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(99m)Tc-sestamibi myocardial perfusion imaging is frequently performed in conjunction with exercise or pharmacologic stress testing for evaluation of coronary heart disease. Interpretation of these studies includes systematic review of unprocessed rotating projectional images for evaluation of cardiac size as well as the presence of motion or attenuation artifacts. Occasionally, incidental noncardiac findings are detected on review of the projectional images. We report a case of a patient with a history of autosomal dominant polycystic kidney disease who was found to have a large abdominal photopenic area on the projectional images. The photopenic area corresponded to the location of large intraabdominal cysts on abdominal CT and was consistent with hepatic cysts associated with the patient's known polycystic kidney disease. We review the differential diagnosis of large abdominal photopenic regions identified on myocardial projectional images and the importance of routinely analyzing these images for incidental noncardiac findings. [ABSTRACT FROM AUTHOR]

A patient with history of coronary bypass surgery was admitted with chest discomfort and noted to have decreased left arm blood pressure. She was found to have severe subclavian artery stenosis causing coronary-subclavian steal syndrome. Subclavian stenting led to resolution of symptoms and normalization of blood pressure.

Purpose: The objective of this study was to determine the pharmacokinetics and safety for NX1838 following injection into the vitreous humor of rhesus monkeys., Methods: Plasma and vitreous humor pharmacokinetics were determined following a single bilateral 0.25, 0.50, 1.0, 1.5, or 2.0 mg/eye dose. In addition, the pharmacokinetics and toxicological properties of NX1838 were determined following six biweekly bilateral injections of 0.25 or 0.50 mg/eye or following four biweekly bilateral injections of 0.10 mg per eye followed by two biweekly bilateral injections of 1.0 mg per eye., Results: Plasma and vitreous humor NX1838 concentrations were linearly related to the dose administered. NX1838 was cleared intact from the vitreous humor into the plasma with a half-life of approximately 94 h, which was in agreement with the plasma terminal half-life. Vascular endothelial growth factor (VEGF)-binding assays demonstrated that the NX1838 remaining in the vitreous humor after 28 days was fully active. No toxicological effects or antibody responses were evident., Conclusions: The no observable effect level was greater than six biweekly bilateral 0.50 mg/eye doses or two biweekly bilateral 1.0 mg/eye doses. These pharmacokinetic and safety data support monthly 1 or 2 mg/eye dose regimens in human clinical trials.

The toxicities of 2'-fluorouridine (2'-FU) and 2'-fluorocytidine-HCl (2'-FC) were separately evaluated in 2 species, male Fischer 344 (F334) rats and woodchucks. Particular attention was focused on the ability of these nucleosides to induce toxicities similar to those induced by the antiviral drug fialuridine (FIAU). 2'-FU or 2'-FC was administered to F344 male rats by intravenous injection at doses of 5, 50, and 500 mg/kg/day for 90 consecutive days and to male and female woodchucks at doses of 0.75 and 7.5 mg/kg/day for 90 consecutive days. Clinical chemistry, hematology, and urinalysis (woodchuck only) profiles were assessed during and at the termination of the study. At necropsy, organs were weighed and tissues collected for routine histologic analysis. Cytochrome c oxidase activity, citrate synthase activity, and mitochondrial DNA content were measured, and micronucleus formation in the bone marrow (rats only) was evaluated. No adverse clinical effects were observed in either species. Rats treated with high doses of either 2'-FU or 2'-FC had body weights that were 90% of those of controls. 2'-FU and 2'-FC both induced a moderate decrease in the median lymphocyte count, and 2'-FC and 2'-FU induced a mild increase in mean corpuscular hemoglobin and mean corpuscular volume. Both compounds caused slight to moderate, reversible, histologic changes in the spleen and thymus. In the woodchuck, 2'-FC caused a slight increase in mean absolute lymphocytes, and 2'-FC and 2'-FU slightly increased hepatic periportal vacuolation and/or mononuclear cell infiltration. In summary, neither compound showed evidence of the toxicity induced by fialuridine in either species. Although compound effects were observed, none of these effects were considered to be adverse, and the no-observed adverse effect level was determined to be 500 mg/kg/day for both compounds in the male F344 rat and 7.5 mg/kg/day in the woodchuck.

