Search

Background: IgA vasculitis (IgAV) is a small vessel vasculitis occurring predominantly in childhood. Studies concerning the genetic background of IgAV have confirmed that susceptibility to the disease may be influenced by Human Leukocyte Antigens (HLA), with HLA-DRB1 gene showing a strong association with the disease. Objectives: We aimed to investigate HLA-DRB1 polymorphism among Croatian patients with IgAV and to determine if there are associations with disease susceptibility and clinical heterogeneity. Methods: 123 IgAV patients, fulfilling the diagnostic EULAR/PRINTO/PRES criteria from three pediatric rheumatology centers and 202 unrelated healthy individuals were enrolled. Genomic DNA was extracted from whole peripheral blood. The HLA- DRB1 alleles were analysed using the Next Generation Sequencing (NGS) method. Results: Among 123 patients with IgAV, 68 were girls and 55 were boys with median age 6.3 (4.5- 8.2) years at the time of diagnosis. All patients had purpuric rash, 75.7% had arthralgia or arthritis, 32.5% had affected gastrointestinal (GI) system, while 25.2% patients developed IgA vasculitis nephritis (IgAVN). The HLA-DRB1*12:01 allele was associated with an increased risk for IgAV (OR 4.45, 95% CI=1.17-16.95, P=0.03), while HLA-DRB1*11:01 allele was associated with an increased risk for GI involvement in patients who developed IgAV (OR 3.29, 95% CI=1.2-8.98, P=0.031). A marginally significant (P=0.068) higher frequency of the HLA DRB1*10:01 allele in patients with GI symptoms was observed. No significant differences were found in the distribution of HLA DRB1 alleles between patients with IgAVN and those who did not develop nephritis. Conclusion: Our results demonstrated that HLA- DRB1*12:01 allele was associated with susceptibility to IgAV in the Croatian children, while HLA-DRB1*11:01 allele showed association with GI manifestations of the disease. SUPPORT: Croatian Science Foundation Project IP- 2019-04-8822.

Estimated glomerular filtration rate (eGFR) is one of the best-performing methods in evaluating kidney function. There are limited data regarding the estimated glomerular filtration rate in children and young adults with hemophilia. The aim of this study was to determine the difference between three commonly used estimated glomerular filtration rate equations in the pediatric population in a cohort of patients with hemophilia. Our prospective study included 36 pediatric patients with moderate or severe hemophilia. eGFR was calculated for each patient using the original creatinine-based “bedside Schwartz” equation, the cystatin C-based equation and the creatinine-cystatin C-based equation. The difference between the equations, calculated using the one-way repeated ANOVA test, was statistically significant (p, Procjena glomerularne filtracije jedna je od najboljih metoda ocjene bubrežne funkcije. Postoje oskudni podaci o procjeni glomerularne filtracije u djece i mladih odraslih oboljelih od hemofilije. Cilj našeg istraživanja je utvrditi razliku između tri često korištene metode za procjenu glomerularne filtracije u pedijatrijskoj populaciji u skupini pacijenata oboljelih od hemofilije. U naše prospektivno istraživanje uključili smo 36 djece s hemofilijom umjerenog ili teškog stupnja. Svakom pacijentu procijenjena je glomerularna filtracija koristeći jednostavnu, kreatinin baziranu jednadžbu po Schwartzu, cistatin C baziranu jednadžbu i kreatinin - cistatin C baziranu jednadžbu. Razlika između tri jednadžbe koristeći jednosmjerni ANOVA test bila je statistički značajna (p

Aim: The aim of this study was to compare the Renal resistive index (RI) measured by the Doppler ultrasound method in children with type 1 diabetes (T1D) who are normoalbuminuric and in normal, age- matched controls. RI is an indicator of increased vasculature intrarenal resistance, that occurs in the impaired renal function of patients suffering from T1D. Increased intrarenal RI could be useful as a marker when diabetic nephropathy is being developed. Materials and methods: In this cross-sectional study 76 healthy children and 76 children with T1D age 10-18 were included, with a disease duration from 2 to 10 years with normal renal function and normoalbuminuria. The Doppler RI was measured in subjects in both groups. In the study group a blood sample was taken for HbA1C and in both groups blood samples for serum creatinine, serum lipids and first-morning urine samples for albumin / creatinine ratio were taken. Results: Statistically significant differences were found in mean RI (mRI), p

IgA vasculitis (IgAV) is a desease in which genetic background also plays an important role. Some small studies have indicated the importance of variants in various non-HLA genes in the manifestation of different disease phenotypes. The aim of this research was to investigate single nucleotide polymorphisms (SNPs) of genes HMGB1 and AGER encoding for high mobility group box-1 (HMGB1) and receptor for advanced glycation endproducts (RAGE), both acting as mediators of inflammation, in the susceptibility and clinical features of patients with IgAV. HMGB1 and RAGE gene polymorphisms were genotyped using a real- time polymerase chain reaction. The presence and frequency of polymorphisms in HMGB1 (rs2249825, rs1045411, rs1060348, rs1412125 and rs41369348) and RAGE (rs1800625, rs1800624, rs2070600 and rs3134940) were determined. Clinical data were collected from database of IgAV patients from two Croatian University Centers for pediatric rheumatology. 81 pediatric IgAV patients were included, of whom 45 were boys and 36 girls, as well as 150 age- and sex-matched healthy controls without any history of autoimmune disease. The median (range) age of IgAV patients was 6.25 (4.60-8.20) years, and among them 71.6% had joint involvement, 29.62% had gastrointestinal manifestations, while 27.16% developed nephritis. The purpuric rash which extended from lower extremities to the trunk, upper extremities and face (generalized rash) was present in 43.20% of patients and 27.16% had at least one relapse. Among the analyzed polymorphisms, only in the rs1412125 there was a deviation from the Hardy Weinberger equilibrium. There was no statistically significant association of the analyzed polymorphisms with the IgAV susceptibility, compared to healthy controls. Polymorphism rs2070600 was significantly related with the development of nephritis in IgAV, while rs1412125 was associated with gastrointestinal involvement. The IgAV patients carrying the T allele (rs2070600) of the AGER had significantly increased risk of nephritis development compared with the IgAV patients with homozygous CC genotype in dominant (OR 4.05, CI 1.09-15.03, p = 0.037) and additive genetic models (OR 3.95, CI 1.16- 13.47, p = 0.049). The minor C allele (rs1412125) of the HMGB1 was found to significantly increase the risk of gastrointestinal involvement in overdominant model with an allelic odd ratio of 2.78 (CI 1.04-7.43, p = 0.04). Although neither of analyzed HMGB1 and RAGE polymorphisms was not associated with IgAV susceptibility, our results indicated that these polymorphisms may be involved in the pathogenesis of IgAV with possible effect on different disease phenotypes. SUPPORT: Croatian Science Foundation project IP- 2019-04-8822.

