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Biomedical subjects

J H Simon

Publications and source records attributed to J H Simon.

At least 73 records · Page 4Linked to original sources
PubMed1996

Human immunodeficiency virus type 1 Vif does not influence expression or virion incorporation of gag-, pol-, and env-encoded proteins.

The Vif protein of human immunodeficiency virus type 1 is required for productive replication in peripheral blood lymphocytes and a limited number of immortalized T-lymphoid lines (nonpermissive cells). In contrast, Vif is fully dispensable for virus replication in other T-cell lines (permissive cells). Because the infection phenotype of released virions is determined by producer cells and by the presence of Vif in those cells, we have analyzed the protein contents of purified viral particles in an attempt to define compositional differences that could explain the infection phenotype. Surprisingly, we were unable to discern any Vif- or cell-type-dependent quantitative or qualitative difference in the Gag, Pol, and Env proteins of virions or virus-producing cells that correlates with virus infectivity. We were, however, able to demonstrate that Vif itself is present in virions and, using semiquantitative Western blotting (immunoblotting), that there is an average of 30 to 80 molecules of Vif incorporated into each virion. Importantly, parallel analyses of total lysates of the producer cells revealed that the cell-associated expression levels of Vif are close to those of the Gag proteins. Given the dramatically higher abundance of Vif in cells than in virions, we speculate that Vif exerts its principal activity during the processes of virus assembly and budding and that this function could be of a structural-conformational nature.

Gene Deletion↗
PubMed1996

The human immunodeficiency virus type 1 Vif protein modulates the postpenetration stability of viral nucleoprotein complexes.

The vif gene of human immunodeficiency virus type 1 is absolutely required for productive infection of primary cells derived from human blood and certain immortalized T lymphoid cells, for example, H9. Cells with this restrictive phenotype are termed nonpermissive, whereas cell lines in which vif-deficient virus can replicate efficiently are known as permissive. In this paper, we describe experiments in which virus stocks derived from single-cycle infections of strictly nonpermissive H9 cells were used to determine the fate of vif-deficient infections. By PCR-based approaches, it was found that Vif has no significant impact on the biosynthetic capability of the virion reverse transcriptase in infected C8166 T cells. Specifically, the initial appearance of all DNA species up to and including initiated second (plus) strands as well as the early accumulation of these replicative intermediates is equivalent for wild-type and vif-deficient infections. However, whereas these viral DNAs are stably maintained in wild-type infections and can proceed to establish proviruses, they are largely degraded by the later time points of vif-deficient infections and, as a result, are prevented from forming proviruses. Subcellular fractionation analyses indicated that the majority of viral DNA is localized to the nucleus within 2 h of infection and that the turnover of reverse transcripts that occurs in these vif-deficient infections presumably takes place in the nucleus. Given that the ultimate infection phenotype of the virions is determined during virus production, we propose that Vif is required for an aspect of virus assembly and/or maturation that endows penetrating viral nucleoprotein cores with the ability to mature into functional preintegration complexes that can proceed to provirus establishment. In contrast, viruses that are produced in the absence of Vif give rise to nucleoprotein complexes that disassemble prematurely in challenged cells and fail to protect their RNA/DNA contents from nucleolytic destruction.

Cell Nucleus↗
PubMed1996

Magnetic resonance imaging of multiple sclerosis lesions. Measuring outcome in treatment trials.

Magnetic resonance-based measures of disease activity and progression are now routinely used in definitive phase III treatment trials of multiple sclerosis as important secondary outcome measures because they provide quantitative and objective confirmation of the primary clinical outcome measures. Magnetic resonance-based activity measures can also be used as an efficient mechanism for screening therapies in phase I and II trials. In this review I consider the natural history of multiple sclerosis lesions and the relationships between magnetic resonance measures and clinical observations of disease as the basis for the use of magnetic resonance markers in current and future treatment trials.

Brain↗
PubMed1995

Complementation of vif-defective human immunodeficiency virus type 1 by primate, but not nonprimate, lentivirus vif genes.

The productive infection of many susceptible human cells, including lymphocytes and macrophages derived from peripheral blood, by the pathogenic lentivirus human immunodeficiency virus type 1 requires expression of the virally encoded vif (for virion infectivity factor) gene. Interestingly, this gene appears to have been conserved among all of the lentiviruses of primates and almost all of the lentiviruses of nonprimates. Using T cells constitutively expressing vif genes derived from diverse sources and virus replication assays, we show that the vif gene of a second primate lentivirus, simian immunodeficiency virus from macaques, complements vif-defective human immunodeficiency virus type 1 but that those of three distinct nonprimate lentiviruses do not. Although the molecular basis for Vif function has yet to be defined, the potential implications of this noted restriction of vif complementarity are discussed.

