Publications by authors named "George A Parker"

42 Publications

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

Acute Radiation-induced Lung Injury in the Non-human Primate: A Review and Comparison of Mortality and Co-morbidities Using Models of Partial-body Irradiation with Marginal Bone Marrow Sparing and Whole Thorax Lung Irradiation.

Health Phys 2020 11;119(5):559-587

Rockville, MD.

The nonhuman primate, rhesus macaque, is a relevant animal model that has been used to determine the efficacy of medical countermeasures to mitigate major signs of morbidity and mortality of radiation-induced lung injury. Herein, a literature review of published studies showing the evolution of lethal lung injury characteristic of the delayed effects of acute radiation exposure between the two significantly different exposure protocols, whole thorax lung irradiation and partial-body irradiation with bone marrow sparing in the nonhuman primate, is provided. The selection of published data was made from the open literature. The primary studies conducted at two research sites benefitted from the similarity of major variables; namely, both sites used rhesus macaques of approximate age and body weight and radiation exposure by LINAC-derived 6 MV photons at dose rates of 0.80 Gy min and 1.00 Gy min delivered to the midline tissue via bilateral, anterior/posterior, posterior/anterior geometry. An advantage relative to sex difference resulted from the use of male and female macaques by the Maryland and the Washington sites, respectively. Subject-based medical management was used for all macaques. The primary studies (6) provided adequate data to establish dose response relationships within 180 d for the radiation-induced lung injury consequent to whole thorax lung irradiation (male vs. female) and partial-body irradiation with bone marrow sparing exposure protocols (male). The dose response relationships established by probit analyses vs. linear dose relationships were characterized by two main parameters or dependent variables, a slope and LD50/180. Respective LD50/180 values for the primary studies that used whole thorax lung irradiation for respective male and female nonhuman primates were 10.24 Gy [9.87, 10.52] (n = 76, male) and 10.28 Gy [9.68, 10.92] (n = 40, female) at two different research sites. The respective slopes were steep at 1.73 [0.841, 2.604] and 1.15 [0.65, 1.65] probits per linear dose. The LD50/180 value and slope derived from the dose response relationships for the partial-body irradiation with bone marrow sparing exposure was 9.94 Gy [9.35, 10.29] (n = 87) and 1.21 [0.70, 1.73] probits per linear dose. A secondary study (1) provided data on limited control cohort of nonhuman primates exposed to whole thorax lung irradiation. The data supported the incidence of clinical, radiographic, and histological indices of the dose-dependent lung injury in the nonhuman primates. Tertiary studies (6) provided data derived from collaboration with the noted primary and secondary studies on control cohorts of nonhuman primates exposed to whole thorax lung irradiation and partial-body irradiation with bone marrow sparing exposure. These studies provided a summary of histological evidence of fibrosis, inflammation and reactive/proliferative changes in pneumonocytes characteristic of lung injury and data on biomarkers for radiation-induced lung injury based on matrix-assisted laser desorption ionization-mass spectrometry imaging and gene expression approaches. The available database in young rhesus macaques exposed to whole thorax lung irradiation or partial-body irradiation with bone marrow sparing using 6 MV LINAC-derived radiation with medical management showed that the dose response relationships were equivalent relative to the primary endpoint all-cause mortality. Additionally, the latency, incidence, severity, and progression of the clinical, radiographic, and histological indices of lung injury were comparable. However, the differences between the exposure protocols are remarkable relative to the demonstrated time course between the multiple organ injury of the acute radiation syndrome and that of the delayed effects of acute radiation exposure, respectively.
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http://dx.doi.org/10.1097/HP.0000000000001346DOI Listing
November 2020

Lack of Cellular Inflammation in a Non-human Primate Model of Radiation Nephropathy.

Health Phys 2020 11;119(5):588-593

Radiation Oncology, University of Maryland, School of Medicine, Baltimore, MD.

Inflammation is commonly cited as a mechanism of delayed effects of acute radiation exposure (DEARE). Confirmation of its presence could provide significant insight to targeted use of treatments or mitigators of DEARE. We sought to quantify the presence of cellular inflammation in kidneys of non-human primates that developed acute and chronic kidney injury after a partial body irradiation exposure. We show herein that cellular inflammation is not found as a component of either acute or chronic kidney injury. Other mechanistic pathways of injury must be sought.
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http://dx.doi.org/10.1097/HP.0000000000001329DOI Listing
November 2020

MALDI-MSI spatially maps N-glycan alterations to histologically distinct pulmonary pathologies following irradiation.

Sci Rep 2020 07 14;10(1):11559. Epub 2020 Jul 14.

Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, MD, USA.

Radiation-induced lung injury is a highly complex combination of pathological alterations that develop over time and severity of disease development is dose-dependent. Following exposures to lethal doses of irradiation, morbidity and mortality can occur due to a combination of edema, pneumonitis and fibrosis. Protein glycosylation has essential roles in a plethora of biological and immunological processes. Alterations in glycosylation profiles have been detected in diseases ranging from infection, inflammation and cancer. We utilized mass spectrometry imaging to spatially map N-glycans to distinct pathological alterations during the clinically latent period and at 180 days post-exposure to irradiation. Results identified alterations in a number of high mannose, hybrid and complex N-glycans that were localized to regions of mucus and alveolar-bronchiolar hyperplasia, proliferations of type 2 epithelial cells, accumulations of macrophages, edema and fibrosis. The glycosylation profiles indicate most alterations occur prior to the onset of clinical symptoms as a result of pathological manifestations. Alterations in five N-glycans were identified as a function of time post-exposure. Understanding the functional roles N-glycans play in the development of these pathologies, particularly in the accumulation of macrophages and their phenotype, may lead to new therapeutic avenues for the treatment of radiation-induced lung injury.
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http://dx.doi.org/10.1038/s41598-020-68508-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7360629PMC
July 2020

A Pathology Review of the Lower Gastrointestinal Tract in Relation to Ulcerative Colitis in Rats and Cynomolgus Macaques Treated With Ammonium Perfluorooctanoate.

