Novel alleles at the lymphotoxin alpha (LTalpha) locus mark extended HLA haplotypes in native Africans.

Genetic variations at the closely related tumor necrosis factor alpha (TNFalpha or TNF) and lymphotoxin alpha (LTalpha, formerly TNFbeta) loci have been well documented in various human populations, and several haplotypes spanning the MHC class I and class II loci are known to carry specific TNF alleles. Genotyping of the TNFc microsatellite within the first intron of LTalpha in 285 Rwandans and 319 Zambians revealed two predominant alleles, c1 at frequencies of 0.598 and 0.683 and c2 at 0.384 and 0.307, respectively. Overall, the distribution of TNFc genotypes containing the major alleles conformed well to the Hardy-Weinberg equilibrium in both cohorts. Two previously unrecognized minor TNFc alleles were also detected: the first, designated c0, was found in 10 native Africans and was the only allele present in 10 chimpanzees; the second, designated c3, was seen in 6 other African patients. Further genotyping at loci for HLA class I, class II, and for transporters associated with antigen processing, subunit 1 (TAP1) in those 16 individuals suggested a tight, stable extended haplotype involving c0 and 26Asn (LTalpha)-TNF3 (TNF promoter -238A and -308G)-DRB1*1503-DQB1*0602-TAP1.2 (333Val)-TAP1.4 (637Gly). The c3 allele was observed on another extended haplotype with 26Thr (LTalpha)-TNF1 (TNF promoter -238G and -308G)-DQB1*0102-DQB1*0501-TAP1*0101 (333Ile and 637Asp). The c3-tagged haplotype further extended to Cw*15 at the HLA class I C locus, but no specific A or B alleles could be unambiguously assigned. Positive associations between c2 homozygosity and HIV-1 seronegative status in both Rwandans and Zambians (odds ratio = 2.03 and 2.00, p = 0.04 and 0.07, respectively) had little effect on the haplotype assignments. These findings suggest a preferential expansion of the human TNFc dinucleotide (CT/AG) repeat sequence and further imply the existence of two extended MHC lineages that have not been disrupted by recombinations.

In vivo attenuation of simian immunodeficiency virus by disruption of a tyrosine-dependent sorting signal in the envelope glycoprotein cytoplasmic tail.

Attenuated simian immunodeficiency viruses (SIVs) have been described that produce low levels of plasma virion RNA and exhibit a reduced capacity to cause disease. These viruses are particularly useful in identifying viral determinants of pathogenesis. In the present study, we show that mutation of a highly conserved tyrosine (Tyr)-containing motif (Yxxphi) in the envelope glycoprotein (Env) cytoplasmic tail (amino acids YRPV at positions 721 to 724) can profoundly reduce the in vivo pathogenicity of SIVmac239. This domain constitutes both a potent endocytosis signal that reduces Env expression on infected cells and a sorting signal that directs Env expression to the basolateral surface of polarized cells. Rhesus macaques were inoculated with SIVmac239 control or SIVmac239 containing either a Tyr-721-to-Ile mutation (SIVmac239Y/I) or a deletion of Tyr-721 and the preceding glycine (DeltaGY). To assess the in vivo replication competence, all viruses contained a stop codon in nef that has been shown to revert during in vivo but not in vitro replication. All three control animals developed high viral loads and disease. One of two animals that received SIVmac239Y/I and two of three animals that received SIVmac239DeltaGY remained healthy for up to 140 weeks with low to undetectable plasma viral RNA levels and normal CD4(+) T-cell percentages. These animals exhibited ongoing viral replication as determined by detection of viral sequences and culturing of mutant viruses from peripheral blood mononuclear cells and persistent anti-SIV antibody titers. In one animal that received SIVmac239Y/I, the Ile reverted to a Tyr and was associated with a high plasma RNA level and disease, while one animal that received SIVmac239DeltaGY also developed a high viral load that was associated with novel and possibly compensatory mutations in the TM cytoplasmic domain. In all control and experimental animals, the nef stop codon reverted to an open reading frame within the first 2 months of inoculation, indicating that the mutant viruses had replicated well enough to repair this mutation. These findings indicate that the Yxxphi signal plays an important role in SIV pathogenesis. Moreover, because mutations in this motif may attenuate SIV through mechanisms that are distinct from those caused by mutations in nef, this Tyr-based sorting signal represents a novel target for future models of SIV and human immunodeficiency virus attenuation that could be useful in new vaccine strategies.

