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D L Kolson

Publications and source records attributed to D L Kolson.

51 records · Page 3Linked to original sources
PubMed1996

Quantitative volumetric magnetization transfer analysis in multiple sclerosis: estimation of macroscopic and microscopic disease burden.

Magnetization transfer imaging (MTI) has been shown to be sensitive to both macroscopic and microscopic disease in multiple sclerosis (MS). In this study three-dimensional MTI was used to estimate the global burden of disease in large volumes of brain tissue. MTI was performed in 15 MS patients and 11 normal controls. In seven MS patients MTI was performed on two different occasions. MTI data were displayed as magnetization transfer ratio (MTR) histograms and analyzed. The peak height of the histograms, presumably reflecting the residual amount of normal brain tissue, was lower in MS patients as compared with normal controls (P < 0.001), and was found to correlate with the duration of disease (P < 0.05). A decrease of the MTR histogram peak height was observed in the course of the disease (P < 0.01). These findings suggest that in MS, volumetric MTI provides quantitative information reflecting the global burden of disease.

Adult↗
PubMed1995

Acetylcholinesterase expression in NTera 2 human neuronal cells: a model for developmental expression in the nervous system.

Acetylcholinesterase (AChE; EC 3.1.1.7) is expressed in the central nervous system in multiple molecular forms that may subserve multiple functions and may be selectively lost in neurodegenerative illnesses such as Alzheimer's disease. AChE expression has been studied in primary cultures of developing vertebrate nervous system, but investigation has been limited by the lack of a suitable human CNS surrogate cell model system for in vitro studies and the inability of primary brain cultures to provide large numbers of pure neurons. To develop an in vitro model for studies of neuronal AChE expression and function, we utilized a neuronally committed human teratocarcinoma cell line, NTera 2, that can be induced to differentiate to a post-mitotic CNS neuronal phenotype. We found that NTera 2 cells express multiple molecular forms of AChE that are similar to CNS-derived AChE isoforms in velocity sedimentation profile, anion exchange elution profile, and sensitivity to inhibitors. At least two forms of AChE are expressed (G1 and G4), similar to human and rodent brain, and induction of NTera 2 cell differentiation results in an increased G4/G1 ratio, which is characteristic of mature neurons. As in primary CNS neurons, AChE is present in NTera 2 cells in both the cytosolic fraction and in the outer membrane, and is also released in a soluble form. These observations indicate that NTera 2 cells provide a useful human model system for studies of expression of cell-associated and soluble cell-free AChE in developing and mature human neurons and for elucidating the potential role(s) of acetylcholinesterase metabolism in both normal development and neurodegenerative disease states.

Acetylcholinesterase↗
PubMed1995

V3-independent determinants of macrophage tropism in a primary human immunodeficiency virus type 1 isolate.

Human immunodeficiency virus type 1 isolates differ in their ability to productively infect macrophages, and several groups have mapped the genetic basis for macrophage tropism to regions of env that include the third hypervariable region (V3 loop). We recently described a primary isolate (89.6) which is highly macrophage tropic and yet differs from other macrophage-tropic strains studied in that it is cytopathic in T cells. Genetic mapping of macrophage tropism determinants in this virus was done by using chimeras generated with the prototypic non-macrophage-tropic strain HXB2. Replacement of a 2.7-kb env-containing region of HXB with corresponding sequences from 89.6 conferred the macrophage-tropic phenotype, but insertion of the 89.6 V3 loop along with V4/V5 sequences did not. Conversely, placement of HXB sequences that included V3 into 89.6 did not impair this strain's ability to replicate in macrophages. Sequence analysis of V3 shows that 89.6 differs markedly from previously described macrophage-tropic consensus sequences and that it is more similar to highly charged non-macrophage-tropic strains. This suggests either that macrophage tropism is defined by structural determinants resulting from complex interactions among multiple env regions rather than V3 sequence-specific requirements or that there are multiple mechanisms by which different strains may establish productive macrophage infection. In addition, because the HXB V3 loop supports productive macrophage infection in the background of 89.6, phenotypic characterization of V3 sequences should be considered specific to the viral context in which they are placed.

