Publications by authors named "Justin D Vidal"

22 Publications

  • Page 1 of 1

Scientific and Regulatory Policy Committee Best Practices: Documentation of Sexual Maturity by Microscopic Evaluation in Nonclinical Safety Studies.

Toxicol Pathol 2021 Mar 4:192623321990631. Epub 2021 Mar 4.

510456Idorsia Pharmaceuticals Limited, Allschwil, Switzerland.

The sexual maturity status of animals in nonclinical safety studies can have a significant impact on the microscopic assessment of the reproductive system, the interpretation of potential test article-related findings, and ultimately the assessment of potential risk to humans. However, the assessment and documentation of sexual maturity for animals in nonclinical safety studies is not conducted in a consistent manner across the pharmaceutical and chemical industries. The Scientific and Regulatory Policy Committee of the Society of Toxicologic Pathology convened an international working group of pathologists and nonclinical safety scientists with expertise in the reproductive system, pathology nomenclature, and Standard for Exchange of Nonclinical Data requirements. This article describes the best practices for documentation of the light microscopic assessment of sexual maturity in males and females for both rodent and nonrodent nonclinical safety studies. In addition, a review of the microscopic features of the immature, peripubertal, and mature male and female reproductive system and general considerations for study types and reporting are provided to aid the study pathologist tasked with documentation of sexual maturity.
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http://dx.doi.org/10.1177/0192623321990631DOI Listing
March 2021

International Harmonization of Nomenclature and Diagnostic Criteria (INHAND): Nonproliferative and Proliferative Lesions of the Dog.

Toxicol Pathol 2021 Jan;49(1):5-109

Novartis Pharmaceutical Corporation, East Hanover, NJ, USA.

The INHAND (International Harmonization of Nomenclature and Diagnostic Criteria for Lesions) Project (www.toxpath.org/inhand.asp) is a joint initiative of the societies of toxicologic Pathology from Europe (ESTP), Great Britain (BSTP), Japan (JSTP), and North America (STP) to develop an internationally accepted nomenclature for proliferative and nonproliferative lesions in laboratory animals. The purpose of this publication is to provide a standardized nomenclature for classifying lesions observed in most tissues and organs from the dog used in nonclinical safety studies. Some of the lesions are illustrated by color photomicrographs. The standardized nomenclature presented in this document is also available electronically on the internet (http://www.goreni.org/). Sources of material included histopathology databases from government, academia, and industrial laboratories throughout the world. Content includes spontaneous lesions, lesions induced by exposure to test materials, and relevant infectious and parasitic lesions. A widely accepted and utilized international harmonization of nomenclature for lesions in laboratory animals will provide a common language among regulatory and scientific research organizations in different countries and increase and enrich international exchanges of information among toxicologists and pathologists.
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http://dx.doi.org/10.1177/0192623320968181DOI Listing
January 2021

The Application, Challenges, and Advancement Toward Regulatory Acceptance of Digital Toxicologic Pathology: Results of the 7th ESTP International Expert Workshop (September 20-21, 2019).

Toxicol Pathol 2020 Dec 10:192623320975841. Epub 2020 Dec 10.

Department of Histopathology, Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom.

With advancements in whole slide imaging technology and improved understanding of the features of pathologist workstations required for digital slide evaluation, many institutions are investigating broad digital pathology adoption. The benefits of digital pathology evaluation include remote access to study or diagnostic case materials and integration of analysis and reporting tools. Diagnosis based on whole slide images is established in human medical pathology, and the use of digital pathology in toxicologic pathology is increasing. However, there has not been broad adoption in toxicologic pathology, particularly in the context of regulatory studies, due to lack of precedence. To address this topic, as well as practical aspects, the European Society of Toxicologic Pathology coordinated an expert international workshop to assess current applications and challenges and outline a set of minimal requirements needed to gain future regulatory acceptance for the use of digital toxicologic pathology workflows in research and development, so that toxicologic pathologists can benefit from digital slide technology.
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http://dx.doi.org/10.1177/0192623320975841DOI Listing
December 2020

Pharmacokinetics and tolerability of a novel progesterone intravaginal ring in sheep.

