Biomedical subjects

E J Thompson

Publications and source records attributed to E J Thompson.

At least 37 records · Page 2Linked to original sources

PubMed2004

Herpes simplex encephalitis: an audit of the use of laboratory diagnostic tests.

BACKGROUND: The combination of both PCR and intrathecal antibody studies is recommended to confirm or refute the diagnosis of herpes simplex encephalitis (HSE). AIM: To investigate the pattern of use of laboratory tests in the diagnosis of suspected cases of HSE, and to determine the final diagnosis in cases proven not to be HSE. DESIGN: Structured audit. METHODS: We reviewed the case-notes of all patients who, over a five-year time period, presented with suspected encephalitis; and/or were prescribed aciclovir. Clinical and laboratory criteria were used to categorize the likelihood of HSE. RESULTS: We identified 222 patients: 10 (5%) had definite HSE, 24 (10%) possible HSE, and 144 (65%) a definite alternative diagnosis. In 44 (20%), no final diagnosis was made, but the diagnosis of HSE was excluded. PCR was performed in 68 (31%), intrathecal antibody studies in 24 (11%), and brain biopsy in 17 (8%). A wide range of diseases mimicked HSE, but most common were inflammatory diseases and other infections of the central nervous system. DISCUSSION: Laboratory tests, particularly intrathecal antibody assays, are under-used in the diagnosis of HSE. Although early empirical treatment of suspected HSE is essential, confirmation or exclusion of the diagnosis is equally important to avoid overlooking alternative diagnoses. Identification of the aetiology of encephalitis is of particular importance, given the current concerns of emerging infections and bioterrorism.

Acyclovir↗

PubMed2004

Cerebrospinal fluid levels of brain specific proteins in optic neuritis.

This study evaluates levels of cerebrospinal fluid (CSF) brain-specific proteins (BSP) in subjects with optic neuritis (ON) who are at high risk of progression to multiple sclerosis (MS). Forty-one subjects had acute ON and 17 subjects with other neurological diseases (OND) served as controls. Twenty-one subjects with ON had white matter lesions on magnetic resonance imaging (MRI) and intrathecal synthesis of oligoclonal IgG bands (OB) consistent with being at high risk of progression to MS; eight of whom later were diagnosed with clinically definite MS (CDMS). Levels of S100B, ferritin and two neurofilament heavy chain phosphoforms (NfH(SM134) and NfH(SM135)) were analysed using ELISA technique. A putative index of 'axonal health' was expressed as a ratio of NfH(SM134) to NfH(S135). NfH(SM134) and the NfH(SM134:SM135) were significantly elevated in subjects with ON compared to controls. No significant differences in levels of CSF BSP were seen between ON subjects with CDMS plus those at high risk of progression to MS and ON subjects with normal MRI and negative CSF analysis. In conclusion, there is evidence of axonal damage in subjects who present with ON, which is independent of the diagnosis of CDMS.

Adult↗

PubMed2004

Treatment response in relation to inflammatory and axonal surrogate marker in multiple sclerosis.

BACKGROUND: This study aimed to investigate if treatment response could retrospectively be related to inflammatory or axonal pathology as measured by plasma surrogate markers. METHODS: In this 1-year observational study 30 multiple sclerosis (MS) patients with relapsing-remitting disease were treated with intramuscular IFNbeta-1a or subcutaneous IFNbeta-1b. Responders and nonresponders were defined according to clinical and magnetic resonance imaging criteria. The control group consisted of 14 healthy subjects. Plasma levels of surrogate markers for inflammation (nitric oxide metabolites (NOx)), astrocytic activation (S100B) and axonal damage (NfH(SM135)) were measured using standard assays. RESULTS: There were 11 nonresponders and 19 responders to IFNbeta treatment. Median S100B levels were elevated in a higher proportion of treatment responders (63%, 42.9 pg/mL) compared to nonresponders (18%, 11.7 pg/mL, P < 0.05, Fisher's exact test) and controls (0%, 2 pg/mL, P < 0.001). Levels of NOx were found to be more frequently elevated in nonresponders (72%, 39 microM) compared to healthy controls (0%, 37 microM, P < 0.05). Levels of NfH(SM135) were more frequently elevated in responders (58%, 300 pg/mL, P < 0.001) and nonresponders (72%, 500 pg/mL, P < 0.001) compared to controls (0%, 4.5 pg/mL). CONCLUSION: Patients with relapsing-remitting MS who had surrogate marker supported evidence for astrocytic activation responded more frequently to treatment with IFNbeta.

