Serum concentrations of fibroblast growth factor 2 are increased in HIV type 1-infected patients and inversely related to survival probability.

HIV-1-infected patients develop a generalized vasculopathy that is clinically most evident as Kaposi's sarcoma (KS), a multifocally appearing endothelial cell-derived tumor. Fibroblast growth factor 2 (FGF-2) is a potent autocrine and paracrine mitogen of endothelial cells and has been implicated in the cell proliferation and angiogenesis observed in KS. Here we determined by ELISA the FGF-2 serum concentrations in different clinical groups of HIV-1-infected patients. AIDS-KS patients (n = 53) and HIV-1-infected patients without KS (n = 39) revealed significantly increased FGF-2 serum concentrations (median, 4.5 and 4.6 pg/ml, respectively), as compared with the healthy control group (n = 22; median, 2.2 pg/ml; p < 0.01). FGF-2 concentrations were highest in untreated HIV-1-infected patients (median, 8.6 pg/ml) and were significantly decreased in patients undergoing antiretroviral therapy (AZT-median, 4.5 pg/ml; HAART-median, 2.5 pg/ml; p < 0.01). In addition, FGF-2 serum concentrations above 5.2 pg/ml were associated with a statistically significant higher risk of death in HIV-1-infected patients. Multivariate analysis showed that this effect is independent of CD4 levels, localization of KS (cutaneous or visceral), AIDS-defining opportunistic diseases, and therapy. Circulating FGF-2 may contribute to AIDS-associated vasculopathy and may be a sensitive and easily accessible surrogate marker to determine the survival time of HIV-1-infected patients and the efficacy of antiretroviral therapy.

Expression of K13/v-FLIP gene of human herpesvirus 8 and apoptosis in Kaposi's sarcoma spindle cells.

BACKGROUND: Human herpesvirus 8 (HHV8) infection is associated with all forms of Kaposi's sarcoma (KS). The HHV8 genome locus ORFK13-72-73 (ORF = open reading frame) encodes proteins that may be important in HHV8-mediated pathogenesis, i.e., the latency-associated nuclear antigen (encoded by ORF73), viral-cyc-D (v-cyc-D), a viral homologue of cellular cyclin D (encoded by ORF72), and viral-FLIP (v-FLIP), a homologue of the cellular FLICE (Fas-associated death domain-like interleukin 1 beta-converting enzyme) inhibitory protein (encoded by ORFK13; is an inhibitor of apoptosis [programmed cell death]). Through differential splicing events, this locus expresses individual RNA transcripts that encode all three proteins (tricistronic transcripts) or just two of them (v-FLIP and v-cyc-D; bicistronic transcripts). We examined expression of these transcripts in KS tissues. METHODS: We collected tissues from patients with KS of different stages. By use of an optimized in situ hybridization procedure, we examined different ORFK13-72-73 locus transcripts in HHV8-infected cells in skin lesions and in one adjacent lymph node. Apoptosis in KS lesions was determined by use of an in situ assay. RESULTS AND CONCLUSIONS: Our results indicate the following: 1) Transcripts from the ORFK13-72-73 locus appear to be spliced differentially in latently infected KS cells in skin lesions and in HHV8-infected cells in lymph nodes; specifically, ORFK13-ORF72 bicistronic transcripts were expressed abundantly in KS cells, whereas ORFK13-ORF72-ORF73 tricistronic transcripts were detected only in lymph node cells. 2) Sequences encoding the antiapoptotic protein v-FLIP are expressed at very low levels in early KS lesions, but expression increases dramatically in late-stage lesions. 3) The increase in expression of v-FLIP-encoding transcripts is associated with a reduction in apoptosis in KS lesions. IMPLICATIONS: These data suggest that functional v-FLIP is produced in vivo and that antiapoptotic mechanisms may be involved in the rapid growth of KS lesions, where only a few cells undergoing mitosis are generally observed.

Expression of human herpesvirus-8 (HHV-8) encoded pathogenic genes in Kaposi's sarcoma (KS) primary lesions.

Transcription of six different HHV-8 specific mRNAs was examined in early- and late-stage KS primary lesions. Expression of the latency-associated T0.7 mRNA and of VP23 mRNA which is a specific marker of lytic/productive infection suggested that HHV-8 is secondarily recruited into the KS lesions by productively infected monocytes, macrophages. From these cells HHV-8 is transmitted to the KS spindle cells, which are latently infected. v-BCL-2, v-MCP-1 and v-IL-6 were not expressed in latently infected KS spindle cells, therefore the impact of these factors in KS pathogenesis appears to be low. By contrast, v-Cyclin D was highly expressed in almost all latently infected spindle cells and may therefore be an important factor triggering progression of late-stage KS lesions.

Reactivation and persistence of human herpesvirus-8 infection in B cells and monocytes by Th-1 cytokines increased in Kaposi's sarcoma.

