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Biomedical subjects

M Mora

Publications and source records attributed to M Mora.

At least 73 records · Page 4Linked to original sources
PubMed1997

Blood thrombopoietin, IL-6 and IL-11 levels in patients with agnogenic myeloid metaplasia.

Agnogenic myeloid metaplasia (AMM) is a disease characterized by bone marrow megakaryocyte hyperplasia and clusters of megakaryocytes, in which many of the megakaryocytes are atypical. In order to elucidate the mechanisms of megakaryocytosis, ELISA assays of blood levels of thrombopoietin (TPO), interleukin-6 (IL-6) and interleukin-11 (IL-11) were done in 45 patients with AMM and compared with normal volunteer controls. Higher blood TPO levels were found in AMM than in controls (P < 0.0001), and blood TPO levels were correlated with the degree of marrow fibrosis (P = 0.0078). Blood levels of IL-6 were also significantly higher in AMM, when compared with controls (P < 0.0001). However, no correlation was found between blood IL-6 levels and degree of marrow fibrosis. No correlation was found between either TPO or IL-6 and the number of blood platelet counts, the number of marrow megakaryocytes, WBC counts, or the degree of splenomegaly. Blood IL-11 levels were undetectable in most patients and no significant difference was found in AMM as compared to controls. The present study demonstrated that, while in idiopathic thrombocytopenic purpura (ITP) or aplastic anemia, blood TPO levels are relatively correlated with the numbers of platelet and/or megakaryocyte mass, blood TPO levels do not correlate with blood platelet counts, or marrow megakaryocyte mass in AMM. Therefore, in AMM, other mechanisms such as the number of TPO receptors on platelets or megakaryocytes, c-MPL receptor abnormalities, abnormal production of TPO mRNA and so on, will have to be studied. Furthermore, TPO may play a significant role in the pathogenesis of marrow fibrosis; IL-6 may be a factor in the development of marrow megakaryocytosis but its elevated blood levels may represent a secondary immune phenomenon; and IL-11 probably does not play a significant role in causing marrow megakaryocytosis in this disease.

Biomarkers↗
PubMed1997

Heart-specific localization of emerin: new insights into Emery-Dreifuss muscular dystrophy.

Emery-Dreifuss muscular dystrophy (EDMD) is an X-linked inherited disease characterized by early contracture of the elbows, Achilles tendons and post-cervical muscles, slow progressive muscle wasting and weakness and cardiomyopathy presenting with arrhythmia and atrial paralysis: heart block can eventually lead to sudden death. The EDMD geneencodes a novel ubiquitous protein, emerin, which decorates the nuclear rim of many cell types. Amino acid sequence homology and cellular localization suggested that emerin is a member of the nuclear lamina-associated protein family. These findings did not explain the role of emerin nor account for the skeletal muscle- and heart-specific clinical manifestations associated with the disorder. Now we report that emerin localizes to the inner nuclear membrane, via its hydrophobic C-terminal domain, but that in heart and cultured cardiomyocytes it is also associated with the intercalated discs. We propose a general role for emerin in membrane anchorage to the cytoskeleton. In the nuclear envelope emerin plays a ubiquitous and dispensable role in association of the nuclear membrane with the lamina. In heart its specific localization to desmosomes and fasciae adherentes could account for the characteristic conduction defects described in patients.

Arrhythmias, Cardiac↗
PubMed1996

Developmental expression of dystrophin, dystrophin-associated glycoproteins and other membrane cytoskeletal proteins in human skeletal and heart muscle.

Dystrophin, utrophin and the dystrophin-associated glycoproteins, beta-dystroglycan and adhalin, were analyzed, together with the membrane cytoskeletal proteins beta-spectrin, vinculin and talin, and adult and fetal myosin heavy chains, in 25 normal human fetuses from 8 to 24 weeks of gestation. Dystrophin was present in heart and skeletal muscle from 8 weeks although in the latter was mainly in the cytoplasm at this stage. Utrophin expression increased until around gestational weeks 19/21, but by 24 weeks immunostaining and immunoblot band intensities had reduced. Beta-dystroglycan was scarce in skeletal muscle at 8 weeks, increased with maturation and was more abundant in heart of the same age. Adhalin appeared later than beta-dystroglycan on skeletal muscle fiber surfaces, positivity became more intense as the fibers matured. In heart adhalin was detectable only in groups of cells at 12-16 weeks. From 8 weeks all fetal myotubes expressed beta-spectrin on their surfaces, while vinculin and talin positivity was mainly at the periphery of the fascicles, increasing with age. Adult slow myosin was seen in most myotubes at 10 weeks. Secondary myotubes then formed which increasingly expressed adult fast myosin, while still retaining fetal myosin. By 24 weeks most fibers expressing adult slow myosin had lost fetal myosin and were more mature in the expression of most membrane proteins. Muscle membrane organization during human fetal development is a complex process and takes place earlier in heart than skeletal muscle.

