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Toxicologic Pathology

Janet M Petruska, Amera K Remick, Typhaine Lejeune, Mark Vezina, Keith Robinson, Martin Bussières, Brian C Gilger, Richard R Dubielzig
In a juvenile toxicology program, an unexpected finding of vacuolation of inner nuclear, ganglion cell, and nerve fiber layers of the retina was observed microscopically in routine Davidson's fixed and hematoxylin and eosin-stained tissue sections of eyes in beagle dogs at approximately 5 weeks of age. There was no necrosis or degeneration of the affected cells and no associated inflammation. Fluorescein angiography revealed no vascular leakage. Optical coherence tomography (OCT) indicated swollen cells in the same layers of the retina as observed at light microscopic examination...
May 7, 2019: Toxicologic Pathology
Sundeep Chandra, Patrizia Cristofori, Carlos Fonck, Charles A O'Neill
A therapeutic option for monogenic disorders is gene therapy with ex vivo-transduced autologous hematopoietic stem cells (HSCs). Safety or efficacy studies of ex vivo-modified HSCs are conducted in humanized mouse models after ablation of the murine bone marrow and transfer of human CD34+ HSCs. Engrafted human CD34+ cells migrate to bone marrow and differentiate into various human hematopoietic lineages. A 12-week study was conducted in NSG™ mice to evaluate engraftment, differentiation, and safety of human CD34+ cells that were transduced ( ex vivo) with a proprietary lentiviral vector encoding a human gene (BMRN-1) or a mock (green fluorescent protein) vector...
May 7, 2019: Toxicologic Pathology
Kyathanahalli S Janardhan, Priyanka Venkannagari, Heather Jensen, Mark J Hoenerhoff, Ronald A Herbert, David E Malarkey, Robert C Sills, Arun R Pandiri
The majority of the tumors in the gastrointestinal (GI) tract of rats and mice, with spindle cell morphology, are diagnosed as smooth muscle tumors (SMTs). Similarly, several decades ago human GI tumors with spindle cell morphology were also diagnosed as SMTs. However, later investigations identified most of these tumors in humans as gastrointestinal stromal tumors (GISTs). The GISTs are considered to arise from the interstitial cells of Cajal located throughout the GI tract. Positive immunohistochemical staining with CKIT antibody is a well-accepted diagnostic marker for GISTs in humans...
May 7, 2019: Toxicologic Pathology
Alexandra M Dieterly, Gozde Uzunalli, Chinyere M Kemet, Arvin H Soepriatna, Craig J Goergen, L Tiffany Lyle
Vertebral metastases of non-small cell lung cancer (NSCLC) are frequently diagnosed in the metastatic setting and are commonly identified in the thoracic vertebrae in patients. Treatment of NSCLC bone metastases, which are often multiple, is palliative, and the median survival times are 3 to 6 months. We have characterized spontaneous vertebral metastases in a brain metastases model of NSCLC and correlated these findings with epithelial-mesenchymal transition (EMT). Brain metastases were established in athymic nude mice following intracardiac injection of brain-seeking adenocarcinoma NSCLC cells...
May 7, 2019: Toxicologic Pathology
Natalie D Keirstead, Evan B Janovitz, James T Meehan, Bruce E LeRoy, John R Megill, Richard A Peterson, Regis G Masson, Heike A Marxfeld
Anatomic pathology and clinical pathology end points are standard components of almost every nonclinical general toxicity study conducted during the risk assessment of novel pharmaceuticals and chemicals. On occasion, an ultrastructural pathology evaluation using transmission electron microscopy (TEM) may be included in nonclinical toxicity studies. Transmission electron microscopy is most commonly used when a light microscopic finding may require further characterization that could inform on the pathogenesis and/or mechanism of action...
April 24, 2019: Toxicologic Pathology
Karen M Walters, Magalie Boucher, Germaine G Boucher, Alan C Opsahl, Peter R Mouton, Chang-Ning Liu, Casey R Ritenour, Thomas T Kawabe, Hayley N Pryski, Christopher J Somps
The potential for neurogenesis in the cranial (superior) cervical ganglia (SCG) of the sympathetic nervous system was evaluated. Eleven consecutive daily doses of guanethidine (100 mg/kg/d) were administered intraperitoneally to rats in order to destroy postganglionic sympathetic neurons in SCG. Following the last dose, animals were allowed to recover 1, 3, or 6 months. Right and left SCG from guanethidine-treated and age-matched, vehicle-treated control rats were harvested for histopathologic, morphometric, and stereologic evaluations...
