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Biomedical subjects

I Elovaara

Publications and source records attributed to I Elovaara.

At least 37 records · Page 2Linked to original sources
PubMed2000

Plasminogen activator inhibitor 1 gene and risk of MS in women.

In view of the potential importance of the proteolytic mechanisms in the evolution of MS lesions, the authors studied the 4G/5G promoter polymorphism of the plasminogen activator inhibitor 1 (PAI-1) gene in the susceptibility of MS. The 5G5G genotype was associated with MS in women at an odds ratio of 2.3 (95% confidence interval, 1.04 to 5.23). The genotype seems to be a low producer of PAI-1, suggesting that reduced capacity for proteinase inhibition may be involved in the etiopathogenesis of MS in women.

Adult↗
PubMed2000

Adhesion molecules in multiple sclerosis: relation to subtypes of disease and methylprednisolone therapy.

OBJECTIVES: To determine levels of adhesion molecules in blood and cerebrospinal fluid (CSF) samples from patients with different subtypes and activities of multiple sclerosis (MS) and to assess the effect of intravenous methylprednisolone sodium succinate treatment on the levels of soluble adhesion molecules. DESIGN: The expressions of very late activation antigen 4 (VLA-4), lymphocyte function associated antigen 1 (LFA-1), vascular cell adhesion molecule 1 (VCAM-1), and intercellular adhesion molecule 1 (ICAM-1) were determined immunocytochemically, and levels of soluble VCAM-1, ICAM-1, and E-selectin, by means of enzyme immunoassay technique. The volumes of T2- and T1-weighted MS plaques and brain atrophy were determined by means of the semiautomatic magnetic resonance imaging (MRI) segmentation technique. SETTING: A university hospital in Finland. PATIENTS: One hundred subjects (71 patients with MS and 29 healthy control subjects). The subtypes of MS were relapsing-remitting (RRMS [n = 26]), secondary progressive (SPMS [n = 20]), and primary progressive (PPMS [n = 25]). RESULTS: In patients with RRMS and SPMS, the expressions of VLA-4 and LFA-1 on immune cells from blood were at least 1.5- to 3-fold higher than in controls (RRMS, P = .002 and P<.001, respectively; SPMS, P = .03 and P =.001, respectively). In RRMS, LFA-1 and ICAM-1 expression in blood was more up-regulated than in SPMS (P = .03 and P = .01, respectively). The expressions of adhesion molecules on CSF lymphocytes in RRMS and SPMS were of similar magnitude, but the proportions of CSF VLA-4- and LFA-1-expressing lymphocytes were 3- to 4-fold higher than in controls (P = .04 and P = .008, respectively). The levels of serum soluble VCAM-1 were higher in SPMS than in RRMS (P = .005) or PPMS (P = .04). Intravenous methylprednisolone treatment of patients with RRMS in exacerbation caused a significant reduction in the serum levels of soluble VCAM-1 and E-selectin (P<.001). In SPMS, the volumes of T2-weighted plaques correlated with the serum level of soluble ICAM-1 (r = 0.64; P = .03). CONCLUSIONS: Up-regulated adhesion molecules in blood and CSF indicate sustained potential for inflammation in the CNS throughout the clinical spectrum of MS. Therapies interfering with cell adhesion may be of key importance in suppressing MS.

Adult↗
PubMed1999

Volumes of brain atrophy and plaques correlated with neurological disability in secondary progressive multiple sclerosis.

