Iron-induced oxidative DNA damage and its repair in primary rat hepatocyte culture

Iron-overload diseases frequently develop hepatocellular carcinoma. The genotoxic mechanism whereby iron is involved in hepatocarcinogenesis might involve an oxidative process via the intermediate production of reactive oxygen species. This was presently investigated by examining kinetics of formation and repair of DNA base lesions in primary rat hepatocyte cultures supplemented with the iron chelate, ferric nitrilotriacetate Fe-NTA (10 and 100 microM). Seven DNA base oxidation products have been identified in DNA extracts by gas chromatography- mass spectrometry, which showed a predominance of oxidized-purines (8- oxo-guanine, xanthine, fapy-adenine, 2-oxo-adenine) above oxidized pyrimidines (5-OHMe-uracil, 5-OH-uracil, 5-OH-cytosine) in control cultures. All these DNA oxidation products revealed a significant dose- dependent increase at 4 to 48 h after Fe-NTA supplementation, among which fapy-adenine showed the highest increase and 5-OH-cytosine was the least prominent. Involvement of iron in this oxidative process was established by a correlation between extent in DNA oxidation and intracellular level of toxic low molecular weight iron. DNA excision- repair activity was estimated by release of DNA oxidation products in culture medium. All the seven DNA oxidation products were detected in the medium of control cultures and showed basal repair activity. This DNA repair activity was increased in a time- and dose-dependent fashion with Fe-NTA. Oxidized-pyrimidines, among which was 5-OHMe-Uracil, were preferentially repaired, which explains the low levels detected in oxidized DNA. Since oxidized bases substantially differed from one another in terms of excision rates from cellular DNA, specific excision- repair enzymes might be involved. Our findings, however, demonstrate that even though DNA repair pathways were activated in iron-loaded hepatocyte cultures, these processes were not stimulated enough to prevent an accumulation of highly mutagenic DNA oxidative products in genomic DNA. The resulting genotoxic effect of Fe-NTA might be relevant in understanding the hepatocarcinogenic evolution of iron-overload diseases.      

Economic choice between remifentanil and food in squirrel monkeys

Traditional approaches for evaluating if compounds are reinforcing, and thus a risk for abuse, include preclinical self-administration procedures conducted in the absence of alternative reinforcers. While the track record of this approach for determining abuse potential is good, that for predicting efficacy of addiction treatments is not. An alternate approach would be economic choice between drug and nondrug rewards, with parametrically varied options from trial to trial. This would promote goal-directed decisions between reward modalities and should provide metrics that reflect changes in internal state that influence desirability of a given option. We report herein a high throughput economic choice procedure in which squirrel monkeys choose between a short-lived opiate, remifentanil, and a palatable food reward. Stimuli on touchscreens indicate the amount of each reward type offered by varying the number of reward-specific elements. The rapid clearance of remifentanil avoids accumulation of confounding levels of drug, and permits a large number of trials with a wide range of offers of each reward modality. The use of a single metric encompassing multiple values of each reward type within a session enables estimation of indifference values using logistic regression. This indifference value is sensitive to reward devaluation within each reward domain, and is therefore a useful metric for determining shifts in reward preference, as shown with satiation and pharmacological treatment approaches.Subject terms: Addiction, Decision     

Diet Modification before or during Pregnancy on Maternal and Foetal Outcomes in Rodent Models of Maternal Obesity

The obesity epidemic has serious implications for women of reproductive age; its rising incidence is associated not just with health implications for the mother but also has transgenerational ramifications for the offspring. Increased incidence of diabetes, cardiovascular disease, obesity, and kidney disease are seen in both the mothers and the offspring. Animal models, such as rodent studies, are fundamental to studying maternal obesity and its impact on maternal and offspring health, as human studies lack rigorous controlled experimental design. Furthermore, the short and prolific reproductive potential of rodents enables examination across multiple generations and facilitates the exploration of interventional strategies to mitigate the impact of maternal obesity, both before and during pregnancy. Given that obesity is a major public health concern, it is important to obtain a greater understanding of its pathophysiology and interaction with reproductive health, placental physiology, and foetal development. This narrative review focuses on the known effects of maternal obesity on the mother and the offspring, and the benefits of interventional strategies, including dietary intervention, before or during pregnancy on maternal and foetal outcomes. It further examines the contribution of rodent models of maternal obesity to elucidating pathophysiological pathways of disease development, as well as methods to reduce the impact of obesity on the mothers and the developing foetus. The translation of these findings into the human experience will also be discussed.     

