PubMed Health⌕ Search

Biomedical subjects

B Kalman

Publications and source records attributed to B Kalman.

At least 19 recordsLinked to original sources
PubMed2001

Spectrum and classification of inflammatory demyelinating diseases of the central nervous system.

The aim of this review is to highlight recent observations concerning the pathogenesis of acute and chronic inflammatory demyelinating diseases in the central nervous system. Without attempting to provide a didactic classification or a complete survey, we emphasize the discriminative nature of new clinical, imaging, and immunopathologic data, which, even in the absence of specific molecular markers, modify our views about the nosologic relations among these overlapping clinicopathologic entities. In the light of new findings, multiple sclerosis may represent a spectrum of demyelinating diseases rather than a single entity.

Animals↗
PubMed2000

Oxidative damage to mitochondrial DNA and activity of mitochondrial enzymes in chronic active lesions of multiple sclerosis.

Soluble products of activated immune cells include reactive oxygen species (ROS) and nitric oxide (NO) with a high potential to induce biochemical modifications and degenerative changes in areas of inflammation in the central nervous system (CNS). Previously, we demonstrated an increased production of ROS by activated mononuclear cells (MNC) of patients with multiple sclerosis (MS) compared to those of controls, and development of oxidative damage to total DNA in association with inflammation in chronic active plaques. The current study aimed to determine whether mitochondrial (mt)DNA is affected by oxidative damage, and whether oxidative damage to mitochondrial macromolecules (including mtDNA) is associated with a decline in the activity of mitochondrial enzyme complexes. Using molecular and biochemical methods we demonstrate a trend for impaired NADH dehydrogenase (DH) activity and a possible compensatory increase in complex IV activity in association with oxidative damage to mtDNA in chronic active plaques. Immunohistochemistry confirms the increase of oxidative damage to DNA predominantly located in the cytoplasmic compartment of cells in chronic active plaques. These observations suggest that oxidative damage to macromolecules develops in association with inflammation in the CNS, and may contribute to a decline of energy metabolism in affected cells. As observed in neurodegenerative diseases of non-inflammatory origin, decreased ATP synthesis can ultimately lead to cell death or degeneration. Therefore, elucidation of this pathway in MS deserves further studies which may identify neuroprotective strategies to prevent tissue degeneration and the associated clinical disability.

Adolescent↗
PubMed2000

Is Chlamydia pneumoniae present in brain lesions of patients with multiple sclerosis?

We investigated the presence of Chlamydia pneumoniae in 81 normal and pathological specimens obtained from postmortem brain tissues of patients with multiple sclerosis and with other neurological or nonneurological diseases. The assays used included PCR amplification of all DNA samples in the initial study. Culture and a second PCR amplification of the organism in a subset of 19 brain specimens were also performed in two separate laboratories. All results were negative. Thus, this study on a large number of brain tissues suggests that C. pneumoniae is not involved in inflammatory demyelination.

Brain↗
PubMed1999

Autoreactive IgG to intracellular proteins in sera of MS patients.

IgG binding to multiple protein constituents in lysates of Jurkat cells was detected by Western blot in sera of patients with multiple sclerosis (MS) and systemic lupus erythematosus (SLE). The distribution patterns of bands with sera tested against protein lysates from normal Jurkat cells or from Jurkat cells exposed to apoptosis or oxidative stress inducing conditions were similar in most patients, but with inter-individual differences. The number of bands with sera of both patient populations far exceeded those (0 or 2 bands) detected with sera of healthy controls. Proteinase K, RNase and DNase pre-treatment of cell lysates suggested a protein nature for all of the antigens and a ribonucleoprotein (RNP) nature for some of the antigens recognized by serum IgG of MS and SLE patients. Only two MS patients had positive anti-nuclear antibody (ANA) titers, while all of them had positive Western blots. In addition to similarities, dissimilarities were also recognized between the humoral immune responses in MS and SLE. No IgG molecules were detected against phosphorylated proteins in the sera of MS patients, while multiple phosphoproteins were recognized by IgG molecules of SLE patients in immunoprecipitation experiments. These data suggest that in addition to ANA, the sera of MS patients contain autoantibodies directed against multiple intracellular proteins. The protein recognition patterns of immunoglobulins in MS share similarities, but also have distinct features when compared to those in SLE. The biological significance of these autoantibodies in MS remains to be understood.