Adjuvants, Immunologic↗

PubMed2004

Chlamydophila pneumoniae infection of the central nervous system in patients with multiple sclerosis.

BACKGROUND: Chlamydophila pneumoniae has been postulated as an aetiological agent in the pathophysiology of multiple sclerosis. Previous studies show conflicting results. OBJECTIVE: To investigate patients with multiple sclerosis and other neurological diseases for evidence of past or present infection with C pneumoniae. METHODS: 19 patients with multiple sclerosis and 29 with other neurological diseases were studied. Evidence was sought for past or present infection with C pneumoniae using polymerase chain reaction (PCR) and cell culture of cerebrospinal fluid (CSF), and enzyme linked immunosorbent assay and microimmunofluorescence of serum. RESULTS: C pneumoniae was grown from the CSF of one patient with multiple sclerosis. PCR was negative in all cases. Anti-chlamydial antibodies were detected in the same proportion in each group. CONCLUSIONS: This study does not support the theory of an association between C pneumoniae and multiple sclerosis.

Adult↗

PubMed2003

Cerebrospinal fluid (CSF) and serum S100B: release and wash-out pattern.

S100B is an important brain specific protein for monitoring damage and activation of astrocytes. Using a straight forward, non-resource demanding in-house ELISA technique we measured S100B in cerebrospinal fluid (CSF) and serum in patients with traumatic brain injury (TBI) (serum), subarachnoid hemorrhage (SAH) (CSF, serum), intracranial hemorrhage (ICH) (CSF, serum), normal controls (NC) (serum) and a reference population (CSF, N=409). The release and wash-out pattern found in CSF and serum are discussed in relation to the three main determinants for increased brain specific protein levels in body fluids: (i) total mass effect; (ii) pathology; and (iii) time effect.

Adult↗

PubMed2003

Serum and urine nitrate and nitrite are not reliable indicators of intrathecal nitric oxide production in acute brain injury.

This study examined the correlation between nitric oxide (NO) metabolites in the three major body fluid compartments and assessed performance of newly described vanadium-based assay for simultaneous detection of nitrite and nitrate (NO(x)) in human samples. Vanadium reduces nitrate to nitrite, which can be measured after a colorimetric reaction with Griess reagents. Cisternal cerebro spinal fluid (CSF), serum and urine samples from 10 patients with acute brain injury (ABI) were compared to control subjects. Significantly higher CSF NO(x) levels were found in brain injury patients compared to control patients (19.7+/-13.7 vs. 6.5+/-2.3 microM; p=0.01), which persisted for 10-day period of observation. The serum and urine levels of NO(x) on admission were not statistically different (42.8+/-28.2 microM; 584.1+/-337.8 micromol/g Cr, respectively) from controls (36.8+/-14.8 microM; 819.7+/-356.0 micromol/g Cr), but tended to decrease during the disease course reaching the lowest level on day 6 (serum: 19.3+/-8.4 microM, urine: 300.4+/-111.9 micromol/g Cr). CSF levels of NO(x) correlated moderately with those in serum (p=0.001, R=0.5). Serum NO(x) concentrations correlated weakly with urine levels (p=0.04, R=0.3). There was no significant correlation between CSF NO(x) and urine NO(x) levels. In conclusion, patients suffering brain injury had increased NO(x) concentrations in CSF, which remained independent from other body fluid compartments. Serum and urinary NO(x) levels cannot be used as a reliable index to assess intrathecal NO production.

Adult↗

PubMed2003

Multiple sclerosis: Neurofilament light chain antibodies are correlated to cerebral atrophy.

