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Inflammation has also been reported as a consequence of release of secretory material from the duct system into the mammary stroma (Boorman et al blood pressure potassium discount plavix 75 mg buy on line. In older female beagle dogs, lymphocytic inflammation may be observed in the mammary stroma as a spontaneous finding (Cameron and Faulkin 1971). It should be noted that in normally cycling female dogs, the histology of the mammary gland during the first estrus/metestrus may mimic an inflammatory reaction as the gland is enlarged with ductal proliferation within a spectrum of stromal changes, which are characterized by a loose, swirling pattern of fibroblasts against an edematous or myxomatous background accompanied by foci of extravasated erythrocytes and scattered lymphocytes (Chandra et al. Dilated ducts are typically lined by flattened to cuboidal epithelium with a thin connective tissue wall, and the lumen contains 986 Toxicologic Pathology proteinaceous residue, cell debris, and sometimes inflammatory cells. Marked dilation of ducts or alveoli may be visible grossly as white secretion-filled cysts and are referred to as galactoceles (van Zwieten et al. In rodents, duct dilation is a fairly common finding, particularly in older females, but has also been described in up to 5% of males in 2-year bioassays using Sprague-Dawley rats (van Zwieten et al. In macaques, cystic changes in lobular or ductal elements of the mammary gland are a common incidental finding usually observed in parous females (Cline 2007). In older animals, they may be associated with various hyperplastic lesions (Wood et al. While dilation of the mammary duct system has been reported in the general canine population (Hampe and Misdorp 1974; Miller et al. Dilation of mammary ducts has occasionally been reported as an effect of treatment in nonclinical safety studies, as with the administration of thalidomide to dogs (Teo et al. Spontaneous fibrosis is often observed in older rats, mainly around ducts (periductal), though it may also occur in intralobular or interlobular areas (Boorman et al. In mice, replacement of adipose tissue with fibrous connective tissue is reported in older animals in association with decreased size of the mammary gland (Kenney et al. Fibrosis of the mammary gland may also be induced experimentally and has been reported in association with iodine deficiency (Eskin et al. Fibrosis and inflammation may also be seen in association with the testing of implants of foreign materials (Greaves 2007). In many cases, it may be used to convey a physiological response to an abnormal hormonal stimulus. The lack of clarity around the term in veterinary pathology has arisen for a variety of reasons, including differences in morphology due to species and strain, the use of inconsistent or imprecise terminology often borrowed from human medicine, and a lack of descriptive clarity in the literature (Cline 2007; Greaves 2007). Given potential differences in usage and application, it is always important to consider the biological context when interpreting this change. Much of our understanding of mammary gland hyperplasia comes from work done in rodents and humans. While mammary tumors often arise in the terminal ductal regions of humans and many rodent models (Allred et al. Additionally, there is considerable evidence that hyperplasia is a risk factor for cancer and in some cases part of a continuum leading to the mammary gland cancers (Allred et al.
Gotshall R blood pressure chart bhf cheap 75 mg plavix amex, Hess T, Mills T: Efficiency of canine renal blood flow autoregulation in kidneys with or without glomerular filtration. Just A, Wittmann U, Ehmke H, et al: Autoregulation of renal blood flow in the conscious dog and the contribution of the tubuloglomerular feedback. Loutzenhiser R, Griffin K, Williamson G, et al: Renal autoregulation: new perspectives regarding the protective and regulatory roles of the underlying mechanisms. Takenaka T, Suzuki H, Okada H, et al: Mechanosensitive cation channels mediate afferent arteriolar myogenic constriction in the isolated rat kidney. Hayashi K, Epstein M, Loutzenhiser R: Enhanced myogenic responsiveness of renal interlobular arteries in spontaneously hypertensive rats. Hayashi K, Epstein M, Loutzenhiser R: Determinants of renal actions of atrial natriuretic peptide. Lack of effect of atrial natriuretic peptide on pressure-induced vasoconstriction. Bayliss W: On the local reactions of the artrial wall to changes in internal pressure. Just A: Mechanisms of renal blood flow autoregulation: dynamics and contributions. Hayashi K, Epstein M, Loutzenhiser R, et al: Impaired myogenic responsiveness of the afferent arteriole in streptozotocin-induced 283. Olivera A, Lamas S, Rodriguez-Puyol D, et al: Adenosine induces mesangial cell contraction by an A1-type receptor. Brown R, Ollerstam A, Johansson B, et al: Abolished tubuloglomerular feedback and increased plasma renin in adenosine A1 receptor-deficient mice. Thomson S, Bao D, Deng A, et al: Adenosine formed by 5-nucleotidase mediates tubuloglomerular feedback. Schnermann J, Traynor T, Yang T, et al: