Biomedical subjects

D L Kolson

Publications and source records attributed to D L Kolson.

At least 37 records · Page 2Linked to original sources

PubMed1999

Relapsing-remitting multiple sclerosis: longitudinal analysis of MR images--lack of correlation between changes in T2 lesion volume and clinical findings.

PURPOSE: To determine the relationship between T2 lesion volume and either disability measurements or change in T2 lesion volume over time in multiple sclerosis (MS). MATERIALS AND METHODS: Eighteen patients (age range, 26-53 years) with clinically proved relapsing-remitting MS were examined every 6 months for over 2 years. Three-millimeter-thick contiguous images of the whole brain were obtained. T2 lesion volume was calculated with a highly reproducible volumetric computer method. RESULTS: A substantial annual increase in T2 lesion volume, with a median annual increase of approximately 8%, was demonstrated. However, there was no significant correlation between absolute T2 lesion volume and either the absolute expanded disability status scale (EDSS) grade (P = .32) or the absolute ambulation index (AI) (P = .20). In addition, no significant correlation between change in T2 lesion volume and change in EDSS grade (P = .42) or AI (P = .37) was found. There was no significant correlation between T2 lesion volume and duration of disease (P = .08). CONCLUSION: There is no significant correlation between T2 lesion volume and standardized disability measurements despite a substantial increase in T2 lesion volume over time. Patients have an increase in total T2 lesion volume in the brain regardless of their clinical status or disability measurements. T2 lesion volumes as outcomes in therapeutic clinical trials on MS should be viewed as secondary outcomes rather than as surrogate markers of clinical responses.

Adult↗

PubMed1999

Familial multiple sclerosis: volumetric assessment in clinically symptomatic and asymptomatic individuals.

A genetic basis for clustering of multiple sclerosis (MS) cases, based on studies of MS families, has been proposed for decades. Few reports provide detailed neurological as well as neuroradiological findings on these patients. We report total T2-weighted intracranial lesion volumes on members of three familial MS cohorts: a mother and father with conjugal MS with one affected son and a neurologically normal son and daughter, one pair of monozygotic twin sisters with MS, and a female sibling pair with MS. We hypothesized that asymptomatic siblings in a family with two affected parents and another affected child might demonstrate clinically silent T2-weighted lesions; and that monozygotic twins with MS are more likely to express similar T2-weighted lesion volumes than non-twin sibling pairs. We found clinically silent lesions in unaffected children of the symptomatic parent couple, with a significant difference in total T2 lesion volume between these unaffected siblings and their parents, as well as their affected brother. In our other sibling pairs, T2 lesion volumes were similar between the twins and significantly different in the non-twin pair, despite similar levels of clinical functioning as determined by EDSS scoring. These results suggest that foci of demyelination might be expected in clinically normal offspring of parents with MS, possibly reflecting a genetic predisposition to subsequent development of MS.

Adult↗

PubMed1999

Chemokines and peripheral nerve demyelination.

It has been speculated that beta-chemokines play a pivotal role in the development of peripheral nervous system (PNS) disorders characterized by mononuclear cell infiltration. In experimental allergic neuritis (EAN), an animal model for human Guillain-Barré syndrome (GBS) with mononuclear cell infiltration, we found by quantitative PCR that beta-chemokine messages were upregulated during the active stage. Moreover, an increase in the monocyte chemoattractant protein-1 (MCP-1) message was found in the preclinical stage of EAN, suggesting the critical role of MCP-1 for inducing mononuclear cell infiltrations in this model. Since many cell lineages other than immune cells can produce chemokines, this early upregulation of MCP-1 may be mediated by non-immune cells, probably endothelia or Schwann cells. To date, apart from MCP-1, only RANTES (Regulated on activation, normal T cell expressed and secreted) and macrophage inflammatory protein (MIP)-1alpha have been examined in EAN and found to have similar kinetics of induction. Therefore, understanding the regulation of production of these chemokines as well as mechanisms of inhibiting chemokine/receptor interactions in the PNS may ultimately lead to disease-specific therapy for GBS and related demyelinating disorders.