Drug Deliv Transl Res 2019 10;9(5):1008-1016

Daré Bioscience, Inc., 3655 Nobel Drive, Suite 260, San Diego, CA, 92122, USA.

The objectives of this work were to evaluate the in vitro release and in vivo pharmacokinetics and local tolerability of a novel, segmented ethylene-vinyl acetate (EVA) intravaginal ring (IVR) delivering progesterone (P) in drug-naïve ovariectomized female Dorset crossbred sheep. Following preparation and assessment of in vitro release of P, animals were randomized into one of six treatment groups: group 1 Crinone® 8% gel (90 mg); group 2 Prometrium® 200-mg capsules; group 3 placebo IVR; group 4 progesterone (P) IVR 4 mg/day; group 5 P IVR 8 mg/day; or group 6 P IVR 12 mg/day. Crinone 8% gel and Prometrium capsules were administered once daily for 28 days. IVRs were inserted vaginally on day 1 and remained in place through day 14; a new ring was administered on day 15 and was removed at day 28. Animals underwent daily examinations to confirm ring placement, and vaginal irritation was scored from 0 (none) to 4 (severe). Blood samples were taken at scheduled times for pharmacokinetic analysis. Postmortem examinations performed on all IVR groups included vaginal irritation, macroscopic, and microscopic evaluations, including irritation scoring and histopathology. Intravaginal rings were retained over 28 days in all animals. Clinical observations showed no significant abnormal findings in any group. Pharmacokinetic analysis in animals showed sustained release of P over from days 0 through 14 of ring use. Irritation scores and microscopic assessments were consistent with the IVRs being well tolerated. These results will guide future human clinical studies to ultimately develop an IVR for use in women for the prevention of preterm birth.
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http://dx.doi.org/10.1007/s13346-019-00646-xDOI Listing
October 2019

Pharmacokinetics and Tolerability of a Novel 17β-Estradiol and Progesterone Intravaginal Ring in Sheep.

J Pharm Sci 2019 08 5;108(8):2677-2684. Epub 2019 Apr 5.

Daré Bioscience, Inc., San Diego, California 92122. Electronic address:

This study reports the preparation, in vitro release, pharmacokinetics, and local tolerability of novel ethylene-vinyl acetate intravaginal rings (IVRs) delivering 17β-estradiol (E) and progesterone (P), in drug-naïve ovariectomized female Dorset crossbred sheep. After preparation and assessment of in vitro release of E and P, animals were randomized to treatment groups 1 or 2 (comparator rings releasing 50 or 100 μg/d E, respectively), groups 3 or 4 (ethylene-vinyl acetate IVRs, 160 μg/d E with 4 [160/4 IVR] or 8 mg/d P [160/8 IVR], respectively), or group 5 (160 μg E and 10 mg P administered intravenously). IVRs were placed on day 1 and remained in place through day 29. Animals underwent daily examinations to confirm ring placement, and vaginal irritation was scored from 0 (none) to 4 (severe). Blood samples were taken at scheduled times for pharmacokinetic analysis. Postmortem examinations performed on groups 1-4 were macroscopic and microscopic evaluations, including irritation scoring and histopathology. IVRs were retained over 28 days in all but 1 animal (group 4). In all animal groups, clinical observations showed no significant abnormal findings. Pharmacokinetic analysis in the animals showed sustained release of E and P over a 28-day period. Irritation scores and microscopic assessments were consistent with foreign object placement. A novel 2-drug IVR delivery system was well tolerated in a sheep model and pharmacokinetic release was as expected over a 28-day release period. These results will guide future human clinical studies.
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http://dx.doi.org/10.1016/j.xphs.2019.03.032DOI Listing
August 2019

Evaluation of the Estrous Cycle, Reproductive Tract, and Mammary Gland in Female Mice.

Curr Protoc Mouse Biol 2017 Dec 20;7(4):306-325. Epub 2017 Dec 20.

