ABSTRACT
BACKGROUND: Event-related potentials (ERPs) have been proposed as a neurophysiological biomarker to capture cognitive dysfunction in multiple sclerosis (MS). Few studies have evaluated the relationships between ERPs and brain atrophy as known marker of structural brain damage related to cognitive impairment (CI). OBJECTIVES: To explore the relationships of brain atrophy, including of the cortex and deep grey matter, with ERP abnormalities and cognitive function, as defined using the Brief Repeatable Battery of Neuropsychological Tests (BRBN). RESULTS: Seventy-eight patients with relapsing-remitting MS were enroled, of which 38 (48.7%) had CI. Independent t-test comparisons of the ERP parameters found a significant difference in P300 wave latency, with a latency of 343.7 ± 32.6 ms in the CI group vs. 320.3 ± 16.5 ms in the cognitively preserved (CP) group (p = 0.001). Significant differences in the MRI measurements, including the cortex (p = 0.02) and deep grey matter structures [thalamus (p = 0.001), amygdala (p = 0.030), and nucleus accumbens (p = 0.004)) were observed, with lower measurements in the CI group. Regression models were also performed to explore the impact of brain volumes on ERP parameters. This showed a relationship between P300 latency and the lower amygdala (p = 0.02) and hippocampus (p = 0.03) volumes, while the amplitude of the P300 was significantly associated with a lower cortex volume (p = 0.01). CONCLUSION: Cortex volume emerged as the most significant predictor of the P300 amplitude. The amygdala and hippocampal volumes were found to influence P300 latency, highlighting the role of deep grey matter atrophy in ERPs for the first time. The combination of structural MRI and neurophysiological techniques, sensitive to diverse aspects of MS pathology, could improve the understanding of CI in MS and its neurodegenerative and inflammatory substrate.
Subject(s)
Multiple Sclerosis, Relapsing-Remitting , Multiple Sclerosis , Atrophy/pathology , Cognition , Evoked Potentials , Gray Matter/diagnostic imaging , Gray Matter/pathology , Humans , Magnetic Resonance Imaging , Multiple Sclerosis/diagnostic imaging , Multiple Sclerosis/pathology , Multiple Sclerosis, Relapsing-Remitting/diagnostic imaging , Multiple Sclerosis, Relapsing-Remitting/pathology , Neuropsychological TestsABSTRACT
OBJECTIVE: A multicentre observational study was aimed to assess the prevalence of late-onset Pompe disease (LOPD) in a large high-risk population, using the dried blood spot (DBS) as a main screening tool. DESIGN/METHODS: 17 Italian neuromuscular centres were involved in the late-onset Pompe early diagnosis (LOPED) study. Inclusion criteria were: (1) age ≥5â years, (2) persistent hyperCKaemia and (3) muscle weakness at upper and/or lower limbs (limb-girdle muscle weakness, LGMW). Acid α-glucosidase (GAA) activity was measured separately on DBS by fluorometric as well as tandem mass spectrometry methods. A DBS retest was performed in patients resulted positive at first assay. For the final diagnosis, GAA deficiency was confirmed by a biochemical assay in skeletal muscle, whereas genotype was assessed by GAA molecular analysis. RESULTS: In a 14-month period, we studied 1051 cases: 30 positive samples (2.9%) were detected by first DBS screening, whereas, after retesting, 21 samples were still positive. Biochemical and molecular genetic studies finally confirmed LOPD diagnosis in 17 cases (1.6%). The median time from the onset of symptoms/signs to diagnosis was 5â years. Among those patients, 35% showed presymptomatic hyperCKaemia and 59% showed hyperCKaemia+LGMW, whereas 6% manifested with LGMW. CONCLUSIONS: LOPED study suggests that GAA activity should be accurately screened by DBS in all patients referring for isolated hyperCKaemia and/or LGMW. A timely diagnosis was performed in five patients with presymptomatic hyperCKaemia, but two had already manifested with relevant changes on muscle morphology and MRI. Consequently, enzyme replacement therapy was started in 14/17 patients, including the 2 patients still clinically presymptomatic but with a laboratory evidence of disease progression.