Amino Acid Sequence↗
PubMed1995

Microscopic disease in normal-appearing white matter on conventional MR images in patients with multiple sclerosis: assessment with magnetization-transfer measurements.

PURPOSE: To assess for the presence of microscopic abnormalities in otherwise normal-appearing white matter on T2-weighted images in patients with multiple sclerosis (MS) by using magnetization-transfer (MT) measurements. MATERIALS AND METHODS: Twenty-three patients with MS and nine healthy control subjects underwent magnetic resonance (MR) imaging with a 1.5-T system. MT ratios (MTRs) were measured in 16 areas of normal-appearing white matter identified on conventional T2-weighted images in patients with MS. MTRs in the same white-matter locations in control subjects were determined. The two groups were compared. RESULTS: The mean whole-brain MTR of normal-appearing white matter in patients was 40.13% +/- 1.37 (standard deviation; range, 36.31%-42.09%); in control subjects, 42.93% +/- 0.95 (range, 41.62%-44.50%). The difference was statistically significant (P < or = .001). Except for the internal capsules, the difference in mean MTRs in each sublocation of the brain between patients and control subjects was statistically significant (P < or = .05). CONCLUSION: MT measurements are more sensitive than conventional MR imaging in the detection of abnormalities beyond the resolution of T2-weighted imaging.

Adult↗
PubMed1994

Distinct effects in primary macrophages and lymphocytes of the human immunodeficiency virus type 1 accessory genes vpr, vpu, and nef: mutational analysis of a primary HIV-1 isolate.

Macrophages and lymphocytes are the two main targets for productive HIV-1 infection in vivo. To compare the effects of the "nonessential" HIV-1 accessory genes vpr, vpu, and nef on viral replication in these primary cell types, we generated a panel of mutant viruses derived from a molecularly cloned macrophage-tropic HIV-1 primary isolate. Mutant viruses had markedly different patterns of replication in macrophages, in contrast to lymphocytes in which differences were modest. Loss of vpr or vpu reduced viral antigen production in macrophages by up to 1000-fold, while replication in lymphocytes was only marginally affected. Loss of nef did not affect lymphocyte infection, but decreased replication in macrophages to a small extent. Mutation of multiple accessory genes restricted replication in both cell types, but to a much greater extent in macrophages, and frequently resulted in nonproductive infection. The degree to which replication depended on intact accessory genes varied in macrophages from different donors. The essential functions of these accessory genes in HIV-1 infection may be related to their combined effects in facilitating productive infection of macrophages.

Base Sequence↗
PubMed1994

Human immunodeficiency virus type 1 causes productive infection of macrophages in primary placental cell cultures.

To characterize the role of the placenta in vertical transmission of human immunodeficiency virus type 1 (HIV-1), the susceptibility of primary human placental cultures and of transformed trophoblast cell lines to infection by several HIV-1 isolates was examined. Placental cultures supported the replication of all strains tested, including lymphocyte-, macrophage-, and amphotropic isolates. All viruses replicated to modest levels, with production of both viral antigen and infectious virus in the culture supernatants. Placental cells demonstrated a pattern of permissiveness for HIV-1 isolates distinct from that seen with lymphocytes, blood-derived macrophages, or T cell lines. Immunofluorescent staining showed that 5%-10% of the cultured placental cells expressed viral antigens, and double labeling revealed that the HIV-positive cells were macrophages not trophoblasts. None of the trophoblast cell line (JEG-3, Jar, BeWo, HP-W1) could be infected by HIV. These results support the hypothesis that infection of the placenta could play a role in maternofetal transmission of HIV-1 and suggest that the placental macrophage is likely to be the primary cell type responsible.

Cell Line, Transformed↗
PubMed1994

Human immunodeficiency virus type 1 Tat activity in human neuronal cells: uptake and trans-activation.

