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Biomedical subjects

D L Friedman

Publications and source records attributed to D L Friedman.

At least 19 recordsLinked to original sources
PubMed1992

Purification and localization of brain-type creatine kinase in sodium chloride transporting epithelia of the spiny dogfish, Squalus acanthias.

The targeting of creatine kinase isoenzymes to specific sites within muscle cells provides a system for the regeneration of ATP in situ from ADP and creatine phosphate. We have recently reported the colocalization of brain-type (B) creatine kinase and the nonsarcomeric mitochondrial creatine kinase isoenzymes in the thick ascending limb of the loop of Henle in the rat kidney, suggesting that creatine kinase may regenerate ATP for sodium transport (Friedman, D.L., and Perryman, M.B. (1991) J. Biol. Chem. 266, 22404-22410). In order to test the hypothesis regarding the association of B creatine kinase with sodium transport, we examined the creatine kinase enzymes in the rectal (salt-secreting) gland of the dogfish shark which contains high levels of the Na+/K(+)-ATPase. The creatine kinase isoform composition was determined by non-denaturing electrophoresis, immunoblotting, protein purification, and amino acid sequence analysis. The results demonstrate both B creatine kinase and mitochondrial creatine kinase proteins are present in the rectal gland, an isoform composition which is the same as in the mammalian kidney. By using a combination of chromatographic techniques, shark B creatine kinase was purified to homogeneity and partial sequence data was obtained from two cyanogen bromide peptide fragments. One of these fragments contains the active site and is identical at all sequenced residues with the corresponding region from the echinoderm sperm flagellar creatine kinase, and is 96% homologous with both chicken and rat B creatine kinase subunits. The other fragment corresponds to a region near the N-terminal of mammalian creatine kinases and is 89% homologous with B creatine kinase from chicken. The localization of these isoforms was examined by immunocytochemistry using subunit specific antisera. Mitochondrial creatine kinase and B creatine kinase immunoreactivity are detected in all tubules, and is restricted to the basal region of the cells, which is the site of the Na+/K(+)-ATPase. The conservation of creatine kinase isoform expression in excretory tissue, and the localization of creatine kinase immunoreactivity in the basal region of the tubule cells, demonstrate that subcellular compartmentation of B creatine kinase may underly the functional coupling of creatine kinase activity with sodium transport.

Amino Acid Sequence↗
PubMed1992

Verapamil and valproic acid treatment of prolonged mania.

The case of an adolescent with severe mental retardation, blindness, and a complex of behavioral symptoms consistent with mania is reported. Symptoms include an increased activity level, mood liability, irritability, hyposomia, and severe self-injurious behavior. The successful use of verapamil and valproic acid in the treatment of prolonged mania in this child is described.

Adolescent↗
PubMed1992

Carbamazepine-induced hyponatremia in patients with mental retardation.

Carbamazepine-induced hyponatremia has been reported in 21.7% of 61 patients with mental retardation who received the medication for a variety of reasons. We studied 40 patients with mental retardation receiving carbamazepine to determine the prevalence of hyponatremia. Overall, hyponatremia was found in only 5.0% of these patients. Correlations with sodium level and carbamazepine dose, serum drug level, and concomitant neuroleptic and anticonvulsant polytherapy were also examined. Treatment with carbamazepine resulted in a statistically, but not clinically, significant decrease in serum sodium levels in patients receiving anticonvulsant polytherapy. Decreases in serum sodium were not related to carbamazepine dose or blood levels. Only one patient with underlying schizophrenia and psychogenic polydipsia demonstrated clinically significant hyponatremia during carbamazepine therapy.

Carbamazepine↗
PubMed1992

Adverse behavioral effects in individuals with mental retardation and mood disorders treated with carbamazepine.

The incidence of carbamazepine-associated behavioral side effects in 65 individuals with mental retardation and additional seizure and/or psychiatric or behavioral disorders was evaluated. We identified 6 patients (9.2%) who experienced medication side effects, ranging from irritability to mania. Four of the 20 patients (20%) who received carbamazepine purely for treatment of a behavioral or psychiatric disorder experienced medication side effects, whereas none of the 21 patients treated for an isolated seizure disorder experienced similar effects. This difference was statistically significant, p less than .05. The incidence of behavioral side effects of medication was not associated with age, sex, or serum carbamazepine level. The chemical structure and mechanism of carbamazepine use in various disease processes were discussed.

Adolescent↗
PubMed1991

Compartmentation of multiple forms of creatine kinase in the distal nephron of the rat kidney.