Down-regulation of macaque gammadelta + T cells in lymphoid compartments after rectal infection with SIVsmmPBj14.

The dynamics of T cells expressing the gammadelta T-cell receptor in mucosae and other compartments during the course of human immunodeficiency virus (HIV)-1 infection are poorly understood. To examine the impact of an acquired immunodeficiency syndrome virus on the gammadelta + T-cell population, rectal inoculation of macaques with simian immunodeficiency virus (SIV)-PBj14 was used as a model. After rectal inoculation, five macaques were sacrificed on days 4, 5, or 7 and then assessed for changes in the gammadelta T-cell receptor repertoire in different lymphoid compartments. There was decreased representation of gammadelta + T cells in the intestinal mucosae, blood, and spleens. Overall, the reduced number of total gammadelta + T cells was consistent with decreases in the Vgamma or Vdelta T-cell sub-populations. Nevertheless, there was no consistent deletion or expansion of a selected Vdelta + or Vdelta + cell sub-population. These results demonstrate that SIV-PBj14 replication and dissemination after mucosal inoculation resulted in a decline of detectable gammadelta + T cells, suggesting that macaque gammadelta + T cells are susceptible to down-regulation or destruction during acute SIV-PBj14 infection.

Distribution and quantification of human immunodeficiency virus type 1, strain JC499, proviral DNA in tissues from an infected chimpanzee.

Data are accumulating to show that the natural history of human immunodeficiency virus type 1 (HIV-1) in chimpanzees closely reproduces that in humans and is influenced by biologic properties of the infecting HIV-1 strain. To determine the distribution and relative amounts of HIV-1, proviral DNA in multiple tissues from a chimpanzee euthanized because of an abdominal tumor and kidney failure was quantified by nested PCR limiting-dilution assays. At death, 21 months after infection with HIV-1(JC499), this animal had a CD4(+) T-cell count of 268 and 1.7 x 10(5) copies of virion RNA/ml of plasma. The highest proviral burdens were in peripheral lymph nodes and blood, followed by lung, colon, and spleen; values ranged from 130 to 3350 proviral copies/microg DNA (equivalent to DNA in 150,000 cells). The lowest levels of virus were in the spinal cord, brain, and cecum (0.3 to 2.5 copies/microg DNA), with all other tissues harboring intermediate levels (6.8 to 114 copies/microg DNA). Viral burdens in all tissues were comparable to or greater than those reported for HIV-1-infected humans in all stages of disease. Immunohistochemistry for HIV-1 p24 Gag antigen revealed (i) trapping of HIV-1 on follicular dendritic cells in lymph node germinal centers and (ii) virus in the brain, where it was localized primarily to capillary endothelial cells in the cerebral cortex. Analysis of the genetic diversity of the Env V3 loop in tissues indicated that there was no apparent compartmentalization of HIV-1 variants. Of interest, in 83 of 94 (88.3%) clones sequenced, the unique GYGR motif at the tip of the V3 loop of HIV-1(JC499) had reverted to the more common GPGR. The results support the conclusion that HIV-1 has the potential to maintain high viral burdens in chimpanzees and to disseminate to most organs, including the central nervous system. The use of the chimpanzee model with HIV-1(JC499) (or related strains) in vaccine efficacy studies should prove valuable, especially when assessing protection against disease. Furthermore, comparison of both replicative properties of HIV-1(JC499) with SIVcpz strains and immune responses of chimpanzees infected with these viruses might provide new information about HIV pathogenesis.

Delayed computed tomographic characterization of renal masses: preliminary experience.