Uvod. U manifestaciji različitih fenotipova IgA vaskulitisa (IgAV) važnu ulogu imaju i varijante gena izvan HLA sustava. Cilj je bio istražiti ulogu polimorfizama pojedinačnih nukleotida gena HMGB1 i AGER koji kodiraju za protein visoke pokretljivosti iz skupine 1 (HMGB1) i receptor za krajnje produkte uznapredovale glikozilacije (RAGE), u predispoziciji i kliničkim značajkama bolesnika s IgAV-om. Ispitanici i metode. Genotipizirani su polimorfizmi gena za HMGB1 i RAGE metodom lančane reakcije polimeraze. Utvrđena je prisutnost i učestalost polimorfizama u HMGB1 (rs2249825, rs1045411, rs1060348, rs1412125 i rs41369348) i RAGE (rs1800625, rs1800624, rs2070600 i rs3134940). Klinički podaci prikupljeni su iz baze podataka bolesnika s IgAV- om iz dva hrvatska tercijarna centra za pedijatrijsku reumatologiju. Rezultati. Istraživanje je obuhvatilo 81 bolesnika s IgAV-om, među kojima je bilo 45 dječaka i 36 djevojčica, te 150 kontrolnih ispitanika koji se po dobi i spolu nisu razlikovali od djece s IgAV- om. Medijan (raspon) dobi bolesnika s IgAV-om iznosio je 6, 25 (4, 60–8, 20) godina, a među njima 71, 6% imalo je zahvaćene zglobove, 29, 62% imalo je gastrointestinalne manifestacije, dok je 27, 16% bolesnika razvilo nefritis. Generalizirani purpurični osip bio je prisutan u 43, 20% bolesnika, a 27, 16% imalo je barem jedan recidiv bolesti. Nije bilo statistički značajne povezanosti analiziranih polimorfizama s predispozicijom za IgAV u usporedbi sa kontrolama. Polimorfizam rs2070600 bio je značajno povezan s razvojem nefritisa u IgAVu dok je rs1412125 bio povezan sa zahvaćanjem probavnog sustava. Bolesnici s IgAV-om koji su imali alel T (rs2070600) u genu AGER imali su značajno veći rizik za razvoj nefritisa u usporedbi s bolesnicima s homozigotnim genotipom CC u dominantnom (OR 4.05, CI 1.09–15.03, p = 0.037) i aditivnom modelu (OR 3, 95, CI 1, 16–13, 47, p = 0, 049). Utvrđeno je da minor alel C (rs1412125) u HMGB1-u značajno povećava rizik od zahvaćanja probavnog sustava u superdominantnom modelu s omjerom izgleda od 2, 78 (CI 1, 04–7, 43, p = 0, 04). Zaključak. Iako niti jedan od analiziranih polimorfizama gena za HMGB1 i RAGE nije bio povezan s predispozicijom za IgAV, naši rezultati pokazali su da ti polimorfizmi mogu biti povezani s različitim fenotipovima IgAV. Potpora: Projekt Hrvatske zaklade za znanost IP- 2019-04-8822

Introduction: IgA vasculitis (IgAV) is the most common systemic vasculitis in children. The mandatory clinical feature of the disease is purpuric rash, which predominantly affects the lower extremities, accompanied by diffuse abdominal pain, joint involvement, nephritis and/or IgA deposition in biopsy specimen (skin, intestinal tract, kidney). In most cases, IgAV is a self-limiting disease with favorable outcomes, however, relapses are not uncommon. Objectives: The aim of this study is to evaluate the usefulness of supervised machine learning (ML) algorithms in the identification of patients which could develop IgAV relapses. Methods: A large set of predictive variables related to demographic variables, clinical history, symptoms, laboratory values, and medications were used in the initial data collection for developing a predictive ML model. After preparing the dataset, handling missing values and data imbalances, a random forest (RF) decision tree and support vector machine (SVM) model with polynomial kernel were trained, crossvalidated and tested. Results: This pilot study included 539 IgAV patients (260 males, and 279 females), with a median age of 6.17 (4.42 to 8.75) years. Among them, 78.11% had joint involvement, 44.53% had gastrointestinal involvement, and in 18.92% nephritis has developed. Atypically distributed rash (not affecting lower limbs as well as rash that had been generalized from the onset of the disease) was found in 5.19% IgAV patients, while 8.91% had persistent purpura for a month or more. The incidence of IgAV relapses was 10.2%. The RF model produced an overall accuracy of 95%, with a sensitivity of 100%, and specificity of 94.48%. The SVM model produced an accuracy of 87.58%, with a sensitivity of 100%, and specificity of 86.21%. The most useful predictor variable was the presence of persistence rash in both models. Other common predictors in both models included the presence of rash on atypical locations, age, and nephritis. Conclusion: The results of this pilot study show promising applications of ML as an useful aid in predicting vulnerable patients who developed IgAV. Support: Croatian Science Foundation project IP- 2019-04-8822.

