Clinical outcomes using a flexible regimen of GnRH-antagonists and a 'step-up' of additional gonadotropins in donor oocyte cycles.

OBJECTIVE: To assess the impact of serum estradiol upon oocyte donor cycle stimulation characteristics and clinical outcomes using flexible GnRH-antagonist (GnRH-ant) with additional FSH supplementation. RESEARCH DESIGN AND METHODS: A retrospective chart review of 99 oocyte donor cycles using ovarian hyperstimulation with recombinant FSH (rFSH) and GnRH-ant was analyzed. Following discontinuation of oral contraceptives, controlled ovarian hyperstimulation was begun using rFSH (150-300 IU daily). GnRH-ant (ganirelix, Organon) and an additional 75 IU of FSH/day were begun when lead follicles were 13-14 mm in greatest diameter. Cycles were analyzed based on serum estradiol response following administration of GnRH-ant (Group 1: progressive rise and Group 2: no rise or a decline). Primary endpoints were cycle stimulation characteristics based on serum estradiol following GnRH-ant, clinical pregnancy and implantation rates. RESULTS: A decline in serum estradiol was seen after GnRH-ant administration in 45% of cycles. Clinical pregnancy rates per transfer (70 vs. 72%) and implantation rates (43 vs. 56%) were similar for each group. CONCLUSION: Flexible regimens of GnRH-ant even with additional rFSH in a 'step-up' fashion frequently result in a decline in serum estradiol during ovulation induction. While our study is non-randomized, it does not appear to result in any adverse affect in clinical outcomes in donor oocyte cycles.

A retrospective comparison of clinical outcomes and satisfaction using reconstituted recombinant gonadotropins (rFSH) or cartridge rFSH with a pen device in donor oocyte cycles.

BACKGROUND: Use of recombinant follicle stimulating hormone (rFSH) in a cartridge pen device offers obvious benefits for donor oocyte cycles including the administration of fewer and more patient-friendly injectable medications. METHODS: In a University-based IVF program, a total of 98 oocyte donor cycles using rFSH either reconstituted or as a pen device given to 118 recipients (eight split cycles) were retrospectively reviewed. Following discontinuation of oral contraceptive, controlled ovarian hyperstimulation was begun using either reconstituted rFSH (n = 19) or rFSH with a cartridge pen device (n = 79) (150-300 IU qd). GnRH-antagonists (Ganirelix, Organon) and an additional 75 IU of rFSH/day were begun when lead follicles were 13-14 mm in greatest diameter. The primary endpoints analyzed included cycle stimulation characteristics for each donor group and donor medication tolerance assessment with respect to each rFSH formulation, while secondary outcome measures included clinical pregnancy and implantation rates. RESULTS: Oocyte donors using the pen required significantly less rFSH (2734 IU vs. 3276 IU, p < 0.05) and scored significantly higher medication tolerance scores (3.9 +/- 0.4 vs. 3.1 +/- 0.6, p < 0.05). No other differences in cycle stimulation for oocyte donors and clinical outcomes for recipients were seen including pregnancy rates (pen, 77% vs. reconstituted, 55%, p - NS) and clinical pregnancy rates (61% vs. 45%, p - NS). However, significantly greater implantation rates (57% vs. 31%, p < 0.01) occurred in the pen group. CONCLUSION: Compared to reconstituted formulations, the pen device results in lower gonadotropin requirements and provides a simplified dosing method with better tolerance.

Observation of muon neutrino disappearance with the MINOS detectors in the NuMI neutrino beam.

This Letter reports results from the MINOS experiment based on its initial exposure to neutrinos from the Fermilab NuMI beam. The rates and energy spectra of charged current nu(mu) interactions are compared in two detectors located along the beam axis at distances of 1 and 735 km. With 1.27 x 10(20) 120 GeV protons incident on the NuMI target, 215 events with energies below 30 GeV are observed at the Far Detector, compared to an expectation of 336+/-14 events. The data are consistent with nu(mu) disappearance via oscillations with |Delta(m)2/32|=2.74 +0.44/-0.26 x10(-3)eV(2) and sin(2)(2theta(23))>0.87 (68% C.L.).

Promoter hypermethylation frequency and BRAF mutations distinguish hereditary non-polyposis colon cancer from sporadic MSI-H colon cancer.

BACKGROUND: Colorectal cancers resulting from defective DNA mismatch repair can occur in both hereditary non-polyposis colon cancer (HNPCC) and in the sporadic setting. They are characterised by a high level of microsatellite instability (MSI-H) and superficially resemble each other in that they are frequently located in the proximal colon and share features such as circumscribed tumour margins and tumour-infiltrating lymphocytes. However, significant differences can be demonstrated at the molecular level including widespread promoter hypermethylation and BRAF -activating mutations which occur significantly less often in HNPCC. AIMS: In this study, we sought to determine whether the presence of widespread promoter hypermethylation and BRAF mutations would exclude HNPCC. MATERIALS AND METHODS: We investigated the methylation status of four methylated in tumour markers (MINTs 1,2,12 and 31), and the promoter regions of 5 genes hMLH1, HPP1, MGMT, p16INK4A and p14ARF, in 21 sporadic MSI-H colorectal cancers and compared these with 18 cancers from HNPCC patients. The methylation status of CpG islands were determined by either methylation specific PCR (MSP) or combined bisulfite restricton analysis (COBRA). In addition we considered the BRAF mutation status of 18 HNPCC tumours and 19 sporadic MSI-H cancers which had been previously determined by RFLP analysis and confirmatory sequencing. RESULTS: Methylation of the promoter regions in target genes occurred less frequently within the HNPCC tumours (27% of analyses), compared with the sporadic MSI-H tumours (59% of analyses) (P < 0.001). Methylation of MINTs 1, 2, 12 and 31 occurred in 4% of analyses for HNPCC tumours contrasted with 73% for sporadic MSI-H tumours (P < 0.001). BRAF mutations were detected in 74% of sporadic tumours but none of the HNPCC cancers tested. CONCLUSIONS: The total number of genes and MINTs methylated in HNPCC was lower than in MSI-H colorectal tumours. No HNPCC tumour showed evidence of widespread promoter hypermethylation or BRAF mutation suggesting this feature could be used as a discriminator between familial and sporadic cases.