Creatine kinase enzymes are present in tissues such as muscle and brain to interconvert creatine phosphate and ADP, thus providing a system to interconnect energy production and utilization (Bessman, S. P., and Carpenter, C. L. (1985) Annu. Rev. Biochem. 54, 831-862). Creatine kinase isoenzymes in kidney have received little attention since kidney contains relatively low creatine kinase activity compared with muscle and brain and because there is disagreement regarding the identity of the specific isoforms expressed in kidney. Using a combination of chromatographic and immunological techniques, we have identified two isoforms of creatine kinase in rat kidney supernatants, B creatine kinase, and the non-sarcomeric form of the mitochondrial creatine kinase, which represent 82 and 15%, respectively, of the total creatine kinase activity in this tissue. The identity of the non-muscle form of the mitochondrial creatine kinase was confirmed by N-terminal sequence analysis and compared with recently published cDNA sequences (Haas, R. C., and Strauss, A. W. (1990) J. Biol. Chem. 265, 6921-6927). We prepared multiple antisera specific for each isoform using synthetic peptide immunogens based upon nonhomologous regions from the primary sequence of each creatine kinase isoform. Immunocytochemical results demonstrate that both creatine kinase isoforms are colocalized in the inner stripe of the outer medulla in tubules of the distal nephron. A similar distribution of creatine kinase isoforms was obtained when different layers of the renal cortex and medulla were examined for creatine kinase activity and isozyme content using nondenaturing electrophoresis. In general, the distribution of creatine kinase enzymes in kidney corresponds to the regions of greatest ATP utilization, oxygen consumption, and sodium transport. These results suggest a role for creatine kinase enzymes in the coupling of ion transport and oxidative phosphorylation in the distal nephron of the mammalian kidney.

Amino Acid Sequence↗
PubMed1990

Muscle creatine kinase isoenzyme expression in adult human brain.

Previous studies have suggested that MM creatine kinase is a muscle-specific protein and is not present in adult brain tissue. We have isolated a protein from human brain with an apparent molecular weight of 43,000 as determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis which is identical to the muscle M creatine kinase isoenzyme subunit at all 30 sequenced amino acid residues and possesses creatine kinase enzymatic activity following nondenaturing agarose-gel electrophoresis. Immunohistochemistry localizes M creatine kinase to discrete areas of adult human brain. Northern blot analysis of both total and poly(A)-selected RNA isolated from brain did not detect M creatine kinase mRNA. However, polymerase chain reaction amplification of cDNA synthesized from human placenta, heart, and brain mRNA detected M creatine kinase message in both heart and brain but not placenta which contains no detectable M creatine kinase protein. N1E115 and NS20Y, mouse neuroblastoma cell lines which have been used as models of neural cell differentiation, were found also to express MM creatine kinase. Moreover, a transiently transfected reporter gene with 4,800 base pairs of M creatine kinase upstream region fused to chloramphenicol acetyltransferase was expressed during differentiation of these neural cell lines. In summary, MM creatine kinase is present in human brain and we suggest the M creatine kinase upstream region is sufficient to modulate M creatine kinase expression in certain neuronal cells and may be regulated independently from other muscle genes.

Adult↗
PubMed1990

Evidence for functionally distinct subclasses of gamma-aminobutyric acid receptors in rabbit retina.

gamma-Aminobutyric acid (GABA) is a major inhibitory neurotransmitter in the mammalian retina, where it serves many roles in establishing complex response characteristics of ganglion cells. We now provide biochemical and physiological evidence that at least three subclasses of GABA receptors (A1, A2, and B) contribute to different types of synaptic integration. Receptor binding studies indicate that approximately three-fourths of the total number of [3H]GABA binding sites in retina are displaced by the GABAA receptor antagonist, bicuculline, whereas one-fourth are displaced by the GABA-B receptor agonist, baclofen. GABAA receptors can be described by a three-site binding model with KD values of 19 nM, 122 nM, and 5.7 microM. Benzodiazepines and barbiturates potentiate binding to the GABAA site, which suggests that significant numbers of GABAA receptors are coupled to regulatory sites for these compounds and thus are classified as GABAA1 receptors. The response to pentobarbital appears to involve a conversion of low-affinity sites to higher-affinity sites, and is reflected in changes in the densities of sites at different affinities. Functional studies were used to establish which of the different receptor subclasses regulate release from cholinergic amacrine cells. Our results show that GABA suppresses light-evoked [3H]acetylcholine release via GABAA2 receptors not coupled to a benzodiazepine or barbiturate regulatory site, and enhances release via GABAB receptors. GABAA1 sites do not appear to control acetylcholine release in rabbit retina.

Acetylcholine↗
PubMed1990

Recent newspaper coverage about persons with disabilities.