Optimal treatment strategies for serious infections caused by Staphylococcus aureus have not been fully characterized. The combination of a beta-lactam plus an aminoglycoside can act synergistically against S. aureus in vitro and in vivo. MiKasome, a new liposome-encapsulated formulation of conventional amikacin, significantly prolongs serum half-life (t1/2) and increases the area under the concentration-time curve (AUC) compared to free amikacin. Microbiologic efficacy and left ventricular function, as assessed by echocardiography, were compared in animals administered either oxacillin alone or oxacillin in combination with conventional amikacin or MiKasome in a rabbit model of experimental endocarditis due to S. aureus. In vitro, oxacillin, combined with either free amikacin or MiKasome, prevented the bacterial regrowth observed with aminoglycosides alone at 24 h of incubation. Rabbits with S. aureus endocarditis were treated with either oxacillin alone (50 mg/kg, given intramuscularly three times daily), oxacillin plus daily amikacin (27 mg/kg, given intravenously twice daily), or oxacillin plus intermittent MiKasome (160 mg/kg, given intravenously, a single dose on days 1 and 4). The oxacillin-alone dosage represents a subtherapeutic regimen against the infecting strain in the endocarditis model (L. Hirano and A. S. Bayer, Antimicrob. Agents Chemother. 35:685-690, 1991), thus allowing recognition of any enhanced bactericidal effects between oxacillin and either aminoglycoside formulation. Treatment was administered for either 3 or 6 days, and animals were sacrificed after each of these time points or at 5 days after a 6-day treatment course (to evaluate for posttherapy relapse). Left ventricular function was analyzed by utilizing serial transthoracic echocardiography during treatment and posttherapy by measurement of left ventricular fractional shortening. At all sacrifice times, both combination regimens significantly reduced S. aureus vegetation counts versus control counts (P < 0.05). In contrast, oxacillin alone did not significantly reduce S. aureus vegetation counts after 3 days of therapy. Furthermore, at this time point, the two combinations were significantly more effective than oxacillin alone (P < 0.05). All three regimens were effective in significantly decreasing bacterial counts in the myocardium during and after therapy compared to controls (P < 0.05). In kidney and spleen abscesses, all regimens significantly reduced bacterial counts during therapy (P < 0.0001); however, only the combination regimens prevented bacteriologic relapse in these organs posttherapy. By echocardiographic analysis, both combination regimens yielded a significant physiological benefit by maintaining normal left ventricular function during treatment and posttherapy compared with oxacillin alone (P < 0.001). These results suggest that the use of intermittent MiKasome (similar to daily conventional amikacin) enhances the in vivo bactericidal effects of oxacillin in a severe S. aureus infection model and preserves selected physiological functions in target end organs.

The following material was derived from a synthesis of case histories taken from investigational new drug (IND) applications and drug sponsors' experiences, utilizing fictionalized data to avoid any resemblance to any proprietary information; any such resemblance is accidental. These examples are used as an instructional scenario to illustrate appropriate handling of a difficult toxicology issue. In this scenario, a drug caused a toxicity in animals that was detected only by histopathologic analysis; if it were to develop in patients, no conventional clinical methods could be identified to monitor for it. It is not unusual for a firm to cancel clinical development plans for a lead drug candidate that causes such a toxicity, especially if such a drug is intended for use as a chronic therapeutic in a population of patients with a chronic disease. This case synthesis was inspired by a Food and Drug Administration (FDA) agreement to allow such a product to proceed into clinical trials after substantive pre-IND discussions and agreement on well-considered toxicology program designs. The scientists most closely involved in the strategy development included the sponsor's toxicologist, veterinary toxicologic pathologist, and pharmacokineticist, as well as the FDA's reviewing pharmacologist. The basis of this decision was thorough toxicity characterization (1-month studies in 2 species); correlating toxicities with a particular cumulative area under the curve (AUC) in both species; identification of the most sensitive species (the species that showed the lower AUC correlating with toxicity); allometric assessment of clearance of the drug in 3 nonhuman species; construction of a model of human kinetics (based on extrapolation from animal kinetics); and finally, estimation of clinical safety factors (ratios of the human estimated cumulative AUC at the proposed clinical doses, over the animal cumulative AUC that correlated with the no adverse effect levels). Industry and FDA scientists negotiated a joint assessment of risk and benefit in patients, resulting in the FDA permitting such a compound to enter into clinical trials for a serious autoimmune disease. Such constructive, early communication starts with the pre-IND meeting, and the conduct and planning for this meeting can be very important in establishing smooth scientific and regulatory groundwork for the future of a drug under IND investigation.

