Phospholipidosis, a phospholipid storage disorder, defines an excessive accumulation of intracellular phospholipids. Phospholipids are structural components of mammalian cytoskeleton and cell membranes. The metabolism of this essential cell component is regulated by the individual cell and may be altered by drugs that interact with phospholipids or the enzymes that affect their metabolism. Xenobiotics or their metabolites that induce phospholipidosis include a wide variety of pharmacologic agents, including antibacterials, antipsychotics, antidepressants, antiarrhythmics, antianginals, antimalarials, anorexic agents, cholesterol-lowering agents, and others. Each of these drugs shares several common physiochemical properties: hydrophobic ring structure on the molecule and a hydrophilic side chain with a charged cationic amine group, hence the class term cationic amphiphilic drugs (CADs). This paper reviews the phospholipid metabolism, physiochemical characteristics of CADs, specificity of phospholipidosis in animals and humans, functional effects of phospholipidosis, interaction of CADs with biologic membranes and lysosome metabolism, influence of CADs on phospholipases and phospholipid synthesis, and a proposed mechanism for induction of phospholipidosis in the lung. In human risk assessment, investigators should consider the many factors in evaluating a drug that induces phospholipidosis in animals. These include: the therapeutic class of drug, presence of active metabolites, tissue or organ selectivity in animals and humans, influence of concurrently administered drugs, reversibility of effect, and other factors that increase or decrease the induction of phospholipidosis. Generalities regarding the etiology, incidence, and effect of the drug on a specific host may not be made. Each drug must be evaluated separately to identify the risk when administered for therapeutic effect in humans.

Analysis 2.4. Comparison 2 Comparison of theoretical basis of behavioural interventions, Outcome 4 Complex theoretical model with stage of change, motivational interviewing, cognitive behavioural therapy and/or social cognitive theory vs control.

The clinical, laboratory, and pathologic features ofa syndrome in dogs characterized by intermittent pain, fever, neutrophilia, and necrotizing arteritis are described to alert others involved in toxicity testing to the existence of this disorder. It is considered that this idiopathic syndrome is a latent condition, the expression of which can be precipitated in predisposed dogs by experimental treatment, and thus, its occurrence could complicate interpretation of toxicity studies. We have observed the disorder in 14 beagle dogs. The syndrome is rare and most cases for study were supplied by the breeder. Typical clinical signs observed included evidence of pain when the mouth was opened, grunting when lifted, and standing with an arched back and lowered head. Appetite was usually reduced. Body temperature was elevated (e.g., 104-106°F). There was progressive, bilateral atrophy of temporal and cervical musculature. Such signs have been observed to persist unremittingly or, more commonly, with periods of expression and remission. Neutrophilic leukocytosis and thrombocytosis were present. Hemoglobin and hematocrit were usually slightly decreased. Serum total protein was usually normal but albumin was reduced and alpha-2 globulins were markedly increased. Rheumatoid factor was elevated in several dogs. Arteritis was observed histologically and was characterized by necrosis, intimal proliferation, neutrophil and mononuclear cell infiltration in the media and periarterial tissues, and hemorrhage. Amyloidosis was observed in several dogs. The cause of this disorder is unknown. Knowledge of the distinct features of this syndrome should obviate complication of interpretation of results in toxicity studies and hopefully will lead to studies ofthis syndrome to provide an understanding ofits etiopathogenesis.

A unique morphologic change has been described in the submucosa of the urinary bladder of mice since the 1950s. These lesions. variously referred to as vegetative changes, reactive lesions, submucosal granulomas, leiomyosarcomas, atypical hemangiosarcomas, or submucosal mesenchymal tumors have been considered rare and of questionable etiology. Although the morphologic criteria are fairly well defined, the pathobiology of the lesion is not well characterized and the previously listed nomenclature reflects this uncertainty. The lesion may not be limited to the urinary bladder, the cell of origin is controversial, the biology is unknown, and whether the lesion is granulomatous, hypertrophy, hyperplasia, metaplasia, or a benign or malignant neoplasm is not well defined. Data compiled from multiple sources are discussed to review the strain of mouse most often affected, sex, age at diagnosis, anatomic location, incidence, descriptive morphology, immunohistochemical staining results, and other features of the submucosal mesenchymal tumor of the mouse urinary bladder. Presented are suggested terminology for the lesion, submucosal mesenchymal tumor of the mouse urinary bladder; the relevance of the tumor for human risk assessment; and discussion of the possible histogenesis of this lesion from primitive mesenchymal cells of the submucosa (lamina propria) of the urinary bladder of mice.

A retrospective study of red blood cell parameters in 53 dogs with experimental radiation-induced hemangiosarcoma showed 24 had anemia. Morphologic alterations in red blood cells in peripheral blood films from anemic dogs included signs of regeneration (anisocytosis and polychromasia), hypochromasia, red cell fragmentation and acanthocytosis. The degree and type of red cell changes varied from dog to dog and generally correlated with the principal site of tumor involvement. Blood from dogs with tumors principally involving liver had red cell regeneration, fragmentation and acanthocytosis. Blood from dogs with tumors primarily involving the heart had only red cell fragmentation. Blood films from dogs with skeletal and pulmonary hemangiosarcomas were similar to blood films from dogs with hepatic hemangiosarcoma except that red cell alterations generally were less severe. Scanning and transmission electron micrographic evaluation of neoplastic tissue showed large amounts of fibrin within neoplastic vascular sinuses and disruption and distortion of red blood cells traversing these abnormal vascular beds. The red blood cell fragmentation syndrome associated with radiation-induced hemangiosarcomas therefore was considered to be a microangiopathic hemolytic anemia of localized origin.