Lhermitte's sign in paroxetine withdrawal.
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Adult↗
Biomedical subjects
H B Pinkofsky
Publications and source records attributed to H B Pinkofsky.
Unreliability of current screening tests for syphilis in chronic psychiatric patients.
OBJECTIVE: This study examined whether psychiatrists perform adequate diagnostic screening for syphilis in patients with chronic mental illness. METHOD: Two hundred patients with chronic mental illness underwent testing for syphilis with the commonly used RPR test and the microhemagglutination assay for Treponema pallidum (MHA-TP). Sensitivities of the two tests were compared. RESULTS: A substantial number of patients with negative results on RPR tests had reactive MHA-TPs and would have not been identified as having had syphilis with the use of RPR testing alone. CONCLUSIONS: Nontreponemal tests such as the RPR test are less likely than treponemal tests to detect syphilis appropriately in chronically mentally ill patients, and specific treponemal tests such as the MHA-TP should be considered.
Adult↗
Mood alterations and tramadol.
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Depressive Disorder↗
Naloxone-reversible coma unrelated to opiate drugs.
A role for endogenous opioids in central nervous system disorders has often been proposed. A case report is presented of a 47-year-old male, medicated only with carbamazepine and lithium, who developed a precipitous alteration of consciousness (Glascow coma scale = 4). An extensive medical workup did not reveal an underlying cause. He exhibited a graded awakening with two intravenous doses of naloxone, which gradually reversed as the last naloxone dose was eliminated. Immunoassay and thin-layer chromatography of two urine samples (to evaluate the possibility of a medication error, alcohol ingestion, or illicit drug use) revealed only the presence of carbamazepine. A dysregulation of the endogenous opioid system is believed to underlie this episode.
Atrophy↗
ADP, chloride ion, and metal ion binding to bovine brain glutamine synthetase.
The binding of divalent cations and nucleotide to bovine brain glutamine synthetase and their effects on the activity of the enzyme were investigated. In ADP-supported gamma-glutamyl transfer at pH 7.2, kinetic analyses of saturation functions gave [S]0.5 values of approximately 1 microM for Mn2+, approximately 2 mM for Mg2+, 19 nM for ADP.Mn, and 7.2 microM for ADP.Mg. The method of continuous variation applied to the Mn2+-supported reaction indicated that all subunits of the purified enzyme express activity when 1.0 equiv of ADP is bound per subunit. Measurements of equilibrium binding of Mn2+ to the enzyme in the absence and presence of ADP were consistent with each subunit binding free Mn2+ (KA approximately equal to 1.5 X 10(5) M-1) before binding the Mn.ADP complex (KA' approximately equal to 1.1 X 10(6) M-1). The binding of the first Mn2+ or Mg2+ to each subunit produces structural perturbations in the octameric enzyme, as evidenced by UV spectral and tryptophanyl residue fluorescence changes. The enzyme, therefore, has one structural site per subunit for Mn2+ or Mg2+ and a second site per subunit for the metal ion-nucleotide complex, both of which must be filled for activity expression. Chloride binding (KA' approximately equal to 10(4) M-1) to the enzyme was found to have a specific effect on the protein conformation, producing a substantial (30%) quench of tryptophanyl fluorescence and increasing the affinity of the enzyme 2-4-fold for Mg2+ or Mn2+. Arsenate, which activates the gamma-glutamyl transfer activity by binding to an allosteric site, and L-glutamate also cause conformational changes similar to those produced by Cl- binding. Anion binding to allosteric sites and divalent metal ion binding at active sites both produce tryptophanyl residue exposure and tyrosyl residue burial without changing the quaternary enzyme structure.
Adenosine Diphosphate↗
Further characterization and chemical purity assessment of the human erythrocyte glucose transporter preparation.
