A rare case of a simultaneous post-dissection saccular aneurysm of the ascending aorta and large pulmonary artery aneurysm with secondary embolism: a case report.

BACKGROUND: Aneurysms of the pulmonary arteries and the ascending aorta are rare, and both bear a high mortality risk if left untreated. In general, these entities are primarily caused by etiologies such as hypertension, pulmonary arterial hypertension, infection or congenital disorders. Treatment requires a rapid diagnostic work-up or even immediate surgical intervention in acute cases. Nevertheless, surgery entails serious perioperative risks, in particular in patients with multiple comorbidities. CASE PRESENTATION: We discuss a 70-year-old woman presented with decompensated heart failure based on severe pulmonary artery hypertension, coincided by a massive pulmonary artery aneurysm with secondary embolism. Additional diagnostic imaging also showed a chronic post-dissection, saccular aneurysm of the ascending aorta. To our knowledge, this simultaneous diagnosis of a saccular aneurysm of the ascending aorta and a large aneurysm of the pulmonary artery with secondary embolism has not yet been described. Nonetheless, conservative treatment was chosen due to extensive pulmonal and cardiovascular comorbidities and the high-risk profile of surgery. CONCLUSIONS: Extensive aneurysmatic disease of the pulmonary arteries and ascending aorta come with a serious burden of disease, especially if coincided by severe pulmonal and cardiovascular comorbidities. Both conditions can be curatively treated by surgical intervention. However, in every case the risk of surgery and the patient's vitality, comorbidities and wishes should be taken into account to formulate an adequate treatment plan. Therefore, shared decision making is of utter importance.

Tumor necrosis factor identified in multiple sclerosis brain.

Frozen brain specimens from patients with multiple sclerosis (MS) and other neurologic diseases were analyzed using immunocytochemical techniques for the presence of TNF. In brain lesions in MS, and subacute sclerosing panencephalitis, TNF+ cells were demonstrated. At the lesion site in MS, TNF+ staining is associated with both astrocytes and macrophages. These observations were not made in Alzheimer's disease or normal brain tissue. The presence of TNF in MS lesions suggests a significant role for cytokines and the immune response in disease progression.

Proliferation of astroglia and oligodendroglia in response to human T cell-derived factors.

Human T lymphocytes transformed by human T cell leukemia-lymphoma viruses or activated by lectins were found to produce stimulating factors that promoted both proliferation and maturation of oligodendroglial and astroglial cells in vitro.

Virus-induced neuronal apoptosis blocked by the herpes simplex virus latency-associated transcript.

Latent infections with periodic reactivation are a common outcome after acute infection with many viruses. The latency-associated transcript (LAT) gene is required for wild-type reactivation of herpes simplex virus (HSV). However, the underlying mechanisms remain unclear. In rabbit trigeminal ganglia, extensive apoptosis occurred with LAT(-) virus but not with LAT(+) viruses. In addition, a plasmid expressing LAT blocked apoptosis in cultured cells. Thus, LAT promotes neuronal survival after HSV-1 infection by reducing apoptosis.

Anti-inflammatory, antithrombotic, and neuroprotective effects of activated protein C in a murine model of focal ischemic stroke.

BACKGROUND: Activated protein C (APC) contributes to systemic anticoagulant and anti-inflammatory activities. APC may reduce organ damage by inhibiting thrombin generation and leukocyte activation. Neutrophils and cerebrovascular thrombosis contribute to ischemic neuronal injury, suggesting that APC may be a potential protective agent for stroke. METHODS AND RESULTS: We examined the effects of APC in a murine model of focal ischemia. After middle cerebral artery occlusion/reperfusion, the average survival time in controls was 13.6 hours. Animals that received purified human plasma-derived APC 2 mg/kg IV either 15 minutes before or 10 minutes after stroke induction survived 24 hours and were killed for neuropathological analysis. APC 2 mg/kg given before or after onset of ischemia restored cerebral blood flow, reduced brain infarct volume (59% to 69%; P:<0.003) and brain edema (50% to 61%; P:<0.05), eliminated brain infiltration with neutrophils, and reduced the number of fibrin-positive cerebral vessels by 57% (P:<0.05) and 25% (nonsignificant), respectively. The neuroprotective effect of APC was dose-dependent and associated with significant inhibition of ICAM-1 expression on ischemic cerebral blood vessels (eg, 61% inhibition with 2 mg/kg APC). Intracerebral bleeding was not observed with APC. CONCLUSIONS: APC exerts anti-inflammatory, antithrombotic, and neuroprotective effects in stroke. Central effects of APC are likely to be related to improved maintenance of the blood-brain barrier to neutrophils and to reduced microvascular obstructions and fibrin deposition.

