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Biomedical subjects

P S Becker

Publications and source records attributed to P S Becker.

At least 37 records · Page 2Linked to original sources
PubMed1993

Beta spectrin kissimmee: a spectrin variant associated with autosomal dominant hereditary spherocytosis and defective binding to protein 4.1.

We analyzed the DNA sequence of the cDNA encoding the NH2 terminal region of beta spectrin from members of a kindred with autosomal dominant hereditary spherocytosis associated with defective protein 4.1 binding. We found a point mutation at codon 202 within the 272 amino acid NH2-terminal region of beta spectrin. TGG was changed to CGG, resulting in the replacement of tryptophan by arginine. The base change eliminates a normally occurring PvuII restriction site and creates a new MspI site. This finding enabled rapid detection or exclusion of the mutation at the DNA level among the family members, including one member for whom this analysis was performed prenatally. The mutation was found only in the affected family members and occurred as a de novo mutation in the proband. It has not been found in 20 other kindreds. The recombinant peptide derived from the normal cDNA retains the capacity to sediment with protein 4.1 and F-actin. The mutant peptide spontaneously degrades. This variant represents both the first point mutation and the first beta spectrin mutation demonstrated in autosomal dominant hereditary spherocytosis. Furthermore, the mutation is located within a conserved sequence among spectrinlike proteins and may define an amino acid critical for protein 4.1 binding activity.

Adult↗
PubMed1993

Cytokine expression of macrophages in HIV-1-associated vacuolar myelopathy.

Macrophages are frequently present within the periaxonal and intramyelinic vacuoles that are located primarily in the posterior and lateral funiculi of the thoracic spinal cord in HIV-associated vacuolar myelopathy. But the role of these macrophages in the formation of the vacuoles is unclear. One hypothesis is that cytokines, such as interleukin-1 (IL-1) and tumor necrosis factor (TNF)-alpha, are produced locally by macrophages and have toxic effects on myelin or oligodendrocytes. The resulting myelin damage eventually culminates in the removal of myelin by macrophages and vacuole formation. We studied thoracic spinal cord specimens taken at autopsy from HIV-positive (+) and HIV-negative individuals. The predominant mononuclear cells present in HIV+ spinal cords are macrophages. They are located primarily in the posterior and lateral funiculi regardless of the presence or absence of vacuolar myelopathy. Macrophages and microglia are more frequent in HIV+ than HIV-negative individuals and these cells frequently stain for class I and class II antigens, IL-1, and TNF-alpha. Activated macrophages positive for IL-1 and TNF-alpha are great increased in the posterior and lateral funiculi of HIV+ individuals with and without vacuolar myelopathy, suggesting they are present prior to the development of vacuoles. Cytokines, such as TNF-alpha, may be toxic for myelin or oligodendrocytes, leading to myelin damage and removal by macrophages and vacuole formation.

Acquired Immunodeficiency Syndrome↗
PubMed1992

Cytokine expression in the brain during the acquired immunodeficiency syndrome.

The pathogenesis of central nervous system (CNS) disease in acquired immunodeficiency syndrome (AIDS) is poorly understood but may be related to specific effects of the immune system. Cytokines such as tumor necrosis factor and interleukin-1 may have toxic effects on CNS cells and have been postulated to contribute to the pathogenesis of the neurological complications of human immunodeficiency virus (HIV) infection. To characterize viral and immunological activity in the CNS, frozen specimens taken at autopsy from the cerebral cortex and white matter of HIV-seropositive and -seronegative individuals were stained immunocytochemically for mononuclear cells, major histocompatibility complex (MHC) antigens, HIV, astrocytes, and the cytokines interleukin-1 and -6, tumor necrosis factor-alpha and -beta, and interferon gamma. Levels of soluble CD4, CD8, and interleukin-2 receptor, as well as interferon gamma, tumor necrosis factor-alpha, beta 2-microglobulin, neopterin, and interleukin-6 and -1 beta were assayed in the cerebrospinal fluid and plasma of many of these individuals during life. The HIV-seropositive group included individuals without neurological disease, those with CNS opportunistic infections, and those with HIV encephalopathy. Perivascular cells, consisting primarily of macrophages with some CD4+ and CD8+ T cells and rare B cells, were consistently MHC class II positive. MHC class II antigen was also present on microglial cells, which were frequently positive for tumor necrosis factor-alpha. HIV p24 antigen, when present, was found on macrophages and microglia. Endothelial cells were frequently positive for interleukin-1 and interferon gamma and less frequently for tumor necrosis factor and interleukin-6. There were gliosis and significant increases in MHC class II antigen, interleukin-1, and tumor necrosis factor-alpha in HIV-positive patients compared to HIV-negative brains. Cerebrospinal fluid from most of the patients tested had increased levels of tumor necrosis factor, beta 2-microglobulin, and neopterin. There was no correlation in HIV-positive individuals between levels of cytokines and the presence or absence of CNS disease. These data indicate that there is a relative state of "immune activation" in the brains of HIV-positive compared to HIV-negative individuals, and suggest a potential role for the immune system in the pathogenesis of HIV encephalopathy.