Toxicol Pathol 2020 06 18;48(4):593-602. Epub 2020 Mar 18.

3M Company, St Paul, MN, USA.

Among many short-term, subchronic, and chronic toxicology studies with ammonium perfluorooctanoate (PFOA), the gastrointestinal tract has not been identified as a target organ for PFOA-related toxicity in laboratory animals where the corresponding serum PFOA concentrations typically approach several orders of magnitude higher than the general human population. These lack of gastrointestinal tract-related findings were in direct contrast to an epidemiological observation where a positive trend was observed for ulcerative colitis, an idiopathic chronic inflammatory condition of the gut, in a Mid-Ohio River community whose drinking water contained higher levels of PFOA. This study was conducted to perform a histological reevaluation of large intestine sections in laboratory animals from 2 long-term toxicological studies: one was with Sprague Dawley rats that received ammonium PFOA in their diet for 2 years and the other one was with cynomolgus macaques that received daily capsules of ammonium PFOA for 6 months. In both studies, there was a lack of histological evidence of treatment-related inflammatory lesions that was suggestive of the occurrence of ulcerative colitis in these laboratory animals even under the most rigorous treatment schedules. These findings do not offer support for the biological plausibility of the epidemiological associations reported.
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http://dx.doi.org/10.1177/0192623320911606DOI Listing
June 2020

Lung and Heart Injury in a Nonhuman Primate Model of Partial-body Irradiation with Minimal Bone Marrow Sparing: Histopathological Evidence of Lung and Heart Injury.

Health Phys 2019 03;116(3):383-400

University of Maryland, School of Medicine, Department of Radiation Oncology, Baltimore, MD.

Male rhesus macaques were subjected to partial-body irradiation at 10, 11, or 12 Gy with 5% bone marrow protection. Animals were euthanized when dictated by prospectively determined clinical parameters or at approximately 180 d following irradiation. Histological sections of lung and heart were stained with hematoxylin and eosin as well as a battery of histochemical and immunohistochemical stains. Histopathological alterations in the lung were centered on fibrosis, inflammation, and reactive/proliferative changes in pneumocytes. These changes were noted in animals necropsied after approximately 85-100 d postirradiation and extending through the observation period. Interstitial and pleural fibrosis demonstrated by Masson's trichrome staining were associated with increased alpha smooth muscle actin and collagen 1 immunohistochemical staining. Areas of interstitial fibrosis had reduced microvascular density with CD31 immunohistochemical staining. Accumulations of CD163- and CD206-positive alveolar macrophages were present in areas of interstitial fibrosis. Unidentified cells termed "myxoid" cells in alveolar walls had histochemical and immunohistochemical staining characteristics of epithelial-, endothelial-, or pericyte-mesenchymal transition states that were developing myofibroblast features. Distinctive focal or multifocal alveolar-bronchiolar hyperplasia had microscopic features of preneoplastic proliferation. Delayed radiation-associated changes in the heart consisted primarily of myocardial fibrosis, with rare histological evidence of myofiber degeneration.
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http://dx.doi.org/10.1097/HP.0000000000000936DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6381599PMC
March 2019

Characterizing the Natural History of Acute Radiation Syndrome of the Gastrointestinal Tract: Combining High Mass and Spatial Resolution Using MALDI-FTICR-MSI.

Health Phys 2019 04;116(4):454-472

University of Maryland, School of Pharmacy, Department of Pharmaceutical Sciences, Baltimore, MD.

The acute radiation syndrome of the gastrointestinal tract has been histologically characterized, but the molecular and functional mechanisms that lead to these cellular alterations remain enigmatic. Mass spectrometry imaging is the only technique that enables the simultaneous detection and cellular or regional localization of hundreds of biomolecules in a single experiment. This current study utilized matrix-assisted laser desorption/ionization mass spectrometry imaging for the molecular characterization of the first natural history study of gastrointestinal acute radiation syndrome in the nonhuman primate. Jejunum samples were collected at days 4, 8, 11, 15, and 21 following 12-Gy partial-body irradiation with 2.5% bone marrow sparing. Mass spectrometry imaging investigations identified alterations in lipid species that further understanding of the functional alterations that occur over time in the different cellular regions of the jejunum following exposure to high doses of irradiation. Alterations in phosphatidylinositol species informed on dysfunctional epithelial cell differentiation and maturation. Differences in glycosphingolipids of the villi epithelium that would influence the absorptive capacity and functional structure of the brush border membrane were detected. Dichotomous alterations in cardiolipins indicated altered structural and functional integrity of mitochondria. Phosphatidylglycerol species, known regulators of toll-like receptors, were detected and localized to regions in the lamina propria that contained distinct immune cell populations. These results provide molecular insight that can inform on injury mechanism in a nonhuman primate model of the acute radiation syndrome of the gastrointestinal tract. Findings may contribute to the identification of therapeutic targets and the development of new medical countermeasures.
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http://dx.doi.org/10.1097/HP.0000000000000948DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6384159PMC
April 2019

Histopathological Features of the Development of Intestine and Mesenteric Lymph Node Injury in a Nonhuman Primate Model of Partial-body Irradiation with Minimal Bone Marrow Sparing.

Health Phys 2019 03;116(3):426-446

University of Maryland, School of Medicine, Department of Radiation Oncology, Baltimore, MD.

Male rhesus macaques were subjected to partial-body irradiation at 10, 11, or 12 Gy with 5% bone marrow protection. Animals were euthanized when dictated by prospectively determined clinical parameters or at approximately 180 d following irradiation. Histological sections of jejunum, colon, and mesenteric lymph node were stained with hematoxylin and eosin as well as a battery of histochemical and immunohistochemical stains. The immediate postirradiation histopathological alterations in the jejunum and colon were based primarily on injury to rapidly proliferating crypt epithelial cells, though there was evidence of additional radiation-induced fibrogenic responses. There was substantial resolution of the radiation-related mucosal injury through the observation period, but microscopically visible defects in mucosal structure persisted to the end of the observation period. In the later stages of the observation period, the jejunum and colon had overt fibrosis that was most commonly located in the submucosa and serosa, with less microscopically discernible involvement of the mucosa. Mesenteric lymph nodes had an immediate postirradiation reduction in cellularity due to the known effects of irradiation on lymphoid cell populations. In later stages of the observation period the lymph nodes also developed fibrotic changes, possibly related to transmigration of immunomodulatory cells and/or signaling molecules from the radiation-damaged intestine.
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http://dx.doi.org/10.1097/HP.0000000000000932DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6362996PMC
March 2019

The Gastrointestinal Subsyndrome of the Acute Radiation Syndrome in Rhesus Macaques: A Systematic Review of the Lethal Dose-response Relationship With and Without Medical Management.

