Morphine place conditioning is differentially affected by CCKA and CCKB receptor antagonists.

In the present study we have examined the interaction between the selective cholecystokinin (CCK)A and CCKB receptor antagonists, devazepide and L365-260 on morphine conditioned place preference (CPP). Using an unbiased procedure, morphine (1.5 mg/kg) produced a reliable CPP which was observed irrespective of the conditioning compartment type. Pretreatment with devazepide (0.001-0.01 mg/kg s.c.) produced a dose related attenuation of this response. At higher doses (0.1-1 mg/kg) this antagonism became variable and dependent on the training compartment with blockade only observed when conditioning was to the white/rough textured environment. This profile has also been reported for the serotonin (5-HT)3 receptor antagonist ondansetron. The CCKB antagonist L365-260 (0.000001-0.01 mg/kg) failed to antagonize the morphine CPP, if anything a mild potentiation was observed. To study this further we examined the interaction between L365-260 (0.01 mg/kg) and a subthreshold dose of morphine (0.3 mg/kg). At these doses neither drug elicited CPP, however when co-administered a significant CPP was recorded. Finally, L365-260 at 1 mg/kg induced a mild but significant CPP when administered alone. These results suggest a differential role of CCK receptor subtypes on reward-related behaviour and complement previous studies suggesting bimodal effects of CCK systems on mesolimbic dopamine function.     

Class III antiarrhythmic activity of novel substituted 4-[(methylsulfonyl)amino]benzamides and sulfonamides.

The synthesis and Class III antiarrhythmic activity of a series of 4-[(methylsulfonyl)amino]benzamides and sulfonamides are described. Selected compounds show a potent Class III activity and are devoid of effects on conduction both in vitro (dog Purkinje fibers) and in vivo (anesthetized dogs). Compounds having a 2-aminobenzimidazole group were found to be the most potent, and one compound having this heterocycle (5, WAY-123,398) was selected for further characterization. Compound 5 was shown to have good oral bioavailability and a favorable hemodynamic profile to produce a 3-fold increase of the ventricular fibrillation threshold and to terminate ventricular fibrillation, restoring sinus rhythm in anesthetized dogs. Voltage-clamp studies in isolated myocytes show that 5 is a potent and specific blocker of the delayed rectifier potassium current (IK) at concentrations that cause significant prolongation of action potential duration.     

Maintenance of long-term adaptation of synaptic transmission requires axonal transport following induction in an identified crayfish motoneuron

Motoneurons can adapt to altered levels of electrical activity by effecting semi-permanent changes in their neuromuscular synaptic physiology. In the present study, we tested the hypothesis that maintenance of activity-dependent long-term adaptation of synaptic transmission in a crayfish abdominal extensor motoneuron (phasic axon 3) required axonal transport following induction. Intact crayfish were chronically wired for periodic in vivo stimulation of axon 3. Periodic unilateral stimulation for 3-5 consecutive days (2 h/day) induced long-term adaptation (LTA) of neuromuscular synaptic transmission in axon 3. Initial EPSP amplitudes (measured at 0.1 Hz) were significantly reduced to approximately 40% of contralateral control amplitudes over a 7-day poststimulation period. Additionally, synaptic depression during 5 Hz test stimulation of axon 3 was significantly less in chronically stimulated neurons: excitatory postsynaptic potential (EPSP) amplitudes measured after 20 min of 5 Hz test stimulation (final EPSPs) were significantly larger in conditioned neurons than in unstimulated controls. The depression of initial EPSP amplitudes persisted for 7 days postinduction, while the increased synaptic stamina persisted for 4 days but was absent at 7 days postinduction. Axotomy of axon 3 following induction of LTA had no effect on long-term maintenance of the activity-induced reduction in initial EPSP amplitudes. Initial EPSP amplitudes in conditioned, axotomized neurons were still reduced to 42% of control amplitudes over the 7-day postinduction period. In contrast, postinduction axotomy of axon 3 elicited an accelerated decay of the enhanced synaptic stamina. Following axotomy, final EPSP amplitudes were significantly larger in conditioned neurons for only 1 day poststimulation.(ABSTRACT TRUNCATED AT 250 WORDS)     

View ordering for magnetization prepared steady state free precession acquisition: application in contrast-enhanced MR angiography.