Tubuloglomerular feedback: new concepts and developments. Vallon V: Tubuloglomerular feedback in the kidney: insights from gene-targeted mice. Thorup C, Erik A, Persson G: Macula densa derived nitric oxide in regulation of glomerular capillary pressure. Hishikawa K, Nakaki T, Suzuki H, et al: Transmural pressure inhibits nitric oxide release from human endothelial cells. Hishikawa K, Nakaki T, Marumo T, et al: Pressure enhances endothelin-1 release from cultured human endothelial cells. Barajas L, Liu L, Powers K: Anatomy of the renal innervation: intrarenal aspects and ganglia of origin. Kon V, Yared A, Ichikawa I: Role of sympathetic nerves in mediating hypoperfusion of renal cortical microcirculation in experimental congestive heart failure and acute extracellular volume depletion. Chagnac A, Weinstein T, Korzets A, et al: Glomerular hemodynamics in severe obesity.
The lymph glands are small oval or bean-shaped bodies blood pressure under 60 buy plavix 75 mg with visa, situated in the course of lymphatic and lacteal vessels so that the lymph and chyle pass through them on their way to the blood. The stream of lymph in its passage through the lymph sinuses is much retarded by the presence of the reticulum, hence morphological elements, either normal or morbid, are easily arrested and deposited in the sinuses. Many lymph corpuscles pass with the efferent lymph stream to join the general blood stream. Over the years, there have been changes in the perception of lymph nodes from being small universally simple structures, such as the description by Gray, and typified by the node of a mouse to nodes that display a significant range of distinctly different architectures that vary within an animal and across species. Therefore, while the basic premises of nodal histomorphology and function might remain the same for lymph nodes in general, the pathologist must be prepared to factor in a number of variables depending on which specific lymph nodes are examined as well as the age, species, and strain of animals from which the nodes are collected. An accurate knowledge of the number, location, and anatomy of draining lymph nodes and their regional lymphatics is essential to accurately assess potential xenobiotic damage to the lymphoid system. In comparison to other species, the lymph nodes of mice are relatively few (approximately 22) and organized into simple chains (Dunn 1954). Conversely, as species get larger, lymph nodes become more numerous (approximately 450 in humans) and are organized into more complex chains that individually drain proportionately smaller areas of tissue. For example, the lung of the rat is drained by two posterior mediastinal nodes (Tilney 1971), while in the dog this is achieved by three-to-five tracheobronchial nodes (Hare 1975), and in man 35 or more tracheobronchial nodes classified into five separate groups. The increased number of smaller nodes in larger species is accompanied by an increased number of anastomoses of afferent lymphatic vessels within lymph node chains compared to that in smaller species. The rat, having a relative lack of lymphatic anastomosis, translocates small amounts of material to subportions of the node rather than the entire node. Extensive anastomoses of lymphatic channels in larger species results in the mixing of lymph arising from a specific site that culminates in lymph nodes that have a more uniform drainage pattern with simultaneous exposure of more nodal compartments to the lymph. Elegant work by Belisle and Sainte-Marie (1981a,b,c) has delineated the complexities of lymph nodes; while some nodes have a continuous subcapsular sinus and peripheral cortex, most have highly variable segmentation by extension of the medullary sinus into the subcapsular sinus. Understanding this variability is key to recognizing the limitations of histologic examination in identifying subtle alterations in lymph nodes following xenobiotic administration. Belisle and Sainte-Marie were the first to describe "functional complexes" within the node that are comprised of semi-rounded structures with a dense lymphocyte population in the center surrounded by a loose population of lymphocytes, reticulum network, postcapillary venules, and lymphatic sinuses. Lymph nodes from mice, guinea pigs, hamsters, rabbits, dogs, and humans share similar tridimensional architecture (Belisle and Sainte-Marie 1981d), but in larger species there is an increase in the number of functional units rather than an increase in the size of individual units. Thus, the microscopic complexity seen in large versus small animals recapitulates what is seen grossly. Variation of lymph node microanatomy can be seen within an individual, depending on the location of the node. Exceptions to this are nodes that drain tissues with high exposure to external microbes and pathogens such as the mandibular and mesenteric nodes, and as a result, they frequently contain large secondary follicles with germinal centers and wider medullary cords filled with plasma cells. Normal dogs maintained in kennels or in cages usually have numerous, well-developed secondary follicles with large, reactive germinal centers that may extend into the deep cortex.
