Defective repair of oxidative base lesions by the DNA glycosylase Nth1 associates with multiple telomere defects

Telomeres are chromosome end structures and are essential for maintenance of genome stability. Highly repetitive telomere sequences appear to be susceptible to oxidative stress-induced damage. Oxidation may therefore have a severe impact on telomere integrity and function. A wide spectrum of oxidative pyrimidine-derivatives has been reported, including thymine glycol (Tg), that are primarily removed by a DNA glycosylase, Endonuclease III-like protein 1 (Nth1). Here, we investigate the effect of Nth1 deficiency on telomere integrity in mice. Nth1 null (Nth1(-/-) ) mouse tissues and primary MEFs harbor higher levels of Endonuclease III-sensitive DNA lesions at telomeric repeats, in comparison to a non-telomeric locus. Furthermore, oxidative DNA damage induced by acute exposure to an oxidant is repaired slowly at telomeres in Nth1(-/-) MEFs. Although telomere length is not affected in the hematopoietic tissues of Nth1(-/-) adult mice, telomeres suffer from attrition and increased recombination and DNA damage foci formation in Nth1(-/-) bone marrow cells that are stimulated ex vivo in the presence of 20% oxygen. Nth1 deficiency also enhances telomere fragility in mice. Lastly, in a telomerase null background, Nth1(-/-) bone marrow cells undergo severe telomere loss at some chromosome ends and cell apoptosis upon replicative stress. These results suggest that Nth1 plays an important role in telomere maintenance and base repair against oxidative stress-induced base modifications. The fact that telomerase deficiency can exacerbate telomere shortening in Nth1 deficient mouse cells supports that base excision repair cooperates with telomerase to maintain telomere integrity.Haritha Vallabhaneni, Nathan O'Callaghan, Julia Sidorova, Yie Li

Continuous Three-Dimensional Control of a Virtual Helicopter Using a Motor Imagery Based Brain-Computer Interface

Brain-computer interfaces (BCIs) allow a user to interact with a computer system using thought. However, only recently have devices capable of providing sophisticated multi-dimensional control been achieved non-invasively. A major goal for non-invasive BCI systems has been to provide continuous, intuitive, and accurate control, while retaining a high level of user autonomy. By employing electroencephalography (EEG) to record and decode sensorimotor rhythms (SMRs) induced from motor imaginations, a consistent, user-specific control signal may be characterized. Utilizing a novel method of interactive and continuous control, we trained three normal subjects to modulate their SMRs to achieve three-dimensional movement of a virtual helicopter that is fast, accurate, and continuous. In this system, the virtual helicopter's forward-backward translation and elevation controls were actuated through the modulation of sensorimotor rhythms that were converted to forces applied to the virtual helicopter at every simulation time step, and the helicopter's angle of left or right rotation was linearly mapped, with higher resolution, from sensorimotor rhythms associated with other motor imaginations. These different resolutions of control allow for interplay between general intent actuation and fine control as is seen in the gross and fine movements of the arm and hand. Subjects controlled the helicopter with the goal of flying through rings (targets) randomly positioned and oriented in a three-dimensional space. The subjects flew through rings continuously, acquiring as many as 11 consecutive rings within a five-minute period. In total, the study group successfully acquired over 85% of presented targets. These results affirm the effective, three-dimensional control of our motor imagery based BCI system, and suggest its potential applications in biological navigation, neuroprosthetics, and other applications

The safety of device registries for endovascular abdominal aortic aneurysm repair: systematic review and meta-regression

