Effects of azimilide, a new class III antiarrhythmic drug, on reentrant circuits causing ventricular tachycardia and fibrillation in a canine model of myocardial infarction.

INTRODUCTION: Azimilide blocks the slow (I(Ks)) and fast (I(Kr)) components of the delayed rectifier potassium channel. It also has blocking effects on sodium (I(Na)) and calcium currents (I(CaL)). Its effects on reentrant circuits in infarct border zones causing ventricular tachyarrhythmias are unknown. METHODS AND RESULTS: Activation in reentrant circuits causing sustained ventricular tachycardia (SVT) and the initial polymorphic tachycardia that leads to ventricular fibrillation (VF) was mapped in the epicardial border zone (EBZ) of 4-day-old canine infarcts. Azimilide prolonged the effective refractory period (ERP) in both normal myocardium and EBZ, but reverse use-dependence in EBZ was prominent. Azimilide abolished SVT initiation by programmed electrical stimulation by prolonging the ERP at the site of stimulation either in normal or EBZ, preventing the occurrence of early premature impulses and the formation of lines of block in the EBZ necessary for formation of reentrant circuits. Azimilide prevented VF initiation by programmed electrical stimulation by causing conduction block of reentrant impulses in the EBZ during the initial beats of rapid polymorphic ventricular tachycardia, despite the reverse use-dependent effects on ERP. CONCLUSION: Azimilide has antiarrhythmic effects to prevent reentry causing SVT and VF in a canine infarct model.

Intramuscular versus surface electromyography of the diaphragm for determining neuromuscular blockade.

We determined the neuromuscular blockade of 0.2 mg. kg(-1) mivacurium at the diaphragm by using two new methods of electromyographic (EMG) monitoring and compared it with acceleromyography of the orbicularis oculi (OO) and the corrugator supercilii (CS) muscle. After the induction of anesthesia in 15 patients undergoing gynecologic laparoscopic surgery, evoked EMG responses at the diaphragm were obtained by using skin electrodes at the back of the patient, placed lateral to T12/L1 or L1/L2, and a laparoscopically applied wire electrode inserted into the dorsolateral portion of the diaphragm. Acceleromyography at the right OO and the left CS was performed. The facial and phrenic nerves were stimulated transcutaneously (onset: every 10 s, offset: every 15 s, single twitch stimulation). Lag and onset time, peak effect, and clinical duration (time to reach 75% of control value and time to reach 90% of control value) were measured and the results were compared by using analysis of variance; P < 0.05 showed significant difference. Pearson's correlation test and the Bland-Altman test were used to compare the two diaphragmatic monitoring methods. Mean peak effects of >98% were reached at all sites. Onset times at diaphragm (skin, IM) were significantly (P < 0.005) shorter than at the CS or OO (100 +/- 14 s and 98 +/- 16 s vs 147 +/- 39 s, 185 +/- 38 s) without being statistically different between OO and CS. There was a good correlation of lag, onset time, time to reach 75% of control value, and time to reach 90% of control value (r = 0.8, 0.9, 0.8, and 0.75; P < 0.01) between the two diaphragmatic methods. Mean difference and limits of agreements are -2 +/- 15 s, 1 +/- 21 s, -1 +/- 2.3 min, and -2 +/- 3.4 min. We showed a shorter onset and clinical duration at the diaphragm in comparison with CS and OO. Two methods of EMG of the diaphragm correlated well and showed good comparability. The novel method of surface diaphragmatic EMG at the patient's back may be useful during routine clinical anesthesia.

[Acupuncture treatment of low back pain]. / Akupunktur zur Behandlung von Schmerzen im Bereich der Lendenwirbelsäule.

OBJECTIVES: This prospective, non-controlled pilot-study examines the potential benefit of acupuncture in patients with low back pain and radicular symptoms. METHODS: 60 patients with low back pain and lumbar disc herniation diagnosed by magnetic resonance imaging or computed tomography were treated by acupuncture. Pain intensity was assessed before and after treatment on a 100 mm visual analogue scale. RESULTS: Intensity of low back pain dropped from 59 to 19 mm, and intensity of radicular pain from 64 to 12 mm. Three to twelve months after the end of acupuncture, 88% of patients were satisfied with treatment outcome. CONCLUSION: Acupuncture as a noninvasive treatment with very few complications is a promising therapeutical option of low back pain, especially when associated with radicular symptoms.

Experimental and theoretical 31P and 77Se nuclear magnetic shielding tensors for bis(dineopentoxyphosphorothioyl) diselenide.

