Autoantibodies to IL-17A may be correlated with the severity of mucocutaneous candidiasis in APECED patients.

The relative roles of various autoantibodies against IL-17-type cytokines in susceptibility to chronic mucocutaneous candidiasis (CMC) in patients with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) remain poorly defined. The purpose of this longitudinal study was to analyze the relationship between the occurrence of mucocutaneous candidiasis and levels of anti-IL-17A, anti-IL-17F and anti-IL-22 autoantibodies. We studied six APECED patients from four families with various disease manifestations. Clinical data were collected during regular follow-up. Anti-endocrine organ antibody levels and clinical chemistry and immunology parameters were determined in routine laboratory assays on freshly isolated serum. Levels of autoantibodies against IL-17A, IL-17F, IL-22, IFN-α, IFN-ω and TNF-α, and cytokine release by Candida-exposed blood cells were determined by ELISA. Mutations were analyzed by sequencing genomic DNA. Four patients carried the germline c.769C > T homozygous nonsense mutation, which results in R257X truncation of the AIRE protein, and two patients from the same family were compound heterozygous for the c.769C > T/c.1344delC mutation. We found persistently high levels of antibodies against IL-17A in the serum samples of one patient presenting CMC since infancy and low or undetectable anti-IL-17A antibody levels in the sera of five patients with no candidiasis or without severe candidiasis. By contrast, levels of autoantibodies against IL-17F and IL-22 were higher in all patients than in healthy controls. Release of IL-17-type cytokines by Candida-exposed blood mononuclear cells was low or negligible in all patients tested. We suggest that anti-IL-17A antibodies may play an important role in the predisposition to candidiasis of APECED patients. However, the lack of severe CMC in APECED patients with high levels of IL-17F and anti-IL-22 autoantibodies clearly calls into question the role of these antibodies as the principal cause of cutaneous and mucosal candidiasis in at least some APECED patients. These data also suggest that the impaired release of IL-17-type cytokines by blood cells may be an element of the immunopathology of CMC in APECED patients

Analysis of Landscape geographic Impacts of Potential Climate Change in Hungary

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Analysis of landscape geographic impacts of potential climate change in Hungary

Change of climate can be a remarkable turning point in the 21st century history of mankind. An important task of landscape geographic research is forecasting environmental, nature protection, land use demands and helping mitigation of disadvantageous processes from the aspect of society. ALADIN and REMO numeric climate models predict strong warming and lack of summer precipitation for the area of Hungary for the period between 2021 and 2100. There is a predicted growth in frequency of extreme weather events (heat waves, droughts hailstorms). Changes have been forecasted using data presented in table 1. For analyses of complex landscape geographic impacts of climate change the area of Hungary have been divided into 18 mesoregions with 5.000-10.000 km2 area each (figure 1). The main aspect of choosing the regions was that they should have homogeneous physical, geographic and land use endowments and, for this reason, they should react to climate change the same way. Relationships between landscape forming factors and meteorological elements examined by us have been taken into consideration. Results of analyses of impacts of the meteorological factors on the changes of relief through the mass movements are presented in this paper. Changes of landscape sensibility of mesoregions to mass movements have been presented in the last chapter for the periods between 2021-2050 and 2071-2100 according to numeric climate models

Tonsillectomia versus tonsillotomia

Összefoglaló. Bevezetés és célkitűzés: A szerzők a posztoperatív fájdalom és a sebgyógyulás tekintetében prospektív vizsgálattal hasonlították össze gyermekeken (67 fő, 1-12 év) a hagyományos hidegeszközzel történő extracapsularis tonsillectomiát (23 fő) a microdebriderrel (23 fő) és a coblatorral (21 fő) végzett intracapsularis tonsillotomiával. Módszer: A vizsgálatok a betegek által kitöltött kérdőívek, valamint prospektív klinikai adatgyűjtés alapján történtek. Eredmények: Az intracapsularis tonsillotomia gyógyulási idejét 50%-kal rövidebbnek találtuk, és az első 13 napban szignifikánsan kevesebb fájdalommal és fájdalomcsillapító igénnyel járt, mint az extracapsularis tonsillectomia eseteiben. A tonsillotomiás csoporton belül egyedül a posztoperatív első napi fájdalom tekintetében észleltünk szignifikáns különbséget a két különböző módszer között a coblator javára (p<0,05). A vizsgálatokat retrospektív áttekintéssel is kiegészítettük, 4 évi gyermek- (1-15 éves) tonsillaműtéten átesett beteganyagunk (1487 fő) eredményeinek feldolgozásával. Tonsillectomia (1253 fő) után 7,7%-os utóvérzési arányt észleltünk, műtéti vérzéscsillapításra 1,3%-ban volt szükség. Tonsillotomia esetén (234 fő) 0,43%-os utóvérzési arányt regisztráltunk. Ebben a csoportban vérzés miatt nem, de 2 esetben ismételt obstrukciót okozó hypertrophia, 1 esetben góctünetek miatt reoperációt végeztünk (1,28%). Következtetés: Eredményeiket a szerzők a nemzetközi ajánlások tükrében elemezték. Az intracapsularis tonsillotomia kisebb fájdalommal, kisebb vérzéssel és kisebb megterheléssel jár. A közösségbe való aktív visszatérés akár egy hét után lehetséges a tonsillectomiára jellemző 3 héttel szemben, mindez jelentős szocioökonómiai előnyökkel járhat

