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Dutta S.,Syracuse University | Mark-Kappeler C.J.,University of Arizona | Mark-Kappeler C.J.,WIL Research | Hoyer P.B.,University of Arizona | Pepling M.E.,Syracuse University
Biology of Reproduction | Year: 2014

Primordial follicle assembly is essential for reproduction in mammalian females. Oocytes develop in germ cell cysts that in late fetal development begin break down into individual oocytes and become surrounded by pregranulosa cells, forming primordial follicles. As they separate, many oocytes are lost by apoptosis. Exposure to steroid hormones delays cyst breakdown, follicle formation, and associated oocyte loss in some species. One model for regulation of follicle formation is that steroid hormones in the maternal circulation keep cells in cysts and prevent oocyte death during fetal development but that late in pregnancy hormone levels drop, triggering cyst breakdown and associated oocyte loss. However, herein we found that, while maternal circulating levels of progesterone drop during late fetal development, maternal estradiol levels remain high. We hypothesized that fetal ovaries were the source of hormones and that late in fetal development their production stops. To test this, mRNA and protein levels of steroidogenic enzymes required for estradiol and progesterone synthesis were measured. We found that aromatase and 3-beta-hydroxysteroid dehydrogenase mRNA levels drop before cyst breakdown. The 3-beta-hydroxysteroid dehydrogenase protein levels also dropped, but we did not detect a change in aromatase protein levels. The steroid content of perinatal ovaries was assayed, and both estradiol and progesterone were detected in fetal ovaries before cyst breakdown. To determine the role of steroid hormones in oocyte development, we examined the effects of blocking steroid hormone production in organ culture and found that the number of oocytes was reduced, supporting our model that steroid hormones are important for fetal oocyte survival. © 2014 by the Society for the Study of Reproduction, Inc. Source


Tomlinson M.J.,Nova Pathology | Leininger J.R.,WIL Research
Toxicologic Pathology | Year: 2014

The transparency and documentation of the peer review process have been discussed recently. Our position is that transparency is best achieved when peer review is a collaborative process, in which both parties are open-minded but both also realize that the study pathologist retains complete control over the findings (raw data) and over the content of the pathology report. For these reasons, we believe that histopathology raw data should be defined as the observations made by the study pathologist (printed and/or electronic formats) rather than as the tissue slides recommended by the Organisation for Economic Co-operation and Development (OECD). Also, because the study pathologist retains control over the histopathology raw data, any notes or tabulations of findings by the study pathologist and peer review pathologist during the peer review are interim notes and should not be included as an appendix to the pathology report though they may be retained if desired, as currently recommended. Because the histopathology raw data have not been created until completion of the peer review, the performance of a peer review should be documented in the study report, as currently recommended, but that it not be a GLP-compliant process. © 2013 by The Author(s). Source


Martin K.J.,Saint Louis University | Pickthorn K.,Amgen | Huang S.,Amgen | Block G.A.,Denver CO | And 5 more authors.
Kidney International | Year: 2014

AMG 416 (velcalcetide), a novel peptide agonist of the calcium-sensing receptor, lowers plasma parathyroid hormone in preclinical uremic animal models and in normal healthy individuals. Here, we studied its efficacy in hemodialysis patients suffering from secondary hyperparathyroidism. Major inclusion criteria were hemodialysis for at least 3 months, serum parathyroid hormone over 300 pg/ml, a corrected serum calcium of 9.0 mg/dl or more, and stable doses of vitamin D analogs for at least 3 weeks prior to screening. Twenty-eight patients were enrolled in one of five cohorts (5, 10, 20, 40, 60 mg). Cohorts 1-3 (four patients each) were treated in a two-period crossover design, while cohorts 4 and 5 (eight patients each) were randomized 1:1 to AMG 416 or placebo. Patients were admitted to a clinical research unit following hemodialysis and studied for 3 days prior to discharge for hemodialysis. Single intravenous doses of AMG 416 from 5 to 60 mg were well tolerated, and plasma levels increased in a dose-related manner. AMG 416 treatment was associated with significant, dose-dependent reductions in serum parathyroid hormone and fibroblast growth factor 23. Compared with placebo, all dose groups of 10 mg or more were associated with attenuation in the rise in serum phosphate during the interdialytic period. Dose-dependent reductions in serum calcium were observed and were well tolerated. Thus, AMG 416 represents a novel therapeutic approach for the treatment of secondary hyperparathyroidism in hemodialysis patients © 2013 International Society of Nephrology. Source