Neurological dysfunction in AIDS occurs in the absence of productive infection of neurons, and may involve modulation of neuronal cell function by viral or cellular products released from surrounding infected cells. The human immunodeficiency virus type 1 (HIV-1) trans-activator protein Tat may be one such factor, as it can act as a neurotoxin, induces marked morphological changes in neurons and astrocytes in primary embryonic rodent brain cultures, and is released by certain HIV-1-infected cells. In addition, Tat can alter expression of cellular genes in several non-neuronal cell types. To explore the possibility that Tat may also mediate neuronal dysfunction in AIDS through non-lethal effects on neurons, we determined the trans-activating ability of Tat in human neuronal cells. We generated human neuronal cell lines stably expressing several HIV-1 tat genes, and also tested human neuronal cells exposed to extracellular recombinant Tat protein. Both endogenously expressed Tat as well as exogenous recombinant Tat protein up-regulated HIV-1 long terminal region (LTR)-driven gene expression by several hundred-fold. Only brief exposure to recombinant Tat was necessary and no toxic effects were seen at levels sufficient for trans-activation. Furthermore, Tat significantly enhanced virus expression in neuronal cells transfected with molecular clones of HIV-1. These results show that Tat is trans-activationally active in human neuronal cells, and can be taken up from the extracellular compartment by these cells in a biologically active form. Neurons represent an important potential target for Tat-mediated cellular dysfunction.

Gene Expression Regulation, Viral↗
PubMed1993

HIV-1 Tat alters normal organization of neurons and astrocytes in primary rodent brain cell cultures: RGD sequence dependence.

The HIV-1 trans-activator protein Tat has been implicated as a mediator of neuronal dysfunction in several model systems. To explore the possibility that Tat can affect primary brain cells, we examined the effect of recombinant Tat protein on rat cortical brain cell cultures. Tat induced marked aggregation of neurons and astrocytes in developing cultures and caused the neuritic processes to coalesce into fascicles. Cell death was not seen and brain macrophages were not affected. These effects mapped to a different region from the trans-activation domain of Tat, as mutating the RGD (arginine-glycine-aspartic acid) sequence within the second exon abrogated aggregation and fascicle formation without affecting trans-activation capacity. Such effects on primary neurons and astrocytes may reflect specific interactions of Tat with uninfected cells within the CNS in vivo.

Amino Acid Sequence↗
PubMed1992

An infectious molecular clone of an unusual macrophage-tropic and highly cytopathic strain of human immunodeficiency virus type 1.

We isolated and molecularly cloned a human immunodeficiency virus type 1 (HIV-1) strain (89.6) which is unusual because it is both macrophage-tropic and extremely cytopathic in lymphocytes. Moreover, this is the first well-characterized infectious molecularly cloned macrophage-tropic HIV-1 strain derived from peripheral blood. HIV-1 89.6 differs markedly from other macrophage-tropic isolates within the envelope V3 region, which is important in determining cell tropism and cytopathicity. HIV-1 89.6 may thus represent a transitional isolate between noncytopathic macrophage-tropic viruses and cytopathic lymphocyte-tropic viruses.

Amino Acid Sequence↗
PubMed1985

New acetylcholinesterase-deficient mutants of the nematode Caenorhabditis elegans.

We have used visual screening for a mutationally induced uncoordinated phenotype, coupled with subsequent enzymatic assay, to isolate 19 new mutations producing acetylcholinesterase (AChE) deficiencies in the nematode Caenorhabditis elegans. At least 13 of these are independent, and all fall within two genes, ace-1 X and ace-2 I, previously shown to control respectively two kinetically distinct major AChE classes, A and B. Three of the 4 new ace-1 alleles and one of the 15 new ace-2 alleles are apparently leaky; the rest are probably null. For the 3 leaky ace-1 alleles, qualitative changes in the residual class A AChE strongly support the contention that ace-1 is a structural gene. In ace-2;ace-1 mutants, marked reduction in class A and B AChE reveals a third, minor, previously unrecognized AChE class, designated C.

Acetylcholinesterase↗
PubMed1985

A novel class of acetylcholinesterase, revealed by mutations, in the nematode Caenorhabditis elegans.

In ace-2;ace-1 double mutants of the nematode C. elegans, where the major acetylcholinesterase (AChE) classes A and B have been eliminated by mutation, the animals are viable and residual AChE activity remains. This residual activity differs markedly from AChE classes A and B; its Km for acetylcholine is 1000-5000-fold lower, its resistance to eserine is 3000-260,000-fold higher, it is markedly more thermolabile, and it can be separated from classes A and B by ion exchange chromatography. It has been designated class C AChE. Class C AChE of indistinguishable properties is also present in wild type C. elegans, at levels approximating those seen in ace-2;ace-1 double mutants, suggesting that it is controlled by a third, as yet unidentified, gene. Amongst other sources examined, class C-like AChE has been detected in another nematode species, Stephanurus dentatus, but not in Drosophila melanogaster, Torpedo californica, or Rattus rattus.

