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Biomedical subjects

E J Thompson

Publications and source records attributed to E J Thompson.

At least 73 records · Page 4Linked to original sources
PubMed1999

Increased urinary nitric oxide metabolites in patients with multiple sclerosis correlates with early and relapsing disease.

Nitric oxide (NO) has been implicated in the immunopathogenesis of MS as a potential mediator of neuronal loss. To investigate the role of.NO in the development of progressive disease we measured the NO metabolites (nitrate and nitrite) and neopterin, in the urine of 129 patients with demyelinating disease (DD): 23 with clinically isolated syndromes compatible with demyelination and in 46 relapsing remitting (RR) and 60 patients with progressive MS. Eighty-nine of these 129 patients underwent Gd-enhanced MRI. In addition 58 normal control subjects (NC), 19 AIDS and 35 rheumatoid arthritis (RA) patients were studied. Patients with DD, AIDS and RA had significantly elevated urinary nitrate plus nitrite (nit : creat. urine) and neopterin (neopt : creat.urine) to creatinine ratios compared to NC subjects. (Median[25th - 75th%] nit : creat.urine: NC=1183[962 - 1365] vs DD=1245[875 - 2403], AIDS=1686[1231 - 2531], and RA=1950[1214 - 2726] mumol/mol, P<0.001 and median[25th - 75th%] neopt : creat.urine: NC=99[76 - 151] vs DD=163[119 - 266], AIDS=972[653 - 1456], and RA=389[257 - 623] mu mol/mol, P<0.001). Patients with early DD and RR MS had significantly elevated nit : creat.urine compared to patients with progressive MS (nit : creat. urine: 1612[1020 - 2733] vs 1159[790 - 1641] mu mol/mol, P=0.006). The nit : creat.urine and neopt : creat.urine did not correlate with clinical relapse or MRI activity. Excretion of.NO metabolites is increased in patients with early or relapsing-remitting disease.NO appears to be a double-edged sword, mediating tissue damage and modulating complex immunological functions which may be protective in MS.

Acquired Immunodeficiency Syndrome↗
PubMed1998

Antigen-dependent intrathecal antibody synthesis in the normal rat brain: tissue entry and local retention of antigen-specific B cells.

The intrathecal Ab response to Ag introduced into the normal brain has not been fully explored. Involvement of Ag-specific, peripheral B cells in an intrathecal response was studied using a normal rat model of Ag infusion through an indwelling cannula into defined brain sites, while maintaining a functionally intact blood-brain barrier. Specific Ab was detected in serum and cerebrospinal fluid. The intrathecal response is first detectable at day 14. Isoelectric focusing of cerebrospinal fluid reveals banding patterns consistent with local Ab production. To increase Ag-specific, circulating peripheral lymphocytes available for trafficking to Ag-stimulated brain and for enhancing intrathecal Ab synthesis, rats were preimmunized peripherally. Subsequently, Ag or saline (control) was infused through the cannula. Under this protocol, intrathecal synthesis is detectable earlier (day 5 postinfusion). Immunohistochemical studies at the infusion site assessed Ag-specific B cells, T cells, and activated APCs. Rats receiving peripheral preimmunization followed by Ag into caudate nucleus have far greater numbers of these cells, including plasma cells, within the infusion site compared with saline controls. Results confirm previous indirect evidence of intrathecal Ab synthesis in normal rat brain and provide the first direct evidence for B cell trafficking across normal brain barriers plus retention at the Ag deposition site. Our studies indicate that the normal brain microenvironment supports development of Ag-directed humoral immunity. We propose that immune privilege in normal brain is characterized by down-regulation of cell-mediated but not Ab immune responses within the central nervous system.

Animals↗
PubMed1998

Elevated cerebrospinal fluid and serum nitrate and nitrite levels in patients with central nervous system complications of HIV-1 infection: a correlation with blood-brain-barrier dysfunction.

As nitric oxide (.NO) is hypothesised to play a role in the immunopathogenesis of neurological complications associated with inflammation, we compared levels of cerebrospinal fluid (CSF) and serum .NO metabolites in 24 patients with HIV-1 infection, to those in 58 non-HIV infected patients with neurological disorders. Levels of .NO metabolites were correlated with blood-brain-barrier dysfunction. CSF and serum nitrate and nitrite levels were measured by the nitrate reductase and Griess reaction methods. The .NO metabolites, nitrate and nitrite, were raised in the CSF and serum of patients with AIDS and central nervous system complications, when compared to non-HIV infected patients with inflammatory and non-inflammatory neurological disorders (median nitrate and nitrite: CSF=18.3 microM vs. 11.1 microM vs. 7.0 microM, P<0.001, and serum=53.8 microM vs. 50.3 microM vs. 41.4 microM, P=0.04, respectively). CSF nitrate and nitrite levels correlated with the albumin quotient. This study supports the evidence that .NO is a potential mediator of blood-brain-barrier breakdown in inflammatory diseases of the central nervous system.

