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.

     

Platelet Reactivity and Risk of Ischemic Stroke After Coronary Drug-Eluting Stent Implantation: From the ADAPT-DES Study

Objectives

The authors sought to investigate the association between P2Y₁₂ reaction units (PRU) and the risk of ischemic stroke (IS) after successful coronary drug-eluting stents (DES) implantation.

The Effect of Diet on Simvastatin and Losartan Enhancement of Endothelial Function

Patients with hypertension take antihypertensive agents and cholesterol-lowering drugs; however, few studies describe the effects of the interaction of antihypertensive agents with statins. Therefore, the purpose of this study was to characterize the effects of losartan, simvastatin, and their combination on the progression of hypertension in the spontaneously hypertensive rats (SHRs). Also, we determined whether diet influenced the drug responses. Rats were fed three different diets—low-salt (LS), high-salt (HS), and lipid-rich (LR)—and treated with either no drug (control), losartan (LOS, 10 mg/kg/day), simvastatin (SIM, 2 mg/kg/day) or LOS combined with SIM for four weeks. After four weeks on the diets, systolic blood pressure rose in all groups and remained elevated. Treatment with LOS alone or in combination with SIM reduced BP in the rats fed the LS and HS diet, respectively. Furthermore, LOS alone increased NO in the LS and LR groups; however, LOS combined with SIM completely abolished this rise in NO in LS group. Plasma PGI₂ and TXA₂ levels were increased in the presence of SIM alone; however LOS combined with SIM completely blocked SIM-induced increases in PGI₂ and TXA₂. Kidney levels of angiotensin II were higher in the LS group and significantly increased in the HS group following treatment with LOS alone. However, kidney aldosterone levels were significantly reduced in the presence of LOS in the HS group. Total cholesterol, LDL cholesterol, and triglycerides were significantly higher in the LR group. Together, these data suggest a contribution of endogenous NO and PGs in the antihypertensive effect of LOS and SIM that may be affected by the type of diet.     

Telmisartan effects on insulin resistance in obese or overweight adults without diabetes or hypertension

Angiotensin receptor blockers (ARBs) are antihypertensive agents associated with reduced risk of new-onset diabetes mellitus. The ARB telmisartan is a partial agonist of peroxisome proliferator-activated receptor-gamma (PPAR-γ). This study evaluated the effect of telmisartan on insulin resistance, a known target of PPAR-γ agonism. Overweight/obese persons with body mass index ≥28 kg/m2, waist circumference≥35 inches, and components of the metabolic syndrome without hypertension or diabetes who were not preselected for insulin resistance were enrolled. Patients were randomized to telmisartan or matching placebo for 16 weeks. The primary efficacy measure was changed from baseline in the insulin sensitivity index (SI), calculated from oral glucose tolerance testing. SI was also evaluated in a subset of patients using a hyperinsulinemic euglycemic clamp. Secondary end points included measures of insulin sensitivity and glucose and lipid metabolism. A total of 138 patients were randomized and received ≥1 dose of study medication; 128 completed the study. At end point, no significant difference was found between telmisartan and placebo groups regarding change from baseline in SI or in glucose area under the curve. No significant between-group differences were found regarding glucose metabolism or lipoprotein levels. In the population with abdominal obesity and components of the metabolic syndrome, telmisartan did not increase insulin sensitivity.     

Refractoriness and Conduction Interaction During Modulation of Non-Ischemic Ventricular Fibrillation by Flecainide