Expression of HLA-DR antigens in human fetal pancreas tissue.

The expression of HLA-DR antigens in human fetal pancreas tissue was studied using four independently derived monoclonal antibodies recognizing nonpolymorphic HLA-DR antigens. Immunoperoxidase staining of frozen sections revealed numerous DR-antigen-positive cells. Two major cell types could be distinguished. Large, strongly DR-positive cells with dendritic morphology were distributed throughout the dendritic morphology were distributed throughout the pancreatic parenchyma and interstitial connective tissue. Dual staining of DR antigens and insulin using a two-color immunoperoxidase technique clearly showed that some of these DR-positive dendritic cells were located within and in close association with insulin-producing islets. Also observed as a regular feature of fetal pancreas tissue sections were large clusters of DR-positive cells with lymphoid morphology. Positive staining of many cells within these clusters with monoclonal antibodies against T-cell marker (Leu-1) and T-cell subset markers (Leu-2 and -3) supported their classification as lymphoid cells. In contrast, no positive staining with anti-T-cell antibodies was observed outside of lymphoid cell clusters, confirming the distinction between these cells and the DR-positive cells distributed throughout the pancreas. The presence of other DR-bearing cell types in fetal pancreas could not be excluded, but most endothelial cells appeared to be DR-negative. The demonstration of numerous DR-bearing cells associated with fetal pancreas tissue may require that we alter our views on DR-antigen ontogeny and develop new strategies for fetal pancreas transplantation.

Soluble TNF-alpha receptors are constitutively shed and downregulate adhesion molecule expression in malignant gliomas.

The regulation of adhesion molecule expression in malignant gliomas by tumor necrosis factor-alpha (TNF) and soluble TNF receptors (TNFR) was examined in the malignant glioma cell line A-172 and in 2 primary glioblastoma cell cultures (LA-492 and LA-567). A-172 cells expressed only the p55 TNF receptor transcripts and protein. The 2 primary cell cultures expressed both the p55 and p75 TNF receptors. In A-172 cells and in 1 of 2 primary glioma cell cultures, TNF upregulated the expression of ICAM-1 and VCAM-1, A-172 and both primary glioma cultures also shed their TNF receptors in the absence of activation by stimulating agents. Soluble p55 (sp55) receptors, but not soluble p75 (sp75) receptors, were found to reduce the TNF induced VCAM-1 and ICAM-1 expression in both the glioma cell line and the primary cell culture. Immunostaining of malignant glioma sections confirmed the presence of soluble TNFR and adhesion molecule expression in glioma cells in situ. These data suggest that soluble TNF receptors may play a role in the mechanism by which malignant gliomas downregulate the effects of infiltrating immune-competent cells.

Circulating antibody against tumor necrosis factor-alpha protects rat brain from reperfusion injury.

The role of tumor necrosis factor-alpha (TNF alpha) in brain injury is controversial. We studied the effect of anti-TNF-alpha antibody in a rat model of reversible middle cerebral artery occlusion. During focal ischemia and early reperfusion, TNF-alpha was rapidly and transiently released into circulation. Pretreatment with intravenous anti-TNF-alpha antibody reduced cortical (71%, P < 0.015) and subcortical (58%, P < 0.007) injury, enhanced the cerebral blood flow during reperfusion, and improved the neurologic outcome. This further supports the contention that TNF-alpha is a deleterious cytokine in stroke, whereas circulating antibody against TNF-alpha may protect brain from reperfusion injury.

Primary central nervous system lymphoma in homosexual men. Clinical, immunologic, and pathologic features.

Primary central nervous system lymphoma constitutes one of the criteria for the acquired immune deficiency syndrome (AIDS), yet a paucity of information is currently available regarding the clinical, immunologic, or pathologic features of these patients. Six homosexual men presenting with primary central nervous system lymphoma were evaluated. Five of these patients presented with altered mental status. All lymphomas were intracranial. B cell immunoblastic sarcoma was found in five. Immune phenotyping studies performed in five patients revealed monoclonal lambda light chain in three, whereas one expressed only IgG heavy chain, and one demonstrated another B cell (LN-1) surface antigen. Hypodense, contrast-enhancing lesions were apparent on computed axial tomographic scanning of the brain, in sharp contrast to isodense or hyperdense lesions reported in primary central nervous system lymphomas without underlying immunodeficiency. Immunologic abnormalities in these patients were similar to those in AIDS presenting as Kaposi's sarcoma or with opportunistic infections. In spite of therapeutic interventions, survival was short, and only one patient is currently alive.

