N6-Methyladenine Progressively Accumulates in Mitochondrial DNA during Aging.

N6-methyladenine (6mA) in the DNA is a conserved epigenetic mark with various cellular, physiological and developmental functions. Although the presence of 6mA was discovered a few years ago in the nuclear genome of distantly related animal taxa and just recently in mammalian mitochondrial DNA (mtDNA), accumulating evidence at present seriously questions the presence of N6-adenine methylation in these genetic systems, attributing it to methodological errors. In this paper, we present a reliable, PCR-based method to determine accurately the relative 6mA levels in the mtDNA of Caenorhabditis elegans, Drosophila melanogaster and dogs, and show that these levels gradually increase with age. Furthermore, daf-2(-)-mutant worms, which are defective for insulin/IGF-1 (insulin-like growth factor) signaling and live twice as long as the wild type, display a half rate at which 6mA progressively accumulates in the mtDNA as compared to normal values. Together, these results suggest a fundamental role for mtDNA N6-adenine methylation in aging and reveal an efficient diagnostic technique to determine age using DNA.

Downregulation of transposable elements extends lifespan in Caenorhabditis elegans.

Mobility of transposable elements (TEs) frequently leads to insertional mutations in functional DNA regions. In the potentially immortal germline, TEs are effectively suppressed by the Piwi-piRNA pathway. However, in the genomes of ageing somatic cells lacking the effects of the pathway, TEs become increasingly mobile during the adult lifespan, and their activity is associated with genomic instability. Whether the progressively increasing mobilization of TEs is a cause or a consequence of ageing remains a fundamental problem in biology. Here we show that in the nematode Caenorhabditis elegans, the downregulation of active TE families extends lifespan. Ectopic activation of Piwi proteins in the soma also promotes longevity. Furthermore, DNA N6-adenine methylation at TE stretches gradually rises with age, and this epigenetic modification elevates their transcription as the animal ages. These results indicate that TEs represent a novel genetic determinant of ageing, and that N6-adenine methylation plays a pivotal role in ageing control.

Does the dose of the culprit drug matter in hypersensitivity reactions? / Számít-e a gyógyszer dózisa a túlérzékenységi reakciókban?

Összefoglaló. Két fiatal nobetegnél a valproátról lamotriginre történo gyógyszerátállítás során a 3-4. héten influenzaszeru prodromalis tüneteket követoen toxikus epidermalis necrolysis (TEN), más néven Lyell-szindróma alakult ki. Mindkét beteg 5 napja kezdodött bor- és nyálkahártyatünetekkel, kiterjedt hámleválást okozó hámnekrózissal került felvételre a Debreceni Egyetem Borgyógyászati Klinikájának Égési Intenzív Osztályára. Multidiszciplináris szupportív terápia mellett nagy dózisú szteroid- és immunglobulin-terápiát alkalmaztunk. A 37 éves nobetegnél 3 hét után a kórkép fatális kimenetellel végzodött. A 19 éves nobeteg tünetei 4 hét intenzív terápia után szövodményekkel gyógyultak. A TEN ritka, gyógyszer által okozott, életet veszélyezteto, késoi hiperszenzitivitási reakció. Patogenezisében a gyógyszermolekula, a humán leukocytaantigén (HLA) I. osztályú molekula és a T-sejt-receptor kóros interakciója szerepel. Kezelésében a legfontosabb a kiváltó gyógyszer elhagyása, valamint az azonnal kezdett komplett szupportív terápia alkalmazása. A specifikus kezelést illetoen nincsenek egységes szakmai irányelvek. A veszélyes gyógyszerek titrált bevezetése csökkentheti a kialakuló hiperszenzitivitás súlyosságát, ezenfelül a beteg szoros követése és az adverz tünetek korai felismerése javíthatja a TEN kimenetelét. Orv Hetil. 2020; 161(46): 1959-1965. Summary. After switching from valproate to lamotrigine, on the 3rd-4th weeks, two young female patients developed flu-like prodromal symptoms, followed by the development of toxic epidermal necrolysis (TEN), also known as Lyell syndrome. Both patients were admitted to the Burn Intensive Care Unit of the Department of Dermatology, University of Debrecen with skin and mucosa symptoms; extensive epithelial death and detachment started 5 days earlier. In addition to multidisciplinary supportive treatment, high-dose corticosteroid and immunoglobulin therapy were administered. In the case of the 37-year-old female patient, the disease resulted in a fatal outcome. The 19-year-old patient healed with some sequelae. TEN is a rare, life-threatening delayed-type hypersensitivity reaction caused by drugs. Its pathogenesis involves an interaction between small-molecule drug, human leukocyte antigen class I molecule and T-cell receptor. The most important treatment is immediate withdrawal of potentially causative drugs and prompt application of supportive therapy. There is no standard guidance on specific treatment. Slow dose escalation of dangerous drugs can be beneficial in avoiding severe reactions, furthermore, close patient follow-up and early detection of the possible adverse reactions contribute to a more favourable outcome of TEN. Orv Hetil. 2020; 161(46): 1959-1965.

[Ebstein's anomaly--experiences with surgical treatment in adulthood]. / Ebstein-anomália--a felnottkorban végzett mutétekkel kapcsolatos tapasztalatok.

INTRODUCTION: Long time results with operative treatment of Ebstein anomaly were examined. PATIENTS AND METHODS: From January 1985 to March 2001 16 patients with Ebstein anomaly were operated on. Ages ranged from 16 to 49 years at the time of operation. In 7 cases tricuspid valve repair was possible, and in 9 cases prosthetic valve was inserted. In all but one biological prosthesis has been used. In 15 cases atrial septal defect occurred as a concomitant anomaly, which was closed by direct suture in 9 cases and with patch (2 Dacron, 4 pericardium) in 6 cases. RESULTS: There was no early death (30 days postoperatively). 1 patient following tricuspid repair was reoperated on at the 9th postoperative day because of significant tricuspid insufficiency. Tricuspid valve replacement was performed with a biological prostheses. There were 3 late deaths: 2 patients (12.5%) in the first postoperative year (1 cardiac cause, 1 unknown), 1 patient died 6 years postoperatively following reoperation. There were 3 more patients requiring reoperation (total reoperation rate 28.6%) one of them a few days after the primary operation and two others 9 and 11 years following the first operation. 13 patients were recalled to control investigations. The authors could not contact 2 patients, 1 patient living abroad could not appear at our clinic. 10 patients have been investigated 6 months to 16 years after the operation. There were 9 patients in New York Heart Association class I or II. 2 patients had their own repaired valve; both had tricuspid insufficiency grade III. Both were completely active. 8 patients had previously tricuspid valve replacement and good valve function, but six of them have not been working any more. There were 5 female patients under 35 at the time of operation and 2 of them had successful pregnancies. CONCLUSIONS: Patients with Ebstein anomaly in NYHA stage III-IV. can be successfully treated surgically.