Amoebic encephalitis due to Sappinia diploidea.
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Adult↗
Biomedical subjects
B B Gelman
Publications and source records attributed to B B Gelman.
The National NeuroAIDS Tissue Consortium: a new paradigm in brain banking with an emphasis on infectious disease.
The National NeuroAIDS Tissue Consortium (NNTC) was founded in 1998, in response to the scientific need for well-characterized central nervous system (CNS) and peripheral nervous system (PNS) tissues and fluids from HIV-infected individuals. In addition to performing the routine functions of non-transplant anatomic tissue banks, the Consortium offers a unique model for the integration of independent research entities in order to provide well-characterized tissues and fluids for the international research community. Herein, we describe the structure of the Consortium, pointing out the inherent strengths of linking together multiple independent sites for the purpose of banking HIV-infected nervous system tissues. We describe the neuropathology protocol that was adopted and successfully implemented at the four participating banks of the Consortium.
AIDS Dementia Complex↗
Oncocytoma in melanocytoma of the spinal cord: case report.
OBJECTIVE AND IMPORTANCE: Oncocytoma in the central nervous system is extremely unusual. The first reported example of oncocytoma in a melanocytoma of the spinal cord was successfully excised, and its pathological appearance is described. CLINICAL PRESENTATION: A 71-year-old woman presented with a 25-year history of back pain and myelographic evidence of a lumbar spinal cord mass. After declining surgical treatment for two decades, she elected eventually to have the mass excised. Preoperative magnetic resonance imaging revealed a large intraspinal mass that spanned spinal levels L3 through S1. TECHNIQUE: The mass was excised en bloc through posterior laminectomies, and histopathological analysis revealed a benign neoplasm composed predominantly of monotonous sheets of plump oncocytes. Electron microscopy confirmed that the cytoplasm of the oncocytes was packed full of mitochondria. Focal areas of the tumor contained spindle cells, with abundant intracytoplasmic granular deposits of brown melanin pigment that contained melanosomes. Positive Fontana-Masson, HMB-45, and S-100 staining confirmed the final diagnosis of melanocytoma, oncocytic variant. CONCLUSION: The first reported case of oncocytoma arising in spinal melanocytoma is described. After surgical excision, the patient recovered completely and has remained free of symptoms for 4 years.
Adenoma, Oxyphilic↗
A novel mechanism of CD4 lymphocyte depletion involves effects of HIV on resting lymphocytes: induction of lymph node homing and apoptosis upon secondary signaling through homing receptors.
Recently, we reported that abortive HIV infection of resting human T lymphocytes up-regulated expression of CD62L, the receptor for homing to lymph nodes (LNs), and enhanced homing of these cells from the blood into the LNs (Wang et al., 1997, Virology 228:141). This suggested that HIV-induced homing of resting lymphocytes (which comprise >98% of all lymphocytes) may be a major mechanism for the reduction of CD4+ lymphocytes in the blood of infected individuals. This mechanism also could be partially responsible for the lymphadenopathy that often develops at the same time that CD4+ lymphocytes are disappearing from the blood. In this study, we show that secondary signaling through the homing receptors (CD62L, CD44, CD11a) of abortively infected resting CD4+ T lymphocytes induced apoptosis. These signals would occur as the cells home into the LNs. Apoptosis did not occur after secondary signaling through some other receptors (CD26, CD4, CD45, and HLA class I) or in HIV-exposed resting CD8+ lymphocytes signaled through the homing receptors. These findings indicate that HIV-induced homing of resting CD4+ lymphocytes to LNs results in death of many of these cells. This was confirmed in the LNs of SCID mice that were i.v. injected with HIV-exposed resting human lymphocytes. Thus, these effects of HIV upon binding to resting CD4+ T lymphocytes, which are not permissive for HIV replication, may significantly contribute to their depletion in vivo. These findings also offer an explanation for the bystander effect observed in the LNs of AIDS patients, whereby cells not making virus are dying.
Animals↗
A host defense role for a natural antiviral substance in the nervous system.