Antibodies, Antinuclear↗
PubMed1999

The activation of protein kinase C induces higher production of reactive oxygen species by mononuclear cells in patients with multiple sclerosis than in controls.

OBJECTIVE: Recent findings have increasingly shown the importance of reactive oxygen species (ROS) in causing oxidative damage to macromolecules and in contributing to tissue degeneration in target organs of autoimmune diseases. This study was aimed at comparing the base line and induced production of ROS by peripheral blood mononuclear cells (PB MNCs) of patients with multiple sclerosis (MS) in remission and relapse, of patients with other neurological diseases (OND) and of healthy controls. In addition, we analyzed the underlying mechanism of ROS production. METHODS: PB MNCs were separated from 28 MS patients in remission and 13 in relapse, and from 29 healthy controls and 10 OND. ROS was measured by spectrofluorometry. Expression of proinflammatory cytokines was assessed by semi-quantitative reverse transcription polymerase chain reaction (RT-PCR). Mitochondrial (mt) DNA haplotypes were determined by using restriction site polymorphism analysis. RESULTS: The base line and tumor necrosis factor (TNF)-alpha or interferon (IFN)-gamma induced ROS values were similar in the four groups, and the individual measures did not show a correlation with MS associated mtDNA haplotypes. Phorbol ester activation of protein kinase C (PKC) induced higher ROS production in all groups, however, with significantly greater values in the MS remission group. Calphostine C, a PKC inhibitor decreased or eliminated ROS production in a dose-dependent manner, suggesting further that it was predominantly or exclusively generated by PKC activated NADPH oxidase. A trend of increased TNF-alpha and IFN-gamma expression was noted in the MS relapse group, in contrast to the high ROS release in the MS remission group. CONCLUSION: The detected phase difference between the highest ROS production vs TNF-alpha expression is compatible with the hypothesis that different subpopulations of monocytes/macrophages are involved. We suggest that the ROS producing subpopulation preferentially migrates into the central nervous system (CNS) during a relapse. The present study together with our previous observation on oxidative damage to DNA in active plaques delineates a molecular pathway likely involved in the histologic evolution of inflammatory demyelination.

DNA, Mitochondrial↗
PubMed1999

The genetics of multiple sclerosis. A review.

Multiple sclerosis (MS) is characterized by chronic inflammation and demyelination in the central nervous system (CNS). Although the etiology of MS is unknown, both genetic and environmental contributions to the pathogenesis are inferred from epidemiologic studies. Geographic distributions and epidemics of MS and data from migration studies provide evidence for some, thus far unidentified, environmental effects. The co-occurrence of MS with high and low frequencies in ethnic groups often sharing an environment, the increased recurrence rate in families, and the high concordance rate among identical twins point to inheritable determinants of susceptibility. Based on the autoimmune hypothesis of demyelination, genetic studies sought associations between MS and polymorphic alleles of candidate genes which regulate either the immune response or myelin production. The most consistent finding in case-control studies was the association with the major histocompatibility complex (MHC) (also called human leukocyte antigen--HLA) class II, DR15, DQ6, Dw2 haplotype. Studies on other gene products encoded within or close to the MHC complex on chromosome 6p21.3 (e.g., HLA DP, complement components, transporter proteins, tumor necrosis factor, and myelin-oligodendrocyte glycoprotein) resulted in conflicting observations in different patient populations. The potential contribution of polymorphic alleles within the genes of the T-cell receptor alpha beta chains, immunoglobulins, cytokines, and oligodendrocyte growth factors or their receptors to MS susceptibility either remains equivocal or is rejected. Studies on families with multiple affected members have revealed that MS is a complex trait, that the contribution of individual genes to susceptibility is probably small, and that differences are possible between familial and sporadic forms. The development of molecular and computer technologies have facilitated the performance of comprehensive genomic scans in multiplex families, which have confirmed the possible linkage of multiple loci to susceptibility, each with a minor contribution. Several provisional sites were reported, but only 6p21 (MHC complex), 5p14, and 17q22 were positive in more than one study. The British update demonstrated segregation among regions of interest depending on DR15 sharing, and excluded a gene of major effect from 95%, and one with a moderate effect from 65% of the genome. The extended study by the US collaboration group revealed that the MHC linkage was limited to families segregating HLA DR2 alleles, which suggested that linkage to the MHC is related to the HLA DR2 association, and that sporadic and familial MS share at least one common susceptibility marker. Further identification of MS susceptibility loci may involve additional family sets, more polymorphic markers, and the exploration of telomeric chromosomal regions. Data from these studies may further elucidate pathogenic mechanisms of MS.