Purpose: To study refractoriness and conduction interaction during modulation of non-ischemic ventricular fibrillation (VF) by flecainide. Methods: Isolated feline and rabbit hearts were used. (a) In the feline hearts (n = 8), electrophysiological parameters were measured before and after flecainide administration (0.6, 1.2 × 10^–6 M). During pacing the parameters were: epicardial conduction time, refractoriness and 1:1 pacing/response capture. During 8 min of electrically-induced tachyarrhythmias they included heart rate and normalized entropy reflecting the degree of organization. (b) In rabbit hearts (n = 4), three-dimensional mapping was performed before and after flecainide administration (2 × 10^–6 M). To follow changes in organization, local RR-intervals and differences in activation time between adjacent epicardial electrodes were measured immediately and 80 sec after VF induction. Results: In feline hearts with flecainide, fibrillation was more difficult to induce, more frequently terminated spontaneously and was slower and more organized; conduction time was markedly lengthened, and refractoriness less than 1:1 capture, was moderately prolonged. An inverse correlation was observed between arrhythmia properties, rate and organization, and changes in refractoriness and conduction time. In rabbit, the number of wave fronts was reduced, RR-intervals were prolonged but at the same time activation time differences between adjacent electrodes were smaller following flecainide administration. Conclusions: It is suggested that flecainide modulation of VF properties is associated with conduction suppression and refractoriness prolongation, which act in a synergistic, additive way.     

Association of RBC transfusion with mortality in patients with acute lung injury

BACKGROUND: RBC transfusion has been associated with increased morbidity and mortality in a variety of clinical settings. We assessed the effect of RBC transfusion on in-hospital mortality in patients with acute lung injury (ALI). METHODS: Cohort study of 248 consecutive patients with ALI. RBC transfusion was evaluated as both dichotomous and continuous variables, with outcome being in-hospital mortality adjusted for clinical confounders and length of total hospital stay. RESULTS: Overall in-hospital mortality rate was 39.5%. Of these patients, 207 of 248 patients (83.5%) received > or = 1 U of packed RBCs. The transfusion of any packed RBCs was associated with an increased risk of death (adjusted odds ratio [OR], 3.12; 95% confidence interval [CI], 1.28 to 7.58; p < 0.001). The overall OR per unit was 1.06 (95% CI, 1.04 to 1.09; p < 0.001) in the complete multivariable model. Transfusion after ALI onset was associated with an adjusted OR of 1.13 (95% CI, 1.07 to 1.20; p < 0.001), while transfusion before ALI onset was not associated with higher risk. The adjusted OR per unit of nonleukoreduced RBC transfused was 1.14 (95% CI, 1.07 to 1.21; p < 0.001), while the adjusted OR for leukoreduced cells per unit transfused was 1.06 (95% CI, 1.03 to 1.09; p < 0.001). CONCLUSIONS: Transfusion of RBCs in patients with ALI was associated with increased in-hospital mortality. This risk occurred with RBC transfusion after the onset of ALI, and was greater for nonleukoreduced than for leukoreduced RBCs. Aggressive transfusion strategies in patients with established ALI should be questioned, pending further study.     

Effects of the angiotensin II receptor blockers telmisartan vs valsartan in combination with hydrochlorothiazide 25 mg once daily for the treatment of hypertension

To attain recent goals of blood pressure (BP) control, multiple drug therapy combinations are required, including higher doses of thiazide diuretics in combination with other classes of antihypertensive drug therapy. Thus, the authors evaluated the antihypertensive effects of telmisartan vs valsartan when combined with hydrochlorothiazide (HCTZ) 25 mg in a large (N=1066), placebo-controlled trial in patients with stage 1 or 2 hypertension. The primary end points were the changes from baseline in seated diastolic and systolic BP at the end of the 8-week treatment period. Safety end points included adverse events, changes in laboratory parameters, and pulse rate. Changes from baseline in BP following telmisartan-HCTZ (-24.0/-17.6 mm Hg) were significantly greater than both placebo (-4.4/-6.8 mm Hg) and valsartan-HCTZ (-21.2/-16.1 mm Hg) (vs placebo, P<.001 for systolic and diastolic BP; vs valsartan-HCTZ, P=.004 for systolic BP and P=.019 for diastolic BP). The total number of patients with at least 1 adverse event reported were similar among the 3 treatment groups (placebo, 49%; telmisartan-HCTZ, 43%; and valsartan-HCTZ, 38%). In conclusion, telmisartan-HCTZ at doses of 80/25 mg lowered both systolic and diastolic BP to a greater extent than valsartan-HCTZ at doses of 160/25 mg. These data support using a higher dose of a thiazide diuretic (25 mg) with a long-acting angiotensin receptor blocker as a useful strategy for improving hypertension control.