MPI Research, Mattawan, Michigan.

Evaluation of the female reproductive system is an important part of basic reproductive biology research, toxicology testing, and mutant mouse phenotype assessment. The female reproductive system is dynamic and the onset of puberty and the normal changes observed during estrous cyclicity can create challenges for an investigator. Experimental work in the female mouse requires an understanding of the potential impact of the estrous cycle and tracking normal changes throughout the cycle allows for control of this key variable. The estrous cycle can be evaluated using vaginal cytology, which provides the researcher a daily assessment of the entire reproductive endocrine axis and allows for samples to be collected at precise times within the cycle. These protocols describe the basic approach to evaluating the onset of cyclicity, tracking the normal cycle, and collection and microscopic evaluation of the reproductive system and mammary gland in the mouse. © 2017 by John Wiley & Sons, Inc.
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http://dx.doi.org/10.1002/cpmo.35DOI Listing
December 2017

Species Comparison of Postnatal Development of the Female Reproductive System.

Birth Defects Res 2018 02 15;110(3):163-189. Epub 2017 Dec 15.

MPI Research, Mattawan, Michigan.

The postnatal development of the female reproductive system in laboratory animals and humans is reviewed. To enable a meaningful species comparison of the developing female reproductive system, common definitions of developmental processes were established with a focus made on aspects that are similar across species. A species comparison of the key endocrine, morphologic, and functional (onset of ovarian cycles and ability to reproduce) features of postnatal development of the female reproductive system is provided for human, nonhuman primate, dog, rat, and also mouse, minipig, and rabbit where possible. Species differences in the timing and control of female sexual maturation are highlighted. Additionally, a species comparison of the type and timing of female reproductive ovarian cycles was compiled. Human development provided the frame of reference, and then other common laboratory species were compared. The comparison has inherent challenges because the processes involved and sequence of events can differ greatly across species. Broad strokes were taken to assign a particular average age to an event and are to be used with caution. Methods of evaluation of postnatal female reproductive development in laboratory animals are discussed. Lastly, control rodent data from one of the author's laboratory on vaginal opening, first estrus, estrous cyclicity, and the histopathology involved with the developing female rat and mouse are presented. The information provided in this review is intended to be a resource for the design and interpretation of juvenile animal toxicity testing and ultimately, the relevance of the data to characterize potential risks for women and girls. Birth Defects Research 110:163-189, 2018. © 2017 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/bdr2.1132DOI Listing
February 2018

The Impact of Age on the Female Reproductive System.

Authors:
Justin D Vidal

Toxicol Pathol 2017 01 17;45(1):206-215. Epub 2016 Oct 17.

1 MPI Research, Mattawan, Michigan, USA.

Evaluation of the female reproductive system in a general toxicity setting can be challenging for the toxicologic pathologist due to the cyclic nature of the estrous and menstrual cycles, timing of puberty and reproductive senescence, and species differences. Age in particular can have a significant impact on the histologic appearance of the female reproductive system and create challenges when trying to distinguish test article-related findings from normal developmental or senescent changes. This review describes the key physiologic and histologic features of immaturity, the transition through puberty, sexual maturity, and reproductive senescence in the female reproductive system, with an emphasis on practical applications for the toxicologic pathologist, and includes recommendations for distinguishing and documenting these developmental periods. Rats and cynomolgus monkeys are used as examples throughout with correlations to clinically observed end points to better aid the toxicologic pathologist in understanding how age may impact study interpretation.
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http://dx.doi.org/10.1177/0192623316673754DOI Listing
January 2017

Regulatory Forum Opinion Piece: Review of FDA Draft Guidance Testicular Toxicity-Evaluation during Drug Development Guidance for Industry.

Toxicol Pathol 2016 10 29;44(7):927-30. Epub 2016 Jun 29.

MPI Research, Mattawan, Michigan, USA.