Effects of Osseodensification on Immediate Implant Placement: Retrospective Analysis of 211 Implants

Osseodensification is a new method of bone instrumentation for dental implant placement that preserves bulk bone and increases primary implant stability, and may accelerate the implant rehabilitation treatment period and provide higher success and survival rates than conventional methods. The aim of this retrospective study was to evaluate and discuss results obtained on immediate implant placement with immediate and delayed loading protocols under Osseodensification bone instrumentation. This study included private practice patients that required dental implant rehabilitation, between February 2017 and October 2019. All implants were placed under Osseodensification and had to be in function for at least 12 months to be included on the study. A total of 211 implants were included in the study, with a 98.1% total survival rate (97.9% in the maxilla and 98.5% in the mandible). For immediate implants with immediate load, 99.2% survival rate was achieved, and 100% survival rate for immediate implant placement without immediate load cases. A total of four implants were lost during this period, and all of them were lost within two months after placement. Within the limitations of this study, it can be concluded that Osseodensification bone instrumentation provided similar or better results on survival rates than conventional bone instrumentation.     

Liquid profiling of circulating tumor DNA in colorectal cancer: steps needed to achieve its full clinical value as standard care

The analysis of circulating tumor DNA (ctDNA) is at the threshold of implementation into standard care for colorectal cancer (CRC) patients. However, data about the clinical utility of liquid profiling (LP), its acceptance by clinicians, and its integration into clinical workflows in real‐world settings remain limited. Here, LP tests requested as part of routine care since 2016 were retrospectively evaluated. Results show restrained request behavior that improved moderately over time, as well as reliable diagnostic performance comparable to translational studies, with an overall agreement of 91.7%. Extremely low ctDNA levels at < 0.1% in over 20% of cases, a high frequency of concomitant driver mutations (in up to 14% of cases), and ctDNA levels reflecting the clinical course of disease were revealed. However, certain limitations hampering successful translation of ctDNA into clinical practice were uncovered, including the lack of clinically relevant ctDNA thresholds, appropriate time points of LP requests, and integrative evaluation of ctDNA, imaging, and clinical findings. In conclusion, these results highlight the potential clinical value of LP for CRC patient management and demonstrate issues that need to be addressed for successful long‐term implementation in clinical workflows.     

Effects of Sand-Based Plyometric-Jump Training in Combination with Endurance Running on Outdoor or Treadmill Surface on Physical Fitness in Young Adult Males

This study aimed at examining the effects of nine weeks of sand-based plyometric-jump training (PJT) combined with endurance running on either outdoor or treadmill surface on measures of physical fitness. Male participants (age, 20.1 ± 1.7 years) were randomly assigned to a sand-based PJT combined with endurance running on outdoor surface (OT, n = 25) or treadmill surface (TT, n = 25). The endurance running intervention comprised a mixed training method, i.e., long slow distance, tempo, and interval running drills. A control group was additionally included in this study (CG, n = 25). Participants in CG followed their regular physical activity as OT and TT but did not receive any specific intervention. Individuals were assessed for their 50-m linear sprint time, standing long jump (SLJ) distance, cardiorespiratory fitness (i.e., Cooper test), forced vital capacity (FVC), calf girth, and resting heart rate (RHR). A three (groups: OT, TT, CG) by two (time: pre, post) ANOVA for repeated measures was used to analyze the exercise-specific effects. In case of significant group-by-time interactions, Bonferroni adjusted paired (within-group) and independent (between-group comparisons at post) t-tests were used for post-hoc analyses. Significant group-by-time interactions were found for all dependent variables (p < 0.001 – 0.002, ɳ_p² = 0.16 – 0.78). Group-specific post-hoc tests showed improvements for all variables after OT (p < 0.001, Hedges’g effect size [g] = 0.05 – 1.94) and TT (p < 0.001, g = 0.04 – 2.73), but not in the CG (p = 0.058 – 1.000, g = 0.00 – 0.34). Compared to CG, OT showed larger SLJ (p = 0.001), cardiorespiratory fitness (p = 0.004), FVC (p = 0.008), and RHR (p < 0.001) improvements. TT showed larger improvements in SLJ (p = 0.036), cardiorespiratory fitness (p < 0.001), and RHR (p < 0.001) compared with CG. Compared to OT, TT showed larger improvements for SLJ (p = 0.018). In conclusion, sand-based PJT combined with either OT or TT similarly improved most measures of physical fitness, with greater SLJ improvement after TT. Coaches may use both concurrent exercise regimes based on preferences and logistical constrains (e.g., weather; access to treadmill equipment). Key points

• Concurrent training in the form of sand-based plyometric-jump training and endurance running exercise can enhance physical fitness in young individuals;
• Compared to treadmill running, rating of perceived exertion was higher in outdoor running sessions;
• Sand-based plyometric-jump training may induce greater standing long jump performance when combined with endurance running on treadmill surface as compared to outdoor surface.

Key words: Muscle strength, musculoskeletal and neural physiological phenomena, movement, resistance training, high-intensity interval training, exercise