The ultrastructural features of AA-2 cells infected with either of two strains of simian immunodeficiency virus (SIVMne-E11S or SIVSMM-PBj) were examined by scanning electron microscopy (SEM). Transformed CD4+ human B lymphocytes (AA-2) were inoculated with SIV and observed at 2, 4, and 7 days post-inoculation (dPI). Infected AA-2 cells were distinguished by the progressive loss of microvilli, and variable numbers of free or protruding spherical particles measuring 90-120nm in diameter along the cell surface. Syncytial cell formation (complexes of fused cells) and necrotic cells were evident at each time point with the most numerous observations at 7 dPI. While the distribution and severity of the viral induced changes increased with time and affected virtually all cells by 7 dPI, the alterations were detected sooner and were more pronounced in SIVSMM-PBj infected cells. This finding is consistent with the in vivo data from primate studies using the same strains of SIV. Syncytial cells exhibited slight to moderate indentations which appeared to coincide with the boundaries of individual cells forming the complex. The plasma membrane of syncytial cells was relatively smooth and lacked microvilli. Spherical particles and buds protruding from the plasma membrane were predominate features of syncytial cell surfaces. By the employment of antisera generated against whole SIVMne-E11S, both transmission and scanning immunoelectron microscopy confirmed the identity of the spherical structures as free and budding SIV virions.

The decline in CD4/CD8 ratios in lymph nodes (LNs) of SIV macaques and HIV-infected individuals occurs later than that in blood. In a previous study, long-term SIV-infected macaques were delineated into two groups: (1) those whose LNs had normal CD4/CD8 ratios and (2) those whose LNs had low CD4/CD8 ratios. In the present investigation, LNs, spleens, and blood from these groups have been further analyzed to ascertain the cellular and virological events, particularly those involving CD8+ cells, that occur concomitantly with LN CD4% decline. An increase in the percent of CD69-, IL-2R(p75)-, CD45RA1o CD8+ cells was the most constant event observed in lymphoid tissue from mid- to late-stage SIV-infected monkeys. Such cells were sometimes observed in LNs prior to any other immunological or morphological changes. However, decline in LN CD4/CD8 ratios and the associated degeneration of follicular dendritic cells (FDCs) in the germinal centers (GCs) of these nodes were observed only when both CD8+ cell infiltration of GCs and accumulation of viral antigens within the FDC network could be demonstrated. These dramatic changes were also associated with significantly reduced responsiveness to mitogens throughout the lymphoid compartment. In terms of viral burden, immunological and structural collapse of LNs was not always associated with increased viral DNA levels. Despite the CD4+ cell decline in blood during HIV and SIV infections, the immunological and architectural collapse of the lymphoid compartment, which comprises the bulk of the lymphocytes in the body, appears to be a critical event leading to the onset of AIDS. The present findings suggest that increased CD8+ cell activity as well as decrease in CD4+ cell function both contribute to this process.

Simian immunodeficiency virus (SIV) infection of macaques is a useful and relevant model for evaluating candidate human immunodeficiency virus (HIV) vaccines. One important feature of this model is that SIV vaccines can be evaluated for their ability to prevent infection as well as to prevent or delay the onset of AIDS. In the present study, a group of macaques was vaccinated with whole inactivated SIV and challenged with peripheral blood mononuclear cells from an SIV-infected macaque. This challenge represented a rigorous and realistic test of the immunization protocol. All macaques became infected after challenge; however, immunized animals survived significantly longer (P < .03) than naive controls. These data suggest that similar vaccines administered to humans at risk for HIV-1 infection might delay or prevent AIDS even if the vaccine failed to prevent infection.

The most virulent primate lentivirus identified to date, the simian virus SIVsmmPBj14 (SIV-PBj14), is unique not only because it causes acute disease and death within days instead of months or years, but also because of its replicative and cellular activation properties. The acute disease syndrome has many features in common with primary HIV-1 disease, but differences in the respective outcomes of these two acute lentiviral infections appear to be linked to the rapidity with which SIV-PBj14 replicates and the high titers of virus that subsequently accumulate in lymphoid tissues. The most prominent pathologic feature of SIV-PBj14 is extensive lymphoid hyperplasia of T-cell zones, especially in the gut-associated lymphoid tissue. These expanded T-cell zones contain a high proportion of lymphoblasts, activated macrophages and syncytial cells, which are positively correlated with high numbers of SIV antigen-positive cells. Replication of the virus to high titers, accompanied by extensive cellular activation and proliferation, leading to high levels of cytokines, such as interleukin-6 and tumor necrosis factor-alpha, are consistent with acute inflammatory disease. The pathogenesis of SIV-PBj14 also appears to correlate most directly with some of its unique biologic properties, such as the ability to replicate in resting peripheral blood mononuclear cells, to activate lymphocytes, and to induce lymphocyte proliferation. Biologically and molecularly cloned viruses derived from SIV-PBj14 and isolates obtained from macaque PBj at earlier times, are being used to identify viral determinants that influence biologic and pathogenic properties of SIV-PBj14. Further characterization of this virus should provide new insights into lentivirus-cell interactions and their contributions to disease.