BACKGROUND: To evaluate the performance of delayed contrast enhanced computed tomography (DCT) in characterizing renal masses. METHODS: Twenty-four patients with suspected renal masses or indeterminate renal masses on previous imaging studies were prospectively evaluated with preintravenous contrast imaging, conventional contrast-enhanced computed tomography (imaging initiated 2 min after intravenous contrast injection), and DCT (imaging initiated 13 min after injection of intravenous contrast). Only lesions larger than 1.0 cm were evaluated, with scanning parameters kept constant across the three scans. RESULTS: All pathologically confirmed renal cell carcinomas (n = 6) were detected on DCT using a threshold attenuation decrease of 10 Hounsfield units (HU). A significant decrease (p = 0.031) in attenuation occurred in renal cell carcinomas (mean = 29.6 +/- 23.6 HU) compared with the attenuation change (mean decrease = 1.1 +/- 7.1 HU), which occurred in non-neoplastic renal cysts (n = 34). Non-neoplastic renal cysts were correctly classified by DCT 32 of 34 times (94%). CONCLUSIONS: In this study, DCT distinguished renal cell carcinomas from non-neoplastic cysts in a vast majority of cases and may aid in characterizing incidentally discovered renal lesions on postcontrast CT.

Ovarian cancer: comparison of observer performance for four methods of interpreting CT scans.

PURPOSE: To assess the effects of four interpretative methods on observers' mean sensitivity and specificity by using computed tomography (CT) of ovarian carcinoma as a model. MATERIALS AND METHODS: CT scans in 98 patients with ovarian carcinoma and 49 women who were disease free were retrospectively reviewed by four experienced blinded radiologists to compare single-observer reading, single-observer reading with an anatomic checklist, paired-observer reading (simultaneous double reading), and replicated reading (combination of two independent readings). Confidence level scoring was used to identify three possible disease forms in each patient: extranodal tumor, lymphadenopathy, and ascites. Patient conditions were then categorized as abnormal or normal. RESULTS: There were no significant improvements in sensitivity or specificity for classification of patient conditions as abnormal or normal when comparing single-observer interpretation with single-observer interpretation with a checklist or paired-observer interpretation. Although there was no significant improvement in the mean sensitivity (93% vs 94%) by using the replicated reading method, there was a statistically significant improvement in mean specificity (85% vs 79%) for the replicated readings compared with single-observer interpretations (P < .05). CONCLUSION: Diagnostic aids such as checklists and paired simultaneous readings did not lead to an improved mean observer performance for experienced readers. However, an increase in the mean specificity occurred with replicated readings.

Virus-specific cytotoxic T lymphocytes in human immunodeficiency virus type 1-infected chimpanzees.

Chimpanzees have been important in studies of human immunodeficiency virus type 1 (HIV-1) pathogenesis and in evaluation of HIV-1 candidate vaccines. However, little information is available about HIV-1-specific cytotoxic T lymphocytes (CTL) in these animals. In the present study, in vitro stimulation of peripheral blood mononuclear cells (PBMC) from infected chimpanzees with HIV-1 Gag peptides was shown to be a sensitive, reproducible method of expanding HIV-1-specific CD8(+) effector CTL. Of interest, PBMC from two chimpanzees had CTL activity against Gag epitopes also recognized by major histocompatibility complex class I-restricted CTL from HIV-1-infected humans. The use of peptide stimulation will help to clarify the role of CTL in vaccine-mediated protection and HIV-1 disease progression in this important animal model.

Pathogenicity and comparative evolution in vivo of the transitional quasispecies SIVsmmPBj8.