Objectives New and re-designed stent grafts for endovascular aortic aneurysm repair (EVAR) are released regularly. Manufacturers use data from registries to assess stent graft performance, but little is known about the ability of such registries to detect rates of clinically relevant complications. The aim of this paper was to perform a systematic review and meta-analysis to determine pooled failure rates for EVAR stent grafts, to define an acceptable non-inferiority limit for these devices, and then to calculate the number of patients needed for a new device to achieve non-inferiority against published devices. Data sources and review methods MEDLINE and EMBASE were searched for studies reporting outcomes of specific EVAR grafts being used for intact infrarenal abdominal aortic aneurysms, from inception to November 2016. Meta-regression was performed to pool data and calculate the patient numbers needed to detect non-inferiority of a future graft performance. An expert consensus was performed to define adequate standards for device safety. Results One hundred and forty-seven moderate quality papers involving 27,058 patients were included. Multiple outcomes were pooled. Of these, the estimated rate (±standard error) of overall endoleak (excluding Type II) at 2 years was 5.7 ± 0.6%. The pooled re-intervention rate was 11.1 ± 0.7% at 2 years. There were differences in pooled endoleak rates between different stent graft types. Expert consensus defined non-inferiority as better performance than the worst performing 25% of stent grafts. The most popular outcome in the expert consensus was cumulative endoleak rate (excluding Type II). The number of patients who would need to be enrolled in a registry to demonstrate non-inferiority at this level was 525. Only two of 147 included studies achieved this. The second most popular choice in the expert consensus was re-intervention rate; 492 patients are required to demonstrate this. Conclusions Five hundred and twenty-five patients need to be entered into a registry to demonstrate non-inferiority to previous stent grafts. Almost all previous publications have captured lower patient numbers. With performance varying between devices, and new devices being introduced regularly, there is an urgent need to capture higher quality long-term data on EVAR stent grafts

Systematic review of tonsil surgery quality registers and introduction of the Nordic Tonsil Surgery Register Collaboration

Surgical quality registers provide tools to measure and improve the outcome of surgery. International register collaboration creates an opportunity to assess and critically evaluate national practices, and increases the size of available datasets. Even though millions of yearly tonsillectomies and tonsillotomies are performed worldwide, clinical practices are variable and inconsistency of evidence regarding the best clinical practice exists. The need for quality improvement actions is evident. We aimed to systematically investigate the existing tonsil surgery quality registers found in the literature, and to provide a thorough presentation of the planned Nordic Tonsil Surgery Register Collaboration. A systematic literature search of MEDLINE and EMBASE databases (from January 1990 to December 2016) was conducted to identify registers, databases, quality improvement programs or comprehensive audit programs addressing tonsil surgery. We identified two active registers and three completed audit programs focusing on tonsil surgery quality registration. Recorded variables were fairly similar, but considerable variation in coverage, number of operations included and length of time period for inclusion was discovered. Considering tonsillectomies and tonsillotomies being among the most commonly performed surgical procedures in otorhinolaryngology, it is surprising that only two active registers could be identified. We present a Nordic Tonsil Surgery Register Collaboration-an international tonsil surgery quality register project aiming to provide accurate benchmarks and enhance the quality of tonsil surgery in Denmark, Finland, Norway and Sweden.Peer reviewe

The Tyrosine Kinase Inhibitor Dasatinib Induces a Marked Adipogenic Differentiation of Human Multipotent Mesenchymal Stromal Cells

BACKGROUND: The introduction of specific BCR-ABL inhibitors in chronic myelogenous leukemia therapy has entirely mutated the prognosis of this hematologic cancer from being a fatal disorder to becoming a chronic disease. Due to the probable long lasting treatment with tyrosine-kinase inhibitors (TKIs), the knowledge of their effects on normal cells is of pivotal importance. DESIGN AND METHODS: We investigated the effects of dasatinib treatment on human bone marrow-derived mesenchymal stromal cells (MSCs). RESULTS: Our findings demonstrate, for the first time, that dasatinib induces MSCs adipocytic differentiation. Particularly, when the TKI is added to the medium inducing osteogenic differentiation, a high MSCs percentage acquires adipocytic morphology and overexpresses adipocytic specific genes, including PPARγ, CEBPα, LPL and SREBP1c. Dasatinib also inhibits the activity of alkaline phosphatase, an osteogenic marker, and remarkably reduces matrix mineralization. The increase of PPARγ is also confirmed at protein level. The component of osteogenic medium required for dasatinib-induced adipogenesis is dexamethasone. Intriguingly, the increase of adipocytic markers is also observed in MSCs treated with dasatinib alone. The TKI effect is phenotype-specific, since fibroblasts do not undergo adipocytic differentiation or PPARγ increase. CONCLUSIONS: Our data demonstrate that dasatinib treatment affects bone marrow MSCs commitment and suggest that TKIs therapy might modify normal phenotypes with potential significant negative consequences

