A krónikus vénás elégtelenség klasszifikációja és korszerű kezelése

L

Acetylation State of Lysine 14 of Histone H3.3 Affects Mutant Huntingtin Induced Pathogenesis

Huntington’s Disease (HD) is a fatal neurodegenerative disorder caused by the expansion of a polyglutamine-coding CAG repeat in the Huntingtin gene. One of the main causes of neurodegeneration in HD is transcriptional dysregulation that, in part, is caused by the inhibition of histone acetyltransferase (HAT) enzymes. HD pathology can be alleviated by increasing the activity of specific HATs or by inhibiting histone deacetylase (HDAC) enzymes. To determine which histone’s post-translational modifications (PTMs) might play crucial roles in HD pathology, we investigated the phenotype-modifying effects of PTM mimetic mutations of variant histone H3.3 in a Drosophila model of HD. Specifically, we studied the mutations (K→Q: acetylated; K→R: non-modified; and K→M: methylated) of lysine residues K9, K14, and K27 of transgenic H3.3. In the case of H3.3K14Q modification, we observed the amelioration of all tested phenotypes (viability, longevity, neurodegeneration, motor activity, and circadian rhythm defects), while H3.3K14R had the opposite effect. H3.3K14Q expression prevented the negative effects of reduced Gcn5 (a HAT acting on H3K14) on HD pathology, while it only partially hindered the positive effects of heterozygous Sirt1 (an HDAC acting on H3K14). Thus, we conclude that the Gcn5-dependent acetylation of H3.3K14 might be an important epigenetic contributor to HD pathology

Protective Effect of Prunus Cerasus (Sour Cherry) Seed Extract on the Recovery of Ischemia/Reperfusion-Induced Retinal Damage in Zucker Diabetic Fatty Rat

K

A magyar tüdőtranszplantációs program indulása és első eredményei

Absztrakt: Magyarországon az első tüdőtranszplantációt 2015. 12. 12-én végeztük el az Országos Onkológiai Intézet és a Semmelweis Egyetem együttműködésével. Cikkünkben az elmúlt két és fél év eredményeit összegezzük. 2018 augusztusáig 55 tüdőtranszplantációra került sor. Az adatfeldolgozást retrospektív módszerrel végeztük. A várólistára helyezés a Tüdő Transzplantációs Bizottság javaslatára történt. A donortüdők agyhalott donorokból származtak. A posztoperatív gondozás a Semmelweis Egyetemen folytatódott. 2015. 12. 12. és 2018. 07. 31. között 76 szervkivételen vettünk részt: 45 magyar, 23 Eurotransplant-, 8 Eurotransplanton kívüli országban, ezekből 54 kétoldali és 1 egyoldali tüdőtranszplantáció valósult meg. A műtéteket egyoldali (n = 1), kétoldali thoracotomiából (n = 1) vagy ’clamshell’ betolásból (n = 53), venoarterialis extrakorporális membránoxigenizáció-támogatással végeztük. Három esetben az extrakorporális membránoxigenizáció-támogatást a posztoperatív szakban prolongáltuk, másik két betegnél extrakorporális membránoxigenizáció-bridge terápiát követően végeztük el a transzplantációt. Egy kombinált tüdő-vese transzplantáció is történt. A recipiensek alapbetegsége krónikus obstruktív tüdőbetegség (n = 28); fibrotizáló tüdőbetegség (n = 8); cystás fibrosis (n = 12); elsődleges pulmonalis hypertonia (n = 2); histiocytosis-X (n = 1); bronchiectasia (n = 2); lymphangioleiomyomatosis (n = 1) és bronchiolitis obliterans szindróma miatti retranszplantáció (n = 1) volt. Átlagéletkoruk 47,5 ± 15,18 év volt. A legfiatalabb beteg 13 éves volt. A várólistán 12 beteg hunyt el. A betegek átlagosan 24,6 ± 18,18 napot töltöttek az intenzív osztályon. A korai posztoperatív időszakban 2 beteget vesztettünk el. Tartós lélegeztetési igény miatt tracheostomát 13 esetben készítettünk. A betegek 1 éves túlélése 82,96% volt. A hazai tüdőtranszplantációs programban gyorsan emelkednek az esetszámok, ami más centrumok indulásához képest kivételes eredmény. A szövődmények és halálozások aránya más, nagy esetszámú centrumok számainak megfelel. A jövőben a várólista bővítését, az esetszámok további növelését, és az ’ex vivo lung perfusion’ (EVLP-) rendszer használatának bevezetését szeretnénk megvalósítani. Orv Hetil. 2018; 159(46): 1859–1868. | Abstract: The first lung transplantation in Hungary was performed on 12th of December, 2015. It was a joint effort of the National Institute of Oncology and the Semmelweis University. Hereby we summarise the results and experiences from the first three years. Until August, 2018, 55 lung transplantations were performed in Hungary. This was a retrospective analysis. All patients were listed according to the recommendation of the Lung Transplantation Committee. All implanted lungs have been procured from brain dead donors. Postoperative treatment and rehabilitation of the patients were continued at the Semmelweis University. Between 12. 12. 2015 and 31. 07. 2018, our team performed 76 organ retrievals: out of 45 Hungarian offers, 23 came from Eurotransplant countries and 8 outside of the Eurotransplant region. From these donations, 54 double and 1 single side transplantations were successfully performed. The surgical approach was single side thoracotomy (n = 1), bilateral thoracotomy (n = 1) and in the majority of the cases clamshell incision (n = 53). For the intraoperative veno-arterial extracorporeal membrane oxygenation support was used. The extracorporeal membrane oxygenation support had to be prolonged in 3 patients into the early postoperative period, two other recipients were bridged to transplant with extracorporeal membrane oxygenation. In the same time period, one combined lung-kidney transplantation was also performed. The distribution of recipients according to the underlying disease was: chronic obstructive pulmonary disease (n = 28); idiopathic pulmonary fibrosis (n = 8); cystic fibrosis (n = 12); primary pulmonary hypertension (n = 2); hystiocytosis-X (n = 1); bronchiectasis (n = 2); lymphangioleiomyomatosis (n = 1); and re-transplantation following bronchiolitis obliterans syndrome (n = 1), respectively. The mean age of recipients was 47.5 ± 15.18 years. The youngest recipient was 13 years old. We unfortunately lost 12 patients on our waiting list. The mean intensive care unit stay was 24.6 ± 18.18 days. Two patients were lost in the early postoperative phase. Tracheostomy was necessary in 13 cases due to the need of prolonged ventilation. 1-year survival of the recipients was 82.96% (until 31. 07. 2018). When looking at the first three years of the program, the case numbers elevated quickly throughout the years which is rather unique when compared to other centres in their starting period. Perioperative mortality and morbidity is comparable with high-volume lung transplantation centres. In the future we would like to increase the number of patients on the waiting list, thus increasing the total number of transplantations performed, and we are also planning to implement the use of the ex vivo lung perfusion system (EVLP) in our program. Orv Hetil. 2018; 159(46): 1859–1868