OBJECTIVE: To evaluate markers of axonal damage in CSF and serum of patients with different subtypes of MS in relation to measures of disease progression on MRI. METHODS: In 51 patients with MS (21 relapsing-remitting, 20 secondary progressive, 10 primary progressive), levels of heavy and light neurofilaments (NfH and NfL) and antibodies to neurofilaments (anti-NfL and -NfH) as well as the total immunoglobulin G (IgG) were analyzed. MRI analysis included T2 hyperintense, T1 hypointense, and gadolinium enhancing lesions and markers of cerebral atrophy (ventricular and parenchymal fractions). RESULTS: For the total group, correlations were found between the anti-NfL index and the parenchymal fraction (PF) (r = -0.51, p < 0.001), T2 lesion load (r = 0.41, p < 0.05), ventricular fraction (r = 0.37, p < 0.05), and T1 lesion load (r = 0.37, p < 0.05). For the anti-NfH index, a correlation was found with the PF (r = -0.39, p < 0.05). No correlations were found between the IgG index and MRI measures. CONCLUSIONS: Intrathecal production of anti-NfL antibodies may serve as a marker of tissue damage, particularly axonal loss, in MS.

Adult↗

PubMed2003

Cerebrospinal fluid S100B correlates with brain atrophy in Alzheimer's disease.

S100B is a predominantly astrocytic protein with dose-dependent cytotoxic and neurotrophic properties encoded on chromosome 21q22.3. Concentrations of S100B were measured in the cerebrospinal fluid (CSF) of 31 patients with Alzheimer's disease (AD), 36 patients with frontotemporal lobe dementia (FTLD) and 49 patients with other non-inflammatory neurological diseases. Additional CSF S100B concentrations were correlated with normalised brain volume measurements in AD and FTLD. CSF S100B was significantly higher in AD (Mean+/-standard deviation=0.4+/-0.2 ng/ml) and FTLD (0.42+/-0.19 ng/ml) patients when compared with control subjects (0.25+/-0.08, P<0.001). In patients with AD, S100B correlated negatively with normalised brain volume (R(S)=-0.53, P<0.001). No such correlation was found for FTLD patients. This study supports the concept that S100B is of pathological relevance for degeneration of the central nervous system in AD.

Adult↗

PubMed2003

A specific ELISA for measuring neurofilament heavy chain phosphoforms.

Neurofilaments (Nf) are the major constitutents of the axoskeleton and body fluid Nf levels are an important tool for estimating axonal degeneration in vivo. This paper presents a new sandwich ELISA allowing quantification of the NfH(SMI35) phosphoform from CSF, brain tissue and cell culture homogenates. The sensitivity of the NfH(SMI35) ELISA is 0.2 ng/ml with a recovery of 119% and a mean within- and between-batch precision of 10.6% and 23%, respectively. CSF NfH(SMI35) was stable at 4 degrees C, is not influenced by freeze-thaw cycles, and proteolysis present at room temperature could be prevented by adding protease inhibitors. Aggregate formation was observed for HPLC-purified bovine NfH and could be resolved by sonication. The upper reference value for CSF NfH(SMI35) levels (0.73 ng/ml) was defined as the 95% cumulative frequency from 416 CSF samples. Based on this cutoff, a significantly higher proportion of patients with amyotrophic lateral sclerosis, space-occupying lesions, disc prolapse and subarachnoid haemorrhage had pathologically elevated NfH(SMI35) levels compared to patients with cluster headache or demyelinating disease.A new nomenclature is proposed to facilitate the comparison between ELISA, immunoblotting and immunocytochemistry.

Animals↗

PubMed2003

Herpes simplex encephalitis. A study of seven patients and their immunological response prior to routine acyclovir treatment.

OBJECTIVES: A retrospective study on cerebrospinal fluid (CSF) samples was made possible by access to a large CSF bank, which has been supplemented by the well characterised prior collection of CSF from patients with Herpes simplex encephalitis (including serial samples from some patients and kindly donated by Professor Maurice Longson, Manchester). These samples are of particular interest because they were collected prior to the routine administration of acyclovir. METHODS: Although an earlier study had shown that there was indeed a correlation between higher titres of antibody and a better outcome, the data did not emerge with statistical significance. The current study was based upon an improved method, which demonstrates the antigen-specific clonality of the immune response. RESULTS: The primitive polyclonal anamnestic response was contrasted with the strong antigen-specific response, which was manifested by a monoclonal pattern in some patients. A clear distinction emerged between two sub-groups of patients on the basis of these findings, which showed a statistically significant (P<0.03) correlation with outcome. CONCLUSIONS: This has allowed us to further support the hypothesis that a strong immunological response has positive prognostic value during the course of the disease.