Acquired Immunodeficiency Syndrome↗
PubMed1998

Protein adsorption to hydrocephalus shunt catheters: CSF protein adsorption.

OBJECTIVE: To assess the quantity and nature of the proteins that adsorb to hydrocephalus shunt catheters after implantation, and to determine whether sufficient could accumulate to obstruct the catheter. DESIGN: Elution of proteins from 102 explanted shunt catheters, with protein assay and electrophoresis of the eluate, and scanning electron microscopy (SEM) of the catheters. RESULTS: The amount of protein elutable was extremely low, and significant protein, apart from a thin film, was not found on SEM. Qualitative analysis disclosed that most of the adsorbed protein was albumin. CONCLUSIONS: Protein deposition on hydrocephalus catheters does not occur in sufficient quantities to cause catheter obstruction.

Adsorption↗
PubMed1998

Protein markers of brain damage.

Brain proteins are released into body fluids in a fashion which reflects the underlying pathogenetic mechanisms for individual diseases. It is therefore important to distinguish not only different protein markers (reflecting various brain cells from which they have been released), but also their metabolism at different sites within the body (e.g. reticulo-endothelial system vs renal clearance) which will have an important bearing on whether fragments of the protein are found in urine or blood. It is clear that different patterns of protein abnormalities would be helpful in differential diagnosis of the individual diseases which afflict the nervous system. It would also be useful to monitor these proteins either as surrogate markers of the natural history of the condition or in the various therapies for each disease.

Biomarkers↗
PubMed1998

Are there any body fluid markers of brain atrophy in multiple sclerosis?

The weak correlation between inflammatory activity and disease progression in patients with multiple sclerosis has shifted the emphasis from inflammatory monitoring to the investigation of the pathological processes of demyelination, axonal loss, and gliosis. New magnetic resonance imaging (MRI) techniques that have been developed to measure these processes appear very promising. This paper will briefly discuss potential body fluid markers of axonal loss, gliosis and demyelination, as the pathological substrates of brain atrophy, their function and the principles behind their future study in patients with multiple sclerosis.

Atrophy↗
PubMed1998

The potential role of nitric oxide in multiple sclerosis.

Nitric oxide (.NO) and its reactive derivative peroxynitrite (ONOO-) have been implicated in the pathogenesis of multiple sclerosis (MS). They are cytotoxic to oligodendrocytes and neurones in culture by inhibiting the mitochondrial respiratory chain (complexes II/III and IV) and inhibiting certain key intracellular enzymes. Recently .NO has been implicated as a possible aetiological factor in reversible conduction block in demyelinated axons. Inducible nitric oxide synthase (iNOS) is upregulated in the central nervous system of animals with experimental allergic encephalomyelitis (EAE) and in patients with MS. In some EAE models inhibiting iNOS activity decreases disease severity whilst in other models disease activity is exacerbated. Raised levels of nitrate and nitrite, stable end-products of .NO/ONOO-, are found in the cerebrospinal fluid, serum and urine of patients with MS. CSF levels of nitrate and nitrite correlate with blood-brain-barrier dysfunction, which suggests that .NO may play a role in inflammatory blood-brain-barrier dysfunction. In a longitudinal study on 24 patients with relapsing remitting and secondary progressive MS, raised serum nitrate and nitrite levels correlated with a relapsing course and infrequent relapses. However, no correlation was found between raised serum levels of nitrate and nitrite and MRI activity, disease progression, or the development of cerebral atrophy. In autoimmune mediated CNS demyelinating disease .NO may be a double-edged sword, mediating tissue damage on the one hand and on the other hand modulating complex immunological functions which may be protective.

Animals↗
PubMed1998

Urinary markers of disease activity in multiple sclerosis.

Numerous markers of disease activity, representing different aspects of the inflammatory cascade and pathogenic process in multiple sclerosis, can be detected in the urine. Urinary monitoring provides distinct advantages over blood and cerebrospinal fluid: it is easier to collect, allows frequent sampling and acts as a natural integrator by capturing the excretion of a substance over a prolonged period of time. We will discuss the principles, advantages, and pitfalls of urinary monitoring in relationship to multiple sclerosis.

Biomarkers↗
PubMed1998

Body fluid markers to monitor multiple sclerosis: the assays and the challenges.

