The cholinergic REM induction test with RS 86 after scopolamine pretreatment in healthy subjects.

A shortened latency of rapid eye movement (REM) sleep is one of the most stable biological abnormalities described in depressive patients. According to the reciprocal interaction model of non-REM and REM sleep regulation, REM sleep disinhibition at the beginning of the night in depression is a consequence of heightened central nervous system cholinergic transmitter activity in relation to aminergic transmitter activity. A recent study has indicated that muscarinic supersensitivity, rather than quantitatively enhanced cholinergic activity, may be the primary cause of REM sleep abnormalities in depression. The present study tested this hypothesis by treating healthy volunteers for 3 days with a cholinergic antagonist (scopolamine) in the morning, in an effort to induce muscarinic receptor supersensitivity. On the last day of scopolamine administration, RS 86, an orally active cholinergic agonist, was administered before bedtime to test whether this procedure would induce sleep onset REM periods. Whereas scopolamine treatment tended to advance REM sleep and to heighten REM density in healthy controls in comparison to NaCl administration, the additional cholinergic stimulation did not provoke further REM sleep disinhibition. This result underlines the need to take a hypofunction of aminergic transmitter systems into account in attempts to explain the pronounced advance of REM sleep typically seen in depressives.     

The disposition of quinine in the rat isolated perfused liver: effect of dose size

We have investigated the pharmacokinetics of both free and total quinine in the rat isolated perfused liver at three doses, 6.25, 12.5 and 25 mg. The plasma concentrations of free and total quinine decayed biexponentially over 4 h. However, on increasing dose, the terminal half-life of free and total quinine showed marked increases ranging from 12.4 +/- 3.7 min at 6.25 mg to 176.0 +/- 153 min at 25 mg (total quinine). Quinine clearance was reduced approximately by half as the dose was doubled. At 10 min post dosage, quinine extraction at the 6.25 mg dose (56 +/- 16.3%) was more than twice that of the highest dose (25 mg, 25.0 +/- 6.5%). Free quinine at the 6.25 mg dose was cleared at approximately 100% of perfusate flow, whereas at 25 mg, clearance was less than one fifth of that value. Unchanged quinine elimination in bile was low, with less than 1% of the parent drug being detected at the 12.5 and 25 mg doses. Relatively little parent drug was recovered from the liver at 4 h. At the 25 mg dose, less than or equal to 6% was recovered as parent drug. HPLC analysis revealed some polar metabolites of quinine in the bile and in the liver homogenates. Dose dependent kinetics of quinine were demonstrated in this study, as hepatic extraction of quinine decreased with increasing dose and input concentration.     

Die Inkorporation von markiertem Sauerstoff aus Wasser in die ATP-, Kreatinphosphat- und Orthophosphat-Fraktion intakter Muskeln bei Ruhe,tetanischer Reizung und Erholung

Ohne ZusammenfassungMit 7 TextabbildungenDie vorliegenden Studien am Physiologischen Institut Freiburg i. Br. wurden durch einen Bundeszuschuß des Ministeriums für Atomkernenergie und Wasserwirtschaft (Bonn) ermöglicht. Die Untersuchungen in Zürich wurden aus Mitteln des Schweizer Nationalfonds getragen. Den genannten Institutionen gilt unser besonderer Dank. Vorläufige Mitteilungen über die Methode und die hier dargestellten Ergebnisse wurden bereits früher gegeben [siehe Fleckenstein, A. E. Gerlach, u. J. Janke gemeinsam mit P. Marmier: Naturwissenschaften 46, 365 (1959); Pflügers Arch. ges. Physiol. 270, 20 (1959); P. Marmier gemeinsam mit E. Gerlach, J. Janke u. A. Fleckenstein: Pflügers Arch. ges. Physiol. 270, 19 (1959); A. Fleckenstein: University of London Special University Lectures in Physiology 26–28. Oct. 1959: The turnover rates of high energy phosphate compounds during activity and rest as indicated by the oxygen exchange with H₂O¹⁸. Bericht von E. Gerlach sowie von J. Janke vor der Freiburger Med. Ges. vom 24. 11. 1959, vgl. Klin. Wschr. 38, 341–342 (1960)].     

Activation induces apoptosis in Herpesvirus saimiri-transformed T cells independent of CD95 (Fas,APO-1)

Signaling via the T cell receptor (TCR)/CD3 complex of pre-activated T cells induces apoptosis. Such an activation-induced cell death (AICD) is thought to play an important role in the regulation of cellular immune responses. In this study we analyzed pathways of AICD by using human T cells transformed by Herpesvirus saimiri. These growth-transformed T cells show the phenotype of activated mature T cells and continue to express a functionally intact TCR. We show that human H. saimiri-transformed T cell clones readily undergo cell death upon signaling via the TCR/CD3 complex or via phorbol 12-myristate 13-acetate (PMA) + ionomycin. The AICD in H. saimiri-transformed T cells was detectable a few hours after activation and it was not affected by the presence of interleukin (IL)-2 or by anti-CD4 cross-linking. However, AICD required tyrosine phosphorylation, since it could be blocked by herbimycin A. Cyclosporin A (CsA) did not block the development of AICD, but other consequences of activation in H. saimiri-transformed T cells like the production of interferon-γ. Surprisingly, the development of AICD was not reduced by neutralizing antibodies to tumor necrosis factor (TNF)-α or blocking antibodies directed to CD95 (Fas, APO-1), although H. saimiri-transformed T cells were sensitive to CD95 ligation. To confirm that this form of AICD is really independent of CD95, we have established an H. saimiri-transformed T cell line from a patient with a homozygous deletion in the CD95 gene. This CD95-deficient T cell line was as sensitive to AICD as other CD95-expressing H. saimiri-transformed T cells. In conclusion, we describe here a type of AICD in H. saimiri-transformed T cells that is independent of CD95 and TNF-α, not sensitive to CsA, but requires tyrosine phosphorylation. This system should be useful for the investigation of CD95-independent forms of AICD.     