Magnetization prepared segmented acquisition requires a view order that maximizes signal contrast during the acquisition of the central portion of k-space. Steady state free precession (SSFP) acquisition further requires a view order that minimizes changes in phase-encoding gradients from one repetition to the next in order to minimize eddy current artifacts. In this article, optimal view ordering schemes satisfying these two requirements are formulated and applied to inversion prepared 3D SSFP contrast-enhanced MR angiography (MRA). Experiments on phantoms and pigs demonstrated improved background suppression and reduced image artifacts.     

Estimation of the bronchodilatory effect of deep inhalation after a free run in children.

The bronchomotor effects of a deep inhalation (DI) may provide relevant information about the mechanisms of exercise-induced airway obstruction in children and may be assessed by respiratory conductance (Grs) measured using the forced oscillation technique. The aims of the present study were to assess the effect of DI on Grs after exercise in relationship to the lung function response to exercise. Grs at 12 Hz using a head generator and spirometric data were measured in 62 children suspected of asthma before and 5 min after a 6-min free run. After exercise, Grs was significantly increased by DI in 38 subjects, who also showed larger Grs and forced expiratory volume in one second (FEV1)/forced vital capacity (FVC) responses to exercise than the 24 nonresponders. Stepwise regression indicated significant correlation between the response of Grs to DI and both Grs and FEV1/FVC responses to exercise. The data are consistent with exercise-induced bronchoconstriction being reversed by deep inhalation.     

Azide function and polyaddition: reaction of 2-azido-2,4,4-trimethylpentane and monoazidopoly(2-methylpropene) with some dienophiles

The 1,3-dipolar addition of 2-azido-2,4,4-trimethylpentane ( 1 ) to acetylene and ethylene derivatives such as phenylacetylene (2), acrylonitrile, diphenyl fumarate ( 4 ) and N,N′-methylenebis(1,4-phenylene)dimaleimide ( 8 ) leads to the corresponding triazole and triazoline derivatives. This study demonstrates that tertiary azides are able to react with dienophiles, and the application of this reaction for the synthesis of block copolymers was investigated with monoazido-telechelic poly(2-methylpropene) (PMP). It was shown that the azido group is stable under the severe conditions of the polycondensation reaction without decomposition (170°C, 24 h), and the monoadduct PMP- 8 is produced with acceptable yield.     

Analyses and perspectives in cancer immunotherapy.

Since the last two decades, rapid progress has been made in the field of cancer immunotherapy relevant to manipulation of adaptative cytotoxic T lymphocytes (CTLs) and innate immunity natural killer (NK) cells as well as antibodies. Many possibilities are now offered for therapeutic purposes contributing to better approaches in treatment of cancer.     

Interstitial fluids associated with wound repair support proliferation but not differentiation of neonatal rat myoblasts in vitro.

The ability of wound fluids to support events required for skeletal muscle regeneration was examined. Wound fluids were obtained from polyvinyl alcohol sponges 1, 3, 5, 10, and 15 days after implantation. Neonatal rat L8 myoblasts were used to test the ability of early wound fluids to promote myoblast proliferation and late wound fluids to promote myoblast differentiation-two characteristics deemed critical for effective skeletal muscle regeneration. Early wound fluids (1- and 3-day) stimulated DNA replication by myoblasts, as judged by tritiated thymidine uptake, up to ninefold (p < 0.05). Later wound fluids (5-, 10-, and 15-day) displayed decreasing ability to stimulate proliferation, with 15-day wound fluid failing to significantly stimulate proliferation. In contrast, myoblast differentiation, as judged by myotube fusion and creatine kinase activity, was progressively reduced by wound fluids of increasing age. In fact, late wound fluids (5, 10, and 15 days) reduced myotube fusion by 88% to 100% and depressed creatine kinase activity by 60% to 75% (p < 0.05). Thus, wound fluids from a repair environment appear to support myoblast proliferation early but suppress myoblast differentiation later. These characteristics suggest that the wound repair environment cannot fully support skeletal muscle regeneration.