The objectives of the present study was to correlate the segmented magnetic resonance imaging (MRI) volumes of intracranial cerebrospinal fluid (CSF) spaces (expressing the extent of brain atrophy) and cerebral plaques with the neurological disability in secondary progressive multiple sclerosis (MS). Earlier studies have mainly correlated MS plaques and neurological disability measured by expanded disability status scale (EDSS). The data on the association between brain atrophy and EDSS or regional functional scoring scale (RFSS) are very limited. We measured the volumes of intracranial CSF spaces in 28 patients with secondary progressive MS using MRI, and semiautomatic segmentation software. The volumes of T1-weighted hypointense and T2-weighted hyperintense MS plaques were also measured. In multiple regression analysis, increasing volumes of total (P=0.006) and relative (P=0.005) intracranial CSF spaces were significantly associated with worsening neurological disability as expressed by EDSS. No associations were found between these intracranial CSF space volumes and total RFSS scores. The mean volume of T2-weighted plaques showed a tendency to associate with total RFSS score (r=0.40, P=0.03), but no correlations were detected between T1- or T2-weighted plaque volumes and EDSS. The application of a new segmentation technique in quantifying intracranial cerebrospinal fluid spaces allowed an exact and sensitive way of assessing brain atrophy. The associations between brain atrophy and neurological disability expressed by EDSS suggests that the effect of MS therapies should be evaluated by measurement of brain atrophy.

Adult↗
PubMed1999

Computerised volumetric analysis of lesions in multiple sclerosis using new semi-automatic segmentation software.

The paper describes the application of new semi-automatic segmentation software to the task of detection of anatomical structures and lesion and their three-dimensional (3D) visualisation in 23 patients with secondary progressive multiple sclerosis (MS). The purpose is to study the correlation between magnetic resonance imaging (MRI) parameters (volumes of plaques and cerebrospinal fluid spaces) and clinical deficits (neurological deficits in the form of EDSS and RFSS scores, and neuropsychological deficits). The software operates in PC/Windows and PC/NeXTstep environments and utilises graphical user interfaces. Quantitative accuracy is measured by performing segmentation of fluid-filled syringes (relative error of 1.5%), and reproducibility is measured by intra- and inter-observer studies (3% and 7% variability, respectively). The mean volumes of MS plaques show significant correlations with the total RFSS scores (p = 0.04). Relative intracranial cerebrospinal fluid (CSF) space volumes show statistically significant correlation with EDSS scores (p = 0.01). The mean volume of MS plaques shows a significant correlation with the overall neuropsychological deficits (p = 0.03). 3D visualisation helps to understand the relationship of lesions to the surrounding brain structures. The use of semiautomatic segmentation techniques is recommended in the clinical diagnosis of MS patients.

Brain↗
PubMed1999

Upregulated expression of Fas and Fas ligand in brain through the spectrum of HIV-1 infection.

Apoptosis of neurons and glial cells has been shown to occur in the brain of patients with the acquired immune deficiency syndrome (AIDS) and was postulated as contributing to brain atrophy and white matter damage in these patients. Since apoptotic events may be induced by the Fas-Fas ligand (FasL) system, we analyzed the relevance of these molecules to cell depletion in eight brains from HIV-1-infected patients and nine HIV-1-negative controls all of whom were analyzed histopathologically. The presence of Fas and FasL in brain tissue was analyzed by PCR amplification using Fas- and FasL-specific oligonucleotide primers and immunohistochemistry. The visualization of DNA fragmentation was used to evaluate apoptosis. Fas transcripts were detected in brains from each of four AIDS patients, each of three asymptomatic HIV-1 carriers and each of two HIV-1-negative controls. In the brains from AIDS patients the level of Fas expression was higher than in asymptomatic carriers and uninfected controls. FasL transcripts were seen in three of seven HIV-1-infected brains, two AIDS cases and one asymptomatic HIV-1 carrier. The predominant Fas-expressing cells were reactive astrocytes seen in each of two AIDS patients and one pre-AIDS case, but not in HIV-1-negative controls. Occasional Fas-positive oligodendrocyte-like cells were also seen in AIDS and pre-AIDS cases. No significant expression of Fas and FasL was seen in neurons. Fas-positive reactive astrocytes were more frequent in foci of HIV-1 encephalitis (HIVE). In the same area reactive apoptotic astrocytes were seen in close vicinity to FasL-expressing CD3 T lymphocytes, suggesting that apoptosis of astrocytes is mediated by Fas-FasL. The Fas expression on glial cells in asymptomatic HIV-1 infection may indicate apoptosis already in the asymptomatic stage of HIV-1 disease. In AIDS brains expression of Fas and FasL may contribute to the loss of glial cells and indirectly to the loss of neurons.