Animals↗

PubMed1998

Neuronal apoptosis induced by HIV-1 gp120 and the chemokine SDF-1 alpha is mediated by the chemokine receptor CXCR4.

CXCR4, a seven transmembrane domain G-protein-coupled receptor for the Cys-X-Cys class of chemokines, is one of several chemokine receptors that can act as a co-receptor with CD4 for the human immunodeficiency virus (HIV-1) glycoprotein gp120 [1-3]. CXCR4 can mediate the entry of HIV-1 strains that specifically infect T cells, such as the IIB strain (see [4] for review). Recent reports indicate that gp120 can signal through CXCR4 [5] and it has been suggested that signal transduction, mediated by the viral envelope, might influence viral-associated cytopathicity or apoptosis [6]. Neuronal apoptosis is a feature of HIV-1 infection in the brain [7,8], although the exact mechanism is unknown. Here, we address the possible role of CXCR4 in inducing apoptosis using cells of the hNT human neuronal cell line; these cells resemble immature post-mitotic cholinergic neurons and have a number of neuronal characteristics [9-15]. We have previously shown that gp120 from the HIV-1 IIIB strain binds with high affinity to CXCR4 expressed on hNT neurons [15]. We now find that both IIIB gp120 and the Cys-X-Cys chemokine SDF-1 alpha can directly induce apoptosis in hNT neurons in the absence of CD4 and in a dose-dependent manner. To our knowledge, this is the first report of a chemokine and an HIV-1 envelope glycoprotein eliciting apoptotic responses through a chemokine receptor.

Apoptosis↗

PubMed1998

The effects of human immunodeficiency virus in the central nervous system.

More than a decade after the first description of HIV DNA in the nervous system the pathophysiology of HIVD remains largely enigmatic, with data supporting a number of potential mechanisms for the development of neuronal dysfunction. Nevertheless, a few key findings have considerable support in the literature devoted to this subject: 1. HIV dementia is caused by HIV itself; no other pathogen has been consistently found in the brains of patients with HIVD. 2. In comparison with other viral encephalopathies, there appears to be a significant discordance between the amount of virus being produced in the brains of patients with HIVD and the degree of neurological deterioration. 3. The key cell types responsible for viral production within the CNS are the resident macrophages or microglial cells. 4. Other elements within the CNS, particularly astrocytes, are probably infected with HIV as well, but all of these infections are highly restricted in terms of production of virus or viral structural proteins. 5. At least one component of the pathogenesis of HIVD may be the generation of neurotoxins by infected microglia, although the type of neurotoxin, and the specific compound most likely to be involved, are quite controversial. Advances with combination antiviral therapy have successfully reduced plasma viral load in a high proportion of individuals, leading to the speculation (previously almost heretical) that it may be possible to eradicate HIV completely from the systemic immune system. If that were the case, potential "sanctuary" sites such as the immunologically protected CNS might remain as important reservoirs for reseeding of lymphoid tissues. Microglia may be particularly suited for this purpose because they are long lived, can produce HIV for several weeks (at least in culture), and they are apparently relatively immune to virus-induced cytopathology such as syncytium formation. One can speculate about several scenarios resulting from the continued presence of replication-competent HIV within brain. In the worst case, a smoldering infection of the nervous system could lead to neurological deterioration without reinfection of systemic immune cells. The epidemiological data indicating that HIVD is a disease primarily associated with immunodeficiency suggest that the systemic immune system plays a role in maintaining virus residing within the CNS under control. Thus it is quite possible that this scenario would not occur for many years after the systemic infection is controlled. Alternatively, virus could be transported from the CNS by circulating lymphocytes and monocytes and reinfect systemic organs. This would necessitate restarting therapy for those individuals who were previously thought to be cured, but presumably virus within the CNS would not have developed resistance to antivirals. In either case, the techniques currently available do not permit an accurate assessment of CNS HIV load in living people, and this question will remain unanswered until antivirals are discontinued in a few individuals with persistently negative tests for systemic virus. In addition to this most critical question, the relationship between viral levels and HIVD is largely unexplored, as is the possibility that some strains are particularly virulent or neuroinvasive. Furthermore, the potential contribution of host genotype in the development of dementia is unknown. In view of the strong influence of major chemokine receptor (CCR5) truncations on HIV replication, it is entirely possible that more discrete genetic polymorphisms have a subtle effect on either brain invasion or virulence.