Systemic exposure to nanoparticles may be increased by dermabrasion blood pressure medication non prescription generic 75 mg plavix otc, damaged skin, or skin wounds. The reader is referred to a 2017 book on this subject Adverse effects of Engineered Nanomaterials: Exposure, Toxicology, and Impact on Human Health with a chapter by Nancy Monteiro-Riviere specifically on skin exposure to nanoparticles for more Information. Systemic exposure to nanoparticles applied topically can be affected by many factors, including skin thickness, which may affect the choice of test species. Studies in minipigs of sunscreen containing TiO2 nanoparticles applied to intact skin demonstrated no systemic exposure on the basis of the lack of evidence for increased levels of TiO2 concentrations in liver or lymph nodes. Polyethylene glycol-coated cadmium selenide quantum dot (semiconductor) nanoparticles were shown to reach liver levels of 2% of the cadmium applied to dermally abraded skin. Hairless mice did have systemic exposure after topical application of TiO2 nanoparticles, indicating that species-specific systemic exposure may be related to skin thickness. Additionally, other constituents of topical formulations may influence skin penetration of nanoparticles. Aqueous formulations tend to reduce penetration of TiO2 nanoparticles, whereas oily formulations may enhance penetration. In addition to concerns over systemic exposure, nanoparticles may potentially interact with antigen-presenting cells in the skin (reviews by Dobrovolskaia 2015; Pallardy et al. Regulatory guidances for the evaluation of nanoparticle immunotoxicity are still being developed (Dobrovolskaia et al. Nanoparticles do not react with conventional histologic stains, highpower magnification is required, the nanoparticles may be highly dispersed within the tissues, and the depth of field on conventional light microscopes is limiting. Special labeling techniques have been developed to enhance detection of nanoparticles by microscopy including colloidal gold labeling, silver enhancement of gold labeling, and use of fluorescent indicators, as well as the use of specialized Imaging techniques (Breunig et al. Tissue reactions may help guide detection but can be extremely subtle if the particle is designed to be inert. Histopathologic studies of the toxic effects of nanoparticles have largely focused on the lungs after inhalation, where the principal changes observed were granulomatous inflammation and fibrosis, with pleural thickening and dilation of lymphatics. While conventional scanning electron microscopy has been shown to be a useful means for demonstrating micrometer-sized particles, it has proved less than optimal for nanoparticles. Field emission scanning electron microscopy has significantly improved resolution for detecting nanoparticles 1050 Toxicologic Pathology owing to its unique "cold" cathode design, which produces low-voltage images with negligible electrical charging to produce high-quality images. With emergent technologies, biomaterials now include biopolymers, self-assembled systems, nanoparticles, carbon nanotubes, and quantum dots (Williams 2009), as well as various dermal fillers used for rejuvination surgery or medical aesthetics (review by Chiang et al. Medical devices constitute a diverse range of products with similarly divergent uses. These biomaterials typically do not elicit a pharmacologic response (unless in combination with a drug), and reactions are time dependent rather than dose dependent. Potential safety risks associated with implanted biomaterials may be associated with the type of material used, leachables from the implant, local or systemic response (Jacobs and Urban 1996), and the development of biofilms (Kravvas et al. Additionally, inadvertent misadministration (such as accidental injection into a blood vessel) can occur, especially with less experienced technician administering the product, can become a complication of these implanted biomaterials.