Health Phys 2019 03;116(3):305-338

(in memoriam) Epistem Ltd., Manchester, UK.

Well-characterized animal models that mimic the human response to potentially lethal doses of radiation are required to assess the efficacy of medical countermeasures under the criteria of the US Food and Drug Administration's Animal Rule. Development of a model for the gastrointestinal acute radiation syndrome requires knowledge of the radiation dose-response relationship and time course of mortality and morbidity across the acute and prolonged gastrointestinal radiation syndrome. The nonhuman primate, rhesus macaque, is a relevant animal model that has been used to determine the efficacy of medical countermeasures to mitigate major signs of morbidity and mortality relative to the hematopoietic acute radiation syndrome, gastrointestinal acute radiation syndrome, and lung injury. It can be used to assess the natural history of gastrointestinal damage, concurrent multiple organ injury, and aspects of the mechanism of action for acute radiation exposure and treatment. A systematic review of relevant studies that determined the dose-response relationship for the gastrointestinal acute and prolonged radiation syndrome in the rhesus macaque relative to radiation dose, quality, dose rate, exposure uniformity, and use of medical management has never been performed.
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http://dx.doi.org/10.1097/HP.0000000000000903DOI Listing
March 2019

The Time Course of Radiation-induced Lung Injury in a Nonhuman Primate Model of Partial-body Irradiation With Minimal Bone Marrow Sparing: Clinical and Radiographic Evidence and the Effect of Neupogen Administration.

Health Phys 2019 03;116(3):366-382

Statistician, Rockville, MD.

The primary objectives of two companion manuscripts were to assess the natural history of delayed radiation-induced lung injury in a nonhuman primate model of acute high-dose, partial-body irradiation with 5% bone marrow sparing, to include the clinical, radiographic, and histopathological evidence and the effect of Neupogen administration on the morbidity and mortality. Nonhuman primates were exposed to 10.0 or 11.0 Gy with 6 MV linac-derived photons at approximately 0.80 Gy min. All nonhuman primates received subject-based, medical management. Subsets of nonhuman primates were administered Neupogen (10 μg kg) starting on day 1, day 3, or day 5 until recovery (absolute neutrophil count ≥ 1,000 cells μL for three consecutive days). Mortality due to multiple organ injury at 180 d study duration: Mortality at 180 d post either 10.0 Gy or 11.0 Gy was the consequence of concurrent injury due to the acute radiation syndrome (gastrointestinal and hematological) and delayed radiation-induced lung injury. The 180-d all-cause mortality observed in the control cohorts at 10.0 Gy (53%) or 11.0 Gy (86%) did not vary from cohorts that received Neupogen at any administration schedule. Mortality ranged from 43-50% (10 Gy) to 75-100% (11.0 Gy) in the Neupogen-treated cohorts. The study, however, was not powered to detect statistical significant differences between mortality in the control and Neupogen-treated cohorts. Clinical and radiographic evidence of radiation-induced lung injury: The mean nonsedated respiratory rate in the control cohorts exposed to 10 or 11 Gy increased from a baseline value of 37 breaths min to >60 breaths min within 103 d and 94 d postexposure, and the incidence of nonsedated respiratory rate > 80 breaths min was 50% and 70%, respectively. The mean duration of latency to development of clinical pneumonitis and/or fibrosis (nonsedated respiratory rate > 80 breaths min) was not significantly different between the 10.0-Gy or 11.0 Gy-cohorts (range 100-107 d). Neupogen (granulocyte colony-stimulating factor) administration had no apparent effect of the latency, incidence, or severity of nonsedated respiratory rate within either radiation dose or administration schedule. Computed tomography scans were obtained and images were analyzed for evidence of lung injury, e.g., pneumonitis and/or fibrosis, pleural and pericardial effusion. A quantitative, semiautomated method was developed based on differences in radiodensity (Hounsfield units) and lung morphology to extract the volume of pneumonitis/fibrosis and pleural effusion as indexed against total lung at each time point obtained. At both irradiation doses, 100% of the nonhuman primates surviving acute radiation syndrome manifested radiographic evidence of radiation-induced lung injury as pneumonitis and/or fibrosis. There was no apparent effect of Neupogen administration on the latency, incidence, severity, or progression of pneumonitis/fibrosis:total lung volume or pleural effusion:total lung volume at either exposure. A comparative review of the data illustrated the concomitant time course of increased mortality, nonsedated respiratory rate, and pneumonitis/fibrosis:total lung volume and pleural effusion:total lung volume consequent to 10.0-Gy or 11.0-Gy partial-body irradiation with 5% bone marrow sparing. All key parameters proceeded from a latent period of approximately 60 d followed by an increase in all three indices of clinical and radiographic evidence of radiation-induced lung injury within the next 60 d to 120 d postexposure. The subsequent time course and longitudinal analysis was influenced by the persistent progression of radiation-induced lung injury, administration of dexamethasone, and loss of nonhuman primates due to lethality. Companion paper: Lung and Heart Injury in a Nonhuman Primate Model of Partial-body Irradiation With Minimal Bone Marrow Sparing: Histopathological Evidence of Lung and Heart Injury (Parker et al. 2019): Note that the computed tomography-based radiodensity data do not permit differentiation of pneumonitis and fibrosis. The companion paper employed Masson's trichrome, collagen 1, and selected staining to identify the key time and incidence parameters relative to excessive collagen deposition indicative of fibrosis and associated histopathology in the lung. This histological database provided valuable longitudinal analysis in support of the clinical and radiographic evidence associated with the time course of radiation-induced lung injury.
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http://dx.doi.org/10.1097/HP.0000000000000968DOI Listing
March 2019

Radiation Nephropathy in a Nonhuman Primate Model of Partial-Body Irradiation With Minimal Bone Marrow Sparing-Part 2: Histopathology, Mediators, and Mechanisms.