Blotting, Western↗
PubMed1996

Clinical heterogeneity of adhalin deficiency.

We report adhalin deficiency in 8 patients with clinically diagnosed muscular dystrophy, dystrophic histopathological features, high plasma creatine kinase levels, normal expression of dystrophin, and marked variability of symptoms. Although the distribution of hyposthenia was similar in all 8 patients and predominantly involved muscles in the pelvic girdle, age at onset and rate of disease progression were highly variable: In 2 patients onset, at ages 24 and 25, was later than has been previously observed. We found no apparent relation between disease severity and the quantity of adhalin expressed. Two kinds of myopathy with adhalin deficiency have been reported: one caused by a mutation in the adhalin gene on chromosome 17 (primary adhalinopathy) and the other linked to chromosome 13. The product of the gene on chromosome 13 is probably associated with adhalin and its deficiency results in secondary adhalinopathy. The severity of clinical phenotypes in these adhalinopathies seems to relate more to the kind and site of the mutations than to the residual amount of the protein. We also detected a variable reduction in the laminin beta 1 subunit by immunohistochemistry in most patients, confirming that this is commonly associated with adhalin deficiency.

Adolescent↗
PubMed1996

Dystrophin-associated protein abnormalities in dystrophin-deficient muscle fibers from symptomatic and asymptomatic Duchenne/Becker muscular dystrophy carriers.

The absence of dystrophin in muscle fibers is associated with a major reduction in dystrophin-associated proteins (DAPs) and disruption of the linkage between the subsarcolemmal cytoskeleton and the extracellular matrix. We investigated the expression of the DAPs beta-dystroglycan, alpha-sarcoglycan, gamma-sarcoglycan and syntrophin as well as utrophin in the muscles of 13 Duchenne muscular dystrophy (DMD) carriers (with variable percentages of dystrophin-deficient fibers and with a range of clinical symptoms), 2 Becker muscular dystrophy (BMD) carriers (expressing a highly truncated protein in some fibers), 2 girls with a DMD-like phenotype, and 11 BMD carriers with almost normal dystrophin expression (reduced or patchy distribution in a few fibers only and rare dystrophin-deficient fibers). DAPs were highly reduced in all fibers lacking dystrophin in the DMD carriers, but were almost normal in the dystrophin-deficient fibers of the 2 BMD carriers with highly truncated dystrophin. In the 11 BMD carriers with nearly normal dystrophin, the few fibers with reduced or patchy dystrophin immunostaining also showed reduced DAP expression in correlation with dystrophin expression. Immunoblot for beta-dystroglycan and alpha-sarcoglycan confirmed the immunohistochemical findings. Utrophin expression was slightly increased in a proportion of fibers in the DMD and BMD carriers with dystrophin mosaicism. We found no correlation between utrophin expression and DAP expression. We conclude that absence or reduction of dystrophin in muscle fibers of DMD and BMD carriers causes a reduction of DAPs in the same fibers, as observed in DMD and BMD patients, while utrophin does not seem to play a role in DAP expression in adult muscle.

Adolescent↗
PubMed1996

Major histocompatibility complex class II molecule expression on muscle cells is regulated by differentiation: implications for the immunopathogenesis of muscle autoimmune diseases.

Major histocompatibility complex (MHC) class II molecules are expressed on myoblasts after interferon-gamma (IFN-gamma) treatment, suggesting a muscle cell involvement in antigen presentation in inflammatory myopathies. However, they were not observed on normal or pathological myofibers. This discrepancy might be related to different responsiveness of developmentally differentiated muscle cells to IFN-gamma. Myoblasts expressed class II transcripts and proteins after IFN-gamma, while myotubes and innervated contracting muscle cells did not show staining for class II molecules. At all cell stages no loss of IFN-gamma receptor was detected indicating that myofiber maturation blocks their capacity to express MHC class II molecules. This suggests that completely differentiated myofibers cannot participate in class II restricted immunological reactions.

Actins↗
PubMed1996

Mild clinical phenotype in a 12-year-old boy with partial merosin deficiency and central and peripheral nervous system abnormalities.