AIDS Dementia Complex↗

PubMed1998

A cell culture model for androgen effects in motor neurons.

Androgens are known to alter the morphology, survival, and axonal regeneration of lower motor neurons in vivo. To understand better the molecular mechanisms of androgen action in neurons, we created a model system by stably expressing the human androgen receptor (AR) in motor neuron hybrid cells. Motor neuron hybrid cells express markers consistent with anterior horn cells and can be differentiated into a neuronal phenotype. When differentiated in the presence of androgen, AR-expressing cells, but not control cells, exhibit a dose-dependent change in morphology: androgen-treated cells develop larger cell bodies and broader neuritic processes while continuing to express neuronal markers. In addition, androgen promotes the survival of AR-expressing cells, but not control cells, under low-serum conditions. Our results demonstrate a direct trophic effect of androgens on lower motor neurons, mediated through the AR expressed in this population of neurons.

Biomarkers↗

PubMed1998

An orphan seven-transmembrane domain receptor expressed widely in the brain functions as a coreceptor for human immunodeficiency virus type 1 and simian immunodeficiency virus.

Both CD4 and an appropriate coreceptor are necessary for infection of cells by human immunodeficiency virus type 1 (HIV-1) and most strains of HIV-2. The chemokine receptors CCR5 and CXCR4 are the major HIV-1 coreceptors, although some virus strains can also utilize alternative coreceptors such as CCR3 to infect cells. In contrast, most if not all simian immunodeficiency virus (SIV) strains use CCR5 as a coreceptor, and many SIV strains can use CCR5 independently of CD4. In addition, several orphan seven-transmembrane receptors which can serve as HIV-1 and SIV coreceptors have been identified. Here we report that APJ, an orphan seven-transmembrane domain receptor with homology to the angiotensin receptor family, functions as a coreceptor for a number of HIV-1 and SIV strains. APJ was expressed widely in the human brain and in NT2N neurons. APJ transcripts were also detected by reverse transcription-PCR in the CD4-positive T-cell line C8166, but not in peripheral blood leukocytes, microglia, phytohemagglutinin (PHA)- or PHA/interleukin-2-stimulated peripheral blood mononuclear cells, monocytes, or monocyte-derived macrophages. The widespread distribution of APJ in the central nervous system coupled with its use as a coreceptor by some HIV-1 strains indicates that it may play a role in neuropathogenesis.

Animals↗

PubMed1998

Isolated U-fiber involvement in MS: preliminary observations.

We studied the frequency and location of isolated U-fiber involvement in MS and correlated these findings exploratively with physical disability and neuropsychological impairment. Fifty-three MS patients were examined. Three-millimeter-thick, fast spin-echo T2-weighted MR images and spin-echo postgadolinium T1-weighted images were obtained. Computer software that which had been validated previously for quantitation of MS lesions was used to detect lesions on the T2-weighted images. The Expanded Disability Status Scale (EDSS), Ambulation Index (AI), and a battery of neurocognitive tests were performed on each patient. Forty-two arcuate hyperintensities along the U-fiber were detected by the software in 28 patients (53%). Twenty-seven lesions (64.3%) were seen in the frontal lobe, eight (19.0%) in the temporal lobe, three (7.1%) in the parietal lobe, three (7.1%) in the occipital lobe, and one (2.4%) in both frontal and parietal lobes. Four lesions (9.5%) showed gadolinium enhancement. Seventeen lesions (40%) were hypointense on the T1-weighted images. Scores of three of the 11 neuropsychological tests reflecting performance in executive control and memory were significantly different at least at the p = 0.05 level between the eight patients with multiple, isolated U-fiber lesions and the 45 patients without any or with only a single U-fiber lesion. No significant difference was noted for EDSS or AI. Isolated U-fiber involvement is an underappreciated MR finding in MS. Our preliminary hypothesis is that U-fiber lesions may contribute to neuropsychological impairment, although our observation requires confirmation.