Indroduction: IgA vasculitis (IgAV) is the most common childhood-vasculitis in which more than 50% of children develop gastrointestinal (GI) symptoms. In 10-20% of patients serious complications such as intussusception, bowel perforation, and massive bleeding may occur. The most important complication is the development of nephritis with progression to chronic renal failure in about 3% of children. The aim of the research was to analyze clinical and biochemical parameters in patients with IgAV and GI manifestations. Methods: This retrospective study included children with IgAV reviewed in five Croatian University Centers for pediatric rheumatology in the period 2009 to 2019. Results: Out of 611 children with IgAV, 320 were males and 291 were females. The overall GI symptoms prevalence was 45.9% and the median (range) age at diagnosis was 6.42 (4.5- 8.83) years. Among patients with GI symptoms there were 1.44 times more males (N=166) than females (N=115), which was statistically significant (p=0.003). Patients with GI symptoms had less infections before the appearance of purpura (59.8% vs. 70.9%, p=0.005) and were found to be significantly more likely to have rash distributed on the trunk (61.9% vs. 48.5%, p=0.001), and upper extremities (35.2% vs. 24.7%, p=0.006), as well as generalized rash (38.8% vs. 28.3%, p=0.008). These patients also had significantly higher values of C-reactive protein, leukocyte count, erythrocytes and platelets, hemoglobin, hematocrit and D-dimer concentrations and lower levels of IgG and IgM. In our cohort 42 out of 281 children (14.9%) had the most severe GI manifestations (intussusception and/or massive GI bleeding) with significantly higher values of 24-hour urine protein levels and D-dimer concentrations and lower total serum protein, albumin, IgG, IgM and C3 levels in comparison with children whose GI manifestations were not severe. Predictors of severe GI involvement were: relapse of the disease, generalized rash, rash extended on upper extremities, rash extended to the face, recurrent rash and renal involvement, as well as lower values of prothrombin time, fibrinogen and IgM among the laboratory parameters. Patients with GI symptoms were 1.68 times more likely to develop nephritis, and this probability was 2.58 times higher if GI symptoms occurred before other symptoms. Other predictors of nephritis were: severe and moderate GI manifestations, recurrent rash, one or more relapses of IgAV, and older age. Conclusion: Older children with IgAV and severe GI manifestations in whom IgAV begun with GI symptoms had a higher risk of acute and chronic complications of the disease. SUPPORT: Croatian Science Foundation project IP- 2019-04-8822

Uvod. IgA vaskulitis (IgAV) najčešći je sistemski vaskulitis u djece. Ključno kliničko obilježje bolesti je purpu rični osip koji pretežno zahvaća donje ekstremitete popraćen difuznom boli u trbuhu, zahvaćanjem zglobova, nefritisom i/ili odlaganjem IgA depozita u bioptičkim uzorcima (kože, crijeva, bubrega). IgAV je većinom samo ograničavajuća bolest povoljnog ishoda, ipak relapsi su mogući i nisu rijetki. Cilj istraživanja je procijeniti korist algoritama za nadzirano strojno učenje (SU) u identifikaciji onih bolesnika koji bi mogli razviti relaps IgAV. Ispitanici i metode. Veliki skup prediktivnih varijabli vezanih uz demografske varijable, povijest kliničke slike, simptoma, laboratorijskih nalaza i lijekova iskorišten je za početno prikupljanje podataka u razvoju prediktivnog modela strojnog učenja (SU). Nakon pripreme podataka, rukovođenja vrijednostima koje nedostaju i podacima koji nisu uravnoteženi istrenirani su, unakrsno provjereni i testirani modeli stroja za slučajni odabir (SSO) i stroja za podršku s polinomskom jezgrom (SPPJ). Rezultati. Pilot istraživanje obuhvatilo je 539 djece s IgAV-om (260 muške i 279 ženske) s medijanom dobi od 6.17 (4.42–8.75) godina. Među njima, 78.11% imalo je zahvaćene zglobove, 44.53% imalo je zahvaćen probavni sustav, a u 18.92% razvio se nefritis. Atipični raspored purpuričnog osipa (koji nije na donjim ekstremitetima kao ni generalizirani osip od početka bolesti) imalo je 5.19% bolesnika s IgAV-om dok je njih 8.91% imalo perzisti rajući purpurični osip duži od mjesec dana. Incidencija recidiva IgAV bila je 10.2%. SSO model pokazao je sveukupnu točnost od 95% s osjetljivošću od 100% i specifičnost od 94.48%. SPPJ model pokazao je točnost od 87.58% s osjetljivošću od 100% i specifičnost od 86.21%. Prisutnost perzistirajućeg purpuričnog osipa se u oba modela pokazala kao najkorisnija prediktivna varijabla. Prediktivne varijable zajedničke za oba modela također su uključivale i prisutnost purpuričnog osipa na atipičnim mjestima, dob i nefritis. Zaključak. Rezultati ovog pilot istraživanja pokazuju obećavajuću primjenu stroja za učenje i to kao korisnu pomoć u predviđanju skupine bolesnika rizične za razvoj relapsa IgAV. Potpora: Projekt Hrvatske zaklade za znanost IP- 2019-04-8822.

Blood pressure variability (BPV) is a complex physiological phenomenon and it is known that increased BPV exacerbates the progression of hypertension and correlates with adverse cardiovascular outcomes. However, there is paucity of data regarding factors influencing BPV in pediatric population. This study aimed to analyze blood pressure (BP) pattern and assess blood pressure variability and its possible determinants in untreated children with essential hypertension. The study group included 132 children, average age 15 y (7- 18 y), 84 boys and 48 girls with essential hypertension and no use of antihypertensive therapy. Anthropometric parameters, serum glucose level (sG), serum uric acid (sUA), serum creatinine (sCr), total cholesterol (TCh), HDL cholesterol (HDL), LDL cholesterol (LDL) and triglycerides (TG) were measured in all participants. Office blood pressure (BP) and ambulatory blood pressure (AMBP) was measured according to recent European Society of Hypertension (ESH) guidelines. BPV was defined as value of the standard deviation of blood pressure for day and night time periods. In addition to the classical statistical analysis, an unsupervised machine learning approach using the expected maximization algorithm was implemented to find groups of patients with similar characteristics. The average age was 14.98 ± 2.1 years. Comparing sex-specific BP parameters, boys had higher daytime and nighttime systolic BP, although the difference was not statistically significant (p = 0.067 and p = 0.583). Girls had significantly higher daytime and nighttime diastolic BP values (p=0.017 ; p=0.027). There was no difference in BPV according to gender while boys have higher values of sCr, sG, and sUA despite similar body mass index (BMI) [27.18±5.27 kg/m2 (males) vs 27.94±5.27 kg/m2 (females), p= 0.427]. A statistically significant positive correlation was found between the Z-score for BMI and daytime systolic BPV, nighttime systolic BP and total cholesterol, nighttime diastolic BPV and sUA (r= 0.19, r= 0.28 and r = 0.26, respectively). Within the male population two clusters were found. The subjects in cluster 2 had higher daytime and nighttime systolic and diastolic BP values, higher total cholesterol and triglycerides and significantly higher night time systolic and diastolic BPV. Understanding potential determinants of BPV in hypertensive children could help identify patients with increased cardiovascular risk earlier. Our results suggest that clustering of metabolic factors influence BPV in untreated children with essential hypertension which could also be gender specific for male subjects.