Flanagan S.,Cubist Pharmaceuticals Inc. | McKee E.E.,Central Michigan University | Das D.,Catholic University of Louvain | Das D.,Novartis | And 6 more authors.
Antimicrobial Agents and Chemotherapy | Year: 2015

Prolonged treatment with the oxazolidinone linezolid is associated with myelosuppression, lactic acidosis, and neuropathies, toxicities likely caused by impairment of mitochondrial protein synthesis (MPS). To evaluate the potential of the novel oxazolidinone tedizolid to cause similar side effects, nonclinical and pharmacokinetic assessments were conducted. In isolated rat heart mitochondria, tedizolid inhibited MPS more potently than did linezolid (average [± standard error of the mean] 50% inhibitory concentration [IC50] for MPS of 0.31 ± 0.02 μMversus 6.4 ± 1.2 μM). However, a rigorous 9-month rat study comparing placebo and high-dose tedizolid (resulting in steady-state area under the plasma concentration-time curve values about 8-fold greater than those with the standard therapeutic dose in humans) showed no evidence of neuropathy. Additional studies explored why prolonged, high-dose tedizolid did not cause these mitochondriopathic side effects despite potent MPS inhibition by tedizolid. Murine macrophage (J774) cell fractionation studies found no evidence of a stable association of tedizolid with eukaryotic mitochondria. Monte Carlo simulations based on population pharmacokinetic models showed that over the course of a dosing interval using standard therapeutic doses, free plasma concentrations fell below the respective MPS IC50 in 84% of tedi-zolid-treated patients (for a median duration of 7.94 h) and 38% of linezolid-treated patients (for a median duration of 0 h). Therapeutic doses of tedizolid, but not linezolid, may therefore allow for mitochondrial recovery during antibacterial therapy. The overall results suggest that tedizolid has less potential to cause myelosuppression and neuropathy than that of linezolid during prolonged treatment courses. This, however, remains a hypothesis that must be confirmed in clinical studies. © 2015, American Society for Microbiology. All Rights Reserved. Source


Picut C.A.,WIL Research | Dixon D.,National Health Research Institute | Simons M.L.,WIL Research | Stump D.G.,WIL Research | And 2 more authors.
Toxicologic Pathology | Year: 2015

Histopathologic examination of the immature ovary is a required end point on juvenile toxicity studies and female pubertal and thyroid function assays. To aid in this evaluation and interpretation of the immature ovary, the characteristic histologic features of rat ovary through the developmental periods are described. These histologic features are correlated with published changes in neuroendocrine profiles as the hypothalamic-pituitary-gonadal axis matures. During the neonatal stage (postnatal day [PND] 0-7), ovarian follicle development is independent of pituitary gonadotropins (luteinizing hormone [LH] or follicle-stimulating hormone [FSH]), and follicles remain preantral. Antral development of "atypical" follicles occurs in the early infantile period (PND 8-14) when the ovary becomes responsive to pituitary gonadotropins. In the late infantile period (PND 15-20), the zona pellucida appears, the hilus forms, and antral follicles mature by losing their "atypical" appearance. The juvenile stage (PND 21-32) is the stage when atresia of medullary follicles occurs corresponding to a nadir in FSH levels. In the peripubertal period (PND 33-37), atresia subsides as FSH levels rebound, and LH begins its bimodal surge pattern leading to ovulation. This report will provide pathologists with baseline morphologic and endocrinologic information to aid in identification and interpretation of xenobiotic effects in the ovary of the prepubertal rat. Copyright © 2014 by The Author(s). Source

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