The pathogenesis of virus infections of the nervous system (NS) is regulated by host defenses. The defensive role of a major constitutive antiviral substance was studied by determining its distribution in the human nervous system, its concentration and the ability of this viral inhibitor to protect mice against viral infection. The 4000 kDa inhibitor complex in the human nervous system was detected in brain gray and white matter, spinal cord, and sciatic nerve but not in human cerebrospinal fluid. The inhibitor was found in the extracellular medium incubated with minced murine brain. The inhibitory titer ranged from approximately 50 to 200 antiviral units per gram against polio 1, Semliki Forest, Banzi, mengo, Newcastle disease and herpes simplex 1 viruses. The inhibitor is composed of lipid and essential protein and carbohydrate moieties as determined by enzymatic inactivation. Protection of inhibitor-treated mice was demonstrated against both an alphavirus and a picornavirus. Thus a natural defensive role for the broadly antiviral inhibitor is suggested by its constitutively high concentration, wide distribution in nervous system tissues, presence in extracellular fluid and its ability to provide protection in infected mice.
Animals↗
Pulmonary lymphomatoid granulomatosis in acquired immunodeficiency syndrome: lesions with Epstein-Barr virus infection.
We report the clinicopathologic characteristics of pulmonary lymphomatoid granulomatosis (LYG) in 11 patients (identified from a series of 330 consecutive patients who underwent autopsy between 1984 and 1995 at the University of Texas Medical Branch at Galveston, Texas) with a diagnosis of acquired immunodeficiency syndrome (AIDS). We used immunohistochemical stains, RNA in situ hybridization (ISH), and gene rearrangement studies to identify the immunophenotype and the presence or absence of Epstein-Barr virus (EBV) infection. All of the patients were men ranging in age from 27 to 65 years (mean age, 38.6 yr). Autopsy lungs of 21 age-matched controls were examined for EBV using ISH; these included 9 patients with AIDS who did not have pulmonary lesions and 12 HIV-negative individuals who died accidentally (mean age, 38.6 yr). All of the 11 pulmonary lesions showed the gross and microscopic characteristics of LYG, with zonal necrosis and prominent angioinvasion. The tumor nodules consisted of a mixture of atypical large lymphocytes, with vesicular nuclei and prominent nucleoli and with a background of small and intermediate-size lymphocytes, histiocytes, and plasma cells. The large lymphocytes were CD20 positive, consistent with a B-cell phenotype. Ten of the 11 cases demonstrated EBV1-encoded RNA and CD20 positivity in the large, atypical lymphocytes by double labeling. One patient showed EBV positivity in CD20-negative, CD45RO-positive large cells, but these cells were CD3 negative and showed a monoclonal heavy chain gene rearrangement by polymerase chain reaction, indicating that these were of B-cell origin. Aberrant CD43 coexpression was identified in four cases. EBV latent membrane protein was demonstrated in 9 of 11 cases by immunohistochemical stains. The lungs of all of the 21 control patients were negative for EBV by ISH. We conclude that, in our series, AIDS-associated LYG is a B-cell neoplasm and that it has a strong association with EBV infection.
Adult↗
Microglial cell activation in aging and Alzheimer disease: partial linkage with neurofibrillary tangle burden in the hippocampus.
Microglial cells are the main component of the brain's resident immune system and are activated in Alzheimer disease (AD). We quantified the density of activated microglial cells (AMG) in 8 sectors of human hippocampus to determine if their density is correlated with senile plaque (SP) and neurofibrillary tangle (NFT) formation. Ferritin-stained microglia, Bielschowsky-stained neuritic plaques, and perikarya containing NFTs were counted in 8 young adults, 9 nondemented elderly adults, and 9 demented patients with AD. Microglial cell activation was moderately higher in elderly nondemented subjects. In AD there was a more striking activation in all sectors of the hippocampus. Most AMGs were distributed diffusely in neuropil and were not delimited to SPs or NFTs. Senile plaque counts were not linked with AMG counts within any sector. Neurofibrillary tangle counts were correlated significantly with AMG counts within one sector, the subiculum. When variations within and between sectors were factored out statistically, the burden of AMGs was correlated significantly with the burden of NFTs (r = 0.34; p < 0.005), but not SPs. Neuropathologic changes at the origin of the perforant pathway were correlated significantly with orthograde microglial cell activation in the termination field. These observations show that correlations between microglial cell activation and pathologic features of AD are only rarely significant. When significant linkage was present, it involved NFTs and not SPs, and depended on which sector of hippocampus was examined.
Adult↗
Intracranial chondromyxoid fibroma. Report of a case and review of the literature.