Acquired Immunodeficiency Syndrome↗
PubMed1998

Methylprednisolone reduces adhesion molecules in blood and cerebrospinal fluid in patients with MS.

OBJECTIVE: To analyze the expression of adhesion molecules on mononuclear cells from blood and CSF of patients with exacerbations of MS before and after megadose IV methylprednisolone (MP). BACKGROUND: Adhesion molecules regulate transmigration of lymphocytes and monocytes/macrophages to the CNS and have an important role in the pathogenesis of MS. METHODS: The expression of very late activation antigen 4 (VLA-4) and vascular cell adhesion molecule 1, lymphocyte function-associated antigen 1 (LFA-1), and intercellular adhesion molecule 1 (ICAM-1) was analyzed immunocytologically on lymphocytes and monocytes from blood and CSF of 23 patients and 11 healthy control subjects. The results were correlated with the Expanded Disability Status Scale and in half of the patients with the number of T2-weighted MS plaques and brain atrophy analyzed by MRI. RESULTS: After treatment, the mean proportions of VLA-4, LFA-1, and ICAM-1 on blood lymphocytes (p < 0.0003, p < 0.00001, p < 0.01) and monocytes (p < 0.0001, p < 0.0002, p < 0.007) of 23 patients decreased. The expression of these adhesion proteins was also diminished on CSF leukocytes. However, even after treatment, the levels of VLA-4 and LFA-1 on lymphocytes from blood of MS patients remained higher than in the control subjects. The level of VLA-4 and LFA-1 on blood lymphocytes (r=0.67, p=0.023) and VLA-4 on monocytes (r=0.61, p=0.047) correlated with the number of T2-weighted lesions. CONCLUSIONS: Megadose MP may suppress brain inflammation by reducing the expression of adhesion molecules on mononuclear cells from blood and CSF of MS patients. The inhibition of cellular trafficking in MS by MP offers an important means of altering the autoimmune response in MS.

Adult↗
PubMed1996

Subjective complaints of cognitive symptoms are related to psychometric findings of memory deficits in patients with HIV-1 infection.

Eighty-five subjects at various stages of human immunodeficiency virus (HIV-1) infection and 39 seronegative controls underwent neurological and neuropsychological evaluation to assess the relationship between cognitive test results and subjective complaints (cognitive, affective, motor, and other). The effect of psychiatric disorders on the association between cognitive performance and complaints of the patients was also examined. Patients with symptomatic infection had higher frequency of complaints than subjects at asymptomatic stage. Detailed neuropsychological examination confirmed a strong association between poor verbal memory and cognitive complaints. Poor performance on cognitive speed and flexibility was associated with motor complaints and motor abnormalities. These associations were not explained by psychiatric disorders or elevated depression questionnaire scores. Our observations indicate that, especially in symptomatic HIV-1 infection cognitive changes reported by patients often reflect "objective" cognitive decline, and may be the earliest signs of HIV-1 associated cognitive disorder. No direct relationship was observed between "subjective" complaints and neuropsychological performance of asymptomatic subjects. Understanding the significance of reported cognitive changes have important therapeutic implications.

AIDS Dementia Complex↗
PubMed1996

Cognitive decline in patients with symptomatic HIV-1 infection. No decline in asymptomatic infection.

