Different effects of salmeterol, formoterol and salbutamol on cholinergic responses in the ferret trachea

1. In the present study, the inhibitory effects of the selective beta 2-adrenoceptor agonists, salmeterol, formoterol and salbutamol, have been investigated on contractions of ferret trachea induced both by endogenous and exogenous acetylcholine. The aim of the study was to evaluate quantitative and/or qualitative differences in response which may indicate both pre- and post-junctional sites of action. The non-selective beta-antagonist, sotalol, was used to estimate beta-adrenoceptor involvement. 2. Isometric tension was measured in ferret isolated tracheal strips. The inhibitory effects of the drugs were studied on tonic contractions induced by pre-junctional activation with electrical field stimulation (EFS) (2 Hz, 700 mA) or post-junctional activation with exogenous acetylcholine (ACh) (0.5 microM, about EC80), giving a similar degree of smooth muscle response. 3. Concentration-response experiments were performed with formoterol (0.3 nM-0.3 microM) and salmeterol and salbutamol (10 nM-10 microM). The experiments ended with the addition of sotalol (10 microM). 4. All three beta-agonists inhibited the contractions in a concentration-dependent manner. Salbutamol, formoterol and salmeterol inhibited the EFS-induced contractions by 66(8)%, 105(5)% and 103(8)% (mean(s.e. mean)) respectively. ACh-induced contractions were inhibited by 37(6)%, 72(11)% and 33(8)%. Theophylline (10 nM-3 mM) inhibited the contractions to the same degree. 5. beta-Adrenoceptor blockade by sotalol significantly antagonized the inhibitory effects of salbutamol and formoterol on both EFS- and ACh-induced contractions. The effect of salmeterol on ACh-induced contraction was also significantly antagonized, whereas the inhibition of EFS-induced contraction was virtually unaffected. 6. In conclusion, salbutamol, salmeterol and formoterol produced greater inhibitory effects in preparations contracted by EFS than in preparations contracted by exogenously-added ACh. In the case of formoterol and salbutamol, the effects on both levels are most probably due to beta-adrenoceptor stimulation, whereas for salmeterol the dominant pre-junctional effect is probably not mediated via beta-adrenoceptors. This non-beta-mediated effect could represent an additional relaxant mechanism for salmeterol.     

A strategy for improving patient satisfaction by the intensive training of residents in psychosocial medicine: a controlled, randomized study

PURPOSE: To use a controlled, randomized design to assess the effect on patient satisfaction of an intensive psychosocial training program for residents. METHOD: Twenty-six first-year residents, in two internal medicine and family practice community-based programs affiliated with the Michigan State University College of Human Medicine, were randomly assigned during 1991 and 1992 to a control group or a one-month intensive training program. Experiential teaching focused on many psychosocial skills required in primary care. A 29-item questionnaire administered before and after the residents' training evaluated their patients' satisfaction regarding patient disclosure, physician empathy, confidence in physician, general satisfaction, and comparison of the physician with other physicians. Analyses of covariance with groups and gender as factors and pre-training patient satisfaction scores as the covariate evaluated the effect of the training. RESULTS: The patients of the trained residents expressed more confidence in their physicians (p = .01) and more general satisfaction (p = .02) than did the patients of controls. The effect of training on patient satisfaction with patient disclosure (p < .01) and physician empathy (p < .05) was greater for female than for male residents. CONCLUSION: The intensive psychosocial training program for residents improved their patients' satisfaction.     

