Early brain changes in HIV infection: neuropathological study of 11 HIV seropositive, non-AIDS cases.

We examined 11 brains of human immunodeficiency virus (HIV) seropositive cases who died from unnatural causes (10 intravenous drug abusers who died from heroin overdose and 1 homosexual dead from a gunshot injury); 10 brains of HIV seronegative heroin addicts who died from overdose and 1 seronegative drug abuser who died from gunshot injury served as controls. Complete postmortem examination did not show evidence of acquired immune deficiency syndrome (AIDS) or AIDS related complex. Terminal changes including nerve cell ischemia, edema and diffuse vascular congestion were observed in all cases. Perivascular pigment deposition with macrophages was a constant finding in drug addicts and was probably related to chronic intravenous injection. In contrast, cerebral vasculitis was significantly more frequent and marked in HIV seropositive cases and was often associated with lymphocytic meningitis. Granular ependymitis, myelin pallor with reactive astrocytosis and microglial proliferation were also more frequent and more severe in HIV seropositive cases. Immunocytochemistry was negative for HIV antigens. Our study further supports the view that early central nervous system changes occur in HIV infection.

Isolated motor control dysfunction related to progressive multifocal leukoencephalopathy during AIDS with normal MRI.

We describe the case of a human immunodeficiency virus-infected 34-year-old man with progressive multifocal leukoencephalopathy (PML). His case displayed unusual features, including a bizarre movement disorder, predominant involvement of the subcortical U fibers on neuropathologic examination, and the absence of MRI abnormalities suggestive of PML. Anatomic-clinical correlations are discussed.

Epstein-Barr virus (EBV) genomes and EBV-encoded latent membrane protein (LMP) in pulmonary lymphomas occurring in nonimmunocompromised patients.

Recently, in situ hybridization (ISH) techniques have shown that Epstein-Barr virus (EBV) could be detected in tumor cells of most angiocentric T-cell non-Hodgkin's lymphomas (NHL). These studies included only a few cases of T-NHL of the lung and pulmonary B-NHL and have not been investigated. Furthermore, the expression of the EBV-encoded latent membrane protein (LMP), which is known for its oncogenic properties, has not been reported. Twelve pulmonary NHL (six angiocentric T-NHL and six B-NHL) arising in nonimmunocompromised patients were examined for the presence of EBV-EBER mRNAs and LMP with ISH and immunohistochemistry, respectively. Four cases of pulmonary lymphomas arising in immunocompromised patients were also included in the study for comparison (one T-NHL in a patient under immunosuppressive treatment and three B-NHL in AIDS patients). EBV-RNA and LMP were detected in tumor cells in two of six nonimmunocompromised angiocentric T-NHL and in the four immunocompromised NHL. The six nonimmunocompromised B-NHL were EBV negative. These results suggest that EBV is associated with some angiocentric pulmonary T-NHL arising in patients without overt immunodeficiency whereas it is absent in such patients with B-NHL. The presence of the transforming EBV-encoded LMP in tumor cells suggests that EBV may be involved in the pathogenesis of some pulmonary T-NHL.

Phenotype-karyotype correlations in dup(18q): report of a case and review.

We report on a case of dup(18q) due to de novo translocation 46,XX,-21,t(18;21)(18qter----cen----21qter). The patient had many characteristic signs of full trisomy 18 except for internal organ malformations and early death. We review the phenotype-karyotype correlations between full trisomy 18 and dup(18q) and discuss the possibility of the existence of "critical zone(s)" at the proximal or/and distal region of 18q responsible for most signs of trisomy 18, such as congenital heart defect and early death.

HIV-related demyelinating disease.

True demyelination, or at least a leukoencephalopathy with predominant involvement of myelin, may occur in many neurological complications of human immunodeficiency virus (HIV)-infection, resulting from various mechanisms which are not all well understood. These include lesions directly related to infection of the nervous tissue by HIV, opportunistic infections and lymphomas secondary to the cell-mediated immunodeficiency, and changes due to other general or systemic complications of acquired immunodeficiency syndrome (AIDS). HIV-induced pathology of the nervous system includes HIV-specific disease, due to direct infection of the nervous system by the virus. This is characterized by the presence of distinctive multinucleated giant cells and white matter changes, HIV encephalitis and HIV leukoencephalopathy, which may overlap in one third of cases. The pathogenesis of myelin destruction is unclear. Direct infection of neurons or glial cells has never been demonstrated. Indirect immunopathologic, toxic, metabolic, or vascular mechanisms secondary to infection of monocytes/macrophages are more likely. Less specific HIV-associated central nervous system (CNS) pathology including vacuolar myelopathy, and vacuolar leukoencephalopathy are characterized by numerous vacuolar myelin swellings in spinal or cerebral white matter. The exact aetiopathological relationship of these changes to HIV infection is uncertain. It seems likely that factors other than, or additional to, HIV infection play a role in their causation. Apart from these changes which usually occur at the late stages of the disease, acute perivenous inflammatory leukoencephalopathy, presenting either as acute haemorrhagic leukoencephalopathy, acute demyelinating perivenous encephalitis, or acute multiple sclerosis-like leukoencephalopathy revealing HIV-infection occur in rare cases.(ABSTRACT TRUNCATED AT 250 WORDS)

