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Biomedical subjects

A J Thompson

Publications and source records attributed to A J Thompson.

At least 235 records · Page 13Linked to original sources
PubMed1997

Spasticity, ataxia and fatigue in multiple sclerosis.

Multiple sclerosis frequently results in a wide range of symptoms which often coexist, creating a complex pattern of disability. Chief among these symptoms, both in relation to their frequency and their impact on the patient, are spasticity, ataxia and fatigue. This chapter discusses the pathological basis and current treatment of these symptoms and stresses the importance of a multidisciplinary approach to their management, producing a comprehensive care plan which incorporates these and any other coexisting problems.

Ataxia↗
PubMed1996

Double strand break-induced recombination in Chlamydomonas reinhardtii chloroplasts.

The mechanisms of chloroplast recombination are largely unknown. Using the chloroplast-encoded homing endonuclease I-CreI from Chlamydomonas reinhardtii, an experimental system is described that allows the study of double strand break (DSB)-induced recombination in chloroplasts. The I-CreI endonuclease is encoded by the chloroplast ribosomal group I intron of C.reinhardtii and cleaves specifically intronless copies of the large ribosomal RNA (23S) gene. To study DSB-induced recombination in chloroplast DNA, the genes encoding the I-CreI endonuclease were deleted and a target site for I-CreI, embedded in a cDNA of the 23S gene, was integrated at an ectopic location. Endonuclease function was transiently provided by mating the strains containing the recombination substrate to a wild-type strain. The outcome of DSB repair was analyzed in haploid progeny of these crosses. Interestingly, resolution of DSB repair strictly depended upon the relative orientation of the ectopic ribosomal cDNA and the adjacent copy of the 23S gene. Gene conversion was observed when the 23S cDNA and the neighbouring copy of the 23S gene were in opposite orientation, leading to mobilization of the intron to the 23S cDNA. In contrast, arrangement of the 23S cDNA in direct repeat orientation relative to the proximal 23S gene resulted in a deletion between the 23S cDNA and the 23S gene. These results demonstrate that C.reinhardtii chloroplasts have an efficient system for DSB repair and that homologous recombination is strongly stimulated by DSBs in chloroplast DNA.

Animals↗
PubMed1996

Resolution of left hemisphere cognitive dysfunction in multiple sclerosis with magnetic resonance correlates: a case report.

Cognitive impairment is common in multiple sclerosis and although deterioration has been observed in individual patients at the time of relapse, improvement in cognitive function in parallel with remission of neurological impairment has proved more difficult to document. We describe a 21-year-old women with a one-year history of relapsing remitting multiple sclerosis, who was admitted to hospital following a severe relapse which rendered her quadriplegic. Detailed psychometric assessment was carried out during relapse and on recovery of neurological function, eight weeks later. There were improvements in arithmetic, naming, and comprehension tasks. The patient had T2 weighted and gadolinium-enhanced magnetic resonance imaging and magnetic resonance spectroscopy. These showed a reduction in lesion size, lesion enhancement, and changes in brain chemistry which parallel the improvement in cognitive performance.

Journal Article↗
PubMed1996

The acid metabolite of ZD7114 is a partial agonist of lipolysis mediated by the rat beta 3-adrenoceptor.