Simian immunodeficiency virus infection of macaques is a model for human immunodeficiency virus infection of humans. In vivo-titrated stocks of SIV are essential for the utilization of this model for vaccine development. The elicitation of anti-human cell antibodies by some vaccines prepared in human cells and the related protective effects of the vaccine produced in human cells suggest a need for new macaque-derived SIV stocks. Here we describe the titration and characterization of two stocks of SIVmac that were produced in primary rhesus macaque cells. The first virus is SIVmac251, isolated from tissues of macaque 251, and the second is a molecular clone designated as SIVmac239. A 50% rhesus monkey infectious dose (MID50) was titrated for each virus stock by intravenous inoculation. An additional five macaques were inoculated with 10 MID50 of the SIVmac251 stock and were followed for disease outcome. All five monkeys developed antigenemia by 14 days postchallenge. Two of the five monkeys developed strong anti-SIV humoral immunity, whereas three developed little or no humoral immunity. As has been observed previously, the rapidity of disease progression correlated with the lack of a strong antibody response. The three animals with low humoral immunity died within 7 months of challenge, with antigenemia, cachexia, hypoproteinemia, hypoalbuminemia, weight loss, and intractable diarrhea, while maintaining their circulating CD4 numbers. One animal died at 1.5 years of more typical simian AIDS.

Four pigtailed macaques were inoculated with autologous cells expressing low levels of human immunodeficiency virus type 1 (HIV-1). During the first 10 weeks, infectious virus was recovered from peripheral blood mononuclear cells (PBMCs) and lymph nodes from three of the animals. Subsequently, HIV-1 DNA was frequently detected in uncultured PBMCs from all three animals, and virus was isolated from one of them at weeks 38 and 61. The fourth animal, which was rechallenged at week 10 with cell-free virus isolated from one of the others, never became virus isolation positive, but harbored HIV-1 proviral genomes. These virus infections were accompanied by the development of varied HIV-1-specific humoral immune responses. Antibodies to gp160 were first apparent at week 8 in the three initially infected animals and persisted. The animal from whom virus was isolated at late times also developed persisting antibodies to HIV-1 p24 and gp120. Antibodies to gp120 and gp160 became apparent in the rechallenged animal at 1 week following reinoculation, but they waned with time. In vivo passage of the virus was attempted at week 6. One recipient pigtailed macaque and one recipient cynomolgus monkey failed to become detectably infected following transfusion of virus-positive blood and lymph node cells. The long-term presence of HIV-1-specific antibodies and proviral genomes in these animals, and the recovery of infectious virus more than 1 year following inoculation, are indicative of persistent infection, and confirm previous reports that pigtailed macaques are susceptible to HIV-1.

We assessed the significance of transient left ventricular dilation (TLVD) during single photon emission computed tomography (SPECT) dipyridamole thallium-201 scintigraphy (DTS) in 49 patients who underwent both DTS and diagnostic coronary arteriography. Quantitative analysis of DTS images and independent review by 3 experienced observers determined that 17 patients had TLVD and 32 patients had no TLVD. Patients with TLVD were similar to patients without TLVD with respect to age, history of myocardial infarction, coronary risk factors and occurrence of chest pain or electrocardiographic changes during DTS. The frequency of three-vessel coronary artery disease (3VD) was greater in patients with TLVD than in patients without TLVD (94% vs. 16%, p < 0.01). The sensitivity of TLVD was 76% and the specificity 96% for the detection of 3VD. Of the 16 patients with 3VD who manifested TLVD, standard SPECT DTS analysis demonstrated defect or perfusion abnormalities in 14 patients and no abnormalities in 2 patients. In conclusion, the finding of TLVD during SPECT DTS is a specific marker for severe coronary disease and can provide additive information to standard SPECT thallium-201 analysis.

Infection with a variant of simian immunodeficiency virus (SIVsmm/PBj-14) causes death in juvenile pigtailed macaques within 8 days of infection. The primary pathology is localized to the lymphoid tissues of the gut and spleen. Although the virus is present, the lesions are most consistent with acute reactive inflammation. We studied the serum and tissues for evidence of acute cytokine production often associated with acute inflammation. One factor, IL-6, was found to be significantly increased (> 1000-fold) over all other measured cytokines in all the pigtailed macaques who died acutely. Increased levels of IL-6 were found both in the serum and in the inflamed tissues. mRNA for IL-6 was found in the tissues with the highest protein levels of IL-6. The marked increase in IL-6 and IL-6 mRNA correlated with the virus levels in the tissues and serum as determined by viral isolation, immunohistochemistry, and Northern blot analysis. These findings suggest that the underlying pathogenesis of primary tissue damage, necrosis, and death by PBj-14 is the induction of cytokine production. Although the presence of the virus may be critical for the initiation of these events, the intense inflammatory reaction is associated with the cause of death.