[Polyglucosan body disease]. / La maladie des corps polysaccharidiques.

A 78 year-old male presented with a bilateral pyramidal syndrome, urinary incontinence and mild intellectual slowing. He died seven months after onset of the neurological signs from cerebral infarct and heart failure. Neuropathological examination showed predominant involvement of the cerebral white matter including diffuse myelin pallor, astrocytic gliosis and small necrotic foci. Polyglucosan bodies were diffuse in the cerebral cortex, white matter, brainstem, cerebellum and proximal part of the cranial nerves. In these latter, some polyglucosan bodies were found within myelinated axons but the inclusions mostly involved astrocytic processes. This case is characteristic of the polyglucosan body disease. It is compared with the autopsy and biopsy cases previously reported in the literature.

Anti-NKH-1 antibody specifically stains unmyelinated fibres and non-myelinating Schwann cell columns in humans.

Anti-NKH-1 antibody recognizes an isoform of the neural cell adhesion molecule (N-CAM) that is involved in cell-cell interactions during embryonic stages and has been detected in skin autonomic nerves. The specificity of anti-NKH-1 antibody for human unmyelinated fibres (UF) and the distribution of the antigens recognized by this antibody at the ultrastructural level, were evaluated by immunohistochemistry and immunoelectron microscopy on nerve biopsy samples from patients with normal nerve biopsies and a variety of peripheral neuropathies. The anti-NKH-1 antibody strongly stained all unmyelinated fibres while no myelinated fibre was stained. Autonomic nerve fibres were visualized at the periphery of blood vessels. Immunoelectron microscopy showed that the antigen recognized by the antibody was located at Schwann cell-axon interfaces and in portions of joined Schwannian surfaces, i.e. along mesaxons of non-myelinating Schwann cells. Expression of NKH-1 was basically similar in normal and diseased nerves as expression of NKH-1 was similar at the level of apposed plate-like Schwann cell processes than along normal mesaxons. The extent of labelling of diseased nerves by the anti-NKH-1 antibody likely depended on the number of residual Schwann cell columns observed by light microscopy.

Epstein-Barr virus in non-Hodgkin's lymphomas of the upper respiratory tract: association with sinonasal localization and expression of NK and/or T-cell antigens by tumour cells.

Fifty-five cases of non-Hodgkin's lymphoma (NHL) of the upper respiratory tract, comprising 27 sinonasal (SN) and 28 Waldeyer's ring (WR) NHL, were investigated for expression of Epstein-Barr virus (EBV)-encoded EBER transcripts and latent membrane protein-1 (LMP-1) by RNA in-situ hybridization (RISH) and immunohistochemistry, respectively. Thirty-two cases were B-cell tumours (10 SNHLs and 22 WRNHLs) and 23 cases expressed natural killer (NK) and/or T-cell antigens (17 SNHLs and 6 WRNHLs). EBER transcripts were detected in tumour cells in 19 lymphomas expressing NK and/or T-cell antigens (16/17 SHNHLs and 3/6 WRNHLs) but in only 2/32 B-NHLs (1/10 SNHLs and 1/22 WRNHLs). LMP-1 expression was found in tumour cells in the 19 EBER-positive tumours expressing NK and/or T-cell antigens but in none of the B-cell lymphomas. All the LMP-1-positive lymphomas expressed the CD30 molecule in tumour cells. These results indicate that in lymphomas of the upper respiratory tract, EBV is strongly associated with sinonasal localization and expression of NK and/or T-cell antigens by tumour cells. EBV can also be detected in some cases of WRNHLs expressing NK and/or T-cell antigens, whereas it is rarely found in B-cell SNHLs and WRNHLs. Furthermore, the detection of the LMP-1 protein in tumour cells in most SNHLs and some WRNHLs expressing NK and/or T-cell antigens, in view of the LMP-1 transforming potential, suggests that EBV may play a role in the pathogenesis of these lymphomas.

