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Biomedical subjects

E Friedman

Publications and source records attributed to E Friedman.

At least 271 records · Page 15Linked to original sources
PubMed1993

Altered platelet protein kinase C activity in bipolar affective disorder, manic episode.

Protein kinase C (PKC) activity and PKC translocation in response to serotonin were investigated in platelets obtained from bipolar affective disorder subjects before and during lithium treatment. Ratios of platelet membrane-bound to cytosolic PKC activities were elevated in the manic subjects. In addition, serotonin-elicited platelet PKC translocation was found to be enhanced in those subjects. Lithium treatment for up to 2 weeks resulted in a reduction in cytosolic and membrane-associated PKC activities and in an attenuated PKC translocation in response to serotonin. These preliminary results suggest that alteration in platelet PKC is associated with the manic phase of bipolar illness. The results also suggest that lithium treatment reduces the sensitivity of platelets to PKC translocation induced by activation of serotonin-2 receptors.

Adult↗
PubMed1993

Signal transduction through extracellular signal-regulated kinase-like pp57 blocked in differentiated cells having low protein kinase C beta activity.

pp57 is a cytoplasmic kinase which is related antigenically and functionally to the extracellular signal regulated kinase or the mitogen-activated kinase family of signal transduction proteins. Two undifferentiated colon carcinoma cell lines responded to the diacylglycerol diolein by growth and a rapid 3-4-fold increase in tyrosine phosphorylation of pp57, and smaller increases in threonine and serine phosphorylation. By enhancing tyrosine phosphorylation of pp57, diolein increased pp57 kinase activity on myelin basic protein. Two enterocytic differentiated colon carcinoma cell lines, when treated with diolein, exhibited neither increased pp57 tyrosine phosphorylation nor increased growth. Both enterocytic lines exhibited 30% of the total PKC activity, 10-20% of the abundance of PKC beta as detected by Western blotting with anti-peptide antisera, and 10-20% of the PKC beta activity, by immune complex kinase reactions, that was expressed in the undifferentiated cell lines. The abundance of three other PKC isozymes, alpha, epsilon, and zeta appeared unchanged in the undifferentiated and enterocytic lines, reflecting their common parental cell line origin. The association between loss of PKC beta activity and blocked signaling through pp57 in each of two cell lines suggests that PKC beta is part of a signal transduction system activating pp57.

Calcium-Calmodulin-Dependent Protein Kinases↗
PubMed1993

Analysis of receptor-stimulated and basal guanine nucleotide binding to membrane G proteins by sodium dodecyl sulfate-polyacrylamide gel electrophoresis.

A method to study [alpha-32P]GTP binding to the alpha subunit of GTP-binding proteins in rat brain membranes is described. This method measures receptor-stimulated GTP binding to individual alpha subunits. GTP binding is associated with two protein bands following sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis. The bands, 40- and 45-kDa in size, comigrate with the alpha subunits of Gi/Go and Gs, respectively. Binding of [alpha-32P]GTP is saturable and Mg(2+)-dependent. Nucleotides compete with [alpha-32P]GTP binding in the following order: GTP > GDP > Gpp(NH)p > App(NH)p. Dopamine stimulates [alpha-32P]GTP labeling of the 40- and 45-kDa bands. A binding increase of 300-400% is observed at 10 microM dopamine. Isoproterenol (10 microM) stimulates [alpha-32P]GTP binding only to the 45-kDa protein band. The effects of dopamine and isoproterenol are blocked by their respective receptor antagonists, fluphenazine and propranolol. The individual G proteins activated by dopamine are resolved by immunoprecipitation of stimulated [alpha-32P]GTP binding to G alpha s, G alpha i, and G alpha o with specific anti-G alpha antisera. Dopamine stimulates [alpha-32P]GTP binding to G alpha s and G alpha i while the labeling of G alpha o was not significantly changed. Pertussis toxin-mediated ADP ribosylation prevents the activation of G alpha i which is mediated by dopamine receptor stimulation. The methods described are useful in defining the coupling of specific neurotransmitter receptors to specific G proteins in native membranes. These procedures also allow measurements of receptor stimulation of individual G proteins in intact biological membranes.