Chondromyxoid fibroma is an unusual benign tumor of cartilaginous derivation. We describe a rare example of chondromyxoid fibroma of the frontal-sphenoid junction with orbital infiltration in a 35-year-old Hispanic woman who presented with frontal headaches. Gross total excision was performed. The excised mass was composed of neoplastic cells with chondrocytic features within a myxoid matrix. Bony infiltration was present without infiltration of dura mater or brain tissue. The lack of mitotic activity, low cell density, lack of nuclear pleomorphism, and a fused lobular architectural pattern indicated that the lesion was a chondromyxoid fibroma. The lack of hyaline cartilage helped differentiate the lesion from enchondroma. Our case demonstrates the uncommon occurrence of intracranial chondromyxoid fibroma with orbital infiltration. When faced with an intracranial chondrocytic tumor, it is important to distinguish this neoplasm from enchondroma and chondrosarcoma.
Adult↗
Mononuclear phagocyte hydrolytic enzyme activity associated with cerebral HIV-1 infection.
In patients with HIV encephalitis, activated macrophages and microglial cells in the brain are infected by the human immunodeficiency virus (HIV-1). Immune activation can release neurotoxic chemicals including cytokines, free radicals, autocoids, and hydrolytic enzymes. In this study, the presence of hydrolytic enzymes in acquired immune deficiency syndrome (AIDS)-related neurodegeneration was addressed. Activities of four lysosomal hydrolases were assayed in the frontal lobe of 69 males who died with AIDS and 31 age-matched control men. Activities of all four enzymes were increased significantly (1.6 to 3.6 times) in white matter of patients with AIDS. Less pronounced increases were present in cerebral cortex. Of 69 of the subjects with AIDS, 50 (72%), had at least one abnormally active enzyme. Patients with HIV encephalitis and other neuropathological changes were affected as were many subjects without any clear neuropathological anomaly. Lysosomal cathepsin D immunostaining revealed increased lysosomes within perivascular macrophages, multinucleated cells, activated microglial cells, and hypertrophic astrocytes. Increased enzyme activity was correlated significantly with assay results for HIV-1 DNA using the polymerase chain reaction. The release of acid hydrolases associated with cerebral HIV-1 infection could lead to unopposed hydrolysis of matrix and surface proteins. These post-translational disturbances could contribute to white matter and synaptic injury in AIDS.
Acetylgalactosamine↗
Proteolysis in the myelopathy of acquired immunodeficiency syndrome: preferential loss of the C-8 component of myelin basic protein.
Many patients with AIDS have a myelopathy characterized by vacuolization of spinal cord white matter. The biochemical and molecular changes underlying this myelin disturbance have not yet been characterized. Myelin basic protein (MBP) is potentially important because it is a key structural protein of myelin with roles in compaction and stabilization. In the present study, we describe the steady-state protein concentration of MBP in 46 patients with AIDS and 12 control subjects at autopsy. Patients with myelopathy exhibited no change in the abundance of the predominant 18.5- and 17.2-kd isoforms, but a 14-kd MBP-immunoreactive degradation fragment was increased significantly. MBP degradation correlated significantly with the severity of histopathologic changes, including neutral lipid deposition, the density of vacuolated fibers, and the number of ferritin-stained activated microglia. Alkaline gel electrophoresis of isolated MBP showed preferential loss of the least cationic isomer (C-8). The concentration of MBP RNA in slot blots was normal in cords exhibiting myelopathy, and the ratio of mRNA corresponding to the 18.5- and 17.2-kd MBP isoforms, measured using reverse transcriptase-PCR, was not altered. This study suggests that mononuclear phagocyte-mediated degradation of MBP may play a role in AIDS myelopathy, and the preferential loss of the C-8 component of MBP may have mechanistic implications.
Acquired Immunodeficiency Syndrome↗
Increased vulnerability to demyelination in streptozotocin diabetic rats.
