Amyotrophic lateral sclerosis: oxidative energy metabolism and calcium homeostasis in peripheral blood lymphocytes.

There is evidence of oxidative injury in postmortem brain, spinal cord, and CSF of patients with sporadic amyotrophic lateral sclerosis (SALS patients). We investigated the oxidative metabolism and calcium homeostasis in peripheral blood lymphocytes from such patients and did not find statistical differences in the basal oxygen consumption rate (QO2), cytochrome c oxidase activity, catalase activity, and lactate production. However the increase in QO2, induced by an uncoupler of oxidative phosphorylation, was depressed and the basal (resting) level of free cytosolic calcium ([Ca2+]in) was higher in lymphocytes from SALS patients (p < 0.01). Further increase in free [Ca2+]in challenged by a K+ channel blocker or by an uncoupler of oxidative phosphorylation was similar in SALS and control lymphocytes. The results show that systemic changes consistent with the presence of mitochondrial and of calcium metabolism dysfunction are present in SALS.

Detection of HTLV-III-specific IgG bands in the CSF from a patient with AIDS and encephalitis.

Recent evidence would suggest that HTLV-III may be neurotropic. We have found oligoclonal IgG bands by isoelectric focusing in the CSF of a homosexual man with AIDS and encephalitis. Subsequent analysis revealed that such bands contained anti-HTLV-III activity, suggesting that neurologic symptoms in AIDS patients may be caused by replication of HTLV-III inside the CNS.

Devic's neuromyelitis optica: long-term follow-up and serial CSF findings in two cases.

Sixteen cerebrospinal fluid (CSF) specimens serially obtained during long-term follow-up of two patients with Devic's neuromyelitis optica (DNO) were compared with 65 CSF samples from patients with multiple sclerosis (MS). By statistical analysis, the CSF profile in DNO was found to differ from that observed in MS, mainly showing pleocytosis, blood-brain barrier damage, and absence of persistent immunoglobulin G synthesis within the central nervous system. Oligoclonal bands, detected with isoelectric focusing, were present in CSF of 92% of the patients with MS, and in three CSF specimens from one patient with DNO during the first 6 months after disease onset. The bands disappeared in two subsequent samples. This finding has never been described in MS. One patient with DNO had an apparent chronic-relapsing course probably due to steroid dependence. The clinical and CSF features of our cases favour the nosographic independence of DNO and MS.

Circulating levels of tumour necrosis factor-alpha and its soluble receptors are increased in the blood of patients with amyotrophic lateral sclerosis.

An immunologic pathogenesis for amyotrophic lateral sclerosis (ALS) has been recently proposed. We tested the whole tumour necrosis factor (TNF) system in the serum of 51 ALS patients at different stages of the disease and 36 healthy controls. Antigenic TNF-alpha and its soluble receptors (sTNF-Rs), measured by ELISA, were significantly higher in ALS patients than in healthy controls. However, biologically active TNF-alpha, corresponding to the sTNF-Rs-unbound trimeric TNFalpha molecule and assayed by its cytotoxic activity on a sensitive cell line, was similar between ALS patients and healthy controls. Neither antigenic TNF-alpha, bioactive TNF-alpha nor sTNF-Rs correlated with disease severity, disease duration, or weight loss. In conclusion, we reported an activation of the TNF system in ALS. The role of this activation in the pathogenesis of the disease remains elusive.

Heterogeneous distribution of amyotrophic lateral sclerosis patients with SOD-1 gene mutations: preliminary data on an Italian survey.

We report the absence of superoxide dismutase (SOD-1) gene mutations in 30 patients with amyotrophic lateral sclerosis (ALS) including individuals with a confirmed family history of ALS (familial ALS/FALS), ALS with an unclear family history (UFALS) and sporadic ALS (SALS). Single strand conformation polymorphism (SSCP) and sequence analysis of the 5 SOD-1 gene exons were undertaken to improve the accuracy of the mutation detection. Our preliminary data appear to diverge from the results of studies by other groups using different populations. We discuss the possible reasons for this disparity and the apparent heterogeneous distribution of ALS with SOD-1 gene mutations among different ethnic groups.

EEG and behavioural effects of polyamines (spermine and spermidine) on rabbits.

The EEG and behavioural changes induced by the administration of polyamines (spermine and spermidine) were studied in rabbit. Spermine and spermidine were administered at different doses (200 and 400 micrograms) into the mesencephalic ventricle (i.c.v.) both as a bolus and in constant perfusion (60 min duration). We also studied the effects of methamphetamine (MA) in a group of rabbits pretreated with spermine and spermidine 200 and 400 micrograms i.c.v. as bolus. Spermine caused a dose-related cortical synchronization associated with a partial sedation; spermidine induced cortical synchronization at a low dose without any behavioural changes while at higher dose (after perfusion) cortical desychronization with an arousal behavioural pattern occurred. The possible interaction of these substances with the mesolimbic dopaminergic system is discussed on the basis of their potential neuroleptic action.

Neurophysiological changes induced by 5-HT reuptake inhibitors in rabbits.

