Use of monoclonal antibodies in vivo as a therapeutic strategy for alloimmune or autoimmune reactivity: the Besançon experience.
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Adult↗
Biomedical subjects
L Rumbach
Publications and source records attributed to L Rumbach.
Nuclear magnetic resonance T2 relaxation times in multiple sclerosis.
An original method was used to carry out the mathematical analysis of T2 transverse magnetization decay curves and the measure of T2 relaxation times on multiple sclerosis (MS) patients. The presumably normal white matter (WM) of these patients presented higher T2 relaxation times (98.6 msec), in comparison with that found in a population sample (88 msec). In this case, magnetization decay curves remain mostly monoexponential and are characterized by a single T2. On the other hand, areas of increased signal (AIS) curves are always better fitted by a biexponential function characterized by a short (82 msec) and a long (greater than 200 msec) T2. The spreading out of long T2 varies from one AIS to another in the same patient and among different patients; values of long T2 also vary with time, but without any correlation with the clinical state. In fact, no correlation was been established between relaxation times and clinical parameters. Quantitative MRI therefore enables a different approach to interpret MRI images; results suggest that several histobiochemical parameters play a role in the pathogenesis of an AIS and that MS is a dynamic and constantly evolving disease.
Adult↗
In vivo determination of multiexponential T2 relaxation in the brain of patients with multiple sclerosis.
In vivo measurement of T2 relaxation times in multiple sclerosis (MS) lesions by magnetic resonance imaging (MRI) is potentially useful for the evaluation of the disease activity. Seven patients with definite MS were investigated over a period of three years (19 examinations), using a whole-body MRI scanner operating at 0.15 T with a specially designed high-power radio-frequency head coil. A modified CPMG sequence with a 180 degree pulse interval of TE = 6 msec and 128 echoes was used for the T2 relaxation measurement of the areas of increased signal (AIS) and white matter (WM). A biexponential T2 analysis of each pixel of the spin-echo images was computed. The T2 relaxation processes were found to be a monoexponential function in WM. The T2 relaxation times of apparently normal white matter in MS patients was significantly longer than in control subjects. The T2 relaxation curves of the AIS were found in most cases to fit a biexponential function characterized by a short and a long T2. T2 long relaxation times of AIS were spread out over a wide range (150-560 msec). The study of T2 long histograms shows that some AIS can be divided into two or three parts depending on the T2 long values. Each of these parts may correspond to a pathological process such as edema, demyelination and gliosis. Evolution of T2 relaxation times over a period of time cannot as yet be correlated with modifications in the clinical state.
Adult↗
Antibodies to cerebellar soluble lectin CSL in multiple sclerosis.
Cerebrospinal fluid samples from 239 patients with various neurological disorders were tested for the presence of autoantibodies to an endogenous mannose-binding protein, the cerebellar soluble lectin CSL, by means of an immunoblotting test with rat CSL as antigen. 47 of 51 patients with multiple sclerosis were positive for anti-CSL compared with 30 of 188 patients with other neurological disorders. 14 of the 30 false-positive patients were over 60 years old, an age group not typical of multiple sclerosis patients. The specificity of the test for multiple sclerosis was 85% and the sensitivity 93.5%. The possibility that CSL is an important immunological target in multiple sclerosis allows new insights into the possible causes and development of this disorder.
Adult↗
[Magnetic resonance imaging after a one-month interval of lesions of multiple sclerosis in 2 populations, one during an acute attack treated with methylprednisolone, the other stable with no treatment].
Changes in clinical symptoms and MRI lesions of multiple sclerosis (MS) were evaluated on two occasions, one month apart, in 30 patients. Seventeen patients (group 1) with acute exacerbation were treated with methylprednisolone in high, then decreasing doses during a total of 30 days. MRI examinations were performed before and at the end of treatment. The remaining 13 patients (group 2) had been clinically stable for more than 6 months and received no treatment; here again, MRI was performed at 30 days' interval. All patients in group 1 showed functional improvement. The MRI lesions remained stable in 7 of group 1 patients and in 4 of group 2 patients. In the remaining 19 patients (10 in group 1 and 9 in group 2), the number, size and location of MRI lesions were found to have changed over 1 month. There was no correlation between clinical changes and the modification observed at MRI. This study confirms that high-dose corticosteroids are effective, at least clinically, in acute exacerbations, but the main results are that MS is a continually evolving disease, that changes rapidly occur in the lesions observed at MRI and that corticosteroids do not seem to influence the course of MRI lesions. Our study also suggests that MRI is inadequate to evaluate the effectiveness of short-time treatments of MS.
