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Biomedical subjects

M Dalakas

Publications and source records attributed to M Dalakas.

35 records · Page 2Linked to original sources
PubMed1990

Pharmacologic concerns of corticosteroids in the treatment of patients with immune-related neuromuscular diseases.

Traditionally, diseases affecting the motor unit had been subdivided based on anatomic criteria into diseases of the anterior horn cell, the peripheral nerve, the neuromuscular junction, and the muscle itself. For therapeutic considerations, however, a more precise cellular and clinicopathologic characterization of the diseases affecting the motor unit is needed. Based on the site and cell of the primary pathologic change, this article presents an immunotherapy-oriented broad classification of neuromuscular diseases affecting the motor unit.

Adrenal Cortex Hormones↗
PubMed1989

Current concepts in the idiopathic inflammatory myopathies: polymyositis, dermatomyositis, and related disorders.

Idiopathic inflammatory myopathy, a category encompassing polymyositis, dermatomyositis, and a number of other disorders, is very uncommon, but has been the focus of intense study in the Arthritis and Rheumatism Branch of the National Institute of Arthritis and Musculoskeletal and Skin Diseases for the past several years. We describe the clinical picture, stressing the need for biopsy to ensure correct diagnosis. It is especially important to recognize the treatment-resistant variant, inclusion body myositis. The extraskeletal manifestations, particularly the cardiopulmonary, oropharyngeal, gastrointestinal, and endocrine involvement, are described. The cardiopulmonary involvement, especially interstitial lung disease, arrhythmias, and cardiac failure, may dominate the clinical picture. The known causes are varied, and include drugs, toxins, and some infectious agents, however, in most cases a cause cannot yet be identified. Circumstantial evidence suggests that picornaviruses may initiate some cases in humans, and a very similar disease in mice caused by a picornavirus is actively under study. Studies of autoantibodies and cellular immune function support a central role for disordered immunity in the pathogenesis. The myositis-specific autoantibodies, especially those directed at certain enzymes important in protein synthesis (the aminoacyl-transfer RNA synthetases), are found in a clinically distinct subset of patients. Although most patients respond initially to corticosteroids, cytotoxic drugs are sometimes added when steroid toxicity or refractoriness develops. We describe several newer therapies under study for such cases and outline future directions in research.

Animals↗
PubMed1989

Reversible axonal neuropathy from the treatment of AIDS and related disorders with 2',3'-dideoxycytidine (ddC).

A total of 20 patients with acquired immune deficiency syndrome (AIDS) or AIDS-related complex (ARC) received the anti-retroviral drug 2',3',dideoxycytidine in a phase I study at doses ranging from 0.03 mg/kg every 8 hours to 0.25 mg/kg every 8 hours. Of the 11 patients who participated in the study for more than 5 weeks, 9 developed symptoms and signs of a mainly sensory painful neuropathy that was confirmed by electromyography to be mixed sensory and motor neuropathy of axonal type. The neuropathy which developed on dideoxycytidine occurred between 9 and 12 weeks of treatment. One patient, who had the drug stopped at 3 weeks owing to thrombocytopenia, developed a similar clinical picture of a sensory peripheral neuropathy after 2 weeks off dideoxycytidine. However, he did not have electromyographic evidence of a neuropathy, and he subsequently returned to normal clinically while taking a lower dose of dideoxycytidine in an alternating regimen. Five patients were withdrawn from the study because of the neuropathy. The pattern of this neuropathy was different from that of the slowly progressive painful neuropathy of AIDS, in that there was (1) a sudden onset of intense burning discomfort in both feet sparing the hands at about the tenth week (mean 10.4 weeks) of treatment, (2) there was motor involvement in some patients without progression, and (3) onset of the neuropathy was temporally related to the administration of dideoxycytidine and began to resolve 3-5 weeks after its discontinuation. We believe that dideoxycytidine can be an axonal toxin, especially when given in high dose continuous regimens.(ABSTRACT TRUNCATED AT 250 WORDS)

AIDS-Related Complex↗
PubMed1989

The failure of intravenous cyclophosphamide therapy in refractory idiopathic inflammatory myopathy.

