No abstract

Atrial fibrillation after cardiac surgery occurs in approximately one third of patients and is associated with an increase in adverse events in all measurable outcomes of care and increases the use of hospital resources and, therefore, the cost of care. Strategies to reduce the incidence of AF after cardiac surgery should favorably affect surgical outcomes and reduce utilization of resources and thus lower cost of care.

BackgroundA large number of distinct mutations in the BRCA1 and BRCA2 genes have been reported worldwide, but little is known regarding the role of these inherited susceptibility genes in breast cancer risk among Indian women. We investigated the distribution and the nature of BRCA1 and BRCA2 germline mutations and polymorphisms in a cohort of 204 Indian breast cancer patients and 140 age-matched controls.MethodCases were selected with regard to early onset disease (≤40 years) and family history of breast and ovarian cancer. Two hundred four breast cancer cases along with 140 age-matched controls were analyzed for mutations. All coding regions and exon-intron boundaries of the BRCA1 and BRCA2 genes were screened by heteroduplex analysis followed by direct sequencing of detected variants.ResultsIn total, 18 genetic alterations were identified. Three deleterious frame-shift mutations (185delAG in exon 2; 4184del4 and 3596del4 in exon 11) were identified in BRCA1, along with one missense mutation (K1667R), one 5'UTR alteration (22C>G), three intronic variants (IVS10-12delG, IVS13+2T>C, IVS7+38T>C) and one silent substitution (5154C>T). Similarly three pathogenic protein-truncating mutations (6376insAA in exon 11, 8576insC in exon19, and 9999delA in exon 27) along with one missense mutation (A2951T), four intronic alterations (IVS2+90T>A, IVS7+75A>T, IVS8+56C>T, IVS25+58insG) and one silent substitution (1593A>G) were identified in BRCA2. Four previously reported polymorphisms (K1183R, S1613G, and M1652I in BRCA1, and 7470A>G in BRCA2) were detected in both controls and breast cancer patients. Rare BRCA1/2 sequence alterations were observed in 15 out of 105 (14.2%) early-onset cases without family history and 11.7% (4/34) breast cancer cases with family history. Of these, six were pathogenic protein truncating mutations. In addition, several variants of uncertain clinical significance were identified. Among these are two missense variants, one alteration of a consensus splice donor sequence, and a variant that potentially disrupts translational initiation.ConclusionBRCA1 and BRCA2 mutations appear to account for a lower proportion of breast cancer patients at increased risk of harboring such mutations in Northern India (6/204, 2.9%) than has been reported in other populations. However, given the limited extent of reported family history among these patients, the observed mutation frequency is not dissimilar from that reported in other cohorts of early onset breast cancer patients. Several of the identified mutations are unique and novel to Indian patients.

H2O2 induces apoptosis in variety of cells; however, the sensitivities of testicular germ cells to H2O2 are not known. In the present study, H2O2, at concentrations in the range 1–10 μm, was found to induce apoptosis in testicular germ cells in vitro. Following 1 h of treatment with 10 μm H2O2, a 10‐fold rise in the percentage of apoptotic cells was observed. Induction of germ cell apoptosis was directly associated with a significant (P < 0.01) increase in lipid peroxidation and a concomitant decrease in superoxide dismutase and catalase activity. Examination of apoptotic signalling pathways revealed an increased expression of extrinsic (Fas, FasL and caspase‐8) and intrinsic (Bid, Bak, Bad, Bax and caspase‐9) markers, as well as p53, along with a simultaneous decrease in the Bcl‐2 protein at the highest concentration of H2O2 exposure. Both, c‐jun N‐terminal kinase and p38 phosphorylated forms were found to be up‐regulated. Interestingly, up‐regulation of the nuclear transcription factor kappa B was also observed. The respective transcripts for many of the above proteins followed an identical trend. Caspase‐3 activity was also estimated to be 30‐fold higher. Taken together, the above data indicate that testicular germ cells are prone to apoptosis at very low concentrations of H2O2, the mechanism of which involves extrinsic and intrinsic as well other regulatory pathways.

Levosimendan is a new myofilament calcium (Ca2+) sensitizer that increases myocardial contractility by stabilizing the Ca2+-bound conformation of troponin C. We tested the hypothesis that levosimendan enhances cardiac performance after cardiopulmonary bypass (CPB). Anesthesia was induced and maintained with midazolam, sufentanil, and vecuronium in 18 patients randomly assigned to receive levosimendan (18 or 36 microg/kg loading dose and 0.2 or 0.3 microg/kg/min infusion, respectively) or placebo 15 min before and continued for 6 h after CPB. Significant (p < 0.05) increases in heart rate (HR) and decreases in systemic vascular resistance (SVR) occurred 15 min after CPB in patients receiving placebo. Later increases in mean arterial pressure (MAP) and cardiac output (CO) and decreases in stroke volume (SV) and pulmonary vascular resistance also were observed. HR was greater in patients receiving high- but not low-dose levosimendan versus placebo immediately after CPB. MAP also was lower in patients treated with either dose of levosimendan compared with placebo after CPB. Levosimendan increased CO and decreased SVR (4.2 +/- 0.4 to 7.9 +/- 0.4 L/min and 1,150 +/- 99 to 512 +/- 42 dyn/s/cm5, respectively, 15 min after CPB; mean +/- SEM). CO and SV were higher and SVR was lower in patients receiving levosimendan versus placebo after CPB. No differences in arterial oxygenation and perioperative arrhythmias (Holter analysis) were observed between groups. The results indicate that levosimendan enhances cardiac performance after CPB in humans.