Transthoracic defibrillation of swine with monophasic and biphasic waveforms

BACKGROUND: Biphasic waveforms have had a favorable impact on internal defibrillation but have seen minimal use in transthoracic defibrillation systems. The purpose of this study was to compare monophasic and biphasic waveforms for transthoracic defibrillation in swine. METHODS AND RESULTS: Three interrelated studies were performed in 19 swine to establish the relative transthoracic defibrillation efficacy of biphasic shock waveforms. In study 1, we measured voltage (V50) and energy (E50) strength-duration curves for monophasic and biphasic truncated exponential waveforms. We then independently examined the effects of phase duration and tilt on biphasic waveform defibrillation with a total waveform duration from study 1 that provided the minimum V50 (study 2) and the minimum E50 (study 3). At each pulse duration tested in study 1, biphasic waveforms defibrillated with significantly less voltage and energy than monophasic waveforms. At a duration of 12 ms, there was a voltage minimum for biphasic waveform defibrillation. At this duration, V50 was 1378 +/- 505 V for the biphasic waveform compared with 2185 +/- 361 V for the monophasic waveform, P = .01. For both monophasic and biphasic waveforms, E50 increased with pulse duration. With a total pulse duration of 12 ms, E50 was 169 +/- 101 J for the biphasic waveform compared with 414 +/- 114 J for the monophasic waveform, P = .003. In study 2, optimization of phase duration and total tilt reduced the defibrillation requirements of the 12-ms "minimum voltage" biphasic waveform to 1284 +/- 187 V and 129 +/- 36 J. In study 3, the 8-ms "minimum energy" biphasic waveform had an E50 of 115 +/- 35 J that was 11% less than the 12-ms biphasic waveform, P = .11; however, voltage requirements of 1476 +/- 239 V were 15% higher, P = .005. CONCLUSIONS: This study demonstrates the superiority of truncated biphasic waveforms over truncated monophasic waveforms for transthoracic defibrillation of swine. Biphasic waveforms should prove as advantageous at reducing voltage and energy requirements for transthoracic defibrillation as they have for internal defibrillation.     

Evidence for an RNA binding region in the Escherichia coli processing endoribonuclease RNase E

The processing endoribonuclease RNase E (Rne), which is encoded by the rne gene, is involved in the maturation process of messenger RNAs and a ribosomal RNA. A number of deletions were constructed in order to assess functional domains of the rne gene product. The expression of the deletion constructs using a T7 promoter/RNA polymerase overproduction system led to the synthesis of truncated Rne polypeptides. The smallest gene fragment in this collection that was able to complement a temperature sensitive rnets mutation and to restore the processing of 9 S RNA was a 2.3-kilobase pair fragment with a 1.9-kilobase pair N-terminal coding sequence that mediated synthesis of a 70.8-kDa polypeptide. Antibodies raised against a truncated 110-kDa polypeptide cross-reacted with the intact rne gene product and with all of the shorter C-terminal truncated polypeptides, indicating that the N-terminal part of the molecule contained strong antigenic determinants. Furthermore, by analyzing the Rne protein and the truncated polypeptides for their ability to bind substrate RNAs, we were able to demonstrate that the central part of the Rne molecule encodes an RNA binding region. Binding to substrate RNAs correlated with the endonucleolytic activity. RNAs that are not substrates for RNase E did not bind to the protein. The two mutated Rne polypeptides expressed from the cloned gene containing either the rne-3071 or ams1 mutation also had the ability to bind 9 S RNA, while their enzymatic function was completely abolished. The data presented here suggest that the endonucleolytic activity is encoded by the N-terminal part of the Rne protein molecule and that the central part of it possesses RNA binding activity.     

Volume-activated chloride currents in pancreatic duct cells

OBJECTIVE: To determine the effects of stromelysin treatment on biochemical, histologic, and swelling characteristics of intact cartilage explants and to correlate these effects with changes in the functional physical properties of the tissue. METHODS: Bovine articular cartilage explants were cultured for up to 3 days in the presence or absence of recombinant human stromelysin (SLN). Damage to matrix proteoglycans and collagens was assessed and characterized by N-terminal sequencing and Western blot analysis, respectively. Explants were mechanically tested to assess the ability of the tissue to withstand cyclic and static compressive loads. RESULTS: Treatment with SLN resulted in a time- and dose-dependent loss of proteoglycans from cartilage explants, with significant loss seen after 3 days of exposure to 20 nM SLN: Histology indicated that initial loss of proteoglycans occurred in regions near the tissue surface and proceeded inward with increasing time of SLN exposure. SLN treatment resulted in degradation of matrix collagen types IX and II, and a concomitant increase in tissue swelling. This matrix degradation resulted in severe alterations in functional physical properties of the tissue, including compressive stiffness. The initial, focal loss of proteoglycans that resulted from SLN treatment was most accurately detected with high-frequency streaming potential measurements. CONCLUSION: Exposure of intact cartilage to SLN caused specific, molecular-level degradation of matrix molecules, which resulted in changes in the swelling behavior and marked deterioration of functional physical properties of the tissue.