Subject(s)
Glycogen Storage Disease Type II/diagnosis , Adult , Age of Onset , Creatine Kinase/blood , Early Diagnosis , Female , Fluorometry , Glycogen Storage Disease Type II/genetics , Glycogen Storage Disease Type II/therapy , Humans , Male , Middle Aged , Muscle Weakness/etiology , Muscle, Skeletal/pathology , Pathology, Molecular/methods , Reproducibility of Results , Risk , Tandem Mass Spectrometry , alpha-Glucosidases/geneticsABSTRACT
The objective of this study was to describe a large Italian cohort of patients with late-onset glycogen storage disease type 2 (GSDII) at various stages of disease progression and to evaluate the clinical effectiveness of alglucosidase alpha enzyme replacement therapy (ERT). Previous studies showed in late-onset patients ERT efficacy against placebo and variable response in uncontrolled studies. Seventy-four juvenile or adult GSDII patients were treated with ERT in a multicenter open label, non-randomized study, from 12 months up to 54 months. Recombinant human alpha glucosidase (rh-GAA) was injected by intravenous route at 20 mg/kg every second week. Patients were divided into three groups according to ERT duration: Group A received treatment for 12-23 months (n = 16), Group B for 24-35 months (n = 14), and Group C for more than 36 months (n = 44). Clinical assessment included a 6-min walk test (6MWT), forced vital capacity (FVC), the Walton and Gardner-Medwin score, the number of hours of ventilation, body mass index, echocardiography and blood creatine kinase (CK). Included in our cohort were 33 males and 41 females (M:F = 0.8:1), with a mean age at first symptoms of 28.3 years (range 2-55 years) and a mean age of 43 years at study entry (range 7-72 years). Seven wheelchair bound patients, as well as 27 patients requiring ventilation support, were included. After treatment we could observe an increase in distance walked on the 6MWT in the large majority of patients (48/58; 83%), with an overall mean increase of 63 m (from 320 ± 161 to 383 ± 178 m). After treatment in the majority of patients FVC was improved or unchanged (45/69; 65%). In ventilated patients we observed an improvement in average number of hours off the ventilator (from 15.6 to 12.1 h). Six patients stopped mechanical ventilation and two others started it. The effect of therapy was not related to ERT duration. Nine of 64 patients (13%) that underwent to echocardiography showed a variable degree of cardiac hypertrophy (left ventriculum or septum), and a positive effect was observed after 36 months of ERT in one adult case. Discontinuation of treatment occurred in four patients: one drop-off case, one patient died for a sepsis after 34 months of treatment and two patients stopped ERT for worsening of general clinical condition. Mild adverse effects were observed in four cases (5%). This study represents the largest cohort of late-onset GSDII patients treated with ERT, and confirm a positive effect of treatment. These results, obtained in a large case series on therapy, indicate a favourable effect of ERT therapy, even in more advanced stage of the disease.
Subject(s)
Enzyme Replacement Therapy/methods , Glycogen Storage Disease Type II/drug therapy , Observation , alpha-Glucosidases/therapeutic use , Adolescent , Adult , Aged , Body Mass Index , Child , Cohort Studies , Echocardiography , Female , Glycogen Storage Disease Type II/physiopathology , Heart Rate/drug effects , Humans , Italy , Male , Middle Aged , Physical Examination , Respiration/drug effects , Severity of Illness Index , Statistics, Nonparametric , Time Factors , Treatment Outcome , Vital Capacity , Walking/physiology , Young AdultABSTRACT
The objective of this study was to study genetic and phenotypic features of a family with X-linked Charcot-Marie-Tooth consisting of a healthy father, affected mother, two affected sons and one healthy one. A detailed electrophysiological and neuroimaging study, along with sequencing of the Cx32 gene, was performed in all family members. A novel Cx32 123 G>C mutation, determining an aminoacid variation (Glu41Asp), was found in the mother and the affected sons. An alteration in brainstem evoked potentials was found in the mother and one affected son. The affected son, who underwent magnetic resonance imaging, showed symmetrical hyperintensities in paratrigonal white matter, not found in his heterozygous mother, while both subjects exhibited alterations in brain metabolite ratios derived from localised proton-magnetic resonance spectroscopy. These data extend previous findings about central nervous system involvement in Cx32 mutated subjects and further support a functional role of the protein expression in oligodendrocytes.