Eleven patients with idiopathic inflammatory myopathy refractory to treatment with corticosteroids and other immunosuppressive agents were treated with monthly intravenous cyclophosphamide (0.75-1.357 g/m2). Six patients completed a full course of 7 infusions at which point only one patient met predefined criteria for improvement in both strength and function. Five had modest improvement in strength but did not meet the criteria for improvement. All patients have subsequently required treatment with other medications. Major complications observed during therapy included serious infections in 2 patients (streptococcal endocarditis and disseminated Mycobacterium avium intracellulare) and death in one patient in which the contribution of cyclophosphamide cannot be excluded. We conclude that intravenous cyclophosphamide as used in our study cannot be recommended for the treatment of patients with refractory inflammatory myopathy.

Adult↗
PubMed1988

Long-term administration of 3'-azido-2',3'-dideoxythymidine to patients with AIDS-related neurological disease.

3'-Azido-2',3'-dideoxythymidine (AZT) has been administered to 7 patients with human immunodeficiency virus-associated neurological disease: 3 with dementia, 2 with peripheral neuropathy, 1 with dementia and peripheral neuropathy, and 1 with T-10 paraplegia. Six of the patients showed improvement in their neurological dysfunction on being administered AZT, as assessed by clinical evaluation, neuropsychological testing, nerve conduction studies, and/or positron emission tomographic scans. Three of these 6 patients showed sustained improvement 5 to 18 months after the initiation of AZT therapy. These results suggest that certain human immunodeficiency virus-associated neurological abnormalities are at least partially reversible following the administration of antiretroviral therapy and provide a rationale for further studies using antiretroviral chemotherapy.

Acquired Immunodeficiency Syndrome↗
PubMed1988

MRI findings and peripheral neuropathy in Lowe's syndrome.

Neurologic features of oculocerebrorenal (Lowe) syndrome include mental retardation, hypotonia, and areflexia. We performed a sural nerve biopsy, computerized tomography (CT) scan, and magnetic resonance imaging (MRI) scan on a 14-year-old boy with oculocerebrorenal syndrome with very mild renal disease. The nerve biopsy exhibited decreased number of myelinated fibers, normal myelination on remaining axons without redundant basal lamina, and no evidence of active degeneration or regeneration. MRI scan revealed diffuse and irregular foci of increased T2 signal with sparing of commissural fibers, pyramidal tracts, and cerebellar white matter. We conclude that both a peripheral axonopathy and a central demyelinating or gliotic process occurs in oculocerebrorenal syndrome in the absence of the severe renal disease that often complicates this disorder.

Adolescent↗
PubMed1988

Oral carnitine therapy in children with cystinosis and renal Fanconi syndrome.

11 children with either cystinosis or Lowe's syndrome had a reduced content of plasma and muscle carnitine due to renal Fanconi syndrome. After treatment with oral L-carnitine, 100 mg/kg per d divided every 6 h, plasma carnitine concentrations became normal in all subjects within 2 d. Initial plasma free fatty acid concentrations, inversely related to free carnitine concentrations, were reduced after 7-20 mo of carnitine therapy. Muscle lipid accumulation, which varied directly with duration of carnitine deficiency (r = 0.73), improved significantly in three of seven rebiopsied patients after carnitine therapy. One Lowe's syndrome patient achieved a normal muscle carnitine level after therapy. Muscle carnitine levels remained low in all cystinosis patients, even though cystinotic muscle cells in culture took up L-[3H]carnitine normally. The half-life of plasma carnitine for cystinotic children given a single oral dose approximated 6.3 h; 14% of ingested L-carnitine was excreted within 24 h. Studies in a uremic patient with cystinosis showed that her plasma carnitine was in equilibrium with some larger compartment and may have been maintained by release of carnitine from the muscle during dialysis. Because oral L-carnitine corrects plasma carnitine deficiency, lowers plasma free fatty acid concentrations, and reverses muscle lipid accumulation in some patients, its use as therapy in renal Fanconi syndrome should be considered. However, its efficacy in restoring muscle carnitine to normal, and the optimal dosage regimen, have yet to be determined.

Administration, Oral↗
PubMed1985

Plasma and muscle free carnitine deficiency due to renal Fanconi syndrome.