Adult↗

PubMed1998

Correlation of volumetric magnetization transfer imaging with clinical data in MS.

We examined the relations between quantitative volumetric estimates of cerebral lesion load based on magnetization transfer imaging (MTI), clinical data, and measures of neuropsychological function in 44 patients with clinically diagnosed MS. In this population we assessed the correlation between several volumetric MTI measures, measures of neurologic function (Kurtzke Expanded Disability Status Scale and Ambulation Index), and disease duration using Spearman's correlation coefficient. Patients were classified on the basis of neuropsychological test performance as severely impaired, moderately impaired, and normal. We assessed differences between these groups with respect to MTI results using the Kruskal-Wallis test. MTI measures corrected for brain volume were found to correlate with disease duration (p < 0.01) and showed suggestive correlations with measures of neurologic impairment (p < 0.05). Individual neuropsychological tests correlated with MTI measures corrected and not corrected for brain volume (p < 0.001). An MTI measure not corrected for brain volume differed (p < 0.05) between severely impaired, moderately impaired, and normal patients. These preliminary results suggest that volumetric MTI analysis provides new measures that reflect more accurately the global lesion load in the brain of MS patients, and they may serve as a method to study the natural course of the disease and as an outcome measure to evaluate the effect of drugs.

Adult↗

PubMed1998

Chemokine receptors in the human brain and their relationship to HIV infection.

Chemokine receptors have been recently identified as the important co-factors which in conjunction with CD4, mediate entry of HIV into its target cells. The brain is one of the most prominent targets of HIV infection, where it leads to HIV encephalitis (HIVE) and HIV-associated dementia. Knowledge of the distribution, physiology, and pathology of chemokines and chemokine receptors in the human brain is fundamental for understanding the pathogenesis of the interaction between HIV and the central nervous system (CNS). There is also increasing evidence that chemokine receptors expression in the CNS increases during pathological, especially inflammatory, conditions. The major co-factors for HIV infection, CCR5, CCR3, and CXCR4 have been detected in the human brain in a variety of cell types including microglia, astrocytes, neurons, and vascular endothelial cells. Furthermore, antibodies to chemokine receptors can also block HIV infectivity in cultured CNS cells. This indicates that chemokine receptors are likely to have a functional role in the pathogenesis of HIVE.

Acquired Immunodeficiency Syndrome↗

PubMed1998

MR identification of white matter abnormalities in multiple sclerosis: a comparison between 1.5 T and 4 T.

BACKGROUND AND PURPOSE: Although MR spectroscopy and functional MR imaging of the brain have been successful at 4 T, conventional fast spin-echo imaging of the brain at 4 T has not been adequately evaluated. The purpose of this study was to compare the detection of white matter abnormalities in multiple sclerosis (MS) at 1.5 T and 4 T. METHODS: Fifteen patients with clinically definite MS were imaged at both 1.5 T and 4 T within a 1-week period. Comparison was made between fast spin-echo long-TR images at both field strengths. Pulse sequences were tailored to maximize resolution and signal-to-noise ratio in clinically relevant imaging times (< 7 min). Four interpreters independently reviewed the images obtained at both field strengths in separate sessions and evaluated them for lesion identification, size, characterization, and subjective resolution. Differences in interpretations at 1.5 T and 4 T were subsequently recorded. RESULTS: Images obtained at 4 T showed a mean of 88 more lesions as compared with images obtained at 1.5 T. All the lesions measured less than 5 mm and were typically aligned along perivascular spaces. Twenty-five consensually identified lesions on 4-T images were not seen at all on 1.5-T images. Moreover, 4-T images showed 56 additional consensually identified lesions, which were indistinct and seen only in retrospect on 1.5-T images. These lesions were frequently (n = 48) identified in large confluent areas of white matter signal intensity abnormality at 1.5 T. All observers also agreed that 4-T images subjectively enhanced the perception of normal perivascular spaces and small perivascular lesions. CONCLUSION: MR imaging at 4 T can depict white matter abnormalities in MS patients not detectable at 1.5 T through higher resolution with comparable signal-to-noise ratio and imaging times.