Chromosomes, Human, Pair 6↗
PubMed1999

Large scale screening of the mitochondrial DNA reveals no pathogenic mutations but a haplotype associated with multiple sclerosis in Caucasians.

We report the first large-scale screening of mitochondrial (mt) DNA in 77 Caucasian patients with relapsing-remitting or secondary progressive form of multiple sclerosis (MS) and in 84 Caucasian controls by using the method of restriction site polymorphism and haplotype analysis. No pathogenic mtDNA mutation was found in association with MS. However, mtDNA haplotypes K* and J* defined by the simultaneous presence of Ddel restriction sites at nucleotides 10,394 and 14,798 of the mtDNA in haplogroups K and J showed association with MS at a P-value of 0.001. A relative increase of MS patients compared to controls either with the J* or with the K* haplotype (+10,394Ddel/+14,798Ddel in haplogroup J or K) also was detected (each with a P<0.05). No distinct phenotypic characteristics of MS were observed when clinical data of patients with haplotypes K* or J* were analyzed. In addition to previous complete sequencing in several MS patients, the population screening of mtDNA presented here suggests that mtDNA point mutations are not likely to be involved in the pathogenesis of typical forms of MS. However, the mitochondrial genetic background (haplotype K* and J*) may moderately contribute to MS susceptibility. The reported association between MS and Leber's hereditary optic nerve atrophy, a disease caused by mtDNA point mutations preferentially occurring in haplogroup J, may be at least in part related to the overlapping mitochondrial genetic background of the two diseases.

Adult↗
PubMed1998

Is the mitochondrial DNA involved in determining susceptibility to multiple sclerosis?

An increasing number of case reports on Leber's hereditary optic neuropathy (LHON) associated mitochondrial (mt)DNA point mutations in patients with multiple sclerosis (MS) raised the possibility that mitochondrial determinants may contribute to genetic susceptibility to MS. These observations prompted many laboratories including ours to perform comprehensive sequencing or large scale screening of the mtDNA in MS patients. Here we review the available data arguing for or against a mitochondrial hypothesis for MS. We conclude that pathogenic mtDNA point mutations are not associated with typical forms of this disease. A very small subgroup of MS patients, usually with prominent optic neuritis (PON), may carry pathogenic LHON mutations. This partial overlap between the two diseases may be related to the association of MS with a mtDNA haplotype (a set of mtDNA polymorphisms) within which pathogenic LHON mutations preferentially occur.

Adolescent↗
PubMed1998

Oxidative damage to DNA in plaques of MS brains.