Experiments were performed to characterise the lipolytic effects of the acid metabolite, ZM215001, ((S)-4-[2-hydroxy-3-phenoxy-propylamino-ethoxy] phenoxyacetic acid) of the putative beta 3-adrenoceptor agonist, ZD7114 ((S)-4-[2-hydroxy-3-phenoxy-propylamino-ethoxy]-N-(2-methoxyethyl) phenoxyacetamide) on isolated rat white adipocytes. ZM215001 was used for these studies since it is the predominant moiety after in vivo administration of ZD7114. The agonist properties of ZM215001 were assessed in comparison to the standard nonselective beta-adrenoceptor agonist (+/-)-isoprenaline and the beta 3-adrenoceptor-selective agonist BRL 37344. Isoprenaline, BRL 37344 and ZM215001 all stimulated the rate of free fatty acid release from isolated adipocytes with the order of potency being BRL > isoprenaline > ZM215001. The maximum effect of BRL 37344 was equivalent to that of isoprenaline, but ZM215001 achieved only 30% of the maximum isoprenaline response. ZM215001 competitively antagonised the lipolytic response to BRL 37344 (pA2 = 7.26), whereas the agonist effects of BRL 37344 were not antagonised competitively by the selective antagonists ICI 118551 and CGP 20712A, at concentrations which would be expected to block beta 1- and beta 2-adrenoceptors respectively. These results indicate that ZM215001 has low intrinsic activity at the rat adipocyte beta 3-adrenoceptor, and is a partial agonist of lipolysis in rat white adipocytes.

Adipocytes↗
PubMed1996

Rehabilitation of incomplete spinal cord pathology: factors affecting prognosis and outcome.

To determine the factors affecting the outcome of patients with incomplete spinal cord lesions, a retrospective study was performed of all such patients (n = 49) admitted to the neurorehabilitation unit of the National Hospital for Neurology and Neurosurgery, London, over a 2-year period. Disability on admission and discharge as measured by the Functional Independence Measure (FIM), change in disability, presence or absence of neurological recovery, patient age, level of the lesion and length of inpatient stay were the main outcome measures. Data were complete on 39 patients. There were 20 patients with cervical myelopathy, 15 with intrinsic cord abnormalities including syrinxes, 7 with spinal cord infarcts and 7 with other conditions such as tropical spastic paraparesis and hereditary paraparesis. Age ranged from 17 to 88 years (mean 53). Mean duration of stay was 40 days and the duration was related to the diagnosis. Nineteen of the patients made some neurological improvement, while all but one improved on the FIM. This functional gain did not correlate with the patients' age, initial disability or level of the lesion, but was related to the length of stay in the unit, and neurological improvement. We conclude that the needs of patients with progressive incomplete spinal cord lesions due to neurological disease differ from those of patients with acute traumatic spinal cord lesions and are best managed in a neurological rehabilitation unit. Efficacy appears to be related to neurological recovery and the duration of rehabilitation. This study underlines the value of combined neurological and rehabilitation expertise in the management of this patient group and the need to incorporate both disciplines in planning service provision.

Adolescent↗
PubMed1996

Patterns of disease activity in multiple sclerosis patients: a study with quantitative gadolinium-enhanced brain MRI and cytokine measurement in different clinical subgroups.

In this study we assessed the subclinical disease activity in 45 patients with primary progressive, secondary progressive or relapsing-remitting multiple sclerosis (MS). The patients had gadolinium-enhanced brain MRI scans, which were analysed using a semiquantitative method both for lesion load and for degree of enhancement. At the same time cerebrospinal fluid (CSF) and serum samples were collected and, from these, cytokine levels were measured in most cases by enzyme-linked immunoassay using commercially available kits. Enhancing lesions on MRI were found in 73% of the patients. The sensitivity of this test was greatly increased by our method of analysis as far as the primary progressive patients are concerned (70% vs 40% for conventional evaluation). CSF interleukin-1 beta (IL-1 beta) levels were above the normal range in 22% and IL-6 levels in 13% of patients, while tumour necrosis factor alpha (TNF-alpha) was undetectable or below the upper normal limits in all the samples tested. Serum IL-1 beta was above the normal limits in 40%, IL-6 in 42% and TNF-alpha in 7% of patients. No significant differences in cytokine profiles were found between the clinical subgroups. This study confirms the high sensitivity of gadolinium-enhanced MRI in detecting MS activity, which was further increased by our method of analysis. Longitudinal studies performed with more sensitive immunological techniques are needed to define better the relationship between cytokine, clinical and MRI data in MS patients.

Adult↗
PubMed1996

Multiple sclerosis: symptomatic treatment.