Subject(s)
Brain Stem/physiopathology , Charcot-Marie-Tooth Disease/genetics , Connexins/genetics , Genetic Diseases, X-Linked/genetics , Genetic Predisposition to Disease/genetics , Mutation, Missense/genetics , Adolescent , Adult , Aspartic Acid/analogs & derivatives , Aspartic Acid/metabolism , Brain Chemistry/genetics , Brain Stem/metabolism , Brain Stem/pathology , Charcot-Marie-Tooth Disease/diagnosis , Charcot-Marie-Tooth Disease/physiopathology , Creatinine/metabolism , DNA Mutational Analysis , Evoked Potentials/genetics , Female , Genetic Diseases, X-Linked/diagnosis , Genetic Diseases, X-Linked/physiopathology , Genetic Testing , Humans , Lateral Ventricles/pathology , Linkage Disequilibrium/genetics , Magnetic Resonance Spectroscopy , Nerve Fibers, Myelinated/pathology , Neural Conduction/genetics , Neural Pathways/pathology , Neural Pathways/physiopathology , Pedigree , Telencephalon/metabolism , Telencephalon/pathology , Telencephalon/physiopathology , Gap Junction beta-1 ProteinABSTRACT
OBJECTIVE: Immunomodulatory drugs (IDs) (interferon beta (IFNgamma) and glatiramer acetate (GA)) reduce relapse rate and disease progression in relapsing remitting multiple sclerosis (RRMS) but extensive data are not available on the effectiveness and tolerability of these drugs in childhood or adolescence. The aim of this study was to evaluate the impact of IFNbeta and GA in MS patients treated before 16 years of age. METHODS: A research group (Immunomodulatory Treatment of Early onset MS (ITEMS)) was promoted in Italy to collect a large series of patients affected by clinically definite and RRMS and treated with IDs before 16 years of age. Fifteen centres recognized subjects suitable for inclusion: 76 patients (52 females) were collected with a mean age at onset of 12.4 (SD 2.5) years, a mean disease duration of 18.6 (SD 14.7) and a relapse rate of 3.1 (SD 2.9). RESULTS: Results were evaluated in 65 (45 females) subjects with a pretreatment and a treatment duration >3 months: 38 were treated with IFNbeta-1a once weekly (Avonex), 18 with IFNbeta three times weekly (16 with Rebif, 2 with Betaferon) and nine with GA (Copaxone). The mean pretreatment period was respectively 20, 18 and 9.2 months. The treatment duration lasted respectively 23.3, 40.7 and 33.3 months. The mean annualized relapse rate decreased dramatically during the treatment: from 2.4 to 0.4 in the Avonex group, from 3.2 to 0.8 in the Rebif-Betaferon group and from 2.8 to 0.25 in the GA group. The mean final EDSS scores were respectively (in brackets the initial scores): 1.3 (1.4), 1.6 (1.8) and 0.6 (1.1). In the whole group, the final score was unchanged or reduced in all subjects except eight. Clinical side effects were recorded in 41/65 subjects (mainly in subjects treated with IFNbeta), abnormal laboratory findings were observed in 13/65 subjects: they were transient in most cases. IFNgamma was stopped in six cases: in four because of inefficacy and in two cases because of side effects. CONCLUSIONS: Sixty-five clinically definite MS subjects were treated during childhood or adolescence with IDs. The treatment reduced the relapse rate and the progression of the disease in most cases. Side effects were common in subjects treated with IFNbeta but were well tolerated in most cases.