Acquired Immunodeficiency Syndrome↗
PubMed1991

Epstein-Barr virus in AIDS-related primary central nervous system lymphoma.

Primary central nervous system lymphoma occurs more often in patients with AIDS. Epstein-Barr virus (EBV) has been detected in these tumours, but the degree of association has not been defined because of both the highly restricted expression of EBV in malignant tissue and the lack of a technique that is reliable in formalin-fixed paraffin-embedded specimens. EBV-transformed lymphocytes contain short non-protein coding EBV transcripts (EBERs), which are expressed in much higher quantity than other EBV-latency transcripts. We describe a new strategy for detection of latent EBV with these transcripts as targets for in-situ hybridisation. 18 cases of AIDS-related primary CNS lymphoma from a consecutive necropsy series together with specimens from 3 further cases were studied. In each case, a strong positive signal over tumour cells indicated abundant expression of the EBV-EBER1 transcript. This 100% association suggests that the pathogenesis of these AIDS-associated lymphomas may differ from the systemic disease in which only 30-50% of tumours are associated with EBV. A pathogenetic role for EBV was further supported by showing expression of a viral protein (the latent membrane protein) that is implicated as an effector for EBV-associated lymphomagenesis. EBV might have a role as a tumour marker in the diagnosis and management of AIDS-related primary CNS lymphoma.

Central Nervous System Neoplasms↗
PubMed1991

Neuropathologic changes with experimental spinal instrumentation: transpedicular versus sublaminar fixation.

Fifty-six mature beagles underwent lumbar spine destabilization, followed by fusion using four techniques. Spinal cord neuropathologic analysis was carried out to determine the number of abnormalities within each group. Group I (n = 14) had posterolateral bone grafting without instrumentation. Group IIa (n = 14) had Cotrel-Dubousset (CD) pedicle screws and rods. Group IIb (n = 14) had Steffee pedicle screws and plates. Group III (n = 14) had sublaminar wires and rods. All of the animals remained clinically neurologically normal throughout the 6 months of the study. The incidence of moderate to severe neuropathologic changes was 21% in Group I, 18% in Group II, and 64% in Group III. Thus, a significantly higher percentage of neuropathologic abnormalities occurred with sublaminar instrumentation than with no instrumentation (p = 0.027), or with transpedicular instrumentation (p = 0.027). In this controlled animal study, the theoretical advantage of pedicle screws, which should not violate the spinal canal, over sublaminar devices, which must enter the canal, was confirmed.

Animals↗
PubMed1990

Radiolabel-transfer cross-linking demonstrates that protein 4.1 binds to the N-terminal region of beta spectrin and to actin in binary interactions.

Erythrocyte protein 4.1 plays a major role in stabilizing the spectrin-actin junction of the erythrocyte membrane skeleton. The particular sites on spectrin responsible for the binding of actin and protein 4.1 have not been specifically defined, although the general region of the 'tail' end, opposite the self-association site, has been deduced by electron microscopy. Using a photoactivatable, radiolabel-transfer cross-linker, 1-[N-(2-hydroxy-5-azidobenzoyl)-2-aminoethyl]-4-(N-hydroxysuccinimidyl)- succinate, we have determined that the binding site for protein 4.1 on spectrin resides in the N-terminal region of beta spectrin within a sequence homologous to the actin-binding region of alpha actinin. Moreover, this technique provided clear evidence for a direct binding interaction between actin filaments and protein 4.1 that was confirmed by rapid-sedimentation assays. In summary, use of radiolabel-transfer cross-linking has enabled assignment of the protein-4.1-binding site on erythrocyte spectrin and has identified a previously ill-defined binary interaction between protein 4.1 and F-actin.