Reports of new therapeutic agents designed to suppress inflammatory processes in multiple sclerosis have excited much interest but, thus far, have had little influence on symptoms, disability and handicap in patients. The clinical application of recent advances in physical, pharmacological and surgical approaches to management will, at least in the medium-term future, therefore offer significantly greater opportunities for improving the quality of life of patients with multiple sclerosis. Here, symptomatic treatment of the whole range of difficulties encountered by patients with multiple sclerosis is reviewed in the context of the multidisciplinary strategy crucial to an optimal outcome.

Body Temperature↗
PubMed1996

Spinal cord atrophy and disability in multiple sclerosis. A new reproducible and sensitive MRI method with potential to monitor disease progression.

Recent MRI studies in multiple sclerosis have highlighted the potential importance of spinal cord atrophy (implicating axonal loss) in the development of disability. However, the techniques applied in these initial studies have poor reproducibility which limits their application in the serial monitoring of patients. The aim of this study was to develop a highly reproducible and accurate method for the quantification of atrophy. The technique we describe demonstrates an intra-observer coefficient of variation (scan-rescan) of only 0.8%. When applied to 60 patients with clinically definite multiple sclerosis there was a strong correlation between spinal cord area and disability measured by Kurtzke's Expanded Disability Status Scale (EDSS) (r = -0.7, P < 0.001). The correlation was graded providing evidence for a causal connection. At levels 3 and 8 of the EDSS we observed a reduction in average cord area of 12 and 35%, respectively. Given its reproducibility, the magnitude of the change detected and the strong correlation with disability, this new technique should prove to be a sensitive measure of progressive neurological deterioration and could be readily incorporated into imaging protocols aimed at monitoring therapy.

Adult↗
PubMed1996

Spinal MRI in patients with suspected multiple sclerosis and negative brain MRI.

Although MRI detects the white matter lesions of multiple sclerosis within the brain with high sensitivity, a minority of patients have normal brain MRI. We describe 20 patients, selected from over 170 who had undergone brain imaging with minimal (n = 12) or no (n = 8) abnormalities (median number of lesions = I, range, 0-3) but in whom spinal MRI was abnormal. Twelve had clinically definite or laboratory supported definite multiple sclerosis according to the Poser criteria; one had clinically probable disease and seven, not fulfilling the Poser criteria, were classified as possible multiple sclerosis. All had presented with symptoms and signs referable to the spinal cord or optic nerves. Eleven had a primary progressive course, eight relapsing-remitting and only one secondary progressive. Moderate or severe disability was the rule in the primary progressive cases; all the relapsing-remitting patients had minimal disability. All had at least one lesion visible in the spinal cord (median 2; range 1-6). In patients in whom the diagnosis of multiple sclerosis is not supported by abnormalities on brain MRI, imaging of the spinal cord can be of considerable value.

Adult↗
PubMed1996

Progressive cerebral atrophy in multiple sclerosis. A serial MRI study.

Recent studies of the spinal cord and cerebellum have highlighted the importance of atrophy in the development of neurological impairment in multiple sclerosis. We have therefore developed a technique to quantify the volume of another area commonly involved pathologically in multiple sclerosis: the cerebral white matter. The technique we describe extracts the brain from the skull on four contiguous 5 mm periventricular slices using an algorithm integrated in an image analysis package, and quantifies their volume. Intra-observer scan-rescan reproducibility was 0.56%. We have applied this technique serially to 29 patients with multiple sclerosis selected for an 18-month treatment trial with a monoclonal antibody against CD4+ lymphocytes (deemed clinically ineffective). A decrease in volume beyond the 95% confidence limits for measurement variation was seen in 16 patients by the end of the 18-month period. The rate of development of atrophy was significantly higher in those who had a sustained deterioration in their Kurtzke expanded disability status scale (EDSS) score compared with those who did not (respective means: -6.4 ml year-1 and -1.8 ml year-1, P < 0.05) but in both groups these changes differed significantly from baseline (P < 0.05). Baseline T2 lesion load, change in T2 lesion load over 18 months and the volume of new gadolinium enhancing lesions on monthly scans for the first 10 months showed no correlation with the development of atrophy. This study demonstrates that progressive cerebral atrophy can be detected in individual patients with multiple sclerosis, correlates with worsening disability and gives additional information to that obtained with conventional MRI. The effect of putative therapies aimed at preventing disability could be objectively assessed by this measure.