Adenylyl Imidodiphosphate↗
PubMed1993

Differential regulation of release of acetylcholine in the striatum in mice following continuous exposure to selective D1 and D2 dopaminergic agonists.

The effect of continuously infusing the selective D1 and D2 dopamine receptor agonists, SKF 38393 and quinpirole, on the release of [3H]acetylcholine from prelabeled striatal slices was investigated. These biochemical parameters were correlated with the behavioral effects of these agonists. Acute injections of SKF 38393 or quinpirole did not affect either K(+)-stimulated or spontaneous release of [3H]acetylcholine. Chronic exposure to quinpirole reduced the K(+)-evoked release of [3H]acetylcholine by 25.7%; long-term treatment with SKF 38393 did not alter the release of [3H]acetylcholine, induced by K+ stimulation. Added in vitro, SKF 38393 increased the release of [3H]acetylcholine from striatal slices. The effect of the D1 dopamine receptor agonist, SKF 38393 was reduced after 7-days of infusion of SKF 38393 but was enhanced by 7-days of infusion of quinpirole. Activation of D2 dopamine receptors with quinpirole or of muscarinic receptors with carbachol induced an inhibition of release of [3H]acetylcholine. Chronic treatment with quinpirole diminished the response to the in vitro addition of quinpirole. The ability of carbachol to inhibit release of acetylcholine was not altered by continuous treatment with either SKF 38393 or quinpirole. Continuous infusion of SKF 38393 produced an initial grooming behavior; this behavior disappeared by 2 hr and remained absent during the 7 days of infusion of SKF 38393. Similarly, continuous administration of quinpirole produced stereotyped behavior, which peaked at 1 hr and disappeared by 4 hr and remained absent for the duration of the infusion. These findings demonstrate that continuous exposure to D1 or D2 agonists caused receptor-selective functional desensitization of D1 or D2 dopamine receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1993

Colour flow and spectral Doppler imaging after papaverine-induced penile erection in 220 impotent men: study of temporal patterns and the importance of repeated sampling, velocity asymmetry and vascular anomalies.

Of 220 impotent men studied, 52 demonstrated venous leakage, 85 had arterial insufficiency and 65 showed normal vascular response. Persistent diastolic velocity > 7 cm/s diagnosed venous leakage with a sensitivity of 94% and a specificity of 69%, using cavernosography as the reference standard. Using clinical response as the reference standard maximal systolic velocity of 30 cm/s identified normal penile arterial response with a sensitivity of 96% and specificity of 82%. There was a good correlation between penile arterial insufficiency and a strong history of arteriopathy. Time to peak systole > 0.1 s was a reliable predictor of arteriogenic impotence and Pulsatility Index (PI) < 300 was discovered only in patients with either venous leakage or arteriogenic impotence. Peak systolic velocity (Tmax) occurred between 5.2 and 6.5 min after injection, and diastolic velocity was minimal at 9 min with only the normal responders showing reversed diastolic flow. However, 22% had a delayed response (Tmax range 1-18 min). Velocity asymmetry was equally common in the three groups and unilateral sampling would have misdiagnosed 6% of patients studied. Vascular anomalies were seen in 13%, particularly a single feeding artery, dorsal vein flow or collateral arterial flow.

Adult↗
PubMed1993

Nonsense mutations in the C-terminal SH2 region of the GTPase activating protein (GAP) gene in human tumours.

GTPase Activating Protein (GAP) is involved in down-regulating normal ras proteins and in the signal transduction pathway of some growth factors. We have screened 188 human tumours for mutations in the catalytic domain and at the C terminal SH2 region GAP. Three nonsense mutations in basal cell carcinomas were detected in the SH2 region and no mutations could be demonstrated in the catalytic domain. We conclude that mutations in the SH2 region of GAP may play a role in tumorigenesis and that inactivating mutations of the GAP catalytic domain do not contribute to tumour development.

Amino Acid Sequence↗
PubMed1993

Linkage analysis of fifty-seven microsatellite loci to bipolar disorder.