Health Phys 2019 03;116(3):409-425

University of Maryland, School of Medicine, Department of Radiation Oncology, Baltimore, MD.

Male rhesus macaques were subjected to partial-body irradiation at 10, 11, or 12 Gy with 5% bone marrow protection. Animals were euthanized when dictated by prospectively determined clinical parameters or at approximately 180 d following irradiation. Histological sections of kidney were stained with hematoxylin and eosin as well as a battery of histochemical and immunohistochemical stains. Histopathological alterations were centered on glomerular changes and fibrosis of glomeruli and the interstitial compartment. These changes were first noted in animals necropsied approximately 100 d postirradiation and continued in animals necropsied through the observation period. Glomerular changes included congestion, thrombosis, erythrocyte degeneration, capillary tuft dilation, fibrin deposition, altered quantity and dispersion pattern of von Willebrand factor, increased mesangial matrix, and mesangial deposits of material that stained positively with periodic acid-Schiff staining. Areas of interstitial and glomerular fibrosis, as demonstrated by Masson's trichrome staining, were topographically associated with increased immunohistochemical staining for connective tissue growth factor, alpha smooth muscle actin, and collagen 1, but there was little staining for transforming growth factor beta. Fibrotic glomeruli had reduced microvascularity as demonstrated by reduced CD31 immunohistochemical staining. Vascular congestion was commonly noted in the region of the corticomedullary junction, and proteinaceous casts were commonly noted in cortical and medullary tubules. Longitudinal analysis of histopathological alterations provided evidence defining the latency, severity, and progression of delayed radiation-induced kidney injury.
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http://dx.doi.org/10.1097/HP.0000000000000935DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6349488PMC
March 2019

Radiation Nephropathy in a Nonhuman Primate Model of Partial-body Irradiation with Minimal Bone Marrow Sparing-Part 1: Acute and Chronic Kidney Injury and the Influence of Neupogen.

Health Phys 2019 03;116(3):401-408

Department of Radiation Oncology, University of Maryland, School of Medicine, Baltimore, MD 21201.

Acute and chronic kidney injury may occur after accidental prompt radiation exposures. We have modeled their occurrence in a nonhuman primate model. Subjects who are exposed to more than 5-Gy prompt irradiation are apt to show blood cell cytopenias and be treated with granulocyte colony-stimulating factors such as Neupogen® or Neulasta® to mitigate the hematologic injury of the acute radiation syndrome. Neupogen or Neulasta are now approved by the US Food and Drug Administration for this indication. This will significantly increase the number of survivors of acute radiation exposures who will be at risk for delayed effects of radiation exposure, which includes acute and chronic kidney injury. The primary objectives of the present two companion manuscripts were to assess natural history of delayed radiation-induced renal injury in a nonhuman primate model of acute, high-dose, partial-body irradiation with 5% bone marrow sparing to include the clinical and histopathological evidence and the effect of Neupogen administration on morbidity and mortality. In this study, 88 nonhuman primates underwent 10- or 11-Gy partial-body irradiation with 5% bone marrow sparing, of which 36 were treated with Neupogen within 1, 3, or 5 d postirradiation. All animals were followed up to 180 d after irradiation. Renal function and histology end points showed early acute and later chronic kidney injury. These end points were not affected by use of Neupogen. We conclude that use of Neupogen to mitigate against the hematopoietic acute radiation syndrome has no impact on acute or chronic kidney injury.
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http://dx.doi.org/10.1097/HP.0000000000000960DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7323852PMC
March 2019

Reproductive and developmental toxicity of potassium perfluorohexanesulfonate in CD-1 mice.

Reprod Toxicol 2018 06 22;78:150-168. Epub 2018 Apr 22.

Independent Consultant, Alexandria, VA 22301, United States.

Potassium perfluorohexanesulfonate (KPFHxS) was evaluated for reproductive/developmental toxicity in CD-1 mice. Up to 3 mg/kg-d KPFHxS was administered (n = 30/sex/group) before mating, for at least 42 days in F males, and for F females, through gestation and lactation. F pups were directly dosed with KPFHxS for 14 days after weaning. There was an equivocal decrease in live litter size at 1 and 3 mg/kg-d, but the pup-born-to-implant ratio was unaffected. Adaptive hepatocellular hypertrophy was observed, and in 3 mg/kg-d F males, it was accompanied by concomitant decreased serum cholesterol and increased alkaline phosphatase. There were no other toxicologically significant findings on reproductive parameters, hematology/clinical pathology/TSH, neurobehavioral effects, or histopathology. There were no treatment-related effects on postnatal survival, development, or onset of preputial separation or vaginal opening in F mice. Consistent with previous studies, our data suggest that the potency of PFHxS is much lower than PFOS in rodents.
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http://dx.doi.org/10.1016/j.reprotox.2018.04.007DOI Listing
June 2018

A Diagnostic Approach for Rodent Progressive Cardiomyopathy and Like Lesions in Toxicology Studies up to 28 Days in the Sprague Dawley Rat (Part 2 of 2).

