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N J Scolding

Publications and source records attributed to N J Scolding.

At least 19 recordsLinked to original sources
PubMed2000

Oligodendroglia are protected from antibody-mediated complement injury by normal immunoglobulins ("IVIg").

High-dose intravenous immunoglobulin (IVIg) treatment has become a promising immune therapy that can modulate the immune system at several levels, including the complement cascade. In relation to inflammatory demyelinating disease, there is some clinical evidence for the suppression of disease activity by IVIg, while a role in promoting remyelination after experimental myelin damage has been described. Antibody and complement deposition have been implicated in the immune attack in some cases of multiple sclerosis (MS), and to investigate the mechanisms of action of IVIg, we studied the effect of IVIg using the model of complement-mediated cell injury on oligodendroglia in vitro. There was no effect on direct complement lysis of the oligodendroglial cell line CG4, but antibody-dependent complement damage was inhibited in a dose-dependent manner by IVIg. These results were confirmed with primary cultures of oligodendrocyte precursor cells (OPC) and oligodendrocytes. The addition of excess C1, C3, and C4 did not influence the inhibitory effect of IVIg, implying that binding of these complement components does not play a role, in contrast to other experimental models of complement damage. F(ab')2 immunoglobulin fragments were at least partially responsible for the effect. We conclude that IVIg may be protective in antibody-mediated complement injury of oligodendrocytes and their progenitors, and that this effect is likely to be mediated via antibody binding, rather than interference with complement activation. Inhibition of inflammatory mechanisms, as opposed to a direct effect on remyelinating cells, may underlie the role of IVIg in promoting myelin repair in experimental models.

Animals↗
PubMed1999

Polyclonal immunoglobulins for intravenous use do not influence the behaviour of cultured oligodendrocytes.

Treatment studies in multiple sclerosis and the experimental murine model of Theiler's virus encephalomyelitis have suggested that intravenous immunoglobulins (IVIg) promote central nervous system remyelination. It is not clear if this results from a direct effect on myelinating oligodendroglial cells, or from suppression of the immune response permitting better endogenous repair. We systematically explored the effects of IVIg on various aspects of oligodendrocyte precursor cell (OPC) behaviour in vitro. Neither proliferation, differentiation nor migration of OPC was affected by IVIg. These results argue against a direct effect of IVIg on remyelination and are in favour of an indirect yet not clearly defined mechanism that supports remyelination.

Animals↗
PubMed1999

Identification of A2B5-positive putative oligodendrocyte progenitor cells and A2B5-positive astrocytes in adult human white matter.

Spontaneous remyelination of previously demyelinated axons is found in a substantial minority of acute and chronic lesions in multiple sclerosis. In the rodent, central remyelination restores saltatory conduction and helps restore limb function, and it seems likely that endogenous myelin repair contributes to neurological recovery in multiple sclerosis. However, the identity of the remyelinating cell remains enigmatic. Fully differentiated oligodendrocytes have very limited capacity for recapitulating their developmental activities and re-engaging myelination pathways. Proliferative oligodendrocyte progenitors--often known as O-2A cells because of their ability to differentiate in vitro into either oligodendrocytes or ("type 2") astrocytes--are, in contrast, extremely efficient at myelin repair either spontaneously, or after transplantation into the de- or dysmyelinated CNS. Oligodendrocyte progenitors are present in both developing and adult rodent CNS. We have previously demonstrated that proliferative oligodendrocyte progenitors are present in cultures prepared from the adult human CNS. Here, using fresh tissue print preparations, we report that cells with processes and the A2B5-positive immunophenotype of proliferative oligodendrocyte progenitors are present in situ in adult human white matter. This technique also reveals the occurrence of A2B5-positive astrocytes, a cell also not previously identified in the normal adult human CNS. In the light of the rodent data showing the importance of oligodendrocyte progenitors in myelin repair, our findings suggesting the presence of progenitors in the adult human brain may have significant implications for spontaneous remyelination in multiple sclerosis and other demyelinating conditions.

Adult↗
PubMed1999

Mechanisms of damage to myelin and oligodendrocytes and their relevance to disease.