Subject(s)
Adjuvants, Immunologic/therapeutic use , Interferon-beta/therapeutic use , Multiple Sclerosis/immunology , Adolescent , Age of Onset , Child , Drug Administration Schedule , Female , Humans , Interferon beta-1a , Interferon-beta/administration & dosage , Male , Multiple Sclerosis/drug therapy , Multiple Sclerosis/physiopathology , Recurrence , Treatment OutcomeABSTRACT
OBJECTIVE: To estimate the presence of familial aggregation and determine the contribution of genetic factors to familial clustering of MS in patients coming from Sardinia, a Mediterranean island considered a genetically homogeneous, isolated area having high disease incidence and prevalence. METHODS: Recurrence risk in siblings of 901 Sardinian patients and factors influencing risk (patient and sibling sex, patient age at onset, sibling birth cohort, and presence of affected relatives other than siblings) were examined. The presence of distant familial relationships among patients was evaluated by tracing the extended pedigrees of all patients with MS born in one Sardinian village. RESULTS: Twenty-three brothers and 36 sisters of the 2,971 siblings were affected with MS. Recurrence risk was greater in siblings of index patients with onset age less than 30 years (p < 0.01, increased risk 2.33 times) and having a relative with MS other than a sibling or parent (p < 0.01, increased risk 2.90 times). Pedigree analysis of patients from the village of L. showed that all 11 patients descended from 3 pairs of ancestors, whereas no cases occurred in the remaining 2,346 inhabitants. In descendants from the 3 couples, MS prevalence was dramatically greater than the regional average and 1.5 times greater than that observed in siblings of affected cases. CONCLUSIONS: Data from this study indicate that MS familial aggregation in Sardinians is influenced by genetic factors and that founder effect and the isolation of Sardinia can be considered causes of the enrichment of "etiologic" MS genes.
Subject(s)
Founder Effect , Genetic Predisposition to Disease , Life Tables , Multiple Sclerosis/genetics , Adult , Female , Humans , Italy , Male , Multiple Sclerosis/etiology , Nuclear Family , PedigreeABSTRACT
Low level phosphites and hypophosphites were completely converted into phosphates, via hydrogen peroxide generated by cathodic reduction of oxygen in acidic aqueous medium at a reticulated vitreous carbon electrode, in the presence of little amounts of Fe2+. The contemporary regeneration of Fe2+ by cathodic reduction of Fe3+, produced by the well known Fenton reaction, furnishes an excellent way to continuously produce little amounts of the Fenton reactive and, as a consequence, of the powerful oxidant hydroxyl radical HO.. The best conditions for the complete removal of phosphorous as phosphites and hypophosphites are reported.
Subject(s)
Ferrous Compounds/chemistry , Hydrogen Peroxide/chemistry , Phosphates/chemistry , Phosphites/chemistry , Electrolysis , Indicators and Reagents , Iron , Oxidation-Reduction , Oxygen , Water Pollutants, Chemical/analysisABSTRACT
Two methods for the analysis of antioxidants, based on polyacrylamide gel electrophoresis (PAGE) and gel permeation high performance liquid chromatography (HPLC) were developed. Both of them exploit the variations of the signal (band or peak) given by human serum albumin (0.2% w/v in 100 mM sodium phosphate pH 7) upon oxidation with hypochlorite (1% of a solution containing 4% active Cl), quantitatively determined by densitometric analysis or peak integration. Based on such changes, two formulas were defined which allowed the determination of the antioxidant activity of ascorbic acid (EC(50,PAGE)=4.8x10(-4) M, EC(50,HPLC)=3.6x10(-4) M), glutathione (EC(50,PAGE)=1.5x10(-4) M, EC(50,HPLC)=2.0x10(-4) M) and melatonin (EC(50,PAGE)=5.2x10(-4) M, EC(50,HPLC)=3.2x10(-4) M), chosen as reference compounds. A good correlation was found between the activities of these substances in the two assays, which are also in good agreement with literature data, indicating that the two methods are essentially equivalent. These assays could be useful for the screening of new antioxidant drugs for pathological conditions such as cataract, rheumatic diseases, atherosclerosis and Alzheimer's disease.