An intergrown crystal of two phases of bis(dineopentoxyphosphorothioyl) diselenide 1 was investigated by goniometer 31P NMR. From the angular dependence of the chemical shift, the tensors of a triclinic and a monoclinic phase were determined. The principal values sigma11, sigma22, and sigma33, of the absolute nuclear magnetic shielding tensors for the triclinic phase are 134.1, 227.2, and 375.5 ppm and for the monoclinic phase are 132.4, 227.8, and 374.2 ppm, respectively. In both cases, the principal axis 3 of the 31P tensor is directed nearly along the P=S bond and the principal axis 2 is nearly perpendicular to the S=P-Se plane. Calculations of the 31P and 77Se nuclear magnetic shielding tensors were performed for molecules of both phases of 1 and for model compounds by the sum-over-states density functional perturbation theory IGLO method. The rms distances between calculated and experimental 31P NMR icosahedral tensor values sigma(j) (j = 1, ..., 6) amount to 17-21 ppm. The calculated and experimental orientations of the 31P principal axes show a maximum difference of 5 degrees and rms distances of 3.2 and 3.3 degrees. For the principal value sigma33 of the selenium shielding tensor the agreement between calculated and experimental values is satisfactory, but the calculated values sigma11 and sigma22 are distinctly too small. Calculations for a model compound in which the methyl groups of the neopentoxy residue are substituted by protons lead practically to the same results.

"Sunbath polyneuritis": subacute axonal neuropathy in perazine-treated patients after intense sun exposure.

This article aims at drawing attention to the peculiar association of intense exposure to sunlight and subacute development of sensory neuropathy which was seen in 7 psychiatric patients treated with the phenothiazine derivative, perazine. Three patients additionally developed bilateral VII nerve palsy. Symptoms followed a monophasic course with almost complete remission. Routine neurophysiology suggested axonal neuropathy confirmed by sural nerve biopsy in 1 patient. A toxic origin of neuropathy is supposed, possibly induced by phenothiazine photoproducts, which may cause cell damage via lipid peroxidation.

Human trefoil peptides: genomic structure in 21q22.3 and coordinated expression.

Trefoil peptides are small secretory proteins characterized by three intrachain disulfide bonds forming the trefoil motif or P-domain. They are abundantly expressed on mucosal surfaces, especially of the gastrointestinal tract. In pathological conditions such as ulcers, metaplasia and neoplasia, their expression is upregulated. Three human trefoil peptides have been described: the estrogen-inducible pS2 protein, the spasmolytic protein and the intestinal trefoil factor. Recently, their role in the maintenance of surface integrity and ulcer healing was discussed. We already mapped the corresponding three genes (BCEI), SML1, TFF3) to the same genomic region (21q22.3). In this paper, we show that the three genes are clustered in a tandemly orientated fashion within 50 kb on a bacterial artificial chromosome (BAC) recombinant. This cluster is located adjacent to D21S19 and the locus order is cen-D21S212-TFF3-SML1-BCEI-D21S19-tel, whereas transcription of all three genes is directed towards the centromere. The gene structure of SML1 exhibits four exons, two of which encode the two separate trefoil motifs. TFF3 and BCEI, both containing one trefoil motif, are composed of three exons each, suggesting gene duplication and exon-shuffling events during evolution. The 5'-flanking region of SML1 was compared to the corresponding region of other trefoil genes. Two motifs with identical sequence and positions are shared between SML1 and BCEI, thus presenting possible targets for stomach-specific gene regulation. Two other motifs are shared within all known human and rat trefoil genes, suggesting a coordinated regulation and/or a common locus-controlling region. Using RT-PCR, a change in the pattern of trefoil gene expression is detected in tissue samples from normal gastric mucosa, hyperplastic polyps, gastric cancer, and gastric cancer cell lines, respectively.

Evoked otoacoustic emissions and pure tone threshold audiometry in patients receiving cisplatinum therapy.

Eight children and young adults with cancer were evaluated serially using pure tone audiometry as well as registration of click-evoked otoacoustic emissions (EOAE) 1 day prior to therapy as well as after various numbers of doses of cisplatinum. A reduction of EOAE-amplitudes following cisplatinum therapy was observed in all patients. This reduction tended to recover after the end of cisplatinum administration. Since EOAE are believed to result from cochlear bio-mechanical processes, the reduced emissions are interpreted as signs of cochlear dysfunction. We conclude, that EOAE testing may be a simple, non-invasive method that may detect early, transient functional impairment of hearing due to ototoxic agents such as cisplatinum, even in children. Further controlled trials are needed.

[Virus inactivation of plasma]. / Virusinaktivierung von Plasma.

A procedure for the virus inactivation of single donor plasma is described. Virus inactivation is achieved by the combination of 1 mumol of phenothiazin dye, e.g. methylene blue and toluidine blue, and visible light. Using this method VSV, HSV and HIV, as well as other viruses, were inactivated. It could be shown that virus inactivation caused only a minimal reduction in the biological activities of coagulation factors and inhibitors. Furthermore, there was no indication for either neo-antigens or IgE-antibodies. In tolerance studies on dogs it was demonstrated that virus-inactivated autologous plasma caused no toxic effects.

