Benzo(a)pyrene induces similar gene expression changes in testis of DNA repair proficient and deficient mice

<p>Abstract</p> <p>Background</p> <p>Benzo [a]pyrene (B[a]P) exposure induces DNA adducts at all stages of spermatogenesis and in testis, and removal of these lesions is less efficient in nucleotide excision repair deficient <it>Xpc</it>^-/-mice than in wild type mice. In this study, we investigated by using microarray technology whether compromised DNA repair in <it>Xpc</it>^-/-mice may lead to a transcriptional reaction of the testis to cope with increased levels of B[a]P induced DNA damage.</p> <p>Results</p> <p>Two-Way ANOVA revealed only 4 genes differentially expressed between wild type and <it>Xpc</it>^-/-mice, and 984 genes between testes of B[a]P treated and untreated mice irrespective of the mouse genotype. However, the level in which these B[a]P regulated genes are expressed differs between Wt and <it>Xpc</it>^-/-mice (p = 0.000000141), and were predominantly involved in the regulation of cell cycle, translation, chromatin structure and spermatogenesis, indicating a general stress response. In addition, analysis of cell cycle phase dependent gene expression revealed that expression of genes involved in G1-S and G2-M phase arrest was increased after B[a]P exposure in both genotypes. A slightly higher induction of average gene expression was observed at the G2-M checkpoint in <it>Xpc</it>^-/-mice, but this did not reach statistical significance (P = 0.086). Other processes that were expected to have changed by exposure, like apoptosis and DNA repair, were not found to be modulated at the level of gene expression.</p> <p>Conclusion</p> <p>Gene expression in testis of untreated <it>Xpc</it>^-/-and wild type mice were very similar, with only 4 genes differentially expressed. Exposure to benzo(a)pyrene affected the expression of genes that are involved in cell cycle regulation in both genotypes, indicating that the presence of unrepaired DNA damage in testis blocks cell proliferation to protect DNA integrity in both DNA repair proficient and deficient animals.</p

Performance of the BioIntegral Bovine Pericardial Graft in Vascular Infections:VASCular No-REact Graft Against INfection Study

Background: Vascular graft and endograft infections (VGEI) and native vessel infections (NVI) remain considerable challenges in vascular surgery, leading to high mortality and morbidity rates. Although in situ reconstruction is the preferred treatment, the material of choice is still a source of debate. Autologous veins are considered the first choice; however, xenografts may be an acceptable alternative. The performance of a biomodified bovine pericardial graft is assessed when implemented in an infected vascular area. Methods: This is a prospective multicenter cohort study. Patients who underwent reconstruction for VGEI or NVI with a biomodified bovine pericardial bifurcated or straight tube graft were included from December 2017 until June 2021. The primary outcome measure was reinfection at mid-term follow-up. Secondary outcome measures included mortality, patency, and amputation rate. Results: Thirty-four patients with vascular infections were included, of which 23 (68%) had an infected Dacron prosthesis after primary open repair and 8 (24%) had an infected endovascular graft. The remaining 3 (9%) had infected native vessels. At secondary repair, 3 (7%) patients had an in situ aortic tube reconstruction, 29 (66%) had an aortic bifurcated reconstruction, and 2 (5%) had an iliac-femoral reconstruction. At 1-year follow-up after the BioIntegral bovine pericardial graft reconstruction, the reinfection rate was 9%. The 1-year infection-related and procedure-related mortality rate was 16%. The occlusion rate was 6% and in total 3 patients underwent a lower limb amputation during the 1-year follow-up period. Conclusions: In situ reconstruction as treatment of (endo)graft and native vessel infections remains a challenge and reinfection looms as a potential consequence. In cases where time is of essence or when autologous venous repair is not feasible, a swift available solution is needed. The BioIntegral biomodified bovine pericardial graft may be an option as it shows reasonable results in terms of reinfection, in aortic tube and bifurcated grafts.</p

Factors Associated with Revision Surgery after Internal Fixation of Hip Fractures

