[Show abstract][Hide abstract] ABSTRACT: The mRNA levels of NKCC1, an inwardly directed Na(+), K(+)-2Cl(-) cotransporter that facilitates the accumulation of intracellular Cl(-), and of KCC2, an outwardly directed K(+)-Cl(-) cotransporter that extrudes Cl(-), were studied in surgically resected brain specimens from drug-resistant temporal lobe (TL) epilepsy (TLE) patients. Quantitative RT-PCR analyses of the mRNAs extracted from the human TLE-associated brain regions revealed an up-regulation of NKCC1 mRNA and a down-regulation of KCC2 mRNA in the hippocampal subiculum, compared with the hippocampus proper or the TL neocortex, suggesting an abnormal transcription of Cl(-) transporters in the TLE subiculum. In parallel experiments, cell membranes isolated from the same TLE-associated brain regions were injected into Xenopus oocytes that rapidly incorporated human GABA(A) receptors into their surface membrane. The GABA currents elicited in oocytes injected with membranes from the subiculum had a more depolarized reversal potential (E(GABA)) compared with the hippocampus proper or the neocortex. The NKCC1 blocker bumetanide or a temperature decrease of 10 degrees C shifted the GABA-current E(GABA) more negative in oocytes injected with membranes from TLE hippocampal subiculum, matching the E(GABA) of TL neocortex-injected oocytes. We conclude that the anomalous expression of both Cl(-) transporters, NKCC1 and KCC2 [corrected] in TLE hippocampal subiculum probably causes altered Cl(-) transport in the "epileptic" neurons, as revealed in the microtransplanted Xenopus oocytes, and renders GABA aberrantly "exciting," a feature that may contribute to the precipitation of epileptic seizures.
Full-text · Article · Jun 2006 · Proceedings of the National Academy of Sciences
[Show abstract][Hide abstract] ABSTRACT: The main action of erythropoietin (EPO) is to regulate the production of red cells. However both experimental evidence and clinical experience suggest that erythropoietin has a positive effect on skeletal and cardiac muscle. Mice lacking EPO or its receptors suffer from hearth hypoplasia and have a reduced number of proliferating cardiac myocytes. EPO receptors are expressed on mouse primary satellite cells and in cultured myoblasts, and their stimulation appears to enhance proliferation and reduce the differentiation of both cell types. Moreover EPO is capable of promoting angiogenesis in muscle cells, which provides an additional route to increase oxygen supply to active muscles. In men, the effects of EPO on muscle cells are suggested by the illegal use of EPO by agonistic and amateur athletes to enhance their performances. In some athletes EPO improved their long-duration muscular performances much more than expected on the basis of the increment of the blood hemoglobin alone. Our proposal is to investigate the effect of EPO treatment in various animal models of muscular dystrophies (MD), which are common hereditary primary muscle disorders characterized by muscle damage and wasting, to date without any effective treatment. The ability of EPO to induce the proliferation of satellite cells in the presence of differentiating conditions, typical of the damaged muscle, may represent a tool to expand the cellular population competent for muscle repair. This would lengthen the period when muscles can be efficiently repaired. In the presence of positive results, the possibility could be considered of selecting some of the human forms of MD and treating the patients with EPO.
No preview · Article · Feb 2004 · Medical Hypotheses
[Show abstract][Hide abstract] ABSTRACT: Facioscapulohumeral muscular dystrophy has a distinctive regional distribution but variable clinical expression and may be markedly asymmetrical. We report two patients presenting weakness and wasting confined to a single lower limb. Creatine kinase was slightly increased, electromyogram and muscle biopsy were myopathic. Muscle computed tomography showed normal shoulder, mid-arm, pelvic and mid-thigh scans but involvement of calf muscles. In both cases, weakness of facial and periscapular muscles was found in other family members unaware of the disease. Molecular analysis showed 4q35 deletion in one family. These cases broaden the presentation of facioscapulohumeral muscular dystrophy to include isolated monomelic atrophy of lower limb with calf muscle involvement.
No preview · Article · Dec 2002 · Neuromuscular Disorders
[Show abstract][Hide abstract] ABSTRACT: In 1995 Laing et al. (Am J Hum Genet 56(1995)422) described a single family with nine members affected by an autosomal dominant infantile onset distal myopathy. This family generated a LOD score of 2.6 for a locus on chromosome 14. We describe two families with an infantile onset distal myopathy: a new family with four affected members and the family previously described by Scoppetta et al. (Acta Neurol Scand 92(1955)122) in both of which haplotype segregation was compatible with linkage to the same chromosome 14 locus, generating LOD scores of 0.9 at a penetrance of 100% for the markers D14S283 and D14S64 (theta=0) in both families. The loci for autosomal recessive hereditary inclusion body myopathy and Nonaka myopathy on chromosome 9 and for autosomal dominant distal myopathy of Markesberry-Griggs and Udd on chromosome 2q31-33 were excluded by linkage analysis. The disease followed a uniform course with selective wasting of the anterior tibial muscles, starting in infancy and recognizable by a characteristic clinical sign of the 'hanging big toe'. This was followed by slow progression, with involvement of the finger and wrist extensor muscles in the third decade and proximal limb muscles in the fourth decade. Interestingly, we also found evidence of an accompanying mild peripheral neuropathy in the oldest individual with hypomyelination of numerous large myelinated fibres. In addition, this patient's muscle biopsy also showed autophagic vacuoles and numerous intranuclear tubulo-filamentous inclusions of 15-20 nm diameter. Given that all three families with infantile onset distal myopathy are compatible with linkage to the same locus on chromosome 14, this study supports evidence for, and enlarges the clinical and neuropathological spectrum of the distal myopathy on chromosome 14.