A major cause of clinical disability in multiple sclerosis (MS) is related to a degenerative process in the central nervous system (CNS) which ultimately develops from a potentially reversible inflammation and demyelination. The mechanism of this degenerative process within MS lesions is not completely understood. We hypothesize that oxidative damage to DNA secondary to inflammation may contribute to irreversible tissue alterations in a plaque. To test this assumption, we determined the level of a DNA oxidative marker, 8-hydroxy-deoxy-guanosine (8-OH-dG) in the normal appearing white matter (NAWM), plaque and cortical regions of cerebella from MS patients who suffered from severe cerebellar symptoms during the course of the disease, and in NAWM and cortical regions of cerebella from non-neurological controls. We found a significant increase in DNA oxidation within plaques compared to NAWM specimens in MS cerebella. A tendency for increase of oxidative markers in normal appearing cortical tissues located in the proximity of MS plaques was also observed when compared to those in control cortical specimens. Oxidative damage to DNA in MS lesions, and in neuron rich areas located in the proximity of these lesions is likely related to the release of reactive oxygen species (ROS) and nitric oxide (NO) during inflammation in the brain. This biochemical impairment of DNA and of other macromolecules may contribute to the development of severe clinical disability through the induction of degenerative changes within and outside of plaques in MS brains.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed1997

Pyrene excimer fluorescence as a proximity probe for investigation of residual structure in the unfolded state of human carbonic anhydrase II.

The excimer fluorescence from two pyrenyl moieties attached to cysteines in human carbonic anhydrase II has been monitored to characterize residual structure retained under strong denaturing conditions. A position in beta-strand 3, N67C, together with the single naturally occurring cysteine 206 in beta-strand 7, were used as attachment sites. The eximer formation by the pyrenyls, requiring proximity of the probes, revealed an unfolding transition at a GuHCl concentration significantly higher than that required to induce unfolding of the molten globule state as monitored by CD. These results indicate that the excimer transition monitors the unfolding of a residual compact structure that spans beta-strands 3-7. This region constitutes the central and the most hydrophobic part of the molecule, emphasizing the importance of hydrophobic interaction in maintaining residual structure under strong unfolding conditions.

Carbonic Anhydrases↗
PubMed1997

Biochemical and genetic studies in a family with mitochondrial myopathy.

We present a family with severe exercise intolerance, progressive proximal weakness, and lactic acidemia. Fifteen of 24 family members in five generations were affected. Since the affected males do not have offspring at this time, the family pedigree is consistent with either maternal or autosomal dominant inheritance. Muscle histochemistry showed ragged-red fibers and electron microscopy showed globular mitochondrial inclusions. Biochemical analysis showed reduced muscle activities of mitochondrial NADH-cytochrome c reductase (1 of 2 patients), succinate-cytochrome c reductase (2 patients), and cytochrome c oxidase (2 patients). For 1 patient, sequence analysis of 44% of the muscle mitochondrial DNA including all 22 transfer RNA regions showed no point mutation with pathogenic significance. Southern blot analysis showed no deletion. Six affected members of the family were treated with methylprednisolone (0.25 mg/kg) for 3 months. Muscle strength, serum lactate, and energy metabolism at rest (measured by 31P magnetic resonance spectroscopy) significantly improved with treatment.

Adolescent↗
PubMed1997

Impairment of central and peripheral myelin in mitochondrial diseases.

Clinical or sub-clinical impairment of central and peripheral myelin is often part of the overlapping multisystem disorders associated with a variety of mitochondrial (mt)DNA abnormalities. Suboptimal energy metabolism of the oligodendrocytes and Schwann cells carrying mitochondrial defects may cause insufficient production of myelin. Further, edema, vascular and toxic factors may directly damage myelin. The recognition that certain mtDNA point mutations are associated with inflammatory demyelination of the central nervous system suggests that additional mechanisms besides degeneration need to be considered in the development of some forms of myelin damage.

Central Nervous System↗
PubMed1997

Screening for Leber's hereditary optic neuropathy associated mitochondrial DNA mutations in patients with prominent optic neuritis.