Introduction: The pathogenesis of IgA vasculitis (IgAV) is complex and still insufficiently elucidated. It is a multifactorial disease in the development of which, in addition to numerous environmental factors, the genetic background also plays an important role. Previous genome-wide association study studies have established an association between IgAV susceptibility and the HLA class II genes, although many small studies have indicated the importance of variants in various non-HLA genes in the manifestation of different disease phenotypes. Objectives: The aim of this research was to investigate single nucleotide polymorphisms (SNPs) of genes HMGB1 and AGER encoding for high mobility group box-1 (HMGB1) and receptor for advanced glycation endproducts (RAGE), both acting as mediators of inflammation, in the susceptibility and clinical features of patients with IgAV. Methods: Genomic DNA was extracted from whole blood samples after which the HMGB1 and RAGE gene polymorphisms were genotyped using a real-time polymerase chain reaction. The presence and frequency of polymorphisms in HMGB1 (rs2249825, rs1045411, rs1060348, rs1412125 and rs41369348) and RAGE (rs1800625, rs1800624, rs2070600 and rs3134940) were determined. Clinical data were collected from database with systematic analysis of patients with IgAV in Croatian population from two Croatian University Centers for pediatric rheumatology and nephrology care. Results: The research included 81 pediatric IgAV patients, of whom 45 were boys and 36 girls, as well as 150 age- and sex-matched healthy controls without any history of autoimmune disease. The median (range) age of IgAV patients was 6.25 (4.60-8.20) years, and among them 71.6% had joint involvement, 29.62% had gastrointestinal manifestations, while 27.16% patients developed nephritis. The purpuric rash which extended from lower extremities to the trunk, upper extremities and face (generalized rash) was present in 43.20% of patients and 27.16% had at least one relapse. Among the analyzed polymorphisms, only in the rs1412125 there was a deviation from the Hardy Weinberger equilibrium. There was no statistically significant association of the analyzed polymorphisms with the IgAV susceptibility, compared to healthy controls. However, the two polymorphisms proved to be linked with a well- defined clinical phenotype. Polymorphism rs2070600 was significantly related with the development of nephritis in IgAV, while rs1412125 was associated with gastrointestinal involvement. The IgAV patients carrying the T allele (rs2070600) of the AGER had significantly increased risk of nephritis development compared with the IgAV patients with homozygous CC genotype in dominant (OR 4.05, CI 1.09-15.03, p = 0.037) and additive genetic models (OR 3.95, CI 1.16-13.47, p = 0.049). The minor C allele (rs1412125) of the HMGB1 was found to significantly increase the risk of gastrointestinal involvement in overdominant model with an allelic odd ratio of 2.78 (CI 1.04-7.43, p = 0.04). Conclusion: Although neither of analyzed HMGB1 and RAGE polymorphisms was not associated with IgAV susceptibility, our results indicated that these polymorphisms may be involved in the pathogenesis of IgAV with possible effect on different disease phenotypes. SUPPORT: Croatian Science Foundation project IP- 2019-04-8822