April 15, 2019: Toxicologic Pathology
Kei Takahashi, Yasuhiro Morita, Shuji Udagawa, Seiki Yamakawa, Dai Watanabe, Mayu Mutsuga, Mayumi Nakajima, Makoto Kohno, Yohei Miyamoto, Keiyu Oshida
Drug-induced unique cytoplasmic vacuolation was found in the subchronic oral toxicity study of 4-dimethylamino-1-{3-(1-methyl-1H-imidazole-2-yl)propanoyl}piperidine (DMIP), a potential therapeutic agent for neuropathic pain, in beagle dogs. In the first study, DMIP was administered at a dose of 250, 500, or 1,000 mg/kg/day once daily for 14 days. Discoloration of tapetum lucidum accompanied by tapetal swelling was observed at ≥250 mg/kg/day. The tapetal swelling was correlated to the light microscopic observation of cytoplasmic vacuolation in tapetal cells, and similar vacuolation was observed in several other tissues, including the coronary artery and aortal arch, in a dose-dependent manner...
April 15, 2019: Toxicologic Pathology
Daniel Rudmann, Curtis Colleton
The choroid plexus (CP) produces cerebrospinal fluid and has epithelial, interstitial, and vascular compartments. The CP is a potential site of toxicity, and recognizing the normal microanatomy in different animal models is important for the pathologist. In preclinical studies with beagle dog and New Zealand white rabbits, we observed variable numbers of adipocytes in the CP interstitium of control and xenobiotic-treated animals. The adipocytes were unilocular and consistent morphologically with white adipose tissue...
April 15, 2019: Toxicologic Pathology
Emi Tomikawa, Mayu Mutsuga, Kojiro Hara, Chihiro Kaneko, Yuko Togashi, Yohei Miyamoto
Experimental autoimmune neuritis (EAN) is an animal model for Guillain-Barré syndrome (GBS), which results in neurological symptoms and histopathological changes in peripheral nerves. In this model, the correlation between the progression of the disease and the histopathological changes is not clear. To further examine histopathological changes in peripheral nerves in EAN rats, sciatic nerves were sampled at onset (day 10), peak (day 16), and recovery (days 22 and 25) of neurological symptoms in P2(57-81)-peptide-administered rats...
April 15, 2019: Toxicologic Pathology
Tao Chen, Ke Chen, Shaung Qiu, Peter C Mann
In a 2-year carcinogenicity study, we identified a spontaneous cholangiofibrosis in a control male Wistar rat. This lesion has long been considered as a compound-related change, with no spontaneous cases reported in the Wistar rat. In addition to routine hematoxylin and eosin stains evaluation, we applied Masson's trichrome staining, Alcian blue-periodic acid-Schiff staining, and OV-6 immunohistochemistry staining. The special staining demonstrated the fibrous component in the interstitium and intestinal metaplasia of the epithelium (presence of goblet cells), while the positive anti-OV-6 reaction indicated the bile duct origin of the epithelium...
April 15, 2019: Toxicologic Pathology
Yuval Ramot, Shlomo Nedvetzki, Sefi Rosenfeld, Noam Emanuel, Abraham Nyska
Bacterial infections are a common complication after surgical procedures. Therefore, local delivery of antibiotics has been developed, including the use of biodegradable polymers. A newly developed product for prevention of surgical site infections is a polymer-lipid encapsulation matrix loaded with doxycycline, named D-PLEX100 (D-PLEX). We evaluated the toxicity and safety of D-PLEX using a sternal surgical defect model in rabbits. D-PLEX was tested with three different concentrations of doxycycline in comparison to sham-operated control after administration into the sternal surgical defect and on the ventral side of the sternum in New Zealand White (NZW) rabbits, following 15 months of exposure...
April 11, 2019: Toxicologic Pathology
Lars Mecklenburg, C Marc Luetjens, Gerhard F Weinbauer
If nonhuman primates represent the only relevant species for nonclinical safety evaluation of biotechnology-derived products, male and female fertility effects can be assessed in repeat dose toxicity studies given that sexually mature monkeys are used. This opinion piece provides recommendations for determining sexual maturity and when/how fertility assessments should be conducted in the cynomolgus monkey. Male sexual maturity should be proven by presence of sperm in a semen sample, female sexual maturity by at least two consecutive menstrual bleedings...
March 21, 2019: Toxicologic Pathology
Yuval Ramot, Noam Kronfeld, Michal Steiner, Guy Klaiman, Amir Hadid, Michal Sudak, Abraham Nyska
Self-adhesive meshes are being developed to avoid complications due to traumatic fixation methods. LifeMesh™ is a novel self-adhesive mesh with a biodegradable gelatin adhesive layer developed for hernia repair. The aim of this study was to assess the safety and biodegradability of LifeMesh in Sprague-Dawley (SD) rats for 6 weeks, in comparison to a bare polypropylene (BPP) mesh fixed with sutures. LifeMesh was tolerated well and its implantation did not result in any adverse local reaction, and its adhesive layer was substantially degraded after 4 weeks...