Adult↗
PubMed1996

New treatments for multiple sclerosis: a clinical perspective.

The steady flow of potential new treatments for multiple sclerosis continues with data resulting from studies ranging in complexity from early pilot trials to phase three studies. While this is in itself encouraging, interpretation of the data presented, and in particular evaluation of the potential clinical usefulness of an agent, is often less than straightforward. Improved understanding of the immunopathogenesis of multiple sclerosis and better trial design incorporation more appropriate and responsive outcome measures should be grounds for continuing therapeutic optimism.

Humans↗
PubMed1996

MRI dynamics of brain and spinal cord in progressive multiple sclerosis.

OBJECTIVE: To assess the usefulness of serial cord MRI in patients with progressive multiple sclerosis. METHODS: Monthly MRI of the brain and spinal cord with and without gadolinium enhancement was carried out in 19 patients with progressive multiple sclerosis (10 primary progressive, nine secondary progressive) over the course of one year. RESULTS: During this period there were 132 active lesions in the brain and only six in the cord. One hundred and twelve (85%) active brain lesions occurred in the secondary progressive group; three new cord lesions occurred in each group. In the secondary progressive group MRI activity was high in patients who had superimposed relapses, whereas in those who progressed without relapse and in the primary progressive group it was low. Cross sectional areas of the cord decreased at the C5 level in both groups, implying progressive atrophy of fibre tracts. There was no relation between either brain or cord MRI activity and change in disability over the study period. CONCLUSIONS: Although the detection of new lesions by frequent cord imaging using current technology has little role in the monitoring of disease activity in progressive multiple sclerosis, the serial measurement of cord cross sectional area may be important. There is also evidence to suggest that the mechanism underlying irreversible disability in patients with progressive multiple sclerosis may be different in patients who continue to relapse than in those who do not.

Atrophy↗
PubMed1996

Soluble E-selectin in multiple sclerosis: raised concentrations in patients with primary progressive disease.

OBJECTIVE: To determine whether concentrations of soluble E-selectin (sE-selectin), an immunological marker of endothelial activation, were correlated with gadolinium-DPTA enhancement on MRI in patients with multiple sclerosis. METHODS: Serial sE-selectin concentrations were measured in 28 patients with multiple sclerosis undergoing monthly gadolinium (Gd) enhanced MRI of the brain and spinal cord, and in 10 control subjects. C reactive protein (CRP), von Willebrand factor (vWF), and tumour necrosis factor-alpha (TNF alpha) were also determined. RESULTS: Primary progressive patients had significantly increased sE-selectin concentrations compared with the relapsing remitting and secondary progressive patients who had normal sE-selectin concentrations (22.2 (SD1 6.1) ng/ml v 9.8 (SD2.1) ng/ml and 7.7 (SD2.7) ng/ml, respectively, P = 0.03). This difference was attributable to five of the 10 primary progressive patients who had persistently raised sE-selectin concentrations, with relatively inactive MRI studies. No correlation could be found between sE-selectin concentrations and Gd enhancement on MRI, but a close correlation existed between mean concentrations of sE-selectin and TNF alpha (r = 0.71, P < 0.001). Despite raised sE-selectin and TNF alpha concentrations, primary progressive patients had normal CRP concentrations (1.03 (SD1.14) mg/l), which were significantly lower than the relapsing remitting (3.16 (SD2.54) mg/l) and secondary progressive patients (2.28 (SD2.1) mg/l, P = 0.03). Raised CRP concentrations did correlate with infectious episodes, clinical relapse, and Gd enhancement, and were significantly raised when no MRI activity was found. Concentrations of vWF were normal in all patient groups. CONCLUSIONS: The results further high-light the differences between patients with primary progressive and those with relapsing remitting/secondary progressive multiple sclerosis.