Diseases
Planimetric methodologies using nonperfusion-fixed tissues could be used for morphometric analysis of muscular arteries when vascular toxicity is suspected (Lowe 1984) blood pressure pump effective plavix 75 mg. However, the preferred and more accurate assessment requires a sufficient number of vessels 794 Toxicologic Pathology to be studied using morphometric analysis of tissues collected using perfusion fixation at appropriate pressures (Lowe 1984). Thickening of the medial smooth muscle cell layer with reduced lumen size is the hallmark of hypertension, but novel drug candidates may also produce this effect without marked increases in systemic blood pressure, despite possible localized increases in some vascular beds. Though the morphologic changes suggest hypertension, it is also possible that marked vessel wall tension as a result of excessive vasodilation due to exaggerated pharmacology can induce an adaptive vascular response characterized by medial smooth muscle hypertrophy (Wagenaar and Wagenvoort 1978; Weibel 1958). Within the intima of muscular arteries, particularly in humans, longitudal smooth muscle fibers can undergo hypertrophy. This type of hypertrophy has been observed in bronchial arteries in humans, but can also be seen in some systemic vessels in the laboratory rat, characterized by a longitudinally arranged, non-concentric increase in smooth muscle cell size (Wagenaar and Wagenvoort 1978; Weibel 1958). These changes can also be induced in the mesenteric arteries of the rat by local surgical damage and manipulation (Wagenaar and Wagenvoort 1978; Weibel 1958). Arterial injury is the end result of a series of complex interactive events that include derangements in normal vascular physiology, loss of vascular homeostatic tone, and initiation of local and systemic compensatory mechanisms. Drugs and/or chemicals cause arterial damage by directly interacting with vascular wall components, or through direct or indirect interaction of drugs with the cellular and molecular pharmacologic targets within the vessel wall. Inhibition of this enzyme by phenelzine prevents allylamine-induced vascular injury (Hysmith and Boor 1988). Direct-acting vascular toxicants can be detected/predicted using in vitro assays (Boor et al. As a response to sustained and/or profound hypertension, changes of increased medial thickness (resulting from hypertrophy and/or hyperplasia), necrosis, hyalinization, and cytoplasmic vacuolation are seen with light microscopy, and cell-to-cell hernias, ultrastructurally (Joris and Majno 1981). Experimentally, arterial lesions can be induced in rats and dogs administered endogenous vasoconstrictive agents or agonists, and the resulting physiologicallyinduced hypertension causes a morphologically similar arterial lesion, regardless of the inciting cause (Golby and Beilin 1972; Joris and Majno 1981; Wiener and Giacomelli 1973). In nonclinical safety studies, hypertension, renal glomerular capillary injury with proteinuria, and vascular injury have been observed (personal observation). Hypertension and proteinuria have been seen in clinical subjects (Pridjian and Puschett 2002; Roberts et al. It is interesting to note that while the pharmacologic targets are quite diverse, there is often a common second intracellular messenger; hence, a common pharmacologic and toxic response (Table 18. Caveolin-1 is expressed within the vascular wall, specifically on the phenotypically anchored primary targets of drug-induced vascular injury, endothelial and smooth muscles cells (Drab et al. Within these cells, caveolin is an important mediator of many signal transduction pathways, including regulation of vascular tone (Martens et al. Functionally, caveolae appear to be the focal point for compartmentalizing, organizing and modulating signal transduction activities (Linder et al. Pulmonary arteries and veins are large vessels with high blood flow and low vascular resistance. Histologically, the pulmonary veins may have cardiac muscle around the walls, lack internal elastic lamina, and are located at the periphery of the acinus.