Toxicol Pathol 2017 12;45(8):1055-1066

2 GlaxoSmithKline, King of Prussia, Pennsylvania, USA.

To test the diagnostic approach described in part 1 of this article, 2 exercises were completed by pathologists from multiple companies/agencies. Pathologist's examination of whole slide image (WSI) heart sections from rats using personal diagnostic approaches (exercise #1) corroborated conclusions from study #1. Using the diagnostic approach described in part 1, these pathologists examined the same WSI heart sections (exercise #2) to determine whether that approach increased consistency of diagnosis of rodent progressive cardiomyopathy (PCM) lesions. In exercise #2, there was improved consistency of categorization of small borderline morphologies and mild lesions, but a decrement in consistency of categorizing minimal lesions. Exercises 1 and 2 suggest the described diagnostic approach is representative of that in use by the majority of toxicologic pathologists across companies/agencies and that application by all may improve diagnostic consistency of PCM/like lesions. Additionally, a criterion of approximately 5% heart section involvement is suggested for separating mild from moderate or greater severity. While evidence is not absolute, until further investigation shows otherwise, microscopic changes resembling PCM, but located in the epicardial and subepicardial region of the right ventricle, may be considered as part of the spectrum of PCM.
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http://dx.doi.org/10.1177/0192623317743948DOI Listing
December 2017

A Diagnostic Approach for Rodent Progressive Cardiomyopathy and Like Lesions in Toxicology Studies up to 28 Days in the Sprague Dawley Rat (Part 1 of 2).

Toxicol Pathol 2017 12 26;45(8):1043-1054. Epub 2017 Nov 26.

2 GlaxoSmithKline, King of Prussia, Pennsylvania, USA.

Spontaneous rodent progressive cardiomyopathy (PCM) in the Sprague Dawley rat may confound identification and/or interpretation of potential test article (TA)-related cardiotoxicity. Pathologists apply diagnostic term(s) and thresholds for diagnosing and assigning severity grades for PCM and/or PCM-like (PCM/like) lesions consistently within a study, which is necessary to identify and interpret TA-related findings. Due to differences in training and/or experiences, diagnostic terms and thresholds may vary between pathologists. Harmonized terminology and thresholds across studies will generate better historical control data, will likely enhance interpretation of study data, and may further enhance our understanding of the spontaneous change. An assessment of the diagnostic approaches of a group of 37 pathologists identified an approach that is relatively easily applied; and if adopted, it could enhance diagnostic consistency across studies. This approach uses the single "slash" term "necrosis/inflammatory cell infiltrate (NICI)" as the diagnosis for the spectrum of lesions seen in younger rats, uses no threshold for diagnosis (e.g., diagnose all lesions clearly identifiable as PCM/like), and uses aggregate lesion size of approximately ≥45% of the field of view (FOV) using a 10×/22 eyepiece and the 40× objective or approximately ≥100% of the FOV using the 60× objective as the criterion separating minimal from mild severities.
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http://dx.doi.org/10.1177/0192623317743938DOI Listing
December 2017

Acute and Chronic Kidney Injury in a Non-Human Primate Model of Partial-Body Irradiation with Bone Marrow Sparing.

Radiat Res 2017 12 16;188(6):661-671. Epub 2017 Oct 16.

b   Radiation Oncology, University of Maryland, School of Medicine, Baltimore, Maryland; and.

The development of medical countermeasures against acute and delayed multi-organ injury requires animal models predictive of the human response to radiation and its treatment. Late chronic injury is a well-known feature of radiation nephropathy, but acute kidney injury has not been reported in an appropriate animal model. We have established a single-fraction partial-body irradiation model with minimal marrow sparing in non-human primates. Subject-based medical management was used including parenteral fluids according to prospective morbidity criteria. We show herein that 10 or 11 Gy exposures caused both acute and chronic kidney injury. Acute and chronic kidney injury appear to be dose-independent between 10 and 11 Gy. Acute kidney injury was identified during the first 50 days postirradiation and appeared to resolve before the occurrence of chronic kidney injury, which was progressively more severe up to 180 days postirradiation, which was the end of the study. These findings show that mitigation of the acute radiation syndrome by medical management will unmask delayed late effects that occur months after partial-body irradiation. They further emphasize that both acute and chronic changes in kidney function must be taken into account in the use and timing of mitigators and medical management for acute radiation syndrome and delayed effects of acute radiation exposure (DEARE).
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http://dx.doi.org/10.1667/RR24857.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7737227PMC
December 2017

Perfluorooctane Sulfonate-Induced Hepatic Steatosis in Male Sprague Dawley Rats Is Not Attenuated by Dietary Choline Supplementation.

Toxicol Sci 2017 Dec;160(2):284-298

SaluTox LLC, Lake Elmo, Minnesota 55042.

Perfluorooctane sulfonate (PFOS) is an environmentally persistent chemical. Dietary 100 ppm PFOS fed to male mice and rats for 4 weeks caused hepatic steatosis through an unknown mechanism. Choline deficient diets can cause hepatic steatosis. A hepatic choline:PFOS ion complex was hypothesized to cause this effect in mice. This study tested whether dietary choline supplementation attenuates PFOS-induced hepatic steatosis in rats. Sprague Dawley rats (12/sex/group) were fed control, choline supplemented (CS), 100 ppm PFOS, or 100 ppm PFOS + CS diets for 3 weeks. Male rats fed both PFOS-containing diets had decreased serum cholesterol and triglycerides (TGs) on days 9, 16, and/or 23 and increased hepatic free fatty acids and TG (ie, steatosis). Female rats fed both PFOS diets had decreased serum cholesterol on days 9 and 16 and decreased hepatic free fatty acid and TG at termination (ie, no steatosis). Liver PFOS concentrations were similar for both sexes. Liver choline concentrations were increased in male rats fed PFOS (±CS), but the increase was lower in the PFOS + CS group. Female liver choline concentrations were not altered by any diet. These findings demonstrate a clear sex-related difference in PFOS-induced hepatic steatosis in the rat. Additional evaluated mechanisms (ie, nuclear receptor activation, mRNA upregulation, and choline kinase activity inhibition) did not appear to be involved in the hepatic steatosis. Dietary PFOS (100 ppm) induced hepatic steatosis in male, but not female, rats that was not attenuated by choline supplementation. The mechanism of lipid accumulation and the sex-related differences warrant further investigation.
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http://dx.doi.org/10.1093/toxsci/kfx185DOI Listing
December 2017

Four-week dietary supplementation with 10- and/or 15-fold basal choline caused decreased body weight in Sprague Dawley rats.

Toxicol Ind Health 2017 Oct 13;33(10):792-801. Epub 2017 Sep 13.