In July 2015, the U.S. Food and Drug Administration (FDA) posted a new draft guidance entitled "Testicular Toxicity: Evaluation during Drug Development Guidance for Industry," with a 90-day public comment period. As the nonclinical assessment of testicular toxicity often relies on the expert interpretation of pathology affecting the male reproductive tract, this draft guidance is considered directly relevant to the toxicologic pathology community. Therefore, a working group was formed through the Scientific and Regulatory Policy Committee of the Society of Toxicologic Pathologists (STPs) to provide a detailed review of the draft guidance. Specific comments on the guidance were submitted to the FDA by the STP. The draft guidance and all comments received are currently under review with the FDA. This commentary provides a summary of the components of the draft guidance and the comments submitted by the STP with acknowledgment of different perspectives reflected in comments from other respondents.
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http://dx.doi.org/10.1177/0192623316656416DOI Listing
October 2016

Recommendations from the INHAND Apoptosis/Necrosis Working Group.

Toxicol Pathol 2016 Feb 14;44(2):173-88. Epub 2016 Feb 14.

Envigo, East Millstone, New Jersey, USA.

Historically, there has been confusion relating to the diagnostic nomenclature for individual cell death. Toxicologic pathologists have generally used the terms "single cell necrosis" and "apoptosis" interchangeably. Increased research on the mechanisms of cell death in recent years has led to the understanding that apoptosis and necrosis involve different cellular pathways and that these differences can have important implications when considering overall mechanisms of toxicity, and, for these reasons, the separate terms of apoptosis and necrosis should be used whenever differentiation is possible. However, it is also recognized that differentiation of the precise pathway of cell death may not be important, necessary, or possible in routine toxicity studies and so a more general term to indicate cell death is warranted in these situations. Morphological distinction between these two forms of cell death can sometimes be straightforward but can also be challenging. This article provides a brief discussion of the cellular mechanisms and morphological features of apoptosis and necrosis as well as guidance on when the pathologist should use these terms. It provides recommended nomenclature along with diagnostic criteria (in hematoxylin and eosin [H&E]-stained sections) for the most common forms of cell death (apoptosis and necrosis). This document is intended to serve as current guidance for the nomenclature of cell death for the International Harmonization of Nomenclature and Diagnostic Criteria Organ Working Groups and the toxicologic pathology community at large. The specific recommendations are:Use necrosis and apoptosis as separate diagnostic terms.Use modifiers to denote the distribution of necrosis (e.g., necrosis, single cell; necrosis, focal; necrosis, diffuse; etc.).Use the combined term apoptosis/single cell necrosis whenThere is no requirement or need to split the processes, orWhen the nature of cell death cannot be determined with certainty, orWhen both processes are present together. The diagnosis should be based primarily on the morphological features in H&E-stained sections. When needed, additional, special techniques to identify and characterize apoptosis can also be used.
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http://dx.doi.org/10.1177/0192623315625859DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4785073PMC
February 2016

Early Vaginal Opening in Juvenile Female Rats Given BRAF-Inhibitor Dabrafenib Is Not Associated with Early Physiologic Sexual Maturation.

Birth Defects Res B Dev Reprod Toxicol 2015 Dec 1;104(6):244-52. Epub 2015 Dec 1.

Safety Assessment, GlaxoSmithKline, King of Prussia, Pennsylvania.

Dabrafenib (DAB), an inhibitor of BRAF kinase activity, is approved for metastatic melanoma with a BRAF V600E mutation. In support of pediatric cancer development, a nonclinical juvenile rat toxicity study was conducted in which females had early vaginal opening (VO). It was hypothesized that the early VO was not indicative of sexual maturation, but a result of a local effect on the vagina. An investigative study was conducted that mimicked the definitive study design, with rats given DAB or vehicle orally from Postnatal Day (PND) 7 to 35 and with necropsy subsets just before VO, at the first and second estrus, along with age-matched controls. Histopathology was performed on reproductive tissues, including immunohistochemistry for BRAF expression. VO occurred earlier in DAB females than in controls (PND 27.2 vs. 31.5); however, the timing of the first estrus was unaffected (PND 34.0 vs. 33.0). DAB-treated females evaluated just before VO (PND 22.0) had mostly immature reproductive tracts with no evidence of ovulation, similar to age-matched controls; however, DAB-treated females had keratinized and histologically open vaginas. Also, there was raised skin around the urogenital area, which correlated with hyperplasia/keratosis of the vulvar skin and keratinization of the distal vagina. BRAF expression (evaluated in controls) was localized to these tissues. Thus, early VO in rats given DAB likely represents a local effect accelerating vaginal keratinization to become open and not accelerated sexual maturation.
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http://dx.doi.org/10.1002/bdrb.21165DOI Listing
December 2015

