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Biomedical subjects

I Illa

Publications and source records attributed to I Illa.

At least 37 records · Page 2Linked to original sources
PubMed2001

Genomic organization of the dysferlin gene and novel mutations in Miyoshi myopathy.

OBJECTIVE: Mutations in the skeletal muscle gene dysferlin cause two autosomal recessive forms of muscular dystrophy: Miyoshi myopathy (MM) and limb girdle muscular dystrophy type 2B (LGMD2B). The purpose of this study was to define the genomic organization of the dysferlin gene and conduct mutational screening and a survey of clinical features in 21 patients with defined molecular defects in the dysferlin gene. METHODS: Genomic organization of the gene was determined by comparing the dysferlin cDNA and genomic sequence in P1-derived artificial chromosomes (PACs) containing the gene. Mutational screening entailed conformational analysis and sequencing of genomic DNA and cDNA. Clinical records of patients with defined dysferlin gene defects were reviewed retrospectively. RESULTS: The dysferlin gene encompasses 55 exons spanning over 150 kb of genomic DNA. Mutational screening revealed nine novel mutations associated with MM. The range of onset in this patient group was narrow with a mean of 19.0 +/- 3.9 years. CONCLUSION: This study confirms that the dysferlin gene is mutated in MM and LGMD2B and extends understanding of the timing of onset of the disease. Knowledge of the genomic organization of the gene will facilitate mutation detection and investigations of the molecular biologic properties of the dysferlin gene.

Adolescent↗
PubMed2001

[Anti-GQ1b antibodies: usefulness of its detection for the diagnosis of Miller-Fisher syndrome].

BACKGROUND: To study the presence of anti-GQ1b antibodies as a tool for the diagnosis of Miller-Fisher syndrome (MFS). PATIENTS AND METHOD: We studied 54 patients with probable diagnosis of MFS and 10 patients diagnosed as Guillain-Barré syndrome plus ophthalmoplegia (1 case), Bickerstaff's encephalitis (1 case), relapsing ophthalmoplegia (7 cases) and relapsing diplopia (1 case). Results were compared with 130 patients with other disimmune neuropathies. Antibodies were detected by ELISA and checked by thin layer chromatography. Campylobacter jejuni serology was studied using a complement fixation test. RESULTS: Diagnosis of MFS was confirmed in 38 patients. A 97.3% were positive for GQ1b, being all negative for Campylobacter jejuni serology. A second test after 4-5 weeks of nadir was negative in 84.2% (16/19), concomitant with clinical recovery. CONCLUSIONS: Anti-GQ1b antibodies are useful markers for the differential diagnosis of MFS, specially with some acute brainstem disorders. Testing must be performed during the first four weeks of clinical course. This correlation between the triad ataxia, arreflexia and ophthalmoplegia and anti-GQ1b antibodies confirms that they are highly specific of MFS.

Antibodies↗
PubMed2001

Urokinase-dependent plasminogen activation is required for efficient skeletal muscle regeneration in vivo.

Plasminogen activators urokinase-type plasminogen activator (uPA) and tissue-type plasminogen activator (tPA) are extracellular proteases involved in various tissue remodeling processes. A requirement for uPA activity in skeletal myogenesis was recently demonstrated in vitro. The role of plasminogen activators in skeletal muscle regeneration in vivo in wild-type, uPA-deficient, and tPA-deficient mice is investigated here. Wild-type and tPA-/- mice completely repaired experimentally damaged skeletal muscle. In contrast, uPA-/- mice had a severe regeneration defect, with decreased recruitment of blood-derived monocytes to the site of injury and with persistent myotube degeneration. In addition, uPA-deficient mice accumulated fibrin in the degenerating muscle fibers; however, the defibrinogenation of uPA-deficient mice resulted in a correction of the muscle regeneration defect. A similar severe regeneration deficit with persistent fibrin deposition was also reproducible in plasminogen-deficient mice after injury, suggesting that fibrinolysis by uPA-mediated plasminogen activation plays a fundamental role in skeletal muscle regeneration. In conclusion, the uPA-plasmin system is identified as a critical component of the mammalian skeletal muscle regeneration process, possibly because it prevents intramuscular fibrin accumulation and contributes to the adequate inflammatory response after injury. These studies demonstrate the requirement of an extracellular proteolytic cascade during muscle regeneration in vivo.