Animals↗
PubMed1995

A phase III trial of intramuscular recombinant interferon beta as treatment for exacerbating-remitting multiple sclerosis: design and conduct of study and baseline characteristics of patients. Multiple Sclerosis Collaborative Research Group (MSCRG).

The design and conduct of a randomized, double-blinded, placebo-controlled, multicenter, phase III study of recombinant interferon beta-1a (IFN-beta-1a) as treatment for exacerbating-remitting MS are described, as are baseline characteristics of the study population. The purpose of the study was to determine if 6.0 x 10(6) IU (30 micrograms) of IFN-beta-1a, administered by weekly intramuscular (i.m.) injections, was effective in delaying the onset of sustained disability. The primary outcome measure was time to onset of treatment failure, defined as a worsening on the Kurtzke Expanded Disability Status Scale (EDSS) of greater than or equal to 1.0 point compared with baseline, persisting for at least 6 months. An intent-to-treat design was used. The primary outcome measure was analyzed using the Mantel-Cox log-rank statistic and Kaplan-Meier survival curves. Secondary outcomes included quantitative measures of upper and lower extremity function, neuropsychological test performance, functional and quality of life assessments and several measures derived from annual brain MRI studies. Entry criteria included prestudy exacerbation rates of at least 0.67 per year and EDSS scores of 1.0-3.5. A total of 301 MS patients were randomly assigned to receive weekly i.m. injections of IFN-beta-1a or placebo. The average age of the study population at entry was 37 years; 92% were Caucasian and 73% were women. The mean prestudy disease duration was 6.5 years, mean prestudy exacerbation rate was 1.2 per year and the mean EDSS score was 2.3. The randomization yielded well-balanced treatment arms. Various aspects of the study are discussed, including: (1) the decision to focus study design on sustained disability; (2) the rationale for the treatment regimen; (3) measures taken to assure the reliability of the primary outcome measure; and (4) a description of the secondary outcome measures.

Adolescent↗
PubMed1994

Heterokaryons formed between a rat myeloma and a mouse fibroblast are permissive for entry of HIV type 1.

Expression of CD4 is not sufficient for cellular susceptibility to HIV-1 entry. The majority of nonprimate cells appear to lack a factor that plays an accessory role to CD4 during virus-cell fusion. We have previously reported CD4-dependent entry in rat myeloma Y3 cells, and here we show that Y3 and CD4-expressing mouse L929 cells fuse spontaneously to produce heterokaryons susceptible to entry by HIV-1. The results suggest that a putative accessory factor necessary for entry of HIV-1 into cells is expressed by the nonprimate Y3 cell line.

Animals↗
PubMed1994

A rodent cell line permissive for entry and reverse transcription of human immunodeficiency virus type 1 has a pre-integration block to productive infection.

Replication of human immunodeficiency virus type 1 (HIV-1) is restricted to CD4-expressing primate cells. This tropism may be due partly to the absence from nonprimate cells of a species-specific factor which has an accessory role to CD4 during virus penetration. In this study we describe a rat B lymphocyte cell line in which there is efficient CD4-dependent entry of HIV-1. However, this cell line has a block to productive infection of HIV-1 at a stage between reverse transcription and integration. Our results demonstrate that the putative accessory factor for HIV-1 penetration is not restricted to primate cells and that there is a novel, uncharacterized cell-virus interaction at a stage between penetration and integration.

Animals↗
PubMed1994

Quantitation of grey matter, white matter, and cerebrospinal fluid from spin-echo magnetic resonance images using an artificial neural network technique.

An operator independent technique has been developed to quantitate the volume of white matter (WM), grey matter (GM), and cerebrospinal fluid (CSF) using spin-echo magnetic resonance images. Using skull stripped spin-echo images, CSF was removed using an automated thresholding technique. The bimodal histogram of the remaining images was used to train a perceptron and a single hidden layer neural network to output the percentage of GM and WM in the image. The output values were compared with those of a semiautomated technique employing a least square fitting technique [graduated nonconvexity algorithm (GNC)] applied to the bimodal histogram. This semiautomated technique allowed for intervention by the radiologist. Fourteen normal volunteers with eight contiguous slices each were analyzed. The individual percentages of WM, GM, and CSF of 40 slices from five subjects not used in the training set as well as the total percentages of GM, WM, and CSF in each individual were predicted using the two artificial network architectures. GM, WM, and CSF percentages were predicted within 7% for individual slices while total percentages of WM, GM, and CSF were computed accurately with an absolute error of less than 5% when compared to the semiautomated technique involving a trained neuroradiologist.

Adult↗
PubMed1994

Quantitative contrast-enhanced MR imaging of the optic nerve.