Subject(s)
Antioxidants/chemistry , Ascorbic Acid/chemistry , Chromatography, High Pressure Liquid/methods , Electrophoresis, Polyacrylamide Gel , Glutathione/chemistry , Humans , Hydrogen-Ion Concentration , Hypochlorous Acid , Melatonin/chemistry , Oxidation-Reduction , Serum Albumin/chemistryABSTRACT
Charcot-Marie-Tooth disease (CMT), or hereditary motor and sensory neuropathy (HMSN), is a clinically and genetically heterogeneous condition. Mutations of the myelin protein zero (MPZ) gene have been associated with CMT1B, Dejerine-Sottas disease, and congenital hypomyelination, which are inherited demyelinating neuropathies characterized by different clinical severity. HMSN type II (HMSN II) or CMT2, the axonal form of CMT, is genetically heterogeneous. Linkage to 1p35-p36 (CMT2A), 3q (CMT2B), and 7p (CMT2D) chromosomes has been reported in the disease; however, most HMSN II families do not link to any of the reported loci. In a large HMSN II Sardinian family, we found a missense mutation in the chromosome 1q MPZ gene. This Ser44Phe mutation was located in exon 2 and was present in the heterozygous state in all affected individuals. This is the first example of an HMSN II family showing an MPZ point mutation. The MPZ gene Ser44Phe mutation found in the HMSN II family presented in this study suggests that genetic analysis of HMSN II families should also include the MPZ gene, previously not considered to be involved in the axonal form of HMSN.
Subject(s)
Charcot-Marie-Tooth Disease/genetics , Myelin P0 Protein/genetics , Point Mutation , Adult , Aged , Chromosomes, Human, Pair 17 , Female , Genetic Linkage , Humans , Male , Middle Aged , Multigene Family , Pedigree , Sequence Analysis, DNAABSTRACT
From the retrospective study of 3375 patients affected by clinically definite or probable multiple sclerosis (MS), 149 patients were collected with onset of the disease before the age of 16 years (4.4%). Female/male ratio was higher than that of the adult onset MS (AOMS) population (2.2 vs 1.6) particularly at ages of onset after 12 years (3.0, P = 0.007 vs AOMS). Among initial symptoms, those suggesting brainstem dysfunction (25%) were more frequent compared to other systems and compared to AOMs symptoms; motor and sensory disturbances were slightly less frequent (respectively 17.5% and 18.3%). Optic neuritis appeared in 16.5% of cases with onset in childhood and in 16.2% of cases with AOMS, cerebellar disturbances respectively in 9.1% and 7.7%. The first interattack-interval and the clinical course of early onset MS did not differ significantly from AOMS. In early onset MS patients with disease duration < 8 years, cases with EDSS > 6 were slightly more frequent than in the AOMS group (P = 0.04). The frequency of cases for different levels of disability was similar for disease duration > 8 years.
Subject(s)
Multiple Sclerosis/physiopathology , Adolescent , Age of Onset , Child , Disabled Persons , Disease Progression , Female , Humans , Male , Multiple Sclerosis/epidemiology , Recurrence , Retrospective StudiesABSTRACT
We studied the peripheral myelin protein gene PMP-22 in a large Sardinian family with Charcot-Marie-Tooth disease type 1A (CMT1A), in which the duplication commonly found in CMT1A was absent, but with evidence of linkage on chromosome 17. Sequencing of DNA and cDNA showed a missense point mutation G368-->T in exon 5 of PMP22, predicted to determine a valine for glycine substitution at codon 107, which could be plotted in the center of the PMP22 protein putative transmembrane domain III. Using sequence-specific oligonucleotide probes (SSOP), we found the point mutation in all affected CMT1A subjects but not in healthy family members or in 314 chromosomes of controls, thus indicating that the G368-->T point mutation is not a polymorphism. In the hypothetical model of PMP22, the amino acid at position 107 plots deeply into alpha-helical transmembrane domain III, a domain where point mutations have never previously been found. Although the same mutation was present in all CMT1A subjects examined, clinical findings showed a different stereotyped pattern in relation to the generation examined, for a progressive increase in severity and an earlier onset from the first to the third generation examined. Molecular analysis suggests that CMT1A disease in this family is due to the G368-->T point mutation, although other mechanisms may account for the clinical variability in the members of different generations.
Subject(s)
Charcot-Marie-Tooth Disease/genetics , Myelin Proteins/genetics , Point Mutation , Base Sequence , Genetic Linkage , Humans , Molecular Sequence Data , Pedigree , Polymerase Chain Reaction , Sequence Analysis, DNAABSTRACT
Two new cases of dilated cardiomyopathy (DC) caused by dystrophinopathy are reported. One patient, a 24 year old man, had a family history of X linked DC, while the other, a 52 year old man, had sporadic disease. Each had abnormal dystrophin immunostaining in muscle or cardiac biopsy specimens, but neither had muscle weakness. Serum creatine kinase activity was raised only in the patient with familial disease. Analysis of dystrophin gene mutations showed a deletion of exons 48-49 in the patient with familial DC and of exons 49-51 in the other. Dystrophin transcription in cardiac tissue from the patient with sporadic disease showed abundant expression, predominantly of the muscle isoform. This study, together with previous reports, suggests that some patients with DC have a dystrophinopathy that can be diagnosed using a combination of biochemical and genetic analyses.
