Switching yeast from meiosis to mitosis: double-strand break repair, recombination and synaptonemal complex

Background:

When Saccharomyces cerevisiae cells that have begun meiosis are transferred to mitotic growth conditions (‘return-to-growth’, RTG), they can complete recombination at high meiotic frequencies, but undergo mitotic cell division and remain diploid. It was not known how meiotic recombination intermediates are repaired following RTG. Using molecular and cytological methods, we investigated whether the usual meiotic apparatus could repair meiotically induced DSBs during RTG, or whether other mechanisms are invoked when the developmental context changes.

Results:

Upon RTG, the rapid disappearance of meiotic features—double-strand breaks in DNA (DSBs), synaptonemal complex (SC), and SC related structures—was striking. In wild-type diploids, the repair of meiotic DSBs during RTG was quick and efficient, resulting in homologous recombination. Kinetic analysis of double-strand breakage and recombination indicated that meiotic DSB formation precedes the commitment to meiotic levels of recombination. DSBs were repaired in RTG in dmc1, but not rad51 mutants, hence repair did not occur by the usual meiotic mechanism which requires the Dmc1 gene product. In haploids, DSBs were also repaired quickly and efficiently upon RTG, showing that DSB repair did not require the presence of a homologous chromosome. In all strains examined, SC and related structures were not required for DSB repair or recombination following RTG.

Conclusions:

At least two pathways of DSB repair, which differ from the primary meiotic pathway(s), can occur during RTG: One involving interhomologue recombination, and another involving sister-chromatid exchange. DSB formation precedes commitment to recombination. SC elements appear to prevent sister chromatid exchange in meiosis.

     

The antiatherogenic effect of allicin: possible mode of action.

OBJECTIVE: Garlic (Allium sativum) has been suggested to affect several cardiovascular risk factors. Its antiatherosclerotic properties are mainly attributed to allicin that is produced upon crushing of the garlic clove. Most previous studies used various garlic preparations in which allicin levels were not well defined. In the present study, we evaluated the effects of pure allicin on atherogenesis in experimental mouse models. METHODS AND RESULTS: Daily dietary supplement of allicin, 9 mg/kg body weight, reduced the atherosclerotic plaque area by 68.9 and 56.8% in apolipoprotein E-deficient and low-density lipoprotein (LDL) receptor knockout mice, respectively, as compared with control mice. LDL isolated from allicin-treated groups was more resistant to CuSO(4)-induced oxidation ex vivo than LDL isolated from control mice. Incubation of mouse plasma with (3)H-labeled allicin showed binding of allicin to lipoproteins. By using electron spin resonance, we demonstrated reduced Cu(2+) binding to LDL following allicin treatment. LDL treatment with allicin significantly inhibited both native LDL and oxidized LDL degradation by isolated mouse macrophages. CONCLUSIONS: By using a pure allicin preparation, we were able to show that allicin may affect atherosclerosis not only by acting as an antioxidant, but also by other mechanisms, such as lipoprotein modification and inhibition of LDL uptake and degradation by macrophages.     

Nutrient Intake following Vertical Banded Gastroplasty or Gastric Bypass

Background: This study explored eating habits, nutrient intake, and blood vitamin and mineral levels to determine whether severely obese subjects (BMI 40-50 kg m⁻²) post-vertical banded gastroplasty (VBG) or gastric bypass Roux-en-Y (GBR) are at risk of developing compounded under-nutrition. Methods: A dietary follow-up of 36 VBG and 19 GBR was maintained for 18 months via 7-day food intake diaries and 24-h recalls. Food intake was analysed for energy and nutrient composition and for its relative amount to recommended dietary allowances (RDA). Results: Weight loss was greatest during the first 6 months, continued at a slower rate for the next 6 months, nearly ceasing thereafter. The results following GBR were not substantially different from those following VBG 18 months postoperatively. The median weight loss at 1 year postoperatively was 48, 46, 48 and 36 kg; expressed as residual excess body weight: 0.2, 16, 13 and 22% for GBR Men, Women, VBG Men, Women, respectively. According to the classification proposed by Reinhold, all subjects achieved excellent treatment outcomes 18 months postoperatively. Despite the relatively low reported energy intake (20-50% below RDA), no correlation was found between rate of weight loss and energy intake at 6 months postoperatively. The intake of most vitamins and minerals was below 50% of RDA during the 18 months follow-up. The increase in energy intake did not improve the level of the nonenergy-contributing nutrients. Compliance to multivitamin and mineral supplement intake deteriorated with time. Conclusion: The low to within-normal range of blood vitamin and mineral levels 12 months postoperatively suggests the slow development of subclinical nutritional deficiency which could jeopardize the subjects' long-term health status.     