Chemical and functional purity of the human erythrocyte glucose transporter preparation obtained by DEAE column chromatography after octyl glucoside solubilization was assessed. The cytochalasin B binding capacity of the preparation indicates that the preparation is 60-85% functional glucose transporter. Gel filtration chromatography on TSK 250 column separates this preparation into at least three major peptide fractions, namely, P0, P1 and P2, with apparent Mr of approx. 80 000, 43 000 and 17 000, respectively. When the preparation is photolabelled with [3H]cytochalasin B prior to the separation only P0 and P1 are labelled. Exposure of the preparation to octyl glucoside or to ultraviolet light irradiation results in an increase in P0 in a time-dependent manner with a concomitant and proportional reduction in P1, without affecting P2 appreciably. For individual preparations, relative abundance of P0 and P1 vary widely in a reciprocal fashion, while that of P2 is practically fixed at approx. 10% of the total protein. The specific activity of cytochalasin B binding of each preparation correlates linearly with the relative abundance of P1 of the preparation, which gives a calculated specific binding activity of 22 nmol/mg protein for this fraction. These results indicate that P1 and P0 are native and denatured transporter, respectively, while P2 is contaminating protein impurities. These results demonstrate that the glucose transporter preparation contains approx. 10% of nontransporter protein impurities, with a varying amount (up to 30%) of denatured transporter, and that the transporter free of the chemical impurities and the denatured transporter can be obtained by a gel filtration chromatography of this preparation.
Chromatography, Gel↗
Mg2+ is bound to glutamine synthetase extracted from bovine or ovine brain in the presence of L-methionine-S-sulfoximine phosphate.
Purified glutamine synthetase from bovine or ovine brain had no tightly bound Mn2+. By extraction of bovine or ovine brain glutamine synthetase in the presence of L-Met-S-sulfoximine phosphate and ADP in metal ion-free water and 0.1 M KCl, only endogenously bound divalent cations were trapped on the enzyme. Enzyme complexes isolated by immunoprecipitation contained less than 0.05 Mn2+ and 1.5 +/- 0.2 Mg2+ per subunit. Without inactive complex formation, the enzyme immunoprecipitated from extracts contained undetectable Mn2+ (less than 0.01 eq per subunit) and 0.1-2.0 eq of Mg2+ per subunit. Direct binding measurements showed that the purified bovine brain enzyme contained two divalent cations bound at the active site of each subunit. Thus, although either Mg2+ or Mn2+ supports enzyme activity in vitro, Mg2+ rather than Mn2+ appears to be bound to brain glutamine synthetase in vivo.
Adenosine Triphosphate↗
Accessibility of sulfhydryl residues induced by cytochalasin B binding and conformational dynamics in the human erythrocyte glucose transporter.
Studies with intact cells have implicated essential sulfhydryl groups in the carrier-mediated glucose transport of human erythrocytes. In an attempt to identify and characterize such essential sulfhydryl residues we have studied the interaction of p-chloromercuribenzoate (PCMB) with a purified glucose transporter preparation (band 4.5) from human erythrocytes, in the presence and absence of its ligands, and the effects of this interaction on the binding of cytochalasin B (CB) to the transporter. At least 3 mol of PCMB reacted per mol of this preparation. A portion of the reaction was significantly enhanced in the presence of cytochalasin B. This enhancement was a saturable function of CB concentration, and was half-maximal at a CB concentration equal to the dissociation constant for the CB binding to the preparation. This CB-sensitive, PCMB reaction product comigrated with the band 4.5 on lithium dodecyl sulfate-polyacrylamide gel electrophoresis. An excess of D-glucose did not affect the PCMB reaction by itself in the absence of CB, but totally abolished the CB-induced enhancement of the PCMB reaction. PCMB inhibited the CB binding activity of the transporter preparation, and this inhibition was also enhanced in the presence of CB. These results suggest that CB binding perturbs the conformational dynamics of the glucose transporter resulting in an exposure of at least two sulfhydryl residues to PCMB reaction, and that some of these CB-sensitive sulfhydryl groups are essential for CB binding to the transporter.
Binding Sites↗
Lysyl residue 47 is near the subunit ATP-binding site of glutamine synthetase from Escherichia coli.