During 14 months of infection of a pig-tailed macaque, the acutely lethal simian immunodeficiency virus SIVsmmPBj14 (SIV-PBj14) evolved from the minimally pathogenic strain SIVsmm9. The virus isolated at 8 months (SIV-PBj8) exhibited properties of both SIVsmm9 and SIV-PBj14, indicating that a phenotypic transition occurred between 6 and 10 months. To assess the influence that this new composition of biologic properties might have on pathogenicity, three pig-tailed macaques were inoculated intravenously with SIV-PBj8. Although no animals developed the severe acute disease syndrome typical of SIV-PBj14, all had high levels of viremia and died of AIDS at 4, 10. 5, and 32 months. Characterization of the SIV-PBj8-derived quasispecies that evolved in these macaques showed that at 4 days after inoculation, viruses from all three animals exhibited in vitro properties different from those of the inoculum. By 4 months, the initial phenotypic profiles had changed, with the quasispecies in plasma from the animal (J90232) that died at this time most closely resembling SIV-PBj14, not SIV-PBj8. Phylogenetic trees of the gp41/Nef region of viruses in 4-month plasma from J90232 revealed three distinct populations with high bootstrap values: one group branched with SIVsmm9, one with SIV-PBj14, and one with SIV-PBj8 (ratio of clones, 5:9:5). Nucleotide sequence analysis suggested that some members of the original SIV-PBj8 quasispecies may have been evolving toward a SIV-PBj14-like genotype at the time macaque J90232 died. The use of SIV-PBj8, which was more pathogenic than SIVsmm9, but less pathogenic than SIV-PBj14, may provide the optimal genetic background on which to identify the minimal, multigenic determinants of the SIV-PBj14 phenotype. The results of our studies on SIV-PBj14 indicate that in some, but not all, cases of primate lentivirus infection more pathogenic variants evolve, selectively proliferate, and more than likely contribute to disease progression.

Rectal transmission of human immunodeficiency virus type 1 to chimpanzees.

Inoculation of chimpanzees with human immunodeficiency virus type 1 (HIV-1) has been used as a model system to define mechanisms of pathogenesis and to test protective efficacy of candidate HIV-1 vaccines. In most of these studies, the animals were inoculated intravenously. However, because HIV-1 is transmitted primarily across mucosal surfaces, future evaluations of vaccines should employ mucosal routes for administering infectious virus to immunized animals. To develop a model of rectal transmission of HIV-1, chimpanzees were exposed without trauma to 4 different HIV-1 strains at doses ranging from 200 to 10,000 TCIDs. Infection, characterized by seroconversion and repeated isolation of virus from lymphocytes, was established in 1 of 5 animals. This animal was sequentially inoculated with a subtype B and then an E strain and was infected with both strains. The results show that rectal exposure of adult chimpanzees to cell-free HIV-1 was not an efficient mode of transmission in this cohort.

Mucosal immune system of the human genital tract.

In contrast to the pronounced dominance of secretory IgA over other immunoglobulin isotypes in human saliva, tears, milk, and gastrointestinal fluids, secretions of both female and male genital tracts contain more IgG than secretory IgA. Both IgG and IgA are derived, to a variable degree, from the systemic immunoglobulin pool as well as from local synthesis. The origin of IgG- and IgA-plasma cell precursors destined for the genital tract is unknown, but indirect evidence suggests that mucosal inductive sites localized in the rectum, small intestine, and especially in the nasal cavity contribute such precursors to the female genital tract. Several studies indicated that intranasal immunization of various species, including humans, was efficient at inducing antigen-specific antibody responses in the female genital tract; however, whether this route is also effective in males has not been explored.

A multicenter, randomized, double-blind study to evaluate the safety, tolerability, and efficacy of OptiMARK (gadoversetamide injection) compared with Magnevist (gadopentetate dimeglumine) in patients with liver pathology: results of a Phase III clinical trial.

