DNA damage in preimplantation embryos and gametes : specification, clinical relevance and repair strategies

BACKGROUND: DNA damage is a hazard that affects all cells of the body. DNA-damage repair (DDR) mechanisms are in place to repair damage and restore cellular function, as are other damage-induced processes such as apoptosis, autophagy and senescence. The resilience of germ cells and embryos in response to DNA damage is less well studied compared with other cell types. Given that recent studies have described links between embryonic handling techniques and an increased likelihood of disease in post-natal life, an update is needed to summarize the sources of DNA damage in embryos and their capacity to repair it. In addition, numerous recent publications have detailed novel techniques for detecting and repairing DNA damage in embryos. This information is of interest to medical or scientific personnel who wish to obtain undamaged embryos for use in offspring generation by ART. OBJECTIVE AND RATIONALE: This review aims to thoroughly discuss sources of DNA damage in male and female gametes and preimplantation embryos. Special consideration is given to current knowledge and limits in DNA damage detection and screening strategies. Finally, obstacles and future perspectives in clinical diagnosis and treatment (repair) of DNA damaged embryos are discussed. SEARCH METHODS: Using PubMed and Google Scholar until May 2021, a comprehensive search for peer-reviewed original English-language articles was carried out using keywords relevant to the topic with no limits placed on time. Keywords included ‘DNA damage repair’, ‘gametes’, ‘sperm’, ‘oocyte’, ‘zygote’, ‘blastocyst’ and ‘embryo’. References from retrieved articles were also used to obtain additional articles. Literature on the sources and consequences of DNA damage on germ cells and embryos was also searched. Additional papers cited by primary references were included. Results from our own studies were included where relevant. OUTCOMES: DNA damage in gametes and embryos can differ greatly based on the source and severity. This damage affects the development of the embryo and can lead to long-term health effects on offspring. DDR mechanisms can repair damage to a certain extent, but the factors that play a role in this process are numerous and altogether not well characterized. In this review, we describe the multifactorial origin of DNA damage in male and female gametes and in the embryo, and suggest screening strategies for the selection of healthy gametes and embryos. Furthermore, possible therapeutic solutions to decrease the frequency of DNA damaged gametes and embryos and eventually to repair DNA and increase mitochondrial quality in embryos before their implantation is discussed. WIDER IMPLICATIONS: Understanding DNA damage in gametes and embryos is essential for the improvement of techniques that could enhance embryo implantation and pregnancy success. While our knowledge about DNA damage factors and regulatory mechanisms in cells has advanced greatly, the number of feasible practical techniques to avoid or repair damaged embryos remains scarce. Our intention is therefore to focus on strategies to obtain embryos with as little DNA damage as possible, which will impact reproductive biology research with particular significance for reproductive clinicians and embryologists

Impact of routine invasive strategy on outcomes in patients with non-ST-segment elevation myocardial infarction during 2005–2014: A report from the Polish Registry of Acute Coronary Syndromes (PL-ACS)

Background: Non-ST-segment elevation myocardial infarction (NSTEMI) has become the most frequently encountered type of myocardial infarction. The patient clinical profile and management has evolved over the past decade. As there is still a scarcity of data on the latest trends in NSTEMI, changes herein were observed and assessed in the treatment and outcomes in Poland between 2005 and 2014.Methods: A total of 197,192 patients with NSTEMI who enrolled in the Polish Registry of Acute Coronary Syndromes (PL-ACS) between 2005 and 2014 were analyzed. In-hospital and 12-month mortality were assessed.Results: Coronary angiography use increased from 35.8% in 2005–2007 to 90.7% in 2012–2014 (p < 0.05), whereas percutaneous coronary intervention increased from 25.7% in 2005–2007 to 63.6% in 2012–2014 (p < 0.05). There was a 50% reduction in in-hospital mortality (from 5.6% in 2005–2007 to 2.8% in 2012–2014; p < 0.05) and a 30% reduction in 1-year mortality (from 19.4% in 2005–2007 to 13.7% in 2012–2014; p < 0.05). A multivariate analysis confirmed an immense impact of invasive strategy on patient prognosis during in-hospital observation with an odds ratio (OR) of 0.31 (95% confidence interval [CI] 0.29–0.33; p < 0.05) as well as during the 12-month observation with an OR of 0.51 (95% CI 0.49–0.52; p < 0.05).Conclusions: Over the past 10 years, an important advance in the management of NSTEMI has taken place in Poland. Routine invasive strategy resulted in a significant decrease in mortality rates in all groups of NSTEMI patients

