Biomedical subjects
M Brin
Publications and source records attributed to M Brin.
Dopamine beta-hydroxylase gene excluded in four subtypes of hereditary dystonia.
The hereditary dystonias include a clinically heterogeneous group of movement disorders varying in symptoms, age of onset, and drug responsiveness. Dopamine beta-hydroxylase (DBH), the enzyme that converts dopamine to norepinephrine, has been implicated in dystonia because of increased serum levels of DBH in some patients, the influence of catecholaminergic drugs on the human phenotypes, and altered norepinephrine levels in several brain regions in dystonia patients and in genetically dystonic rodents. In addition, markers linked to the dystonia gene in two ethnic groups map close to the DBH locus on human chromosome 9q34. Here we evaluate the inheritance of restriction fragment length polymorphisms near the DBH gene in families with four subtypes of hereditary dystonia: Jewish and non-Jewish, early onset, generalized idiopathic torsion dystonia (ITD); dopa-responsive dystonia; and myoclonic dystonia. In all families, obligate recombination events were observed between the DBH and dystonia genes, thus excluding the DBH gene as the primary defect.
Apolipoprotein synthesis in normal and abetalipoproteinemic intestinal mucosa.
The genetic disease abetalipoproteinemia is characterized by a total absence of apolipoprotein B-containing lipoproteins from plasma. A presumed synthetic defect in apolipoprotein B synthesis was thought to be responsible for this disorder. The present study quantitates apoprotein B synthesis and apolipoprotein B messenger RNA levels in duodenal mucosa from normal patients and four patients with abetalipoproteinemia. After in vitro [3H]leucine incorporation, small intestinal biopsy specimens from three of four patients with abetalipoproteinemia synthesized immunoprecipitable apolipoprotein B of identical mobility (on sodium dodecyl sulfate gel electrophoresis) to normal apolipoprotein B. In abetalipoproteinemia, the apolipoprotein B content of intestinal mucosa by radioimmunoassay was 15% of normal mucosal values, whereas apolipoprotein B messenger RNA quantitation showed 3-20-fold increased levels compared with normal mucosa. In one patient, smaller-molecular-weight fragments of apolipoprotein B were immunoprecipitated from duodenal biopsy specimens. The synthesis rates and messenger RNA levels of two other chylomicron apoproteins (apolipoprotein A-I and apolipoprotein A-IV) were found to be reduced by 50%. These results show the synthesis of immunologically recognizable apolipoprotein B48 in abetalipoproteinemia. The significance of mucosal apolipoprotein B content in abetalipoproteinemia is discussed in terms of factors controlling apolipoprotein B synthesis in normal mucosa and in abetalipoproteinemia.
Double-blind, placebo-controlled trial of botulinum toxin injections for the treatment of spasmodic torticollis.
We enrolled 55 patients in a double-blind, placebo-controlled, parallel design study of the effectiveness of botulinum toxin (Botox) injections for the treatment of spasmodic torticollis. Patients received a standard series of injections, either placebo or Botox. We determined the sites of injection and dose per muscle by the nature of head deviation. Compared with placebo, Botox produced statistically significant improvement in the severity of torticollis, disability, pain, and degree of head turning. There were no serious side effects. During the double-blind phase, 61% of patients injected with Botox improved; 74% of patients subsequently improved during a later open phase at a higher dose of Botox. Direction of head turning, severity of torticollis, and presence or absence of jerky movements did not significantly influence the response rate. We conclude that Botox is a valuable treatment for spasmodic torticollis.
Primary lateral sclerosis. A clinical diagnosis reemerges.
Adults with slowly progressive noninherited gait disorders may show no abnormalities on examination other than signs implicating the corticospinal tracts. That is the syndrome of "primary lateral sclerosis" (PLS), a clinical diagnosis that has been avoided because it is a diagnosis of exclusion, proven only at autopsy. Now, modern technology can exclude other disorders that can cause the syndrome with an accuracy of about 95%. That serves to eliminate the following: compressive lesions at the foramen magnum or cervical spinal cord, multiple sclerosis, amyotrophic lateral sclerosis, Chiari malformation, syringomyelia, biochemical abnormality, and persistent infection with human immunodeficiency virus or human T-lymphotrophic virus type I. We studied three autopsy-proved cases of PLS; six living patients in whom PLS was diagnosed clinically after comprehensive evaluations that excluded the alternative diagnoses; and two patients with this syndrome of PLS and antibodies to human immunodeficiency virus seropositivity that clinically resembled PLS. Primary lateral sclerosis is now a respectable and permissible diagnosis.
Distal axonopathy associated with chronic gluten enteropathy: a treatable disorder.
Our experience with one patient and literature review reveals that patients with chronic gluten enteropathy and severe steatorrhea may develop a generalized peripheral neuropathy of the distal axonopathy type. Vitamin levels are usually normal, and the neuropathy appears to respond to gluten restriction.
Linkage studies in families with dystonia: linkage analysis as a tool to locate and characterize the gene(s) for dystonia.
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Biotin-responsive encephalopathy with myoclonus, ataxia, and seizures.
Prominent neurological abnormalities, including myoclonus, seizures, ataxia, and hearing loss, have been noted in juvenile-onset biotin-responsive MCD. The underlying defect in many of these patients, who generally present in the first year of life, appears to be a deficiency of biotinidase. We have presented a young woman with adult-onset myoclonus, ataxia, hearing loss, seizures, hemianopia, and hemiparesis who responded to pharmacologic dosages of biotin. Although she displayed many of the clinical and biochemical features of juvenile-onset MCD, she did not have a biotinidase deficiency, and the underlying defect remains to be determined. Because of her response to biotin, we have advocated that other patients with unexplained myoclonus syndromes be evaluated for biotin-dependent carboxylase deficiencies and undergo a therapeutic trial with biotin.