The purpose of this study was to evaluate the safety and efficacy of OptiMARK (gadoversetamide injection) compared with Magnevist (gadopentetate dimeglumine) in hepatic MRI of patients with suspected liver pathology. A Phase III, multicenter, randomized, double-blind, parallel group study was performed in adults with suspected liver pathology. All patients underwent contrast-enhanced computed tomography within 3 weeks prior to magnetic resonance scanning. Ninety-nine patients received OptiMARK, and 94 patients received Magnevist at a dose of 0.1 mmol/kg. Precontrast T1- and T2-weighted spin-echo imaging and T1-weighted gradient-echo imaging were performed, followed by T1-weighted gradient-echo imaging at 15-20 seconds, 1 minute, and 5 minutes after intravenous contrast injection. Three primary efficacy endpoints (confidence in lesion diagnosis, level of conspicuity, and lesion border delineation) were evaluated on the precontrast image set and compared with the pre plus postcontrast image set. Vital signs, physical examination, electrocardiograms (ECGs), and laboratory parameters (chemistry, hematology, and urinalysis) were measured at various time points. Adverse events were recorded. The study design and statistical analyses were chosen to demonstrate presumed equivalence of OptiMARK and Magnevist. There were no statistically significant differences in efficacy between OptiMARK and Magnevist as assessed by either blinded readers or the on-site principal investigators. No serious or unexpected adverse events were noted. Of the 193 patients receiving contrast media, 82 experienced a total of 154 adverse events. Thirty-three (21.4%) of these 154 adverse events were felt by the on-site investigators to be probably related to either study agent: 15 events in 9 patients in the OptiMARK group, and 18 events in 13 patients in the Magnevist group. Headache was the most common adverse event, occurring in 10.1% of the OptiMARK patients and 12.8% of the Magnevist patients. No clinically relevant trends were observed in any laboratory parameter or ECG findings in either treatment group. The results demonstrate the safety, efficacy, and equivalence of OptiMARK and Magnevist at a dose of 0.1 mmol/kg in hepatic magnetic resonance imaging of patients with suspected liver pathology.

Coinfection of macaques with simian immunodeficiency virus and simian T cell leukemia virus type I: effects on virus burdens and disease progression.

To test the hypothesis that coinfection with human immunodeficiency virus (HIV) and human T cell leukemia/lymphoma virus types I or II (HTLV-I or -II) accelerates progression to AIDS, pig-tailed macaques were inoculated with the simian counterparts, SIV and STLV-I. During 2 years of follow-up of singly and dually infected macaques, no differences in SIV burdens, onset of disease, or survival were detected. However, in the first coinfected macaque that died of AIDS (1 year after infection), >50% of CD4+ and CD8+ lymphocytes expressed CD25. On the basis of the low incidence of HTLV-I- and STLV-I-associated disease during natural infections, this early evidence of neoplastic disease was unexpected. While these results demonstrate that coinfection with SIV and STLV-I has no influence on the development of immunodeficiency disease, they do establish a reliable macaque model of persistent STLV-I infection.

Allelic variants of human beta-chemokine receptor 5 (CCR5) promoter: evolutionary relationships and predictable associations with HIV-1 disease progression.

Variability in the natural history of HIV-1 infection has been repeatedly associated with genetic variants in the beta-chemokine receptor 5 (CCR5) locus. While CCR5 coding sequences have demonstrated relatively limited variation, sequences of its promoter appear polymorphic in all major populations. Our studies revealed five major CCR5 promoter alleles with distributions that differed widely among the four distinct ethnic groups from Kigali, Rwanda and Bronx, New York. In particular, promoter allele P*0103 (G59029-T59353-T59356-A59402-C59653) was largely restricted to black subjects. The promoter allele P*0202 (A59029-C59353-C59356-A59402-T59653) was tightly linked to the slightly less frequent CCR2b-641, a variant of the CCR2b gene, which is about 12.7 kbp upstream from the promoter region. Another closely related promoter allele P*0201 (A59029-C59353-C59356-A59402-C59653) exclusively carried the far less common CCR5-delta 32, a 32-bp deletion in the CCR5 coding sequence 2 kbp downstream from the promoter. The homozygous P*0201/*0201 genotype can be predicted as a risk factor for more rapid disease progression. Among human, chimpanzee, pig-tailed macaque, and sooty mangabey promoter allelic sequences, the apparent ancestral lineage of the promoter sequence (G59029-T59353-C59356-A59402-C59653 = human P*0102) was highly conserved across the primate species analyzed here while P*0201 and P*0202 arose more recently than the other three major alleles. Further effort to establish the mechanism by which CCR chemokine receptor polymorphisms govern the initiation and pathogenesis of primate lentivirus infection apparently requires fully detailed genotypic characterization of the affected populations.

