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Following implantation of patient-derived xenograft (PDX) breast carcinomas from three separate individuals, 33/51 female NOD. Cg-PrkdcscidIl2rgtm1Wjl/SzJ (NSG) mice presented with progressive, unilateral to bilateral, ascending hindlimb paresis to paralysis. Mice were mildly dehydrated, in thin to poor body condition, with reduced to absent hindlimb withdrawal reflex and deep pain sensation. Microscopically, there was variable axonal swelling, vacuolation, and dilation of myelin sheaths within the ventral spinal cord and spinal nerve roots of the thoracolumbar and sacral spinal cord, as well as within corresponding sciatic nerves. Results of PCR screening of PDX samples obtained at necropsy and pooled environmental swabs from the racks housing affected animals were positive for lactate dehydrogenase–elevating virus (LDV). LDV is transmitted through animal-animal contact or commonly as a contaminant of biologic materials of mouse origin. Infection is associated with progressive degenerative myelopathy and neuropathy in strains of mice harboring endogenous retrovirus (AKR, C58), or in immunosuppressed strains (NOD-SCID, Foxn1nu), and can interfere with normal immune responses and alter engraftment and growth of xenograft tumors in immunosuppressed mice. This is the first reported series of LDV-induced poliomyelitis in NSG mice and should be recognized as a potentially significant confounder to biomedical studies utilizing immunodeficient xenograft models.

Following implantation of patient-derived xenograft (PDX) breast carcinomas from three separate individuals, 33/51 female NOD.

Tetracyclines have been used as in vivo indicators of new bone formation because they form complexes with mineral at bone-forming surfaces. Four of 12 dogs in a bone-labeling study developed clinical signs of renal disease (vomiting, diarrhea, dehydration, and azotemia) within 1 to 2 days of receiving oxytetracycline at a bone-labeling dose of 25 mg/kg of body weight, once daily for 2 consecutive days. To delineate the relationship between oxytetracycline administration and renal damage, six dogs were given the bone-labeling dose intravenously and were subsequently evaluated by determination of clinical signs, serum biochemical analysis, urinalysis, and histologic examination (experiment 1). Drug administration was modified in the five dogs remaining in the bone-labeling orthopedic study. These dogs received the oxytetracycline dose as a slow intravenous infusion diluted with 250 ml of lactated Ringer's solution (experiment 2). All six dogs of experiment 1 developed persistent isosthenuria within 2 days of receiving the bone-labeling dose of oxytetracycline. Clinical illness (three of six dogs) was associated with azotemia, creatinemia, and hyperphosphatemia. All dogs had multifocal, mild to moderate flattening of renal tubular epithelium, characteristic of nephrosis. None of the dogs of experiment 2 developed any clinical indications of renal disease, and the only biochemical abnormality was isosthenuria in two of the five dogs. Thus the development of clinical signs and biochemical abnormalities associated with the intravenous administration of oxytetracycline was obviated by the slow administration of a dilution of the calculated bone-labeling dose of the antibiotic.

Squamous cell carcinoma of the midventral abdominal pad was diagnosed in 3 male gerbils. Two of the gerbils had raised, ulcerated masses on the midventral portion of the abdomen. The first gerbil was 2 years old, and an excisional biopsy was performed. The gerbil survived 23 months after surgery without evidence of metastasis or clinical signs of local recurrence. At necropsy, neoplastic squamous cells were seen on histologic examination of the surgery site. The second gerbil was 4 years old, and surgical excision of the tumor with concurrent castration was curative. The third gerbil was moribund on admission, perhaps because ulceration of the tumor may have allowed bacteria to invade the tissue, resulting in septicemia and disseminated intravascular coagulation. These gerbils illustrated that hematologic, radiographic, and biochemical testing in rodents can be useful and that excision of squamous cell carcinoma tumors of the midventral abdominal pad of gerbils can be an effective treatment.

A spontaneous, severely pruritic ulcerative dermatitis was initially observed in 33/201 (16.4%) aged C57BL/6NNia mice obtained from the National Institute of Aging. This ulcerative dermatis also developed in 21/98 (21%) aged C57BL/6 mice in a subsequent experimental group obtained from the same source. The average age of onset in the initial group was 20 months. These animals were negative for ectoparasite infestation and primary bacterial or fungal infection. The lesions varied from acute epidermal excoriation and ulceration to chronic ulceration with marked dermal fibrosis. In the affected animals, leukocytoclastic vasculitis was present in the dermis in both areas of ulceration and areas covered by normal intact epidermis. Immunofluorescent staining of the skin was positive for deposition of IgG, IgM, and fibrinogen in the dermal vessels of the affected mice. Leukocytoclastic vasculitis was not observed in unaffected animals, nor were deposits of immunoglobulin or fibrinogen present in the skin of the control animals. This study provides strong evidence that the ulcerative dermatitis is caused by an immune complex-induced vasculitis. The elucidation of the pathogenesis of this disease is important because of the significant percentage of animals affected and because the C57BL/6 mouse may be a useful model to study human vasculitides.