[Ring chromosome 14. I. A case report on homogeneous r(14)]. / Chromosome 14 en anneau. I. Une observation de r(14) homogène.

A ring chromosome derived from a no. 14 was observed, without mosaicism, in a 2-month-old male with craniofacial dysmorphism, retarded psychomotor development, seizures and retinal anomalies. Serum immunoglobulins concentrations were normal.

Intraepidermal localization of the clone in cutaneous T-cell lymphoma.

BACKGROUND: No immunohistologic techniques are currently available to demonstrate clonality of T-cell lymphomas. Monoclonal antibodies to the variable region of the T-cell receptor (TCR) have been produced that identify minor populations of normal peripheral blood T lymphocytes. OBJECTIVE: We investigated the expression of TCR V-region genes in cutaneous lymphomas to determine whether immunostaining with these antibodies may be a simple method to detect clonal T-cell proliferations and help to distinguish benign lymphoid infiltrates from malignant lymphoma. METHODS: Cutaneous samples were obtained from 18 cutaneous T-cell lymphomas (14 mycosis fungoides, 1 Sézary syndrome, 2 pleomorphic T-cell lymphoma, and 1 large cell anaplastic lymphoma) and 8 benign lymphoid infiltrates. Frozen sections were incubated with monoclonal antibodies and stained by the alkaline phosphatase-antialkaline phosphatase technique. Staining was performed with a panel of 7 anti-TCR V-region antibodies, 6 T-cell markers, 1 anti-beta chain antibody, and 1 anti-delta chain antibody. RESULTS: Clonality could be demonstrated in 2 of 18 cutaneous lymphomas. We observed the strictly intraepidermal localization of clonal proliferation in one case of early-stage mycosis fungoides. CONCLUSION: Anti-TCR V-region antibodies may identify a strictly epidermotropic clone in early mycosis fungoides. However, the panel of antibodies currently available stains only a minority of cutaneous T-cell lymphomas. The usefulness of these antibodies as a clonotypic marker needs to be reevaluated when a larger panel of antibodies becomes available.

Copper and copper-binding protein in liver tumors.

The presence of copper and copper-binding protein was histochemically investigated in 39 hepatocellular carcinomas, 24 metastatic tumors of the liver, and eight benign hepatic tumors. None of the hepatocellular carcinomas was fibrolamellar. The presence of copper (demonstrated by rhodanine) and of copper-binding protein (demonstrated by modified orcein) was simultaneously observed in 11 of the 39 hepatocellular carcinomas (28%). Deposition was mild in three cases, moderate in two cases, and marked in six cases, and it was significantly related to the presence of bile within the tumor. Copper and copper-binding protein granules were not found in metastatic tumors of the liver, and were observed in two of the eight cases of benign hepatic tumors. These results suggest that the presence of copper and copper-binding protein in tumor cells may be found in all variants of hepatocellular carcinomas and not only in fibrolamellar carcinomas as previously suggested, and might be helpful in differentiating primary from secondary liver tumors.

Mouse hepatic endothelial cells in culture secrete a growth inhibitor for hepatic lipocytes and Balb/c 3T3 fibroblasts.

Hepatic lipocytes are sinusoidal cells in close contact to endothelial cells. They proliferate, switch to a fibroblastic phenotype and synthetize collagen during hepatic fibrosis. Since it is known that vascular endothelial cells can influence the proliferation of neighboring cells such as smooth muscle cells, we investigated the role of hepatic endothelial cells on the growth of lipocytes and Balb/c 3T3 fibroblasts. Concentrated conditioned medium from endothelial cells inhibited both [3H]thymidine incorporation and actual growth of lipocytes and Balb/c 3T3 fibroblasts. The inhibition was lost when conditioned medium was treated with heat or trypsin, or when medium was conditioned in the presence of cycloheximide. We conclude that hepatic endothelial cells secrete a proteic growth inhibitor for lipocytes and hepatic Balb/c 3T3 fibroblasts. This inhibitor could be of importance in limiting lipocyte proliferation in the liver and possibly in preventing hepatic fibrosis.

[Neuropathological study of 134 fetuses in HIV infected mother]. / Etude neuropathologique de 134 foetus dans un contexte d'infection maternelle par le VIH.