Investigation of the Possible Role of the Hippo/YAP1 Pathway in Asthma and Allergy

PURPOSE: Several lines of evidence indicate that the Hippo/Yes-associated protein 1 (YAP1) pathways might play a role in the pathogenesis of asthma. To investigate the possible role of the Hippo/YAP1 pathway in the pathogenesis of asthma or its phenotypes. METHODS: The levels of gene expressions of the members of the Hippo/YAP1 were compared. The presence of the proteins of the YAP1 and FRMD6 were analyzed with Western blot in induced sputum of 18 asthmatic subjects and 10 control subjects. Fourteen single nucleotide polymorphisms (SNPs) in the YAP1 gene were genotyped in 522 asthmatic subjects and 711 healthy controls. The results were evaluated with traditional frequentist methods and with Bayesian network-based Bayesian multilevel analysis of relevance (BN-BMLA). RESULTS: The mRNA of all the members of the Hippo/YAP1 pathway could be detected in the induced sputum of both controls and cases. A correlation was found between YAP1 mRNA levels and sputum bronchial epithelial cells (r=0.575, P=0.003). The signal for the FRMD6 protein could be detected in all sputum samples while the YAP1 protein could not be detected in the sputum samples, of the healthy controls and severe asthmatics, but it was detectable in mild asthmatics. The rs2846836 SNP of the YAP1 gene was significantly associated with exercise-induced asthma (odds ratio [OR]=2.1 [1.3-3.4]; P=0.004). The distribution of genotypes of rs11225138 and certain haplotypes of the YAP1 gene showed significant differences between different asthma severity statuses. With BN-BMLA, 2 SNPs, genetic variations in the FRMD6 gene proved to be the most relevant to exercise-induced asthma and allergic rhinitis. These 2 SNPs through allergic rhinitis and exercise-induced asthma were in epistatic interaction with each other. CONCLUSIONS: Our results provided additional evidence that the FRMD6/Hippo/YAP1 pathway plays a role in the pathogenesis of asthma. If additional studies can confirm these findings, this pathway can be a potential novel therapeutic target in asthma and other inflammatory airway diseases

New and recurrent gain-of-function STAT1 mutations in patients with chronic mucocutaneous candidiasis from Eastern and Central Europe

Background: Chronic mucocutaneous candidiasis disease (CMCD) may result from various inborn errors of interleukin (IL)-17-mediated immunity. Twelve of the 13 causal mutations described to date affect the coiled-coil domain (CCD) of STAT1. Several mutations, including R274W in particular, are recurrent, but the underlying mechanism is unclear. Objective: To investigate and describe nine patients with CMCD in Eastern and Central Europe, to assess the biochemical impact of STAT1 mutations, to determine cytokines in supernatants of Candida-exposed blood cells, to determine IL-17-producing T cell subsets and to determine STAT1 haplotypes in a family with the c.820C>T (R274W) mutation. Results: The novel c.537C>A (N179K) STAT1 mutation was gain-of-function (GOF) for γ-activated factor (GAF)-dependent cellular responses. In a Russian patient, the cause of CMCD was the newly identified c.854 A>G (Q285R) STAT1 mutation, which was also GOF for GAF-dependent responses. The c.1154C>T (T385M) mutation affecting the DNA-binding domain (DBD) resulted in a gain of STAT1 phosphorylation in a Ukrainian patient. Impaired Candida-induced IL-17A and IL-22 secretion by leucocytes and lower levels of intracellular IL-17 and IL-22 production by T cells were found in several patients. Haplotype studies indicated that the c.820C>T (R274W) mutation was recurrent due to a hotspot rather than a founder effect. Severe clinical phenotypes, including intracranial aneurysm, are presented. Conclusions: The c.537C>A and c.854A>G mutations affecting the CCD and the c.1154C>T mutation affecting the DBD of STAT1 are GOF. The c.820C>T mutation of STAT1 in patients with CMCD is recurrent due to a hotspot. Patients carrying GOF mutations of STAT1 may develop multiple intracranial aneurysms by hitherto unknown mechanisms