First Cryptosporidium outbreak in Hungary, linked to a treated recreational water venue in 2015

In June 2015, an outbreak of cryptosporidiosis with 35 cases (23 probable and 12 laboratory-confirmed) occurred among 191 attendees of a residential rehabilitation holiday for paediatric organ transplant patients (n = 49) and their families at a hotel in Somogy county, Hungary. The overall attack rate was 18%. Most of the cases were transplanted children who experienced severe acute disease and required adjustment to their tacrolimus immunosuppression. A retrospective case-control study suggested an association between recreational water exposures and illness: cases were seven times more likely than controls to have swum in the children's pool (odds ratio 7.17; 95% confidence interval 2.9-17.2; P < 0.0001) and five times more likely to have used the jetted whirlpool (odds ratio 5.25; 95% confidence interval 2.1-13.1; P < 0.0001). This was the first outbreak of cryptosporidiosis in Hungary and it is especially unfortunate that it affected vulnerable children who experienced severe symptoms. Cryptosporidium presents specific infection control difficulties in treated recreational water venues; the link to a whirlpool is unusual and highlights the importance of the age-appropriate use of these facilities and reminding users not to immerse their heads or swallow the water. Cryptosporidiosis is more commonly linked to children' pools where improved bather hygiene and promoting exclusion of diarrhoea cases could help to avoid similar outbreaks

D-vitamin és kalciumpótlás az időskori csípőtáji törések megelőzésében | Vitamin D and calcium supplementation in elderly patients considering the prevention of hip fractures

Absztrakt: A D-vitamin fontos szerepet játszik a kalcium- és csontanyagcserében, hiánya rizikófaktora az osteoporosissal és a gyakoribb elesésekkel összefüggő csonttöréseknek. Időskorban a D-vitamin-hiány gyakori, a következményes parathormon-növekedés jelentős csontmátrixveszteséget okoz, ezért a D-vitamin- és kalciumpótlás különösen nagy fontosságú. Jelen dolgozat célja, hogy a számos, részben ellentmondó irodalmi adat áttekintésével tájékoztatást nyújtson. Sok szerző közölt adatot a csípőtáji törés megelőzésével kapcsolatban alkalmazott D-vitamin-dózisokról. Az irodalmi adatokból kitűnik, hogy a szerzők egy része megelégszik a D-vitamin-pótlással, míg mások a D-vitamin és kalcium együttes adásával szereztek jó tapasztalatokat. Egyes metaanalízisek helyenként eltérő eredményekről számolnak be és további prospektív, jól definiált klinikai tanulmányok szükségességét javasolják. Vizsgálni kell még a különböző korcsoportokban a D-vitamin- és kalciumdózisok hatását. Mérlegelni kell a betegek táplálkozási szokásait, életstílusát, továbbá a társuló cardiovascularis és más olyan krónikus betegségek meglétét, amelyek a D-vitamin metabolizmusát befolyásolhatják. Orv Hetil. 2017; 158(43): 1699–1707. | Abstract: Vitamin D plays an important role in maintaining calcium and bone metabolism, a risk factor of osteoporosis, fall and fracture in old age. Reduction in D-vitamin levels associated with compensatory increased level of parathyroid hormone causes significant loss of bone matrix, so substitutions of vitamin D and calcium are very important. Many authors publish their recommended doses used for prevention of hip fracture during the last years. Some authors are satisfied only with vitamin D supplementation while others have better experiences with vitamin D and calcium substitution. On the other hand, some metaanalyses give contradictory results and propose further investigations. It is important to consider the patients’ eating habits and lifestyle as well as the risk of cardiovascular and other chronic diseases. Further trials should be done in different age groups in order to examine the effects of different doses of vitamin D without and with calcium to make a final decision. Orv Hetil. 2017; 158(43): 1699–1707