The EEGraphic, behavioural and autonomic changes induced by the administration of some inhibitors of serotonin (5-HT) reuptake were evaluated in the rabbit. The drugs examined were: Alaproclate (Ala), Citalopram (Cit), Fluoxetine (Fluo), Fluvoxamine (Fluvo), Indalpine (Ind), Zimelidine (Zim). It seems that all these drugs would act exclusively or prevalently on 5-HT uptake. The changes of the parameters studied were not homogeneous. Some of these drugs (Cit, Zim) induced an EEGraphic and behavioural "arousal" pattern, others (Fluo, Fluvo) a "slow wave sleep" one, others (Ala, Ind) a biphasic one (alteration of the two above-mentioned patterns). The possible hypotheses subtending these data are discussed.

Experimental study on central effects of carboxyethyl-gamma-aminobutyric acid (CEGABA).

The central effects of carboxyethyl-gamma-aminobutyric acid (CEGABA) have been studied both in rabbits and in the guinea pig myoclonus model. This drug caused EEG synchronization and behavioural sedation both after intravenous (i.v.) and intracerebroventricular (i.c.v.) administration in a dose-dependent manner, in rabbits. CEGABA showed a protective action against myoclonus induced by means of L-5-HTP in young guinea pigs. These data substantiate the hypothesis that CEGABA is a drug active on the central nervous system and probably exerts its action by strengthening cortical inhibition and/or directly acting on lower brainstem.

Acute experimental allergic encephalitis. Treatment with fungal polysaccharides.

This report describes the effects of a fungal polysaccharide mixture on the Experimental Allergic Encephalitis (EAE) in guinea pigs. The clinical, histopathological and IgG intrathecal synthesis related studies in the EAE sensitized group was compared with that observed in EAE sensitized groups treated with fungal polysaccharides. The results indicate that the fungal polysaccharide mixture is capable of inducing a more localized and milder inflammatory reaction in the guinea pig with EAE. We hypothesize that the fungal polysaccharides can activate complement by the alternative pathway, subtracting it to the specific immune response to EAE.

Transient intrathecal IgG synthesis in herpes zoster myelitis: 2 case reports.

Alterations in cerebrospinal fluid in 2 cases of viral myelopathy associated with herpes zoster infection are reported. Viral myelopathy is a rare complication of herpes zoster. Quantitatively there was a slight increase in IgG production and oligoclonal IgG bands were detected by isoelectric focusing. These parameters returned to normal after 1 year suggesting a transient involvement of the central nervous system.

Influence of L-5-hydroxytryptophan and DL-p-chlorophenylalanine on neurophysiological profiles of serotonin reuptake inhibitors in rabbits.

In a previous study we noted that some drugs, which exert their action by inhibiting serotonin (5-HT) reuptake, caused different EEGraphic, behavioural and autonomic patterns. These drugs (Alaproclate, Citalopram, Fluoxetine, Fluvoxamine, Indalpine, Zimelidine) have now been studied in two groups of animals pretreated with L-5-hydroxytryptophan (L-5-HTP), the 5-HT precursor, and with DL-p-chlorophenylalanine (PCPA), a 5-HT depletor. The administration of 5-HT reuptake inhibitors, after pretreatment with L-5-HTP, caused homogeneous changes, i.e. EEG cortical desynchronization and behavioural serotonergic syndrome. No significant modifications of the parameters examined were observed in the animals of the second group (pretreated with PCPA). The possible mechanisms of action of these drugs and some aspects of the role of serotonin in the central nervous system are discussed.

Serum and cerebrospinal fluid herpes simplex virus type 1 immunoglobulin G and M titers in four cases of herpes simplex encephalitis.

Herpes simplex virus type 1 (HSV-1) IgG and IgM ELISA titers were serially determined in serum and cerebrospinal fluid (CSF) samples from 4 patients with HSV-1 encephalitis during a follow-up period of 1-26 months. In 3 out of 4 patients HSV-1 IgM titers raised in CSF during the acute phase of disease, thus allowing differentiation between primary and reactivated forms of HSV-1 encephalitis. HSV-1 IgG titers showed a sharp elevation earlier in serum than in CSF. Specific IgG index documented a large intrathecal production of HSV-1 IgG and their persistence 2 years following clinical onset. The initial trend of serum and CSF specific IgG titer represents a reliable tool for a retrospective diagnosis of HSV-1 encephalitis.

Specific activation of B-cell clones within the central nervous system in course of herpes simplex encephalitis.

Total and virus-specific immunoglobulin (Ig) G oligoclonal bands were studied in paired serum and cerebrospinal fluid (CSF) of four patients with herpes simplex virus type 1 (HSV-1) encephalitis. We used the isoelectric focusing in agarose gel, a sensitive technique for protein separation, followed by passive transfer of proteins on nitrocellulose paper and specific immunostaining. Oligoclonal bands were observed in serum and CSF of all patients. HSV-1-specific oligoclonal IgG bands were present in the CSF only during a limited period of the disease, having their counterpart in serum during the remaining periods. Our findings contribute to tackle the issue of B-cell activation within central nervous system and peripheral blood compartments in course of HSV-1 encephalitis.