4 SaluTox LLC, Lake Elmo, MN, USA.

Choline is an essential nutrient utilized for phosphatidylcholine biosynthesis and lipoprotein packaging and secretion. Recently, choline supplementation has been used by athletes and the public for weight loss. However, the potential toxicological impact of choline dietary supplementation requires further investigation. This study examined the effects of choline dietary supplementation in Sprague Dawley rats for 4 weeks. Rats were fed diets containing basal choline levels (control) or 5-, 10-, or 15-fold (5×, 10×, or 15×) basal diet concentration. In groups fed choline-supplemented diets, there were no toxicologically relevant findings in clinical observations, food intake, clinical chemistry, liver weights, or liver histopathology. However, decreased mean body weights (8.5-10.2%) and body weight gains (24-31%) were noted for the 10× choline-supplemented (females only) and 15× choline-supplemented (both sexes) groups relative to the control groups from day 3 onward. These body weight effects were not related to a persistent reduction in average food intake. Serum cholesterol was increased in the 15× choline-supplemented male rats relative to the controls, an expected effect of choline supplementation; however, there were no changes in the serum cholesterol of female rats. Serum choline concentrations were increased in female rats relative to the male rats across all treatment groups. The maximum tolerated dose for male and female rats were the 15× and 10× choline supplements, respectively, based on decreased mean body weight and body weight gains. This study supported the conclusions of a clinical trial that showed a high choline diet can decrease body weight in humans.
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http://dx.doi.org/10.1177/0748233717711361DOI Listing
October 2017

Postnatal Organ Development as a Complicating Factor in Juvenile Toxicity Studies in Rats.

Toxicol Pathol 2017 01 17;45(1):248-252. Epub 2016 Oct 17.

1 Charles River Laboratories, Hillsborough, North Carolina, USA.

Toxicologic pathologists must evaluate tissues of immature animals from a number of types of nonclinical toxicity studies. The pathologist who is familiar with normal postnatal organ development is in a better position to appropriately detect and differentiate between abnormal, delayed, or precocious development. Vacuolation and apoptosis in multiple tissue types are normal components of development that could influence the interpretation of some tissues. Unique postnatal features such as the germal matrix in the brain, gonocytes in the testes, and saccules in the lung may complicate the histopathological evaluation. With the knowledge of normal organ development and critical windows therein, it is possible to design targeted studies to identify xenobiotic toxicity.
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http://dx.doi.org/10.1177/0192623316671609DOI Listing
January 2017

Immune- and Nonimmune-Compartment-Specific Interferon Responses Are Critical Determinants of Herpes Simplex Virus-Induced Generalized Infections and Acute Liver Failure.

J Virol 2016 Dec 14;90(23):10789-10799. Epub 2016 Nov 14.

Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire, USA

The interferon (IFN) response to viral pathogens is critical for host survival. In humans and mouse models, defects in IFN responses can result in lethal herpes simplex virus 1 (HSV-1) infections, usually from encephalitis. Although rare, HSV-1 can also cause fulminant hepatic failure, which is often fatal. Although herpes simplex encephalitis has been extensively studied, HSV-1 generalized infections and subsequent acute liver failure are less well understood. We previously demonstrated that IFN-αβγR mice are exquisitely susceptible to liver infection following corneal infection with HSV-1. In this study, we used bone marrow chimeras of IFN-αβγR (AG129) and wild-type (WT; 129SvEv) mice to probe the underlying IFN-dependent mechanisms that control HSV-1 pathogenesis. After infection, WT mice with either IFN-αβγR or WT marrow exhibited comparable survival, while IFN-αβγR mice with WT marrow had a significant survival advantage over their counterparts with IFN-αβγR marrow. Furthermore, using bioluminescent imaging to maximize data acquisition, we showed that the transfer of IFN-competent hematopoietic cells controlled HSV-1 replication and damage in the livers of IFN-αβγR mice. Consistent with this, the inability of IFN-αβγR immune cells to control liver infection in IFN-αβγR mice manifested as profoundly elevated aspartate transaminase (AST) and alanine transaminase (ALT) levels, indicative of severe liver damage. In contrast, IFN-αβγR mice receiving WT marrow exhibited only modest elevations of AST and ALT levels. These studies indicate that IFN responsiveness of the immune system is a major determinant of viral tropism and damage during visceral HSV infections.

Importance: Herpes simplex virus 1 (HSV-1) infection is an incurable viral infection with the most significant morbidity and mortality occurring in neonates and patients with compromised immune systems. Severe pathologies from HSV include the blindness-inducing herpetic stromal keratitis, highly debilitating and lethal herpes simplex encephalitis, and generalized infections that can lead to herpes simplex virus-induced acute liver failure. While immune compromise is a known factor, the precise mechanisms that lead to generalized HSV infections are unknown. In this study, we used and developed a mouse model system in combination with real-time bioluminescence imaging to demonstrate the relative importance of the immune and nonimmune compartments for containing viral spread and promoting host survival after corneal infection. Our results shed light on the pathogenesis of HSV infections that lead to generalized infection and acute liver failure.
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http://dx.doi.org/10.1128/JVI.01473-16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5110161PMC
December 2016

Well-differentiated neuroendocrine tumor of the stomach: A rare case at an uncommon site.

Medicine (Baltimore) 2016 Jul;95(29):e4260

Bon Secours Health System, Pediatric Hematology-Oncology Division of Hematology-Oncology, Department of Pediatrics, University of Virginia Bon Secours Health System, General Surgery Bon Secours Health System, Monument Pathologists Inc. Bon Secours Health System, Pediatric Gastroenterology Associates, Richmond, VA.

Introduction: A 13-year-old African-American female presented to her primary care physician's office with fatigue, syncope, and hematemesis. After initial evaluation, the patient was referred to pediatric gastroenterology clinic for further evaluation.

Main Concerns, Important Findings: An upper gastrointestinal endoscopy was performed to evaluate the source of her bleeding. Endoscopy revealed a 3-cm mass in the lesser curvature of the stomach, and a biopsy of the mass revealed a concern for carcinoid (neuroendocrine) features.