During the acute stages of optic neuritis damage to the blood-optic nerve barrier can be detected using i.v. paramagnetic contrast-enhanced MR imaging. Quantification of the enhancement pattern of the optic nerve, intraorbital fat and muscle was determined in 15 normal subjects using 3 fat-suppression MR imaging methods: T1-weighted spin-echo and spoiled gradient-echo sequences preceded by a fat-frequency selective pulse (FATSAT+SE and FATSAT+SPGR, respectively) and a pulse sequence combining CHOPPER fat suppression with a fat-frequency selective preparation pulse (HYBRID). Pre- and postcontrast-enhanced studies were acquired for FATSAT+SE and FATSAT+SPGR. There was no significant enhancement of the optic nerve by either method (mean increase of 0.96% and 5.3%, respectively), while there was significant enhancement in muscle (mean 118.2% and 108.2%, respectively; p < 0.005) and fat (mean increase of 13% and 37%, respectively; p < 0.05). Postcontrast optic nerve/muscle signal intensity ratios (mean, SD) were 0.51 (0.07), 0.58 (0.05) and 0.75 (0.05) for FATSAT+SE, FATSAT+SPGR and HYBRID, respectively. These results suggest a practical methodology and range of values for normal signal intensity increases and ratios of tissue signal that can be used as objective measures of optic neuritis for natural history studies and treatment trials.

Adipose Tissue↗
PubMed1994

White matter changes in patients with breast cancer treated with high-dose chemotherapy and autologous bone marrow support.

PURPOSE: To study MR changes in the white matter of the brain in patients with breast cancer treated with a widely used protocol of high-dose chemotherapy and autologous bone marrow support. METHODS: Thirteen patients with high-risk stage II or stage IV breast cancer treated with high-dose cyclophosphamide, cisplatin, carmustine, and bone marrow support underwent posttransplant MR examination of the brain. Serial posttransplant MR examinations were performed in 5 of the 13 patients and single MR examinations in 8. The severity of the white matter change was evaluated by two neuroradiologists and rated mild, moderate, or severe. RESULTS: In 9 of the 13 patients, central and peripheral cerebral white matter changes were observed. Four patients had severe changes, extending from the ependyma of the lateral ventricles to the gyri. An additional 4 patients had moderate white matter change at the last observation. One had mild change, and 4 had no white matter change. In all patients, there was sparing of inferior frontal, posterior inferior occipital, and anterior temporal lobes, and of the centrosylvian brain. CONCLUSIONS: White matter change occurred in patients treated with a high-dose chemotherapy and bone marrow support protocol. Most of the changes, and the more severe ones, occurred 5 or more months after the transplants. There was no apparent relationship between these changes and central nervous system function. Because of the increased longevity with this treatment, it is important to appreciate these white matter changes, recognizing however that their expression may be subclinical.

Adult↗
PubMed1994

Contrast-enhanced fat-suppression neuroimaging.

The commercially available fat-suppression methods currently do not produce quantitative fat suppression but in regions of minimal magnetic susceptibility effects and high magnetic and radiofrequency homogeneity are clinical tools that can increase confidence and specificity of diagnoses when applied appropriately. The advantages of these methods include a reduction in CSMA, improved tissue contrast allowing contrast-enhanced studies in fat-rich regions for greater sensitivity to pathology, and improved staging of lesions. These methods allow better use of the full dynamic range of the gray scale. Future improvements will include thin-section three-dimensional methods and susceptibility correction schemes, which will broaden the indications and increase the usefulness of fat suppression in clinical MR imaging.

Adipose Tissue↗
PubMed1994

Venous sinus occlusive disease: MR findings.

PURPOSE: To study MR patterns of venous sinus occlusive disease and to relate them to the underlying pathophysiology by comparing the appearance and pathophysiologic features of venous sinus occlusive disease with those of arterial ischemic disease. METHODS: The clinical data and MR examinations of 26 patients with venous sinus occlusive disease were retrospectively reviewed with special attention to mass effect, hemorrhage, and T2-weighted image abnormalities as well as to abnormal parenchymal, venous, or arterial enhancement after intravenous gadopentetate dimeglumine administration. Follow-up studies when available were evaluated for atrophy, infarction, chronic mass effect, and hemorrhage. RESULTS: Mass effect was present in 25 of 26 patients. Eleven of the 26 had mass effect without abnormal signal on T2-weighted images. Fifteen patients had abnormal signal on T2-weighted images, but this was much less extensive than the degree of brain swelling in all cases. No patient showed abnormal parenchymal or arterial enhancement. Abnormal venous enhancement was seen in 10 of 13 patients who had contrast-enhanced studies. Intraparenchymal hemorrhage was seen in nine patients with high signal on T2-weighted images predominantly peripheral to the hematoma in eight. Three overall MR patterns were observed in acute sinus thrombosis: 1) mass effect without associated abnormal signal on T2-weighted images, 2) mass effect with associated abnormal signal on T2-weighted images and/or ventricular dilatation that may be reversible, and 3) intraparenchymal hematoma with surrounding edema. CONCLUSION: MR findings of venous sinus occlusive disease are different from those of arterial ischemia and may reflect different underlying pathophysiology. In venous sinus occlusive disease, the breakdown of the blood-brain barrier (vasogenic edema and abnormal parenchymal enhancement) does not always occur, and brain swelling can persist up to 2 years with or without abnormal signal on T2-weighted images. Abnormal signal on T2-weighted images may be reversible and does not always indicate infarction.