Eight chronically instrumented conscious dogs were used to test the hypothesis that left ventricular (LV) relaxation is accelerated during cardiac tamponade. The time constant of LV transmural pressure fall was measured before and during intrapericardial (IP) saline infusion (baseline) with and without beta-adrenergic blockade (propranolol 1 mg/kg iv). Heart rate was controlled by atrial pacing. Increasing IP pressure caused a progressive linear decrease in stroke volume before and during beta-blockade in each animal. The time constant of LV transmural pressure fall also decreased continuously with an increase in IP pressure from 26 +/- 7 ms during baseline to 18 +/- 5 ms during severe cardiac tamponade (P < 0.01) before beta-blockade. However, after beta-blockade, the time constant of LV transmural pressure fall was constant over a wide range of IP pressures despite a continuous decrease in LV end-diastolic volume. The time constant of LV transmural pressure fall was not altered by vena caval occlusions that caused the same decrease in LV preload observed during cardiac tamponade. We concluded that despite decreased pump function, LV relaxation was accelerated progressively during graded cardiac tamponade, and this change was dependent not on changes in loading conditions but on an intact beta-adrenergic influence.

Droperidol and diazepam were evaluated for sedative properties in 12 male Sprague Dawley rats (Rattus norvegicus). Over a period of several weeks, each rat was treated subcutaneously with 0.5 mg droperidol/kg, 2.0 mg droperidol/kg, 5.0 mg diazepam/kg, 15.0 mg diazepam/kg, and physiologic saline according to a randomized schedule. After each treatment, the animals were evaluated for their response to a series of four common clinical manipulations (tail-vein bleeding, orbital bleeding, teeth clipping, and toenail bleeding) at five time points over the 90 min following the injection. Rats were scored on the basis of their responses to each manipulation. Response to cardiac puncture was assessed once in each animal immediately prior to euthanasia. Histologic lesions associated with subcutaneous and intramuscular administration of these drugs were evaluated in a separate group of animals. Results indicate that both droperidol and diazepam (at either dose) allow easier manipulation for toenail bleeding and teeth clipping when compared with saline control. There was no advantage in using these sedatives for tail-vein bleeding. Orbital bleeding could not be performed humanely with either drug. Diazepam at a dose of 15.0 mg/kg allowed humane cardiac puncture. Subcutaneous injection of diazepam or 2.0 mg droperidol/kg resulted in various degrees of inflammation revealed by histologic examination, although no clinical signs were associated with these lesions. Subcutaneous administration of droperidol at a dose of 0.5 mg/kg is recommended for nonpainful, noninvasive manipulations as it provides adequate sedation for most procedures without inducing the subcutaneous inflammation observed with diazepam or 2.0 mg droperidol/kg.(ABSTRACT TRUNCATED AT 250 WORDS)

A ligature fracture technique was used to obtain multiple large (2 to 4 g) liver biopsy samples in both African green and cynomolgus monkeys. The technique was performed 195 times in 84 animals using three different surgical approaches, with no associated illness or mortality. In a subset of 18 animals, a slight decline in hematocrit percentage was noted during 14 days postsurgery (44.6 to 39.4%), but total plasma protein remained unchanged (5.98 to 5.95 g/dl). Serum alanine aminotransferase concentrations rose to 178.11 U/l at day 1 postoperatively, from a baseline value of 93.61 U/l. This elevation was transient, however, and declined to 49.65 U/l by day 14. Our experience has shown that the partial lobectomy via the ligature fracture technique is a safe and effective means to obtain multiple large samples of liver in nonhuman primates.

The transplantation of whole skeletal muscles is a common clinical procedure. Although atypical blood flows have been reported in small free muscle grafts, the blood flow of large neurovascular-intact (NVI) and neurovascular-anastomosed (NVA) grafts have not been measured. Because the maximum specific force (N/cm2) of NVI and NVA grafts is 65% that of control muscles, we hypothesized that total and regional blood flows (ml.min-1.100g-1) of NVI and NVA grafts at rest and during twitch contractions are significantly lower than lower flows of control muscles. In rabbits, blood flows of control rectus femoris (RFM) muscles and NVI and NVA grafts of RFM muscles were measured by the radioactive-microsphere technique. In control muscles, blood flow increased linearly from 6.8 +/- 1 ml.min-1.100 g-1 at rest to 64.4 +/- 7 ml.min-1. 100 g-1 at a stimulation frequency of 3 Hz with no further increase at 4 Hz. Total blood flows in grafts were not different from the control RFM muscle values, except for a higher resting flow in NVA grafts and a lower flow at 3 Hz in NVI grafts. Minor variations in regional flows were observed. We conclude that the operative procedures of grafting and repair of blood vessels affect the vascular bed of muscles minimally, and the deficits observed in grafts do not arise from inadequate perfusion.