Genetic relationships between bovine herpesvirus 4 and the gammaherpesviruses Epstein-Barr virus and herpesvirus saimiri.

The overall arrangement of genes in the unique central part of the bovine herpesvirus type 4 (BHV-4) genome has been deduced by analysis of short DNA sequences. Twenty-three genes conserved in at least one of the completely sequenced herpesviruses have been identified and localized. All of these genes encoded amino acid sequences with higher similarity to proteins of the gammaherpesviruses Epstein-Barr virus (EBV) and herpesvirus saimiri (HVS) than to the homologous products of the alphaherpesviruses varicella-zoster virus and herpes simplex virus type 1 or the betaherpesvirus human cytomegalovirus. The genome organization of BHV-4 had also an overall colinearity with that of the gammaherpesviruses EBV and HVS. Furthermore, the BHV-4 genes content and arrangement were more similar to those of HVS than to those of EBV, suggesting that BHV-4 and HVS are evolutionarily more closely related to each other than either are to EBV. BHV-4 DNA sequences were generally deficient in CpG dinucleotide. This CpG deficiency is characteristic of gammaherpesvirus genomes and suggests that the BHV-4 latent genome is extensively methylated. Despite several biological features similar to those of betaherpesviruses, BHV-4 displays the molecular characteristics of the representative members of the gammaherpesvirinae subfamily.     

Selective inhibition of the transmembrane Ca conductivity of mammalian myocardial fibres by Ni,Co and Mn ions

Pflügers Archiv - European Journal of Physiology - According to earlier studies on mammalian papillary muscles, Ni and Co ions reduce the Ca dependent mechanical response whilst the action...     

Purification and properties of Herpesvirus saimiri DNA

³H-Thymidine-labeled Herpesvirus saimiri (HVS) was purified from supernatant and cells of infected owl monkey kidney monolayer cultures. Pronase/SDS-extracted HVS DNA was characterized in neutral sucrose gradients. Cocentrifugation of this DNA with ¹⁴C-labeled T4-phage DNA resulted in s⁰₂₀, w = 58 ± 1.5 S as the sedimentation constant, corresponding to a molecular weight of 91 ± 5 × 10⁶ daltons. Unsheared HVS DNA banded in cesium chloride at 1.709 g/ml, but it broke down during the different manipulations to at least two double-stranded DNA molecules of largely different base composition which shared no sequence homologies. One part (42% of the total viral genome) had a density of 1.729 g/ml, corresponding to 70% cytosine plus guanine content, the other one (representing 58% of the intact molecule) banded at 1.694 g/ml, corresponding to 35% cytosine plus guanine.     

Herpesvirus saimiri has a gene specifying a homologue of the cellular membrane glycoprotein CD59.

Herpesvirus saimiri (HSV) is a T-lymphotropic tumor virus that causes fulminant lymphomas and leukemias in various New World primates other than its natural host, the squirrel monkey (Saimiri sciureus). In the course of completing the nucleotide sequence of its genome, we identified an open reading frame of 363 nucleotides, designated HVS-15, that has no detectable homology to any other viral sequences to date. HVS-15 encodes a 121-amino-acid protein which shows significant similarities to human CD59, a phosphatidyl-inositol-glycan-anchored glycoprotein involved in T-cell activation and restriction of complement-mediated lysis. The predicted HVS-15 gene product is more similar to human CD59 than to the related murine Ly-6 antigens. A nucleotide sequence identity of 64% was found between HVS-15 and the CD59 reading frame, and a 48% identity exists between the corresponding protein sequences. The comparison of the amino acid sequences revealed a number of conserved structural features such as a similar pattern of hydrophobic termini and an identical cysteine skeleton.     

Mechanism of the cardioprotective effect of triamterene in the rat heart. Myocardial protection via elevation of extracellular K+ and Mg++ concentrations

1. 2,4,7-Triamino-6-phenyl-pteridine (triamterene) protects the rat heart against isoproterenol-induced myocardial lesions: Whilst cardiotoxic doses of isoproterenol produce deleterious myocardial Ca overload, simultaneous admistration of triamterene diminishes myocardial Ca incorporation considerably. 2. As to the mechanism of action, triamterene increases the plasma contents of K and Mg by inhibiting renal excretion. Accordingly, oral administration of K and Mg salts, leading to a similar rise in the K and Mg concentrations of the plasma, also prevents abundant myocardial Ca incorporation. 3. Cardioprotection by triamterene can, in fact, be simply explained by its action on the plasma K and (particularly) Mg levels. This conclusion is drawn from a quantitative comparison of the inhibitory effects of triamterene (40 mg/kg s.c.) with those of KCl or MgCl2 (10 mMol/kg p.o.) on the isoproterenol-induced increase in myocardial 45Ca uptake and absolute Ca concentration. 4. Isoproterenol induced cardiomyopathy of the rat, an experimental model of non-coronarogenic myocardial lesions, has hitherto been successfully prevented with the use of Ca-antagonists (verapamil, D 600, prenylamine, fendiline). These compounds reduce Ca influx by restricting the Ca conductivity of the myocardial sarcolemma membrane ("slow channel"). The action of triamterene, on the other hand, is based on a totally different cardioprotective principle, namely competitive inhibition of intracellular myocardial Ca accumulation via an increase in K and Mg supply. In the future treatment of cardiomyopathy it seems rather promising to try a combination of both a Ca-antagonist and triamterene, thus applying two different therapeutic principles simultaneously.