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

Inflammation, underweight, malignancy and a marked catabolic state as predictors for worse outcomes in COVID-19 patients with moderate-to-severe disease admitted to Internal Medicine Unit

Introduction: During COVID-19 pandemic, Internal Medicine Units (IMUs) accounted for about 70% of patients hospitalized. Although a large body of data has been published regarding the so-called first wave of the pandemic, little is known about the characteristics and predictors of worse outcomes of patients managed in IMUs during the second wave. Methods: We prospectively assessed demographics, comorbidities, treatment and outcomes, including ventilation support (VS) and death, in patients admitted to our IMU for SARS-CoV-2 between October 13th, 2020 and January 21st, 2021. Clinical evolution and biochemical testing 1, 7 and 14 days after COVID-19 diagnosis were recorded. Results: We studied 120 patients (M/F 56/64, age 71±14.5 years) admitted to our IMU. Most of them had at least one comorbidity (80%). Patients who died were older, more frequently underweight, affected by malignant neoplasms and on statin therapy compared to patients eventually discharged. Both worse outcome groups (VS and death) presented higher neutrophils, ferritin, IL-6 and lower total proteins levels than controls. Age was significantly associated with mortality but not with VS need. The multivariate analysis showed age and gender independent association of mortality with underweight, malignancy and antibiotics use at the admission. With regard to biochemical parameters, both unfavourable outcomes were positively associated with high WBC count, neutrophils, blood urea nitrogen and low serum total proteins. Conclusions: Our study identified inflammation, underweight, malignancy and a marked catabolic state as the main predictors for worse outcomes in COVID-19 patients admitted to IMU during the so-called second wave of the pandemic

Rationale and design of an independent randomised controlled trial evaluating the effectiveness of aripiprazole or haloperidol in combination with clozapine for treatment-resistant schizophrenia

<p>Abstract</p> <p>Background</p> <p>One third to two thirds of people with schizophrenia have persistent psychotic symptoms despite clozapine treatment. Under real-world circumstances, the need to provide effective therapeutic interventions to patients who do not have an optimal response to clozapine has been cited as the most common reason for simultaneously prescribing a second antipsychotic drug in combination treatment strategies. In a clinical area where the pressing need of providing therapeutic answers has progressively increased the occurrence of antipsychotic polypharmacy, despite the lack of robust evidence of its efficacy, we sought to implement a pre-planned protocol where two alternative therapeutic answers are systematically provided and evaluated within the context of a pragmatic, multicentre, independent randomised study.</p> <p>Methods/Design</p> <p>The principal clinical question to be answered by the present project is the relative efficacy and tolerability of combination treatment with clozapine plus aripiprazole compared with combination treatment with clozapine plus haloperidol in patients with an incomplete response to treatment with clozapine over an appropriate period of time. This project is a prospective, multicentre, randomized, parallel-group, superiority trial that follow patients over a period of 12 months. Withdrawal from allocated treatment within 3 months is the primary outcome.</p> <p>Discussion</p> <p>The implementation of the protocol presented here shows that it is possible to create a network of community psychiatric services that accept the idea of using their everyday clinical practice to produce randomised knowledge. The employed pragmatic attitude allowed to randomly allocate more than 100 individuals, which means that this study is the largest antipsychotic combination trial conducted so far in Western countries. We expect that the current project, by generating evidence on whether it is clinically useful to combine clozapine with aripiprazole rather than with haloperidol, provides physicians with a solid evidence base to be directly applied in the routine care of patients with schizophrenia.</p> <p>Trial Registration</p> <p><b>Clincaltrials.gov Identifier</b>: NCT00395915</p

Effectiveness of lithium in subjects with treatment-resistant depression and suicide risk: results and lessons of an underpowered randomised clinical trial

BACKGROUND: As lithium treatment might be effective in reducing the risk of deliberate self-harm (DSH) in adult patients with unipolar affective disorders, we designed a pragmatic randomised trial to assess its efficacy in more than 200 patients with treatment-resistant depression. However, we randomised 56 patients only. The aim of this report is therefore twofold: first, to disseminate the results of this underpowered study which may be incorporated into future meta-analytical reviews; second, to analyse some critical aspects of the study which might explain failure to reach the target sample size.METHODS: We carried out a randomised, parallel group, assessor-blinded superiority clinical trial. Adults with a diagnosis of major depression, an episode of DSH in the previous 12 months and inadequate response to at least two antidepressants given sequentially at an adequate dose for an adequate time for the current depressive episode were allocated to add lithium to usual care (intervention arm) versus usual care alone (control arm). Suicide completion and acts of DSH during the 12 months of follow-up constituted the composite primary outcome.RESULTS: Of 58 patients screened for inclusion, 29 were allocated to lithium plus usual care and 27 were assigned to usual care without lithium. Six patients in the lithium plus usual care group and seven in the usual care group committed acts of DSH during the follow-up phase. The survival probability did not differ between the two treatment arms (Chi2 = 0.17, p =0.676). With regard to changes in the severity of depressive symptomatology from baseline to endpoint, no significant differences were detected.CONCLUSIONS: The present study failed to achieve the minimum sample size needed to detect a clinically meaningful difference between the two treatment arms. Consequently, the finding that lithium, in addition to usual care, did not exert a positive effect in terms of reduction of DSH after 12 months of follow-up is likely due to the lack of sufficient statistical power to detect a difference, if a difference existed. The dissemination of the results of this underpowered study will inform future meta-analytical reviews on lithium and suicide-related outcomes.TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00927550

Intervista a Dario Fo sulla censura e gli anni Settanta

La testimonianza di Dario Fo, raccolta nell'intervista, si riferisce alle forme di censura presenti nello spettacolo italiano degli anni settanta del Novecento. In particolare ricostruisce il suo tormentato rapporto con la RAI in uno spettacolo di Canzonissima. Una sua scenetta satirica, riferita al tema scottante degli incidenti sul lavoro, fu vietata dai dirigenti della televisione di stato provocando l’esclusione del popolare attore-regista dalla TV per molti anni