Follow-Up Studies↗
[Contribution of MRI to the topography of oculomotor disorders in multiple sclerosis].
Magnetic resonance imaging (MRI) was performed in 20 patients with multiple sclerosis and abnormal electro-oculographic examination. All but 2 patients showed MRI abnormalities in the infratentorial region: hypersignal on T2-weighted sequences and/or images of atrophy. Usually, each patient had multiple abnormalities, which could prevent anatomico-oculographic correlations. With oculomotor disorders of cerebellar origin, correlations between clinical findings and MRI images were satisfactory, but with disorders due to brainstem lesions correlations were not so good, as shown by the results in 9 patients with internuclear ophthalmoplegia.
Adult↗
Valproate-induced hyperammonemia of renal origin. Effects of valproate on glutamine transport in rat kidney mitochondria.
The antiepileptic sodium valproate (VPA) systematically induces an asymptomatic hyperammonemia of renal origin in fasting normal human volunteers and in fasting rats, accompanied by an increased renal glutamine uptake. Fasting rats were injected with VPA and their mitochondria isolated, or isolated mitochondria of fasting rats were incubated with VPA. Transmembranal mitochondrial glutamine uptake and activities for five mitochondrial and three cytosolic enzymes involved in ammoniagenesis were measured. In VPA-incubated mitochondria, glutamine transport increased for VPA concentrations between 10(-3) and 10(-5) M; enzyme activities did not change. In mitochondria of VPA-treated rats, Km and Vmax were unaffected. These findings reflect membrane effects of VPA observed in other experimental settings.
Ammonia↗
Succinate transport inhibition by valproate in rat renal mitochondria.
Sodium valproate is an antiepileptic drug which may have side effects on different organs. Its mechanism of action, as yet unclear, may involve an effect on membranes. One possibility, an effect on mitochondrial membranes via an inhibition of oxidative phosphorylation, has been studied here by observing the transmembranal transport of a respiratory substrate, succinate, in rat kidney mitochondria incubated with valproate, or from rats injected with valproate. Succinate transport was inhibited in both conditions, which suggests that the effect was probably due to a direct effect of valproate rather than to an action of a valproate metabolite. For the valproate-incubated mitochondria, inhibition, described by a bell-shaped curve, started at a valproate concentration of 10(-7) M and was maximum at valproate 10(-5)M. Valproate's effect on mitochondrial transmembranal succinate transport can be compared to other evidence for membranal actions of valproate, actions which may clarify certain therapeutic or toxic properties of this drug.
Animals↗
Multiple sclerosis, sleep latencies and HLA antigens.
The role of HLA antigens, and HLA-DR2 in particular, in the determination of mean sleep onset latencies (MSOLs) in multiple sclerosis (MS) was studied. It has been suggested that this antigen may play a part in the reduction of MSOLs, since nearly 100% of patients suffering from narcolepsy are DR2-positive. A multiple sleep latency test was performed in 37 patients suffering from MS without spontaneous complaints of sleep disturbances and who were typed for HLA-A, B, C, DR and DQ. The MSOL was reduced in a total of 21 patients, in only 7 of 15 DR2-positive patients and in 12 of 21 DQw1-positive patients. However, it was reduced in 13 of 16 B8- or B14-positive patients. In contrast with this, in the absence of an early sleep onset (MSOL greater than 30 min), no HLA antigens were found to be over-represented when considered individually; only those patients positive for a group of cross-reacting HLA antigens (B5, B15, B18, B21 or B35) had an MSOL greater than 30 min. These results suggest that the genes which code for the DR2 or DQw1 antigens, which are present in nearly 100% of narcoleptics, are not solely responsible for the appearance of an early sleep onset in MS.
Adult↗
Multiple sclerosis and corpus callosum atrophy: relationship of MRI findings to clinical data.