Newspapers are considered a powerful medium for developing public opinion about issues. In a representative sample of large-city newspapers, we found that three issues--budget, expenditures, or taxes; housing or normalization; and treatment in institutions--were the most frequently featured issues about persons with disabilities. The least frequently mentioned issues were school related, such as instruction, mainstreaming, and Public Law 94-142 compliance. A suggestion was made that if articles about special education are to appear in newspapers, special educators must develop strong relationships with newspaper reporters and their editors.

Persons with Disabilities↗
PubMed1990

Metoprolol for aggressive behavior in persons with mental retardation.

Persons with mental retardation sometimes exhibit behaviors that are difficult to control. Use of neuroleptic medications may be limited by side effects or ineffectiveness. Beta blockers such as propranolol and metoprolol have been shown to decrease aggressive and impulsive behaviors in some patients with mental retardation.

Adolescent↗
PubMed1989

Developmental expression of creatine kinase isozymes in mammalian lens.

Four different isoforms are thought to comprise the creatine kinase of enzymes which regulate energy metabolism through the interconversion of ADP and creatine phosphate. In addition to these well characterized isoforms, MM, MB, BB and mitochondrial creatine kinase, several uncharacterized variants with atypical electrophoretic mobility have been described. In mammalian lens, creatine kinase isoforms exhibit both a regional and developmental pattern of expression. In neonatal rat and human lens, the only isoform expressed is a variant cathodic creatine kinase. Near the time of sexual maturation (11-13 yr) there is a dramatic increase in the expression of BB creatine kinase in human lens. In rat lens, a similar pattern of isoenzyme expression is also seen near the time of sexual maturation (5-6 weeks). In the mature rat lens, in addition to the cathodic variant, there is expression of BB and, to a lesser extent, MM creatine kinase. Using a polyclonal antisera, we have localized BB creatine kinase to the cuboidal epithelial cells of the adult rat lens. This unique pattern of isoenzyme expression and developmental regulation suggests a more complex scheme for the regulation of creatine kinase gene expression than previously postulated.

Adolescent↗
PubMed1989

The C proteins of HeLa 40S nuclear ribonucleoprotein particles exist as anisotropic tetramers of (C1)3 C2.

The C proteins (C1 and C2) of HeLa 40S heterogeneous nuclear ribonucleoprotein particles copurify under native conditions as a stable complex with a fixed molar protein ratio (S.F. Barnett, W.M. LeStourgeon, and D.L. Friedman, J. Biochem. Biophys. Methods 16:87-97, 1988). Gel filtration chromatography and velocity sedimentation analyses of these complexes revealed a large Stokes radius (6.2 nm) and a sedimentation coefficient of 5.8S. On the basis of these values and a partial specific volume of 0.70 cm3/g based on the amino acid composition, the molecular weight of the complex was calculated to be 135,500. This corresponds well to 129,056, the sequence-determined molecular weight of a (C1)3C2 tetramer. Reversible chemical cross-linking with dithiobis(succinimidyl propionate) and analysis of cross-linked and cleaved complexes in sodium dodecyl sulfate-polyacrylamide gel electrophoresis confirmed that the C proteins exist as tetramers, most or all of which are composed of (C1)3C2. The tetramer is stable in a wide range of NaCl concentrations (0.09 to 2.0 M) and is not dissociated by 0.5% sodium deoxycholate. This stability is not the result of disulfide bonds or interactions with divalent cations. The hydrodynamic properties of highly purified C-protein tetramers are the same for C-protein complexes released from intact particles with RNase or high salt. These findings support previous studies indicating that the core particle protein stoichiometry of 40S heterogeneous nuclear ribonucleoproteins is N(3A1-3A2-1B1-1B2-3C1-1C2), where N = 3 to 4, and demonstrate that the C-protein tetramer is a fundamental structural element in these RNA-packaging complexes. The presence of at least three tetramers per 40S monoparticle, together with the highly anisotropic nature of the tetramer, suggesting that one-third of the 700-nucleotide pre-mRNA moiety packaged in monoparticles is associated through a sequence-independent mechanism with the C protein.

Carrier Proteins↗
PubMed1989

Child life services and persons with mental retardation.

We admitted an adult with mental retardation and an eating disorder to a pediatric inpatient unit. Child life services were a core feature in the assessment and treatment of the patient. The role of child life services in the care of persons with mental retardation should be expanded.

Adult↗
PubMed1989

Thyroid dysfunction in individuals with Down syndrome.