Drug--vitamin B6 interaction.
In conclusion, there are several drug types that can interfere with vitamin B6 metabolism. In most cases, the interaction involves a complex formation between the drug (or a derivative) and the reactive coenzyme PLP, resulting in a Schiff base. Such an interaction leads to an inactivation of PLP (and also of the drug). Other types of interaction involve (a) stimulation of vitamin B6-dependent pathways and (b) competition with PLP for the binding site on the enzyme. Examples of the above are the steroid hormones (oral contraceptives). In most instances, overt symptoms of vitamin B6 deficiency due to chronic ingestion of these drugs are observed, and neurological problems seem to be rather frequent. Because of the reactive nature of the coenzyme PLP and the ease with which it can interact with drugs, sub-clinical (marginal) vitamin B6 deficiency should be suspected in the absence of overt clinical signs. Once the vitamin B6 problem has been identified, the condition can usually be treated by judicious use of large doses of vitamin B6 without compromising the clinical efficacy of the drug.
Thiamin in the elderly--relation to alcoholism and to neurological degenerative disease.
Status of thiamin in the elderly North American population is reviewed. Most Americans eat sufficient thiamin but about 5% of those over 60 yr old show impaired thiamin status. This is more marked in the poor, those confined in institutions, or those with illness. Thiamin responsive heart disease and Wernicke Korsakoff CNS syndromes occur in the elderly but there is no increased prevalence. Minor heart or neurological syndromes related to thiamin deficiency cannot be identified. The Recommended Dietary Allowance of thiamin provides at least 50% excess thiamin for those over 60 yr old--this amount is adequate. There is no known toxicity for thiamin.
Biopotency of alpha-tocopherols as determined by curative myopathy bioassay in the rat.
The decrease in plasma pyruvate kinase activity after administration of various tocopherols to vitamin E-deficient rats provided the basis for a 3-point parallel-slope assay for vitamin E activity. Based on 6 replicate assays, RRR-alpha-tocopheryl acetate (RRR-alpha-TA) was 141% as active as all-rac-alpha-tocopheryl acetate (all-rac-alpha-TA). This confirms many previous reports with other bioassays and is in agreement with the unit-weight relationships assigned by The National Formulary. 2-ambo-alpha-Tocopheryl acetate was 97% as active as all-rac-alpha-TA indicating that only the configuration of the 2-position on the chromanol ring is important in determining the biological activity of alpha-tocopherol.
[Cerebral metastases of malignant germinal tumors of the testis].
Cerebral metastases occur in 6% of cases of testicular cancer. In our study of 5 cases they occurred during the course of the disease (with a delay of 4-18 months, at the same time as pulmonary and abdominal metastases). The prognosis in these cases is poor (presence of choriocarcinomatous or vitelline elements, advanced stages). The diagnosis is easily established (clinical, encephalogram, scanner); the prognosis is hopeless (5 deaths in 3-90 days). When a metastasis is the first diagnostic clue (one case), the prognosis is slightly better (9 month survival). The incidence of cerebral metastasis is the same now as it was before the introduction of effective chemotherapy in patients who die from testicular cancer, but the death rate from this malignancy has decreased since the introduction of active chemotherapy with cisplatin. Hence, there is no indication for prophylactic treatment for cerebral metastases in patients in remission since metastases only appear in cases which are resistant to treatment.
Fructose ingestion does not affect serum lipids in human subjects.
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Bioequivalence of RRR-alpha-tocopheryl acetate and all-rac-alpha-tocopheryl acetate.
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Fatal pneumonia. Emergence of an amikacin sulfate-resistant strain of Escherichia coli.
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Red cell transketolase as an indicator of nutritional deficiency.
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A decrease in irreversibly sickled erythrocytes in sicle cell anemia patients given vitamin E.
Patients with sickle cell anemia were given 450 IU of vitamin E (as alpha-tocopherol) per day for 6 to 35 weeks. Plasma tocopherol levels increased from 0.7 +/- 0.2 mg/g lipid pretreatment, to 2.3 +/- 0.3 mg/g lipid. The percentage of circulating irreversibly sickled red cells decreased from 25 +/- 3% pretreatment to 11 +/- 1% after vitamin E administration (P less than 0.001). The percentage of irreversibly sickled red cells remained below pretreatment levels as long as the vitamin was administered (up to 35 weeks). The biochemical and clinical implications of these observations are discussed.
Effects of aspirin and related drugs in vitamin E-deficient rats.
Evidence from the literature indicates that in vitamin E-deficient animals prostaglandin (PG) synthesis in platelets is enhanced while it is decreased in the muscle and testis. In the present study the effects of aspirin, a known inhibitor of PG biosynthesis, on vitamin E deficiency signs in the rat were investigated. Administration of aspirin to vitamin E-deficient rats had no protective effect on fetal mortality, incisor depigmentation, body weight gain or red blood cell peroxidative hemolysis. Aspirin prevented the anemia and thrombocythemia observed in vitamin E-deficient rats. Aspirin, salicylic acid and a carbazole prostaglandin inhibitor exacerbated testis degeneration in vitamin E-deficient animals. Addition of aspirin to the diet more than doubled the vitamin E requirement for reversal of necrotizing myopathy.