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Biomedical subjects

G Giovannoni

Publications and source records attributed to G Giovannoni.

At least 73 records · Page 4Linked to original sources
PubMed2000

Cerebrospinal fluid tau concentrations in HIV infected patients with suspected neurological disease.

OBJECTIVES: To measure cerebrospinal fluid (CSF) tau in HIV infected patients with acute neurological episodes and to correlate the findings with the type and severity of neurological disease. METHODS: CSF tau was prospectively measured in 76 consecutive HIV infected patients admitted to a specialist unit at UCL Hospitals, London, for investigation of acute neurological episodes: the results were compared with the clinical diagnoses. RESULTS: 24 patients had HIV associated dementia complex (HADC), 10 had lymphoma (including four with primary CNS lymphoma), 20 had cerebral infections (including five with CMV encephalitis, five with VZV infection, seven with cryptococcal meningitis, two with toxoplasmosis, and one with progressive multifocal leucoencephalopathy); 22 patients had miscellaneous conditions, including nine with self limiting headache/fever. 62 patients (82%) had normal CSF tau concentration and 14 patients (18%) had elevated tau. In those with HADC, there was no correlation between the degree of dementia or atrophy on magnetic resonance imaging and CSF tau. Elevated CSF tau was associated with poor outcome as six of eight patients who died within 4 weeks of lumbar puncture had elevated tau (p = 0.0024, two tailed Fisher's exact test). CONCLUSIONS: CSF tau levels are not elevated in the majority of HIV infected patients presenting with acute neurological episodes. CSF tau levels show no correlation with severity of dementia/atrophy on magnetic resonance imaging. Although elevated CSF tau was observed in some patients with conditions causing cerebral necrosis, the finding did not delineate underlying pathology but was associated with poor outcome.

AIDS Dementia Complex↗
PubMed2000

Immunological time-course of gadolinium-enhancing MRI lesions in patients with multiple sclerosis.

In multiple sclerosis (MS) gadolinium (Gd)-enhanced MRI activity correlates weakly with immunological markers of disease activity. We, therefore, tested the hypothesis that the poor correlation could be partly explained by the temporal profile of Gd enhancement. We measured urinary neopterin:creatinine ratios (neopt.:creat.(urine)) in 5 patients with active MS undergoing weekly Gd-enhanced MRI studies of the brain. The neopt.:creat.(urine) associated with new Gd-enhancing lesions (<8 days) was significantly higher than the ratio not associated with new Gd-enhancing lesions [mean(geometric) neopt.: creat.(urine) = 413 micromol/mol (range = 207-521) vs. 250 micromol/mol (range = 132-492), p = 0.03]. Pro-inflammatory immunological markers, which are probably produced early on in the life cycle of an active MS lesion, should preferably be correlated with newly enhancing lesions (<8 days). Failure to do this may explain the poor and unpredictable correlations between immunological markers and Gd-enhanced MRI activity, which cannot be accurately aged in cross-sectional and serial monthly MRI studies.

Adrenal Cortex Hormones↗
PubMed1999

Matrix metalloproteinases in inflammatory demyelination: targets for treatment.

Matrix metalloproteinases (MMPs) degrade all protein components of the extracellular matrix. Functionally, they contribute to several different physiologic conditions, such as angiogenesis or bone remodeling, as well as pathologic conditions in humans, such as rheumatoid arthritis and tumor growth. MMPs seem to be important in the pathogenesis of inflammatory demyelinating diseases of the central and peripheral nervous system, especially in MS and in Guillain-Barré syndrome (GBS). Key mechanisms in the genesis of inflammatory demyelination, such as leukocyte recruitment, blood-brain barrier or blood-nerve barrier breakdown, myelin destruction, and release of disease-promoting cytokines, are considered to be MMP-dependent processes. In experimental autoimmune encephalomyelitis, an animal model of MS, and experimental autoimmune neuritis, an animal model of GBS, different synthetic inhibitors targeting MMP activity are able to suppress and even reverse ongoing disease. This evidence points to MMPs as new targets for treatment in inflammatory demyelination.