Diagnosis: She underwent an open gastrectomy. Post-surgical pathology reports confirmed a well-differentiated neuroendocrine tumor of the stomach.

Conclusion: Neuroendocrine tumors of the stomach in children are rare and we presently do not have pediatric-specific diagnostic and treatment guidelines. Although adult-based The North American Neuroendocrine Tumor Society (NANETS) guidelines are helpful, they are clearly not geared toward pediatric patients. To establish pediatric guidelines and to assess effectiveness of treatments, multicenter data collection is essential. In the long run, accumulation of clinically useful treatment information and long-term follow-up guidelines should enable clinicians to improve standard of care given to children with neuroendocrine tumors.
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http://dx.doi.org/10.1097/MD.0000000000004260DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5265773PMC
July 2016

Scientific and Regulatory Policy Committee (SRPC) Points to Consider: Histopathology Evaluation of the Pubertal Development and Thyroid Function Assay (OPPTS 890.1450, OPPTS 890.1500) in Rats to Screen for Endocrine Disruptors.

Toxicol Pathol 2015 Dec 6;43(8):1047-63. Epub 2015 May 6.

The Dow Chemical Company, Midland, Michigan, USA Department of Comparative Medicine, University of Washington, Seattle, Washington, USA.

The U.S. Environmental Protection Agency Endocrine Disruptor Screening Program (EDSP) is a multitiered approach to determine the potential for environmental chemicals to alter the endocrine system. The Pubertal Development and Thyroid Function in Intact Juvenile/Peripubertal Female and Male Rats (OPPTS 890.1450, 890.1500) are 2 of the 9 EDSP tier 1 test Guidelines, which assess upstream mechanistic pathways along with downstream morphological end points including histological evaluation of the kidneys, thyroid, and select male/female reproductive tissues (ovaries, uterus, testes, and epididymides). These assays are part of a battery of in vivo and in vitro screens used for initial detection of test article endocrine activity. In this Points to Consider article, we describe tissue processing, evaluation, and nomenclature to aid in standardization of assay results across laboratories. Pubertal assay end points addressed include organ weights, estrous cyclicity, clinical pathology, hormonal assays, and histological evaluation. Potential treatment-related findings that may indicate endocrine disruption are reviewed. Additional tissues that may be useful in assessment of endocrine disruption (vagina, mammary glands, and liver) are discussed. This Points to Consider article is intended to provide information for evaluating peripubertal tissues within the context of individual assay end points, the overall pubertal assay, and tier I assays of the EDSP program.
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http://dx.doi.org/10.1177/0192623315579943DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4636471PMC
December 2015

Histologic Features of Postnatal Development of Immune System Organs in the Sprague-Dawley Rat.

Toxicol Pathol 2015 Aug 16;43(6):794-815. Epub 2015 Apr 16.

WIL Research, Ashland, Ohio, USA.

The immune system of the rat undergoes substantial functional and morphological development during the postnatal period. Some aspects of this development are genetically predetermined, while other aspects depend on environmental influences. Detailed information on postnatal development is important in the interpretation of histopathologic findings in juvenile toxicology and pubertal assay studies, as well as other studies conducted in juvenile rats. Studies were conducted to provide detailed characterization of histologic features of the major functional compartments of immune system organs in male and female Sprague-Dawley rats at weekly intervals from the day of birth through postnatal day (PND) 42. Maturation of the individual immune system organs occurred across a range of ages, with histologic maturation of T-cell-related compartments typically occurring prior to maturation of B-cell-related compartments. The sequence of histologic maturation was bone marrow and thymus on PND 14, mesenteric lymph node on PND 21, Peyer's patches and bronchus-associated lymphoid tissue on PND 28, mandibular lymph node, nasopharynx-associated lymphoid tissue, and diffuse mucosal mononuclear cell population of small intestine on PND 35, and spleen on PND 42. An estimation of functional maturation can be made based on the morphological indications of maturity of each compartment of immune system organs, but histologic indications of maturity do not confirm functional immunocompetence.
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http://dx.doi.org/10.1177/0192623315578720DOI Listing
August 2015

Postnatal development of the testis in the rat: morphologic study and correlation of morphology to neuroendocrine parameters.

Toxicol Pathol 2015 Apr 11;43(3):326-42. Epub 2014 Sep 11.

WIL Research, Hillsborough, North Carolina, USA.

Histopathologic examination of the testis from juvenile rats is often necessary to characterize the safety of new drugs for pediatric use and is a required end point in male pubertal development and thyroid function assays. To aid in evaluation and interpretation of the immature testis, the characteristic histologic features of the developing rat testis throughout postnatal development are described and correlated with published neuroendocrine parameter changes. During the neonatal period (postnatal day [PND] 3-7), seminiferous tubules contained gonocytes and mitotically active immature Sertoli cells. Profound proliferation of spermatogonia and continued Sertoli cell proliferation occurred in the early infantile period (PND 8-14). The spermatogonia reached maximum density forming double-layered rosettes with Sertoli cells in the late infantile period (PND 15-20). Leptotene/zygotene spermatocytes appeared centrally as tubular lumina developed, and individual tubules segregated into stages. The juvenile period (PND 21-32) featured a dramatic increase in number and size of pachytene spermatocytes with the formation of round spermatids and loss of "infantile" rosette architecture. In the peri-pubertal period (PND 32-55), stage VII tubules containing step 19 spermatids were visible by PND 46. The presented baseline morphologic and endocrinologic information will help pathologists distinguish delayed development from xenobiotic effects, determine pathogenesis when confronted with nonspecific findings, and identify sensitive time points for targeted study design.
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http://dx.doi.org/10.1177/0192623314547279DOI Listing
April 2015

Postnatal ovary development in the rat: morphologic study and correlation of morphology to neuroendocrine parameters.

Toxicol Pathol 2015 Apr 8;43(3):343-53. Epub 2014 Aug 8.

WIL Research, Hillsborough, North Carolina, USA.

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.
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http://dx.doi.org/10.1177/0192623314544380DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4320985PMC
April 2015

Loss of leucine-rich repeat kinase 2 (LRRK2) in rats leads to progressive abnormal phenotypes in peripheral organs.