The ATP analog 5'-p-fluorosulfonylbenzoyladenosine (FSBA) inactivates dodecameric glutamine synthetase from Escherichia coli with concomitant labeling of one site/subunit (Foster, W.B., Griffith, M.J., and Kingdon, H.S. (1981) J. Biol. Chem. 246, 882-886). Cyanogen bromide cleavage of the FSBA-inactivated enzyme in 70% HCOOH produced a large peptide (Mr congruent to 4600) in approximately 75% yield containing N epsilon-4-carboxybenzenesulfonyl (CBS) lysine. The CBS-peptide was purified by high performance liquid chromatography on the basis of its relatively high UV absorbance at 246 nm (delta epsilon congruent to 19,000 M-1 cm-1). The appearance of the labeled peptide coincided with the loss of a peptide (lacking tyrosine and tryptophan) from the unmodified, active enzyme; the CBS-peptide also could be distinguished from cysteine-containing peptides labeled with thionitrobenzoate and from the adenylylated peptide. The identical peptide was labeled when the unadenylylated enzyme was inactivated with FSBA in the absence or presence of Mn2+ or Mg2+ (+/- L-glutamate) or when the enzyme was adenylylated. Conformational differences among these enzyme forms therefore are not detected by affinity labeling of ATP sites. The FSBA-labeled peptide spans residues 9-48 from the N-terminal end of the subunit polypeptide chain, and sequence analysis by automated Edman degradation revealed that CBS-lysine was at position 47. Thus, lysyl residue 47 appears to be near the subunit gamma-phosphate-binding site for ATP in the native glutamine synthetase structure. The primary structure of the CBS-labeled peptide is presented.
Adenosine↗
Cytochalasin B-binding proteins in rabbit erythrocyte membranes and their post-natal change in relation to the glucose carrier activity.
Two distinct, carrier-mediated glucose uptake processes, a fast, cytochalasin B-sensitive and a slow, cytochalasin B-insensitive flux are identified in parallel in newborn rabbit erythrocytes. The fast, cytochalasin B-sensitive carrier function disappears as rabbits age, and only the slow cytochalasin B-insensitive carrier function is observed with adult rabbit erythrocytes. Three different cytochalasin B binding sites are distinguished in newborn rabbit erythrocytes; a glucose-sensitive site (site I), a cytochalasin E-sensitive site (site II), and a site insensitive to both glucose and cytochalasin E. With adult rabbit erythrocytes, only a cytochalasin E-sensitive site is detected. With glucose-sensitive site disappears as rabbits age, with a time course which is comparable to that of the disappearance of the cytochalasin B-sensitive glucose carrier function. The cytochalasin E-sensitive cytochalasin B binding site does not increase during this change, thus the disappearance of the glucose-sensitive site is not due to its conversion to a cytochalasin E-sensitive site. Sodium dodecyl sulfate polyacrylamide gel electrophoresis of rabbit erythrocyte ghosts revealed a partial decrease in each of the membrane polypeptides of approximate molecular weights of 240 000, 160 000 and 50 000 as rabbits aged. It is concluded that the cytochalasin B-sensitive glucose carrier of fetal rabbit erythrocytes, like that of the human erythrocyte, is tightly associated with the site I cytochalasin B-binding protein, while the cytochalasin B-insensitive glucose carrier, operative in adult rabbit erythrocytes, is not.
Aging↗
Structure of cytochalasins and cytochalasin B binding sites in human erythrocyte membranes.
Twenty cytochalasins were tested for binding to and for inhibition of glucose transport in human erythrocyte membrane. In this membrane three cytochalasin B (CB) binding sites have been identified. All but three of the cytochalasins bind at site II. On the other hand, only nine of them, which are structurally closely related, bind at site I and inhibit glucose transport. For site I (and site III) binding and glucose transport inhibitory activities (a) the macrocyclic ring in the cytochalasin molecule must be at least 13-membered, (b) the nature of the aromatic ring at C-10 is not important, (c) the C-20-C-23 region makes a major contribution, and (d) the C-5-C-7 segment has a relatively minor influence. These findings do not support a proposed mechanism which involves 24, C-23, C-20, and C-1 oxygen atoms for interaction of CB with glucose carrier. The structural requirements for site II activity are less stringent. The size and the structure of the macrocyclic ring and the nature of the aromatic residue at C-10 modulate this activity only slightly, if at all. Modifications in the C-5-C-7 region of the molecule, however, result in substantial changes in this activity.