The need for reliable markers of disease activity in multiple sclerosis (MS) to better guide basic research, diagnosis, treatment, and monitoring of therapy is well-recognized. A recent European Charcot Foundation Symposium (Body fluid markers for course and activity of disease in multiple sclerosis (Madrid, Spain, October 2-4, 1997) organized by the European Charcot Foundation and the Fundación Española de Esclerosis Múltiple (the Spanish Multiple Sclerosis Foundation) brought together experts in the field to review the state of the art for the technology measuring markers in body fluids. An array of different approaches was presented to measure a wide diversity of classic and novel marker molecules, including cytokines, adhesion molecules, myelin compounds, and free antibody light chains, in either blood, urine, or cerebrospinal fluid. Here, recent progress in these approaches is assessed in the context of distinct pathophysiological stages of the disease, the requirements which such molecules and assays should ideally meet, and the practical and conceptual challenges which they face. Recommendations for further improvements are described.

Body Fluids↗
PubMed1997

Increased S100beta in the cerebrospinal fluid of patients with frontotemporal dementia.

Levels of S100beta, a calcium-binding protein found in astrocytes, were measured using a sandwich ELISA in the cerebrospinal fluid (CSF) of patients with frontotemporal dementia and Alzheimer's disease and compared with controls. Mean CSF S100beta concentrations were significantly raised in patients with frontotemporal dementia when compared with healthy controls (0.49 +/- 0.28 vs. 0.22 +/- 0.08 ng/ml, P < 0.001). There was no correlation between age at disease onset, disease severity or length of illness. The increased concentration of CSF S100beta seen in frontotemporal dementia may reflect the marked astrocytosis seen in this condition.

Adult↗
PubMed1997

A specific and sensitive ELISA for measuring S-100b in cerebrospinal fluid.

A sensitive, simple and specific sandwich ELISA for S-100b is described. This method involves the binding of a monoclonal anti-S-100b antibody to the wall of a microtitre plate. This capture antibody is subsequently incubated with S-100b standard, control or patient sample in the form of cerebrospinal fluid (CSF). After incubation, the microtitre plate is washed and horseradish peroxidase-labelled polyclonal anti-S-100b is added (detector antibody). The amount of detector antibody bound to the microtitre plate is proportional to the amount of S-100b in the sample. The assay has a lower limit of detection of 0.04 ng/ml and shows < 0.006% reactivity with the closely related polypeptide S-100a. The assay has a mean within-batch precision of 9.3 and 5.6% at S-100b concentrations of 0.38 and 0.8 ng/ml, respectively. The between batch precision is 8.9 and 8.1% at S-100b concentrations of 0.12 and 0.34 ng/ml, respectively. The recovery of S-100b from CSF spiked with 0.5 ng/ml was 94% with a CV of 8.5%. The assay may be completed in less than 5 h using precoated microtitre plates, thus lending itself to routine use in clinical laboratories. Using this ELISA, 154 CSF samples were analysed and 19% of samples were found to have elevated levels. The highest levels were found in patients with cerebral haemorrhage or central nervous system malignancy. S-100b concentrations from individuals without evidence of neurological disease were found to be less than 0.4 ng/ml. Only 5% of patients with multiple sclerosis were found to have elevated CSF S-100b concentrations. Serial CSF samples taken from a patient with an infected in-dwelling shunt showed a dramatic decline, suggesting that S-100b is rapidly cleared.

Enzyme-Linked Immunosorbent Assay↗
PubMed1997

An improved, ultrasensitive method for the detection of IgM oligoclonal bands in cerebrospinal fluid.

A new, 10-fold more sensitive method, based on an improved immunofixation technique, has been devised to detect oligoclonal IgM bands in unconcentrated cerebrospinal fluid (CSF). Using agarose gel electrophoresis, 5 microliters of an unconcentrated sample containing oligoclonal bands was separated and blotted on to a polyvinyldifluoride membrane. To visualise the pattern, a peroxidase-labelled double-antibody technique was used. No prior concentration of CSF was needed and the process required only 5 h. The technique may prove very useful in diagnosing an early intrathecal immune response.

Cross Reactions↗
PubMed1997

Raised serum nitrate and nitrite levels in patients with multiple sclerosis.