Polynucleotide immunization of nonhuman primates against carcinoembryonic antigen.

In preparation for a Phase I trial of DNA immunization against carcinoembryonic antigen (CEA) in patients with colorectal carcinoma, we have produced a single plasmid DNA encoding CEA and hepatitis B surface antigen (HBsAg) under transcriptional regulatory control of two separate cytomegalovirus promoters within separate eukaryotic expression cassettes, designated pCEA/HBsAg. Hepatitis B surface antigen was included to provide an internal positive control for the efficacy of this immunization strategy without regard to the issue of breaking tolerance to a self-antigen. In the present work, we sought to examine the immunogenicity of this plasmid in a nonhuman primate model with close phylogenetic relationship to humans. Groups of pig-tailed macaques were immunized with pCEA/ HBsAg by i.m. injection or particle bombardment of the skin according to a dose and schedule thought to be optimal for the respective technique of DNA immunization. Both administration techniques produced humoral and lympho-proliferative responses of comparable magnitude. However, delayed type hypersensitivity to CEA and CEA-specific interleukin-2 release were observed only in the i.m. group, suggesting a qualitative difference in the character of the immune response elicited by the two techniques of DNA immunization. The antibody responses to CEA and HBsAg were surprisingly persistent in that all immunized animals maintained moderate antibody titers against both antigens for more than 15 months after the last boost. No toxicity was observed during 2 years of follow-up, including no measurable levels of anti-DNA antibody. This antitumor immunization strategy is presently being examined in patients with metastatic colorectal carcinoma using pCEA/HBsAg administered by i.m. injection.

Genital infection of female chimpanzees with human immunodeficiency virus type 1.

To develop an animal model for mucosal HIV-1 infection, adult chimpanzees were inoculated without trauma by depositing the virus inoculum at the entrance to the cervical canal with a rigid catheter to which flexible tubing was attached. By this procedure, persistent infections were established in some chimpanzees with various infectious doses of either cell-associated HIV-1LAI(IIIB) (peripheral blood mononuclear cells from an infected chimpanzee) or with cell-free HIV-1 strains representing subtypes B and E, but not with a subtype A strain. Although some animals did not become infected until after the second or third cervicovaginal exposure, one chimpanzee was clearly infected after one exposure by several criteria, including virus isolation, but this animal did not seroconvert. A second chimpanzee appeared to be resistant to infection despite repeated mucosal exposures at irregular intervals. However, lymphocytes from both of these animals exhibited low-level proliferative responses to HIV-1 but not SIV antigens. Despite these apparently abortive or latent infections, after exposure to HIV-1 by the intravenous route, both animals developed systemic infections and seroconverted. Overall, 8 of 10 chimpanzees were infected systemically after one to three cervicovaginal exposures to HIV-1LAI(IIIB). The results indicate that (1) HIV-1 productive infection of female chimpanzees by the cervicovaginal route generally requires more than one exposure, just as with humans; (2) low level infections without seroconversion can be established after mucosal exposure to HIV; and (3) vaccine efficacy studies involving a single virus challenge of immunized chimpanzees by the cervicovaginal route probably will not be possible.

Extravisceral masses in the peritoneal cavity: sonographically guided biopsies in 52 patients.

OBJECTIVE: Our objective was to determine the effectiveness of sonographically guided biopsies of extravisceral masses (masses outside the solid organs) in the peritoneal cavity. MATERIALS AND METHODS: We retrospectively reviewed the results of sonographically guided biopsies of extravisceral masses found in the peritoneal cavity of 52 patients (age range, 25-90 years old; mean age, 52 years) from June 1990 to December 1996. Fifty-one patients underwent biopsy through the abdominal wall, and one patient underwent transvaginal biopsy. Sonographic guidance was obtained using 3.5- to 7.0-MHz vector probes. The size, depth, and sonographic characteristics of the mass and the type of biopsy (aspirate versus core) were determined for all lesions. Pathology reports and clinical courses were reviewed. RESULTS: Placement of the biopsy needle within the lesion was successful in all patients. The mean depth from skin surface to lesion was significantly less (p < .0001) when shown by sonography (2.4 cm) than when shown by CT (3.8 cm). Biopsy results were true-positive for malignancy in 37 patients (no false-positives), true-negative for benign masses in 10 patients, and false-negative for malignancy in three patients (sensitivity, 93%; specificity, 100%; accuracy, 94%). Nondiagnostic samples were obtained in two patients (4%). Treatment was based on diagnostic biopsy results in 43 patients (86%). CONCLUSION: Sonography is an effective alternative to CT in guiding biopsy of extravisceral masses in the peritoneal cavity.