Thirty-six HIV-1-infected predominantly well-functioning subjects were followed up for one year by repeated neuropsychological, clinical neurological, neuroradiological, and immunological examinations. Changes in cognitive performance related to the severity of HIV-1 infection as well as to neuroradiological or immunological changes were studied. A decline in cognitive speed and flexibility was found in symptomatic subjects (ARC, AIDS). The impairment was especially pronounced in patients with progression of brain atrophy. These findings suggest a brain pathology underlying the cognitive decline in ambulatory outpatients with symptomatic HIV-1 infection. A practice effect was found in asymptomatic subjects (ASX, LAS) and in those with unchanged CT/MRI scans. No systematic relationship was found between cognitive change and immunological change.

Adult↗
PubMed1995

Limited T cell receptor usage by HTLV-I tax-specific, HLA class I restricted cytotoxic T lymphocytes from patients with HTLV-I associated neurological disease.

T cell receptor (TCR) V alpha and V beta chain usage of HTLV-I tax-specific, HLA class I restricted CD8+ cytotoxic T cells (CTL) was determined from lymphocytes obtained from peripheral blood of patients with HTLV-I associated neurological disease. To characterize TCR repertoire, CD8+ lymphocytes from peripheral blood were cloned in limiting dilution, and the resulting wells were screened for HTLV-I-specific precursor CTL activity. RNA was isolated from HLA-A2 restricted HTLV-I tax peptide-specific (tax 11-19; LLFGYPVYV) CD8+ CTL lines and cDNA was analyzed by PCR amplification using V alpha and V beta chain family-specific oligonucleotide primers. The results indicate that CD8+ cytotoxic T cell lines from HLA-A2 HAM/TSP patients express a limited repertoire of T cell receptor chains which may correlate with duration and severity of disease. The restricted use of TCR genes expressed by antigen-specific CTL may play a critical role in the pathogenesis of HAM/TSP and may be of value in developing immunotherapeutic strategies that focus on eliminating these cells or inhibiting their activity.

Amino Acid Sequence↗
PubMed1995

Abundant expression of HIV Nef and Rev proteins in brain astrocytes in vivo is associated with dementia.

OBJECTIVE: To relate the expression of HIV regulatory proteins and HIV-specific mRNA in the brain cells of infected individuals with clinical neurological disease. DESIGN: Formalin-fixed postmortem brain tissue from 14 HIV-infected adult patients, with previous repeated neurological and neuroradiological examinations, was studied by immunohistochemical and molecular biological methods. Samples from non-infected brains served as controls. METHODS: Immunohistochemistry with monoclonal antibodies (MAb) was combined with in situ RNA hybridization. Target cells were identified with MAb to glial fibrillary acidic protein (GFAP; astrocytes), CD68 (activated macrophages) and Ricinus communis agglutinin (RCA-1; microglia, endothelial cells). For HIV, a panel of MAb against HIV Nef, Tat, Rev and Env proteins or probes specific for all classes of mRNA (nef), for singly or non-spliced mRNA (env) and for non-spliced mRNA (gag/pol) were used. RESULTS: Nef protein was detected in subcortical or subpial astrocytes in seven out of 14 samples, and in multinucleated giant cells in two cases. Gag/pol or env mRNA-expressing astrocytes were detected in four cases. In four out of five cases studied, HIV Rev, but not Tat, was also expressed in astrocytes. Six out of the seven patients with Nef-positive astrocytes had suffered from moderate to severe dementia. The patient with most rapidly progressing severe dementia showed extensive HIV mRNA expression together with Nef and Rev expression in astrocytes. CONCLUSION: In adult human brain, astrocytes are infected by HIV and preferentially express HIV Nef and Rev proteins but are also sometimes productively infected. Astrocyte infection is associated with moderate to severe dementia which agrees with recent knowledge on the housekeeping activities of astrocytes and their eventual role in learning and memory.

AIDS Dementia Complex↗
PubMed1994

Zidovudine reduces intrathecal immunoactivation in patients with early human immunodeficiency virus type 1 infection.