U ovom radu bavimo se tematikom rata koji je ostavio trag na svim poljima ljudskog djelovanja tijekom 17. stoljeća, ali i kasnije. Rat koji je trajao od 1618. do 1648. bio je prvi totalni rat na europskom tlu, a prema vremenskom okviru u kojem se odvijao naziva se Tridesetogodišnji rat. Taj naziv ustvari označava niz meĎunarodnih oružanih sukoba na širem prostoru Svetog Rimskog Carstva u prvoj polovici 17. stoljeća. Iako se često prikazuje kao klasični vjerski sukob, Tridesetogodišnji rat je bio puno više od toga. Na vidjelo je izašla dugo potiskivana meĎusobna mržnja i netrpeljivost velikih europskih vladarskih kuća. Iako je povod i početni sukob nastao radi vjerske raznolikosti, uzroci su kao i uvijek bili puno kompleksniji. Slabljenje feudalizma, a samim time i nastanak prvih kapitalističkih odnosa, dodatno su opterećivali veliki broj europskih zemalja. Nakon stotina godina vjerskog jedinstva europskih zemalja, pojavom Martina Luthera stvari su se zauvijek mijenjaju. Najizraženija podjela na protestante i katolike dogodila se upravo na području Njemačke, u kojoj će desetak godina kasnije bjesnjeti rat velikih razmjera. Sam rat započinje fazom koja se najčešće naziva češkom ili češko-falačkom. Defenestracijom u Pragu, kojom češki staleži dižu pobunu i smjenjuju regente, dolazi do neizbježnog početka sukoba. Car šalje vojsku da smiri pobunu, ali je ona ubrzo poražena i prisiljena na povlačenje i sukobljene strane ostaju u pat poziciji. Borba za vlast u Češkoj bila je od krucijalne važnosti za obje strane, prije svega jer su u Carstvu trojica kneževa izbornika bili protestanti, a trojica katolici. Vjera češkoga kralja, kao sedmog kneza izbornika, nosila je prevagu. Nakon odreĎenog vremena carska vojska ipak uspijeva poraziti ustanike, a Ferdinand u Frankfurtu biva izabran za cara. Danska faza rata nastavila se u istom tonu. Protestantski danski kralj Kristijan IV. uz potporu Engleske i Nizozemske prelazi sjeverne granice Carstva, meĎutim, grof Tilly i general von Wallenstein najprije zasebno, a nakon toga i udruženi, nanose težak poraz Dancima. Ubrzo se u rat uključila i Švedska, koja je takoĎer zauzimala stranu reformista te je u ozbiljnoj mjeri zaprijetila carskoj moći. Gustav II. Adolf svoje je bitke pažljivo birao, često nanoseći teške poraze carskoj vojsci (pogotovo onoj na čijem je čelu bio grof Tilly). U većini bitaka švedska koalicija odnosila je pobjede, meĎutim, kod Nördlingena doživljavaju težak poraz s kojim su bili primorani napustiti južnu Njemačku. Već sljedeće godine raspada se i Heilbronnška liga, nakon čega se direktno uključuje sila koja je do sada ratovala iz sjene. Francuska je dugo vremena s prijezirom gledala na habsburšku vladarsku kuću. Iako je bila uglavnom katolička zemlja, Francuska se pridružila protestantskoj strani prije svega zbog rivaliteta sa Svetim Rimskim Carstvom i Španjolskom. Kardinal Richelieu je bio predsjednik vlade kralja Luja XIII. te je donosio sve bitnije vanjskopolitičke odluke u ime cara. Nakon niza sukoba, većinom sa Španjolskom koja je u jednom trenutku zaprijetila čak i samom Parizu, većih teritorijalnih izmjena nije bilo. Nakon smrti Richeliea i Luja XIII. nova vlast pokušava postići mir. Konačni mir dolazi 1648., a dogovoren je u Münsteru i Osnabrücku, dok je u povijesti ostao zapamćen kao Westfalski mir. Posljedice Tridesetogodišnjeg rata bile su strašne, neviĎene za stanovništvo do tada, a društvu je trebalo dugo vremena kako bi se oporavilo. In this paper, we deal with the theme of the war which left its mark on all fields of human activity during the 17th century and later. The war that lasted from 1618 to 1648 was the first total war on European soil, and because of the time frame in which it took place it is called the Thirty Years' War. This name actually denotes a series of international armed conflicts in the wider area of the Holy Roman Empire in the first half of the 17th century. Although often portrayed as a classic religious conflict, the Thirty Years’ War was much more than that. The long-suppressed mutual hatred and intolerance of the great European ruling houses had finally come to light. Although the cause and the initial conflict arose due to religious diversity, the causes were, as always, much more complex. The weakening of feudalism and thus the emergence of the first capitalist relations further burdened a large number of European countries. After hundreds of years of religious unity in European countries, things are forever changed with the appearance of Martin Luther. The most pronounced division into Protestants and Catholics took place in the area of Germany, where a large-scale war would rage ten years later. The war itself begins with a phase that is most often called the Bohemian Revolt. The defenestration in Prague, in which the Czech classes revolted and removed the regents, led to the inevitable beginning of the conflict. The king sent an army to quell the rebellion, but it was soon defeated and forced to withdraw, and the conflicting parties remained in a stalemate. The struggle for power in the Czech lands was of crucial importance to both sides primarily because in the Empire, three of the Dukes electors were Protestants and three were Catholics. The faith of the Czech king, as the seventh Duke elector, would prevail. After some time, however, the imperial army managed to defeat the insurgents and Ferdinand was elected emperor in Frankfurt. The Danish Phase of the war continued in the same tone. The Protestant Danish King Christian IV crosses the northern borders of the empire with support from England and the Netherlands, however Count Tilly and General Wallenstein first separately and then jointly inflict a heavy defeat on the Danes. The war was soon joined by Sweden, which also sided with the reformists and seriously threatened imperial power. Gustav II Adolf chose his battles carefully, often inflicting heavy defeats on the imperial army (especially the one led by Count Tilly). In most battles the Swedish coalition claimed victories, however at Nördlingen, they suffered a heavy defeat with which they were forced to leave southern Germany. The following year, the Heilbronn League disintegrated, after which the force that had been fighting from the shadows until now was directly involved. France had long been watching the Habsburg ruling house with disdain. Although it was a predominantly Catholic country, France joined the Protestant side primarily because of its rivalry with the Holy Roman Empire and Spain. Cardinal Richelieu was the prime minister of King Louis XIII, and made all the important foreign policy decisions on behalf of the emperor. After a series of conflicts, mostly with Spain, which at one point threatened even Paris itself, there were no major territorial changes. After the deaths of Richelieu and Louis XIII, the new government was trying to achieve peace. Finally, it was reached in 1648 and was negotiated in Münster and Osnabrück. it is remembered as the Peace of Westphalia. The consequences of the Thirty Years' War were terrible, unprecedented for the population until then, and it took society a long time to recover.

The prevalence of generalized skin symptoms, as well as the most severe forms in childhood IgA vasculitis is much less than the classical findings. However, the more severe the skin symptoms are, the more severe the course of the disease is, and aggressive treatment will be needed.

Uvod: IgA vaskulitis (IgAV) najčešći je vaskulitis u djece. Iako se uglavnom radi o samoograničavajućoj bolesti, u više od 50% djece mogu se razviti gastrointestinalni (GI) simptomi, a u oko 10 do 20% djece moguća je pojava ozbiljnih komplikacija kao što su intususcepcija, perforacija crijeva ili opsežno krvarenje iz probavnog sustava. Ispitanici i metode: U ovo retrospektivno istraživanje uključili smo djecu s IgAV-om koja su se liječila u 5 tercijarnih ustanova za pedijatrijsku reumatologiju u Hrvatskoj u razdoblju od 2009. do 2019. godine. Razlike među kategorijskim varijablama ispitane su χ2 i Fisherovim egzaktnim testom, a među numeričkim Mann-Whitneyevim U testom. Rezultati: Od 611 djece s IgAV-om u njih 281 (45, 9%) bio je zahvaćen GI sustav. Među djecom s GI simptomima bilo je 1, 44 puta više dječaka (p = 0, 003), više ih je dolazilo iz mediteranske Hrvatske (38% u odnosu na 27%, p = 0, 007), imala su manje infekcija prije pojave purpure (59, 8% u odnosu na 70, 9%, p = 0, 005) i manje respiratornih infekcija (35, 6% u odnosu na 45, 2%, p < 0.001). U djece koja su imala GI simptome postojala je 1, 68 puta veća šansa za razvoj nefritisa, a ako je IgAV započeo s GI simptomima, tada je ta šansa bila čak 3, 55 puta veća. Nije bilo razlike u zahvaćenosti zglobova i središnjeg živčanog sustava. U djece s GI simptomima osip je bio značajno češće proširen po trupu (61, 9% u odnosu na 48, 5%, p = 0, 001) i gornjim ekstremitetima (35, 2% u odnosu na 24, 7%, p = 0, 006), a češće se pojavljivao generalizirani osip (38, 8% vs. 28, 3%, p = 0, 008). Ova je skupina djece imala više razine C-reaktivnog proteina, veći broj leukocita, eritrocita i trombocita, više koncentracije hemoglobina i D-dimera te niže koncentracije IgG i IgM. Najteže GI manifestacije imalo je 42 od 281 djece (14, 9%) i ona su imala značajno veću 24- satnu proteinuriju i povišene koncentracije D- dimera te niže koncentracije serumskih bjelančevina, albumina, IgG, IgM i komponente C3 komplementa u odnosu na djecu s lakšim GI manifestacijama. Zaključak: Pronašli smo skupinu djece s IgAV-om i GI simptomima koja su se razlikovala u svojim demografskim, kliničkim i biokemijskim obilježjima od djece bez GI simptoma. Ova skupina djece imala je statistički značajno veću šansu za razvoj nefritisa, a time i veći rizik za pojavu akutnih i kroničnih komplikacija IgAV-a. Potpora: Projekt Hrvatske zaklade za znanost, IP- 2019-04-8822