Although loss of CD4+ lymphocytes in peripheral blood is a standard criterion for evaluating the course of HIV disease, little is known about changes within lymphoid organs, which contain the bulk (> 50%) of the body's lymphocytes. Because such studies are feasible only by using non-human primates, we have examined lymph nodes (LNs), spleen, and blood from monkeys infected with two isolates of simian immunodeficiency virus (SIV). During both the acute and chronic phases of these infections, characteristic reductions in the blood CD4+ cell levels are not reflected in LN, where the CD4+ pool remains within normal levels. However, when circulating CD4/CD8 ratios have consistently fallen to approximately 0.5, striking decreases in the percentage of CD4 cells (CD4%) and CD4/CD8 ratios in LN occur concomitantly with dramatic increases in viral antigen expression on follicular dendritic cells within LN germinal centers (GCs). The data suggest that loss from the total T cell pool in minimal until the final stages of SIV and HIV disease and that the immunological deterioration of LN is the event that precipitates the increased susceptibility to infections and progression to AIDS.

Our studies confirmed the susceptibility of Macaca radiata (bonnet macaques) to Kyasanur Forest disease (KFD) and enabled us to demonstrate KFD virus-specific gastrointestinal and lymphoid lesions. Significant histopathological changes occurred in the small and large intestine, spleen and lymph nodes; and viral antigens were found in these same organs by immunohistochemistry. Viral antigen-positive cells were always associated with histological evidence of necrosis, which suggests that cell death occurred directly from viral replication or secondarily from attack by immune mechanisms. In contrast, M. radiata infected with Omsk virus did not show any signs of clinical disease, and no virus could be isolated from tissues or blood at the end of the experiment. However, M. radiata infected with Russian spring-summer encephalitis (RSSE) developed clinical signs in the central nervous system; and, in one monkey, RSSE virus was isolated from the brain, and viral antigen was localized in neurons. Our data indicate that M. radiata is an excellent model to study human disease caused by KFD virus and could serve as a model for human disease caused by other, related strains of this group of viruses.

A variant of simian immunodeficiency virus (SIVSMM/PBj), isolated from a chronically infected pig-tailed macaque has been shown in previous studies to produce acutely fatal disease uniformly in pig-tailed macaques and in some rhesus macaques. The present study extends investigation of SIVSMM/PBj pathogenesis in rhesus and cynomolgus monkeys. Cynomolgus and rhesus macaques were found to be uniformly susceptible to infection, but as previously reported, the rhesus were found to not be uniform in their response during the acute disease. Homogenized tissues from a rhesus that died acutely from SIVSMM/PBj were passaged to 6 rhesus monkeys in an attempt to increase lethality. Five of 6 rhesus monkeys receiving intravenous inoculation of either spleen (10(3) TCID50) or lymph node (10(5) TCID50) homogenate developed acute disease; 4 died (days 8-10), 1 recovered, and one rhesus remained asymptomatic. Three of 3 cynomolgus macaques and 4 of 4 pig-tailed macaques receiving the same inoculum died acutely within 9 days. Clinical disease in macaques that died was characterized by diffuse lymphadenopathy within 5 days of inoculation and severe diarrhea beginning 1 to 3 days before death. Anorexia, lymphopenia (< 1000 cells/mm3), and mild hypoalbuminemia preceded onset of diarrhea by 24 h. Viral p27 was detected in circulation by day 6 postinfection, with all animals dying acutely having detectable serum p27 and no detectable humoral response. Acute lethality was attributed to severe metabolic acidosis (pH < 7.20) which was observed 24-48 h prior to death in the pig-tailed and cynomolgus macaques. Immunohistochemistry revealed numerous SIV antigen-positive lymphocytes and macrophages in the lymph nodes, spleen, gut-associated lymphoid tissues and gastrointestinal lamina propria. Histopathologic lesions included marked to severe hyperplasia of the T-cell-dependent areas in lymphoid tissues and diffuse nonulcerative lymphohistiocytic gastroenteritis. Surviving rhesus developed strong humoral immune responses to the major SIV proteins.