Subject(s)
Cardiomyopathy, Dilated/genetics , Dystrophin/genetics , Gene Deletion , Adult , Cardiomyopathy, Dilated/metabolism , Dystrophin/analysis , Genetic Linkage , Humans , Immunohistochemistry , Male , Middle Aged , Muscle, Skeletal/chemistry , Myocardium/chemistry , Pedigree , Polymerase Chain Reaction , X ChromosomeABSTRACT
We have previously shown in a large X-linked pedigree that a deletion removing the dystrophin muscle promoter, the first muscle exon and part of intron 1 caused a severe dilated cardiomyopathy with no associated muscle weakness. Dystrophin expression was present in the muscle of affected males and transcription studies indicated that this dystrophin originated from the brain and Purkinje cell isoforms, upregulated in this skeletal muscle. We have now studied dystrophin transcription and expression in the heart of one member of this family. In contrast to the skeletal muscle, dystrophin transcription and expression were absent in the heart, with the exception of the distal Dp71 dystrophin isoform, normally present in the heart. The 43- and 50-kD dystrophin-associated proteins were severely reduced in the heart, despite the presence of Dp71, but not in skeletal muscle. The absence of dystrophin and the down-regulation of the dystrophin-associated proteins in the heart accounted for the severe cardiomyopathy in this family. The mutation present in these males selectively affects dystrophin expression in the heart; this could be secondary to the removal of cardiac-specific regulatory sequences. This family may represent the first example of a mutation specifically affecting the cardiac expression of a gene, present physiologically in both the skeletal and cardiac muscles.
Subject(s)
Cardiomyopathy, Dilated/genetics , Dystrophin/genetics , Gene Expression Regulation , Myocardium/metabolism , Sequence Deletion , Base Sequence , Cardiomyopathy, Dilated/metabolism , Cardiomyopathy, Dilated/pathology , Dystrophin/biosynthesis , Humans , Male , Molecular Sequence Data , Muscle, Skeletal/metabolism , Muscle, Skeletal/pathology , Myocardium/pathology , Organ Specificity , Pedigree , Polymerase Chain Reaction , Regulatory Sequences, Nucleic Acid , Transcription, GeneticABSTRACT
Intraventricular interferon (IFN) administration has been shown to improve the course of SSPE. However, in 2 patients treated with intraventricular IFN-alpha-2a over a long period, we observed the appearance of clinical and EMG signs suggestive of upper and lower motor neuron pathology. These signs improved slightly in one patient after the discontinuation of IFN. It is suggested that this poly-peptide may act on specific kinds of nervous cells which selectively suffer together in various well-known neurological diseases.
