech Republic; 3Department of Paediatric Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic

Purpose: The aim of the study was to determine the side effect of anthracycline antitumour therapy. This is a continuation of the last-year study enlarged by a file of patients and controls which was accompanied by the intima-media thickness parameter (IMT).

Methods: We examined 62 former cancer patients after anthracycline therapy in childhood (group A, age: 18.8±6.8 years, time from discontinuation by date of examination 10.8±5.9 years, the cumulative dose of anthracyclines 220.5±60.8 mg/m2) and 98 healthy subjects (group Z, age: 17.3±0.9 years). To determine the basic characteristics of arterial stiffness – pulse-wave velocity (PWV), augmentation index standardised on a heart rate of 75/min (AIx75), augmentation pressure (AP), Buckberg index (SEVR), we used a non-invasive method of applanation tonometry (SfygmoCor). We used standard ultrasound for 50 healthy subjects and 56 patients to determine IMT carotid artery. Statistical analysis was performed using the non-parametric Mann-Whitney test.

Results: There was a statistically significant increase in the value AIx75 (Z vs. A: -4.53±8.75 vs. 1.79±8.1%, p<0.01). The other parameters were not statistically significantly different (SEVR: 180.0±29.7 vs. 164.0±30.6%, p=ns; PWV: 6.64±1.02 vs. 6, 79±1.09 m/s, p=ns; IMT 0.586±0.214 vs. 0.572±0.218 mm).

Conclusion: We concluded that the functional changes of the vessel wall properties are not accompanied by echo-detected structural changes in former oncological patients.

Supported by a special research project MUNI/A/0951/2012.

Proteinuria in children after renal transplantation and its relationship to allograft survival

Rosik T., Seeman T.

Department of Pediatrics, 2nd Faculty of Medicine, Charles University in Prague and University Hospital Motol, Prague, Czech Republic

Purpose: In adult population proteinuria is associated with reduced kidney allograft survival. Purpose of this study was to assess the association between proteinuria and graft survival in children transplanted University Hospital Prague-Motol between January 1997 and December 2007.

Methods: In University Hospital Prague-Motol were transplanted 91 children between January 1997 and December 2007. Final cohort includes 75 children (40 boys), excluding criteria were recurrence of focal-segmental glomerulosclerosis, lost of graft in first year after renal transplantation and incomplete documentation. Average time on dialysis before transplantation was 356 days, average age of recipient was 12.1 years, average age of donor was 31 years, average follow-up time was 5.5 years. Proteinuria was considered positive if index protein/creatine in urine was higher than 30 mg/mmol. We collected demographic characteristics and data of proteinuria a glomerular filtration at 1, 2, 4 year after transplantation and at last year of follow-up after transplantation.

Results: At 1 year after transplantation there were 26 patients (35%) with proteinuria. There was a statistical significant difference between overall survival of patients with and without proteinuria (8 patients with proteinuria vs. no patient without proteinuria, p<0.0001). Univariate analysis showed that patent survival was related also to presence of acute rejection and corticoresistant rejection in first year after transplantation and value of glomerular filtration at 1 year after transplantation. Proteinuria and acute rejection was significant also in multivariate analysis.

Conclusions: 1 year after transplantation proteinuria was a predictor of graft survival. Other risk factors for graft failure were acute and corticoresistant rejection at first year after transplantation.

Molecular genetic analysis of patients with persistent hyperinsulinemic hypoglycemia of infancy and genotype-phenotype correlation

Roženková K.1, Dušátková L.1, Kytnarová J.2, Dušátková P.1, Průhová Š.1

1Department of Paediatrics, 2nd Faculty of Medicine, Charles University in Prague and University Hospital Motol, Prague, Czech Republic; 2Department of Paediatrics, General University Hospital and First Faculty of Medicine, Charles University in Prague, Czech Republic

Purpose: The project aims, for the first time in the Czech Republic, to systematically gather clinical data and DNA samples for genetic analysis from patients with the diagnosis of persistent hyperinsulinemic hypoglycaemia of infancy (PHHI). In this pilot study we investigate 5 of the 9 known PHHI genes (ABCC8, KCNJ11, GCK, HNF4A and HNF1A) and we introduce the analysis of the 4 remaining genes (GLUD1, HADH, SLC16A1 and UCP2).

Methods: DNA samples from 19 patients (7 females, median age of diagnosis 2 months (0–6 months)) have been collected. The DNA was investigated by direct sequencing of the selected genes.

Results: The genetic analysis of the target genes revealed mutations in 12 of 19 patients: 9 mutations in ABCC8 (out of which 4 were novel – F48delT, R657Q, Q444H and IVS37+5G>C), 1 novel mutation Q52X in KCNJ11, 1 novel mutation S72del in HNF4A and 1 mutation M197I in GCK. The novel homozygous mutation Q444H in ABCC8 manifested itself as a severe diffuse form of hyperinsulinism, the patient repeatedly underwent subtotal pancreatectomy and died at the age of 12 years. Focal form of PHHI was confirmed in one patient with a heterozygous mutation in ABCC8 and partial pancreatectomy was performed. The patients without identified mutations in target genes have a mild form of the disease which is diazoxid-responsive or requires no treatment.