We found partial merosin deficiency in a boy presenting at 12 yr with marked limb weakness and a waddling gait. Magnetic resonance imaging (MRI) showed the characteristic white matter abnormalities of merosin-negative congenital muscular dystrophy. There were also peripheral demyelinating polyneuropathy and evoked potential abnormalities. Unlike classic merosin-negative congenital muscular dystrophy, however, our patient was less hypotonic and weak and was able to achieve independent walking. Both by immunohistochemistry and Western blot merosin was shown to be moderately reduced. By immunostaining the alpha 1 laminin chain was overexpressed and beta 1 laminin chain was reduced. A spectrum of clinical phenotypes is likely to become evident in merosin-deficient patients in relation to the discovery of a range of molecular defects in, and variable expression of, this protein.

Central Nervous System Diseases↗
PubMed1996

Rhmod phenotype: a parentage problem solved by denaturing gradient gel electorphoresis of genomic DNA.

Initial Rh phenotyping of a man with hemolytic anemia, his wife, and son appeared to exclude paternity. No exclusion was found in other blood groups or in the human leukocyte antigen (HLA) system; excluding Rh, the paternity index was 98.58 percent. Samples from these three family members, and two other family members, were tested with additional Rh antisera. The results indicated that the propositus has an Rhmod phenotype with expression of c, weak e, and very weak D, E, and G antigens. To support this hypothesis, DNA analysis of the RHD and RHCE genes was performed on the five family members. Polymerase chain reaction (PCR) products from exons 2 and 5 were analyzed by denaturing gradient gel electrophoresis (DGGE). The DNA results corroborated the serologic findings and refuted the exclusion of paternity.

Journal Article↗
PubMed1996

An unusual association: celiac disease and Becker muscular dystrophy.

A history of poor growth in early childhood associated with persistent diarrhea and iron deficiency anemia led to a diagnosis of celiac disease in a 9-yr-old boy hospitalized for acute rhabdomyolysis. Elevated serum creatine kinase levels had been documented over the previous years, and Becker's muscular dystrophy was diagnosed by immunostaining of dystrophin and DNA analysis.

Acute Disease↗
PubMed1995

DMD and BMD in the same family due to distinct mutations.

We report on a family with a boy affected by Duchenne muscular dystrophy (DMD) and an asymptomatic cousin with a Becker-type dystrophin abnormality, diagnosed by chance. Dystrophin gene analysis showed that these conditions were caused by two distinct deletions with breakpoints in different exons. In Xp21 families, DNA analysis and dystrophin testing of asymptomatic males with high CK plasma levels might detect different dystrophin mutations in separate haplotypes as in our family, although we stress there should be clear clinical or familial indications for such testing.

Adolescent↗
PubMed1995

N-palmitoylphosphatidylethanolamine stabilizes liposomes in the presence of human serum: effect of lipidic composition and system characterization.

Liposomes containing negatively-charged phospholipid, N-palmitoylphosphatidylethanolamine (NPPE) were examined for stability in the presence of human serum, using the release of the entrapped 5,6-carboxyfluorescein as an aqueous marker. Either small unilamellar vesicles (SUV) or large unilamellar vesicles (LUV) were used. Incorporation of NPPE into PC SUV decreases leakage in the presence of serum or phosphate-buffered saline, no strictly related to size increase observed and to the surface negative charge present. The stabilizing effect of NPPE and Chol were synergistic. Inhibition of destabilization induced by serum of PC/Chol liposomes was observed when NPPE concentrations were above 12 mol%. Change in the membrane fluidity or incorporation of a monosialoganglioside into liposomes do not significantly change the half-life of liposomes in the presence of a high NPPE concentration. Incorporation of NPPE into PC/Chol liposomes increases membrane rigidity which does not change after serum incubation. The presence of NPPE in liposomes decreases lipid transfer/exchange between liposomes and lipoproteins although the same amount of serum proteins were incorporated as in PC/Chol liposomes. As expected, these proteins are accessible to trypsin digestion. In accordance with these results, the liposome agglutination assay shows no steric barrier activity. As a whole, the results obtained in this paper suggest a complex mechanism for stabilization of NPPE containing liposomes in human serum.

Blood↗
PubMed1995

Early-onset encephalomyopathy associated with tissue-specific mitochondrial DNA depletion: a morphological, biochemical and molecular-genetic study.