No preview · Article · Feb 2001 · Neuromuscular Disorders
[Show abstract][Hide abstract] ABSTRACT: The aim of this study was to investigate the clinical efficacy of clozapine, an atypical neuroleptic, on L-dopa induced dyskinesias of Parkinson's disease.
In an open study, a group of 10 PD patients was treated with low dosage clozapine (mean 30 mg/day) for a 4-month period and L-dopa dyskinesias were evaluated in basal conditions and during clozapine treatment after the usual morning dose of clozapine. We utilized the AIMS for evaluation of dyskinesias and UPDRS for the assessment of motor performances.
Clozapine produced a significant (P<0.05) reduction of dyskinesias 1 week after the therapy onset. This effect was more pronounced at the end of the 2nd week and remained stable through the following months. We did not observe significant variations of motor performances.
A low dose of clozapine appears to be beneficial for patients with L-dopa induced dyskinesias that do not respond to other drugs and therapeutic measures.
No preview · Article · Jun 1998 · Acta Neurologica Scandinavica
[Show abstract][Hide abstract] ABSTRACT: The “distal myopathies” include autosomal dominant, autosomal recessive, and sporadic disorders. Two of the recessive disorders are considered to be definitive entities: Miyoshi's myopathy, which has an early adult onset and first involves the calf muscles, and distal myopathy with rimmed vacuoles.
We here describe the cases of two sisters and compare them with previously reported cases. The disorder in our patients is characterised by: a) autosomal recessive inheritance; b) onset in early adult life; c) initial involvement of the tibialis anterior and peroneal muscles; d) subsequent involvement of the calf muscles spreading to the proximal muscles of the legs and, later, the arms; e) a moderately disabling evolution over a period of 10–12 years; f) marked and stably high serum levels of CK and other enzymes; g) EMG evidence of myopathic damage, with fibrillation at rest; and h) a histological picture of dystrophic myopathy, with atrophy of mainly type 2 fibres.
We think that this syndrome is different from the two forms of autosomal recessive distal myopathy mentioned above.
No preview · Article · Nov 1997 · The Italian Journal of Neurological Sciences
[Show abstract][Hide abstract] ABSTRACT: The term Distal Myopathy is used to describe a heterogeneous group of primary muscle disorders characterized by muscular weakness and atrophy beginning in the hands or legs or feet. Because of the limited number of cases and since there are no definite molecular criteria available so far, the existing classifications are still temporary, based on a few large kindreds with homogeneous and distinctive clinical picture. We are here presenting a classification which identifies 7 forms of Distal Miopathy, four of whom with autosomal dominant inheritance, three with autosomal recessive one. The main clinical and laboratory features of each form are then described.
No preview · Article · Jan 1997 · Nuova Rivista di Neurologia
[Show abstract][Hide abstract] ABSTRACT: Multiple symmetric lipomatosis (MSL) is characterized by enlarging, painless fat deposits in the neck and upper trunk. It is regarded as a benign proliferative disorder of adipose tissue. Recently a link with mitochondrial disorders has been suggested: 1. MSL occurs in patients with mitochondrial DNA (mtDNA) mutations 2. Mitochondrial abnormalities have been shown in some MSL patients. It has been suggested that MSL is a speciphic disorder of brown adipose tissue (BAT) based on the typical distribution and morphological and biochemical findings on cultured adipocytes obtained from lipectomy. BAT is peculiarly enriched in mitochondria and shows a highly active oxidative metabolism. We present two families with mitochondrial encephalomyopathy in which MSL is associated with two different mtDNA point mutations in the same gene: In family 1, several members harboring the A8344G in tRNA gene mutation presented unilateral or bilateral lipomas. The abundance of the mutation could be correlated to the clinical presentation of the lipomas. In Family 2 MSL was associated to multisystem involvement and a G8363A mutation in the same gene. We propose that due to mitochondrial dysfunction, BAT adipocytes could undergo to progressive lipid accumulation proliferation eventually leading to MSL.
[Show abstract][Hide abstract] ABSTRACT: Distal myopathies are currently regarded as a non-homogeneous group of disorders including different autosomal dominant, recessive and sporadic forms.
The cases of a mother and her son and daughter are described and compared to previously reported cases from 4 families. Despite minor differences, the clinical picture is remarkably homogeneous, both within the same family and among different families.
