Failure of allogeneic bone marrow transplantation to arrest disease activity in multiple sclerosis.

Multiple sclerosis (MS) is thought to be an autoimmune disease in which activated T-cells initiate a macrophage mediated destruction of CNS myelin. Bone marrow transplantation (BMT) is currently being evaluated in the treatment of MS in patients with aggressive disease activity. Autologous BMT could potentially reset the immune response to myelin antigens leading to immune tolerance and decreased disease activity. Allogeneic transplantation could reconstitute the immune system potentially arresting the progression of autoimmune disease. The purpose of this paper is to report a patient with MS who underwent allogeneic BMT for chronic myelogenous leukemia (CML) and showed continued evidence of active demyelinating disease by clinical and radiologic criteria over a period of two years. While this is only a single case report with inherent limitations, it suggests that the immune mediated destruction of CNS myelin in MS may not be prevented or aborted by immune system reconstitution, and is consistent with the idea that immune mediated tissue destruction in MS could be targeted against an abnormal antigen.

Identifying and treating patients with suboptimal responses.

Multiple sclerosis (MS) is an immune-mediated neurologic disease in which acute inflammatory events early in the disease course contribute to subsequent neurologic disability. The early relapsing inflammatory phase is followed by a progressive degenerative phase in which the frequency of acute inflammatory attacks diminishes but progressive loss of neurologic function continues. Current immune therapies are most effective in suppressing the acute inflammatory events that characterize the earlier stages of disease. Optimal suppression of these inflammatory events is likely to have the best potential for delaying or preventing loss of axons and decline in neurologic function. In view of these considerations, and because MS is a heterogeneous disease and response to disease-modifying agents (DMA) varies across individuals, it is important to identify suboptimal responders as early as possible to allow therapeutic modification while the opportunity to avert future loss of function remains. At present, no criteria for identifying suboptimal responders have been validated. In January 2004, a group of neurologists from 16 MS centers in the United States met to develop a consensus on criteria for defining suboptimal response for use in compelling clinical situations and to prompt clinical studies to validate the efficacy of these criteria. Consensus criteria included relapse rates of either 1/year or unchanged from pretreatment rates, incomplete recovery from multiple attacks, evolution of polyregional neurologic involvement, recurrent brainstem or spinal cord lesions, and cumulative loss of neurologic function sufficient to disrupt daily activities. The panel then considered the use of mitoxantrone for patients with worsening MS and a suboptimal response to DMA therapy.

Relationship between disease activity and dose-response relationships with beta interferon therapies in the treatment of multiple sclerosis.

Beta-interferon (IFNbeta) therapy in patients with multiple sclerosis has proven efficacious in the treatment of multiple sclerosis (MS). Numerous studies have demonstrated a decrease in relapse rates, decreases in new gadolinium enhanced lesions, slowed accumulation of disability, and decreases in the accumulation of lesion burden on T2 weighted MRI scans. There has been a heterogeneity of responsiveness to IFNbetas in individual patients. Responsiveness to IFNbeta therapy is discussed in view of pre-existing disease activity. Disease activity can be objectively measured using the frequency and volume of new gadolinium enhancing lesions. Disability may be dependent upon lesion location, frequency, and by the intensity of inflammation within lesions. The presence of a dose-response relationship with IFNbeta therapy in MS is supported by available data. Evidence is reviewed supporting the argument that responsiveness to IFNbeta therapy depends, in part, on pre-existing disease activity.

Cortical deficits in multiple sclerosis on the basis of subcortical lesions.

Patients suffering from multiple sclerosis have a high frequency of cognitive deficits usually attributable to demyelination and axonal loss in the subcortical white matter. Neurologic abnormalities referable to cortical function are uncommon but have been described. The present study describes three patients with clinically definite MS with deficits in cognitive function referable to cortical location. Two of the patients underwent positron emission tomography and showed profound cortical hypometabolism adjacent to subcortical white matter lesions seen on MRI. This paper points out that neurologic deficits referable to cortical sites may be caused by subcortical white matter lesions and that cognitive dysfunction in patients with MS may progress rapidly in the absence of motoria deficits or other evidence of clinical deterioration. Multiple Sclerosis (2000) 6 50 - 55

Interferon-beta1A-induced polyarthritis in a patient with the HLA-DRB1*0404 allele.

Human interferon-alpha (IFNalpha) and IFNbeta are administered for treatment of several diseases, including viral infections, malignancies, and multiple sclerosis (MS). IFNalpha therapy has been associated with the production of autoantibodies and the development of a variety of autoimmune disorders, including polyarthritis. This report describes the development of seronegative, symmetric polyarthritis in a patient with relapsing-remitting MS, after 8 weeks of therapy with IFNbeta1a. HLA phenotyping analysis of the patient revealed the presence of HLA-DRB1*0404, an allele known to be associated with the development of rheumatoid arthritis. Therefore, IFNbeta1a may have induced arthritis in a patient who was genetically predisposed to develop arthritis on the basis of HLA determinants. The English-language literature regarding IFNalpha- and IFNbeta-induced polyarthritis is reviewed, and possible mechanisms for IFNalpha- and IFNbeta-induced autoimmunity, including the contribution of HLA determinants and nitric oxide overproduction, are discussed.