Adult↗

PubMed1998

Case of the month: May 1998--a patient with HIV infection and multiple cranial neuritis.

A 36-year old male with a three year history of HIV infection and more recently, CMV retinitis, had several episodes of polyradiculitis with severe bilateral leg pain and urinary retention which resolved slowly over several months. He then presented with high fevers and severe dysphagia with dehydration. Examination showed oral thrush, dyarthric speech and mild memory impairment. Fundoscopic exam showed CMV retinitis and HIV retinopathy. Further examination revealed other cranial nerve signs and leg weakness. MRI scans showed several contrast enhancing abnormalities of cranial nerve roots. The patient died from massive barium aspiration. At autopsy the brain showed multiple CMV cranial neuritis, CMV polyradiculitis and CMV ventriculo-ependymitis. While spinal nerve root involvement by CMV may occur in up to 1% of AIDS patients, involvement of cranial nerves is unusual and CMV infection of multiple cranial nerves is distinctly rare.

Adult↗

PubMed1997

Targeting of HIV- and SIV-infected cells by CD4-chemokine receptor pseudotypes.

Retroviral vectors containing CD4 and an appropriate chemokine receptor were evaluated for the ability to transduce cells infected with human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV). These CD4-chemokine receptor pseudotypes were able to target HIV- and SIV-infected cell lines and monocyte-derived macrophages in a manner that corresponded to the specificity of the viral envelope glycoprotein for its CD4-chemokine receptor complex. This approach could offer a way to deliver antiviral genes directly to HIV-infected cells in vivo and could provide an additional treatment strategy in conjunction with existing antiviral therapies.

Animals↗

PubMed1997

CD4-independent association between HIV-1 gp120 and CXCR4: functional chemokine receptors are expressed in human neurons.

BACKGROUND: Chemokines are a family of proteins that chemoattract and activate immune cells by interacting with specific receptors on the surface of their targets. We have shown previously that chemokine receptors including the interleukin-8 receptor B (CXCR2) and the Duffy blood group antigen are expressed on subsets of neurons in various regions of the adult nervous system. RESULTS: Using a combination of immunohistochemical staining and receptor binding studies, we show that hNT cells, which are differentiated human neurons derived from the cell line NTera2, express functional chemokine receptors of the C-X-X and C-C types. These chemokine receptors include CXCR2, CXCR4, CCR1 and CCR5. We demonstrate high-affinity binding of both types of chemokines to hNT neurons and dose-dependent chemotactic responses to these chemokines in differentiated, but no t undifferentiated, NTera 2 cells. In addition, we show that the envelop glycoprotein from the T-cell-tropic human immunodeficiency virus 1 (HIV-1) strain IIIB is a CD4-independent, dose-dependent inhibitor of the binding of stromal cell-derived factor 1 to its receptor, CXCR4. CONCLUSIONS: These data support recent findings that members of the chemokine family, including CCR5 and LESTR/Fusin (CXCR4), function as coreceptors in combination with CD4 for HIV-1 invasion. This is the first report of functional expression of chemokine receptors on human neurons. Furthermore, our studies provide for direct CD4-independent association of the viral envelope protein of the HIV-1 strain III with the chemokine receptor CXCR4.

Adult↗

PubMed1997

Alzheimer's A beta(1-42) is generated in the endoplasmic reticulum/intermediate compartment of NT2N cells.

Alzheimer's disease (AD) is a neurodegenerative disorder involving the florid deposition of vascular and cerebral plaques composed chiefly of amyloid beta-peptide (A beta) derived from cleavage of the amyloid precursor protein (APP). Varying in length from 39 to 43 amino acids, A beta, particularly the longer A beta(42), is thought to play a significant role in AD pathogenesis. To better understand AD it is important to identify the subcellular organelles generating A beta. Studies using agents that disrupt endosomal/lysosomal function suggest that A beta is generated late in the secretory and endocytic pathways. However, much of what is known about A beta biosynthesis has been inferred by monitoring extracellular A beta levels since intracellular A beta is undetectable in most cell types. Consequently, the precise site or sites that generate A beta, or whether A beta(1-40) and A beta(1-42) are generated at the same point in the biosynthetic pathway, is not known. Using human NT2N neurons, we found that retention of APP in the endoplasmic reticulum/intermediate compartment (ER/IC) by three independent approaches eliminated production of intracellular A beta(1-40), but did not alter intracellular A beta(1-42) synthesis. These findings suggest that the ER/IC may be an important site for generating this highly amyloidogenic species of A beta.