Previous case reports demonstrated the presence of Leber's hereditary optic neuropathy (LHON) associated mitochondrial (mt) DNA mutations in patients presenting with prominent optic neuritis (PON). By screening the mtDNA, we have excluded the presence of these mutations in 22 patients with PON, indicating that the frequency of these mutations is less than 4.5% in our selected patient population. Reviewing the clinical data of these patients revealed that severe optic nerve atrophy developed in association with both the benign and the severely disabling form of Multiple Sclerosis (MS). This observation suggests that the prominent feature of ON in MS may be related to local factors or to a selective vulnerability of the optic nerve in some patients. However, it also may be consequence of a deleterious process associated with inflammatory demyelination in the central nervous system (CNS) of another, genetically probably distinct subgroup of severely disabled patients.

Adult↗
PubMed1996

Characterization of the mitochondrial DNA in patients with multiple sclerosis.

Mitochondrial DNA (mtDNA) abnormalities with primary pathogenic significance for optic nerve atrophy have been detected in inflammatory demyelinating conditions indistinguishable from multiple sclerosis (MS). However, the degree of involvement of mtDNA alterations in the pathogenesis of MS is not clear. To further clarify this question, we sequenced the entire mtDNA in three MS patients. A number of nucleotide alterations were defined relative to the standard mtDNA sequence in each patient. After excluding the silent mutations and common polymorphisms, eight unusual mtDNA variants within the ribosomal (r) RNA, transfer (t) RNA or protein encoding regions were identified and characterized. Two mutations remained as putative MS related alterations after screening a population of 49 patients and 63 controls for the presence of these mutations. An A to G transition at nucleotide (nt) 13966 causing a threonine to phenylalanine exchange in a non-conserved region of the ND-5 was detected in two independent MS patients and in none of the sixty-three controls or in any of the large control population in the literature. The second mutation of interest at 14798 is a T to C transition changing a phenylalanine to leucine in a relatively conserved domain of the cytochrome b. Although it is a known polymorphism, a tendency for prominent optic nerve involvement was observed among patients carrying this mutation. As we have performed the first complete mtDNA sequence analysis on MS patients, we conclude that MS may occur without mtDNA abnormalities of primary pathogenic significance. However, contribution of the mtDNA to genetic susceptibility or phenotypic presentation of MS is possible in certain subgroups of patients, and merits further investigation.

Adult↗
PubMed1996

The evolutionary relationship among Caucasian MS patients and controls.

Previous observations suggest that the mitochondrial (mt)DNA may confer susceptibility to multiple sclerosis (MS). However, the proportion of affected individuals and the range of contributing mtDNA abnormalities are unknown. To help clarify this question, we analyzed the first hypervariable D-loop sequences of the mtDNA in a group of randomly selected Caucasian MS patients, in MS patients with prominent optic neuritis (PON) and in controls. Phylogenetic analysis of these D-loop sequences revealed that individuals in both groups of patients are generally scattered in the Caucasian phylogeny. However, a small cluster of unrelated MS patients identified by this analysis suggests that a maternal lineage with MS relevant mtDNA sequences may exist, and merits a more comprehensive study.

Base Sequence↗
PubMed1995

Junctional region of the myelin basic protein-specific T cell receptor beta chain in mice.

Evidence for the existence of both conserved and diverse amino acid sequences in the junctional regions of the myelin basic protein (MBP)-specific T cell receptors (TCR) in mice is presented. The junctional region of the Nac1-11 MBP peptide-specific, H-2u-restricted TCR beta-chains is characterized by the utilization of similar amino acid sequences. In contrast, diverse junctional sequences within the TCR beta-chains of the p89-101 MBP peptide and H-2s-restricted T cell clones are reported. These findings demonstrate that a limited heterogeneity of the MBP-specific T cell clones does exist. However, it may not be universal even in inbred mouse strains.

Amino Acid Sequence↗