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Biomedical subjects

Z Argov

Publications and source records attributed to Z Argov.

At least 37 records · Page 2Linked to original sources
PubMed1999

Distribution of serum creatine kinase activity in young healthy persons.

The normal distribution of serum creatine kinase (CK) was determined in 428 men (mean age = 21.5) and 540 women (mean age = 20.2). The bootstrap method was employed to obtain statistical parameters of CK reference range and correlations with physical activity habits, BMI, cigarette smoking and alcohol consumption. CK distribution was non-Gaussian and skewed toward the higher values; 18.9% of the men and 4.6% of the women had values above the upper reference limits defined for the commercial assay kit. The median 97.5 percentile value was 532 u/l for men and 248 u/l for women (95% confidence interval of 384-738 u/l and 184-340 u/l, respectively). A significant correlation was found only between CK and alcohol consumption in men. Myoglobin level in a representative group of subjects correlated well with CK activity for both genders. Our findings define the range of CK values in a healthy, young, heterogeneous population. We suggest that only CK levels above the determined 97.5 percentile should warrant further clinical investigation.

Adult↗
PubMed1999

Dysferlin is a plasma membrane protein and is expressed early in human development.

Recently, a single gene, DYSF, has been identified which is mutated in patients with limb-girdle muscular dystrophy type 2B (LGMD2B) and with Miyoshi myopathy (MM). This is of interest because these diseases have been considered as two distinct clinical conditions since different muscle groups are the initial targets. Dysferlin, the protein product of the gene, is a novel molecule without homology to any known mammalian protein. We have now raised a monoclonal antibody to dysferlin and report on the expression of this new protein: immunolabelling with the antibody (designated NCL-hamlet) demonstrated a polypeptide of approximately 230 kDa on western blots of skeletal muscle, with localization to the muscle fibre membrane by microscopy at both the light and electron microscopic level. A specific loss of dysferlin labelling was observed in patients with mutations in the LGMD2B/MM gene. Furthermore, patients with two different frameshifting mutations demonstrated very low levels of immunoreactive protein in a manner reminiscent of the dystrophin expressed in many Duchenne patients. Analysis of human fetal tissue showed that dysferlin was expressed at the earliest stages of development examined, at Carnegie stage 15 or 16 (embryonic age 5-6 weeks). Dysferlin is present, therefore, at a time when the limbs start to show regional differentiation. Lack of dysferlin at this critical time may contribute to the pattern of muscle involvement that develops later, with the onset of a muscular dystrophy primarily affecting proximal or distal muscles.

Amino Acid Sequence↗
PubMed1998

Intracellular phosphates in inclusion body myositis--a 31P magnetic resonance spectroscopy study.

Muscle phosphorus magnetic resonance spectroscopy was used to study oxidative metabolism at rest and during recovery from exercise in 7 patients with sporadic inclusion body myositis (s-IBM), compared with normal controls (n=8) and mitochondrial myopathies (n=20). At rest, 6/7 patients had elevated inorganic phosphates. Recovery parameters were not different from controls, in contrast with mitochondrial myopathies, who showed abnormal rest and recovery. The normal recovery suggests that mitochondrial oxidative capacity is not impaired in s-IBM.

Aged↗
PubMed1998

Adult polyglucosan body disease in Ashkenazi Jewish patients carrying the Tyr329Ser mutation in the glycogen-branching enzyme gene.

Adult polyglucosan body disease (APBD) is a late-onset, slowly progressive disorder of the nervous system caused by glycogen branching enzyme (GBE) deficiency in a subgroup of patients of Ashkenazi Jewish origin. Similar biochemical finding is shared by glycogen storage disease type IV (GSD IV) that, in contrast to APBD, is an early childhood disorder with primarily systemic manifestations. Recently, the GBE cDNA was cloned and several mutations were characterized in different clinical forms of GSD IV. To examine whether mutations in the GBE gene account for APBD, we studied 7 patients from five Jewish families of Ashkenazi ancestry. The diagnosis was based on the typical clinical and pathological findings, and supported by reduced GBE activity. We found that the clinical and biochemical APBD phenotype in all five families cosegregated with the Tyr329Ser mutation, not detected in 140 controls. As this mutation was previously identified in a nonprogressive form of GSD IV and was shown in expression studies to result in a significant residual GBE activity, present findings explain the late onset and slowly progressive course of APBD in our patients. We conclude that APBD represents an allelic variant of GSD IV, but the reason for the difference in primary tissue involvement must be established.

1,4-alpha-Glucan Branching Enzyme↗
PubMed1998

A gene related to Caenorhabditis elegans spermatogenesis factor fer-1 is mutated in limb-girdle muscular dystrophy type 2B.

The limb-girdle muscular dystrophies are a genetically heterogeneous group of inherited progressive muscle disorders that affect mainly the proximal musculature, with evidence for at least three autosomal dominant and eight autosomal recessive loci. The latter mostly involve mutations in genes encoding components of the dystrophin-associated complex; another form is caused by mutations in the gene for the muscle-specific protease calpain 3. Using a positional cloning approach, we have identified the gene for a form of limb-girdle muscular dystrophy that we previously mapped to chromosome 2p13 (LGMD2B). This gene shows no homology to any known mammalian gene, but its predicted product is related to the C. elegans spermatogenesis factor fer-1. We have identified two homozygous frameshift mutations in this gene, resulting in muscular dystrophy of either proximal or distal onset in nine families. The proposed name 'dysferlin' combines the role of the gene in producing muscular dystrophy with its C. elegans homology.