Chronic progressive myelopathy: diagnostic analysis of cases with and without sensory involvement.

Chronic progressive myelopathies occurring in the absence of lesion dissemination continue to present a difficult diagnostic challenge. In the present study 19 patients with progressive myelopathy were evaluated retrospectively. Patients were divided into groups based on the presence or absence of sensory involvement. Thirteen patients had both motor and sensory involvement and only 6 had a pure motor syndrome. Of the 13 patients with sensory involvement seven (54%) had evidence of lesion dissemination and probable MS. Only 1/6 (16%) of those with pure motor syndromes had evidence of lesion dissemination. Those patients were more likely to suffer from hereditary spastic paraparesis or primary lateral sclerosis. It is suggested that patients with chronic progressive myelopathies involving both sensory and motor systems without evidence of lesion dissemination may have a variant of MS in which there is isolated involvement of the spinal cord.

Fibrosarcomatous metastasis the central nervous system with overt hemorrhage: case report and review of the literature.

Sarcomatous metastasis to the central nervous is generally considered uncommon and rarely shows evidence of hemorrhage. Consequently, patients with fibrosarcoma are rarely screened for metastatic disease in the central nervous system. We present a case of fibrosarcoma with metastasis to brain accompanied by overt hemorrhage into the tumor. It is suggested that patients with fibrosarcoma be routinely screened for metastasis to the central nervous system and that sarcomatous metastasis be considered in the differential diagnosis of hemorrhagic CNS tumors.

Rehabilitation of the stroke patient.

Research into stroke rehabilitation is an active area of investigation, and ample evidence suggests that patients with moderate deficits benefit from focused rehabilitation programs. Increasing age, stroke severity, and neuropsychological deficits are associated with a poor outcome. In this review we will discuss the most recent literature on stroke rehabilitation, with special emphasis on outcome predictors, motor recovery, and therapeutic strategies for aphasia and neuropsychological deficits.

Devic's neuromyelitis optica: a clinicopathological study of 8 patients.

We report the clinical, imaging, and laboratory features of 8 patients with Devic's neuromyelitis optica. All patients had severe myelopathy and optic neuritis. In no patient was the brain, the brainstem, or the cerebellum affected, even after several years of disease. Various immunosuppressive treatments failed to benefit the patients, 5 of whom died. Autopsies of these 5 patients demonstrated a severe necrotizing myelopathy with thickening of blood vessel walls and no lymphocyte infiltrates. In the appropriate clinical setting, the lack of white matter abnormalities demonstrated by magnetic resonance imaging of the head facilitates the recognition of Devic's syndrome during life. Inasmuch as Devic's myelopathy is necrotizing, rather than demyelinating, the prognosis of this syndrome is poor.

Transverse myelitis. Retrospective analysis of 33 cases, with differentiation of cases associated with multiple sclerosis and parainfectious events.

OBJECTIVE: A study was undertaken to determine whether cases of parainfectious-associated transverse myelitis (TM) and multiple sclerosis-associated TM could be distinguished on the basis of clinical criteria, radiologic features, or cerebrospinal fluid examination. A secondary objective was to determine the incidence of TM in a US population. DESIGN: A retrospective analysis of 33 cases was conducted. Cases were classified as being related to parainfectious multiple sclerosis, or spinal cord ischemia, or idiopathic. SETTING: All cases occurring in the Albuquerque, NM, area from 1960 through 1990 were reviewed. The population base was 500,000. OUTCOME MEASURES: Clinical presentation, radiologic features, cerebrospinal fluid, recovery of ambulation and bladder function, and recurrence rates were compared. RESULTS: Thirty-three patients satisfied study criteria, corresponding to an incidence of 4.6 per million per year. Forty-five percent of these cases were categorized as parainfectious, 21% as associated with multiple sclerosis, 12% as associated with spinal cord ischemia, and 21% as idiopathic. Patients with parainfectious TM suffered from spinal shock more frequently than did those with multiple sclerosis-associated TM. Patients with parainfectious TM showed evidence of spinal cord swelling, whereas patients with multiple sclerosis-associated TM had spinal cord plaques on magnetic resonance images but none showed swelling. Oligoclonal bands were absent in patients with parainfectious TM and present in three of five patients with multiple sclerosis-associated TM. CONCLUSIONS: Parainfectious TM may be distinguishable from that associated with multiple sclerosis on the basis of presentation, findings on imaging, and the presence of cerebrospinal fluid oligoclonal bands.

Kinetic reaction mechanism for magnesium binding to membrane-bound and soluble catechol O-methyltransferase.