HLA-DR (Ia)-positive dendritic-like cells in human fetal nonlymphoid tissues.

Nonlymphoid tissues from human fetuses ranging in age from 12 to 21 weeks' gestation were examined for the presence of HLA-DR (Ia)-positive cells. Immunoperoxidase staining of cryostat sections revealed Ia-positive cells with dendritic-like morphology, in kidney, heart, pancreas, and lung--but not in brain tissue. These Ia-bearing cells were present at 12 weeks' gestation, and by 21 weeks had increased to substantial numbers in all the organs tested, except for the brain, which remained negative. To further characterize the nature of these Ia-positive cells serial sections were studied with a panel of monoclonal antibodies (MAb) consisting of four reagents identifying monocyte/macrophages and two reagents staining lymphoid cells. The four anti-monocyte/macrophage MAb stained few if any cells in all the tissues examined. Lymphoid cells, as identified by anti-B-cell and anti-T-cell MAb, were also present in very low numbers. Additional studies using a double-staining technique provided direct evidence that the Ia-positive cells bear the human common leukocyte antigen detected by MAb T29 /33 and, with few exceptions, are negative for the macrophage antigen detected by MAb OKM1. The data suggest that nonlymphoid fetal tissues contain Ia-positive dendritic-like cells that are not monocyte/macrophage or lymphoid in origin. These Ia-bearing cells may be related to the dendritic cells found in lymphoid tissues, which are highly stimulatory in mixed leukocyte reactions and are thought to be responsible for the initiation of allograft rejection.

Exogenous tat protein activates central nervous system-derived endothelial cells.

Tat protein, an HIV gene product known to be secreted extracellularly, was tested to determine its role in the dissemination of HIV into the central nervous system (CNS). Tat was shown to activate human CNS-derived endothelial cells (CNS-EC) by the increase in the expression of E-selectin, the synthesis of IL-6, and the secretion of plasminogen activator inhibitor-1 (PAI-1). Tat also functioned synergistically with tumor necrosis factor alpha (TNF). AIDS brains stained for tat in situ, demonstrated positive cells. These data suggest that secreted tat protein may increase leukocyte binding, and alter the blood-brain barrier permeability to enhance dissemination of HIV-infected cells into the CNS.

Endothelin-1 and monocyte chemoattractant protein-1 modulation in ischemia and human brain-derived endothelial cell cultures.

Brain tissue damage due to ischemia/reperfusion has been shown to be caused, in part, by activated macrophages infiltrating into the post-ischemic brain. Using the Middle Cerebral Artery Occlusion (MCAO) mouse model, this study demonstrated that, in vivo, both endothelin-1 (Et-1), a potent vasoconstrictor, and the macrophage chemokine, monocyte chemoattractant factor-1 (MCP-1) are induced in ischemia. Further studies, using human brain-derived endothelial cells (CNS-EC), showed that in vitro, Et-1 can directly stimulate MCP-1 mRNA expression and MCP-1 protein; and this Et-1-induced MCP-1 production is mediated by the ET(A) receptor. Inflammatory cytokines, tumor necrosis factor alpha and interleukin-1beta, functioned additively and synergistically, respectively, with Et-1 to increase this MCP-1 production. Partial elucidation of the signal transduction pathways involved in Et-1-induced MCP-1 production demonstrated that protein kinase C-, but not cAMP-dependent pathways are involved. These data demonstrate that Et-1, functioning as an inflammatory peptide, increased levels of MCP-1, suggesting a mechanism for chemokine regulation during ischemia/reperfusion injury.

TGF-B2 and soluble p55 TNFR modulate VCAM-1 expression in glioma cells and brain derived endothelial cells.

Transforming growth factor beta-2 (TGF-B2) is secreted by glioma cells and is known to decrease leukocyte-endothelium interaction. TGF-B2 alone and in conjunction with soluble tumor necrosis factor (TNF) p55 receptor, was found to decrease the expression of TNF induced VCAM-1 on the malignant glioma cell line A-172 and human cerebral microvessel endothelial (CNS-EC) cells. Co-culture of A-172 glioma cells led to a decrease in VCAM-1 expression; this effect on CNS-EC in co-culture could be simulated by glioma supernatant alone. These results suggest that malignant gliomas, by secreting TGF-B2 and releasing soluble TNF receptors, modulate adhesion molecules.