Simian hemorrhagic fever (SHF) virus and a new strain of Ebola virus were isolated concurrently in recently imported cynomolgus monkeys (Macaca fascicularis) being maintained in a quarantine facility. Ebola virus had never been isolated in the U.S. previously and was presumed to be highly pathogenic for humans. A chronology of events including measures taken to address the public health concerns is presented. The clinicopathologic features of the disease were abrupt anorexia, splenomegaly, marked elevations of lactate dehydrogenase, alanine aminotransferase, and aspartate aminotransferase, with less prominent elevations of blood urea nitrogen, creatinine, and other serum chemistry parameters. Histologically, fibrin deposition, hemorrhage, and necrosis of lymphoid cells and reticular mononuclear phagocytes were present in the spleens of SHF and of Ebola virus-infected animals. Intravascular fibrin thrombi and hemorrhage were also present in the renal medulla and multifocally in the gastrointestinal tract. Necrosis of lymphoid and epithelial cells was occasionally noted in the gastrointestinal tract. The histopathologic findings considered specific for Ebola virus infection include hepatocellular necrosis, necrosis of the zona glomerulosa of the adrenal cortex, and interstitial pneumonia, all of which were generally associated with the presence of 1 to 4 mu intracytoplasmic amphophilic inclusion bodies. The disease spread within rooms despite discontinuation of all direct contact with animals, and droplet or aerosol transmission was suspected. Antibody to Ebola virus developed in animal handlers but no clinical disease was noted, suggesting a less virulent strain of virus.(ABSTRACT TRUNCATED AT 250 WORDS)

During 1989-1990, an epizootic involving a filovirus closely related to Ebola virus occurred in a Reston, Virginia, primate-holding facility. Tissues were collected from cynomolgus monkeys and examined by electron microscopy and immunohistochemistry for Ebola-related viral antigen. Viral replication was extensive in fixed tissue macrophages, interstitial fibroblasts of many organs, circulating macrophages and monocytes, and was observed less frequently in vascular endothelial cells, hepatocytes, adrenal cortical cells and renal tubular epithelium. Viral replication was observed infrequently in epithelial cells lining ducts or mucous membranes, intestinal epithelial cells, eosinophils and plasma cells. Replication of Reston virus in lymphocytes was never observed, in contrast to reports of lymphocytes of monkeys experimentally infected with the Ebola-Zaire virus. Free filoviral particles were seen in pulmonary alveoli and renal tubular lumina, which correlates with epidemiological evidence of droplet and fomite transmission. Viral infection of interstitial fibroblasts and macrophages caused multisystemic disruptive lesions involving connective tissue. Focal necrosis in organs where viral replication was minimal may have been secondary to ischaemia caused by fibrin deposition and occasional platelet-fibrin thrombi. Immunoelectron microscopy on sections of liver, differentiated viral tubular inclusion masses and precursor material from non-viral tubuloreticular inclusions. Immunohistochemistry showed that the distribution of viral antigen in affected tissue correlated well with ultrastructural localization of virions.

Chylous ascites was diagnosed in 3 dogs. Mesenteric lymphangiography was performed in 2 dogs and helped delineate abnormalities of the lymphatic system. The cause of chylous ascites in each dog appeared to be different. In 1 dog, a ruptured mesenteric lymphatic was identified at surgery. Evidence of abdominal lymphatic obstruction was found in another dog. Chylous ascites in the third dog appeared to be a complication of mesenteric lymphangiography for chylothorax.

The purpose of our work was to determine if aerosols of Junin virus can infect rhesus macaques and if the disease is the same as that produced by virus inoculated parenterally. The 6 macaques exposed to the virus by aerosol became acutely ill during the 3rd week after exposure, and all died. Three died by day 21, while the remainder died after 1 month. Junin virus was found primarily in visceral organs of those animals dying before 21 days after infection and in the central nervous system tissues from animals dying later. Histological changes were similar to those reported in rhesus monkeys after parenteral Junin viral infection. Gastrointestinal necrosis, however, was less severe in aerosol-infected animals and the associated septicemia was not seen. High levels of alpha interferon were detected by the 3rd day in all infected macaques. Experimental Argentine hemorrhagic fever induced by aerosol infection in rhesus macaques was similar to that seen after parenteral challenge and mimicked closely the clinical syndrome observed in humans.

Four simian immunodeficiency virus (SIV)-infected macaques in the terminal stages of AIDS were studied. Easily detectable unintegrated proviral DNA was present in nearly every tissue (lymphoid and nonlymphoid) examined. SIV-specific immunohistochemistry revealed that macrophages or macrophage-like cells were the predominant reservoirs for SIV. High burdens of infectious SIV were also characteristic of end-stage disease. At the molecular level, sequence analyses of molecular clones derived directly from tissue demonstrated that SIV, like other RNA viruses, exists as a mixture of closely related genomes. Viruses derived by cocultivation seemed to be selected for their ability to grow in tissue culture and did not represent the wide spectrum of genotypes in tissues. These data indicate that SIV-induced immunodeficiency is a complex, multisystem disease and that SIV replication, in addition to impairing the immune system, may have direct deleterious effects on multiple organ systems.