Characterization of Oxidative Guanine Damage and Repair in Mammalian Telomeres

8-oxo-7,8-dihydroguanine (8-oxoG) and 2,6-diamino-4-hydroxy-5-formamidopyrimidine (FapyG) are among the most common oxidative DNA lesions and are substrates for 8-oxoguanine DNA glycosylase (OGG1)–initiated DNA base excision repair (BER). Mammalian telomeres consist of triple guanine repeats and are subject to oxidative guanine damage. Here, we investigated the impact of oxidative guanine damage and its repair by OGG1 on telomere integrity in mice. The mouse cells were analyzed for telomere integrity by telomere quantitative fluorescence in situ hybridization (telomere–FISH), by chromosome orientation–FISH (CO–FISH), and by indirect immunofluorescence in combination with telomere–FISH and for oxidative base lesions by Fpg-incision/Southern blot assay. In comparison to the wild type, telomere lengthening was observed in Ogg1 null (Ogg1−/−) mouse tissues and primary embryonic fibroblasts (MEFs) cultivated in hypoxia condition (3% oxygen), whereas telomere shortening was detected in Ogg1−/− mouse hematopoietic cells and primary MEFs cultivated in normoxia condition (20% oxygen) or in the presence of an oxidant. In addition, telomere length abnormalities were accompanied by altered telomere sister chromatid exchanges, increased telomere single- and double-strand breaks, and preferential telomere lagging- or G-strand losses in Ogg1−/− mouse cells. Oxidative guanine lesions were increased in telomeres in Ogg1−/− mice with aging and primary MEFs cultivated in 20% oxygen. Furthermore, oxidative guanine lesions persisted at high level in Ogg1−/− MEFs after acute exposure to hydrogen peroxide, while they rapidly returned to basal level in wild-type MEFs. These findings indicate that oxidative guanine damage can arise in telomeres where it affects length homeostasis, recombination, DNA replication, and DNA breakage repair. Our studies demonstrate that BER pathway is required in repairing oxidative guanine damage in telomeres and maintaining telomere integrity in mammals

Effects of Neonatal Nutrition Interventions on Neonatal Mortality and Child Health and Development Outcomes: A Systematic Review