The authors' goal was to screen for genetic linkage with highly informative deoxyribonucleic acid (DNA) microsatellite markers on a series of moderately sized North American bipolar disorder (BP) pedigrees. These BP pedigrees were genotyped with 57 short tandem-repeat polymorphic systems (microsatellites) that were enzymatically amplified from genomic DNA. We did not find significant evidence for genetic linkage. We found isolated LOD scores greater than 2 on chromosome 1 at two loci in individual pedigrees. Simulation studies for multiple analyses under the assumptions of linkage and nonlinkage were performed. The simulations show that LOD scores greater than 2 could be expected even when linkage is absent. Significance levels need to be considered carefully in systematic linkage studies.

Bipolar Disorder↗
PubMed1993

Rare renal transcription of the atrial natriuretic factor gene in rats. Demonstration by polymerase chain reaction.

Renal synthesis of a peptide homologous to atrial natriuretic factor (ANF) has been demonstrated. The aim of the present study was to determine if transcription of the ANF gene occurs in the kidney. Rat renal RNA was extracted from whole kidneys, and, separately, from the cortex and outer and inner medulla of rat kidneys. Probing with rat ANF-cDNA did not reveal a detectable message in Northern blot analysis, even when large quantities of RNA were used at low stringency hybridization conditions. Therefore, reverse transcription (RT) followed by 35 cycles of polymerase chain reaction (PCR) was used to search for the renal message for ANF. Two 21-mer primers encompassing the 450 base pairs (bp) of the coding region of the gene were used. Each cycle consisted of annealing at 56 degrees C, extension at 72 degrees C, and denaturation at 94 degrees C. The PCR product was proven to be identical to the ANF gene by high stringency hybridization, which revealed the expected 450-bp hybrid band. Furthermore, the sequence of this product was identical to that of the coding region of the ANF gene. We used an RNA-specific PCR to obtain this band as a single reaction product. We conclude that the transcript of the ANF gene exists in the kidney, at extremely low levels. The low abundance of the RNA message raises major concerns about its physiologic relevance. Direct evidence for the translation of this transcript, and its quantification and localization, is still required to determine its significance.

Animals↗
PubMed1993

Diet restriction prevents aging-induced deficits in brain phosphoinositide metabolism.

Receptor-activated hydrolysis of [3H]inositol-labeled phosphoinositides was evaluated in brain slices of 6-month-old (6M) and 24-month-old (24M) F344 rats that had been fed ad libitum (AL) or restricted (60% of normal) diet (RD). The muscarinic cholinergic agonist, carbachol, and the dopamine receptor agonist, SKF3893, stimulated significantly lower accumulation of [3H]inositol phosphates in striatal and cortical slices of the 24M AL rats compared to the 6M AL group. This observation suggests a decreased capacity of the aged brain to respond to receptor-activated phosphoinositide hydrolysis. Furthermore, the 24M RD tissues gave significantly higher responses to carbachol (p < .01) or SKF38393 (p < .01) compared to the 24M AL group. The 24M RD responses were not significantly different from corresponding responses in the 6M AL rats, implying complete prevention of the aging effect in the diet-restricted animals up to at least 24 months of age. Concomitant observations of decreased phosphoinositide labeling in the 24M AL tissues and prevention of this decrease in diet restriction may contribute to the observed effects of aging on inositol phosphate formation.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1993

Exclusion of FAU as the multiple endocrine neoplasia type 1 (MEN1) gene.

The FAU gene (FBR-MuSV associated ubiquitously expressed gene) encodes the ribosomal protein S30 fused with a Ubiquitin-like molecule. The FAU gene is expressed in a wide range of tissues, is evolutionarily conserved, and has putative tumour suppressor activity in vitro. The human FAU gene maps to the long arm of chromosome 11 band q13, close to the PYGM locus. This locus is tightly linked to the Multiple Endocrine Neoplasia type 1 (MEN1) locus. The FAU gene properties, together with its chromosomal localisation on 11q13, make it a candidate gene for MEN1. To test this hypothesis we screened 33 unrelated patients with MEN1 for constitutional genetic alterations in the FAU gene by Southern blot analysis, denaturing gradient gel electrophoresis (DGGE) and in two cases complemented by DNA sequencing to confirm the DGGE data. Furthermore, 10 parathyroid and pancreatic tumours from MEN1 patients and 15 each of sporadic parathyroid and pituitary tumours were similarly examined. In addition, we studied the expression of the FAU gene at the RNA level in 9 MEN1-associated tumours by Northern blot analysis. No FAU gene anomalies could be demonstrated by any of these techniques. We conclude that FAU is not likely to be the MEN1 tumour suppressor gene.