Down-modulation of the ZAP-70 protein tyrosine kinase in macaque T lymphocytes infected with SIVsmmPBj14.

The simian immunodeficiency virus SIV-PBj14 is the most virulent primate lentivirus identified to date. Other SIV strains, including the parental SIVsmm9, require mitogen-activated peripheral blood mononuclear cells (PBMC) for replication in vitro; however, SIV-PBj14 replicates in quiescent pig-tailed macaque PBMC and induces cellular proliferation, consistent with its in vivo pathogenesis. To identify mechanisms involved in SIV-PBj14-induced T-cell proliferation, kinases important in early T-cell receptor-mediated activation pathways were studied. Immunoblot analyses showed that ZAP-70 protein, a tyrosine kinase, was downregulated, primarily in CD8+ T cells, as early as 30 minutes after in vitro infection of quiescent macaque PBMC with SIV-PBj 14. Furthermore, this downregulation required the presence of either CD4+ T cells or adherent cells or both cell populations. In agreement with the in vitro results, ZAP-70 expression was downregulated in macaque PBMC, spleen, and rectal lymph node cells as early as 2 days after rectal inoculation of pig-tailed macaques with SIV-PBj14. This phenomenon, however, was not observed in cells obtained from distal lymph nodes to which the virus had not disseminated, implying that the presence of SIV-PBj14 is necessary to induce downregulation of ZAP-70.

Nontraumatic rupture of the thoracic aorta: chest radiographic features of an often unrecognized condition.

OBJECTIVE: The purpose of our study was to evaluate chest radiographic features of nontraumatic mediastinal hemorrhage occurring after extrapericardial thoracic aorta rupture. MATERIALS AND METHODS: Twenty-seven consecutive chest radiographs obtained at admission of patients with hemorrhage from ruptured thoracic aorta aneurysms, aortic dissections, or penetrating aortic ulcers were randomized with radiographs of 23 subjects with nonruptured thoracic aorta aneurysms, 20 subjects with nonruptured dissections, and 20 control subjects. Diagnoses were established by interpreting CT scans, MR images, and findings at surgery or autopsy or both. A retrospective review was performed by three independent radiologists who were unaware of patients' diagnoses. Observers assessed 20 parameters on each of these 90 radiographs and summarized their findings with final diagnoses. The 20 parameters were analyzed with logistic regression and rank correlation to determine the best predictors of hemorrhage. RESULTS: Logistic regression analysis showed a combination of obscuration or convexity of the aorticopulmonary window and a displaced left paraspinal interface to be the most useful predictor of hemorrhage (p < .05). Rank correlation analysis indicated obscuration or convexity of the aorticopulmonary window; a displaced left paraspinal interface; enlarged aortic knob width; enlarged thoracic aorta size; an enlarged, obscured, or irregular aortic margin; and left pleural or extrapleural space fluid were potential individual predictors of hemorrhage (p < .05). Observer sensitivities for recognizing hemorrhage were 30-59% and specificities were 83-91%. Sensitivities for distinguishing an abnormal (n = 70) from a normal (n = 20) mediastinum were 79-90% and specificities were 65-90%. CONCLUSION: Obscuration or convexity of the aorticopulmonary window and a displaced left paraspinal interface on radiographs may indicate mediastinal hemorrhage. Further imaging is required to establish a definitive diagnosis.