Biological effects of staphylococcal protein A (SPA) immunotherapy were studied in 5 viremic and 6 nonviremic cats with induced FeLV infection and in 6 control cats. The SPA therapy neither reversed FeLV viremia nor resulted in consistent improvement in humoral immune responses to FeLV antigens. However, SPA immunotherapy induced a proliferative response in bone marrow granulocytic lineage, possibly resulting in expression of FeLV-free mature neutrophils in the blood. Seemingly, viral burden and chemiluminescent responses were reversed in viremic cats during SPA immunotherapy.

Tissues from SIV-infected, immunodeficient macaques were analyzed by southern blot and polymerase chain reaction (PCR) amplification of env sequences. Provirus was readily detected in both lymphoid and non-lymphoid tissues by southern blot analysis. The majority of virus was in an unintegrated state. Analysis of envelope sequences by PCR revealed that tissues contain many distinct, but closely related genotypes; however, only a subset of these proviral genomes are recovered after tissue culture passage in human cell lines. Thus, tissue culture isolates of SIV do not represent the complete spectrum of genotypes in an infected macaque.

The Kawakami-Theilen strain of feline leukemia virus (FeLV-KT) was used experimentally to produce erythroid aplasia in cats. The in vivo effects of goat anti-feline-thymocyte globulin (ATG) on hematopoiesis were investigated in FeLV-negative normal and FeLV-positive anemic cats. Treatment was initiated in anemic cats between 4 and 6 weeks postinoculation (PI) when erythroid progenitors were reduced to 10% of normal levels. During the first 2 weeks of treatment, ATG significantly increased the numbers of erythroid precursors in bone marrow from 15 to 35% in anemic cats and from 28 to 43% in normal cats. ATG stimulated a twofold increase of CFU-E and a threefold increase of CFU-GM in normal cats between 2 and 4 weeks after initiation of treatment but had no effect on CFU-E or CFU-GM in anemic cats. The in vivo effects of ATG were transient despite weekly treatment. Cats treated with normal globulin were not significantly different from untreated anemic control cats. In vitro treatment of low density bone marrow mononuclear cells with ATG plus complement increased CFU-E and BFU-E of bone marrow from cats prior to inoculation but not from viremic cats. These results indicate that, although ATG stimulates erythropoiesis and granulopoiesis in normal cats, it does not reverse retrovirus-induced erythroid aplasia.

Baseline, clinical, and angiographic features of 1014 Coronary Artery Surgery Study (CASS) registry patients with combined proximal left anterior descending and proximal left circumflex coronary disease were examined to define determinants of prognosis in this clinical high-risk patient subset. A stepwise Cox regression analysis identified congestive heart failure score, left ventricular contraction score, mitral regurgitation, age, and digitalis usage as independent variables predictive of 8-year survival. When patients were stratified by left ventricular contraction score, the 8-year survival rate was 62%, 49%, and 19%, respectively, for patients with a left ventricular score of 5 to 9, 10 to 14, and greater than or equal to 15 (p less than 0.0001). The presence of a stenosis greater than or equal to 70% in the right coronary artery was associated with worse survival (47% versus 54% at 8 years; p = 0.051). In conclusion, the diagnosis of combined proximal left anterior descending and left circumflex coronary artery disease represents a large prognostic spectrum that needs to be considered when counselling individual patients.

To decrease the risk of iatrogenic side branch occlusion during coronary angioplasty of bifurcational lesions, we evaluated a technique in which two over-the-wire dilatation systems are positioned within the stenosed coronary artery and the side branch in jeopardy. The technique was used in eight patients undergoing angioplasty for a lesion in the left anterior descending or circumflex artery located near a large side branch. Successful dilatation of the major vessel lesion was achieved in all eight patients, and dilatation within the side branch was successful in all three patients whose lesion involved the side branch ostium. In one patient, dilatation within the major vessel led to partial closure of the side branch and the prepositioned guide wire facilitated prompt dilatation of the iatrogenic closure. There were no complications associated with use of the additional dilatation system. The technique appears to provide an efficacious method to perform safe coronary angioplasty in selected patients with bifurcational lesions.

Myocardial ischemia has been reported occasionally to produce transient T-wave normalization in certain patients. We present a case of "pseudonormalization" of T-waves occurring in the setting of coronary angioplasty. This case illustrates the potential of the transient coronary occlusion which occurs during coronary angioplasty as a model for understanding acute myocardial ischemia.

A juvenile granulosa cell tumour is described in a 3-month-old Arabian filly. The 32 X 27 X 27 cm tumour had replaced the right ovary. The neoplasm was composed of multiple nodules of neoplastic granulosa cells which formed microfollicles, macrofillicles and cysts, as well as solid nests and trabeculae. The supporting stroma contained theca cells. Mixing of the neoplastic granulosa cells and theca cells in disorderly fashion was noted. The diagnosis was based on age of occurrence and histological appearance.