Patients with Kaposi's sarcoma (KS) have a human herpesvirus-8 (HHV-8) load higher than patients without KS and present a CD8(+) T-cell activation with production of Th1-type cytokines both in tissues and peripheral blood mononuclear cells (PBMC). Because in tissues of KS patients detection of inflammatory cytokines (IC) can precede detection of HHV-8 DNA and because signs of immunoactivation and/or dysregulation can precede KS development, we investigated the effect of IC on HHV-8 infection. To achieve this goal, PBMC and purified cell populations from 45 patients with KS and 45 patients at risk of KS were analyzed for HHV-8 DNA and/or gene expression and for cell survival, growth, and phenotype before or after culture with or without the IC increased in KS. The results indicate that PBMC that are polymerase chain reaction (PCR)-positive at day 0 generally loose the virus upon culture. However, the presence of IC maintains HHV-8 DNA load in cultured cells. In addition, IC increase viral load to detectable levels in PBMC from serologically positive patients that were PCR-negative before culture. gamma Interferon is sufficient for these effects, whereas tumor necrosis factor and interleukin-6 have little or no activity. The increase of HHV-8 DNA by IC is observed after short-term (7 days) or long-term (28 days) culture of the cells and occurs in one or both of the two circulating cell types that are infected in vivo: B cells and monocytes. In both cases it is associated with lytic gene expression, suggesting that virus reactivation is one of the most likely mechanisms for the effect of IC on virus load. However, IC have also effects on the cells target of HHV-8 infection, because they increase B-cell survival and induce the growth and differentiation of monocytes into KS-like spindle cells with markers of endothelial macrophages. Because cells with markers of endothelial macrophages are present in blood and lesions from KS patients and are infected by HHV-8, these data may explain the high HHV-8 load associated with KS development and suggest that infected monocytes may carry the virus to tissues, transmit the infection, or differentiate in loco in spindle cells with endothelial macrophage markers.

Infection with human immunodeficiency virus-1 increases expression of vascular endothelial cell growth factor in T cells: implications for acquired immunodeficiency syndrome-associated vasculopathy.

Alterations in the vascular system and the onset of angioproliferative lesions such as Kaposi's sarcoma (KS) are common traits of human immunodeficiency virus-1 (HIV-1)-infected patients. To investigate possible factors involved in acquired immunodeficiency syndrome (AIDS)-associated vasculopathy and vascular malfunction, expression of vascular endothelial cell growth factor-A (VEGF-A) was analyzed in HUT 78 T lymphocytes upon infection with HIV-1. VEGF-A was found to be increased in supernatants from infected cells as compared with uninfected cells. In addition, VEGF-A mRNA expression and protein secretion were significantly increased in HUT 78 cells incubated with conditioned medium (CM) derived from HIV-1 chronically infected HUT 78 cells (HIV-TCM) as compared with CM from uninfected cells (TCM). Increase of VEGF-A production in T cells was promoted by inflammatory cytokines (IC) present in HIV-TCM, including tumor necrosis factor alpha (TNFalpha), interferon gamma (IFNgamma), interleukin-1beta (IL-1beta), and IL-6. These IC that have been shown to be increased in sera of HIV-1-infected patients and to be increased by HIV-1 infection or cell activation in these individuals as well as HIV-TCM also increased VEGF-A expression in primary T lymphocytes. Consistent with this, VEGF-A concentrations were found to be higher in sera of HIV-1-infected patients with (mean, 357.1 +/- 197.9 pg/mL) and without KS (mean, 256.7 +/- 137.5 pg/mL) as compared with uninfected individuals (mean, 188.6 +/- 91.7 pg/mL). These data suggest that increased secretion of VEGF-A by T lymphocytes of HIV-1-infected individuals may induce vascular leakage and stimulate proliferation of vascular endothelial cells, which are hallmarks of AIDS-associated vasculopathy and especially of KS development.

Expression of HHV-8 latency-associated T0.7 RNA in spindle cells and endothelial cells of AIDS-associated, classical and African Kaposi's sarcoma.

Analysis by polymerase chain reaction (PCR) and serological studies have demonstrated a close association between the novel human herpes virus, Kaposi's sarcoma-associated herpes virus (KSHV) or human herpes virus-8 (HHV-8) and the development of Kaposi's sarcoma (KS). To clarify the role of HHV-8 in KS pathogenesis, we investigated at the cellular level by in situ hybridization the expression of a recently described 0.7-kb HHV-8-encoded mRNA (T0.7 mRNA) in KS tissues of different epidemiological origin (AIDS-KS, African endemic KS and classical KS). The T0.7 mRNA likely encodes a small membrane protein, supposedly expressed in latently HHV-8-infected cells. Indeed, we detected T0.7 mRNA in virtually all cells of the cell line BCBL-1 established from a body cavity-based lymphoma (BCBL) and latently infected with HHV-8. In all KS biopsies examined, independent of their epidemiological type, the late-stage (nodular) KS tissues showed a high level of T0.7 mRNA expression in typical KS spindle cells but also in endothelial cells lining blood vessels, indicating latent HHV-8 infection of these cells. The presence of T0.7-expressing cells was restricted to KS tumor tissue and therefore appears to indicate an important role of latent HHV-8 infection in KS pathogenesis.