Catechol O-methyltransferase (COMT, EC 2.1.1.6) from human brain occurs in both a membrane-bound (MB-COMT) and a soluble form (SOL-COMT). While these enzymes appear to be distinct molecular entities, both catalyze the O-methylation of catecholamines through an ordered reaction mechanism in which S-adenosylmethionine (SAM) is the leading substrate [Rivett, A. J., & Roth, J. A. (1982) Biochemistry 21, 1740-1742; Jeffery, D. R., & Roth, J. A. (1985) J. Neurochem. 44, 881-885]. Both MB-COMT and SOL-COMT require the presence of divalent cations for catalytic activity. This series of experiments provides evidence indicating that magnesium ions bind to both MB-COMT and SOL-COMT in a rapid equilibrium sequence prior to the addition of SAM. An equation is presented that predicts the qualitative results obtained in all kinetic experiments carried out with either MB-COMT or SOL-COMT.

Purification and kinetic mechanism of human brain soluble catechol-O-methyltransferase.

The soluble form of human brain catechol-O-methyltransferase (EC 2.1.1.6, COMT) has been purified approximately 4,000-fold from a 250,000 X g supernatant solution. The purified enzyme exhibits a molecular weight near 27,500 and a pI value equal to approximately pH 5.0. Initial velocity and product inhibition studies are consistent with an ordered reaction mechanism for soluble COMT. Tropolone, a dead-end inhibitor, exhibited a competitive pattern of inhibition when dopamine (DA) was the varied substrate and an uncompetitive pattern when S-adenosyl-L-methionine (SAM) was the varied substrate. These observations strongly suggest that the soluble form of COMT from human brain catalyzes the O-methylation of catecholamines via an ordered reaction mechanism in which SAM is the leading substrate. Since the membrane-bound form of COMT catalyzes the O-methylation of catecholamines through an identical reaction mechanism, these data provide further evidence that two forms of COMT, while being localized in distinct subcellular compartments, are quite similar in their molecular structure.

Characterization of membrane-bound and soluble catechol-O-methyltransferase from human frontal cortex.

Catechol-O-methyltransferase (COMT; E.C. 2.1.1.6) from human frontal cortex occurs in both a soluble and membrane-bound form. Attempts to solubilize the membrane-bound transferase by repeated washing or by extraction into solutions of high ionic strength were unsuccessful. The finding that Triton X-100 was capable of solubilizing membrane-bound COMT suggested that the membrane-bound transferase is an integral membrane protein. The membrane-bound and soluble enzymes did not differ in their requirements for magnesium ions or in their pH-activity profiles; both enzymes showed an optimum near pH 8.0 when assayed in phosphate buffer. In addition, the two enzymes did not differ in the degree of inhibition caused by CaCl2, both enzymes displaying 65% inhibition at 2.5 mM CaCl2. The competitive inhibitors tropolone and nordihydroguaiaretic acid displayed Ki values for the membrane-bound transferase five- to 10-fold lower than those observed for the soluble transferase. Solubilization of membrane-bound COMT in Triton X-100 resulted in an increase in the apparent Km value of the membrane-bound transferase for dopamine. The increase in Km appeared to be due to apparent competitive inhibition by Triton X-100 and reached a limiting value of approximately 80 microM. These results confirm that membrane-bound COMT is an integral membrane protein that may be structurally distinct from soluble COMT.

Reconstitution of turkey erythrocyte beta-adrenergic receptors into human erythrocyte acceptor membranes. Demonstration of guanine nucleotide regulation of agonist affinity.

Digitonin-solubilized turkey erythrocyte beta-adrenergic receptors were reconstituted by dialysis into human erythrocyte acceptor membranes which lack beta receptors. Incorporation of turkey beta receptors into acceptor membranes was directly proportional to the quantity of soluble protein added to the reconstitution system. Reconstituted beta receptors demonstrate saturable [125I]iodohydroxybenzylpindolol binding (Bmax = 11.1 +/- 0.8 fmol/mg, K = 77.8 +/- 8.6 pM) and stereospecificity ((-)-propranolol, K = 11.0 nM; (+)-propranolol, K = 2000 nM; (-)-isoproterenol, K = 250 nM; (+)-isoproterenol, K = 82 micro M). Reconstituted beta receptors appear to be incorporated into acceptor membranes as integral proteins. Reconstituted beta receptors cannot be extracted by high salt or pH (3 to 11); detergent is required for resolubilization of reconstituted beta receptors. Adenylate cyclase stimulation was not obtained in reconstituted membranes since acceptor membranes lack a catalytic subunit. However, guanine nucleotide regulation of agonist affinity was observed indicating a functional reconstitution. GTP (100 micro M) produces a 5-fold decrease in the affinity of isoproterenol for reconstituted beta receptors. Experiments with sulfhydryl reagents indicate that the reconstituted beta receptor couples with the guanine nucleotide regulatory protein of the acceptor membranes. These data describe the successful reconstitution of a beta receptor and indicate that the reconstituted beta receptor can interact with the GTP binding protein of human erythrocyte acceptor membranes.

Effects of chlordiazepoxide on comparable rates of punished and unpunished responding.

Identical overall rates and patterns of key pecking by pigeons were maintained under a multiple fixed-interval schedule of food presentation. In one component, every thirtieth response produced an electric shock (punishment) whereas during the other component the response that produced food had to be preceded by a pause of a minimum (10 or 11 s) duration. Although chlordiazepoxide (1.0--17.0 mg/kg) increased both punished and unpunished responding, greater increases were uniformly obtained with punished responding.