Conclusion: So far the genetic background has been identified in 63% of patients with PHHI, the mutations in ABCC8 are the most frequent, being found in 47.4% of our patients.

The study was supported by a grant from the Czech Ministry of Health (NT 11402) and by the Grant Agency of the Charles University in Prague (GAUK 248 213).

Hypertrophic cardiomyopathy – molecular-genetic testing

Skutková L.1,2, Pešl M.1,4,5, Vaníčková P.3, Hrstková H.2, Grochová I.4

1The International Clinical Research Center of St. Anne’s University Hospital, Brno, Czech Republic; 2Department of Pediatrics, The University Hospital, Brno, Czech Republic; 3P&R LAB a.s., AGEL a.s.; 4First Department of Internal Medicine-Cardioangiology, St. Anne’s University Hospital, Brno, Czech Republic; 5Department of Biology, Masaryk University, Brno, Czech Republic

Purpose: Hypertrophic cardiomyopathy (HCM) is the second most common form of heart muscle disease affecting children and adolescents. The etiology is heterogenous. The most common forms are caused by mutations in the genes for cardiac sarcomeric proteins, mainly for myosin heavy chain (MYH7; 14q12,) in 75%, but also myosin binding protein C (MyBPC3; 11p11.2), troponin T (TNNT2; 1q32) and troponin I (TNNI3; 19q13.42). The aim of this study is to map genetic profile of pediatric patient with HCM in our region and to set up the strategy for clinical and genetic testing.

Methods: Genealogy. Molecular-biological analysis of DNA isolated from the peripheral blood of patients with proved HCM or with a positive family history. Analysis of the genes MYH7, MyBPC3 and TNNT2 by SSCP analysis and sequencing.

Results: We preselected and examined 60 patients. From those 10 patients have genotype which predict the clinical course of hypertrophic cardiomyopathy. In one of those 10 families we started to optimize the methods for preimplantation genetic diagnosis of HCM of embryos in a cycle of assisted reproduction.

Conclusions: Genetic examination does help early diagnosis of HCM. If the mutation responsible for the disease is detected, it is possible to perform molecular diagnostics also in relatives and initiate an early prophylactic therapy. In case of negative outcome, the patient does not need further close cardiological attention. Diagnosis is influenced by a wast genetic heterogeneity of this disease and the limited possibilities of molecular biology laboratories in routine practice.

Supported by the European fund for regional development – Project ICRC (No. CZ.1.05/1.1.00/02.0123).

Role of matrix metalloproteinase (MMP)-12 in the pathomechanism of chronic renal injury

Sziksz E.1,2, Szebeni B.1,2, Himer L.1,2, Pap D.2, Nagy Szakál D.2, Ónody A.2, Kis É.2, Kovács K.2, Jávorszky E.2, Fekete A.2,3, Reusz G.2, Tulassay T.1, Vannay Á.1

1Research Group for Paediatrics and Nephrology, Semmelweis University and Hungarian Academy of Sciences, Budapest, Hungary; 21st Department of Paediatrics, Semmelweis University, Budapest, Hungary; 3“Momentum” Diabetes Research Group, Semmelweis University and Hungarian Academy of Sciences, Budapest, Hungary

Purposes: Renal fibrosis is an uncontrolled wound-healing process defined by extracellular matrix (ECM) remodeling leading to kidney architecture disruption and impaired organ function. Recently the determinative role of interleukin (IL)-17 and matrix metalloproteinase (MMP)-12 has been suggested in ECM remodeling therefore we aimed to depict the role of IL-17 and MMP-12 in renal fibrosis.

Methods: Unilateral ureteral obstruction (UUO) was accomplished on male C57BL/6J (WT) and IL-17A knock out (IL-17 KO) mice. In vitro experiments were performed using human proximal tubular epithelial cell line (HK-2).

Results: Five and seven days after the onset of UUO the number of IL17+ T cells was elevated in the kidney of WT mice compared to controls. Seven days after the beginning of UUO the number and mean fluorescent intensity of MMP12 positive proximal tubular epithel cells (PTECs) increased in WT but not in IL-17 KO mice. After 72h treatment with recombinant TGF-β, IL-17 or both the number and mean fluorescent intensity of MMP-12 positive HK-2 cells were also higher compared to untreated cells. Administration of specific JNK inhibitor decreased the number of these MMP-12 positive HK-2 cells. In selective MMP-12 inhibitor treated mice collagen-1 mRNA expression and alpha-smooth muscle actin protein level were decreased seven days after the onset of UUO compared to WT animals.