Uvod s ciljem: Ciljevi ovog istraživanja bili su odrediti parametre regulacije glikemije (glikemija natašte, HbA1c), bubrežnu funkciju i ITM u bolesnika s tipom 2 šećerne bolesti u Domu zdravlja Osijek kako bi se utvrdila kvaliteta regulacije pacijenata sa šećernom bolesti tipa 2 te ispitati postoji li razlika u navedenim parametrima između muškaraca i žena. Ispitanici i metode: Studija je ustrojena kao presječna studija s povijesnim podacima (od siječnja do travnja 2019.g.). Iz dvije ambulante obiteljske medicine s ukupno 2400 pacijenata uključeno je 136 ispitanika oba spola s tipom 2 šećerne bolesti. Prosječna dob ispitanika bila je 69, 33 godina, a prosječno trajanje šećerne bolesti 9 godina. U ambulantama obiteljske medicine prikupljeni su opći podaci o bolesnicima, a iz laboratorijskih nalaza koncentracija glukoze natašte, HbA1C i koncentracija kreatinina te je izračunata procijenjena brzina glomerularne filtracije. Rezultati: Prosječna glikemija natašte bila je 8, 43 mmol/L, HbA1c 7, 15 %, eGFR 80, 56 mL/min/1, 73m2 i ITM 29, 48 kg/m². Muškarci su imali nižu koncentraciju glikemije natašte, HbA1c, ITM, opseg bokova, ali i višu procijenjenu brzinu glomerularne filtracije, opseg struka i omjer opsega struka i bokova. 19, 12 % ispitanika imalo je eGFR < 60 mL/min/1, 73m2. Nije bilo statistički značajne razlike u glikemiji natašte, vrijednosti HbA1c, procijenjenoj brzini glomerularne filtracije, opsegu struka i omjeru opsega struka i bokova između muškaraca i žena. Muškarci su imali statistički značajno manji indeks tjelesne mase (p = 0, 019) i opseg bokova nego žene (p = 0, 002). Zaključak: U bolesnika s tipom 2 šećerne bolesti važna je dobra glukoregulacija, ali postavljanju ciljnih vrijednosti pristupa se individualno. U ispitanika nije postignuta ciljna vrijednost glikemije natašte (

Uvod: Henoch Schönleinova purpura ili IgA vaskulitis (IgAV) najčešći je vaskulitis dječje dobi. Iako etiologija bolesti i dalje nije poznata, čini se da u nastanku sudjeluju geni i okoliš. Dosadašnje prostorne analize uglavnom su korištene u promatranju širenja zaraznih bolesti, međutim novija istraživanja pokazuju i obećavajuću primjenu kod nezaraznih bolesti u koje ubrajamo i reumatske bolesti. Cilj ovog rada jest opisati incidenciju i prostornu raspodjelu raširenosti IgAV-a te istražiti mogu li se geoprostorni analitički modeli primijeniti i na neku reumatsku bolest. Ispitanici i metode: Prikupljeni su podaci o bolesnicima iz pet tercijarnih centara u Hrvatskoj u razdoblju od 2009. do 2019. godine. Prosječna godišnja incidencija IgAVa izračunata je prema podacima o broju stanovnika iz 2011. godine. Izrađena je koropleta karta za promatranje prostorne raspodjele i interpolaciju koristeći prostornoempirijsko Bayesijansko zaglađivanje. Postojanje lokalne prostorne autokorelacije procijenjeno je Moranovim I koeficijentom, a značajnost ispitana pomoću parametara lokalnih pokazatelja prostornog povezivanja. Rezultati: Uključeno je 596 pacijenata, 52, 52% muškog i 47, 48% ženskog spola prosječne dobi od 6, 42 (4, 42 – 8, 84) godine. Procijenjena prosječna godišnja incidencija IgAV-a bila je 7, 47 na 100 000 djece s 95%-tnim intervalom pouzdanosti između 6, 88 i 8, 98. Primarni podaci očekivano su pokazali da najveći broj slučajeva dolazi iz gradova s većim brojem stanovnika. Međutim, Bayesijanskom metodom pokazalo se da je prosječna godišnja incidencija IgAV-a zapravo grupirana oko velikih gradova. Dobiveni Moranov koeficijent bio je 0, 493, što ukazuje na značajnu pozitivnu prostornu autokorelaciju IgAV-a. Izdvojene su tri statistički značajne grupacije: dvije u mediteranskom i jedna u kontinentalnom dijelu Hrvatske. Naknadno su ta mjesta definirana kao žarišta s većom incidencijom od ostalih mjesta jer je procijenjena prosječna godišnja incidencija IgAV-a tamo bila više od 13 oboljelih na 100 000 djece. Zaključak: Ovo istraživanje pokazalo je da postoji prostorno grupiranje incidencije IgAV-a. Međutim, potrebne su daljnje geostatističke analize kako bi se procijenila značajnost stvaranja takvih vremensko-prostornih grupacija kod nezaraznih bolesti, uključivo i reumatskih. Potpora: Projekt Hrvatske zaklade za znanost, IP- 2019-04-8822

Aim To determine parameters of glycaemic control, renal function and anthropometric measurements in patients with type 2 diabetes in family medicine offices and to examine whether there is a difference in these parameters between genders. Methods This cross-sectional study included 136 patients of both genders diagnosed with type 2 diabetes, with an average age of 69.33±10.87. General and demographic data were collected, anthropometric measurements were taken, as well as data on fasting plasma glucose, HbA1 c and creatinine level from laboratory findings. Estimated glomerular filtration rate (eGFR) was calculated. Results The average results of fasting plasma glucose test were 8.43 mmol/L, of HbA1c 7.15%, and of creatinine 79.00 µmol/L. In 19.12% of patients eGFR was

This pilot study investigated the usefulness in expanding the epidemiological toolbox with applying spatial analyses. The results of this study suggested that the IgAV incidence might be clustered in space. However, for a more definitive conclusion, a geostatistical analytical approach is needed to evaluate the significance of observed clusters.