Extensive peroxynitrite activity during progressive stages of central nervous system inflammation.

Nitric oxide (NO) production has been associated with disease activity in multiple sclerosis and experimental autoimmune encephalomyelitis (EAE). This free radical can be transformed by superoxide to peroxynitrite, an extremely toxic oxidant which causes lipid peroxidation. In addition, peroxynitrite nitrates tyrosine residues, resulting in nitrotyrosine, which can be identified immunohistochemically. The results of this study indicate that peroxynitrite is formed very early during EAE development, correlating with clinical disease activity. Nitrotyrosine-positive cells display a widespread distribution in brain and spinal cord during severe disease and are associated with both perivascular infiltrates and parenchymal sites. Double-staining procedures demonstrated that a subpopulation of CD11b-positive cells (macrophages/microglia) reacted with nitrotyrosine antibodies. Immunostaining for inducible NO synthase demonstrated a similar distribution as nitrotyrosine staining. These experiments indicate that peroxynitrite is formed during progressive stages of disease activity.

HIV-1 tat protein induces the production of interleukin-8 by human brain-derived endothelial cells.

This study focused on the role of the HIV-derived viral protein, tat, in activating central nervous system (CNS)-derived endothelial cells (EC) to produce interleukin-8 (IL-8), a stimulator and chemoattractant for neutrophils and lymphocytes. Human CNS-EC treated with tat (100 ng/ml) demonstrated a 2 to 3 fold upregulation in IL-8 mRNA and protein. Tumor necrosis factor-alpha (TNF) and tat were found to act additively in upregulating IL-8 production. In contrast, transforming growth factor beta (TGF beta), appeared to down modulate tat-induced IL-8 production. These data suggest that extracellular tat, especially in the presence of TNF, may be responsible for the local production of IL-8.

Tumor necrosis factor-alpha in the retina in acquired immune deficiency syndrome.

The presence of specific cytokines and the number and distribution of leukocytes were determined in the retinas of patients with acquired immune deficiency syndrome (AIDS). Using immunohistocytochemical techniques, three retinas from patients with AIDS had focal infiltration by T-lymphocytes and macrophages. These specimens stained positively for tumor necrosis factor-alpha (TNF-alpha) in cells identified morphologically as macrophages and glial cells and showed prominent reactive gliosis. The retinas from seven other affected patients had minimal leukocytic infiltration and no TNF-alpha reactivity; gliosis was present in only one. The retinas from clinically normal patients without human immunodeficiency virus (HIV) contained no TNF-alpha-positive cells. Using in situ hybridization for HIV, four of five patients with AIDS had rare positive cells. No interferon-gamma was detected in any of the retinal tissues tested. These data suggest a role for TNF-alpha in the development of AIDS-related retinal disease.

Class II antigen expression by lacrimal epithelial cells. An updated working hypothesis for antigen presentation by epithelial cells.

It has been suggested that aberrant expression of Class II histocompatibility antigens (HLA) is involved in T cell activation and leads to autoimmunity. Although Class II antigen expression was found in various nonlymphoid tissues, including salivary glands, its expression on lacrimal epithelial cells has not been reported. In this study, 12 cadaver lacrimal glands were analyzed for HLA-DR and for the numbers and distributions of T suppressor cells (Ts), T helper cells (Th), B cells, and macrophages. None of these cases exhibited the high numbers of inflammatory cells, tissue damage, and fibrosis characteristic of Sjogren's syndrome. The HLA-DR-positive epithelial cells were detected in ten cases; they represented from less than 1% to more than 70% of the epithelial cells. In these ten positive cases, there were greater numbers of T cells per millimeter squared (229 +/- 94 [mean +/- the standard error of the mean]) than in the two HLA-DR-negative cases (37 +/- 1 [mean +/- range]). Three lacrimal gland specimens tested were negative for immunoglobulin (Ig) G-bearing B cells, and two of the three specimens tested had IgA-bearing cells. Acinar cells were isolated from rat and rabbit lacrimal glands and cultured overnight in serum-free media supplemented with several potential mediators of Class II antigen expression: interferon-gamma, carbachol, or isoproterenol. Freshly isolated cells did not express Class II antigens at detectable levels, but in most experiments, they began to express the antigen even in the absence of putative mediators.(ABSTRACT TRUNCATED AT 250 WORDS)

Induction of intercellular adhesion molecule-1 by tumor necrosis factor-alpha through the 55-kDa receptor is dependent on protein kinase C in human retinal pigment epithelial cells.