Acetylation State of Lysine 14 of Histone H3.3 Affects Mutant Huntingtin Induced Pathogenesis

Huntington’s Disease (HD) is a fatal neurodegenerative disorder caused by the expansion of a polyglutamine-coding CAG repeat in the Huntingtin gene. One of the main causes of neurodegeneration in HD is transcriptional dysregulation that, in part, is caused by the inhibition of histone acetyltransferase (HAT) enzymes. HD pathology can be alleviated by increasing the activity of specific HATs or by inhibiting histone deacetylase (HDAC) enzymes. To determine which histone’s post-translational modifications (PTMs) might play crucial roles in HD pathology, we investigated the phenotype-modifying effects of PTM mimetic mutations of variant histone H3.3 in a Drosophila model of HD. Specifically, we studied the mutations (K→Q: acetylated; K→R: non-modified; and K→M: methylated) of lysine residues K9, K14, and K27 of transgenic H3.3. In the case of H3.3K14Q modification, we observed the amelioration of all tested phenotypes (viability, longevity, neurodegeneration, motor activity, and circadian rhythm defects), while H3.3K14R had the opposite effect. H3.3K14Q expression prevented the negative effects of reduced Gcn5 (a HAT acting on H3K14) on HD pathology, while it only partially hindered the positive effects of heterozygous Sirt1 (an HDAC acting on H3K14). Thus, we conclude that the Gcn5-dependent acetylation of H3.3K14 might be an important epigenetic contributor to HD pathology

Genetic Modulation of the GLUT1 Transporter Expression—Potential Relevance in Complex Diseases

The human GLUT1 (SLC2A1) membrane protein is the key glucose transporter in numerous cell types, including red cells, kidney, and blood-brain barrier cells. The expression level of this protein has a role in several diseases, including cancer and Alzheimer’s disease. In this work, to investigate a potential genetic modulation of the GLUT1 expression level, the protein level was measured in red cell membranes by flow cytometry, and the genetic background was analyzed by qPCR and luciferase assays. We found significant associations between red cell GLUT1 levels and four single nucleotide polymorphisms (SNP) in the coding SLC2A1 gene, that in individuals with the minor alleles of rs841848, rs1385129, and rs11537641 had increased, while those having the variant rs841847 had decreased erythrocyte GLUT1 levels. In the luciferase reporter studies performed in HEK-293T and HepG2 cells, a similar SNP-dependent modulation was observed, and lower glucose, serum, and hypoxic condition had variable, cell- and SNP-specific effects on luciferase expression. These results should contribute to a more detailed understanding of the genetic background of membrane GLUT1 expression and its potential role in associated diseases