Plasma and urine free and acyl carnitine were measured in 19 children with nephropathic cystinosis and renal Fanconi syndrome. Each patient exhibited a deficiency of plasma free carnitine (mean 11.7 +/- 4.0 [SD] nmol/ml) compared with normal control values (42.0 +/- 9.0 nmol/ml) (P less than 0.001). Mean plasma acyl carnitine in the cystinotic subjects was normal. Four subjects with Fanconi syndrome but not cystinosis displayed the same abnormal pattern of plasma carnitine levels; controls with acidosis or a lysosomal storage disorder (Fabry disease), but not Fanconi syndrome, had entirely normal plasma carnitine levels. Two postrenal transplant subjects with cystinosis but without Fanconi syndrome also had normal plasma carnitine levels. Absolute amounts of urinary free carnitine were elevated in cystinotic individuals with Fanconi syndrome. In all 21 subjects with several different etiologies for the Fanconi syndrome, the mean fractional excretion of free carnitine (33%) as well as acyl carnitine (26%) greatly exceeded normal values (3 and 5%, respectively). Total free carnitine excretion in Fanconi syndrome patients correlated with total amino acid excretion (r = 0.76). Two cystinotic patients fasted for 24 h and one idiopathic Fanconi syndrome patient fasted for 5 h showed normal increases in plasma beta-hydroxybutyrate and acetoacetate, which suggested that hepatic fatty acid oxidation was intact despite very low plasma free carnitine levels. Muscle biopsies from two cystinotic subjects with Fanconi syndrome and plasma carnitine deficiency had 8.5 and 13.1 nmol free carnitine per milligram of noncollagen protein, respectively (normal controls, 22.3 and 17.1); total carnitines were 11.8 and 13.3 nmol/mg noncollagen protein (controls 33.5, 20.0). One biopsy revealed a mild increase in lipid droplets. The other showed mild myopathic features with variation in muscle fiber size, small vacuoles, and an increase in lipid droplets. In renal Fanconi syndrome, failure to reabsorb free and acyl carnitine results in a secondary plasma and muscle free carnitine deficiency.

Carnitine↗
PubMed1983

Phosphoglycerate kinase deficiency: another cause of recurrent myoglobinuria.

A 14-year-old boy had myoglobinuria and renal failure after intense exercise; a year earlier he had experienced a milder episode. There was no consanguinity and no family history of neuromuscular diseases or hemolytic anemia. Strength was normal. Forearm ischemic exercise caused prolonged contracture with no rise of venous lactate. Muscle morphology showed only a mild increase of lipid droplets. Glycogen concentration was normal. Muscle phosphoglycerate kinase (PGK) activity was 5% of the normal mean, and all other glycolytic enzymes were normal. The residual PGK activity of muscle was heat stable but showed slower than normal electrophoretic mobility and decreased Michaelis constants for 3-phosphoglycerate and adenosine triphosphate. The enzyme defect was also expressed in erythrocytes and in fibroblast and muscle cultures. PGK activity was decreased in tissues from the patient's mother but normal in the father. PGK deficiency is an X-linked recessive trait usually associated with hemolytic anemia, mental retardation, and seizures; myopathy had not been recognized previously. Muscle PGK deficiency is now added to two other newly recognized glycolytic defects, phosphoglycerate mutase and lactate dehydrogenase deficiencies, as a cause of recurrent myoglobinuria.

Acute Kidney Injury↗
PubMed1980

Nature of the reversible white matter lesion in multiple sclerosis. Effects of acute inflammation on myelinated tissue studied in the rabbit eye.

Arthus reactions of different intensities were induced in the rabbit eye using measles vaccine as the immunogen. In the presence of a mild Arthus reaction in the vitreous, myelinated nerve fibre bundles on the retinal surface revealed extracellular oedema together with marked swelling and rupture of astrocyte processes, including those bearing a special relationship to nodes of Ranvier. These changes improved or disappeared over the course of six days. No demyelination occurred. The findings implicate an astrocytic lesion as a possible cause of reversible neurological deficit and conduction block associated with acute inflammation in central white matter.

Animals↗
PubMed1978

Leukoencephalopathy in oculocraniosomatic neuromuscular disease with ragged-red fibers. Mitochondrial abnormalities demonstrated by computerized tomography.

In a group of 13 patients affected by oculocraniosomatic neuromuscular disease with mitochondrial abnormalities and ragged-red fibers, a major, diffuse leukoencephalopathic process was recognized by computerized tomography (CT) in three cases. Clinically, these three patients were the most severely affected. The areas involved by the leukoencephalopathic process did not show enhancement after contrast medium injection. In several of the remaining ten cases, various forms and grades of CSF cavity dilation were encountered. Four of the 13 patients had very high CSF protein levels, three had CT-demonstrated leukoencephalopathy, and the fourth had substantial sulcal dilation. The CT findings in this group of patients corresponded well to the previously reported histopathological observations and indicated the clinical usefulness of CT in identifying brain involvement in this syndrome.

Adolescent↗