Oligodendrocytes synthesize and maintain myelin in the central nervous system (CNS). Damage may occur to these cells in a number of conditions, including infections, exposure to toxins, injury, degeneration, or autoimmune disease, arising both in the course of human disease and in experimental animal models of demyelination and dysmyelination; multiple sclerosis is the commonest human demyelinating disorder. Conventional classical accounts of the pathology of this and other myelin diseases have given great insights into their core features, but there remain considerable uncertainties concerning the timing, means and cause(s) of oligodendrocyte and myelin damage. At present, therapeutic efforts largely concentrate on immune manipulation and damage limitation, an approach that has produced only modest effects in multiple sclerosis. One reason for this must be the limited understanding of the mechanisms underlying cell damage - clearly, successful therapeutic strategies for preserving the oligodendrocyte-myelin unit must depend on knowledge of how oligodendrocyte damage and death occurs. In this review, mechanisms of oligodendrocyte and myelin damage are considered, and attempts made to relate them to disease processes, clinical and experimental. The hallmarks of different cell death processes are described, and oligodendrocyte-myelin injury by cellular and soluble mediators is discussed, both in vitro and invivo. Recent developments concerning the pathological involvement of oligodendrocytes in neurodegenerative disease are summarized. Finally, these neuropathological and applied neurobiological observations are drawn together in the context of multiple sclerosis.

Cell Death↗
PubMed1999

Central nervous system sarcoidosis--diagnosis and management.

A series of 68 patients with neurosarcoidosis is reported, with particular emphasis on clinical aspects, diagnosis and treatment. A classification system based on clinical diagnostic probability is proposed, consisting of probable and definite disease, the latter being dependent on finding sarcoid granulomas on nervous system histology, which was obtained in 12 patients (18%). The role of investigations, including magnetic resonance imaging (MRI), chest radiography, Kveim skin test, Gallium 67 isotope scanning and cerebrospinal fluid (CSF) studies, is considered. Sixty-two percent of patients presented with nervous system disease, most commonly affecting the optic nerve and chiasm. Other common presentations included cranial nerve palsies, spinal cord and brainstem manifestations. Investigations yielding most diagnostic information included the Kveim test (41/48, 85% positive), raised CSF protein and/or cells (50/62, 81%) and gallium 67 scan (14/31, 45%). Eleven out of 29 patients (38%) patients showed meningeal enhancement on MRI scanning and 43% of scans demonstrated multiple white-matter lesions. Mean follow-up for the group was 4.6 years. Forty-seven patients were seen for > 18 months, and over half of these patients progressed despite corticosteroid and other immunosuppressive therapies. The benefit of a large patient database prospectively studied, with extended follow-up is discussed in order to learn more about prognosis and advance therapy in neurosarcoidosis.

Adrenal Cortex Hormones↗
PubMed1999

Microangiopathy of the brain and retina with hearing loss in a 50 year old woman: extending the spectrum of Susac's syndrome.

A 50 year old woman presented with a subacute onset of vertigo and diplopia followed by an encephalopathy with confusion, spasticity, ataxia, myoclonus, and multiple branch retinal arteriolar occlusions and unilateral sensorineural deafness. Brain biopsy confirmed multiple microinfarcts with no vasculitis. After the procedure she had a right iliofemoral deep vein thrombosis and was found to be heterozygous for the factor V Leiden mutation. She was treated with anticoagulants and made a marked recovery with no relapses 6 months after presentation. This case extends the age range at which Susac's syndrome can present, and raises the possibility that the condition may be associated with abnormalities of coagulation.

Brain↗
PubMed1998

Interferon-beta inhibits mitogen induced astrocyte proliferation in vitro.

The central nervous system response to injury and inflammation commonly includes astrocytosis. This process, which is manifest by astrocyte hypertrophy and proliferation, is particularly prominent in multiple sclerosis (MS), where in chronic lesions it may contribute to the lack of repair by restricting the migration of remyelinating cells. Interferon-beta (IFN-beta) modestly reduces the frequency of relapses in MS and may have a small effect on the accumulation of permanent disability. Here, we show that IFN-beta inhibits the in vitro proliferative response of rodent astrocytes to a wide variety of growth factors and cytokines. Although important species differences exist in these glial responses this previously unrecognised property of IFN-beta may have implications for reducing astrocytosis and thereby promoting endogenous repair.