BRAF mutation is associated with DNA methylation in serrated polyps and cancers of the colorectum.

BACKGROUND AND AIMS: Mutations in BRAF have been linked with colorectal cancers (CRC) showing high level microsatellite instability (MSI-H). However, the distribution of BRAF mutations in MSI-H cancers remains to be clarified with respect to precursor lesions and the CpG island methylator phenotype (CIMP). METHODS: Forty three hyperplastic polyps (HP), nine mixed polyps (MP), five serrated adenomas (SA), 28 conventional adenomas (AD), 18 hereditary non-polyposis colorectal cancers (HNPCC), and 127 sporadic CRC (46 MSI-H and 81 non-MSI-H) were collected from patients undergoing colectomy for either CRC or hyperplastic polyposis. Twenty five of 57 serrated lesions were derived from four patients with hyperplastic polyposis. HP were further subdivided according to recently documented morphological criteria into 27 classical HP and 16 variant lesions described as "sessile serrated adenoma" (SSA). All tumours were screened for BRAF activating mutations. RESULTS: The BRAF mutation was more frequent in SSA (75%) and MP (89%) than in classical HP (19%), SA (20%), and AD (0%) (p<0.0001), and also in sporadic MSI-H cancers (76%) compared with HNPCC (0%) and sporadic non-MSI-H cancers (9%) (p<0.0001). The BRAF mutation was identified more often in CIMP-high serrated polyps (72%) and CIMP-high CRC (77%) than in CIMP-low (30%) and CIMP-negative (13%) polyps (p = 0.002) as well as CIMP-low (18%) and CIMP-negative (0%) CRC (p<0.0001). CONCLUSIONS: The BRAF mutation was frequently seen in SSA and in sporadic MSI-H CRC, both of which were associated with DNA methylation. Sporadic MSI-H cancers may originate in SSA and not adenomas, and BRAF mutation and DNA methylation are early events in this "serrated" pathway.

Ultrastructural alterations in the fibrous sheath, endocardium, and myocardium of dogs shocked with chronically implanted automatic defibrillator leads.

Catheter-mounted automatic implantable defibrillator leads were implanted in 10 dogs for 11 to 21 months (mean 15.0 months). Single shocks of 10 A, 20 A, or 30 A (peak current) were then delivered through the chronically implanted leads. Two days after the shock, the dogs were euthanatized and necropsied. The intracardiac segment of the lead was covered by a fibrous sheath, the endocardium in contact with the lead was thickened by fibrous tissue, and shock-induced myocardial necrosis was present surrounding the distal pair of electrodes, with the largest amount of damage found in the dogs given the large shocks. Ultrastructurally, the fibrous sheath was covered by endothelium and contained numerous spindle cells and identified as smooth muscle cells by their prominent cytoplasmic filaments and external laminae or myofibroblasts with prominent endoplasmic reticulum. The spindle cells were surrounded by abundant collagen fibrils but not by elastic fibers. The thickened endocardium contained numerous fibroblasts, abundant collagen fibrils, and a few small elastic fibers. The shock-induced myocardial alterations included necrosis of cardiac muscle cells with prominent mitochondrial mineralization, interstitial edema, and infiltration of macrophages.

Free-field tests of hearing-impaired listeners: early results.

Results are reported from a series of free-field tests of five hearing-impaired listeners. The tests provide relatively crude estimates of listeners' abilities in three types of experiments: free-field masked detection, source angle discrimination (both horizontal and vertical), and identification of source direction. Relations between abilities in the various tasks are noted.

The effect of newer antiarrhythmic drugs on defibrillation threshold.

This study was conducted to determine the effects of clofilium phosphate and bretylium tosylate on ventricular defibrillation threshold. Dogs were anesthetized with pentobarbital and subjected to repeated fibrillation-defibrillation episodes. Defibrillation thresholds were determined at 15-min intervals, using underdamped 5--6 msec sinusoidal current shocks, from 30 min before drug injection to 120 min after injection. Eight dogs were given clofilium phosphate (0.34 mg/kg, iv). Another 10 dogs were given bretylium tosylate (10.0 mg/kg, iv). Both drugs lowered defibrillation threshold from 15--90 min after injection. The maximum clofilium effect was a 31% decrease in threshold current and a 54% decrease in threshold energy. The greatest decrease in defibrillation threshold produced by bretylium was 16% for current and 31% for energy. These drug induced changes in defibrillation threshold are of potential clinical benefit if they occur in human subjects at doses which are effective for control of ventricular arrhythmias.