Morphologic manifestations of testicular and epididymal toxicity.

Spermatogenesis 2014 May-Aug;4(2):e979099. Epub 2014 Dec 31.

AbbVie; GPRD Preclinical Safety ; Chicago, IL USA.

Histopathologic examination of the testis is the most sensitive means to detect effects on spermatogenesis; however, the complexity of testicular histology, interrelatedness of cell types within the testis, and long duration of spermatogenesis can make assessment of a testicular toxicant challenging. A thorough understanding of the histology and morphologic manifestations of response to injury is critical to successfully identify a testicular effect and to begin to understand the underlying mechanism of action. The basic patterns of response to xenobiotic-induced injury to the testis and epididymis are detailed and discussed.
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http://dx.doi.org/10.4161/21565562.2014.979099DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4581048PMC
December 2014

The inhibin B response to a motilin receptor agonist in male rats.

Birth Defects Res B Dev Reprod Toxicol 2013 Feb 24;98(1):63-71. Epub 2013 Jan 24.

Department of Safety Assessment, Reproductive and Developmental Toxicology, GlaxoSmithKline Research & Development, King of Prussia, PA 19406, USA.

Background: In a repeat oral dose toxicity study, all of 16 male rats given 100 mg/kg/day GSK1322888 sustained testicular injury after 4 weeks of treatment; the findings were not reversible after 12 weeks off-dose. The current study was conducted to further characterize testicular toxicity and to explore the possible relationship between onset of lesions, and changes in circulating hormone levels.

Methods: Male Sprague Dawley rats were orally administered 30 or 100 mg/kg/day GSK1322888 for 2 weeks with a 4-week off-dose period. Blood was collected via tail vein twice during the treatment period (days 4 and 11) and three times during the off-dose period (days 28, 36, and 42) for measurement of serum testosterone, dihydrotestosterone, and Inhibin B, luteinizing hormone, and follicle stimulating hormone concentrations. A histopathologic examination of testes was performed at the end of the treatment and off-dose periods.

Results: At 100 mg/kg/day, microscopic findings of the testis (degeneration of the germinal epithelium) were evident for 9 of 10 male rats on day 14 and all 10 rats at the end of the 4-week recovery period. There was no testicular toxicity observed at 30 mg/kg/day. During all stages of evaluation, there was no apparent difference among control and treated animals in hormone concentrations.

Conclusion: There was poor correlation between changes in serum levels of Inhibin B and testis histopathology. Based on these observations, the utility of Inhibin B as a hormonal marker for germ cell toxicity is limited.
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http://dx.doi.org/10.1002/bdrb.21042DOI Listing
February 2013

Antitumor activity of an allosteric inhibitor of centromere-associated protein-E.

Proc Natl Acad Sci U S A 2010 Mar 18;107(13):5839-44. Epub 2010 Feb 18.

Cytokinetics Inc, South San Francisco, CA 94080, USA.