Computed tomography of the carotid space and related cervical spaces. Part II: Neurogenic tumors.

Fourteen neurogenic tumors of the neck were examined with computed tomography (CT) and, in ten cases, angiography. Schwannomas and paragangliomas occurred in the carotid space. These tumors could be distinguished on CT from those occurring more anteriorly, in relation to the parapharyngeal space, and more posteriorly, in relation to the paraspinal space. Schwannomas alone occurred in the paraspinal space. Schwannomas were heterogeneously hypodense before contrast enhancement and at least partially hyperdense after contrast enhancement, with displacement of adjacent vessels on CT, and, if they were of vagal origin, anteromedial displacement of the internal carotid artery on angiography. Paragangliomas usually were homogeneously hyperdense after contrast enhancement, with incorporation of adjacent vessels on CT, and, if they were of carotid body origin, lateral displacement of the internal carotid artery on angiography.

Craniosynostosis: computed tomographic evaluation of skull base and calvarial deformities and associated intracranial changes.

Computed tomography has proven useful in children with craniosynostosis for the evaluation of deformity of the skull base, calvarium, and parenchymal brain structures. A retrospective analysis of 24 children seen during a 4-year period who had adequate preoperative, postoperative, and follow-up scans was carried out. Bone windows were used, and both bone thinning adjacent to fused sutures and thickening of affected sutures were demonstrated. Changes in calvarial contour were easily followed. Current trends in craniofacial reconstructive surgery have placed emphasis on skull base abnormalities; these are readily measured on axial computed tomographic (CT) sections, and postoperative progress may be monitored by serial scanning. In addition, new data revealing distortion of brain structures and cerebrospinal fluid pathways in these children have been obtained with CT scans. These soft tissue abnormalities had not been appreciated before the CT era, and they add a new dimension to the evaluation of these disorders. We think that these abnormalities indicate a local pressure increase on the brain at the fusion site. The restoration of parenchymal changes toward normal during the postoperative period correlated well with cosmetic improvement.

Cerebellar metastasis from ovarian carcinoma.

The most common sources of metastatic disease of the brain are lung and breast carcinoma. Considerably less common are metastases from malignant melanoma, hypernephroma, and carcinomas of the alimentary tract. All other sources are rare. This report presents a unusual case of a single cerebellar metastatic lesion from ovarian carcinoma.

Computed tomography of disseminated meningeal and ependymal malignant neoplasms.

We studied computed tomography (CT) scans of 50 patients with clinical signs and symptoms compatible with disseminated meningeal tumor, all documented by cerebrospinal fluid cytology, surgical biopsy or autopsy. Twenty-three patients also had nuclear scans, and 13 had cerebral angiograms. Represented in the series were patients with metastatic carcinoma, gliomas, and lymphomas. The characteristic CT findings included gyral enhancement without edema; sulcal and basilar cisternal obliteration and enhancement, and ependymal-subependymal enhancement. The correct diagnosis was made by CT in 28 of the 50 cases (56%).

Variations of the ophthalmic and middle meningeal arteries: relation to the embryonic stapedial artery.

Recognition of the anatomic variations of the ophthalmic and middle meningeal arteries may be pertinent in tailoring the angiographic study to resolve a given clinical problem. An understanding of these anomalies is based on knowledge of the normal embryology. Unfortunately some early aspects of vascular development remain obscure. Fragmentary observations gleaned from the embryologic literature were correlated with selective and/or subselective angiography performed in 42 patients with such anomalies. This analysis has provided the basis for a tenable scheme for development of the ophthalmic and middle meningeal arteries as they relate to the embryonic stapedial artery. A classification for anomalies of these arteries is proposed based on deviation from this normal embryologic mechanism.

Cerebral cysticercosis: occurrence in the immigrant population.

Six cases of cerebral cysticercosis have been diagnosed at the Neurological Institute of New York during the past 18 years. Three recent cases are discussed, with emphasis on the variability of signs and symptoms and the best available diagnostic techniques. One must have a high index of suspicion when evaluating patients who have immigrated to the United States from endemic areas, although the disease may be acquired through food contaminated by carriers in nonendemic areas. Conventional radiography (e.g., plain films and pneumography) and, more recently, computerized tomography are the most effective tests to confirm this diagnosis. Cerebrospinal fluid and serum eosinophilia and indirect hemagglutination titers are nonspecific but occasionally helpful. Therapy is currently confined to surgical excision of lesions where possible and symptomatic treatment otherwise.

Cerebral cysticercosis.

Five patients with cerebral cysticercosis, two within the year preceding the date of this article, were seen at the New York Neurological Institute. The patients presented with mental changes, seizures, and symptoms of increased intracranial pressure, and had a history of having immigrated from an area endemic for cysticercosis. They were found to have parenchymal or intraventricular cysticercosis cysts. The interval from immigration to onset of symptoms was as long as 3 years. Plain radiograms of the skull and soft tissues, ventriculograms, and especially the CT scan, as well as the CSF examination, were useful in making the diagnosis. Surgical removal of an intraventricular cyst was curative in two patients and seizures were controlled with anticonvulsants in the other three.