Background: Femoral neck fractures are associated with high rates of revision surgery after management with internal fixation. Using data from the Fixation using Alternative Implants for the Treatment of Hip fractures (FAITH) trial evaluating methods of internal fixation in patients with femoral neck fractures, we investigated associations between baseline and surgical factors and the need for revision surgery to promote healing, relieve pain, treat infection or improve function over 24 months postsurgery. Additionally, we investigated factors associated with (1) hardware removal and (2) implant exchange from cancellous screws (CS) or sliding hip screw (SHS) to total hip arthroplasty, hemiarthroplasty, or another internal fixation device. Methods: We identified 15 potential factors a priori that may be associated with revision surgery, 7 with hardware removal, and 14 with implant exchange. We used multivariable Cox proportional hazards analyses in our investigation. Results: Factors associated with increased risk of revision surgery included: female sex, [hazard ratio (HR) 1.79, 95% confidence interval (CI) 1.25-2.50; P = 0.001], higher body mass index (fo

Minimal correlation between physical exercise capacity and daily activity in patients with intermittent claudication

Background Walking capacity measured by a treadmill test (TT) reflects the patient's maximal capacity in a controlled setting and is part of the physical exercise capacity (PEC). Daily physical activity (PA) is defined as the total of actively freely produced movements per day. A lower PA level has been increasingly recognized as a strong predictor of increased morbidity and mortality in patients with intermittent claudication (IC). Recent insights suggested that an increased PEC does not automatically lead to an increase in daily PA. However, the precise relation between PEC and PA in patients with IC is still unclear. Methods A cross-sectional study was conducted to assess the association between several PEC outcomes and PA in a general IC population. PEC was determined by well-established tests (Gardner-Skinner TT, a physical performance battery, a timed up-and-go test, and a 6-minute walk test distance). PA was obtained during 7 consecutive days using a triaxial accelerometer (Dynaport MoveMonitor; McRoberts BV, The Hague, The Netherlands). Five PA components (lying, sitting, standing, shuffling, and locomotion) and four parameters (total duration, number of periods, mean duration per period, and mean movement intensity per period) were analysed. Correlation coefficients between PEC and PA components were calculated. Results Data of 46 patients were available for analysis. Patients were sedentary (sitting and lying) during 81% of the day and were physically active (standing, shuffling, and locomotion) for the remaining 19% of the time. Correlations between PEC outcomes and PA ranged from very weak (0.025) to moderate (0.663). Moderate correlations (as therefore assumed to be relevant) were only found for outcomes of both the TT and 6-minute walk test and the locomotion components of PA. For instance, functional claudication distance (measured by TT) and number of steps per day correlated reasonably well (Spearman correlation ρ = 0.663; P <.01). Conclusions Exercise capacity and PA correlate minimally in patients with IC. PA may be preferred as a novel outcome measure and future treatment target in patients with IC

New methods for assessing male germline mutations in humans and genetic risks in their offspring.

Germline mutations resulting from chemical or radiation exposure are a particular problem in toxicology as they affect not only the exposed generation, but an infinite number of generations thereafter. Established methods to show that these mutations occur in an F1 or subsequent population require the use of a large number of progeny for statistical significance. Consequently, many thousands of animals have been used in the past. Such a use is no longer considered desirable and is also very expensive. Several new molecular techniques (including analysis of tandem repeats and randomly amplified polymorphic DNA) now provide alternative methods of assessment, which also allow the quantification of individual mutations in individual sperm cells. These can also be applied to human offspring, making extrapolation obsolete. The downside of these methods is that they effectively determine the mutation rate in certain regions of DNA and the relevance of these to diseases, particularly cancer, is not always apparent. Therefore it must be assumed that an increase in mutation rates in these selected regions correlates with altered phenotype. However, disease types linked to changes in tandem repeat length indicate that these may act as relevant markers for the development of phenotypes. Further research and evaluation is required to more closely link changes in DNA with altered phenotype and validate the use of tandem repeats and randomly amplified polymorphic DNA in transgenerational genotoxicity testing. This paper introduces and compares recently developed methods to assess mutations in sperm due to stem cell damage