Among 110 patients (45 men, 65 women), aged 15 to 66, with clinical and/or biological diagnosis of multiple sclerosis (MS), severe to moderate corpus callosum (CC) atrophy was observed in 67 (60%) patients. Correlation between CC atrophy, brain atrophy, duration and severity of clinical symptoms, and high signal white matter areas, was carried out in 90 patients. Mean age was 46 years for patients with severe CC atrophy, and 33 years for those without atrophy. Mean duration of the disease was 14 years in patients with severe atrophy, and 5 years in patients without atrophy. Severity of clinical symptoms is more pronounced in patients with severe CC atrophy. Numerous or large white matter high signal areas are observed in patients with severe CC atrophy on T2-weighted images. CC atrophy appears earlier than brain atrophy in the course of MS.
Adolescent↗
Effects of drugs affecting dopaminergic neurotransmission in rats with spontaneous petit mal-like seizures.
Drugs interacting with dopaminergic neurotransmission were studied on a model of genetic petit mal-like seizures in a strain of Wistar rats. Dopamine participates in the control of seizures in this model, as in other models of petit mal or of genetic epilepsy. Mixed dopaminergic D1/D2 agonists: L-DOPA, apomorphine, amphetamine and nomifensine, gave dose-dependent reductions of the duration of spike and wave discharges. Mixed D1/D2 antagonists: haloperidol, flupentixol and pimozide, caused dose-dependent increases of duration of spike and wave discharges. The findings with specific agonists or antagonists of D1 or D2 receptors did not reveal clearly the respective roles of these receptors in controlling the spike and wave discharges. The D2 agonists, lisuride and pergolide, had no effect on spike and wave discharges, except at toxic doses; bromocriptine decreased the duration of the discharges, but without clear-cut dose-dependency. The D2 antagonists: sulpiride and tiapride, had no effect. The D1 agonist SKF 38393 decreased duration of the spike and wave discharges in a dose-dependent manner. The D1 antagonist SCH 23390 had a biphasic effect: increasing the duration of spike and wave discharges at small doses and decreasing it at large doses. These results suggest that the simultaneous stimulation or inhibition of both receptors, D1 and D2, is necessary for influencing spike and wave discharges in this model.
Animals↗
[Biochemical analysis of the cerebrospinal fluid in multiple sclerosis: study of various formulas].
Multiple sclerosis (MS) is often characterized by a intrathecal synthesis of immunoglobulins (Ig) in cerebrospinal fluid (CSF), which may be evaluated in several ways: ratio methods (IgG index, Schuller's or Tourtelotte's formulae) or demonstration of an oligoclonal distribution, or both. In a retrospective study, 256 CSF analyses were evaluated. The 4 parameters studied were disturbed in about the same proportions in each of the 3 MS subgroups of Mac Alpine's classification. An oligoclonal distribution is more rarely present in pathologies other than MS. None of these tests is specific for the diagnosis of MS. Haptoglobin index variations do not distinguish between the different groups of patients. From a physiopathological point of view, however, they may perhaps reveal an acute local inflammatory reaction, different from the immune reaction giving rise to the Ig synthesis.
Adult↗
[Magnetic resonance imaging and herpetic encephalitis].
Cerebral lesions in two cases of herpetic encephalitis were detected by MRI using a spin-echo sequence and delayed echo signal recordings, whereas CT scans were normal. In one case pathology showed lesions to be more extensive than MRI anomalies. This suggests that even in the absence of EEG and CT anomalies, an encephalitis can be suggested by MRI.
Electroencephalography↗
Effects of drugs affecting noradrenergic neurotransmission in rats with spontaneous petit mal-like seizures.
Wistar rats of a strain displaying spontaneous petit mal-like seizures and spike-wave EEG discharged (SWD) were injected i.p. with drugs affecting noradrenergic neurotransmission. The EEG and behavior were recorded. Drugs which decrease alpha-noradrenergic neurotransmission, prazosin (alpha 1-antagonist) and clonidine (alpha 2-agonist), increased SWD and were sedative in a dose-dependent manner. Drugs which increase alpha-noradrenergic neurotransmission, ST 587, cirazoline (alpha 1-agonists) and yohimbine (alpha 2-antagonist), reduced SWD and the latter two caused agitation. Drugs which interact with beta-noradrenergic transmission (salbutamol, isoprenaline and propranolol), monoamine oxidase inhibitors (nialamide and iproniazid), and a noradrenaline reuptake inhibitor (desipramine), did not affect SWD. These findings suggest that noradrenaline participates in the control of petit mal-like seizures in the rat, as in other types of seizures and other animal models.