Base Sequence↗
PubMed1993

Repeated reserpine increases striatal dopamine receptor and guanine nucleotide binding protein RNA.

In the present study the effects of repeated administration of reserpine on striatal dopamine receptor and guanine nucleotide binding protein mRNAs were determined. Twenty-four hours after seven consecutive daily injections of reserpine--a treatment that is known to produce functional sensitization of D1 and D2 dopamine receptors--the level of striatal D1 dopamine receptor mRNA was unchanged. However, the level of mRNA for the G protein Gs alpha was increased by 127%. After extended reserpine treatment for 14 days, levels of both striatal D1 DA receptor and Gs alpha mRNAs were elevated by 99 and 78%, respectively. Seven days of reserpine treatment also increased levels of mRNA of the striatal D2 dopamine receptor and of G proteins Gi2 alpha and Go alpha by 200, 79, and 32%, respectively. After 14 days of reserpine treatment the level of striatal D2 dopamine receptor mRNA was increased by twofold. In contrast, levels of the mRNAs coding for the G proteins Gi2 alpha and Go alpha were unchanged. These data suggest that dopamine receptors and their respective G proteins play important roles in the development of sensitization of striatal dopamine receptors during repeated reserpine treatment. Furthermore, the persistent increase in level of striatal Gs alpha mRNA suggests that this G protein is necessary to maintain supersensitivity of the striatal D1 dopamine receptor system following long-term dopamine depletion.

Animals↗
PubMed1993

Use of psychopathology vignettes by patients with schizophrenia or schizoaffective disorder and by mental health professionals to judge patients' insight.

OBJECTIVE: The goal of this study was to clarify more precisely where patients with psychotic disorders and the mental health professionals who care for them disagree regarding whether the patient is ill or needs treatment. METHOD: The authors prepared brief vignettes in everyday descriptive language that provided examples of the classical positive and negative psychopathological features of schizophrenia. Fifteen men and 11 women diagnosed as having schizophrenia or schizoaffective disorder and one physician used these vignettes as a common frame of reference to rate 1) the degree to which the patients demonstrated the features described in each vignette and 2) the degree to which the features signified the presence of mental illness. RESULTS: Disagreements between the physician's and patients' ratings, indicating deficits in insight, were associated with the recognition of the presence of conceptual disorganization, avolition-apathy, and affective blunting in the patients by the physician but not the patients and with the conceptualization of hallucinatory behavior and suspiciousness as signs of mental illness by the physician but not the patients. CONCLUSIONS: The authors conclude that the failure to acknowledge conceptual disorganization, avolition-apathy, and affective blunting and the failure to view hallucinatory behavior and suspiciousness as signs of mental illness, which proved to be additive in this study, contribute to deficits in insight.

Adult↗
PubMed1993

The thyrotropin receptor (TSH-R) is not an oncogene for thyroid tumors: structural studies of the TSH-R and the alpha-subunit of Gs in human thyroid neoplasms.