[Primary degeneration of the thalamus with dementia--2 cases with family background]. / Primäre Degeneration des Thalamus mit Demenz--Zwei Beobachtungen mit familiärem Hintergrund.

This is a report on two male patients aged 22 and 43 years, respectively, who developed a fatal progressive demential syndrome that lead to the death of one after 16 months and of the other patient after 25 months and that presented with the typical clinical pattern of "subcortical dementia". In both the cases, the hospital had suspected Creutzfeldt-Jacob's disease but this was not confirmed by microscopy of the tissue; the typical form of manifestation was absent. Instead, microscopy of the brain revealed a marked symmetric degeneration of the thalamus with special preference given to the anterior and media nuclear groups. Predilection for the neothalamic against the palaeothalamic and archithalamic structures produced a very strong impression of a system-related thalamic degeneration process of the type occasionally discussed on the basis of similar observations. Parallel to the atrophic process there were also degenerative changes that were less pronounced, in the rubro-olivo-cerebellar system and in one case a moderately pronounced involvement of the second motor neuron. Both observations of a "thalamic dementia" are discussed against the background of relevant literature published so far on the subject.

Aerosol amphotericin B is effective for prophylaxis and therapy in a rat model of pulmonary aspergillosis.

Invasive pulmonary aspergillosis is a major life-threatening complication among transplant recipients and patients receiving cancer chemotherapy. In a rat model of progressive pulmonary aspergillosis that is characterized by hyphal bronchopneumonia, aerosol amphotericin B (aero-AmB; 1.6 mg/kg given 2 days before infection) significantly delayed mortality in rats compared with animals in a control group. The first death in the aero-AmB-treated group occurred on day 11, by which time seven of the eight control animals had died. The same dose of aero-AmB given as treatment (1.6 mg/kg given 24 h after infection and then daily for 6 days) was also effective. In this trial, eight of the ten animals treated with aero-AmB survived for 7 days, whereas only one of ten control animals survived. Colony counts in lung homogenates obtained 24 h after infection showed an 80-fold reduction in the number of viable spores in animals that had received 6.4-mg/kg doses of aero-AmB 2 days prior to infection. At 48 h after administering a single 1.6- or 3.2-mg/kg dose of aero-AmB, mean lung concentrations were 2.79 and 5.22 micrograms/g of tissue, respectively. We conclude, therefore, that aero-AmB kills inhaled spores and delays the progression of pulmonary aspergillosis by inhibiting mycelial proliferation.

Characterization of cloned sequences complementary to F9 cell double-stranded RNA and their expression during differentiation.

In a cDNA library prepared from the RNA of cultured murine F9 teratocarcinoma cells, we identified sequences exhibiting strong hybridization to double-stranded RNA (dsRNA) of F9 cells but weak hybridization to mouse liver dsRNA. Northern-blot hybridization of RNA extracted from F9 cells with or without treatment with retinoic acid revealed differences in the expression of some of these sequences in undifferentiated and differentiated cells. As shown by Southern-blot hybridization experiments, these differences of expression were not related to a gross rearrangement of the corresponding genomic DNA sequences of the differentiated cells. When RNA from F9 cells was used, one of the cloned dsRNA-related sequences selected mRNA which was translated in vitro to a polypeptide with an Mr of 24,000; the level of this mRNA was reduced in F9 cells that had been treated with retinoic acid. Our results show that the differentiation of F9 cells induced by retinoic acid results in the differential expression of some middle-repetitive sequences.

Chronic electrical stimulation of the thalamic unspecific activating system in a patient with coma due to midbrain and upper brain stem infarction.

Chronic intermittent bipolar electrical stimulation of the left nucleus reticulatus polaris thalami was performed in a patient in a state of subcoma due to ischaemic infarction of wide medial parts of the midbrain, mainly the tegmentum, and the right-sided mediobasal parts of the forebrain. Stimulation immediately resulted in autonomic reactions and behavioural arousal reactions during the periods of stimulation. Longterm effect consisted of a rise in the level of clinical responsiveness for a period of seven weeks. A preexistent severe pneumonia disappeared completely after one week of stimulation and returned after seven weeks. The results are discussed on the basis of the pathoanatomical findings and of the physiological functions of the damaged as well as of the stimulated areas.

Inhibition of [3H]-dihydroalprenolol binding to rat cardiac membranes of various beta-blocking agents.