Centromere-associated protein-E (CENP-E) is a kinetochore-associated mitotic kinesin that is thought to function as the key receptor responsible for mitotic checkpoint signal transduction after interaction with spindle microtubules. We have identified GSK923295, an allosteric inhibitor of CENP-E kinesin motor ATPase activity, and mapped the inhibitor binding site to a region similar to that bound by loop-5 inhibitors of the kinesin KSP/Eg5. Unlike these KSP inhibitors, which block release of ADP and destabilize motor-microtubule interaction, GSK923295 inhibited release of inorganic phosphate and stabilized CENP-E motor domain interaction with microtubules. Inhibition of CENP-E motor activity in cultured cells and tumor xenografts caused failure of metaphase chromosome alignment and induced mitotic arrest, indicating that tight binding of CENP-E to microtubules is insufficient to satisfy the mitotic checkpoint. Consistent with genetic studies in mice suggesting that decreased CENP-E function can have a tumor-suppressive effect, inhibition of CENP-E induced tumor cell apoptosis and tumor regression.
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http://dx.doi.org/10.1073/pnas.0915068107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2851928PMC
March 2010

Spontaneous findings in the heart of Mauritian-origin cynomolgus macaques (Macaca fascicularis).

Toxicol Pathol 2010 Feb 2;38(2):297-302. Epub 2010 Feb 2.

GlaxoSmithKline, King of Prussia, PA 19406-0939, USA.

The cynomolgus macaque is the most commonly used nonhuman primate in nonclinical toxicity testing, but the impact of the geographic source of cynomolgus macaque on differences in spontaneous pathology and response to xenobiotics has only recently been explored. Previous work from the authors' facility has described spontaneous cardiac findings in predominantly Indonesian-source animals; however, the authors have recently observed a novel spectrum of cardiac findings in Mauritian-source animals. This review evaluated the spontaneous macroscopic and microscopic cardiac findings in vehicle control Mauritian-source macaques used for routine toxicity testing. When compared to the prior review in predominantly Indonesian macaques, a higher incidence of myocardial degeneration was observed with additional novel findings including macroscopic and microscopic subendocardial hemorrhage with hemosiderin, myocardial fibrosis, and arterial medial degeneration/hemorrhage. Other findings including inflammatory cell infiltrates, anisokaryosis, and squamous plaques were observed with a comparable incidence as previously reported in Indonesian macaques. Myocardial degeneration, subendocardial hemorrhage, and myocardial fibrosis can mimic test-article-related cardiac toxicity, and a thorough understanding of the incidence and severity of these spontaneous findings is necessary to prevent misidentifying test-article-related cardiac findings in this genetic source of cynomolgus macaque in nonclinical safety testing.
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http://dx.doi.org/10.1177/0192623309358906DOI Listing
February 2010

Selected Background Findings and Interpretation of Common Lesions in the Female Reproductive System in Macaques.

Toxicol Pathol 2008 Dec;36(7):142s-163s

Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA.

The authors describe a selection of normal findings and common naturally occurring lesions in the reproductive system of female macaques, including changes in the ovaries, uterus, cervix, vagina, and mammary glands. Normal features of immature ovaries, uteri, and mammary glands are described. Common non-neoplastic lesions in the ovaries include cortical mineralization, polyovular follicles, cysts, ovarian surface epithelial hyperplasia, and ectopic ovarian tissue. Ovarian neoplasms include granulosa cell tumors, teratomas, and ovarian surface epithelial tumors. Common non-neoplastic uterine findings include loss of features of normal cyclicity, abnormal bleeding, adenomyosis, endometriosis, epithelial plaques, and pregnancy-associated vascular remodeling. Hyperplastic and neoplastic lesions of the uterus include endometrial polyps, leiomyomas, and rarely endometrial hyperplasia and endometrial adenocarcinoma. Vaginitis is common. Cervical lesions include endocervical squamous metaplasia, polyps, and papillomavirus-associated lesions. Lesions in the mammary gland are most often proliferative and range from ductal hyperplasia to invasive carcinoma. Challenges to interpretation include the normal or pathologic absence of menstrual cyclicity and the potential misinterpretation of sporadic lesions, such as epithelial plaques or papillomavirus-associated lesions. Interpretation of normal and pathologic findings is best accomplished with knowledge of the life stage, reproductive history, and hormonal status of the animal.
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http://dx.doi.org/10.1177/0192623308327117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3070965PMC
December 2008

Yolk coelomitis in Fiji Island banded iguanas (Brachylophus fasciatus).