Acetylcholine↗
PubMedDate not supplied

MR lesion load and cognitive function in patients with relapsing-remitting multiple sclerosis.

BACKGROUND AND PURPOSE: Multiple sclerosis (MS) is a demyelinating disease most often associated with progressive physical impairment; however, its effects are noted to extend beyond physical disability. Our purpose was to determine the relationship between T2 lesion volume and neurocognitive and physical disability in relapsing-remitting multiple sclerosis. METHODS: We studied a cohort of 19 patients with relapsing-remitting MS. Of this group, there were 15 women and four men from varying socioeconomic backgrounds. This volunteer sample was selected from a larger group of 53 patients with MS in our longitudinal MS study because they had been untreated with any beta-interferon medications, had been followed for at least 12 months, and had a clinical status of relapsing-remitting MS. RESULTS: Of 12 neurocognitive parameters tested, two correlated significantly with lesion loads. The correlation of the Symbol-Digit Modalities test, which analyzes information-processing speed, was significant (P = .0204). The correlation of the fifth trial of the Rey Auditory Verbal Learning test, which tests verbal long-term memory, was also significant (P = .0348). None of the other 10 neurocognitive examinations, however, showed a significant correlation with total lesion volume (Paced Auditory Serial Addition test-1.6, P = .7381; Paced Auditory Serial Addition test-2.0, P = .4180; Controlled Oral Word Association test, P = .8906; Category Fluency test, P = .4423; Bells test, P = .9097; Rey Auditory Verbal Learning test-delay, P = .9843, Rey Auditory Verbal Learning test-recognition, P = .7467; Word Span test, P = .4939; Road Map test, P = 0.4939). The lesion load also did not correlate with the physical disability scales as rated according to the Expanded Disability Status Scale (P = .68) or Ambulation Index (P = .95). CONCLUSION: Our results indicate that T2 lesion volume does not seem to be a robust surrogate marker of neuropsychological impairment in patients with MS. We think that global measurements of parameters that are more specific to the disease process may offer more precise correlation with cognitive dysfunction and other disability parameters.

Adult↗
PubMedDate not supplied

Comparison of T2 lesion volume and magnetization transfer ratio histogram analysis and of atrophy and measures of lesion burden in patients with multiple sclerosis.

PURPOSE: The purpose of this study was twofold: first, to compare two different measures of lesion burden in patients with multiple sclerosis (MS), the magnetization transfer ratio (MTR) histogram and T2 lesion volume; and, second, to investigate the relationship between lesion burden and atrophy in patients with MS. METHODS: Thirty patients with MS were examined with MR imaging, including fast spin-echo T2- and proton density-weighted sequences as well as magnetization transfer sequences. The lesion burden in each subject was quantitated by MTR histographic analysis and by a computer-based method for calculating the total volume of lesions on T2-weighted images. Additionally, the CSF volume, the brain parenchymal volume, and the percentage of brain parenchymal volume were determined in all patients by using this method and were compared with measurements in eight control subjects. RESULTS: Significant loss of parenchymal volume was seen in patients with MS as determined by increased CSF volume and decreased percentage of brain parenchymal volume relative to that in age-matched control subjects. An inverse correlation was observed between the peak height of the MTR histogram and T2 lesion volume. T2 lesion volume corresponded positively with CSF volume and inversely with percentage of brain parenchymal volume. The peak height of the MTR histogram corresponded positively with percentage of brain parenchymal volume and inversely with CSF volume. CONCLUSION: MS patients sustain a significant loss of parenchymal volume (atrophy), which corresponds strongly with increasing lesion burden. T2 lesion volume and peak height of the MTR histogram show good correlation, and the peak height of the MTR histogram shows a superior correlation with measures of brain atrophy as compared with measurements of T2 lesion volume, suggesting that the MTR histogram may be a better indicator of global disease burden than is T2 lesion volume.

Adult↗