Survival benefit from recent changes in management of men and women with ST-segment elevation myocardial infarction treated with percutaneous coronary interventions

Background: Nowadays, the majority of patients with myocardial infarction with ST-segment elevation (STEMI) are treated with primary percutaneous coronary interventions (PCI). In recent years, there have been ongoing improvements in PCI techniques, devices and concomitant pharmacotherapy. However, reports on further mortality reduction among PCI-treated STEMI patients remain inconclusive. The aim of this study was to compare changes in management and mortality in PCI-treated STEMI patients between 2005 and 2011 in a real-life setting. Methods: Data on 79,522 PCI-treated patients with STEMI from Polish Registry of Acute Coronary Syndromes (PL-ACS) admitted to Polish hospitals between 2005 and 2011 were analyzed. First, temporal trends of in-hospital management in men and women were presented. In the next step, patients from 2005 and 2011 were nearest neighbor matched on their propensity scores to compare in-hospital, 30-day and 1-year mortality rates and in-hospital management strategies and complications. Results: Some significant changes were noted in hospital management including shortening of median times from admission to PCI, increased use of drug-eluting stents, potent antiplatelet agents but also less frequent use of statin, beta-blockers and angiotensin converting enzyme inhibitors and angiotensin II receptor blockers. There was a strong tendency toward preforming additional PCI of non-infarct related arteries, especially in women. After propensity score adjustment there were significant changes in inhospital but not in 30-day or 1-year mortality rates between 2005 and 2011. The results were similar in men and women. Conclusions: There were apparent changes in management and significant in-hospital mortality reductions in PCI-treated STEMI patients between 2005 and 2011. However, it did not result in 30-day or 1-year survival benefit at a population level. There may be room for improvement in the use of guideline-recommended pharmacotherapy

Prognostic value of red blood cell distribution width in patients with left ventricular systolic dysfunction: Insights from the COMMIT-HF registry

Background: Previous studies have reported that in patients with heart failure, an increased value of red cell distribution width (RDW) is associated with adverse outcomes. Nonetheless, data regarding the association between RDW values and long-term mortality in patients with left ventricular systolic dysfunction (LVSD) are lacking. The aim of this investigation was to examine the relationship between mortality and RDW in patients with ischemic and non-ischemic LVSD. Methods: Under analysis was 1734 patients with a left ventricular ejection fraction (LVEF) ≤ 35% of whom were hospitalized between 2009 and 2013. Patients were divided into three groups based on RDW tertiles. Low, medium and high tertiles were defined as RDW ≤ 13.4%, 13.4% < RDW ≤ 14.6% and RDW > 14.6%, respectively. Results: There was a stepwise relationship between RDW intervals and comorbidities. Patients with the highest RDW values were older and more often diagnosed with anemia, diabetes, atrial fibrillation and chronic kidney disease. The main finding of our analysis was the presence of an 8-fold increase in all-cause mortality in the entire cohort between high and low RDW tertile. Cox hazard analysis identi­fied RDW as an independent predictive factor of mortality in all patients (HR 2.8; 95% CI 2.1–3.8; p < 0.0001) and in subgroups of patients with ischemic (HR 2.8; 95% CI 2.0–3.9; p < 0.0001) and non-ischemic (HR 3.3; 95% CI 2.01–5.5; p < 0.0001) LVSD. Conclusions: The highest RDW tertile was independently associated with higher long-term mortality compared with low and medium tertiles, both in all patients with a LVEF ≤ 35% and in subgroups of patients with ischemic and non-ischemic LVSD

One‑year survival of ambulatory patients with end‑stage heart failure : the analysis of prognostic factors