Animals↗
PubMed2001

Randomized controlled trial of intravenous immunoglobulin versus oral prednisolone in chronic inflammatory demyelinating polyradiculoneuropathy.

This multicenter, randomized, double-blind, crossover trial compared a six week course of oral prednisolone tapering from 60 mg to 10 mg daily with intravenous immunoglobulin (IVIg) 2.0 g/kg given over one to two days for treating chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Twenty-four of the thirty-two randomized patients completed both treatment periods. Both treatments produced significant improvements in the primary outcome measure, change in an 11-point disability scale two weeks after randomization. There was slightly, but not significantly, more improvement after IVIg than with prednisolone, the mean difference between the groups in change in disability grade being 0.16 (95% CI = -0.35 to 0.66). There were also slightly, but not significantly, greater improvements favoring IVIg in the secondary outcome measures: time to walk 10 meters after two weeks and improvement in disability grade after six weeks. Results may have been biased against IVIg by the eight patients who did not complete the second arm of the trial. A serious adverse event (psychosis) attributable to treatment occurred in one patient while on prednisolone and in none with IVIg.

Administration, Oral↗
PubMed2001

Cathepsins are upregulated by IFN-gamma/STAT1 in human muscle culture: a possible active factor in dermatomyositis.

The aim of this work was to study which genes upregulated by the IFN-gamma/STAT1 system in human muscle might be involved in the process of muscle fiber atrophy in dermatomyositis (DM). These proteins included proteases (cathepsins B and L, calpain), proteins implicated in apoptosis and cell cycle (Bcl-x(l), Fas, p21), structural proteins (beta-actin, utrophin, desmin), and other proteins whose expression is known to be modified by IFN-gamma (neural cell adhesion molecule (N-CAM), major histocompatibility complex-I (MHC-I)). We performed immunocytochemistry, Western blot, and semiquantitative reverse transcriptase-polymerase chain reaction using human muscle cultures. We found upregulation of cathepsins B and L, bcl-x(l) and p21 while N-CAM, calpain, utrophin, desmin, beta-actin and Fas remained at basal levels. Immunohistochemistry on frozen sections from biopsies of patients with different muscle diseases showed upregulation of cathepsin L and calpain in perifascicular muscle fibers in DM. In view of these results, the increased expression of cathepsins L and B after IFN-gamma stimulation in muscle cultures and its inhibition using fludarabine, a STAT1 blocker, further support our previous studies and suggest that the increased expression of cathepsins detected in perifascicular muscle fibers in DM is mediated by IFN-gamma/STAT1 and contributes to their atrophy.

Adult↗
PubMed2001

Distal anterior compartment myopathy: a dysferlin mutation causing a new muscular dystrophy phenotype.

We report a family with a new phenotype of autosomal recessive muscle dystrophy caused by a dysferlin mutation. The onset of the illness is distal, in the muscles of the anterior compartment group. The disease is rapidly progressive, leading to severe proximal weakness. Muscle biopsy showed moderate dystrophic changes with no vacuoles. Dysferlin immunostaining was negative. Gene analysis revealed a frameshift mutation in the exon 50 (delG5966) of the DYSF gene. This phenotype further demonstrates the clinical heterogeneity of the dysferlinopathies.

Adult↗
PubMed2001

Chronic idiopathic sensory ataxic neuropathy: immunological aspects of a series of 17 patients.