A group of 138 community-based patients with Down syndrome were examined for evidence of autoimmune thyroid dysfunction at the time of their referral for routine health care services provided as part of a model program. Twenty-eight patients (20.3%) were found to have previously unrecognized hypothyroidism, and 2 patients (1.4%) had previously unrecognized hyperthyroidism. In addition, 66 patients were tested for thyroid autoantibodies, and 26 were found to have positive antimicrosomal and/or antithyroglobulin antibody test results. There was no statistically significant association between age or sex and the mean thyrotropin value or the presence of thyroid autoantibodies. The relationship between the mean thyroxine level and sex was mildly significant. Of the patients with hypothyroidism, 78.5% were female, and most were between the ages of 30 and 50 years. However, a higher-than-expected number of patients with autoimmune hypothyroidism were under age 30 years. These findings highlight the lack of adequate health care services available to persons with Down syndrome who live in the community. All persons with Down syndrome must undergo regular clinical and laboratory screening for the presence of thyroid disease.

Adolescent↗
PubMed1988

Provision of health care for persons with developmental disabilities living in the community. The Morristown model.

Persons with developmental disabilities living in the community have a greater number and variety of health care needs than the average population of the same age and sex. The erroneous assumption that the generic health care system would be able to provide all necessary services to the large number of individuals recently transferred from state residential facilities to the community has proved to be an unexpected disappointment to human service policymakers. In an effort to remedy this situation, a program of health care services was established by the New Jersey Department of Human Services at a community teaching hospital to supplement the existing generic system of medical care. Within four years, the program had rapidly grown to provide care for 729 patients who had come to rely on the center for primary care, specialty medical and dental services, and medical case management. The demographic characteristics of this program are described as well as data on morbidity, service utilization, and special problems encountered when care was provided to this complex and medically underserved population.

Adolescent↗
PubMed1988

Insulin stimulates incorporation of 32Pi into nuclear lamins A and C in quiescent BHK-21 cells.

The in vivo effect of insulin upon the incorporation of 32Pi into nuclear proteins was investigated in quiescent baby hamster kidney fibroblasts (BHK-21). Insulin has previously been shown to be mitogenic in these cells (Richman, R. A., Johnson, R. A., and Friedman, D. L. (1981) Proc. Soc. Exp. Biol. Med. 168, 196-203). Incorporation into two proteins (Mr = 62,000 and 72,000) in the 0.4 M salt-resistant nuclear fraction was enhanced 2-6-fold by insulin. The effect of insulin (20 nM) was observable within 5 min of treatment, reached a maximum at 15 min, and continued for at least 90 min. The half-maximal effect of insulin was obtained at a concentration of approximately 1 nM. Analysis of nuclear matrix preparations indicated that the two insulin-sensitive proteins were prominent nuclear matrix proteins and suggested that they were lamins A and C. This was confirmed by immunostaining with lamin antibodies and by two-dimensional electrophoresis. These studies indicate that insulin rapidly stimulates the incorporation of phosphate into nuclear lamins A and C in quiescent BHK-21 fibroblasts.

Animals↗
PubMed1988

Rapid purification of native C protein from nuclear ribonucleoprotein particles.

A rapid three step procedure is described for the purification of C protein from HeLa 40 S hnRNP particles. The procedure takes advantage of the salt resistant RNA binding of C protein, the size of the C protein-RNA complex, and the strong binding of C protein to an anion-exchange resin. Typically 120 micrograms of C protein is obtained from 4.0 X 10(9) cells with greater than 95% electrophoretic purity. Proteins C1 and C2 copurify in the ratio of 3.5 Cl to 1 C2. The purified C protein participates in hnRNP particle reconstitution and on this basis is judged to be native. The purified C protein binds to a gel filtration matrix at 0.5 M NaCl but at higher salt concentrations it elutes before the marker protein, apoferritin (Mr = 443,000). An abbreviated two step purification procedure utilizing anion-exchange chromatography is also described. This procedure results in relatively pure C protein, as well as a useful separation of the other hnRNP proteins.

Carrier Proteins↗
PubMed1986

Polyamine-activated protein phosphatase activity in HeLa cell nuclei.

Protein phosphatase activity towards endogenous nuclear substrates in sonicates of isolated nuclei was activated 2-4-fold by spermine. Exogenous casein was dephosphorylated by these preparations only in the presence of spermine. Activation by spermine was half maximal at about 0.1 mM. Spermidine also activated, with half maximal stimulation at 1mM; putrescine activated poorly. Mg++ and Ca++ appeared to activate the same phosphatase activity but were only 50% as effective as spermine. Spermine activation was inhibited by 200 mM NaCl, 50 mM NaF, or 40 mM beta-glycerol phosphate. Nuclear phosphatase activity, with or without spermine, was inhibited 50% by inhibitor 2 of protein phosphatase 1. These observations suggest that protein phosphatase 1 is a major nuclear protein phosphatase and that its activity against endogenous nuclear substrates is activated by physiological concentrations of spermine.

Calcium Chloride↗