A miniature and mobile intermittent pneumatic compression device for the prevention of deep-vein thrombosis after joint replacement

The WizAir-DVT is a miniature, lightweight (690 g), battery-operated and mobile intermittent pneumatic compression device (ICD), which enables continuous intraoperative use and immediate patient mobilization postoperatively. We compared its efficacy with a commonly used ICD, the Kendall SCD. Peak femoral vein flow velocity was measured in 20 apparently healthy volunteers at rest and with each device: we found no significant differences between them. A second prospective, randomized, clinical trial was used to compare the efficiency of the device in preventing deep venous thrombosis (DVT) after joint replacement in 50 patients (n=25/group). None developed DVT. Doppler ultrasonography revealed no significant differences. The WizAir-DVT antithrombotic compression device is as safe and effective as the Kendall SCD.     

The elephant in the room: talking race in medical education

The deaths of black men and women while in police custody, rising anti-immigrant sentiment and rhetoric in high-income countries, and the continued health disparities experienced by Indigenous communities globally have brought race and racism to the forefront of public discourse in recent years. In a context where academic health science centres are increasingly called to be “socially accountable,” ignoring the larger social context of race and racism is something that medical education institutions can little afford to do. However, many such institutions have largely remained silent on the issue of race and racism, both within and outside of healthcare. Most medical education continues to emphasize a primarily biological understanding of race. We argue that a different approach is needed. Highlighting the social construction of race is an essential starting point for educators and trainees to tackle racialized health disparities in our clinics and to challenge racism in our classrooms, educational and research institutions, and communities.     

Icosapent Ethyl for Primary Versus Secondary Prevention of Major Adverse Cardiovascular Events in Hypertriglyceridemia: Value for Money Analysis

BackgroundIcosapent ethyl (IPE) is approved for the prevention of major adverse cardiovascular events (MACE) in patients with hypertriglyceridemia. However, due to budget constraints, access to IPE will inevitably be limited to a fraction of eligible patients. To help maximize value for money spent, we estimated the number of preventable MACE when providing IPE for primary versus secondary prevention.MethodsThe number of preventable MACE was estimated by dividing the available budget by the cost needed to treat (CNT) to prevent one MACE. CNT was calculated as the product of the number needed to treat (NNT) to prevent 1 MACE by therapy cost. NNT values were determined according to the Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial (REDUCE-IT) results. The budget limit was set as the United States’ threshold suggested by the Institute for Clinical and Economic Review. Sensitivity analysis was performed regarding the cost of IPE in the United States.ResultsThe NNT to prevent 1 MACE over 4.9 years in the Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial primary prevention cohort was 59 (95% confidence interval [CI]: 24-∞) versus 14 (11-21) for secondary prevention. At an annual IPE cost of $2915, the CNT to prevent 1 MACE was $842,726 (95% CI: $342,804-∞) and $199,969 ($157,118-$299,953) accordingly. A total of $819 million worth of IPE can avoid 4762 MACE (95% CI: 0-11,707) versus 20,069 (13,379-25,541), when provided as primary versus secondary prevention therapy; P < .001. The number of avoided MACE is sensitive to IPE price.ConclusionsPrioritizing IPE therapy for patients with an established cardiovascular disease may provide significantly more value for money than primary prevention.