Binding, Competitive↗
Cytochalasin B binding proteins in human erythrocyte membranes. Modulation of glucose sensitivity by site interaction and partial solubilization of binding activities.
We have previously described three different cytochalasin B binding sites in human erythrocyte membranes, a D-glucose-sensitive site (Site I), a cytochalasin E-sensitive site (Site II), and a site (Site III) insensitive to both D-glucose and cytochalasin E. Ligand bindings to each of these sites were considered to be independent (Jung, C., and Rampal, A. (1977) J. Biol. Chem. 252, 5456-5463). However, we have obtained subsequently the following evidence which indicated that an interaction occurs between Sites II and III, and this modulates sensitivity of Site III to the sugar. The displacement of cytochalasin E greatly exceeds the sum of their independent displacements. This ghosts extracted with EDTA or 2,3-dimethylmaleic anhydride at low ionic strength lack Site II activity but retain Site I and III activities, and both of these activities are displaceable by D-glucose alone. This indicated that the removal of Site II from the membrane confers glucose sensitivity to Site III. These observations are consistent with a model that Sites II and III in the membrane exist in a close association through which unliganded Site II maintains the glucose insensitivity of Site III, and once site II is liganded or removed by extraction this association is disrupted and Site III becomes glucose-sensitive. The ghosts extracted with Triton X-100 retain a cytochalasin B binding activity similar to that of site II (Kd = 1.8 X 10(-7) M, cytochalasin E-sensitive, glucose-insensitive), whereas a binding activity similar to that of Site I (Kd = 4 X 10(-7) M, cytochalasin E-insensitive, glucose-sensitive) is recovered in the Triton extract. A cytochalasin B binding activity similar to that of Site II is solubilized by EDTA at low ionic strength.
Cytochalasin B↗
A nifedipine-induced inhibition of lithium clearance.
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Adult↗
Effects of antipsychotics on the unborn child: what is known and how should this influence prescribing?
The onset of psychosis during pregnancy presents difficult management decisions. A complete and thorough physical and obstetric examination is always warranted to look for possible physiological precipitants. The treatment of pregnant patients with psychotic symptomatology requires close contacts between family members, non-physician professionals involved in the patient's care (e.g. social workers, case managers and home healthcare nurses), and the physicians overseeing the patient's management (e.g. internists, obstetricians and psychiatrists). In mild and less disabling cases it may be possible to avoid medication intervention but this approach risks adverse behaviour consequences resulting from a possible worsening of the patient's symptomatology. Avoiding medication requires an environment in which the patient has strong social supports. Risks are present whether medication is initiated or not, and treatment decisions require a careful assessment of the risks and benefits involved. Initiating medication raises the possibility of obstetric, teratogenic, neurobehavioural and neonatal toxic effects. Research on the risks imposed by antipsychotic drug use during pregnancy is incomplete and raises questions regarding appropriate management. The first trimester represents a period of increased susceptibility to medication-induced teratogenesis. The use of low potency phenothiazines during the first trimester may increase the risk of congenital abnormalities by an additional 4 cases per 1000 (odds ratio = 1.21, p = 0.04) The pharmacological profiles of antipsychotic medications also present adverse effects which need to be considered during pregnancy (hypotension, sedation, etc.). Less is known about the risk of adverse consequences resulting from the use of newer atypical antipsychotic medications. Electroconvulsive therapy is another treatment modality and its use may circumvent the need to introduce antipsychotic medication during pregnancy. It must be stressed that. given current knowledge, no treatment regimen can be considered completely safe. Ultimately many factors must be evaluated when treating psychosis during pregnancy, however, no decision is risk-free.
Adult↗