OBJECTIVE: To evaluate the effect of zidovudine on human immunodeficiency virus type 1 (HIV-1)-associated central nervous system infection in Centers for Disease Control and Prevention stage II or III disease. DESIGN: In an open-ended trial, patients received 500 mg of zidovudine twice a day for 12 months. Lumbar punctures, neurological, neuropsychological, and neuroradiological examinations were repeatedly performed during the trial period and were compared with pretrial values. In 11 patients post-trial neurological follow-up of 10 to 20 months was performed. PATIENTS: Initially, 14 volunteers with stage II or III disease and intrathecal synthesis of HIV-1-specific antibodies were enrolled. Additionally, patients had slight neuropsychological disturbance or brain atrophy unrelated to other agents than HIV-1. Two patients dropped out because of poor compliance. MAIN OUTCOME MEASURES: Intrathecal and systemic immune and virological responses, cognitive performance, and brain images were repeatedly monitored. RESULTS: After 6 weeks of zidovudine therapy, initial low-grade pleocytosis and elevated levels of beta 2-microglobulin, both in cerebrospinal fluid and in serum samples, declined. Intrathecal HIV-1 antibody synthesis could no longer be detected in half of the patients after 12 months of zidovudine therapy. Patients with defective cognition transiently improved cognitive speed and flexibility after 6 months of therapy. Slight atrophic brain changes, however, remained unchanged. CONCLUSIONS: Zidovudine reduces intrathecal immuno-activation and transiently improves cognitive functioning in HIV-1-infected subjects who show evidence of central nervous system involvement by HIV-1 but are otherwise asymptomatic.

Adult↗
PubMed1993

High human T cell lymphotropic virus type 1 (HTLV-1)-specific precursor cytotoxic T lymphocyte frequencies in patients with HTLV-1-associated neurological disease.

The frequencies of human T cell lymphotropic virus type 1 (HTLV-1)-specific CD8+ precursor cytotoxic T lymphocytes (pCTL) were quantitated from lymphocytes obtained from the peripheral blood and cerebrospinal fluid (CSF) of infected individuals with and without HTLV-1-associated neurological disease. An estimate of the pCTL was obtained by separating CD8+ cells, plating these cells in limiting dilution, and testing wells for HTLV-1 specific lysis. Targets consisted of autologous lymphoblastoid cell lines (LCL) infected with vaccinia constructs expressing HTLV-1 gene products or LCL pulsed with HTLV-1 synthetic peptides. In patients with HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), the frequency of HTLV-1 p40X-specific pCTL was at least 40-280-fold higher than in asymptomatic HTLV-1-infected individuals. All HAM/TSP patients (five of five) predominantly recognized HTLV-1 products encoded within the pX region. Lower pCTL to env were demonstrated in three patients, and only one of five HAM/TSP patients had pCTL to gag. A synthetic peptide corresponding to the tax region of HTLV-1 (peptide 11-19, amino acid sequence LLFGYPVYV) was recognized in association with human histocompatibility leukocyte antigen (HLA)-A2 in two HLA-A2 HAM/TSP patients with a high CD8+ pCTL frequency of 1/325 and 1/265, respectively. A second immunodominant region of HTLV-1 tax (peptide 90-55, amino acid sequence VPYKRIEEL) was identified to be restricted by HLA-B14 in two HLA-B14 HAM/TSP patients with a CD8+ pCTL frequency of 1/640 and 1/1,125, respectively. Lymphocytes from the CSF of a patient with HAM/TSP also showed a pCTL frequency against p40X of similar magnitude to that demonstrated from peripheral blood lymphocytes (PBL). The HLA-A2-mediated CSF pCTL activity to the immunodominant tax-specific peptide 11-19 was also comparable to pCTL from PBL. These results indicate that an extremely high pCTL frequency to HTLV-1 tax-encoded peptides may be related to pathogenesis of myeloneuropathy associated with HTLV-1.

Adult↗