Binding of [3-H]-dihydroalprenolol ([3-H]-DHA) to rat cardiac membranes was rapid and reversible (k1 = 0.633-0.701 x 10(6) M(-1) S(-1) And k(-1) = 0.0017-0.0043 s(-1). 2 [3-H]-DHA bound to a single class of binding sites with an equilibrium dissociation constant (Kd25degreesc) of 5.7+/-1.1 x 10(-9) M. 3 This binding was specific and the order of potency of adrenoceptor agonists in competing for the binding sites was (-)-isoproterenol greater than (+/-)-isoproternol greater than (+)-isoproterenol greater than (-)-adrenaline greater than (-)-noradrenaline. This was in agreement with the beta1 nature of the cardiac beta-receptors. 4 Cardioselective beta-blockers (i.e. metoprolol, acebutolol and practolol) were shown to have lower binding site affinities, when compared to other blockers. This may be related to steric hindrance by the side-chain at the aromatic end of these molecules.

[Electromagnetic stimulation of infected experimental pseudarthrosis in a left-right study of beagles]. / Elektromagnetische Stimulation infizierter Defektpseudarthrosen im Rechts-Links-Versuch am Beagle.

Electromagnetic AC-stimulation according to the method of KRAUS was applied in 9 infected ununited ulnar fractures in the beagle. New cortical bone formation, bridging of the bone defect and the number of blood vessels in bone and soft tissue was assessed. Electromagnetic stimulation had no significant influence on bone healing or on the number of vessels.

Properties and synthesis of tubulin in neuroblastoma cells.

Cloned neuroblastoma cell lines derived from the spontaneous mouse tumor C-1300 were used to study nerve cell differentiation. Our findings included a) morphologic and electrical differentiation was induced by the addition of dimethyl sulfoxide to the culture medium of some of the neuroblastoma clonal lines; b) a contrasting difference existed between the percentage of the phenylalanine-specific, tRNA species deficient in the peroxy Y-nucleoside in the mouse embryo or rat brain (6-10%) and that of mouse neuroblastoma cells (85%); c) the assembly of neuroblastoma microtubules and neurofilaments that are necessary for neurite outgrowth proceeded from preexisting pools of tubulin and actin, but a sustained level of phosphorylated tubulin was not required for this regulation; and d) the in vitro translation of tubulin and actin was accomplished with mRNA from rat brains in a wheat-germ cellfree system.

Localization of the central sympatho-inhibitory effect of a narcotic analgesic agent, fentanyl, in cats.

Fentanyl (10 and 30 mug/kg), a narcotic analgesic, induced in cats a decrease in blood pressure and heart rate and reduced spontaneous splanchnic nerve activity. Fentanyl reduced the pressor response to medullary stimulation, but did not change the pressor response to hypothalamic or cervical spinal cord stimulation. Fentanyl reduced the potential evoked in the splanchnic nerve by stimulation at low frequency of a pressor area of the medulla oblongata. The potentials evoked in the splanchnic nerve by hypothalamic or cervical spinal cord stimulation were only slightly changed. Nalorphine (0.5 mg/kg) or naloxone (30 mug/kg) induced a recovery in blood pressure, heart rate and spontaneous splanchnic discharges which had been reduced by fentanyl, but nalorphine or naloxone did not restore pressor response to medullary stimulation or potentials evoked in the splanchnic nerve by medullary stimulation, which had been decreased by fentanyl.

[Action of delta 9 tetrahydrocannabinol on the central cardiovascular regulation : mechanism and localization]. / Action du delta9-tétrahydrocannabinol sur la régulation cardiovasculaire centrale : mécanisme et localisation

Delta9-tetrahydrocannabinol (30-300 mug.kg-1 i.v.) induced in cats and dogs a decrease in blood pressure and heart rate. This decrease appears to be centrally mediated. In fact, the splanchnic and cardiac discharges were reduced in intact animals as well as in debuffered cats ruling out a reflexly mediated action. The mechanism of this central decrease in the sympathetic tone appears to be different from the mechanism of the reduction induced by clonidine or by narcotic analgesics agents. In fact, piperoxan (1 mg.kg-1 i.v.), an alpha adrenoceptor blocking agent, antagonized or reversed the centrally mediated reduction in the sympathetic tone induced by clonidine or L-dopa, but did not change the effects of narcotic analgesic agents and of delta9-tetrahydrocannabinol. Naloxone (30 mug.kg-1 i.v.) prevented or reversed the cardiovascular effects of fentanyl and the reduction in splanchnic discharges induced by this agent, but no change was found after naloxone in the effects of clonidine or delta9-tetrahydrocannabinol. The pressor response to high frequency stimulation of the medulla oblongata was abolished by small doses of delta9-tetrahydrocannabinol. This agent did not reduce the pressor response to stimulation of the posterior hypothalamus induced by supramaximal stimulation and did not alter the hypertensive effect induced by stimulation of the cervical spinal cord. Medulla oblogata appears therefore to be the main site of action.