A neuropathological study performed in 134 foetuses from HIV infected mothers, between 16 and 35 weeks of gestation, revealed two cases of hypoxic-ischemic brain damage, related to long labor and drug abuse. Immunostains against HIV proteins were negative in all cases. Nests of migrating cells in the cerebrum and cerebellar heterotopias were found in most cases and were considered to be common findings in fetal brain. Our study clearly showed the absence of cerebral HIV infection during early pregnancy and raises the question of the frequency of vertical transmission during HIV infection. However, the evaluation of cerebral changes in infants with HIV infection should take into consideration the features of the developing brain and the existence of other adverse factors that may interfere with its development during pregnancy.

Immunosuppressive effects of 1,25-dihydroxyvitamin D3 and its analogue calcipotriol on epidermal cells.

1,25-Dihydroxyvitamin D3 (1,25(OH)2D3; calcitriol) is the biologically active form of vitamin D. This hormone is a potent immunoregulatory agent. Calcipotriol is a synthetic analogue of 1,25(OH)2D3, with similar receptor binding, and comparable effects on cell proliferation and differentiation, but less potent effects on calcium metabolism. As a step towards understanding the mechanisms by which vitamin D compounds affect T-cell activation by epidermal cells (EC), we assessed the effects of 1,25(OH)2D3 and calcipotriol on the human allogeneic mixed epidermal cell-lymphocyte reaction. All experiments were performed both with 1,25(OH)2D3, and calcipotriol, with similar results. Both compounds had potent immunoinhibitory properties on this model, and enhanced the immunosuppressive effects of cyclosporin A. Using preincubation experiments, we found that pretreatment of EC with 1,25(OH)2D3 resulted in a more pronounced inhibition than preincubation of lymphoid cells. The epidermal targets of this inhibitory effect have been further investigated, using cultures with freshly isolated Langerhans cells (LC) or LC-depleted keratinocytes, separated by an immunomagnetic particle technique. Pretreatment of LC induced a 30% decrease of proliferation, compared with vehicle-treated LC. These calcitriol-pulsed LC did not decrease the proliferation induced by unmodified autologous EC. As expected, LC-depleted keratinocytes failed to stimulate allogenic lymphocytes. When added to autologous unmodified EC, however, calcitriol-pulsed keratinocytes induced an 85% decrease of proliferation, compared with vehicle-treated keratinocytes. The phenotypic expression of HLA-DR, -DQ, and -DP antigens on EC, assessed by immunoalkaline phosphatase staining, was not modified after a 2-h or 24-h pulse with 1,25(OH)2D3 or calcipotriol.(ABSTRACT TRUNCATED AT 250 WORDS)

In vitro toxicity of polymorphonuclear neutrophils to rat hepatocytes: evidence for a proteinase-mediated mechanism.

Human polymorphonuclear neutrophils, when exposed to soluble or particulate stimuli, can destroy various types of cells. The aim of this study was to investigate their toxicity against hepatocytes. Human polymorphonuclear neutrophils were incubated in basal conditions and after stimulation with 5 mg per ml opsonized zymosan in the presence of rat hepatocytes isolated by collagenase digestion. Cytotoxicity was quantified by the percentage of ALT activity released by hepatocytes in culture medium. Whereas unstimulated neutrophils exhibited only minor effects, opsonized zymosan-stimulated neutrophils induced, after 16 hr incubation, a 24.0 +/- 4.1% (mean +/- 1 S.E.) ALT activity release at a neutrophil/hepatocyte ratio of 5, and a 51.7 +/- 6.8% ALT activity release at a ratio of 20. At this ratio of 20, the ALT activity release was 9.0% at 1 hr and 24.0% at 4 hr. Three proteinase inhibitors (i.e., soybean trypsin inhibitor, alpha 1-proteinase inhibitor and fetal calf serum) decrease cytotoxicity by 78, 76 and 78%, respectively. The protective effect of proteinase inhibitors was not due to a nonspecific effect of proteins, since bovine serum albumin did not decrease the toxicity of stimulated polymorphonuclear cells. The supernatant of stimulated neutrophils was also found to be toxic against hepatocytes, and again, this effect was inhibited by soybean trypsin inhibitor, alpha 1-proteinase inhibitor and fetal calf serum. Finally, the role of proteinases was supported by the demonstration of a cytotoxic effect of two purified proteinases: porcine pancreatic elastase and human neutrophil cathepsin G. The toxicity of these proteinases was also markedly reduced by the specific inhibitors used in the study.(ABSTRACT TRUNCATED AT 250 WORDS)

The spectrum of vasculitis in human immunodeficiency virus-infected patients. A clinicopathologic evaluation.