PLoS One 2013 14;8(11):e80705. Epub 2013 Nov 14.

Research Programs, The Michael J. Fox Foundation for Parkinson's Research, New York, New York, United States of America.

The objective of this study was to evaluate the pathology time course of the LRRK2 knockout rat model of Parkinson's disease at 1-, 2-, 4-, 8-, 12-, and 16-months of age. The evaluation consisted of histopathology and ultrastructure examination of selected organs, including the kidneys, lungs, spleen, heart, and liver, as well as hematology, serum, and urine analysis. The LRRK2 knockout rat, starting at 2-months of age, displayed abnormal kidney staining patterns and/or morphologic changes that were associated with higher serum phosphorous, creatinine, cholesterol, and sorbitol dehydrogenase, and lower serum sodium and chloride compared to the LRRK2 wild-type rat. Urinalysis indicated pronounced changes in LRRK2 knockout rats in urine specific gravity, total volume, urine potassium, creatinine, sodium, and chloride that started as early as 1- to 2-months of age. Electron microscopy of 16-month old LRRK2 knockout rats displayed an abnormal kidney, lung, and liver phenotype. In contrast, there were equivocal or no differences in the heart and spleen of LRRK2 wild-type and knockout rats. These findings partially replicate data from a recent study in 4-month old LRRK2 knockout rats and expand the analysis to demonstrate that the renal and possibly lung and liver abnormalities progress with age. The characterization of LRRK2 knockout rats may prove to be extremely valuable in understanding potential safety liabilities of LRRK2 kinase inhibitor therapeutics for treating Parkinson's disease.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0080705PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3828242PMC
February 2015

Regulatory forum opinion piece: what are pathology raw data?

Toxicol Pathol 2014 19;42(3):469-71. Epub 2013 Aug 19.

1WIL Research Laboratories, Hillsborough/Ashland, North Carolina/Ohio, USA.

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http://dx.doi.org/10.1177/0192623313501727DOI Listing
December 2014

Histologic features of prepubertal and pubertal reproductive development in female Sprague-Dawley rats.

Toxicol Pathol 2014 18;42(2):403-13. Epub 2013 Apr 18.

1WIL Research, Hillsborough, North Carolina, USA.

In response to growing concerns that environmental chemicals may have adverse effects on human health by altering the endocrine system, the Endocrine Disruptor Screening Program (EDSP), under the auspices of the United States Environmental Protection Agency (U.S. EPA), recently instituted a Tier I battery of tests including a female pubertal assay. This assay requires dosing of female rats from postnatal day (PND) 22 through PND 42 (or 43), the period of pubertal development in the rat, to identify test articles that may have estrogenic or antiestrogenic effects, or may alter hormones or neurotransmitters. While certain landmarks in female rat reproductive development are published, little is published on the microscopic appearance of the female reproductive tract during prepubertal and pubertal development. In this study, reproductive tissues from three female Sprague-Dawley rats were collected each day from PND 20 through PND 50, such that tissues from a total of 93 rats were collected throughout the prepubertal and pubertal period. Tissues were formalin-fixed, trimmed, paraffin-embedded, sectioned at 5-µm thickness, and examined microscopically. The major histologic features of the female reproductive tract throughout this critical period were described in detail. This information will help pathologists interpret findings observed in female pubertal assays.
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http://dx.doi.org/10.1177/0192623313484832DOI Listing
September 2014

Evaluation of propofol containing 2% benzyl alcohol preservative in cats.

J Feline Med Surg 2012 Aug 24;14(8):516-26. Epub 2012 Feb 24.

Taylor Monroe, Ely, UK.

Propofol emulsion containing benzyl alcohol preservative (BA) was evaluated in cats. Eight (PB) received 1% propofol containing 2% benzyl alcohol and eight (PC) preservative-free propofol. In phase 1, cats were anaesthetised (8 mg/kg) three times at 48 h intervals. In phase 2, cats underwent three anaesthetic procedures at 48 h intervals where anaesthesia was maintained until 24 mg/kg had been administered. Clinical examination and haematological and biochemical analyses were performed regularly. Cardiorespiratory function was monitored throughout anaesthesia. Neurological examination was performed daily for 7 days after phase 2. All cats were euthanased 7 days after phase 2 and examined post mortem to determine any organ toxicity and to comply with regulatory requirements. Anaesthesia was as expected for propofol in cats and no clinically relevant differences between PB and PC were detected. The addition of BA has no additional effect when propofol is used at normal-to-high clinical doses in healthy cats.
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http://dx.doi.org/10.1177/1098612X12440354DOI Listing
August 2012

Immune functioning in non lymphoid organs: the liver.

Toxicol Pathol 2012 16;40(2):237-47. Epub 2011 Nov 16.

WIL Research Laboratories, LLC, Hillsborough, North Carolina 27278, USA.

The liver is the primary hematopoietic organ of the mammalian body during the fetal stage. The postnatal liver retains immunologically important functions and contains a substantial population of immunologically active cells, including T and B lymphocytes, Kupffer cells, liver-adapted natural killer (NK) cells (pit cells), natural killer cells expressing T cell receptor (NKT cells), stellate cells, and dendritic cells. The liver is the major site of production of the acute phase proteins that are associated with acute inflammatory reactions. Kupffer cells have an important role in the nonspecific phagocytosis that comprises a major component of the barrier to invasion of pathogenic organisms from the intestine. Hepatic NK and NKT cells are important in the nonspecific cell killing that is important in resistance to tumor cell invasion. The liver has a major role in deletion of activated T cells and induction of tolerance to ingested and self-antigens. Disposal of waste molecules generated through inflammatory, immunologic, or general homeostatic processes is accomplished via the action of specific endocytic receptors on sinusoidal endothelial cells of the liver. Age-related changes in sinusoids (pseudocapillarization), autophagy, and functions of various hepatic cell populations result in substantial alterations in many of these immunologically important functions.
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http://dx.doi.org/10.1177/0192623311428475DOI Listing
August 2012