Actins↗
PubMed1990

Acquired immunodeficiency syndrome: correlation of radiologic and pathologic findings in the brain.

The appearance on magnetic resonance (MR) and computed tomographic (CT) images of specific central nervous system disorders associated with acquired immunodeficiency syndrome in 12 cases was correlated with autopsy findings. There were three cases of human immunodeficiency virus (HIV) encephalopathy; three, primary lymphoma; three, toxoplasmosis; one, cryptococcosis; one, cytomegalovirus infection; and one, progressive multifocal leukoencephalopathy. MR imaging demonstrated the various cranial lesions more clearly than did CT. On the basis of MR imaging characteristics, HIV encephalopathy could be distinguished from other lesions, particularly progressive multifocal leukoencephalopathy. Basal ganglia were the most common sites of involvement in opportunistic infections and primary lymphoma. Reliable distinguishing features among lesions of the basal ganglia were not found, except for cryptococcal lesions, which had a unique appearance.

AIDS Dementia Complex↗
PubMed1989

Bilateral opercular polymicrogyria.

Foix-Chavany-Marie syndrome (FCMS), or faciopharyngoglossomasticatory diplegia, is an uncommon syndrome that can result from vascular or developmental lesions of the anterior opercula bilaterally. We report the first pathological documentation of the developmental form of this disorder. Pathological examination revealed bilateral failure of opercular closure, opercular polymicrogyria, periventricular gray-matter heterotopias, and absence of the septum pellucidum.

Adult↗
PubMed1989

Neuropathological changes in early HIV-1 dementia.

Early pathological abnormalities in human immunodeficiency virus (HIV-1)-related dementia have not been well documented. We report a homosexual man with fatigue and intermittent diarrhea in whom early HIV-1-related dementia was demonstrated during neurological screening in the Multicenter AIDS Cohort Study. Within 4 months he died of massive epistaxis, and the brain revealed astrocytosis of white matter and mild pallor of myelin staining in the absence of inflammation, multinucleated giant cells, and brain atrophy.

AIDS Dementia Complex↗
PubMed1989

Neuropathology with spinal instrumentation.

Neurohistologic examination of the spinal cord and cauda equina were compared for 28 beagles undergoing anterior and posterior spinal destabilization procedures--Group I (n = 7), destabilized operative controls; Group II (n = 7), posterolateral bone grafting; Group III (n = 7), Harrington distraction instrumentation and posterolateral fusion; and Group IV (n = 7), Luque rectangular instrumentation and posterolateral fusion. All dogs had appeared neurologically intact upon repeated examinations prior to death. Neurohistological abnormalities (Wallerian degeneration of the dorsal columns, corticospinal tracts, and nerve roots, focal cystic degeneration, and intraspinal central cavitation) occurred in only 1 of the 14 animals (7%) in Groups I and II (noninstrumented) and in 9 of the 14 animals (64%) in Groups III and IV (instrumented). This result is statistically significant (p less than 0.001). Transient sensory disturbances and radicular paresthesias have been described in clinical reports of spinal instrumentation. It is probable that subclinical neurologic injuries, such as intraspinal and nerve root infarction in posterior neural tissue, can occur with the use of sublaminar hooks or wires. The chondrodystrophic beagle spinal model in this study should be considered a "worst case situation," and the clinical incidence of neurohistologic changes is expected to be lower.

Animals↗
PubMed1989

Heparin-induced thrombocytopenia.

There are two types of heparin-induced thrombocytopenia. Type I is more common, has an early onset, and is mild, transient, and benign. Type I is due to direct heparin-induced platelet aggregation and is rarely associated with thromboembolic sequela. Type II is infrequent, has a late onset, and is more severe. Type II is due to an immune-mediated platelet aggregation caused by IgG and IgM that becomes bound to platelets. In Type II, the antibody titers decline over several months; however, early reexposure can result in a catastrophic secondary immune response. Frequently, Type II is associated with life- or limb-threatening thromboembolic complications (white clots), including stroke.

Cerebrovascular Disorders↗
PubMed1989

Dural scrofula.

A middle-aged woman presenting with multiple cranial neuropathies, hemiparesis, and CSF pleocytosis had tuberculous infection of the cranial dura mater at autopsy. This is the first description of dural scrofula in modern medical literature.