The development and progression of thyroid tumors are associated with phenotype-specific mutations of genes involved in growth control. Thyroid cell growth is controlled in part by the interaction of TSH with its receptor, with subsequent activation of the GTP-binding protein and its effector, adenylyl cyclase. The resulting increase in intracellular cAMP stimulates growth in thyrocytes. The TSH receptor (TSH-R) is a seven-transmembrane domain receptor. Intracellular domains of the TSH-R important for signal transduction and which may serve as targets for mutational activation have been defined. In addition, mutations at specific loci of the alpha-subunit of G-protein in human thyroid tumors have been described. We examined 92 benign and malignant neoplastic thyroid tissues for possible mutations of the intracytoplasmic domains of the TSH-R known to be involved in signal transduction and for mutations within the hot spots of Gs alpha. Screening was carried out by single strand conformation polymorphism (TSH-R) or denaturing gradient gel electrophoresis (Gs alpha) of polymerase chain reaction-amplified tumor DNA. No mutations were observed in the cytoplasmic domains of the TSH-R, except for a neutral base substitution in codon 460 (GCG [Ala]-->GCA [Ala]) in 3 tumors, which was also present in constitutional DNA from the affected individuals. A heterozygous mutation of codon 201 of Gs alpha (GGT [Arg]-CAT [His]) was observed in a nodule from an adenomatous goiter. In addition, a codon 227 mutation (CAG [Glu]-CAT [His]) was identified in a follicular adenoma. We conclude that mutational activation of the intracytoplasmatic domains of the TSH-R is not a significant mechanism of thyroid tumorigenesis, whereas putative activating mutations within exons 8 and 9 of Gs alpha occur infrequently in some benign follicular tumors.

Base Sequence↗
PubMed1993

Activating mutations of the Gs alpha-gene in nonfunctioning pituitary tumors.

The majority of pituitary tumors are of monoclonal origin; however, the molecular basis for their formation is poorly understood. Somatic mutations in the alpha-subunit of the GTP-binding protein, Gs alpha (gsp oncogene) have been found in about one third of GH-secreting tumors. Mutations in another alpha-subunit of a GTP-binding protein, Gi2 alpha (gip mutations) have been described in other endocrine tumors. In this study, we examined 21 nonfunctioning pituitary tumors and 4 macroprolactinomas for gsp mutations and 27 nonfunctioning tumors and 4 macroprolactinomas for gip mutations. Using the polymerase chain reaction and denaturing gradient gel electrophoresis, 2 nonfunctioning pituitary tumors displayed migration abnormalities when the Gs alpha-gene was analyzed. Sequence analysis of these abnormally migrating polymerase chain reaction products revealed two previously known gsp mutations: arginine at codon 201 altered to cysteine, and glutamine at codon 227 changed to leucine. No gip mutations could be demonstrated. These findings emphasize the monoclonal origin of nonfunctioning pituitary tumors and suggest that cAMP may play a role in tumorigenesis of nonfunctioning pituitary tumors.

Adrenocorticotropic Hormone↗
PubMed1993

Familial isolated hyperparathyroidism: a distinct genetic entity with an increased risk of parathyroid cancer.

Familial isolated hyperparathyroidism (FIHP) is a rare heritable disorder characterized by hypercalcemia, inappropriately high PTH levels, and isolated parathyroid tumors with no evidence of hyperfunction of any other endocrine tissues. To establish whether FIHP exists as a distinct disease entity or represents a variant of any of the known multiple endocrine neoplasia (MEN) syndromes, we tested 19 members of a large, well characterized family with FIHP in which the disease is transmitted through 4 generations in an autosomal dominant fashion. Fourteen DNA markers at 10 polymorphic loci closely linked to the MEN1 locus on the long arm of chromosome 11 and 5 markers close to the MEN2A gene on chromosome 10 were tested using Southern blot analysis and polymerase chain reaction-based techniques. Additionally, two polymorphic markers (Mir1 and Mir2) within the prepro-PTH gene on the short arm of chromosome 11 were analyzed using denaturant gradient gel electrophoresis. Linkage was clearly excluded between FIHP and the MEN1 and MEN2A loci as well as to the PTH gene. Comparison of constitutional and tumor genotypes showed that constitutional heterozygosity was retained for markers in the MEN1 and MEN2A regions as well as to the PTH gene in 4 tumors from 3 affected members. In 1 individual, a parathyroid carcinoma was found after recurrence of hypercalcemia. We, therefore, propose that autosomal dominant FIHP can occur as a genetically and clinically distinct entity with an increased risk of malignant transformation of parathyroid tumors.

Adolescent↗