Adolescent↗
PubMed1998

Genetics of inclusion body myopathies.

We review the current knowledge about the genetic susceptibility to develop inflammatory inclusion body myositis, especially in relation to the increased presence of the HLA DR3 allele in patients with familial and sporadic forms, indicating an autoimmune predisposition. The main focus of the review is the clinical and genetic presentations of the various hereditary inclusion body myopathies. Criteria for diagnosis and classification of these myopathies are presented. The spectrum of the recessive forms of hereditary inclusion body myopathies currently linked to chromosome 9p1-q1 is described, with emphasis on the up-to-date status of the gene search for these forms.

Chromosomes, Human, Pair 9↗
PubMed1998

Functional evaluation techniques in mitochondrial disorders.

Most of the mitochondrial disorders affect the brain and muscle metabolism with variable degrees of impairment. The diagnostic usefulness of the following physiological and imaging methods, which also offer functional information that can be used for follow-up, is critically assessed: lactate levels, exercise testing, phosphorus magnetic resonance spectroscopy (MRS), proton MRS, functional magnetic resonance imaging, positron emission tomography, optical tissue oximetry and single photon emission tomography. Knowledge of the advantages, shortcomings and results of each method in the evaluation of mitochondrial diseases is mandatory before they can be applied to other disorders with suspected oxidative impairment.

Evaluation Studies as Topic↗
PubMed1998

Effects of aerobic training in patients with mitochondrial myopathies.

We studied the physiologic adaptation of patients with mitochondrial myopathies to aerobic training. Ten patients underwent individually supervised, moderate-intensity aerobic training on a treadmill for 8 weeks. Biochemical and functional measures improved with training. Estimated aerobic capacity increased by 30%. Blood lactate concentrations at rest and after exercise decreased by 30%. Muscle phosphorus magnetic resonance spectroscopy measurements of adenosine diphosphate recovery after exercise improved by more than 60%. Fatigue and tolerance to daily activities also improved. Although the improvement in exercise tolerance may be due in part to reversal of the effects of secondary deconditioning, this uncontrolled clinical trial suggests that aerobic training can benefit patients with mitochondrial myopathies.

Activities of Daily Living↗
PubMed1997

Stimulated single-fiber electromyography in Lambert-Eaton myasthenic syndrome before and after 3,4-diaminopyridine.

A patient with LEMS unrelated to cancer was studied by stimulated single-fiber electromyography (SFEMG) before and 3 months after the onset of therapy with 3,4-diaminopyridine. All end-plates showed a progressive reduction in blockings and jitter with the increase in stimulation rate. Treatment significantly corrected this feature, but the overall pattern of frequency-improved jitter remained. Such widespread finding is rare but diagnostic for Lambert-Eaton myasthenic syndrome. Stimulated SFEMG can be used to monitor therapy in such patients.

4-Aminopyridine↗
PubMed1997

Biochemical and genetic studies in a family with mitochondrial myopathy.

We present a family with severe exercise intolerance, progressive proximal weakness, and lactic acidemia. Fifteen of 24 family members in five generations were affected. Since the affected males do not have offspring at this time, the family pedigree is consistent with either maternal or autosomal dominant inheritance. Muscle histochemistry showed ragged-red fibers and electron microscopy showed globular mitochondrial inclusions. Biochemical analysis showed reduced muscle activities of mitochondrial NADH-cytochrome c reductase (1 of 2 patients), succinate-cytochrome c reductase (2 patients), and cytochrome c oxidase (2 patients). For 1 patient, sequence analysis of 44% of the muscle mitochondrial DNA including all 22 transfer RNA regions showed no point mutation with pathogenic significance. Southern blot analysis showed no deletion. Six affected members of the family were treated with methylprednisolone (0.25 mg/kg) for 3 months. Muscle strength, serum lactate, and energy metabolism at rest (measured by 31P magnetic resonance spectroscopy) significantly improved with treatment.

Adolescent↗
PubMed1997

Various types of hereditary inclusion body myopathies map to chromosome 9p1-q1.

Hereditary inclusion body myopathies are a clinically heterogeneous group of disorders characterized by adult-onset, slowly progressive muscle weakness and typical histopathology: rimmed vacuoles and filamentous inclusions. The disorders are usually inherited as an autosomal recessive trait. The gene responsible for the disease found in Iranian Jews, who present with quadriceps-sparing myopathy, maps to chromosome 9p1-q1. We address the question of whether hereditary inclusion myopathies are genetically as well as clinically heterogeneous disorders. We mapped the disease gene segregating in two families of Afghani-Jewish and one family of Iraqi-Jewish descent to the chromosome 9 locus. Similarly, the disease gene segregating in a non-Jewish family from India mapped to the same locus. By contrast, the disease gene segregating in a French-Canadian family in which affected individuals had central nervous system involvement as well as hereditary inclusion body myopathy, did not map to this locus. We conclude that many but not all forms of autosomal recessive hereditary inclusion body myopathy are caused by a gene defect that maps to chromosome 9p1-q1.