We detected a group of patients with HSP and GI symptoms that differed in their demographic, clinical, and biochemical characteristics from patients without GI symptoms. This group of patients was found to be significantly more likely to develop renal disease and thus cumulatively have a higher risk of acute and chronic complications of HSP.

Atrioventricular (AV) block is defined as a delay or interruption in the transmission of an impulse from the atria to the ventricles due to an anatomical or functional impairment in the conduction system. The conduction disturbance can be transient or permanent. In third degree AV block, also referred to as complete heart block, there is complete dissociation of the atrial and ventricular activity. Atrioventricular block is considered to be “congenital” when it occurs spontaneously in a fetus or young child. In children, the most common cause of permanent acquired complete AV block is surgery for congenital heart disease. Injury to fetal conduction tissues caused by transpla- cental exposure to maternal autoantibodies related to systemic lupus erythematosus or Sjogren’s syndrome is responsible for 60 to 90 percent of cases of congenital CHB overall1-3. As many as 40 percent of cases of congenital CHB do not present until later in childhood (mean age five to six years). Only rarely do these patients (5 percent) have proven autoimmune etiology. The increased risk of sudden death is associated with the onset of deep bradycardia or ventricular arrhythmia. A routine electrocardiogram is sufficient to diagnose the disease. A 15-year-old girl has been examined at the emergency pediatric outpatient clinic of the University Hospital Centre “Sestre Milosrdnice” for recurrent episodes of presyncope. Physical examination revealed no major devia- tions other than bradycardia. Her vital signs were within the reference range, with the exception of a pulse of about 44 beats per minute. The electrocardiogram showed atrioventricular dissociation consistent with third degree atrioventricular block. The echocardiogram showed a structurally normal heart except for sinus bradycardia. The girl underwent permanent epicardial pacemaker implantation after which there were no symptoms.

Heart rate variability (HRV) has been analyzed using linear and nonlinear methods. In the framework of a controlled neonatal stress model, we applied Tone-Entropy (T-E) analysis at multiple lags to understand the influence of external stressors on healthy term neonates. Forty term neonates were included in the study. HRV was analyzed using multi-lag T-E at two resting and two stress phases (heel stimulation and a heel stick blood drawing phase). Higher mean entropy values and lower mean tone values when stressed showed a reduction in randomness with increased sympathetic and reduced parasympathetic activity. A ROC analysis was utilized to estimate the diagnostic performances of tone and entropy and combining both features. Comparing the resting and simulation phase separately, the performance of tone outperformed entropy, but combining the two in a quadratic linear regression model, resting from stress phases in neonates could be distinguished with high accuracy. This raises the possibility that when applied across short time segments, multi-lag T-E becomes an additional tool for more objective assessment of neonatal stress.

Conclusion. The gentle methods of applying surfactant by LISA and INSURE, as well as non- invasive ventilation were effective in preterm of 28 and more weeks and reduced long-lasting complications. In smaller more immature infants these techniques can lead to unnecessary manipulation and expose the vulnerable patients at a higher risk of ROP.

Sažetak: Adekvatnom osobnom higijenom te higijenom i sanitacijom prostora doprinijeli bi manjem broju dijarealnih oboljenja u svijetu. Prema Svjetskoj zdravstvenoj organizaciji (SZO), u Europi dnevno umire 14 ljudi od dijareje [1]. Parmskom deklaracijom obratila se pažnja na higijenu i sanitaciju u školama implementacijom Regionalnog prioritetnog cilja 1 [2]. Suradnjom SZO i Zavoda za javno zdravstvo Osječko-baranjske županije, 2012. proveo se pilot projekt u dvije srednje škole u Osijeku o higijenskim navikama učenika, higijeni sanitarnih čvorova i sanitaciji [3-4]. Nakon pilot projekta, od 2012. do 2016. pristupilo se nacionalnom programu Ministarstva zdravstva, Ministarstva znanosti i obrazovanja te Hrvatskog zavoda za javno zdravstvo uz potporu SZO u 200 osnovnih škola [5-6]. U Osječko-baranjskoj županiji (OBŽ) sudjelovalo je 606 učenika, pri čemu je obuhvaćeno 10 osnovnih škola (5 urbanih i 5 ruralnih) u kojima je proveden inspekcijski pregled 56 sanitarna čvora. U 2016. nastavljeno je istraživanje u OBŽ u 7 urbanih i 8 ruralnih osnovnih škola (anketirano 350 učenika i pregledano 74 sanitarna čvora). Rezultati istraživanja ukazali su na nedostatak toalet papira i sapuna u sanitarnim čvorovima i na neprovođenje adekvatne edukacije o higijeni. Posebni problem predstavlja što pojedina djeca ne obavljaju nuždu tijekom školskog dana zbog neodgovarajuće higijene i opreme sanitarnih čvorova.

Mode of delivery is connected with newborns after birth adaptation. Inducted or augmentated labor can cause intrauterine hypoxia and provocate plethora as a self defending mechanism. It can cause higher vascular resistance and blood pressure. Those can stimulate bar receptors in blood vessels and glomus caroticus and cause bradicardia of the neonate. The newborn can be irritable with oscillating tonus. He/she can have jaundice and cyanotic crises (as a result of plethora) or can develop respiratory distress. Oxygen must be introduced. These neonates needs longer period of hospitalization. Additional risk factors for prolonged adaptation are male gender and low and high weight for gestation.