Szervtranszplantáció gyermekkorban

Absztrakt: A gyermekkorban végzett szervátültetés mára hazánkban is minden, az átültetésre alkalmas gyermek számára elérhetővé vált. Fontos ismernünk és tudnunk, hogy a végállapotú szervelégtelenség kialakulásához vezető okok szinte minden szerv esetében jelentősen különböznek a felnőttekéitől. Gyermekkorban mindezek mellett mind sebészi, mind gyermekgyógyászi oldalról más kihívásokkal kell megküzdenünk, mint a felnőtteknél (a szervek és a recipiens mérete, más és más formában zajló infekciók, az immunszuppresszív szerek eltérő farmakokinetikája és farmakodinamikája, noncompliance). A gyermekkori szervtranszplantáció ugyanakkor az elmúlt évtizedek egyik sikertörténete, amely csak sok szakterület gondos és összehangolt munkájával érheti el eredményeit. Orv Hetil. 2018; 159(46): 1948–1956. | Abstract: Paediatric organ transplantation today is considered and accepted and widely available therapy in children with end-stage organ failure. It is important to know that in childhood, diseases leading to end-stage organ failure differ from those in adults. Beside this, in children there are different surgical and paediatric challenges before and after transplantation (size differences of the patient and donor organ, special and paediatric infections, different pharmacokinetics and pharmacodynamics of immunosuppressive drugs, noncompliance). However, paediatric organ transplantation in the last decades became a success story of the Hungarian health care owing to several working groups in Hungary and outside the country. Orv Hetil. 2018; 159(46): 1948–1956

Új pathomechanizmusok és kezelési lehetőségek vizsgálata a vese ischémia/reperfúziós károsodásában és krónikus allograft nephropathiában = Investigation of new pathomechanisms and treatment possibilities of renal ischemia/reperfusion injury and chronic allograft nephropathy

Eredményeink az erythropoietin (EPO) védő szerepét igazolták egyoldali vese ischemia/reperfúziós (I/R) károsodásban. Ez a védő szerep elsősorban hímekben igazolható. Hátterében az EPO HSP72-mediálta hatása állhat, amellyel a Na+/K+ ATP-áz funkciójának megtartását segíti elő. Vizsgálataink során az EPO sejt-protektív hatásának hátterében egy új szignál molekulát is sikerült azonosítanunk, a szérum és glükokortikoid aktiválta kináz-1-t (SGK1). Ezek az eredmények az EPO által kifejtett sejtprotekció hátterében álló új pathomechanizmusokat írtak le. Eredményeink alapján az EPO, illetve a leírt útvonalakra ható egyéb szerek további vizsgálata és klinikai hasznosítása jöhet szóba. Másik vizsgálatunk során az I/R-s károsodás kivédésében szerepet játszó mechanizmusok során megfigyelhető nemi különbségeket írtuk le. Igazoltuk, hogy hímekben elsősorban a HIF 1α, míg nőstényekben a HSF útvonal tűnik fontosabbnak. Végül igazoltuk. hogy az SGK1 anti-apoptotikus és sejtvédő funkciójában is nemi különbségek mutathatók ki I/R-t követően. Ezekkel az eredményeinkkel magyarázhatóak az irodalomban korábban leírt és egymásnak ellentmondó közlések, amelyek a tesztoszteron SGK1 reguláló hatását mutatták be. | Our results suggest that EPO protects against severe, unilateral renal I/R injury, especially in male rats. This beneficial effect might be partly the result of EPO’s HSP72-mediated impact on Na+/K+ATPase-α1. Moreover, our data report a new signaling molecule to be involved in EPO cytoprotective actions, since we identified for the first time an important role of SGK1 in the renoprotective effect of EPO. These observations provide insights into a novel signaling mechanism by which EPO partly exerts its potent tissue protective actions. Given our results along with previous reports, the clinical use of EPO possibly leading to reduced cellular damage due to ischemic events should be considered. Our study has revealed a gender-dependent protective mechanism during renal I/R injury. In males mostly the HIF 1α, while in females the HSF is the dominant transcriptional pathway. The EPO treatment results in disappearance of the characteristic signal pathway activation in both genders. The explanation for that could be either a direct negative feedback effect on the transcription factors or an indirect renal protective effect of EPO by which these transcriptional factors do not need to be activated. We could also demonstrate that the anti-apoptotic SGK1 shows a gender-specific expression pattern after renal I/R with higher levels in male rats. These results confirm previous contradictory reports showing that SGK1 might be up-regulated and activated by testosterone

Elevated Systemic Pentraxin-3 Is Associated With Complement Consumption in the Acute Phase of Thrombotic Microangiopathies