Data from the United States Health Examination Surveys were analyzed to determine changes in body fatness between childhood and adolescence. A national probability sample (2,177 children) was examined in both Cycle II (6 to 11 years) and Cycle III (12 to 17 years) of these surveys and comprised the study cohort. The interval between examinations was three or four years. Adiposity was measured as skinfold thickness and correlations between childhood and adolescent adiposity were explored. High rank-order correlations were found between the two examinations for each race-sex group (P less than 0.001). The relationship between childhood and adolescent fatness was independent of stature, skeletal and sexual maturation, and economic status. Childhood fatness was the most predictive factor for adolescent fatness. This strong relationship indicates that the potentially obese adolescent can be identified during childhood.

The influence of body fatness on the direction of the electrocardiographic mean frontal plane QRS axis was investigated in a nationally representative population of 6,913 adults aged 25 to 74 years (the U.S. Health and Nutrition Examination Survey). Adiposity was measured as skinfold thickness and the mean frontal QRS axis was determined by computer analysis of limb lead vectors. A significant leftward shift of the mean QRS axis occurred with increasing fatness in both men and women (p less than 0.001) and was independent of age and blood pressure. However, this association was confined to the range of normal QRS axis. The prevalence of left-axis deviation (LAD) (QRS axis of -30 degrees or less) was not higher among those with greater measures of body fatness. There were no significant differences in mean age-adjusted skinfold thickness, height, weight or chest circumference between those with LAD and those with a normal QRS axis. Thus, although the direction of the mean frontal QRS axis is influenced significantly by body fatness throughout the normal QRS axis range, this association is lost as the QRS axis becomes abnormally deviated to the left. An ECG demonstrating LAD obtained from an obese person probably represents a true abnormality and not merely a reflection of adiposity.

The historic, physical, laboratory, and histologic findings for 74 cats with chronic renal disease were reviewed. Most cats were older, and no breed or sex predilection was detected. This most common clinical signs detected by owners were lethargy, anorexia, and weight loss. Dehydration and emaciation were common physical examination findings. Common laboratory findings were nonregenerative anemia, lymphopenia, azotemia, hypercholesterolemia, metabolic acidosis, hyperphosphatemia, and isosthenuria. The most common morphologic diagnosis was chronic tubulointerstitial nephritis of unknown cause. The other pathologic diagnoses were renal lymphosarcoma, renal amyloidosis, chronic pyelonephritis, chronic glomerulonephritis, polycystic renal disease, and pyogranulomatous nephritis secondary to feline infectious peritonitis.

Pharmacologic modulators of cyclic 3',5'-adenosine monophosphate (cAMP) and calcium were added to cultures of bone marrow cells from normal cats and cats with retrovirus-induced erythroid aplasia (EA). Treatment with the following reagents increased the number of erythroid progenitors (CFU-e and BFU-e) in cells from normal cats: isoproterenol, dibutyryl cAMP, forskolin, RO-20-1724 and A23187. However, treatment of cells collected from viremic cats not only failed to enhance CFU-e and BFU-e but inhibited their growth. These studies suggest that EA is related to a non-reversible block of primitive erythroid progenitors or to direct inhibition of BFU-e and CFU-e growth.

To examine the role of intracoronary thrombus (ICT) in unstable angina, we reviewed the coronary arteriograms of 83 patients with unstable angina (group I) and 37 patients with stable angina (group II) for angiographic evidence of ICT. Group I and group II patients were similar with respect to mean age, presence of single and multiple vessel disease, and past history of myocardial infarction. Group I patients had no ECG or creatine kinase enzyme evidence of acute myocardial infarction. The angiographic criteria for ICT included an intracoronary filling defect, intraluminal staining, and total coronary artery occlusion with convex dye outline. ICT was found in 10 of 83 patients in group I (12.0%) vs 0 of 37 patients in group II (p less than 0.05). These findings suggest that in some patients coronary artery thrombosis plays an important role in the pathogenesis of unstable angina.

Symptomatic coronary artery dissection is a recognized complication of coronary angioplasty that is usually associated with immediate adverse consequences. In contrast, the asymptomatic angiographic finding of an "intimal tear" following otherwise successful angioplasty has been considered clinically unimportant. A case is reported of a primarily successful coronary angioplasty with intimal tear that progressed to occlusive coronary artery dissection requiring coronary bypass surgery at 4 weeks postangioplasty. This case demonstrates that an asymptomatic intimal tear following successful coronary angioplasty is not always an innocuous angiographic finding.