J Zoo Wildl Med 2008 Jun;39(2):161-9

Zoological Society of San Diego, Wildlife Disease Laboratories, San Diego, California 92102, USA.

Yolk coelomitis is a major cause of death in captive sexually mature female Fiji Island banded iguanas (Brachylophus fasciatus) maintained by the Zoological Society of San Diego. The medical records, breeding histories, and pathology archival materials from this group were reviewed to study this health problem. From 1987 through 2004, deaths of nine of 21 adult females were due to yolk coelomitis. Most iguanas had a history of reproduction-related problems, which included reproductive failure, episodes of lethargy associated with ovarian activity, folliculostasis, ovostasis, and behavioral abnormalities. Most affected iguanas either were found dead or presented moribund and subsequently died or were euthanized. Clinical signs were nonspecific and included lethargy, cutaneous discoloration, and coelomic effusion. Yolk leakage in most cases was associated with the presence of large vitellogenic follicles undergoing atresia and resulted in coelomitis characterized by florid mesothelial proliferation.
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http://dx.doi.org/10.1638/2007-0047R1.1DOI Listing
June 2008

Evaluation of the cynomolgus monkey stomach: recommendations for standard sampling procedures in nonclinical safety studies.

Toxicol Pathol 2008 Feb 25;36(2):250-5. Epub 2008 Mar 25.

GlaxoSmithKline, King of Prussia, Pennsylvania 19406-0939, USA.

The cynomolgus macaque is the most commonly used nonhuman primate in nonclinical toxicity testing, but the macroscopic and microscopic anatomy of the stomach in the cynomolgus macaque is poorly described. To develop a reliable sampling method for histologic evaluation of the cynomolgus macaque stomach in regulatory toxicity studies, the stomachs of control animals were prospectively evaluated using an extensive sectioning pattern. The stomach of the cynomolgus macaque differs from that described for the human stomach and has a prominent fundus that lacks parietal cells. A description of the macroscopic and microscopic anatomy is presented along with a recommended sectioning pattern for nonclinical toxicity studies and discussion of species differences. A thorough understanding of normal anatomy and species comparisons are critical to interpretation of potential toxicity findings and assessment of risk in humans.
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http://dx.doi.org/10.1177/0192623307312700DOI Listing
February 2008

In vitro exposure to environmental tobacco smoke induces CYP1B1 expression in human luteinized granulosa cells.

Reprod Toxicol 2006 Nov 18;22(4):731-7. Epub 2006 Jun 18.

Population Health and Reproduction, University of California at Davis, Davis, CA 95616, USA.

Women smokers and women exposed to environmental tobacco smoke (ETS) have reduced ovarian function as evidenced by an earlier menopause, reduced follicular numbers, decreased levels of circulating estradiol, and decreased conception rates; however, the mechanism of action of altered ovarian function by ETS is poorly understood. The direct effects of ETS were evaluated using human luteinized granulosa cells (HLGCs) exposed to ETS in primary cell culture. Exposure to ETS caused a decrease in both estradiol and progesterone production. There was a concentration dependent increase in CYP1B1 gene and protein expression without a change in catechol-O-methyltransferase (COMT) expression. This is the first report of CYP1B1 induction secondary to ETS exposure in cells from the human ovary. CYP1B1 metabolizes both endogenous estrogens and polyaromatic hydrocarbons in ETS to a variety of reactive species and may contribute to the complex effects of ETS on ovarian function.
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http://dx.doi.org/10.1016/j.reprotox.2006.06.001DOI Listing
November 2006

Standard morphologic evaluation of the heart in the laboratory dog and monkey.

Toxicol Pathol 2006 ;34(1):67-74

GlaxoSmithKline, King of Prussia, Pennsylvania 19406, USA.