March 21, 2019: Toxicologic Pathology
Molly C Friedemann, Nicole A Mehta, Staci L Jessen, Fatima H Charara, Anne-Marie Ginn-Hedman, Courtney N Kaulfus, Breanna F Brocklesby, Cedric B Robinson, Steven Jokerst, Alan Glowczwski, Fred J Clubb, Brad R Weeks
Pathologic evaluation is crucial to the study of medical devices and integral to the Food and Drug Administration and other regulatory entities' assessment of device safety and efficacy. While pathologic analysis is tailored to the type of device, it generally involves at a minimum gross and microscopic evaluation of the medical device and associated tissues. Due to the complex nature of some implanted devices and specific questions posed by sponsors, pathologic evaluation inherently presents many challenges in accurately assessing medical device safety and efficacy...
March 7, 2019: Toxicologic Pathology
Taylor A Spangler, Scott A Katzman
The design, production, and preclinical testing of neurothrombectomy devices is in a burgeoning phase as the demand escalates for safe and reliable treatment options following neurovascular stroke. Currently, there is a paucity of published data describing the development of iatrogenic vascular lesions occurring secondary to neurothrombectomy procedures. In an effort to test new devices, demonstrate device safety, satisfy regulatory requirements, and develop an understanding of the potential for associated vascular pathology, investigators are establishing appropriate methodology in suitable animal models...
March 4, 2019: Toxicologic Pathology
Serge D Rousselle, Joan A Wicks, Brian C Tabb, Armando Tellez, Maureen O'Brien
Histology of medical devices poses a variety of unique challenges. Comprehensive histologic assessment of medical devices often requires spatial context and high-quality retention of the device-tissue interface. However, the composition of many medical devices is often not amenable to traditional paraffin embedding and thus alternative specialized methodologies such as hard resin embedding must be used. Hard resin embedding requires specialized laboratory technical expertise and equipment, and the fixation techniques and resin composition used markedly impact the feasibility of immunohistochemistry...
February 14, 2019: Toxicologic Pathology
Armando Tellez, Marco Ferrone, Juan F Granada
Significant improvements in quality of life and mortality have occurred over the last century due to the giant advancements in medical innovation. Medical innovation continues to move forward, and it is expanding to areas never explored before. In particular, the advancement in big data analytics is now enabling the rapid progress in the understanding of gene influence in human diseases. The progress in medical innovation achieved until today is significant; however, the potential that future technologies have to modify patterns of disease thought to be incurable is mind-boggling...
February 11, 2019: Toxicologic Pathology
Akihisa Kangawa, Masayoshi Otake, Satoko Enya, Toshinori Yoshida, Masatoshi Shibata
Microminipigs have become an attractive animal model for the toxicology- and pharmacology-related studies because of their manageable size. In this study, the development of the testicular interstitium and steroidogenesis in microminipigs, from 0 to 12 months of age, were investigated. Testicular interstitium was mostly composed of two types of Leydig cells (large and small Leydig cells) and a few macrophages and mast cells. Large Leydig cells were observed in the peritubular area throughout all the ages. Small Leydig cells were present in the interlobular and subcapsular areas at an early age and then gradually converted into large Leydig cells...
February 10, 2019: Toxicologic Pathology
James R L Stanley, John H Keating, Kathryn J San Souci
The terminal collection and histological processing of medical devices is an expensive, labor-, and material-intensive endeavor, which requires adequate experience, innovation, and preparation for success. It is also an exciting endeavor that continually challenges, intellectually engages, and improves the skills and knowledge of the pathologist. Awareness of the importance of the medical device pathologist's involvement, communication, and oversight throughout the development, implementation, and execution of a nonclinical assessment of a medical device is in the best interest of the test facility, the histopathology laboratory, the pathologist, the sponsor, and, ultimately, the patients...
February 6, 2019: Toxicologic Pathology
William C Stoffregen, Serge D Rousselle, Marian K Rippy
Cardiac electrophysiology utilizes nonimplantable, catheter-based devices for diagnosis and treatment of arrhythmias as well as electroanatomical mapping of cardiac chambers. Gross pathology and histopathological assessments in preclinical studies play critical roles in determining the safety and efficacy of cardiac ablation systems used to treat tachyarrhythmias. The pathologist must assess ablation sites, adjacent structures and organs, and downstream organs to characterize the effects of the ablation treatment and determine whether adverse local reactions, collateral injury, or downstream thromboembolism are present...
February 6, 2019: Toxicologic Pathology
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