Animals↗
PubMed1998

The expression of complement regulatory proteins by adult human oligodendrocytes.

In multiple sclerosis, infiltrating T lymphocytes and perivascular microglia may initiate demyelinating lesions, but a role for antibody and complement in the ensuing inflammatory damage to myelin and oligodendrocytes is likely. In most tissues, ubiquitously expressed complement regulatory proteins prevent autologous destruction, protecting host cells from the powerful cytolytic activity of activated complement. We have studied the surface expression of a comprehensive range of complement regulatory proteins by live adult human oligodendrocytes in vitro. Only DAF of the activation pathway regulators was expressed, not CR1 or MCP. Of the membrane attack pathway regulatory proteins, HRF was not expressed, while substantial heterogeneity of CD59 expression by oligodendrocytes was found. Clusterin expression was not found. A relative deficiency of protective complement regulatory proteins on human oligodendrocytes may contribute to their selective damage in multiple sclerosis.

CD59 Antigens↗
PubMed1998

Adult polyglucosan body disease associated with an extrapyramidal syndrome.

A 50 year old patient is described who presented with parkinsonism, frontal dementia, peripheral neuropathy, neurogenic bladder, and upper motor neuron signs. No improvement in objective measurements of extrapyramidal dysfunction were seen with an incremental apomorphine test or more prolonged oral dopamine challenge. Neurophysiology disclosed changes compatible with a diffuse axonal neuropathy and pathological examination of a length of sural nerve taken at biopsy showed multiple polyglucosan bodies characteristic of adult polyglucosan body disease (APGBD). This case underlines the diverse clinical presentation of this rare neurological disease and the importance of recognising the unusual association of clinical features in making the diagnosis. APGBD should be included in the differential diagnosis of parkinsonism unresponsive to dopaminergic therapy.

Adult↗
PubMed1997

beta-Interferon regulates the immunomodulatory activity of neonatal rodent microglia.

beta-interferon (beta-IFN) has both pro and anti-inflammatory properties, the balance of which leads to some suppression of disease activity in multiple sclerosis patients. Here, we examine the immunomodulation of neonatal rodent microglia, the principal CNS accessory cell, by beta-IFN and consider the interaction of beta-IFN and gamma-interferon (gamma-IFN). beta-IFN and gamma-IFN inhibit microglial proliferation. beta-IFN antagonises both gamma-IFN-induced upregulation of class II expression and the ability of gamma-IFN primed cells to mount a respiratory burst. In contrast, beta-IFN upregulates microglial Fc receptor expression and augments tumour necrosis factor alpha secretion from suboptimally stimulated microglia.

Adjuvants, Immunologic↗
PubMed1997

Beta-interferon and multiple sclerosis.

Interferon-beta (IFN-beta) is the first therapeutic intervention shown to alter the natural history of multiple sclerosis (MS), a relapsing then progressive inflammatory degenerative disease of the CNS. Since publication of the first randomized placebo-controlled trial of IFN-beta, and subsequent acquisition of US and European product licences for use in relapsing-remitting MS, the hopes and expectations of patients have been elevated greatly only to be dampened as more critical analysis of the trial results, in conjunction with the cost of treatment, led to marked limitations on prescription in several countries. IFN-beta is not a cure. Here we review what is known about the mechanisms of action of IFN-beta in demyelinating disease, and propose a possible model of action of IFN-beta in the treatment of MS.

Humans↗
PubMed1997

Cerebral vasculitis--recognition, diagnosis and management.

Cerebral vasculitis is a serious but uncommon condition which presents considerable difficulties in recognition, diagnosis and treatment. We studied eight consecutive patients in whom this diagnosis was made. Despite the great diversity of symptoms and signs, we noted three clinical patterns: (i) acute or sub-acute encephalopathy, (ii) a picture with some similarities to multiple sclerosis ('MS-plus'), and (iii) features of a rapidly progressive space-occupying lesion. The identification of these patterns may help recognition of cerebral vasculitis. The diagnostic value of four investigative procedures not previously studied in cerebral vasculitis was assessed: ophthalmological examination using low-dose fluorescein angiography with slit-lamp video microscopy of the anterior segment (abnormal in 4/5 patients); spinal fluid oligoclonal band analysis (abnormal in 3/6 patients); anti-neutrophil cytoplasmic antibody assay (abnormal in 3/8 patients); and indium-labelled white-cell cerebral imaging (positive in only one patient). Treatment was with steroid alone (n = 2) or steroid with cyclophosphamide (n = 6). Seven patients responded clinically.

