Alpha1-adrenoceptor-mediated inhibition of cellular cAMP accumulation in neonatal rat ventricular myocytes

Summary We studied adrenergic regulation of cellular cAMP in neonatal rat ventricular myocytes. Since CAMP content depends on synthesis, breakdown and egress, the contribution of each of these mechanisms was assessed. In the presence of the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine, cAMP accumulation stimulated by the -adrenoceptor agonist (–)-isoprenaline was diminished when the mixed + adrenoceptor agonist (–)-noradrenaline was coincubated with (–)-isoprenaline. Moreover, adenylyl cyclase activation stimulated by (–)-isoprenaline was decreased by (–)-noradrenaline and by the selective a₁-adrenoceptor agonists (–)-phenylephrine and methoxamine, suggesting that -adrenoceptor agonism regulates CAMP metabolism through its effect on the synthetic pathway. Evidence for ₁-adrenoceptor mediation of this response was enhancement of (–)-noradrenaline-induced cAMP generation by the selective ₁-adrenoceptor antagonist terazosin (10 nmol/l). The selective ₂-adrenoceptor antagonist yohimbine (10 nmol/l) had no effect. The ₁-adrenoceptor mediated depression of (–)-isoprenaline-stimulated CAMP generation and adenylyl cyclase activation was prevented by terazosin and in separate experiments markedly enhanced by pertussis toxin pretreatment, suggesting involvement of a guanine-nucleotide regulatory protein in this process.Occupation of the ₁-adrenoceptor by (–)-noradrenaline did not accelerate the rate of CAMP breakdown in the absence of phosphodiesterase inhibition. Furthermore, there was no enhancement of total phosphodiesterase activity by (–)-noradrenaline in the presence of (–)-propranolol. By contrast, pertussis toxin pretreatment augmented phosphodiesterase activity. Neither pertussis toxin nor (–)-noradrenaline increased CAMP egress.We conclude that in rat neonatal cardiac myocytes agonist occupation of the ₁-adrenoceptor inhibits -adrenoceptor stimulated CAMP accumulation most likely by coupling to a guanine nucleotide inhibitory protein.Supported by a grant from the Department of the Veterans Affairs Research Service and Program Project Grant HL 25847 from the National Heart, Lung and Blood Institute     

Heparin versus saline flushing solutions in a small community hospital

Since no nursing policy on flushing procedures existed in their small community hospital, the authors thought it would be useful to clarify recent reports of the equivalency of saline to heparin flushes in their patient group before establishment of such a policy. They conducted a 2 month double-blinded, cross-over study of catheter failures when using either saline or heparin 10 units/mL flushing solutions. All medical and surgical floor patients were included in the study. Floor nurses were used as observers and characterized catheter failures as either loss of patency or phlebitis. Heparin was shown to cause more phlebitis than saline (p less than .025), but no difference was found between the two flushing solutions in loss of patency. Data revealed a statistically significant advantage to using saline flushes when both loss of patency and phlebitis were combined (p less than .05). They recommended adoption of a flushing procedure which did not contain heparin.     

Cone-beam tomography with discrete data sets

Sufficiency conditions for cone-beam data are well known for the case of continuous data collection along a cone-vertex curve with continuous detectors. These continuous conditions are inadequate for real-world data where discrete vertex geometries and discrete detector arrays are used. In this paper we present a theoretical formulation of cone-beam tomography with arbitrary discrete arrays of detectors and vertices. The theory models the imaging system as a linear continuous-to-discrete mapping and represents the continuous object exactly as a Fourier series. The reconstruction problem is posed as the estimation of some subset of the Fourier coefficients. The main goal of the theory is to determine which Fourier coefficients can be reliably determined from the data delivered by a specific discrete design. A Fourier component will be well determined by the data if it satisfies two conditions: it makes a strong contribution to the data, and this contribution is relatively independent of the contribution of other Fourier components. To make these considerations precise, we introduce a concept called the cross-talk matrix. A diagonal element of this matrix measures the strength of a Fourier component in the data, while an off-diagonal element quantifies the dependence or aliasing of two different components. One reasonable approach to system design is to attempt to make the diagonal elements of this matrix large and the off-diagonal elements small for some set of Fourier components. If this goal can be achieved, simple linear reconstruction algorithms are available for estimating the Fourier coefficients. To illustrate the usefulness of this approach, numerical results on the cross-talk matrix are presented for different discrete geometries derived from a continuous helical vertex orbit, and simulated images reconstructed with two linear algorithms are presented.     

Market testing. What am I bid?

Walsall's experience of marketing testing for urology services was that it is a difficult, time-consuming but thoroughly worthwhile process. We believe that a much improved level of service will be available to Walsall residents, representing excellent value for money. Turning the spotlight on to this particular specialty resulted in local provider trusts showing increased willingness to address the clinical management and quality issues about which the HA had expressed concern.     

NM-Win: A Personal Computer-Based Microsoft® Windows™ Front-End to NONMEM IV

A Microsoft Windows-based front-end, NM-Win, has been written to provide a more user-friendly environment to do nonlinear mixed effect modeling with the NONMEM program. NM-Win utilizes an object-oriented interface design which allows users to view and edit control, PRED, and/or data files using Windows Notepad. In addition, calls made to the Microsoft FORTRAN compiler and linker which generate the final NONMEN executable are performed simply by clicking the Run NONMEN button. During the executive step, iterations can be viewed in a window to check the progress of the run. Errors encountered while NONMEN or NM-TRAN is running are brought to a window for ease in debugging. Advanced options allow the user the flexibility of compiling user-written PRED files and creating linker response files. While the PC platform is not optimal for large data set or complex models, it does permit easier debugging and offers multitasking while Windows is running.     

Destruction of WiDr multicellular tumor spheroids with the novel thymidylate synthase inhibitor 1843U89 at physiological thymidine concentrations

The activity of a novel thymidylate synthase inhibitor, 1843U89, against WiDr human colon carcinoma multicellular tumor spheroids was investigated. Continuous exposure of the spheroids to 3 nM 1843U89 for 10 days resulted in spheroid disruption, whereas 100 nM methotrexate (MTX) was required for similar effects. Short-term treatment experiments demonstrated that a 3-day exposure to 100 nM 1843U89 caused spheroid disruption 9 days after drug removal. A 4-day exposure to 10 nM 1843U89 caused spheroid disruption 8 days after drug removal. In contrast, treatment with 10 or 100 nM 1843U89 for 6–48 h or treatment with 1 nM 1843U89 for up to 5 days caused only growth delay. Continuous exposure of spheroids to 30 nM 1843U89 in the presence of 0.05–0.3 M thymidine was as effective in causing spheroid disruption as treatment in the absence of thymidine, but treatment in the presence of 0.7–3.0 M thymidine caused partial reversal of spheroid disruption. The results of these experiments suggest that 1843U89 should have potent solid tumor activity in humans but should be less effective in mice due to differences in circulating thymidine levels (0.1 vs 1 M, respectively).     

Elephant people: the phenomena of social withdrawal and self-imposed isolation of people dying with AIDS

The phenomena of self-initiated isolation and social withdrawal of people dying from AIDS is described and explained in the context of its irony and detriment to the patients' well being, minimizing access to social support resources. The psychological and the therapeutic relevance of social support during the critical transition phase is explored. Recommendations for curbing the phenomena of self-imposed social death in PWAs, as well as suggestions for future research on the value of psychosocial support to the PWA's well being during the transition phase, are also discussed.