Sensory ataxic neuropathies (SANs) are characterized by loss of proprioceptive sensations and preservation of muscle strength. They may be idiopathic or associated with different toxic, infectious or autoimmune causes. Reactivity against gangliosides containing disialosyl groups, particularly GD1b, has been reported in isolated cases of acute and chronic idiopathic ataxic neuropathies (iSAN) and different experimental findings (in vivo animal models and in vitro preparations) suggest that antidisialosyl or antiGD1b antibodies could play a role in the pathogenesis of some ataxic neuropathies. We present the clinical, immunological and immunohistochemical characteristics of 17 patients who had a chronic iSAN without gammopathy. Patients were selected from a large group of 130 subjects with SAN: 93 with known etiology and 37 with iSAN. IgM and IgG antibodies to GM1, GM2, GM3, aGM1, GD1a, GD1b, GD3, GT1b and GQ1b were investigated by ELISA (INCAT protocol) and thin layer chromatography. Immunohistochemistry, using biotinylated Ig extracted from the patientś serum, was performed on human dorsal root ganglia (DRG), spinal cord, anterior and posterior roots, sural nerve and muscle tissue. The mean age of the 17 patients was 62 (37-80 years). The most disabling features were unsteadiness and severe ataxia of gait. Only one patient of this group was wheelchair-bound. The clinical data of these 17 patients were similar to those of the other patients with SAN, except that progression was slower. Antibodies to GD1b, GD3 and GT1b were found in 1/17. Two more patients (one with an acute iSAN and one with chronic iSAN and gammopathy), also had antibodies to disialosyl or GD1b. No immunohistochemical pattern of reactivity was found in any of the tissues tested with the 17 sera. In summary, this study demonstrates antidisialosyl or anti GD1b antibodies only in 3/37 (8.1p. cent) of patients with iSAN, either acute, chronic, or with gammopathy. However, their value seems to be reinforced by the negativity of antiganglioside antibodies in the large group of patients with SAN of known etiology (0/93). Further studies will be necessary to confirm the importance of target antigens containing disialosyl moieties in a subset of iSAN patients. However, the negativity of antiganglioside antibodies in most cases suggests that the pathology of the sensory neurons and/or axons is probably not humorally mediated in the majority of patients with iSAN.

Adult↗
PubMed2000

Distal myopathies.

Distal myopathies are classified according to clinical, histopathological, and genetic patterns into the following: late adult onset type 1, or Welander myopathy, the first recognized distal myopathy with autosomal dominant inheritance and very recently linked to chromosome 2p; late adult onset type 2, or Markesbery-Griggs/Udd myopathy, autosomal dominant with linkage to chromosome 2q; early adult onset type 1, or Nonaka myopathy, an autosomal recessive disease linked to 9p1-q1 and considered indistinguishable from hereditary inclusion body myopathy; early adult onset type 2, or Miyoshi myopathy, with autosomal recessive inheritance linked to chromosome 2p12-p14; and early adult onset type 3, or Laing myopathy, autosomal dominant with linkage to chromosome 14. Very recently, dysferlin, a novel skeletal muscle gene, has been found mutated in Miyoshi myopathy and also in the limb girdle muscular dystrophy 2B, a disease with a completely different phenotype. This indicates that the classification of the distal and other genetically determined muscle diseases will probably change when these myopathies are understood at the molecular level. For example, it would be reasonable to use the term dysferlinopathies to describe all the diseases due to dysferlin mutations.

Adult↗
PubMed2000

Peripheral neuropathy associated with anti-GM2 ganglioside antibodies: clinical and immunopathological studies.

GM2 ganglioside is a potential peripheral nerve antigen for neuropathy-associated autoantibodies. However little data are available on their pathogenic effects, if any. In this study we have screened both neuropathy-associated and control sera for anti-GM2 antibodies and subsequently used high titre sera for immunohistological and complement mediated cytotoxicity studies. We identified abnormally elevated anti-GM2 antisera in the normal population, as well as in patients with peripheral neuropathies and other neurological diseases. GM2 antibodies were either mono-reactive, cross-reactive with GM1a, or cross-reactive with GalNAc-GM1b and/or GalNAc-GD1a. All GM2 antisera from neuropathy subjects and normal controls bound to, and were capable of complement-mediated lysis of the NSC-34 cell line which expresses high levels of membrane-associated GM2. However, in immunohistological studies on human and rodent peripheral nervous system tissues, no specific binding was seen with GM2 antisera, either cross-reactive with GalNAc-GM1b and GalNAc-GDla, or with GM1a. These data indicate that although GM2 antisera can lyse neural membranes containing GM2, this antigen(s) is not detectable by standard immunohistological techniques in human or rodent peripheral nerve. This raises doubts about their pathophysiological significance in human autoimmune neuropathy.