Acyclovir↗

PubMed2003

Quantification of neurodegeneration by measurement of brain-specific proteins.

Quantification of neurodegeneration in animal models is typically assessed by time-consuming and observer-dependent immunocytochemistry. This study aimed to investigate if newly developed ELISA techniques could provide an observer-independent, cost-effective and time-saving tool for this purpose. Neurofilament heavy chain (NfH(SM135)), astrocytic glial fibrillary acidic protein (GFAP), S100B and ferritin, markers of axonal loss, gliosis, astrocyte activation and microglial activation, respectively, were quantified in the spinal cord homogenates of mice with chronic relapsing experimental allergic encephalomyelitis (CREAE, n=8) and controls (n=7). Levels of GFAP were found to be threefold elevated in CREAE (13 ng/mg protein) when compared to control animals (4.5 ng/mg protein, p<0.001). The inverse was observed for NfH(SM135) (21 ng/mg protein vs. 63 ng/mg protein, p<0.001), ferritin (542 ng/mg protein vs. 858 ng/mg protein, p<0.001) and S100B (786 ng/mg protein vs. 2080 ng/mg protein, N.S.). These findings were confirmed by immunocytochemistry, which demonstrated intense staining for GFAP and decreased staining for NfH(SM135) in CREAE compared to control animals. These findings indicate that axonal loss and gliosis can be estimated biochemically using the newly developed ELISA assays for NfH(SM135) and GFAP. These assays may facilitate the quantification of pathological features involved in neurodegeneration.

Animals↗

PubMed2003

Cross-reactivity between related sequences found in Acinetobacter sp., Pseudomonas aeruginosa, myelin basic protein and myelin oligodendrocyte glycoprotein in multiple sclerosis.

To investigate the possible role of molecular mimicry to bacterial components in multiple sclerosis (MS) pathogenesis we examined antibody responses to mimicry peptide sequences of Acinetobacter, Pseudomonas aeruginosa and myelin components. Antibodies to mimicry peptides from Acinetobacter (p<0.001), P. aeruginosa (p<0.001), myelin basic protein (MBP) (p<0.001) and myelin oligodendrocyte glycoprotein (MOG) (p<0.001) were significantly elevated in MS patients compared to controls. Antisera against MBP (residues 110-124) reacted with both Acinetobacter and Pseudomonas peptides from 4- and gamma-carboxymuconolactone decarboxylase, respectively. MOG (residues 43-57) antisera reacted with Acinetobacter peptide from 3-oxo-adipate-CoA-transferase subunit A. The role of these bacteria in MS is unclear but demonstrates that molecular mimicry is not restricted to viruses suggesting bacterial infections could play a role in MS pathogenesis. Further work is required to evaluate the relevance of these cross-reactive antibodies to the neuropathology of MS.

Acinetobacter↗

PubMed2002

Anti-basal ganglia antibodies in acute and persistent Sydenham's chorea.

OBJECTIVE: To determine the sensitivity and specificity of methods to detect anti-basal ganglia antibodies (ABGA) in Sydenham's chorea (SC). BACKGROUND: SC is a delayed manifestation of group Abeta hemolytic streptococcal infection typically associated with rheumatic fever (RHF). SC is characterized by chorea and motor and neuropsychiatric symptoms. Patients with SC produce antibodies that cross-react with streptococcal, caudate, and subthalamic nuclei antigens detected using an immunofluorescent (IF) method with inconsistent reports of positivity. METHODS: The authors developed ELISA and Western immunoblotting (WB) methods to detect ABGA and compared these assays to IF. They investigated samples from patients with acute SC (n = 20), persistent SC (n = 16), control samples from RHF (n = 16), and healthy pediatric volunteers (n = 11). RESULTS: ABGA ELISA had a sensitivity of 95% and specificity of 93% in acute SC. Both WB and IF had a sensitivity of 100% and specificity of 93%. In the persistent SC group, ABGA sensitivity dropped to 69% using WB and to 63% using IF. Three common basal ganglia antigens were identified by WB in both acute and persistent SC (40 kDa [n = 15], 45 kDa [n = 15], and 60 kDa [n = 13]). There was no antibody reactivity to cerebellum, cerebral cortex, or myelin antigen preparations in any group. CONCLUSIONS: These results support the hypothesis that Syndenham's chorea is an autoantibody-mediated disorder. Western immunoblotting and immunofluorescence are the best methods for detecting anti-basal ganglia antibodies, and reactivity to basal ganglia antigens of 40, 45, and 60 kDa were commonly seen in both acute and persistent cases of SC.