PURPOSE: To determine second messenger signaling pathways associated with tumor necrosis factor-alpha (TNF)-mediated induction of intercellular adhesion molecule (ICAM)-1 expression on human retinal pigment epithelial (HRPE) cells, a cell type known to express only the 55-kDa TNF receptor (TNFR p55). METHODS: SV 40-immortalized HRPE (SVRPE) cells were exposed to TNF with and without pretreatment with the protein kinase C (PKC) inhibitor calphostin C or the protein kinase A (PKA) inhibitor H8. SV40-immortalized HRPE cells also were treated with the PKC activator phorbol 12-myristate 13-acetate (PMA) or with the PKA activators forskolin plus 3-isobutyl-1-methyl-xanthine or dibutyryl cyclic adenosine monophosphate (cAMP) alone. Membrane fractions from untreated and treated SVRPE cells were assayed for PKC activity, and whole cell lysates were assayed for cAMP accumulation and PKA activity. Flow cytometry was performed on SVRPE cells using a monoclonal antibody specific to ICAM-1. RESULTS: Activation of TNFR p55 on SVRPE cells with TNF resulted in a rapid increase of PKC activity at 1 minute, with a subsequent downregulation to baseline. There was no increase in intracellular cAMP accumulation or PKA activity within the first 10 minutes; however, both increased within 30 minutes and returned to baseline within 1 hour. SV40-immortalized HRPE cells treated with TNF for 1 hour showed maximal induction of ICAM-1 expression at 18 hours. ICAM-1 induction by TNF treatment was inhibited by calphostin C pretreatment and not by H8 pretreatment. Protein kinase C activation with PMA for 3 hours was sufficient to induce ICAM-1 on SVRPE cells at 18 hours, whereas treatment with the PKA activators forskolin or dibutyryl cAMP did not induce ICAM-1 expression. CONCLUSIONS: Tumor necrosis factor sequentially activates the PKC and PKA pathways in SVRPE cells by way of the TNFR p55. The PKC pathway in necessary for TNF-mediated ICAM-1 upregulation, and specific activation of the PKC pathway with PMA is sufficient to induce ICAM-1 on these cells. SV40-immortalized HRPE cells may serve as a model in which to study further the functional signaling pathways associated with TNFR p55.

Human immunodeficiency virus Tat protein induces interleukin 6 mRNA expression in human brain endothelial cells via protein kinase C- and cAMP-dependent protein kinase pathways.

The intracellular signal transduction pathways utilized by the HIV-1-derived protein, Tat, in the activation of human central nervous system-derived endothelial cells (CNS-ECs) were examined using specific enzymatic assays. Tat induced an increase in interleukin 6 (IL-6) mRNA within 1 hr of treatment. This biological effect of Tat involved activation of both protein kinase C (PK-C) and cAMP-dependent protein kinase (PK-A) in CNS-ECs. Tat at 10 ng/ml induced a sharp, transient increase in membrane PK-C activity within 30 sec of incubation, and reached maximum levels at 2 min, declining to control values within 10 min. Tat also induced a sharp increase in intracellular cAMP levels and PK-A activity in these cells, with the PK-A activity reaching a maximum at 10 min and slowly declining to control values in 4 hr of incubation. Activation of PK-A was dependent on a Tat-induced increase in membrane PK-C activity as demonstrated by calphostin C (a PK-C inhibitor) abolishing this effect. Incubation of cells with the cyclooxygenase inhibitor indomethacin did not affect Tat-induced activation of PK-A, indicating that prostacyclins are not involved in this process. Tat-induced increase in IL-6 mRNA was abolished in the presence on PK-A inhibitor H-89, demonstrating that activation of PK-A is necessary and sufficient for the increase in IL-6 production by these cells. Both the Tat-induced increase in intracellular cAMP and IL-6 mRNA levels in CNS-ECs may play a role in altering the blood-brain barrier and thereby inducing pathology often observed in AIDS dementia.

Stability of T- and B-cell numbers in human peripheral blood.

A comparison was made between the percentage of T and B cells present in human blood on the day of collection and those recovered from whole blood specimens stored for one, two, and three days. In the peripheral blood of normal individuals, the percentage of E-rosetting and surface-membrane immunoglobulin-positive cells was unchanged throughout the three day period. Furthermore, whole blood samples from patients with various hematological diseases maintained for three days exhibited T- and B-cell percentages equivalent to those tested on day zero.