Introduction An increasing number of ambulatory patients are placed on orthotopic heart transplantation (OHT) waiting lists, which results in an extended waiting time and a higher mortality rate. Objectives The aim of this study was to identify the factors associated with reduced survival during a 1‑year follow‑up in patients with end‑stage heart failure listed for an OHT. Patients and methods We retrospectively analyzed the data of 221 adult patients, who were accepted for OHT in our institution over a 2‑year period between 2013 and 2014. Results The mean (SD) age of the patients was 54.7 (9.6) years, and 90.1% of them were male. The mortality rate during the follow‑up period was 43.3%. The modified Model for End‑Stage Liver Disease (modMELD) score (odds ratio [OR], 1.70; P <0.001), as well as the plasma levels of high‑sensitivity C‑reactive protein (hs‑CRP; OR, 1.10; P <0.01), sodium (OR, 0.74; P <0.001), and uric acid (UA; OR, 1.003; P <0.05) were independent factors affecting death. The receiver‑operating characteristic (ROC) analysis indicated that a modMELD cut‑off of 10 (area under the ROC curve [AUC], 0.868; P <0.001), hs‑CRP cut‑off of 5.6 mg/l (AUC, 0.674; P <0.001), plasma sodium level cut‑off of 135 mmol/l (AUC, 0.778; P <0.001), and a plasma UA cut‑off of 488 μmol/l (AUC, 0.634; P <0.001) were the most accurate factors affecting death. Conclusions In conclusion, although limited to a single center, our study demonstrated that an elevated modMELD score, incorporating a combination of renal and hepatic laboratory parameters, as well as plasma sodium, UA, and hs‑CRP levels at the time of listing are associated with reduced survival in ambulatory patients with end‑stage heart failure, accepted for OHT

Plejotropowe działanie statyn

Statyny, czyli inhibitory reduktazy 3-hydroksy-3-metyloglutarylokoenzymu A, wprowadzono do leczenia jako leki hipolipemizujące. Od tego momentu poznano wiele działań statyn niezależnych od mechanizmu obniżania stężenia cholesterolu. Plejotropizm leków z tej grupy przejawia się między innymi działaniem ochronnym na śródbłonek naczyniowy, stabilizacją blaszki miażdżycowej, efektem przeciwzapalnym oraz wpływem na układ krzepnięcia i fibrynolizy. Działanie statyn wykorzystuje się w pierwotnej i wtórnej prewencji choroby wieńcowej, udaru niedokrwiennego, a także w zapobieganiu powikłaniom naczyniowym u chorych na cukrzycę. W przyszłości, być może, znajdą zastosowanie w leczeniu chorób autoimmunologicznych, neurodegeneracyjnych czy w transplantologii. Siła działania statyn zależy od rodzaju preparatu oraz od dawki. Zastosowanie dużych dawek wiąże się z większą skutecznością, ale także zwiększa ryzyko wystąpienia działań niepożądanych, takich jak zaburzenia żołądkowo-jelitowe, wzrost stężenia transaminaz, miopatia, a w skrajnych przypadkach nawet rabdomioliza. Ze względu na wielokierunkowość działań statyny wykazują duży potencjał terapeutyczny. Obecnie są szeroko stosowane w kardiologii, ale ich przyszłość będzie prawdopodobnie związana również z innymi dziedzinami medycyny

Rewaskularyzacja w skurczowej niedokrwiennej niewydolności serca — prezentacja przypadku i podsumowanie aktualnych wytycznych

Heart failure has become a global pandemic. Despite being identified as the main cause of heart failure, evidence based data on coronary heart disease treatment in this population is scarce. At the same time the clinical characteristics in this group of patients is often very complex and requires an “outside-the-EBM-box” approach. This article is an attempt to summarize the current guidelines. We also present a case of a patient, in whom percutaneous revascularization with support of mechanical circulatory support, despite high risk, has given a very satisfactory short-term result and a good long-term outcome.  Niewydolność serca (NS) stała się światową pandemią. Pomimo że choroba wieńcowa stanowi jej najczęstszą przyczynę, zasób wiedzy opartej na faktach dotyczącej kwalifikacji do diagnostyki inwazyjnej oraz rewaskularyzacji jest ograniczony. Ponadto, wobec często znacznie obciążonej charakterystyki klinicznej pacjentów z NS konieczne do podjęcia w codziennej praktyce decyzje diagnostyczno-terapeutyczne wymykają się wytycznym. Niniejsza praca stanowi próbę podsumowania aktualnych zaleceń oraz przedstawia przypadek kliniczny pacjenta, u którego przeprowadzenie zabiegu przezskórnej rewaskularyzacji z wykorzystaniem mechanicznego wspomagania krążenia, pomimo wysokiego ryzyka, przyniosło bardzo dobry efekt terapeutyczny i pozwoliło na długoterminową poprawę