Reliability and Validity of the Elevated Arm Stress Test in the Diagnosis of Neurogenic Thoracic Outlet Syndrome

OBJECTIVES: To assess the test-retest reliability and validity of the elevated arm stress test (EAST) as measured by the duration in a cohort of patients with suspected neurogenic thoracic outlet syndrome (NTOS). DESIGN: Retrospective analysis of prospectively collected data METHODS: Patients evaluated for NTOS between January 2017 and September 2018 were identified. Test-retest reliability by the intraclass correlation coefficient (ICC) was determined for duration of the EAST. For the validity analysis, patients were classified in a proven NTOS group or a symptomatic control group without NTOS using the SVS-reporting standards and the outcome of thoracic outlet decompression (TOD) surgery. A receiver operating characteristic (ROC) curve was made for the duration of EAST. The area under the curve (AUC), and positive and negative predictive values were calculated for the EAST. RESULTS: In total, 428 patients with suspected NTOS retrospectively analysed. Of these patients, 61 were excluded because no EAST data was available. Another 101 patients were excluded because of inconclusive reporting standards, arterial or venous TOS, or because TOD surgery was not performed or had a negative result. The validity analysis in the remaining 266 patients showed an AUC for the duration of the EAST of 0.62 (95% confidence interval (CI): 0.55-0.69). The positive predictive value of the duration ranged between 65% and 66%, and the negative predictive value between 53% and 58%. For the test-retest reliability analysis, 118 patients were excluded because they performed only one measurement in a 100-day time period. Analysis in the remaining 148 patients showed an ICC value of 0.65 (95% CI: 0.55-0.74) for duration. CONCLUSION: The EAST measured by the duration showed a moderate test-retest reliability, but the discriminative value was low in the diagnosis of NTOS. The outcome of the EAST measured by the duration should be used with caution

Endovascular revascularization plus supervised exercise versus supervised exercise only for intermittent claudication: A cost-effectiveness analysis

BACKGROUND: The ERASE (Endovascular Revascularization and Supervised Exercise) study showed that a combination therapy of endovascular revascularization followed by supervised exercise resulted in greater improvement in walking ability and quality of life as compared with supervised exercise only (standard care) in patients with intermittent claudication. The cost-effectiveness of the combination therapy as compared with supervised exercise is not well defined. In this report, the cost-effectiveness analysis of the ERASE study is presented. METHODS: Two hundred twelve patients were randomly assigned to the combination therapy (n=106) or supervised exercise only (n=106) and were followed for 12 months. Cumulative costs per patient were collected using the in-hospital resource utilization data and cost-questionnaires. Quality-adjusted life years were estimated using the EuroQol-5D questionnaire. Incremental cost-effectiveness ratios were calculated from both the health care and societal perspective. The associated uncertainty was determined using bootstrap techniques and acceptability curves. RESULTS: As compared with supervised exercise only, the combination therapy cost an additional €1.462 (99% CI, 388 to 3862) from the health care perspective and €161 (99% CI, −2286 to 3106) from the societal perspective. Accumulated quality-adjusted life- years during 1 year follow-up were 0.042 (99% CI, −0.009 to 0.118) higher in the combination therapy group. The incremental cost-effectiveness ratio was €34.810 from the health care perspective and €3.833 from the societal perspective. Compared with supervised exercise, at a willingness-to-pay threshold of €80.000 per quality-adjusted life-year, the combination therapy had a probability of 87% and 95% of being cost-effective from the health care and societal perspective, respectively. CONCLUSIONS: Combination therapy of endovascular revascularization followed by supervised exercise is clinically and economically a more attractive approach than supervised exercise only for intermittent claudication up to 12-month followup. Yet, the long-term cost- and clinical effectiveness of both strategies for specific patient groups remains to be defined