Long-term administration of estrogenic compounds (7+ years) has been reported to induce smooth muscle tumors (leiomyoma and leiomyosarcoma) in the uterus and vagina of dogs (Johnson 1989) blood pressure medication breastfeeding order plavix 75 mg on line. They have been reported in mice and rats, Reproductive System and Mammary Gland 977 but are rarely reported in other nonclinical species (Goodman and Hildebrandt 1987c; Reuber et al. Epithelial proliferation and cornification during the estrous cycle occur under the influence of estrogen and this responsiveness is an extremely sensitive indicator of compounds with estrogenic activity (Reel et al. Development of the mucified layer of cells normally observed in proestrus requires the influence of progesterone in combination with estrogen (Barker and Walker 1966). These mucified cells are typically cuboidal to cylindrical and clear to basophilic, with cytoplasmic vacuoles containing sialomucins (Warren and Spicer 1961). Atrophy may also occur as a consequence of debilitation, presumably due to decreased gonadotropin secretion (Maekawa and Maita 1996; Yuan and Foley 2002). Atrophy of the vaginal and/or cervical epithelium may be observed due to any xenobiotic-induced endocrine disruption affecting the production or actions of estrogen (Luo et al. Mucification normally occurs under the influence of progesterone and is observed spontaneously during pregnancy and pseudopregnancy and as a manifestation of reproductive senescence in association with persistent diestrus and elevated progesterone. Epithelial mucification of the vagina, and to a lesser extent the cervix, is a common feature of endocrine disruption in the intact rodent and has been reported after treatment with exogenous progestins, gonadotropins, androgens (including non-aromatizable androgens), anti-estrogens, aromatase inhibitors, and compounds that increase prolactin levels (Brown et al. It is important that mucification due to endocrine disruption be distinguished from the normal cyclical appearance of the vaginal epithelium at proestrus. Non-cyclical mucification may accompany atrophy or hyperplasia of the vaginal epithelium and usually occurs in the absence of an underlying stratum granulosum or stratum corneum. In rodents, an increase in neutrophils is commonly seen from estrus into early diestrus and should not be mistaken for inflammation. This increase in neutrophils is largely driven by estrogen exposure, and decreases in estrogen can cause a reduction 978 Toxicologic Pathology in neutrophil influx. This lesion typically originates from basal cells that extend from the squamous cervix and underlie cervical glands. The cervix can also be a site of test articlerelated changes, and squamous metaplasia of the macaque cervix has been reported with estrogenic compounds and dioxin (Graham 1970; Scott et al. Squamous epithelial cysts are occasionally seen in rodents of all ages (Leininger and Jokinen 1990; Yuan and Lund 1991). These cysts are typically located beneath the mucosal epithelium, lined by squamous epithelium, and often filled with keratin. Additionally, the appearance of the epithelium may vary with the stage of the estrous cycle. In mice, small epithelial-lined cystic structures are often observed microscopically within the vaginal submucosal or adjacent to the cervix (Creasy 2012). Cystic dilatation of the vaginal fornix with luminal accumulation of inspissated material has been reported as a rare finding in aged rats (Yoshitom 1990). In mice, cervicovaginal adenosis, a metaplastic change in which foci of welldifferentiated columnar epithelial cells are present within areas of normal stratified squamous epithelium, has been described as a consequence of estrogenic stimulation and perinatal estrogen exposure in mice (Greaves 2007; Highman et al. Hyperplasia of the cervical and vaginal epithelium has also been reported in rats following treatment with a nucleoside analog for treatment of retroviral infections (Woicke et al.
The first degree is limited to the vaginal mucosa hypertension facts plavix 75 mg order, the second degree affects the perineal body, the third degree involves the sphincter ani muscle, and the fourth degree also involves the rectal mucosa [2]. Vulvar and vaginal hematomas occur with an incidence of 1 in 300 to 1 in 1400 during spontaneous vaginal deliveries [3]. Risk factors for hematoma formation include prolonged labor, birthweight >4000 g, episiotomy, nulliparity, instrumental delivery, breech delivery, delivery of multiples, vulvovaginal varicosity, and hypertensive disorders of pregnancy. However, most hematomas occur during normal labor in the absence of any of these risk factors [4]. Nonobstetric Trauma Blunt Injuries and Hydrotrauma these injuries can vary significantly in their nature, including sports-related injuries, penetrating injuries, insufflation injuries, and human and animal bites. Of the sports injuries, bicycle injuries are the most common, whereas other sports injuries include soccer, gymnastics, horseback riding, wrestling, and tennis. Most of these injuries are considered straddle injuries, in which the patient sustains an injury to the perineum as a result of falling or striking a surface. The labial fat pads of the vulva are usually protective, preventing tears or bruising, but severe forces can be penetrating and result in lacerations, abrasions, bleeding, hematoma formation, and dysuria. Vaginal insufflation injuries occur when water enters the vagina with a high hydrostatic pressure. The high pressure results in overdistention of the vaginal walls, resulting in tears and, in some cases, bleeding if the branches of the anterior division of the internal iliac artery are compromised. These injuries are more common in prepubertal girls since the labia does not offer significant protection to the vagina at that age. Most of the documented animal bites are from dogs, resulting in injuries to the perineal area affecting the external genitalia and anal sphincter. These injuries are associated with high rates of infection requiring antibiotic prophylaxis. Human bites have also been documented, and the injury as a result of these bites is usually milder, rarely causing any avulsion of the tissue, as compared to an animal bite [9]. Sexual Trauma the genital examination protocols to detect trauma after sexual intercourse include performing macroscopic examination, staining, colposcopy, or a combination of the three techniques. The use of toluidine blue dye, which stains damaged epithelium, increases the detection of anogenital injuries in consensual and nonconsensual sexual intercourse compared to macroscopic detection.