Acute Disease↗

PubMed2002

Markers for different glial cell responses in multiple sclerosis: clinical and pathological correlations.

Disease progression in multiple sclerosis occurs within the interface of glial activation and gliosis. This study aimed to investigate the relationship between biomarkers of different glial cell responses: (i) to disease dynamics and the clinical subtypes of multiple sclerosis; (ii) to disability; and (iii) to cross-validate these findings in a post-mortem study. To address the first goal, 51 patients with multiple sclerosis [20 relapsing remitting (RR), 21 secondary progressive (SP) and 10 primary progressive (PP)] and 51 neurological control patients were included. Disability was assessed using the ambulation index (AI), the Expanded Disability Status Scale score (EDSS) and the 9-hole PEG test (9HPT). Patients underwent lumbar puncture within 7 days of clinical assessment. Post-mortem brain tissue (12 multiple sclerosis and eight control patients) was classified histologically and adjacent sites were homogenized for protein analysis. S100B, ferritin and glial-fibrillary acidic protein (GFAP) were quantified in CSF and brain-tissue homogenate by ELISA (enzyme-linked immunosorbent assay) techniques developed in-house. There was a significant trend for increasing S100B levels from PP to SP to RR multiple sclerosis (P < 0.05). S100B was significantly higher in RR multiple sclerosis than in control patients (P < 0.01), whilst ferritin levels were significantly higher in SP multiple sclerosis than in control patients (P < 0.01). The S100B : ferritin ratio discriminated patients with RR multiple sclerosis from SP, PP or control patients (P < 0.05, P < 0.01 and P < 0.01, respectively). Multiple sclerosis patients with poor ambulation (AI > or =7) or severe disability (EDSS >6.5) had significantly higher CSF GFAP levels than less disabled multiple sclerosis or control patients (P < 0.01 and P < 0.001, respectively). There was a correlation between GFAP levels and ambulation in SP multiple sclerosis (r = 0.57, P < 0.01), and between S100B level and the 9HPT in PP multiple sclerosis patients (r = -0.85, P < 0.01). The post-mortem study showed significantly higher S100B levels in the acute than in the subacute plaques (P < 0.01), whilst ferritin levels were elevated in all multiple sclerosis lesion stages. Both GFAP and S100B levels were significantly higher in the cortex of multiple sclerosis than in control brain homogenate (P < 0.001 and P < 0.05, respectively). We found that S100B is a good marker for the relapsing phase of the disease (confirmed by post-mortem observation) as opposed to ferritin, which is elevated throughout the entire course. GFAP correlated with disability scales and may therefore be a marker for irreversible damage. The results of this study have broad implications for finding new and sensitive outcome measures for treatment trials that aim to delay the development of disability. They may also be considered in future classifications of multiple sclerosis patients.

Adult↗

PubMed2002

Role of serum S100B as an early predictor of high intracranial pressure and mortality in brain injury: a pilot study.