Animals↗
PubMed1999

Contribution of nitric oxide to exercise-induced hypotension in human sympathetic denervation.

The cardiovascular, catecholamine, and nitrate/nitrite (NO) responses to bicycle exercise were measured in 14 normal subjects (controls) and two groups with sympathetic denervation; 14 with peripheral autonomic failure (pure autonomic failure [PAF]); and 13 with central autonomic failure (multiple system atrophy [MSA]). With exercise, blood pressure increased in control subjects by 40 +/- 7/24 +/- 5 mm Hg (p < 0.001) and fell in PAF by 24 +/- 8/24 +/- 5 mm Hg (p < 0.02 and p < 0.007) and MSA by 31 +/- 7/11 +/- 3 mm Hg (p < 0.005 and p < 0.04). With exercise, the increase in heart rate was greater in control subjects (60 +/- 3 to 111 +/- 4/min; p < 0.0001) than in PAF (69 +/- 3 to 86 +/- 4/min; p < 0.0001) and MSA (70 +/- 4 to 90 +/- 4; p < 0.001). Resting plasma noradrenaline levels were similar in controls (291 +/- 51 pg ml(-1)) and MSA (257 +/- 49 pg ml(-1)), but lower in PAF (82 +/- 14 pg ml(-1)). With exercise, plasma noradrenaline increased in controls but was unchanged in PAF and MSA. Resting NOx was similar in controls (50 +/- 5 nmol/L; range, 23.3-87.6 nmol/L) and PAF patients (59+/-8 nmol/l; range, 19.3-116.4 nmol/L), but was higher in MSA patients (87 +/-14 nmol/L; p <0.025, range 15.4-157.2 nmol/L). With exercise, NOx was unchanged in control subjects and increased by 10% and 17% in PAF and MSA, respectively; these changes were not statistically significant. This study suggests that circulating changes in NOx levels do not exert a major role in exercise-induced hypotension in subjects with sympathetic denervation.

Autonomic Nervous System Diseases↗
PubMed1999

Bradykinesia akinesia inco-ordination test (BRAIN TEST): an objective computerised assessment of upper limb motor function.

OBJECTIVES: A simple and rapid computerised keyboard test, based on the alternating finger tapping test, has been developed to quantify upper limb motor function. The test generates several variables: (1) kinesia score: the number of keystrokes in 60 seconds; (2) akinesia time: cumulative time that keys are depressed; (3) dysmetria score: a weighted index calculated using the number of incorrectly hit keys corrected for speed; (4) incoordination score: a measure of rhythmicity which corresponds to the variance of the time interval between keystrokes. METHODS: The BRAIN TEST(Copyright ) was assessed on 35 patients with idiopathic Parkinson's disease, 12 patients with cerebellar dysfunction, and 27 normal control subjects. RESULTS: The mean kinesia scores of patients with Parkinson's disease or cerebellar dysfunction were significantly slower than normal controls (Parkinson's disease=107 (SD 28) keys/min v cerebellar dysfunction=86+/- (SD 28) v normal controls=182 (SD 26), p<0.001) and correlated with the UPDRS (r =-0.69, p<0.001). The akinesia time is very insensitive and was only abnormal in patients with severe parkinsonism. The median dysmetria (cerebellar dysfunction=13.8 v Parkinson's disease=6.1 v normal controls=4.2, p=0.002) and inco-ordination scores (cerebellar dysfunction=5.12 v Parkinson's disease=0.84 v normal controls=0.15, p=0.002) were significantly higher in patients with cerebellar dysfunction, in whom the dysmetria score correlated with a cerebellar disease rating scale (r=0.64, p=0.02). CONCLUSION: The BRAIN TEST(Copyright ) provides a simple, rapid, and objective assessment of upper limb motor function. It assesses speed, accuracy, and rhythmicity of upper limb movements regardless of their physiological basis. The results of the test correlate well with clinical rating scales in Parkinson's disease and cerebellar dysfunction. The BRAIN test will be useful in clinical studies. It can be downloaded from the Internet ().