Background The last two decades have seen a significant decrease in mortality for children \u3c 5 years of age in low and middle‐income countries (LMICs); however, neonatal (age, 0–28 days) mortality has not decreased at the same rate. We assessed three neonatal nutritional interventions that have the potential of reducing morbidity and mortality during infancy in LMICs. Objectives To determine the efficacy and effectiveness of synthetic vitamin A, dextrose oral gel, and probiotic supplementation during the neonatal period. Search Methods We conducted electronic searches for relevant studies on the following databases: PubMed, CINAHL, LILACS, SCOPUS, and CENTRAL, Cochrane Central Register for Controlled Trials, up to November 27, 2019. Selection Criteria We aimed to include randomized and quasi‐experimental studies. The target population was neonates in LMICs. The interventions included synthetic vitamin A supplementation, oral dextrose gel supplementation, and probiotic supplementation during the neonatal period. We included studies from the community and hospital settings irrespective of the gestational age or birth weight of the neonate. Data Collection and Analysis Two authors screened the titles and extracted the data from selected studies. The risk of bias (ROB) in the included studies was assessed according to the Cochrane Handbook of Systematic Reviews. The primary outcome was all‐cause mortality. The secondary outcomes were neonatal sepsis, necrotizing enterocolitis (NEC), prevention and treatment of neonatal hypoglycaemia, adverse events, and neurodevelopmental outcomes. Data were meta‐analyzed by random effect models to obtain relative risk (RR) and 95% confidence interval (CI) for dichotomous outcomes and mean difference with 95% CI for continuous outcomes. The overall rating of evidence was determined by the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. Main Results Sixteen randomized studies (total participants 169,366) assessed the effect of vitamin A supplementation during the neonatal period. All studies were conducted in low‐ and middle‐income (LMIC) countries. Thirteen studies were conducted in the community setting and three studies were conducted in the hospital setting, specifically in neonatal intensive care units. Studies were conducted in 10 different countries including India (four studies), Guinea‐Bissau (three studies), Bangladesh (two studies), and one study each in China, Ghana, Indonesia, Nepal, Pakistan, Tanzania, and Zimbabwe. The overall ROB was low in most of the included studies for neonatal vitamin A supplementation. The pooled results from the community based randomized studies showed that there was no significant difference in all‐cause mortality in the vitamin A (intervention) group compared to controls at 1 month (RR, 0.99; 95% CI, 0.90–1.08; six studies with 126,548 participants, statistical heterogeneity I2 0%, funnel plot symmetrical, grade rating high), 6 months (RR, 0.98; 95% CI, 0.89–1.07; 12 studies with 154,940 participants, statistical heterogeneity I2 43%, funnel plot symmetrical, GRADE quality high) and 12 months of age (RR, 1.04; 95% CI, 0.94–1.14; eight studies with 118,376 participants, statistical heterogeneity I2 46%, funnel plot symmetrical, GRADE quality high). Neonatal vitamin A supplementation increased the incidence of bulging fontanelle by 53% compared to control (RR, 1.53; 95% CI, 1.12–2.09; six studies with 100,256 participants, statistical heterogeneity I2 65%, funnel plot symmetrical, GRADE quality high). We did not identify any experimental study that addressed the use of dextrose gel for the prevention and/or treatment of neonatal hypoglycaemia in LMIC. Thirty‐three studies assessed the effect of probiotic supplementation during the neonatal period (total participants 11,595; probiotics: 5854 and controls: 5741). All of the included studies were conducted in LMIC and were randomized. Most of the studies were done in the hospital setting and included participants who were preterm (born \u3c 37 weeks gestation) and/or low birth weight (\u3c 2500 g birth weight). Studies were conducted in 13 different countries with 10 studies conducted in India, six studies in Turkey, three studies each in China and Iran, two each in Mexico and South Africa, and one each in Bangladesh, Brazil, Colombia, Indonesia, Nepal, Pakistan, and Thailand. Three studies were at high ROB due to lack of appropriate randomization sequence or allocation concealment. Combined data from 25 studies showed that probiotic supplementation reduced all‐cause mortality by 20% compared to controls (RR, 0.80; 95% CI, 0.66–0.96; total number of participants 10,998, number needed to treat 100, statistical heterogeneity I2 0%, funnel plot symmetrical, GRADE quality high). Twenty‐nine studies reported the effect of probiotics on the incidence of NEC, and the combined results showed a relative reduction of 54% in the intervention group compared to controls (RR, 0.46; 95% CI, 0.35–0.59; total number of participants 5574, number needed to treat 17, statistical heterogeneity I2 24%, funnel plot symmetrical, GRADE quality high). Twenty‐one studies assessed the effect of probiotic supplementation during the neonatal period on neonatal sepsis, and the combined results showed a relative reduction of 22% in the intervention group compared to controls (RR, 0.78; 95% CI, 0.70–0.86; total number of participants 9105, number needed to treat 14, statistical heterogeneity I2 23%, funnel plot symmetrical, GRADE quality high). Authors\u27 Conclusions Vitamin A supplementation during the neonatal period does not reduce all‐cause neonatal or infant mortality in LMICs in the community setting. However, neonatal vitamin A supplementation increases the risk of Bulging Fontanelle. No experimental or quasi‐experimental studies were available from LMICs to assess the effect of dextrose gel supplementation for the prevention or treatment of neonatal hypoglycaemia. Probiotic supplementation during the neonatal period seems to reduce all‐cause mortality, NEC, and sepsis in babies born with low birth weight and/or preterm in the hospital setting. There was clinical heterogeneity in the use of probiotics, and we could not recommend any single strain of probiotics for wider use based on these results. There was a lack of studies on probiotic supplementation in the community setting. More research is needed to assess the effect of probiotics administered to neonates in‐home/community setting in LMICs