Autopsy↗
PubMed1987

Abnormal oxidant sensitivity and beta-chain structure of spectrin in hereditary spherocytosis associated with defective spectrin-protein 4.1 binding.

Hereditary spherocytosis (HS) is an inherited disorder of erythrocyte shape associated with spectrin deficiency and hemolytic anemia. In a subset of patients with the autosomal dominant form of HS, spectrin displays a reduced capacity to bind protein 4.1 and, therefore, actin; both functions that are critical to the membrane skeleton. A specific structural defect has not been identified in the spectrin from these patients. Chymotryptic digestion of the isolated spectrin chains shows impaired cleavage of the distal peptide of the beta subunit, the beta IV domain. In previous work, we have shown that mild oxidation markedly diminishes the binding capacity of normal spectrin for protein 4.1. Here we observe that chemical reduction of freshly isolated, untreated HS spectrin dramatically improves its function. Thus, a primary structural defect in the beta subunit of spectrin in this subtype of HS may lead to oxidant sensitivity, and secondarily, to a functional defect in the binding of spectrin to protein 4.1 and actin.

Blood Proteins↗
PubMed1986

The effect of mild diamide oxidation on the structure and function of human erythrocyte spectrin.

Oxidants can alter erythrocyte membrane properties and cause ultimate hemolysis, but the mechanisms responsible for these changes are not understood. A protein skeleton preserves the normal integrity of the erythrocyte membrane. In this study, we investigated the effects of limited chemical oxidation on the structure and function of the major skeletal protein, spectrin. After mild treatment of spectrin with 2.5 microM diamide, with formation of an average of only one disulfide bond, we observed a 50% reduction in the ability of protein 4.1 to amplify spectrin-actin binding. The oxidized spectrin specifically lacked the ability to bind protein 4.1, whereas all other spectrin functions remained intact. However, oxidation also produced a structural change in spectrin. A rapidly migrating species appeared on non-denaturing gels in a dose-dependent manner with increasing diamide concentrations. By electron microscopy, the oxidized spectrin appeared as single-stranded signet rings with irregular knob-like protrusions. Fifty per cent of spectrin was converted to the ring form after the formation of an average of two disulfide bonds. Both the structural and functional defects were reversed by chemical reduction. The loss of spectrin function or the structural transformation in spectrin may contribute to erythrocyte membrane failure in the oxidative environment.

Azo Compounds↗
PubMed1985

Hereditary spherocytosis and related disorders.

A number of abnormalities in cellular physiology have been observed in hereditary spherocytes, including alterations in shape, membrane cation permeability and deformability, intracellular metabolism and tendency for splenic entrapment. Many observations have been observed only in a subset of patients with HS and may studies have not been confirmed. Therefore, it is likely that there is heterogeneity with regard to the specific molecular cause of the disease. The major research problem has been to determine primary molecular defects in HS. Much evidence supports a molecular defect in the erythrocyte membrane skeleton and three abnormalities involving spectrin have been demonstrated to be directly related to HS. First, spectrin deficiency has been shown in autosomal recessive spherocytosis in mouse mutants and partial deficiency observed in all human patients with HS. Second, a specific functional defect in spectrin purified from the red cells of some kindreds with autosomal dominant HS has been identified: lack of binding capacity for protein 4.1. Third, a less well characterized functional abnormality has been described in which spectrin binds more tightly to the erythrocyte membrane. These defects may, by an unidentified mechanism, contribute to the spheroidal shape and haemolytic disease ameliorated by splenectomy. More definitive studies are necessary in order to determine the origins of HS. Such studies require: Use of appropriate controls for splenectomy and young red cell age, Tracing a defect through affected family members, Verifying that a defect corresponds to the appropriate heredity pattern, for example that a heterozygote for an autosomal dominant defect had 50% abnormal protein, Differentiating the effects of splenic or circulatory conditioning from the primary red cell defects, Verifying that the defect is present in the intact cell and is not secondary to experimental manipulations, Distinguishing an unrelated, linked polymorphism from the primary mutation responsible for the disorder. Finally, the pathophysiology of the disease will have to be explained on the basis of the primary molecular defect, as well as the mechanism of all secondary physiological changes in the hereditary spherocyte.

Erythrocyte Membrane↗