Animals↗
Multiple sclerosis diagnosis: magnetic resonance imaging compared with other paraclinical examinations.
Examination by magnetic resonance imaging (MRI), evoked potentials (EP) and cerebrospinal fluid (CSF) analyses was carried out on 97 definite, 20 probable and 40 possible multiple sclerosis (MS) patients (McAlpine's clinical criteria). MRI of only 4 transverse brain sections at the level of the ventricles and the analysis of the first 4 echoes showed periventricular or parenchymal lesions, or both, in 114 of the 117 definite and probable MS patients and in 25 of the possible MS patients. MRI was more sensitive than the CSF analyses or EP. The MRI abnormalities were not, however, MS-specific.
Adolescent↗
[Cytotoxic antibodies in multiple sclerosis].
Serum cold cytotoxic activities against allocells: total lymphocytes, B lymphocytes and monocytes were detected in 12 of 21 multiple sclerosis (MS) patients at 15 degrees C using a microcytotoxicity technique. Cytotoxic activity was found at 37 degrees C in certain MS patients. This activity was weak or absent in non MS patients and in healthy controls. Tests with autocells were positive in 6 MS patients. Cerebrospinal fluid cytotoxic activity was found in MS as well as in non-MS diseases; at 37 degrees C CSF produced lysis of monocytes in the absence of complement. No correlation was found between cytotoxic activity and parameters of clinical disease. Our results suggest that there may be a wide variety of cytotoxic antibodies in MS. Their significance is unknown; it may be that they have an effect on certain lymphocyte subsets as it has been suggested in other diseases.
Adult↗
Multiple sclerosis diagnosis: magnetic resonance imaging compared with other instrumental examinations.
Examination by magnetic resonance imaging (MRI), evoked potentials (EP) and cerebrospinal fluid (CSF) analyses was carried out on 97 definite, 20 probable and 40 possible multiple sclerosis (MS) patients (McAlpine's clinical criteria). MRI of only 4 transverse brain sections at the level of the ventricles and the analysis of the first 4 echoes showed periventricular or parenchymal lesions, or both, in 114 of the 117 definite and probable MS, and in 25 of the possible MS. MRI was more sensitive than the CSF analyses or EP; abnormalities more frequently appeared in known MS, and clinically asymptomatic lesions were seen. The MRI abnormalities were not, however, MS-specific; they were present in other neurological patients; none posed a question of differential diagnosis from MS. Complementary examinations, and especially MRI, should be a valuable adjunct for MS diagnosis, as long as the findings are viewed in the clinical context.
Adolescent↗
Effects of sodium valproate on mitochondrial membranes: electron paramagnetic resonance and transmembrane protein movement studies.
Sodium valproate (VPA), the salt of a branched short-chain fatty acid, is a major antiepileptic whose mode of action, as yet unclear, may involve effects on the organization of membranes. VPA was either injected into rats whose liver and kidney mitochondria were then isolated, or was preincubated with isolated mitochondria. First, liver and kidney mitochondria were studied with paramagnetic probes. The electron paramagnetic resonance spectra of proteins of VPA-treated mitochondria spin-labeled with 4-maleimido-2,2,6,6-tetramethyl-1-pyrrolidinoxyl showed that the ratio of weakly immobilized to strongly immobilized SH groups was reduced with respect to control mitochondria, more so in liver than in kidney mitochondria of VPA-injected rats, and more so in kidney than in liver mitochondria for VPA-incubated mitochondria. Spectra of mitochondrial lipids spin-labeled with 5-doxyl stearic methyl ester showed that VPA had no significant effect on order parameters S. Second, the transmembrane movement of aspartate aminotransferase was studied by incubating liver mitochondria in a sucrose-succinate medium and then fractionating them. The translocation of aspartate aminotransferase from mitoplasts, vesicles formed of inner membrane and matrix, to the intermembrane fluid, was significantly higher in VPA-treated than in control mitochondria. Thus, VPA, at concentrations in the range of those used therapeutically, interacted with membranes by modifying the structural organization of the internal mitochondrial membrane, essentially the membrane protein conformation.
Animals↗