Demyelination is a prominent feature in nerve biopsies of patients with diabetic neuropathy. The mechanism is unknown because diabetic rodents, unlike humans, do not consistently develop segmental demyelination. We examined how diabetes influences toxicant-induced demyelination, remyelination, Schwann cell nerve growth factor receptor (p75) expression, and endoneurial macrophage apolipoprotein E (apo E) synthesis in diabetic rats. Postnatal day 17 (P17) rats were given 110 mg/kg streptozotocin intraperitoneally and then fed a diet containing metallic tellurium (Te) from P20 to P27 to induce demyelination. Transverse electron micrographs and immunostained longitudinal cryosections were prepared from sciatic nerve during demyelination and remyelination. Diabetic rats had a mean serum glucose concentration of 490 mg/dl and consumed equivalent doses of peroral Te. The number of demyelinated fibers in electron micrographs was increased significantly by 17% (P < .0011). Endoneurial density of p75-stained Schwann cells was increased in diabetic rats in proportion to the increased number of injured internodes. Density of apo E- and ED1-positive macrophages also was significantly increased in diabetes. There was no delay in macrophage myelin clearance. and remyelination was not compromised. Increased Schwann cell vulnerability to stress, by increasing the turnover rate of myelinated units, may explain why myelin defects accumulate after long-standing diabetes.
Animals↗
Pathological case of the month. Autolyzed brain tissue beneath dermis of thigh and back.
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Autolysis↗
Incarceration and the acquired immunodeficiency syndrome: autopsy results in Texas prison inmates.
The Texas Department of Criminal Justice (TDCJ) houses many subjects with acquired immunodeficiency syndrome (AIDS) who receive medical care in a comprehensive AIDS treatment center. In this case-control autopsy survey, we compared pathological outcomes of TDCJ inmates treated at the center (n = 155) with nonincarcerated patients who died during the same period (n = 155). Using multiple regression analysis and a proportional hazards model, survival time in the prisoners was equivalent to that in the controls. With few exceptions, the prevalences of opportunistic viral, fungal, protozoal, and bacterial infections contributing to mortality were equivalent between groups. Mycobacterium tuberculosis was isolated more frequently in the inmates, and M avium intracellulare was isolated less frequently (P < .0001). The inmates had a higher prevalence of bacterial infection of the central nervous system (CNS) (9.1% v 1.4%; P < .006); half of all CNS bacterial infections were caused by M tuberculosis. Inmates had significantly lower prevalences of vacuolar myelopathy (P < .006) and severe wasting disease (P < .0009). We conclude that survival of prison inmates with AIDS treated in a comprehensive AIDS treatment center was equivalent to that of nonincarcerated subjects with AIDS. Prevalences of certain complications of AIDS differed in the inmates, showing that the prison environment influenced some of the underlying causes of AIDS morbidity and mortality.
AIDS-Related Opportunistic Infections↗
Quantifying apoptosis in banked human brains using flow cytometry.
Fragmentation of genomic DNA, a major biochemical feature of programmed cell death (apoptosis), is easily detected when apoptosis is prevalent. In brain tissue apoptotic cells are usually scarce and detection requires more sensitive techniques. We describe a highly sensitive method to quantify apoptosis in frozen human brain tissue using flow cytometry. Nuclei from homogenized brain specimens were isolated to purity using discontinuous isopyknic centrifugation through 2.2 M sucrose. DNA strand breaks in apoptotic nuclei were conjugated with biotinylated-dUTP using terminal deoxynucleotidyl transferase (TdT) and tagged with streptavidin-conjugated FITC (TUNEL). Negative controls excluding the TdT step, and positive controls using DNAase pretreatment to create 3'-OH strand breaks were run in parallel. The proportion of nuclei with TdT-dependent labeling in adult brain specimens was < 0.01% in 6 out of 7 specimens. In 3 fetal brains it averaged 0.86 +/- 0.11%. Apoptotic cells were readily detected in 2 malignant glial neoplasms and in a patient with HIV encephalitis. Comparable frequencies of stained nuclei were present in adjacent specimens embedded in paraffin and labeled in situ. By screening millions of nuclei cytometry detected very rare apoptotic events, producing quantitative results using banked frozen brains. The method has potential applications to studies of human brain development, neurodegenerative diseases, and brain tumors.
Adult↗
Expansion of the cerebral ventricles and correlation with acquired immunodeficiency syndrome neuropathology in 232 patients.