Adult↗
PubMed1997

Remyelination in demyelinating disease.

In multiple sclerosis, partial remyelination is conspicuous in many lesions, and is thought to contribute significantly to lasting recovery from acute relapse. However, myelin repair ultimately fails during progression of the disease, as disability and handicap accumulate. In this chapter we explore the biological background to myelin repair in CNS demyelinating disease, and the reasons underlying the failure of more widespread and lasting remyelination in multiple sclerosis. Experimental studies provide clear evidence that therapies promoting myelin repair can be highly successful in the CNS, and we discuss the clinical approaches which might allow the translation of these laboratory studies to neurological practice, together with some of the potential hazards and pitfalls likely to arise.

Animals↗
PubMed1996

Wolfram syndrome: hereditary diabetes mellitus with brainstem and optic atrophy.

Wolfram syndrome was originally described as a combination of familial juvenile-onset diabetes mellitus and optic atrophy. Other neurological features subsequently emerged, and "DIDMOAD" (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness) became a commonly accepted acronym. Here, we describe 4 further cases from 2 families, in whom there occurred previously unrecognized neurological features, central apnea and neurogenic upper airway collapse, together precipitating primary respiratory failure (fatal in 1 case), startle myoclonus (in 2 unrelated cases), axial rigidity, and Parinaud's syndrome. Magnetic resonance images revealed striking brainstem atrophy affecting, in particular, the pons and midbrain. The mitochondrial DNA from 3 cases (and relatives) showed no evidence of any of the previously reported abnormalities. These neurological and neuroradiological features, in conjunction with (1) analyses showing the neurodegenerative origin of optic atrophy, deafness, diabetes insipidus, and incontinence, (2) other previously reported neurological complications (including anosmia, ataxia, epilepsy, and neuropsychiatric and cognitive abnormalities), and (3) the very small number of published postmortem studies, indicate that Wolfram syndrome should be reemphasized as a unique hereditary neurodegenerative disorder with prominent optic atrophy and diabetes mellitus.

Adolescent↗
PubMed1995

A proliferative adult human oligodendrocyte progenitor.

The failure of oligodendrocytes to sustain repair of demyelinated axons contributes to the cumulative neurological disability which characterizes multiple sclerosis. In the rodent, transplanted neonatal glial progenitors efficiently remyelinate gliotoxic lesions. Proliferative bipotential progenitors are also present in the adult rat, but have not hitherto been identified in adult human tissue. Here we demonstrate cells in cultures of adult human temporal lobe which are morphologically and immunocytochemically identical to rate progenitors, are bipotential, and exhibit an astrocyte-driven proliferative response. The identification of an adult human oligodendrocyte progenitor is the first step towards developing interventional strategies for promoting repair of demyelinated lesions in patients with multiple sclerosis.

Astrocytes↗
PubMed1995

Growth factors fail to protect rat oligodendrocytes against humoral injury in vitro.

CNS growth factors protect neurons and glia against a wide variety of insults in vitro and in vivo by mechanisms which include buffering toxic rises in intracellular calcium. Cytosolic calcium elevation also plays a key role in complement injury, but the possibility that growth factors protect against antibody-mediated complement attack has not hitherto been addressed. In multiple sclerosis, antibodies and complement appear to contribute to the selective targeting and damage of oligodendrocytes and myelin. Here we have investigated the possibility that growth factors active in oligodendrocyte development and differentiation might protect these cells against injury mediated by antibody and complement in vitro. None was found to be protective.

Animals↗
PubMed1995

Auctioneer's jaw: a case of occupational oromandibular hemidystonia.

An auctioneer is described in whom focal dystonia of the jaw developed as an occupational symptom, occurring solely and predictably when he commenced his selling "patter" and resolving quickly on stopping. He responded well to treatment with intramuscular botulinus toxin.

Adult↗