Adult↗
PubMed1997

Muscle high-energy phosphates in central nervous system disorders. The phosphorus MRS experience.

Phosphorus magnetic resonance spectroscopy (MRS) was used to study muscle phosphates metabolism in several brain disorders. Those with primary mitochondrial encephalomyopathies showed the typical pattern of impaired oxidative metabolism at rest and during recovery after exercise. In migraine, Parkinson's disease and alternating hemiplegia muscle MRS observations lend support to a possible mitochondrial dysfunction. Similar observations in multiple sclerosis are probably the result of secondary deconditioning. In post polio syndrome and in some of the hereditary ataxias, elevated intracellular inorganic phosphates may be the result of another, yet unknown, metabolic impairment. Thus, muscle phosphate metabolism may be altered in various central nervous system (CNS) disorders by different metabolic impairments. All these possibilities should be taken into account when evaluating MRS results in brain diseases.

Central Nervous System Diseases↗
PubMed1997

Abnormal oxidative metabolism in exercise intolerance of undetermined origin.

Twenty-four patients with exercise intolerance of undetermined origin were examined by muscle phosphorus magnetic resonance spectroscopy (31P-MRS) to test for a possible underlying defect in oxidative metabolism. Results were compared to those of 37 normal controls and 22 patients with well-defined mitochondrial disorders. In 17 (71%) patients with exercise intolerance, ADP recovery after exercise, an index of mitochondrial function, was abnormally slow. The energy state of phosphate-containing metabolites at rest was abnormal in 33% of patients. In 17/22 patients with well-defined mitochondrial disorders, ADP recovery was similarly slow. Abnormalities at rest were slightly more prevalent (50%) in this group of patients. Other 31P-MRS measurements did not add to the overall sensitivity in detecting abnormalities in either of these groups. We suggest that many patients with exercise intolerance of undetermined cause may have impaired muscle oxidative metabolism, that is an important causative factor in the pathophysiology of their symptoms.

Adenosine Diphosphate↗
PubMed1996

Impairment of muscle mitochondrial oxidative metabolism in McArdles's disease.

Impairment of muscle glycogenolysis in McArdle's disease (myophosphorylase deficiency) leads to exercise intolerance and exercise-induced myalgia. The pathophysiology of these symptoms is not entirely clear. We used phosphorus magnetic resonance spectroscopy to measure muscle phosphate metabolite concentrations and intracellular pH during brief ischemic exercise and in the period of aerobic metabolic recovery after exercise, with special attention to cytoplasmic adenosine 5'-diphosphate (ADP). In 5 patients with McArdle's disease, calculated muscle intracellular ADP concentrations at the beginning of recovery were higher than in normal control subjects (70-425 mmol/L, control mean: 73 +/- 40 mmol/L, P < 0.05). The half-time for intracellular ADP recovery after exercise, an index of maximal mitochondrial oxidative phosphorylation, was 0.16 +/- 0.07 in normal controls and was independent of metabolic state or intracellular pH. ADP recoveries were abnormally slow in all patients with McArdle's disease (range: 0.32-0.83 min, mean = 0.2 min, P < 0.0001). These results are indicative of a limitation in the rate of oxidative phosphorylation in muscle of patients with McArdle's disease, most likely due to impaired substrate delivery to mitochondria. This impairment of mitochondrial function may contribute to the exercise-related symptoms in McArdle's disease.

Adenosine Diphosphate↗
PubMed1996

ADP recovery after a brief ischemic exercise in normal and diseased human muscle--a 31P MRS study.

The pattern of cytosolic ADP recovery after exercise has not been fully characterized in human skeletal muscle. ADP recovery after brief, ischemic exercise was studied by 31phosphorus magnetic resonance spectroscopy in calf muscles of 33 normal control subjects, four patients with McArdle's disease and 13 patients with mitochondrial myopathy. In normal muscle, the half-time for the initial ADP decline was 0.18 +/- 0.07 min and was unaffected by the pH or the metabolic state at the end of exercise. ADP decreased to below rest values during the second min of recovery in 27 out of 33 control subjects. There was a significant (p < 0.001) linear correlation for both the size (r = 0.65) and duration (r = 0.64) of this ADP undershoot with intracellular pH. Phosphocreatine resynthesis continued during the ADP undershoot. ADP undershoot was also found in patients with mitochondrial diseases (in 11 out of 13), but not McArdle's disease (six patients). Thus ADP recovery follows a complex time course that is partly dependent on pH. Only the initial ADP recovery is independent of pH, which makes it suitable for comparative assessment of muscle mitochondrial function in vivo. As phosphocreatine recovery continues during the ADP undershoot, mitochondrial regulation must be different from that at the onset of recovery. These observations are consistent with variable, changing regulators of mitochondrial metabolism in human skeletal muscle.

Adenosine Diphosphate↗