BACKGROUND: Expansion of the cerebral ventricles is highly prevalent in patients with the acquired immunodeficiency syndrome (AIDS). The mechanism remains unclear. The purpose of this study was to correlate the volume of the cerebral ventricles with histopathologic abnormalities in the brain. METHODS: At autopsy, the volume of the cerebral ventricles in brain slices was estimated planimetrically in 232 patients with AIDS and 77 age-appropriate controls. Estimated volumes were compared with the neuropathologic results using multiple regression analysis. RESULTS: Multiple regression analysis demonstrated a significant relationship between ventricular volume and cerebral cytomegalovirus infection (P < .0004). When human immunodeficiency virus (HIV) encephalitis with multinucleated cells was present, median volume did not differ significantly from other subjects with AIDS. In 11 patients who had HIV-1 proviral DNA detected using the polymerase chain reaction, average volume was not different from 22 patients who tested negatively using polymerase chain reaction. Ventricular expansion did not have a clear-cut neuropathologic substrate in many instances. CONCLUSIONS: In some subjects with AIDS, cytomegalovirus encephalitis was the underlying neuropathologic lesion associated with ventricular expansion. Key indicators of brain HIV-1 infection were related either weakly or not at all, and the role of HIV-1 remains uncertain in most cases.
Acquired Immunodeficiency Syndrome↗
Iron in CNS disease.
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Acquired Immunodeficiency Syndrome↗
Diffuse microgliosis associated with cerebral atrophy in the acquired immunodeficiency syndrome.
The cause of cerebral atrophy in patients with acquired immunodeficiency syndrome (AIDS) is obscure because human immunodeficiency virus type 1 (HIV-1)-related histopathological changes hardly correlate with cerebral atrophy. In this study, brain ventricular expansion was compared to the frontal lobe density of mononuclear and astroglial cells at autopsy. Twenty-eight male patients with AIDS displaying varying degrees of atrophy were compared to 17 age-matched male control subjects without AIDS or atrophy. An index of ventricular expansion was measured in uniformly sliced, formalin-fixed brain specimens, and immunochemically marked cells in coronal sections of the left superior frontal gyrus (Brodmann area 8) were quantified by field counting and planimetry. In the cortex, diffuse ferritin-stained microglia and glial fibrillary acidic protein-positive astrocytes were about twice as numerous in the patients with AIDS. Sixty-five percent (18/28) of the patients with AIDS had a microglial cell density greater than 2 standard deviations above the control mean. Microglial cell density was correlated positively with the severity of ventricular expansion (r = 0.71, p < 0.0001), while hypertrophied astroglial cells were very weakly related. In white matter, Ham-56-positive macrophages and glial fibrillary acidic protein-positive astrocytes were not meaningfully correlated with the index of ventricular expansion. Brain ventricular expansion and diffuse cortical microgliosis are highly prevalent anomalies in patients with AIDS, and their interrelationship may be more important than previously recognized.
Acquired Immunodeficiency Syndrome↗
Morphometry, histopathology, and tomography of cerebral atrophy in the acquired immunodeficiency syndrome.
Patients with the acquired immunodeficiency syndrome (AIDS) commonly display evidence of gross cerebral atrophy, but its true incidence and pathophysiology in the general AIDS population are unknown. In this study, we measured cerebrospinal fluid (CSF) spaces in 64 consecutively autopsied patients with AIDS, compared them with age-matched non-AIDS subjects, and correlated them with the microscopic neuropathology at autopsy. Thirty-seven of the patients with AIDS (58%) had a CSF space index greater than two standard deviations above the mean of the age-matched control subjects. CSF spaces were expanded the most in frontal and temporal lobes; ventricular spaces were expanded more than sulcal spaces. Regression analysis between age and the measured CSF indexes showed that practically none of the deviation in patients with AIDS could be explained by age-related atrophy. Patients with atrophy were much more likely to have human immunodeficiency virus type 1-associated histopathological changes in their brains, but the relationships were too weak to establish the microscopic cause of the atrophy. Measurement of CSF spaces in antemortem computed tomographic (CT) scans from 47 of the patients with AIDS revealed the same regional pattern of brain wasting. CT diagnosis of cerebral atrophy was strongly concordant with the postmortem diagnosis, but its severity was diagnosed slightly more conservatively at autopsy. Thus, quantitative analysis of CSF spaces in a robust sampling of patients with AIDS confirms that cerebral atrophy is a sensitive, common, and frequently subtle indication of central nervous system human immunodeficiency virus type 1 infection that may occur independently from any single specific microscopic abnormality. Its presence, severity, and regional pattern are detected with reasonable consistency using CT scanning.
Acquired Immunodeficiency Syndrome↗