We aim at detecting stress in newborns by observing heart rate variability. Thanks to an asymmetric detrended fluctuation analysis (ADFA), we determine the fractal structure of the series of interbeat intervals, in which we distinguish the periods of acceleration of the heart rate from decelerations. Thus, two scaling exponents, α+ and α-, representing decelerations, and accelerations, respectively, are obtained. Forty healthy term newborns were included in this study, undergoing two different types of stress stimuli, using routine heel lance blood sampling for metabolic screening purposes and its simulation applying dull pressure on the heel. It appears that, when newborns face stress, the scaling exponent related to accelerations significantly increases and becomes higher than the deceleration scaling exponent. To test the diagnostic properties of the scaling exponents, a ROC curve analysis was applied. α- showed good diagnostic performance with an AUC of 0.826 and 0.796 respectively, although having a lower sensitivity, it showed a high specificity of 84.62% for both stress phases. This work thus stresses the relevance of ADFA and particularly of the acceleration scaling exponent as a diagnostic tool for neonatal stress.

Traditional views on neonatal pain neglected long neglected the neonates’ capability of feeling pain. Newborn infants experience at least one painful procedure during their first days of life, but with a lower gestational age, invasive procedures become more frequent and invasive. The modulation of the autonomic nervous system (ANS) is significantly changed during painful procedures. The analysis of the heart rate variability is shown to be a reliable tool in analyzing the ANS. In this study, the dynamic of the system has been examined by applying the Poincaré plot analysis, a primer of nonlinear methods used in the analysis of the ANS. The aim of this study is to assess the occurrence of changes in linear heart rate variability parameters, to determine the changes in the Poincaré plot indices and to evaluate the correlation between their differences in healthy newborns. The results have shown a significant increase in the heart rate, a reduction of the duration of RR intervals, and the square root of the mean squared differences between successive RR intervals (RMSSD), as well as a decrease in the short-term variability (SD1) of the Poincare plot. The results highlight the need for studying the application of nonlinear analyses of the HRV on the effects of pain on the ANS and its long-term effects on the infant.

The neonate must make a transition after birth from intrauterine continuous transplacental supply of oxygen and glucose to different extra uterine conditions. In healthy neonate the period of adaptation almost finished in the perinatal period and newborn can be safely discharged after this time. Retrospective study in the NICU, Clinical Hospital Osijek, during the year 2016 was done. Almost 26% of neonates were admitted in NICU because of the prolonged adaptation to extra uterine life. It was their main diagnosis. The majority of them have been polycytemic, had early jaundice and a part of them had bradycardia. Mother’s illnesses as a possible cause of prolonged neonatal adaptation were found in 21.7%. About 58.3% of newborns with prolonged adaptation have had problems during mother’s pregnancy and delivery. Hypertrophic as well as hypotrophic neonates were risk neonates for prolonged postnatal adaptation, as well as newborns gender. Mode of delivery takes a big role in the neonatal adaptation. Induction and augmentation of the labor acts as a possibly stress factor. Main symptoms among those newborns were: plethora, cyanotic crises, bradicardia, dystonia, irritability, jaundice and respiratory distress. Most of the investigated newborns need oxygen 6-10 days. The majority of them stay in the hospital up to 10 days. Prolonged adaptation has almost equally been found in the first, second and third pregnancy.

Albeit the aetiology of the respiratory distress syndrome (RDS) is well known, the paper shall demonstrate that the causes of RDS changed over the years 2006 and 2010. This retrospective study comprises analysis of the data collected from 60 newborns of over 32 weeks gestation with RDS in the Neonatal Intensive Care Unit at the Clinical Hospital Centre in Osijek. The focus of the paper lies in the difference in the incidence of RDS over two research periods (2006 and 2010), the most common and possible causes of RDS in newborns of over 32 weeks gestation as well as in the potential changes in the aetiology over the two research periods. An increase in the incidence of RDS was established in 2010, but it was statistically significant only for newborns of gestational age of 35 1/7 to 36 6/7 weeks. The most common cause of RDS in both research periods was sepsis, which decreased in its share in 2010, whereas the incidence of asphyxia and complications during pregnancy increased. The new potential cause in 2010 was maternal thrombophilia. The share of unknown causes of RDS decreased, although not significantly so. The results of the research indicate that the causes of RDS changed over the observed periods and that further research should focus on thrombophilia and other complications during pregnancy with the aim of reducing morbidity and improving neonatal outcomes as well as further reducing the incidence of RDS with unknown causes in newborns

Benzen je najjednostavniji aromatski ugljikovodik, prirodni sastojak nafte, a u čistome stanju i pri sobnoj temperaturi bezbojna je, lako hlapljiva i zapaljiva tekućina ugodnoga mirisa. Prema klasifikaciji Međunarodne agencije za istraživanje karcinoma benzen je svrstan u Skupinu 1 koja obuhvaća kemijske elemente i njihove spojeve koji uzrokuju pojavu karcinoma kod ljudi. Prisutnost benzena u zraku najčešće je posljedica sagorijevanja naftnih derivata u transportnim sredstvima te posljedica aktivnosti kemijske i petrokemijske industrije. Čovjek može biti izložen djelovanju benzena inhalacijom ili, u manjoj mjeri, konzumacijom vode i hrane, pri čemu se mogu manifestirati akutni štetni učinci, poput glavobolje, vrtoglavice, tremora i gubitka svijesti, ili kronični štetni učinci, poput pojedinih oblika leukemije. Cilj istraživanja bio je utvrditi tjedne koncentracije benzena u vanjskome zraku na području Osječko-baranjske županije s obzirom na potencijalne izvore onečišćenja okoliša. Istraživanje je provedeno tijekom 2012. i 2014. na četirima mjestima u županiji, pri čemu je zrak uzorkovan pasivnim difuzijskim samplerima tijekom jednoga tjedna u zimskome razdoblju godine. Koncentracije benzena u zraku određene su metodom plinske kromatografije s plamenim detektorom GC/FID. Na četirima mjernim postajama tjedne koncentracije benzena iznosile su: 2, 14 ; 1, 87 ; 0, 65 i 0, 72 μg/m3.Rezultati istraživanja ukazali su na potencijalnu izloženost ljudi onečišćenju zraka od cestovnoga prometa, industrije, parkirališta i benzinskih crpki.