Nitric oxide and its highly reactive derivative peroxynitrite have been implicated as non-specific inflammatory mediators of neuronal and oligodendrocyte damage and death in multiple sclerosis. In a cross-sectional study we found levels of the nitric oxide metabolites nitrate and nitrite to be raised in the serum of patients with demyelinating disease (65.6 microM (SD 32.9)), acquired immune deficiency syndrome (57.9 microM (SD 34.9)) and inflammatory neurological disease (57.5 microM (SD 31.3)), compared with normal control subjects (32.8 microM (SD 12.2)) and patients with non-inflammatory neurological disease (41.1 microM (SD 12.3), p < 0.001). Nitric oxide metabolites were raised in all clinical subtypes of multiple sclerosis, as well as in clinically isolated syndromes compatible with demyelination, and were not related to progressive disease or disability. This study provides further evidence for a role of nitric oxide in the immunopathogenesis of inflammatory diseases of the central nervous system, including multiple sclerosis.

Acquired Immunodeficiency Syndrome↗
PubMed1997

Daily urinary neopterin excretion as an immunological marker of disease activity in multiple sclerosis.

The aim of this study was to assess neopterin, a marker of interferon gamma (IFN-gamma) induced macrophage activity, as a possible surrogate marker of inflammation in patients with multiple sclerosis. Urinary neopterin to creatinine ratios (UNCRs) were measured daily in 10 primary progressive (PP). 10 relapsing remitting (RR) and 11 secondary progressive (SP) patients with multiple sclerosis, and 14 normal control (NC) subjects, for periods of up to 12 weeks. After excluding measurements related to infection, the median of the individuals' average UNCRs was significantly higher in patients than in controls (P < 0.001 for all patients and P < 0.01 for each of the three groups of patients); the median UNCRs (and interquartile ranges) were 187 (135-231), 187 (165-277), 218 (164-517) and 134 (97-152) mumol/mol for PP, RR, SP patients and controls, respectively. Similarly, patients had a greater median proportion of days with a UNCR above normal (P < 0.001 for all patients and P < 0.01 for each group); the median percentage (and interquartile ranges) were 16 (6-62), 28 (21-36), 49 (14-86) and 0 (0-6)% for PP, RR, SP patients and controls, respectively. They also had a greater number of peaks in their serial UNCR measurements than controls (P < 0.001 for all patients and P < 0.01 for each group); the means +/- SD peaks/subject/month were: 2.1 +/- 1.8; 3.0 +/- 1.7; 3.3 +/- 2.3 and 0.2 +/- 0.6 for PP, RR, SP patients and controls, respectively. Nine relapses occurred in nine patients during the study, and all were associated with increased neopterin excretion, which tended to be greater than that on days not associated with a relapse. Three of the nine relapses were preceded by an upper respiratory tract infection. In eight out of 13 patients who had infections during the study, increased neopterin excretion was noted for periods of up to 6 weeks post-infection, significantly longer than that which occurred after infections in controls. This confirms infection as a potent inducer of symptomatic and asymptomatic disease activity in mutiple sclerosis, and provides further support of a pivotal role for IFN-gamma in te pathogenesis of mutiple sclerosis. Urinary neopterin excretion is increased in patients with both progressive and relapsing mutiple sclerosis, and therefore has potential as a surrogate marker of the inflammatory component of mutiple sclerosis disease activity.

Adult↗
PubMed1997

Cerebrospinal fluid ferritin in HIV infected patients with acute neurological episodes.

OBJECTIVES: To measure cerebrospinal fluid (CSF) ferritin in HIV infected patients with acute neurological episodes and to correlate the findings with the type and severity of neurological disease. METHODS: CSF ferritin and the ratio of CSF to serum albumin (QAlb) were prospectively measured in 27 consecutive HIV infected patients admitted to a specialist unit for investigation of acute neurological episodes; the results were compared with their clinical diagnoses. RESULTS: Ten patients had HIV associated dementia complex, six had cryptococcal meningitis, two had primary CNS lymphoma and nine had miscellaneous conditions including herpes simplex virus encephalitis, cytomegalovirus encephalitis, cerebral toxoplasmosis and mononeuritis multiplex. Overall, 16 (59%) patients had raised CSF ferritin levels, ranging from 13.0 to 50.2 micrograms/l, (median = 16.1 micrograms/l: normal range = 1.0-12.0 micrograms/l). Thirteen of the 16 also had normal QAlb values, implying an intact CSF-blood barrier, and thus that local synthesis of ferritin had occurred. Elevated ferritin levels were not associated with particular neurological diagnoses. In those with HIV associated dementia complex there was no correlation between CSF ferritin levels and the severity of clinical cognitive deficit or the extent of magnetic resonance imaging abnormalities. CONCLUSIONS: An elevated CSF ferritin level is a non-specific finding in HIV infected patients presenting with acute neurological episodes.

AIDS Dementia Complex↗