Subject(s)
Interferon-alpha/adverse effects , Subacute Sclerosing Panencephalitis/drug therapy , Adolescent , Electromyography , Female , Humans , Injections, Intraventricular , Interferon-alpha/therapeutic use , Male , Motor Neurons/drug effectsABSTRACT
OBJECTIVE: To study the role of HLA genes in susceptibility and resistance to multiple sclerosis (MS) in Sardinian patients. To verify whether HLA-DQA and HLA-DQB genes differed between unrelated (MSU) and related (MSR) patients, and whether relapsing-remitting and chronic progressive forms of MS are immunogenetically distinct entities. DESIGN: Case-control study of HLA-DQA and HLA-DQB gene frequency. SETTING: All patients investigated were followed up by our MS referral centers. PATIENTS: The study involved 116 MSU patients, 67 of whom had a relapsing-remitting form (MSr), 28 of whom had a chronic progressive from-the-onset form (MSc), and 21 of whom had a benign form (MSb), 32 patients with MSR, 19 parents and 27 healthy siblings of patients with MSR, and 86 controls. Selection of patients was random, while control subjects came from families without known immunologic diseases. All patients had definite MS. MAIN OUTCOME MEASURE: Statistical analysis of gene frequencies was conducted with the chi 2 test with correction (Pc) for the alleles investigated, as was decided before the study began. RESULTS: The DQA1*0301 allele was found to be increased in patients (MSU vs controls, Pc = .008; patients with MSc vs controls, Pc = .001; patients with MSR vs controls, Pc = .02; and parents vs controls, Pc = .04), while the DQA1*0102 allele was found to be diminished in patients with MSr vs controls (Pc = .001). Among the DQB genes, the DQB1*0502 allele was diminished in patients with MSr vs controls (Pc = .04), while the sum of DQB1*0201 and *0302 alleles was significantly increased in patients with MSR vs controls (Pc = .003). CONCLUSION: Both HLA-DQA and HLA-DQB genes influence genetic susceptibility and resistance to MS. The roles of these genes differ in the various forms of MS. Patients with MSU and MSR both share HLA-DQA susceptibility genes.
Subject(s)
Gene Frequency , HLA-DQ Antigens/genetics , Multiple Sclerosis/genetics , Adolescent , Adult , Amino Acid Sequence , Child , Female , HLA-DQ alpha-Chains , HLA-DQ beta-Chains , Humans , Italy , Male , Middle Aged , Molecular Sequence DataABSTRACT
Recent reports in clinical literature have suggested an antiepileptic effect of the xanthine oxidase inhibitor Allopurinol (ALL) when added to traditional drugs. However, other reports have failed to confirm beneficial effects of this drug. In view of these conflicting results, we have carried out a study aimed at evaluate the effects of ALL in different forms of epilepsy. The result that ALL possesses some antiepileptic effects in Lennox-Gastaut syndromes, characterized by numerous and severe fits, while it is scarcely effective in other forms of epilepsy, suggests that ALL might be involved in the purinergic-mediated inhibition similar to that described in experimental "status epilepticus" studies in animal models.
Subject(s)
Allopurinol/therapeutic use , Epilepsy/drug therapy , Anticonvulsants/therapeutic use , Female , Humans , MaleABSTRACT
Administration of diazepam (10 mg i.m.) to seven children (two girls and five boys) affected by infantile autism elicited paradoxical behavioural responses. Mainly, anxiogenic effect, unsocialized aggressive behaviour and explosive aggression were dramatically increased in comparison with the same symptoms present before and after treatment. The results show for the first time that benzodiazepines may elicit paradoxical behavioural response in autistic children. The possible involvement of an altered function at the level of GABA/benzodiazepine receptor complex is discussed.
Subject(s)
Aggression/psychology , Autistic Disorder/drug therapy , Diazepam/adverse effects , Aggression/physiopathology , Attention Deficit Disorder with Hyperactivity/drug therapy , Attention Deficit Disorder with Hyperactivity/physiopathology , Autistic Disorder/physiopathology , Autistic Disorder/psychology , Child , Female , Humans , Male , Receptors, GABA-A/drug effects , Receptors, GABA-A/physiologyABSTRACT
Lymphocyte subpopulations in cerebrospinal fluid (CSF) and peripheral blood (PB) were studied using monoclonal antibodies and the common membrane markers. The results in three groups of patients were compared: 36 subjects with 'non-immunological disorders' (NID), 14 subjects with multiple sclerosis (MS) and 6 with subacute sclerosing panencephalitis (SSPE). It was found that, in patients with NID, (1) 90% of cells were T lymphocytes, reactive with OKT3; (2) the helper/suppressor (T4/T8) ratios were the same in the CSF and the PB; (3) the OKIa1 percentage was lower in the CSF than in the PB; and (4) only a few cells were 'immature', reacting with OKT10. Using the membrane markers (E rosettes, Fc IgG receptors and surface immunoglobulins), on the other hand, it was noted that the majority of cells in the CSF were identified as suppressor T lymphocytes and surface immunoglobulin-positive B cells were less common than the Ia1 marker suggested. There were no significant differences between the CSF results in patients with NID and MS but the OKT3 lymphocytes were reduced in CSF samples from patients with SSPE.