Pentraxin-3 (PTX3) and C-reactive protein (CRP) have been shown to regulate complement activation in vitro, but their role has not been investigated in complement consumption in vivo. Thrombotic microangiopathies (TMA) are often accompanied by complement overactivation and consumption, therefore we analyzed the relation of the systemic pentraxin levels to the complement profile, laboratory parameters and clinical outcome of TMA patients. We determined the PTX3 and CRP levels, complement factor and activation product concentrations in blood samples of 171 subjects with the diagnosis of typical hemolytic uremic syndrome (STEC-HUS) (N = 34), atypical HUS (aHUS) (N = 44), secondary TMA (N = 63), thrombotic thrombocytopenic purpura (TTP) (N = 30) and 69 age-matched healthy individuals. Clinical data, blood count and chemistry were collected from medical records. To determine the in vitro effect of PTX3 on alternative pathway (AP) activation, sheep red blood cell-based hemolytic assay and AP activity ELISA were used. We found that PTX3 levels were elevated in the acute phase of STEC-HUS, aHUS and secondary TMA, whereas PTX3 elevation was exceptional is TTP. Conversely, a significantly higher median CRP was present in all patient groups compared to controls. PTX3, but not CRP was associated with signs of complement consumption in vivo, and PTX3 significantly decreased the AP hemolytic activity in vitro. Our results provide a detailed description of acute phase-TMA patients' complement profile linked to changes in the systemic pentraxin levels that may support further molecular studies on the function of PTX3 in disease pathogenesis and add to the laboratory assessment of complement consumption in TMA

Analysis of Linear Antibody Epitopes on Factor H and CFHR1 Using Sera of Patients with Autoimmune Atypical Hemolytic Uremic Syndrome

Introduction: In autoimmune atypical hemolytic uremic syndrome (aHUS), the complement regulator factor H (FH) is blocked by FH autoantibodies, while 90% of the patients carry a homozygous deletion of its homolog complement FH-related protein 1 (CFHR1). The functional consequence of FH-blockade is widely established; however, the molecular basis of autoantibody binding and the role of CFHR1 deficiency in disease pathogenesis are still unknown. We performed epitope mapping of FH to provide structural insight in the autoantibody recruitment on FH and potentially CFHR1. Methods: Eight anti-FH positive aHUS patients were enrolled in this study. With overlapping synthetic FH and CFHR1 peptides, we located the amino acids (aa) involved in binding of acute and convalescence stage autoantibodies. We confirmed the location of the mapped epitopes using recombinant FH domains 19-20 that carried single-aa substitutions at the suspected antibody binding sites in three of our patients. Location of the linear epitopes and the introduced point mutations was visualized using crystal structures of the corresponding domains of FH and CFHR1. Results: We identified three linear epitopes on FH (aa1157-1171; aa1177-1191; and aa1207-1226) and one on CFHR1 (aa276-290) that are recognized both in the acute and convalescence stages of aHUS. We observed a similar extent of autoantibody binding to the aHUS-specific epitope aa1177-1191 on FH and aa276-290 on CFHR1, despite seven of our patients being deficient for CFHR1. Epitope mapping with the domain constructs validated the location of the linear epitopes on FH with a distinct autoantibody binding motif within aa1183-1198 in line with published observations. Summary: According to the results, the linear epitopes we identified are located close to each other on the crystal structure of FH domains 19-20. This tertiary configuration contains the amino acids reported to be involved in C3b and sialic acid binding on the regulator, which may explain the functional deficiency of FH in the presence of auto antibodies. The data we provide identify the exact structures involved in autoantibody recruitment on FH and confirm the presence of an autoantibody binding epitope on CFHR1.Peer reviewe

FHR-5 Serum Levels and CFHR5 Genetic Variations in Patients With Immune Complex-Mediated Membranoproliferative Glomerulonephritis and C3-Glomerulopathy

Factor H-related protein 5 (FHR-5) is a member of the complement Factor H protein family. Due to the homology to Factor H, the main complement regulator of the alternative pathway, it may also be implicated in the pathomechanism of kidney diseases where Factor H and alternative pathway dysregulation play a role. Here, we report the first observational study on CFHR5 variations along with serum FHR-5 levels in immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN) and C3 glomerulopathy (C3G) patients together with the clinical, genetic, complement, and follow-up data.A total of 120 patients with a histologically proven diagnosis of IC-MPGN/C3G were enrolled in the study. FHR-5 serum levels were measured in ELISA, the CFHR5 gene was analyzed by Sanger sequencing, and selected variants were studied as recombinant proteins in ELISA and surface plasmon resonance (SPR).Eight exonic CFHR5 variations in 14 patients (12.6%) were observed. Serum FHR-5 levels were lower in patients compared to controls. Low serum FHR-5 concentration at presentation associated with better renal survival during the follow-up period; furthermore, it showed clear association with signs of complement overactivation and clinically meaningful clusters.Our observations raise the possibility that the FHR-5 protein plays a fine-tuning role in the pathogenesis of IC-MPGN/C3G