Adolescent↗
PubMed1999

Inter-laboratory validation of an ELISA for the determination of serum anti-ganglioside antibodies.

Anti-ganglioside antibodies are frequently sought in the sera of patients with autoimmune peripheral neuropathy, using an enzyme-linked immunosorbent assay (ELISA) as the principal method for antibody detection. Wide variations in assay performance between laboratories have been reported. In this study, we established a standardized ELISA method between laboratories within the European Inflammatory Neuropathy Cause and Treatment (INCAT) group and determined the inter-laboratory variance in assay performance using both the standardized INCAT method and in-house local methods. As expected, the inter-laboratory variances were greater using local methods than using the standardized method, producing titre estimates which could be 24.8 or 7.6 times larger or smaller, respectively, than the true means for these laboratories. Using the standardized method, the within laboratory measurement error accounted for 41% of the inter-laboratory variation, providing a theoretical upper limit to which technical improvements within laboratories could reduce inter-laboratory variation. These data describe the intrinsic weaknesses within the widely used ganglioside antibody ELISA methods and reinforce the importance of inter-laboratory cooperation within this area. Standardized serological reagents used in this study are available from INCAT members.

Antibodies↗
PubMed1999

Diagnosis and management of diabetic peripheral neuropathy.

Diabetic peripheral neuropathy (DPN) is one of the most commonly occurring major complications of diabetes. The disease may manifest in several clinical patterns: most frequently as distal symmetrical sensory polyneuropathy. Guidelines are available for the diagnosis of DPN by the primary care physician. These recommend that a review of diabetic patients, including a questionnaire and inspection and neurological examination of the feet, is undertaken annually. Techniques used for studying the disease process in clinical trials may include nerve conduction and quantitative sensory function tests, autonomic nervous system testing, post-ganglionic sudomotor function and skin biopsy. Current therapies for managing DPN are strict glycaemic control, palliative treatments and foot ulcer prevention. Future treatments aim to beneficially affect the underlying disease pathology and putative agents are currently being investigated.

Diabetic Neuropathies↗
PubMed1999

[Therapeutic advances in neuromuscular diseases].

The etiology of neuromuscular diseases varies widely as does their treatment. This study reports the treatment of patients with neuromuscular disease of autoimmune origin in addition to the therapy of muscular dystrophies. The mechanisms of action of the immunosuppressive drugs (glucocorticoids, azathiaprin, cyclosporin, methotrexate, chlorambucil, cyclophosphamide) and immunomodulators (plasmapheresis, Ig ev) currently used are analyzed, as are their indications, management and the methods which allow the control of therapeutic efficacy. The immunotherapies presently in experimental phases are also reviewed (oral tolerance, inhibition of cytokines, chemokines, etc.). Both molecular therapy (myoblast transplantation, genetic therapy, gentamycin) and anabolizing drugs administered after the favorable results of clinical trials (glucocorticoids, oxandrolone) and undergoing controlled clinical studies (albuterol, creation, etc.) on the treatment of muscular dystrophies are evaluated. Lastly, symptomatic treatments which improve the quality of life of patients with muscular dystrophy are analyzed.

Humans↗
PubMed1998

Utility of anti-Hu antibodies in the diagnosis of paraneoplastic sensory neuropathy.

Anti-Hu antibodies (Hu-Abs) were positive in 40 patients with paraneoplastic sensory neuropathy (PSN) and in 1 patient with idiopathic sensory neuropathy in a series of 126 patients who presented with clinical features suggestive of PSN. The specificity of Hu-Abs was 99% and the sensitivity was 82%. Nine (18%) PSN patients were Hu-Ab-negative, and their sera did not harbor other specific anti-neuronal or anti-ganglioside antibodies. Small cell lung carcinoma (SCLC) was the leading neoplasm in the Hu-Ab-positive (79%) and Hu-Ab-negative (44%) groups. This study confirms the value of Hu-Abs for the diagnosis of PSN and SCLC and also emphasizes that in patients with possible PSN, the absence of Hu-Abs does not exclude cancer, particularly in those patients with risk factors for SCLC.

Adult↗