Adult↗
PubMed1996

A preliminary study into the sensitivity of disease activity detection by serial weekly magnetic resonance imaging in multiple sclerosis.

Long TR and gadolinium enhanced spin echo brain MRI was performed weekly for three months in three patients with relapsing-remitting or secondary progressive multiple sclerosis. During the study, 38 new enhancing lesions were seen; 11 showed enhancement for less than four weeks, and two enhanced on only one scan. All 16 new lesions seen on long TR scans showed initial enhancement. When only every fourth (monthly) scan was analysed, a total of 33 new enhancing lesions were seen. Subject to confirmation in a larger cohort, the results suggest: (a) that blood brain barrier leakage is an invariable event in new lesion development in relapsing-remitting and secondary progressive multiple sclerosis; (b) the small increase in sensitivity of weekly scanning does not justify its use in preference to monthly scanning when monitoring treatments.

Adult↗
PubMed1996

Clinical, CSF, and MRI findings in Devic's neuromyelitis optica.

OBJECTIVES: Since Devic's original description of neuromyelitis optica in 1894 there has been much debate regarding its aetiology. A specific cause has been identified in a minority of cases but in most the question has arisen whether or not Devic's neuromyelitis optica is a variant of multiple sclerosis. This study was undertaken to help clarify this issue. METHODS: Neuromyelitis optica was defined as (1) a severe transverse myelitis; (2) an acute unilateral or bilateral optic neuropathy; (3) no clinical involvement beyond the spinal cord or optic nerves, and (4) a monophasic or multiphasic illness. The clinical and autoantibody status was documented. Patients underwent CSF examination and MRI of brain and spinal cord. RESULTS: Twelve patients, with a mean age of presentation of 35.1 years, were seen. Eleven were women; vision was reduced to counting fingers or worse in 10 patients and seven became confined to a wheelchair. Examination of CSF showed local synthesis of oligoclonal bands in only two patients and a neutrophil pleocytosis in two. A possible aetiology was identified in five: a specific connective tissue disorder (two), pulmonary tuberculosis (one), and possible acute disseminated encephalomyelitis (two). Six had non-specific increases in various autoantibodies. Eleven patients underwent MRI of the brain and spinal cord. In 10 there were diffuse abnormalities involving cervical and thoracic cords with extensive swelling in the acute phase. Brain MRI was normal in five; in five there were multiple deep white matter lesions, and one patient had minor age related changes. CONCLUSION: It is proposed that Devic's neuromyelitis optica is a distinctive disorder with some clinical, CSF, and MRI features different from those found in classic multiple sclerosis. In most cases a specific aetiology is not identified, but an immunological mechanism of tissue damage seems likely.

Adolescent↗
PubMed1996

A phase II trial of anti-CD4 antibodies in the treatment of multiple sclerosis.

In multiple sclerosis (MS) myelin damage is the result of a chronic inflammatory process mediated by CD4 positive T helper/effector cells. In experimental allergic encephalomyelitis (EAE), the animal model of MS, treatment with anti-CD4 antibodies can prevent the onset of disease. Natural history studies have demonstrated that gadolinium enhanced magnetic resonance imaging (MRI) of the brain is more sensitive and objective in assessing inflammatory disease activity in MS than clinical monitoring, so that less patients and shorter studies suffice to reach the same statistical power as compared to trials using clinical outcome parameters. In this paper we describe the design of an exploratory trial of chimeric monoclonal anti-CD4 antibodies in the treatment of MS. For this study we chose the number of active MS lesions on monthly gadolinium enhanced MRI scans as the primary outcome measure.

Adolescent↗