Conclusion: Elevated MMP-12 expression was detected following UUO, which major sources are the PTECs. Increment of MMP-12 is IL-17 and TGF-ß dependent and JNK mediated. MMP-12 may diminish renal fibrosis through influencing the proliferation and collagen production of fibroblasts.

Exhaled nitric oxide in children and adolescents with allergic rhinitis and atopic asthma

Šenkeřík M.1, Chládková J.1, Havlinová Z.2, Krčmová I.3, Chládek J.2,4

1Department of Pediatrics, Charles University in Prague, Faculty of Medicine in Hradec Kralove, Hradec Kralove, Czech Republic; 2Department of Pharmacology, Charles University in Prague, Faculty of Medicine in Hradec Kralove, Hradec Kralove, Czech Republic; 3Department of Clinical Immunology and Allergology, University Hospital, Hradec Kralove, Czech Republic; 4Department of Medical Biochemistry, Charles University in Prague, Faculty of Medicine in Hradec Kralove, Czech Republic

Purpose: The main aim of this study was examine flow-rate independent parameters of nitric oxide (NO) at varying speeds of 30, 50, 100 and 250 ml/s. Determine parameter changes in children with allergic rhinitis (AR, N=48), bronchial asthma (AA, N=90) in relation to achieving control of asthma in comparation with control group (C, N=33).

Methods: Measurements of FENO were performed with a chemiluminiscence analyzer at five rate levels ranging from 50 to 250 ml/sec in school children and adolescents in all experimental groups. Using simplified models of the lungs and airways were estimated the flow rate independent parameters characterizing NO concentration in the airways: alveolar concentration (CANO), bronchial wall concentration (CawNO) and bronchial wall diffusion capacity (DawNO) of nitric oxide. Thereafter were performed analysis of FENO50 and CawNO values depending on the symptoms good or bad control AA symptoms.

Results: Multiple flow-rate curves NO concentration in exhaled air were different between all groups in all measured speeds. The highest values as were expected were found in group AA, the lowest curve was in control group. FENO, resp. CawNO values were significantly higher in the group of AA against AR and C group. FENO50 and CawNO values were significantly increased in the group of children with poor control of AA compared with group good control of symptoms AA. Differences in CANO and DawNO were not significant between all groups.

Conclusions: Control of asthma is a goal of asthma management worldwide. Control is today based on clinical findings. Future is in combination clinical findings and biochemical markers of airway inflammation. In our study we confirmed the possibility of using FENO50 and CawNO for diagnose AA and assess the level of its control. There were no differences in the values of CANO and DawNO.

Funding source: Ministry of Health of the Czech Repubic, Number: NS9692-3/2008.

Comparison of morphological changes of airway walls in young and adult rats after an allergic challenge

Šimůnková P.1, Uhlík J.2, Vajner L.2, Pohunek P.1

1Department of Paediatrics, 2nd Faculty of Medicine, Charles University and Motol University Hospital, Prague, Czech Republic; 2Department of Histology and Embryology, 2nd Faculty of Medicine, Charles University, Plzenska 221, Prague 5, Czech Republic

Together with the inflammation, various structural changes known as remodeling constantly appear in the bronchial walls of patients suffering from the bronchial asthma. It mainly consists in changes of properties of the bronchial epithelium including hyperplasia of its goblet cells, thickening of the basement membrane predominantly in the area of its reticular lamina, differentiation and activation of myofibroblasts and proliferation of smooth muscle in the airway walls, multiplication of submucosal glands, deposition of extracellular proteins to the lamina propria mucosae and changes of vascularization. We decided to analyze structural changes of intrapulmonary airways in rats of Brown Norway strain, which are especially responsive to sensitization and tend to develop the state that clinically and morphologically resembles the human bronchial asthma when stimulated. Young and adult rats were sensitized by repeated intraperitoneal injections of ovalbumin (OA). During following 2 weeks, the rats inhaled the aerosolized OA. Two control groups of each age were housed simultaneously. The first of them was injected and inhaled by saline (S), the second group was untreated (C). Then the animals were sacrificed, their lungs were processed for the light microscopy. We concentrated to the airway morphometric parameters, occurrence of eosinophilic granulocytes and number of epithelial secretory cells. The airway walls of the OA group were showing marks of remodeling in both young and adult animals. The total wall areas of all intrapulmonary airways were significantly increased compared to groups S and C. The thickening of inner wall areas was more pronounced in adult rats; outer wall areas were more increased in the young. There were some significant signs of the muscular hypertrophy or hyperplasia only in young animals. The number of eosinophilic granulocytes was increased in airway walls of OA young rats. Secretory cells were more multiplicated in airway epithelium of OA adults. The study confirmed the bronchial sensitivity of BN rats and different reactivity of adult and young individuals.


Štítky
Neonatologie Pediatrie Praktické lékařství pro děti a dorost

Článek vyšel v časopise

Česko-slovenská pediatrie

Číslo 6

2013 Číslo 6

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