Adult↗
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

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

Cerebrospinal fluid and serum nitric oxide metabolites in patients with multiple sclerosis.

Nitric oxide is hypothesised to play a role in the immunopathogenesis of multiple sclerosis. Raised cerebrospinal fluid and serum levels of the nitric oxide metabolites nitrate and nitrite have been described in patients with multiple sclerosis. Cerebrospinal fluid and serum nitrate and nitrite were measured in patients with multiple sclerosis, inflammatory and non-inflammatory neurological diseases, and correlated with the albumin quotient, an index of blood-brain-barrier dysfunction. Patients undergoing diagnostic lumbar and vene puncture were prospectively recruited, clinical data were obtained from the hospital records, and the CSF and serum nitrate and nitrite levels were measured by the nitrate reductase and Griess reaction methods. Nitrate and nitrite, were raised in the CSF and serum of patients with multiple sclerosis and other inflammatory neurological diseases compared to patients with non-inflammatory neurological disorders (median nitrate and nitrite: cerebrospinal fluid = 10.3 microM vs 15.4 microM vs 6.6 microM, P < 0.001, and serum = 49.0 microM vs 46.4 microM vs 38.8 microM, P = 0.02, respectively). CSF nitrate and nitrite levels correlated with the albumin quotient (n = 59, r = 0.42, P < 0.001). This study provides further evidence for a role of nitric oxide in the immunopathogenesis of multiple sclerosis and supports a role for nitric oxide as a possible mediator of inflammatory blood-brain-barrier dysfunction.

Adult↗
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

Correlating immunological and magnetic resonance imaging markers of disease activity in multiple sclerosis.

Inflammation plays a central part in the pathogenesis of multiple sclerosis. However, current surrogate magnetic resonance (MR) and immunological markers of inflammation are weakly associated and correlate poorly with clinical progression. Reasons for this are multiple and probably relate to the non-specific changes and insensitivity of current MR techniques, disease dynamics, anatomical factors, and the temporal profile and poorly defined complexities of the inflammatory reaction in multiple sclerosis. This paper provides an overview of the principles involved in the monitoring of inflammation in multiple sclerosis, discusses possible reasons for the weak correlation between MR and immunological markers of inflammation, and briefly reviews the studies correlating these modalities. In addition, the predictive values of MRI and CSF oligoclonal immunoglobulin are compared in determining future progression to clinically definite multiple sclerosis in patients presenting with clinically isolated syndromes compatible with demyelination.

Brain↗
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

Pretreatment of astrocytes with interferon-alpha/beta impairs interferon-gamma induction of nitric oxide synthase.

Excessive nitric oxide/peroxynitrite generation has been implicated in the pathogenesis of multiple sclerosis, and the demonstration of increased astrocytic nitric oxide synthase activity in the postmortem brain of multiple sclerosis patients supports this hypothesis. Exposure of astrocytes, in primary culture, to interferon-gamma results in stimulation of nitric oxide synthase activity and increased nitric oxide release. In contrast to interferon-gamma, interferon-alpha/beta had a minimal effect on astrocytic nitric oxide formation. Furthermore, pretreatment of astrocytes with interferon-alpha/beta inhibited (approximately 65%) stimulation by interferon-gamma of nitric oxide synthase activity and nitric oxide release. Treatment with interferon-alpha/beta at a concentration as low as 10 U/ml caused inhibition of mitochondrial cytochrome c oxidase. Furthermore, the damage to cytochrome c oxidase was prevented by the putative interferon-alpha/beta receptor antagonist oxyphenylbutazone. In view of these observations, our current hypothesis is that the mitochondrial damage caused by exposure to interferon-alpha/beta may impair the ability of astrocytes to induce nitric oxide synthase activity on subsequent interferon-gamma exposure. These results may have implications for our understanding of the mechanisms responsible for the therapeutic effects of interferon-alpha/beta preparations in multiple sclerosis.

Animals↗