Cystic degeneration occurs in approximately 4% of fibroids and typically occurs after hyaline degeneration heart attack cover by sam tsui and chrissy costanza of atc plavix 75 mg purchase. Ring-like calcification can be seen due to thrombosed veins from a previous red degeneration. Although they are rare, they are important because they can be seen in leiomyosarcoma and other malignant tumors [24]. Red or carneous degeneration occurs in 8% of fibroids during pregnancy and 3% of all uterine fibroids. It is suggested to result from peripheral venous obstruction that leads to hemorrhagic infarction and extensive necrosis, which may involve the whole lesion. Degeneration presents clinically with pelvic pain, low-grade fevers, and leukocytosis lasting from a few days to weeks. Occasionally, degeneration can result in menorrhagia that can decrease hemoglobin levels [26]. Fibroid degeneration is commonly confused with adnexal torsion and subacute pelvic inflammatory disease due to the primary symptom of pain. Symptoms are nonspecific, and detection of thin pedicles on imaging can be challenging [27]. Delayed treatment can lead to ischemic gangrene and peritonitis, which can be life threatening [23]. Differential diagnosis includes other emergent pathologies such as acute appendicitis, acute diverticulitis, bowel obstruction, perforated viscus, and adnexal torsion. In theory, large fibroids can compress pelvic veins, leading to stasis and thrombosis. However, due to the high prevalence of fibroids, other risk factors usually present, including pregnancy, surgical procedures, oral contraceptive use, antiphospholipid antibody syndrome, other acquired and inherited thrombophilias, long-term immobility, long-haul air travel, and dehydration [23, 28]. Histopathologic results in these cases show hyaline degeneration with areas of necrosis and hemorrhage [29]. Intraperitoneal hemorrhage secondary to fibroid is rare, although it remains on the differential, especially if the patient has a known history of fibroid [30]. It has been hypothesized that increased intra-abdominal pressure can cause passive venous congestion and subsequent rupture of superficial vessels overlying the fibroid [31]. This can result from trauma, menstruation, pregnancy, strenuous exercise, weight-bearing activity, and abdominal massage. The differential diagnoses to consider include ruptured corpus luteum and ruptured hemorrhagic cyst [30]. Imaging Ultrasound is usually the initial imaging modality to diagnose, monitor, and detect fibroid complications.
Jack, 44 years: In addition, even in the United States, comprehensive sex education is not typically offered to adolescents in public or private schools. Differentiating spontaneous from drug-induced pyelonephritis when small numbers of animals are affected can present a diagnostic dilemma. These endocrine findings reflect the presence of numerous follicular cysts in the ovary, ongoing follicular development, and an absence of corpora lutea (vom Saal et al. Concentric hypertrophy is a disproportionate increase in ventricular wall thickness with a normal or reduced end-diastolic and chamber volume.
Kulak, 29 years: Noise can also induce a physical damage to the sensory cells, resulting in necrosis. Note the marked increased in physeal thickness in the young rat compared with the older rat. They also found the rate of persistent interstitial pregnancy to be higher in ruptured cases (27. Benign melanoma has been reported in a variety of domestic and laboratory animals, including dogs, cats, and pigs, but is 1074 Toxicologic Pathology exceedingly rare in mice and rats (Garma-Avina et al.
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