The lateral borders of an infarcted area are sharply delineated in terms of perfusion, but functional impairment extends a limited distance into adjacent nonischemic myocardium. To determine the distribution of functional impairment we arrayed three ultrasonic dimension gauges to measure two subendocardial segment lengths in series. The center crystal, placed at the perfusion boundary (PB) between left anterior descending and circumflex arteries, radiated ultrasound to receiver crystals 7-17 mm to either side of the PB. The locations of the functional measurements relative to the PB were determined with myocardial blood flow (microsphere) "maps" constructed from multiple small tissue samples obtained circumferentially. On the nonischemic side of the PB, segment shortening (dL) increased from 2.00 +/- 0.37 mm during control conditions to 2.20 +/- 0.43 mm (P less than 0.05) after left circumflex coronary occlusion. Similar results were obtained in four conscious chronically instrumented dogs, supporting the conclusion that segment function adjacent to the ischemic margin is well preserved after coronary occlusion. On the ischemic side of the PB, dL decreased from 2.24 +/- 0.54 to 0.42 +/- 0.39 mm (P less than 0.01). By adding the data from the two segments in series, a combined measurement of dL across heterogeneously perfused myocardium was derived that decreased by 38% from control. The level of shortening represented an integral of normal and abnormal motion that was proportional to the mean reduction in blood flow (-44%) in all of the muscle spanned by the crystals. We conclude that subendocardial segment lengths "average" shortening in the muscle they subtend when arrayed across the perfusion boundary.

To evaluate the degree and lateral extent of dysfunction in nonischemic myocardium adjacent to ischemic muscle, we measured systolic wall thickening with sonomicrometers during circumflex coronary occlusion in 12 anesthetized, open-chest dogs. The locations of the wall thickness measurements relative to the perfusion boundary were determined with myocardial blood flow (microspheres) maps constructed from multiple, small tissue samples. Five minutes after circumflex occlusion, systolic wall thickening in the central ischemic zone decreased from 3.00 +/- 0.61 (mean +/- SD) mm to -0.61 +/- 0.36 mm (P less than 0.01). In nonischemic myocardium greater than 10 mm from the perfusion boundary, systolic wall thickening increased from 2.56 +/- 0.57 to 3.24 +/- 0.72 mm (P less than 0.01). In nonischemic myocardium within 10 mm of the perfusion boundary, systolic wall thickening was slightly but significantly reduced compared with control (2.72 +/- 0.80 to 2.44 +/- 0.79 mm, P less than 0.05), supporting the concept of regional dysfunction in nonischemic myocardium at the lateral borders of an ischemic area. Sigmoid curves were fitted to the data to model changes in wall thickening as a continuous function of distance from the perfusion boundary. This allowed estimation of the extent of dysfunction into nonischemic myocardium which averaged less than 8 mm (approximately 30 degrees of endocardial circumference) at one border. The level of functional impairment in this zone was relatively modest, and systolic wall thickening in the immediate border area was reduced more than 50% from control only in tissue characterized by a blood supply of mixed ischemic and nonischemic origin. We conclude that a functional border zone exists lateral to an acutely ischemic area, but measurement of regional function produces relatively small exaggeration of the size of the acutely ischemic zone if severe reduction in mechanical performance is used to define the extent of the ischemic area.

Blood flow in the corpus luteum of the pseudopregnant rabbit was measured with tracer-labelled microspheres before and at 1 and 3 h after saline treatment (N = 8) or after inhibition of progesterone synthesis with aminoglutethimide (N = 10). Before treatment luteal blood flow (29.5 +/- 3.9 ml/min.g-1 (mean +/- s.e.m.] was much higher than blood flow to other tissues (ovarian stroma = 2.9 +/- 0.6; uterus = 0.5 +/- 0.1; adrenal gland = 2.6 +/- 0.2 ml/min.g-1). Aminoglutethimide reduced serum progesterone by 60% within 1 h but luteal blood flow was unchanged (26.2 +/- 3.5 ml/min.g-1). At 3 h after aminoglutethimide, serum progesterone remained low and luteal blood flow was slightly reduced to 22.5 +/- 3.4 ml/min.g-1. This reduction was associated with a significant decline in mean arterial blood pressure which resulted in luteal vascular resistance being unaltered by aminoglutethimide treatment. Further analysis of these data indicated that serum progesterone concentration was not significantly correlated with blood flow to the corpora lutea or with blood flow to other tissues. In contrast, mean arterial blood pressure was highly correlated with blood flow to the corpus luteum (r = 0.80; P less than 0.001) but not to the ovarian stroma (r = 0.04), or adrenal gland (r = 0.06). These results indicate that luteal blood flow is not acutely responsive to changes in luteal progesterone production and suggest that luteal blood flow changes passively with changes in arterial blood pressure.