A distinct clinical form can be identified including: a) autosomal dominant inheritance; b) onset in infancy or childhood with peroneal muscles weakness; c) not disabling evolution in spite of possible late involvement of muscles others than tibio-peroneal; d) usually normal serum CK and other muscle enzymes; e) EMG evidence of primary myogenic damage; f) morphological findings of non-specific myopathy. Because of the benign evolution and the absence of true dystrophic changes in most biopsies we suggest the term infantile autosomal dominant distal myopathy should be preferred to infantile autosomal dominant distal muscular dystrophy.
[Show abstract][Hide abstract] ABSTRACT: On the long term Parkinson Disease (PD) treatment is often complicated by the occurrence of motor fluctuations. To find out whether early treatment of PD with levodopa, dopaminoagonists or 1-deprenyl is associated with any difference in motor fluctuations occurrence, the Italian Parkinson Study Groups initiated a multicenter, randomized study. Since November 1988, 475 patients cequiring effective treatment for idiopathic PD have been randomized to receive levodopa, dopoamine agonists or deprenyl. After 2 months of therapy, all patients evaluated with the Unified Parkinson Disease Rating Scale showed a significant amelioration. Daily living activities were more impaired in patients treated with deprenyl. Study design is presented and first resuts are discussed.It trattamento a lungo termine del Morbo di Parkinson spesso complicato dalle fluttuazioni motorie. Per valutare se il trattamento precoce della malattia di Parkinson con levodopa, dopaminoagonisti e l-deprenil sia associato a un diverso rischio di comparasa della fluttuazione, l'Italian Parkinson Study Group ha organizzato uno studio multicentrico e randomizzato. Dal novembre 1988, 475 pazienti affetti da parkinson idiopatico sono stati randomizzati alle diverse terapie. A 2 mesi dall'inclusione tutti i pazienti valutati con la Unified Parkinson Disease Rating Scale mostravano un significaativo miglioramento clinico. Non stata osservata una differenza significativa di efficacia fra le diverse terapie sui punteggi a eccezione del punteggio relativo alle attivit quotidiane significativamente meno influenzate dal deprenyl.
No preview · Article · Nov 1992 · The Italian Journal of Neurological Sciences
[Show abstract][Hide abstract] ABSTRACT: Miller Fisher Syndrome (MFS), which is characterized by ophthalmoplegia, ataxia and tendon areflexia, is generally considered as a clinical variant of Guillain-Barré Syndrome. However some features of the disease are still debated, particularly regarding possible central nervous system involvement. After presenting two new cases of MFS, the authors provide a critical review of the literature and discuss the nosographical position of the disease. The main conclusions can be summarized as follows: MFS is a predominantly axonal inflammatory neuropathy with prevailing involvement of oculomotor nerves. It is associated to spinal multi or polyneuropathy, which in mildly affected cases is manifested by areflexia, while in severe ones it can be responsible of sense and/or motor impairment. In addition to peripheral neuropathy CNS involvement, exclusive or more marked in posterior fossa, occurs not infrequently. The prognosis of the disease is often benign, but disabling or even fatal outcome is possible. Corticosteroid treatment, possibly because of antiinflammatory and/or immunosuppressive action, could be effective in some patients. Finally, in spite of some similarities with GBS, MFS should be considered as a separate entity with its own nosographical position.
No preview · Article · Jul 1991 · Rivista di neurologia
[Show abstract][Hide abstract] ABSTRACT: Most of Parkinson's disease patients treated with Levodopa develop the Long Treatment Levodopa Syndrome. Many authors showed a correlation between clinical features and plasma level of Levodopa. In our study, five parkinsonian patients with severe clinical response fluctuations, oral levodopa treatment was replaced by repeated continuous infusions of Levodopa (with oral carbidopa). Our results confirm that repeated intravenous infusion are very effective in PD patients with LTS.
No preview · Article · Jan 1991 · Rivista di neurologia
[Show abstract][Hide abstract] ABSTRACT: In myasthenia gravis (MG) a typical decrementing response is frequently revealed with repetitive stimulation (RS) in clinically unaffected muscles. However, RS is unlikely to give normal results in weak muscles. In two of our patients we found a normal response in clinically affected muscles. However, a decrementing response surprisingly appeared after the administration of anticholinesterase drugs. A possible explanation for this apparently paradoxical effect is as follows: some junctions are already blocked at rest, whereas others function normally both at rest and during RS. As a consequence, the initial compound muscle action potential (CMAP) is reduced in amplitude and shows no further decrement on RS. Anticholinesterase drugs reverse some blocks, therefore causing the CMAP increase in amplitude. However, these labile junctions are more prone than normal to synaptic fatigue, so a decrementing response is produced on RS. This behavior, though not frequently encountered, can account for some negative results of RS in MG.
No preview · Article · Mar 1990 · Electroencephalography and Clinical Neurophysiology
[Show abstract][Hide abstract] ABSTRACT: The authors briefly describe the commonest forms of mitochondrial myopathies particularly those associated with disorders of ocular motility. They report their series of four patients suffering from ptosis of the eyelid caused by mitochondrial myopathies. The ptosis was corrected surgically in all cases by means of Müller's muscle adaptation technique. The authors discuss their results and the indication for this technique.
No preview · Article · Feb 1990 · Annales de Chirurgie Plastique Esthétique