Adolescent↗
PubMed1993

The recognition of chimeras of rat and human CD4 by HIV-1 gp120 and by monoclonal antibodies.

The use of chimeras of rat and human CD4 to probe the HIV-1 gp120 and antibody binding properties of CD4 is reviewed. Short segments of human CD4 sequence were substituted for the equivalent regions of rat CD4 which does not bind gp120, and analysis of the properties of these chimeras established: (i) that residues 33-58 of the NH2-terminal domain of human CD4 encompass the high-affinity gp120 binding site; and (ii) that chimeras containing residues 33-62 mediate HIV-1 infection. The chimera-binding specificities of gp120 and a large panel of anti-CD4 antibodies were also determined. This allowed a critical test of the popular notion that receptor mimics appear at high frequency among antibodies elicited by immunization with receptor ligands and that anti-idiotypic antibodies can be used to identify novel receptors. The data suggest that such mimics appear infrequently, if at all, a result which is consistent with the failure of the anti-idiotype approach to identify new genes encoding receptors with prescribed functions.

Amino Acid Sequence↗
PubMed1993

A rat CD4 mutant containing the gp120-binding site mediates human immunodeficiency virus type 1 infection.

CD4 is the primary receptor for the human immunodeficiency virus type 1 (HIV-1). Early mutational studies implicated a number of residues of CD4, centered in the region 41-59, in binding to gp120. However, further mutational analyses, together with studies using inhibitory antibodies or CD4-derived peptides, have suggested that other regions of CD4 are also involved in binding or postbinding events during infection. To resolve these ambiguities, we used rat CD4 mutants in which particular regions were replaced with the corresponding sequence of human CD4. We have previously shown that some of these are able to bind HIV-1 gp120, and here we test their ability to act as functional receptors. We find that the presence of human CD4 residues 33-62 is enough to confer efficient receptor function to rat CD4, and we conclude that it is unlikely that regions of CD4 outside this sequence are involved in specific interactions with HIV-1 during either infection or syncytium formation.

Animals↗
PubMed1993

In vivo measurement accuracy in vital and necrotic canals with the Endex apex locator.

Currently apex locators are being used to determine working length. This study was undertaken to see what is actually being measured and if the pulp status, i.e. vital or necrotic, makes a difference in the determination. In this in vivo study, 33 teeth, both vital and necrotic, were measured by the Endex apex locator and then radiographed. After the length determination, the file was cemented to place, the tooth extracted, and then shaved back until the file and the apex were exposed. The position of the file was measured in relation to the apical foramen. Results indicate that all measurements were within a narrow range (-0.86 mm to 0.50 mm). There was no statistical difference in measurements between vital and necrotic canals.

Dental Pulp Cavity↗
PubMed1992

Proton (fat/water) chemical shift imaging in medical magnetic resonance imaging. Current status.

Fat/water CSI has recently been transformed from an experimental method to a routine clinical MRI approach, particularly for evaluating paramagnetic contrast enhancement in fat-rich regions and as a piggyback method for decreasing MRI artifacts, such as in MR angiographic and echo-planar imaging. The full and appropriate use of CSI in medical MRI requires consideration of the factors and strategies outlined in this review. As the commercial implementation of fat/water CSI continues, we can expect further applications in clinical and experimental studies. For example, in imaging areas where MRI has been of limited efficacy, such as pancreas imaging, skin microimaging and vascular imaging, there are indications that these CSI methods may have practical importance. It seems reasonable to project that for high chemically specific detail, medical fat/water CSI will ultimately be supplanted by SI methods, and certainly by localized spectroscopy. The power of the fat/water CSI method remains its extremely high anatomic resolution, which cannot be achieved by current spectroscopy or SI methods. The fat/water CSI methods provide a means for clinically relevant MRI with more accurate and chemically specific information. Expansion of these methods into three-dimensional and fast imaging formats is already taking place at or near the commercial level. For example, the feasibility of combining echo-planar imaging and CSI methods has already been demonstrated. Methods based on the phase-contrast techniques, such as susceptibility mapping and interferometry, are additional implementations that can provide detailed and more specific information in a high anatomic detail format.

Adipose Tissue↗