OBJECTIVE: To delineate the different types of inflammatory vascular diseases (IVD) occurring in patients with human immunodeficiency virus (HIV) infection. METHODS: Muscle, nerve, or skin biopsy specimens from 148 symptomatic HIV-infected individuals were reviewed, and subgroups of vasculitis were identified using the American College of Rheumatology (ACR) 1990 clinicopathologic criteria for the classification of vasculitis. RESULTS: IVD was documented in 34 patients (23%) and included necrotizing arteritis (3 patients), non-necrotizing arteritis (1 patient), neutrophilic IVD (7 patients), mononuclear IVD (17 patients), and other small vessel inflammatory changes (6 patients). According to the ACR criteria, 11 patients could be classified as having a distinct category of vasculitis, including polyarteritis nodosa (4 patients), Henoch-Schönlein purpura (1 patient), and drug-induced hypersensitivity vasculitis (6 patients), and 23 were classified in the group "other vasculitis, type unspecified." One patient had hepatitis B virus surface antigenemia, 2 had cryoglobulinemia, and 2 were coinfected by human T lymphotropic virus type I. Cytomegalovirus inclusions and antigens were found in endothelial cells in 1 patient. HIV antigens and genome were detected in perivascular cells of 2 of the 3 patients with necrotizing arteritis; in 1, HIV-like particles were seen by electron microscopy. Immune deposits were found in small vessel walls in 5 skin biopsy samples showing small vessel vasculitis and in the muscle of the 3 patients with necrotizing arteritis. CONCLUSION: A wide range of inflammatory vascular diseases may occur in HIV-infected individuals. Vascular inflammation appears multifactorial and may result from HIV-induced immunologic abnormalities and exposure to a variety of xenoantigens, such as HIV itself, other infectious agents, and drugs.

Varicella-zoster virus encephalitis in acquired immunodeficiency syndrome: report of four cases.

Four patients with acquired immunodeficiency syndrome, a 27-year-old female intravenous drug abuser and three males (two drug addicts aged 27 and 33 years and a 40-year-old homosexual) presented with a rapidly progressive encephalopathy. Two had generalized varicella-zoster virus skin infection, one had had a regressive thoracic zoster rash 7 months previously and one had no history of cutaneous eruption. Neuropathological examination revealed, in each case, multifocal necrotic changes with numerous, intranuclear Cowdry type A inclusion bodies in glial cells, endothelial cells, macrophages and neurons, within and around the lesions. These inclusion bodies were stained positively for varicella-zoster virus by immunocytochemistry and contained herpes virus nucleocapsids by electron microscopy. Molecular biology using the polymerase-chain-reaction method demonstrated viral genome. In one case, zoster-induced non-inflammatory vasculopathy involved medium sized leptomeningeal vessels and was associated with circumscribed areas of cortico-subcortical infarction. In another case, varicella-zoster virus encephalitis was associated with human immunodeficiency virus encephalitis and a secondary cerebral lymphoma. Multinucleated giant cells expressing human immunodeficiency virus proteins in their cytoplasm, were found in the lymphomatous deposits and in the varicella-zoster virus necrotic lesions. In these latter lesions, Cowdry type A inclusion bodies could be seen in the nuclei of some multinucleated giant cells confirming previous observations of MGCs co-infected by HIV and CMV, and supporting the hypothesis that DNA viruses interact with HIV, thus increasing its effect.

[AIDS-related progressive multifocal leukoencephalopathy limited to U fibers, responsible for subacute encephalopathy with normal CT scan findings]. / Leucoencéphalopathie multifocale progressive limitée aux fibres en U au cours du SIDA, responsable d'une encéphalopathie subaiguë avec scanner normal.

A 41-year-old male homosexual with AIDS was hospitalized for temperature elevation to 40 degrees C with confusion. Neurologic evaluation found psychomotor slowing and temporospatial disorientation with no focal signs. The CD4 count was 100/mm3. CSF analysis and the CT scan were normal. Despite antiviral treatment the patient died fifteen days after admission. Gross appearance of the brain was normal. Histologic examination disclosed multiple, small foci of demyelination characteristic of progressive multifocal leukoencephalopathy. These foci were disseminated among the U fibers. In situ hybridization and immunocytochemical studies demonstrated papovavirus particles in oligodendrocytes and a few astrocytes. This case shows that papovavirus infection in AIDS patients may be responsible for a diffuse febrile encephalopathy with normal CT scan findings and a rapidly progressive course.