The INHAND Project (International Harmonization of Nomenclature and Diagnostic Criteria for Lesions in Rats and Mice) 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 changes in rats and mice. The purpose of this publication is to provide a standardized nomenclature for classifying changes observed in the hematolymphoid organs, including the bone marrow, thymus, spleen, lymph nodes, mucosa-associated lymphoid tissues, and other lymphoid tissues (serosa-associated lymphoid clusters and tertiary lymphoid structures) with color photomicrographs illustrating examples of the lesions. Sources of material included histopathology databases from government, academia, and industrial laboratories throughout the world. Content includes spontaneous lesions as well as lesions induced by exposure to test materials. The nomenclature for these organs is divided into 3 terminologies: descriptive, conventional, and enhanced. Three terms are listed for each diagnosis. The rationale for this approach and guidance for its application to toxicologic pathology are described in detail below.
SCH351591, a novel phosphodiesterase-4 inhibitor under investigation as a potential therapeutic for asthma and chronic obstructive pulmonary disease (COPD), was evaluated in a 3-month rising-dose study in Cynomolgus monkeys. Four groups, containing four monkeys/sex, received vehicle control or rising doses up to 12, 24, or 48 mg/kg of SCH351591 daily. Although initial exposure produced clinical signs of emesis, reduced food intake, and reduced body weight, tachyphylaxis to the emesis allowed dose escalation up to 48 mg/kg/day. Two monkeys died and 3 were sacrificed in moribund condition over the course of the study. Early mortality, involving monkeys dosed with 12 or 24 mg/kg, was attributed to sepsis (2 monkeys) or colon inflammation (3 monkeys). Leukocyte function assays on low-and mid-dose group survivors revealed an inhibition of T lymphocyte proliferation for 12 mg/kg group males and 24 mg/kg group monkeys of both sexes. Necropsy findings, unassociated with early mortality, included reduced size and weight of the thymus, depletion of body fat, red discoloration of the gastric mucosa, and perivascular hemorrhage of the stomach and heart. Stomach and heart gross findings were present in the high-dose group only. Histopathologic lesions, in addition to those attributed to concurrent bacterial infection, included thymic atrophy, serous atrophy of fat, myocardial degeneration and acute to chronic inflammation of small to medium-sized arteries in various organs and tissues including the heart, kidneys, stomach, salivary glands, pancreas, esophagus, gallbladder, and mesentery. The findings of this study demonstrate the potential of a PDE4 inhibitor to alter immunologic response as well as to produce arteriopathy in nonhuman primates.
Iodinated radiographic contrast media have traditionally been contraindicated in patients with sickle cell disease because their high osmolality may induce osmotic shrinkage of red blood cells, impair blood¯ow through the microcirculation, and precipitate or exacerbate a sickle cell crisis. This study investigated that concept by comparing the hematological and rheological effects in vitro of four X-ray contrast media of differing osmolalities: Visipaque (290 mOsm/kg), Hexabrix (600 mOsm/kg), Omnipaque (844 mOsm/kg), and RenoCal-76 (1940 mOsm/kg). Blood was tested from 10 normal and 10 sickle cell donors at drug concentrations of 0, 1, 10, and 30% w/v in an attempt to approximate the relative concentrations of contrast medium to blood that might occur during the bolus-injection and circulation-diluted phases of drug administration. Parameters evaluated included hematology, red cell morphology, and red cell¯ow resistance through a micropore ®lter to approximate the microcirculatory effects. Signi®cant hematological effects for both normal and sickle cell donors included a concentration dependent decrease in hematocrit and MCV, and increase in MCHC, all of which varied directly with the osmolality of the contrast media in the order of RenoCal-76 > Omnipaque > Hexabrix > Visipaque. The contrast media had minor effects on red blood cell morphology except for RenoCal-76, 10À30% in which marked echinocytosis was observed. There was no signi®cant increase in the number of irreversibly sickled cells in donors with hemoglobin S. Filterability of red cell suspensions through capillary size pores was impaired in both normal and sickle cell samples in direct proportion to the osmolality of the contrast media, as listed above. Filterability effects were greater for sickle cells than for normal red cells. Visipaque, which was closest to isotonicity, had little effect on red cell volume and had no signi®cant effect on ®lterability of normal or sickle cells. These results suggest that microcirculatory impairment following infusion of contrast media may occur in sickle patients because of the unusual rheological sensitivity of HbSS red cells, and may be avoided by choice of an isotonic medium. Am.
Malformations of the maxillary incisors, diagnosed as dental dysplasia, were observed as a spontaneous background lesion in 3% (females) to 9% (males) of CD-1® mice and 14.5% (females) to 10.5% (males) of CD@ (Sprague-Dawley) rats in a chronic inhalation study. Lesions were reported grossly as overgrown, maloccluded, or malformed incisors. Microscopic findings included tooth pulp and periodontal abscesses, fractured and necrotic teeth, periodontal cysts, malformations of the incisor roots, and expansile masses, including odontomas, of the incisor roots. Development of lesions followed a pattern of tooth pulp necrosis and/or traumatic disruption of the epithelial root sheath at the base of the tooth. Feeding a powdered ration, which reduced the normal wearing of the incisors, and repeated clipping of overgrown incisors were believed to contribute to the incidence of disease.
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