The nonrodent species most commonly utilized in preclinical safety studies are the purpose-bred beagle dog and cynomolgus macaque (Macaca fascicularis). Potential effects of a new chemical entity (NCE) on the heart pose serious concerns; consequently in vivo testing is focused on detection of functional alterations as well as morphological changes. Macroscopic and microscopic evaluation of the heart is based on a standard survey of key structures to properly assess presence of spontaneous and potential drug-induced lesions. Evaluation of historical controls to determine type and frequency of background change is valuable, as studies with non-rodent species generally have a small sample size. Archived control dog and monkey data were retrospectively reviewed, including terminal body weight (BW), heart weight (HW), and archival glass slides of heart. Control dogs had minimal background changes that included myxomatous or cartilagenous change in the cardiac skeleton and a variable degree of vacuolation in Purkinje fibers. Control monkey hearts commonly contained inflammatory cell infiltrates, myocyte anisokaryosis, and handling artifacts, while myocyte degeneration, squamous plaques, pigment, and intimal plaques were occasionally observed. These findings highlight the utility of consistently recorded and readily accessible archived control data when attempting to discern background spontaneous changes and artifacts from test-article induced changes.
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http://dx.doi.org/10.1080/01926230500369915DOI Listing
April 2006

Malignant Sertoli cell tumor in the retained abdominal testis of a unilaterally cryptorchid horse.

J Am Vet Med Assoc 2003 Feb;222(4):486-90, 450

Veterinary Medical Teaching Hospital, School of Veterinary Medicine, University of California, Davis, CA 95616, USA.

A 13-year-old Morgan gelding was evaluated because of a mass in the caudal region of the abdomen. The horse had been presumed to be a gelding, but necropsy findings revealed a retained testis in the right retroperitoneal space. Histologically, the retained testis contained neoplastic cells; metastases were identified in the liver, spleen, lungs, and sublumbar lymph nodes. Immunohistochemical examination of the testis and metastatic tissues confirmed the diagnosis of malignant Sertoli cell tumor. Testicular neoplasms are infrequently reported in stallions. Seminomas are most commonly reported, whereas Sertoli cell tumors are considered to be rare. Typical biological behavior of Sertoli cell tumors in horses is unknown. To the authors' knowledge, there have been 2 reports of Sertoli cell tumors in horses; the tumors developed in descended testes, and 1 tumor was malignant.
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http://dx.doi.org/10.2460/javma.2003.222.486DOI Listing
February 2003

Estrogen replacement therapy induces telomerase RNA expression in the macaque endometrium.

Fertil Steril 2002 Mar;77(3):601-8

Virginia-Maryland Regional College of Veterinary Medicine, Blacksburg, Virginia, USA.

Objective: To evaluate the effects of hormonal therapies on the expression of telomerase RNA (TRNA) in the endometrium of ovariectomized female cynomolgus macaques (Macaca fascicularis).

Design: Randomized long-term experimental trial.

Setting: Animal study at an academic research institution.

Patient(s): Surgically postmenopausal cynomolgus macaques.

Intervention(s): Treatments were given in the diet for three years and included conjugated equine estrogens (CEE), CEE + medroxyprogesterone acetate (MPA), and tamoxifen, at clinically relevant doses.

Main Outcome Measure(s): Expression of TRNA within the basal glands, basal stroma, superficial glands, and superficial stroma of the endometrium by radiolabeled in situ hybridization.

Result(s): Conjugated equine estrogens increased glandular TRNA expression, and the addition of MPA decreased this effect. Tamoxifen induced glandular TRNA expression to a lesser degree. Both CEE + MPA and tamoxifen increased stromal TRNA expression. The expression of TRNA in the endometrial glands was always greater than TRNA expression in the stroma. Treatment groups with greater proliferation and progesterone receptor expression also had elevated TRNA; within-group correlations were not significant. No statistically significant difference occurred between the basal and superficial endometrial layers.

Conclusion(s): These results show for the first time a cell-specific hormonal regulation of TRNA in the primate endometrium, with up-regulation of TRNA by treatments associated with increased risk of endometrial cancer in women.
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http://dx.doi.org/10.1016/s0015-0282(01)03227-7DOI Listing
March 2002