A male infant, born from consanguineous parents, suffered from birth with a progressive neuromuscular disorder characterized by psychomotor delay, hypotonia, muscle weakness and wasting, deep-tendon areflexia and spastic posture. High levels of lactic acid in blood and cerebrospinal fluid suggested a mitochondrial respiratory chain defect. Muscle biopsy revealed ragged-red and cytochrome c oxidase-negative fibres, lipid accumulation and dystrophic changes. Multiple defects of respiratory complexes were detected in muscle homogenate, but cultured fibroblasts, myoblasts and myotubes were normal. Southern blot analysis showed markedly reduced levels of mitochondrial DNA (mtDNA) in muscle, while lymphocytes, fibroblasts and muscle precursor cells were normal. Neither depletion of mtDNA nor abnormalities of the respiratory complexes were observed in innervated muscle fibres cultured for as long as 4 months. No mutations were observed in two candidate nuclear genes, mtTFA and mtSSB, retro-transcribed, amplified and sequenced from the proband's mRNA. Sequence analysis of the mtDNA D-loop and of the origin of replication of the mtDNA light strand failed to identify potentially pathogenic mutations of these replicative elements in the proband's muscle mtDNA. Our findings indicate that mtDNA depletion is due to a nuclear encoded gene and suggest that the abnormality underlying defective mtDNA propagation must occur after muscle differentiation in vivo.

Age of Onset↗
PubMed1995

Dystrophin characterization in BMD patients: correlation of abnormal protein with clinical phenotype.

We have investigated protein expression and genotype in 59 Becker muscular dystrophy (BMD) patients. The aim was to identify possible causes of the marked variability in phenotype in patients with similar deletions/mutations. The patients were examined neurologically and functionally and underwent Manual Muscle Testing. Dystrophin expression was analysed by immunohistochemistry and western blot using antibodies against six different segments of the protein. DNA mutations were investigated by PCR amplification of 30 exons. Based on dystrophin expression at the sarcolemma, two groups of patients were identified: group A (29 patients) with the classic patchy distribution of dystrophin and group B (30 patients) with absence or reduction of one or more dystrophin portions and variable, although mostly normal, expression of the other portions of the protein. Dystrophin molecular weight was normal or slightly reduced in group A and was variably reduced, generally conspicuously so, in group B. The quantity of dystrophin expressed varied markedly in both groups. The pattern of immunohistochemical staining in group B patients correlated with milder clinical phenotype, suggesting that small dystrophin molecules lacking a portion in the N-terminus or in the rod domain, are more functional than proteins with normal or slightly reduced molecular weight that display the BMD-typical patchy distribution at the sarcolemma.

Activities of Daily Living↗
PubMed1995

Lack of mRNA and dystrophin expression in DMD patients three months after myoblast transfer.

We report our experience on myoblast transplantation in three Duchenne muscular dystrophy patients. Pure myoblasts (55 x 10(6) per patient) from HLA-matched donors, were injected into a tibialis anterior and the controlateral muscle was sham injected. Three months after transplantation, biopsies from the injected muscles were negative for dystrophin expression by immunocytochemistry. Reverse transcriptase-PCR (RT-PCR) failed to amplify any fragments of the deleted regions. This result confirms that myoblast transplantation is feasible, although the efficacy of this therapeutic approach is poor.

Adult↗
PubMed1995

Generalized lysosomal storage in Yunis Varón syndrome.

Muscle biopsy in a neonate with features of Yunis Varón syndrome revealed a vacuolar myopathy with evidence of lysosomal storage disease. Similar vacuoles were also present in heart, cartilage, central nervous system and cultured fibroblasts. Although the histologic findings in the central nervous system resembled those of infantile acid maltase deficiency, the essayed lysosomal enzymes were normal. Chromatography of urine revealed abnormal bands of unidentified oligosaccharides. This is the first report of generalized storage disease in Yunis Varón syndrome. The biochemical defect is unknown.

Abnormalities, Multiple↗
PubMed1995

Duplication of dystrophin gene and dissimilar clinical phenotype in the same family.

We report here three related patients with a duplication of exons 19-41 of the dystrophin gene, having dissimilar clinical phenotype and dystrophin immunohistochemistry. Two brothers aged six and three years had myalgia, proximal muscular weakness and hypertrophic calves, with 10- 20-fold increase of serum creatine kinase. Muscle biopsy showed dystrophic changes and reduced, patchy binding of dystrophin. The clinical and laboratory findings were consistent with a diagnosis of Becker muscular dystrophy with early onset. Their 14-year-old cousin had only mild hyperCKemia. His muscle biopsy was normal with only mild reduction of dystrophin immunostaining. At follow-up, he is still without symptoms and signs at age 19. All three patients had the same gene duplication and an increased dystrophin size of 507 kDa. Expression of the dystrophin-associated glycoproteins adhalin, alpha-dystroglycan, and beta-dystroglycan were normal in the three patients. An intrafamilial variability in patients carrying a partial duplication of the dystrophin gene may be related to a quantitative difference in mRNA.

Blotting, Southern↗