Alzheimer Disease↗

PubMed1997

Computer-assisted quantitation of enhancing lesions in multiple sclerosis: correlation with clinical classification.

PURPOSE: To study the utility of a computer-assisted method of quantitating enhancing multiple sclerosis (MS) lesions and to correlate this quantitation with the type and duration of disease. METHODS: Forty untreated patients with MS were studied. The patients had been classified clinically as having either relapsing-remitting (n = 27) or chronic-progressive (n = 13) disease. Postcontrast contiguous 3-mm-thick MR images of the brain were obtained for up to 3 years. The computer program selected potential lesion sites automatically on the basis of the theory of "fuzzy connectedness," which was incorporated into 3DVIEWNIX software. True lesions were selected from these previously detected potential lesions by means of yes/no responses to the program query. The number of enhancing lesions and the enhancing lesions volume were subsequently computed. RESULTS: The enhancing lesion volume in patients with relapsing-remitting disease was statistically significantly higher than that of patients with chronic-progressive disease. There was a strong positive correlation between the number of enhancing lesions and the enhancing lesion volume. No significant correlation was noted between the change in score on the expanded disability status scale (EDSS) and the change in the number of enhancing lesions, or between the change in EDSS score and the change in enhancing lesion volume. A negative correlation was found between enhancing lesion volume and duration of disease, and between the number of enhancing lesions and duration of disease in the patients who had enhancing lesions. CONCLUSIONS: Our data suggest that enhancing lesion volume reflects differences in the classification of clinical MS and in the disease activity over time. Computer-assisted quantitation of enhancing lesion volume is a robust, practical, and objective measure of MS activity.

Adult↗

PubMed1997

Global volumetric estimation of disease burden in multiple sclerosis based on magnetization transfer imaging.

We report a semiautomated postprocessing method based on magnetization transfer MR imaging that can quantify the extent of global disease in patients with multiple sclerosis. The technique combines segmentation and quantitative analysis of imaging data reflecting the structural integrity of white matter. Applications of this technique may include assessment of disease progress and of the efficacy of experimental therapeutic intervention. The height of the histogram peak corresponding to white matter was found to be lowered in patients with multiple sclerosis and the overall distribution of magnetization transfer ratios was shifted to lower values.

Adult↗

PubMed1996

Vaccinia virus serves as an efficient vector for expressing heterologous proteins in human NTera 2 neurons.

The human teratocarcinoma cell line NTera 2 (NT2) can be induced to differentiate into post-mitotic neurons possessing well-defined axonal and dendritic morphology. Highly enriched neurons (NT2-N cells) can be prepared in large numbers, thus combining many of the advantages of both primary and continuous cell culture systems. Unfortunately, it has proven difficult to express foreign genes in NT2-N cells. We examined whether vaccinia virus (VV) can express heterologous proteins in NT2-N cells and characterized the response of NT2-N cells to VV infection. NT2-N cells were infected with VV vectors expressing the envelope glycoprotein (gp160) from the human immunodeficiency type 1 virus (HIV 1). These vectors were chosen because VV-directed synthesis and post-translational processing of gp160 have been well characterized in many cell types. Approximately 85% of the neurons expressed gp160 which underwent native post-translational cleavage. The rate of gp160 synthesis was maximal at 5-48 hours postinfection, but was detectable for as long as 4 days. Surprisingly, NT2-N cells showed no VV-induced alterations in morphology, downregulation of host protein synthesis, or cytotoxicity, as measured by lactate dehydrogenase release. These results indicate that VV can serve as an efficient vector for introducing foreign genes in NT2-N cells without the cytotoxic effects often associated with VV infection. These properties, in conjunction with the advantages provided by NT2-N cells, provide new options for analyzing the cellular and molecular functions of human neurons.

Cell Death↗