OBJECTIVE: To investigate whether serum S100B is suitable as a sensitive biomarker for early prediction of increased intracranial pressure and mortality rates after brain injury. DESIGN: A prospective, longitudinal study. SETTING: Neurosurgical intensive care unit. PATIENTS: Twenty-one patients with acute brain injury and 13 healthy controls. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We assessed Glasgow Coma Scale score and pupil reaction on admission and quantified serum S100B (in-house enzyme-linked immunosorbent assay) and intracranial pressure on admission and the subsequent 6 days. Serum S100B concentrations on admission and day 1 were significantly higher in patients with fatal outcome (p <.05, p<.01, respectively), with a sensitivity of 100% and a specificity of 75-83%. Patients with high serum S100B on admission had an eight-fold and on day 1 a 12-fold increased relative risk of a fatal outcome. Subsequent serum S100B values predicted the development of high intracranial pressure in patients with traumatic brain injury (p <.01). Patients with high intracranial pressure on day 5 had an 11-fold and on day 6 a nine-fold increased risk of fatal outcome. CONCLUSIONS: Serum S100B is a sensitive biomarker for early prediction of the development of high intracranial pressure and fatal outcome following acute brain injury. Monitoring S100B concentrations could contribute to early detection of patients at risk of secondary increases in intracranial pressure and subsequent mortality. This would allow earlier targeting of therapy in selected patients.

Adult↗

PubMed2001

Fatigue is not associated with raised inflammatory markers in multiple sclerosis.

BACKGROUND: The pathogenesis of fatigue in patients with MS is poorly understood. OBJECTIVE: To test the hypothesis that fatigue in MS is related to inflammatory disease activity as measured by systemic markers of inflammation. METHODS: Fatigue as assessed by the Fatigue Questionnaire Scale (FQS) and Krupp's Fatigue Severity Scale (KFSS) was correlated with several inflammatory markers in 38 patients with MS (16 relapsing-remitting [RR; 7 of whom had benign MS), 9 secondary progressive [SP], 13 primary progressive [PP]). The markers included daily urinary neopterin excretion, a marker of interferon-gamma-activated macrophage activity, and serum C-reactive protein (CRP) and soluble intercellular adhesion molecule-1 (sICAM-1) levels. Urinary neopterin excretion was measured daily for 2 weeks. RESULTS: No correlation was found between urinary neopterin excretion, CRP, or sICAM-1 and the fatigue scores. However, patients with a raised serum CRP level had higher KFSS, but not FQS, scores than patients with normal CRP levels (KFSS, 50 +/- 8 vs 41 +/- 14, p = 0.05; FQS, 13 +/- 4 vs 11 +/- 5, p = NS). When assessed using the FQS, patients with RR and SP MS were more fatigued than patients with PP MS (RR = 12.5 [4 to 23] vs SP = 13 [8 to 18] vs PP = 9 [7 to 14], p = 0.02). The patients with benign MS were as fatigued as patients with nonbenign disease. CONCLUSION: The pathogenesis of fatigue in MS is complex and does not appear to be directly related to systemic markers of inflammatory disease activity. Interestingly, patients with PP MS were less fatigued than patients with RR disease.

Adult↗

PubMed2001

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Color↗

PubMed2001

Haptoglobins as markers of blood-CSF barrier dysfunction: the findings in normal CSF.

Cerebrospinal fluid from 39 healthy individuals showed evidence for increasing blood-CSF barrier permeability with age, and confirmed that haptoglobins are more sensitive but less predictive markers of barrier permeability than total protein. Haptoglobin (Hp) species were identified by polyacrylamide gel electrophoresis followed by immunoblotting. Hp 1-1 (35 A, 85 kDa) was detected in all (9/9) subjects who exhibited this phenotype. Hp 2-1 (42 A, 120 kDa) was detected in 53% (8/15) of subjects in whom Hp 2-1 was the phenotype. Hp 2-2 (54 A, 160 kDa) was detected in only 20% (3/15) of subjects who exhibited this phenotype. The likelihood of detecting any haptoglobin species corresponded to the molecular size and the consequent resistance offered by the barrier. Among younger subjects aged < or =45 years, a significant difference in incidence occurred between the two smaller species Hp 1-1 and Hp 2-1. However, among those aged >45, the significant difference in incidence was between the two larger species Hp 2-1 and Hp 2-2. The incidence of detection among those with Hp 2-1 phenotypes was higher in the older age group. The increased likelihood of detecting haptoglobins with age is in keeping with the notion that barrier function is compromised by age, and also indicates that Hp 2-1 and Hp 2-2 are sensitive markers of barrier function. The appreciable incidence of haptoglobins in normal CSF, even of the larger species, suggests reservation in assuming that their presence signifies barrier damage.

Adolescent↗