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Background: Atrioventricular (AV) optimization of cardiac resynchronization therapy (CRT) is typically calculated at rest. However, patients often become symptomatic during exercise., Objective: In this study, we use acute noninvasive hemodynamics to optimize the AV delay of CRT during exercise and investigate whether this exercise optimum can be predicted from a three-phase resting model., Methods: In 20 patients with CRT, we adjusted the sensed AV delay while the patient exercised on a treadmill up to a heart rate of 100 bpm to identify the hemodynamically optimal value. Separately, at rest, by pacing with three different configurations and calculating the sensed-paced difference, we calculated an "expected" value for the exercise optimum., Results: It was possible to perform AV delay optimization while a patient exercised. The resting three-phase model correlated well with the actual exercise optimal AV delay (r = 0.85, mean difference +/- standard deviation [SD] = 3.7 +/- 17 ms). Simply using measurements made at rest during atrial-sensed pacing showed a poorer correlation with exercise (r = 0.64, mean difference +/- SD = 2.2 +/- 24 ms). The three-phase resting model allows improved exercise hemodynamics to be achieved. Programming according to the three-phase resting model yields an exercise blood pressure of only 0.5 mmHg (+/-1.4 mmHg; P = NS) less than the true exercise optimum, whereas programming the resting sensed optimum yields an exercise blood pressure of 1.4 mmHg (+/-2.2 mmHg, P = .02) less than the true optimum., Conclusions: Using acute noninvasive hemodynamics and a protocol of alternations, it is possible to optimize the AV delay of cardiac resynchronization devices even while a patient exercises. In clinical practice, the exercise optimum AV delay could be determined from three phases of resting measurements, without performing exercise.

cAMP receptors mediate some signaling pathways via coupled heterotrimeric G proteins, while others are G-protein-independent. This latter class includes the activation of the transcription factors GBF and STATa. Within the cellular mounds formed by aggregation of Dictyostelium, micromolar levels of cAMP activate GBF function, thereby inducing the transcription of postaggregative genes and initiating multicellular differentiation. Activation of STATa, a regulator of culmination and ecmB expression, results from cAMP receptor-dependent tyrosine phosphorylation and nuclear localization, also in mound-stage cells. During mound development, the cAMP receptor cAR1 is in a low-affinity state and is phosphorylated on multiple serine residues in its C-terminus. This paper addresses possible roles of cAMP receptor phosphorylation in the cAMP-mediated stimulation of GBF activity, STATa tyrosine phosphorylation, and cell-type-specific gene expression. To accomplish this, we have expressed cAR1 mutants in a strain in which the endogenous cAMP receptors that mediate postaggregative gene expression in vivo are deleted. We then examined the ability of these cells to undergo morphogenesis and induce postaggregative and cell-type-specific gene expression and STATa tyrosine phosphorylation. Analysis of cAR1 mutants in which the C-terminal tail is deleted or the ligand-mediated phosphorylation sites are mutated suggests that the cAR1 C-terminus is not essential for GBF-mediated postaggregative gene expression or STATa tyrosine phosphorylation, but may play a role in regulating cell-type-specific gene expression and morphogenesis. A mutant receptor, in which the C-terminal tail is constitutively phosphorylated, exhibits constitutive activation of STATa tyrosine phosphorylation in pulsed cells in suspension and a significantly impaired ability to induce cell-type-specific gene expression. The constitutively phosphorylated receptor also exerts a partial dominant negative effect on multicellular development when expressed in wild-type cells. These findings suggest that the phosphorylated C-terminus of cAR1 may be involved in regulating aspects of receptor-mediated processes, is not essential for GBF function, and may play a role in mediating subsequent development., (Copyright 2001 Academic Press.)

We have examined the role of cAMP-dependent protein kinase (PKA) in controlling aggregation and postaggregative development in Dictyostelium. We previously showed that cells in which the gene encoding the PKA catalytic subunit has been disrupted (pkacat- cells) are unable to aggregate [S. K. O. Mann and R. A. Firtel (1991). A developmentally regulated, putative serine/threonine protein kinase is essential for development in Dictyostelium. Mech. Dev. 35, 89-102]. We show that pkacat- cells are unable to activate adenylyl cyclase in response to cAMP stimulation due to the inability to express the aggregation-stage, G-protein-stimulated adenylyl cyclase (ACA). Constitutive expression of ACA from an actin promoter results in a high level of Mn(2+)-stimulated adenylyl cyclase activity and restores chemoattractant- and GTP gamma S-stimulated adenylyl cyclase activity but not the ability to aggregate. Similarly, expression of the constitutively active, non-G protein-coupled adenylyl cyclase ACG in pkacat- cells also does not restore the ability to aggregate, although ACG can complement cells in which the ACA gene has been disrupted. These results indicate that pkacat- cells lack multiple, essential aggregation-stage functions. As the mound forms, high, continuous levels of extracellular cAMP functioning through the cAMP serpentine receptors activate a transcriptional cascade that leads to cell-type differentiation and morphogenesis. The first step is the induction and activation of the transcription factor GBF and downstream postaggregative genes, followed by the induction of prestalk- and prespore-specific genes. We show that pkacat- cells induce postaggregative gene expression in response to exogenous cAMP, but the level of induction of some of these genes, including GBF, is reduced. SP60 (a prespore-specific gene) is not induced and ecmA (a prestalk-specific gene) is induced to very low levels. Expressing GBF constitutively in pkacat- cells restores ecmA expression to a moderate level, but SP60 is not detectably induced. Overexpression of PKAcat from the Actin 15 (Act15), ecmA prestalk, and the PKAcat promoters in pkacat- cells result in significant aberrant spatial patterning of prestalk and prespore cells, as determined by lacZ reporter studies. Our studies identify new, essential regulatory roles for PKA in mediating multicellular development.

Nine patients were anaesthetized with halothane in oxygen using a closed-circle circuit with a Benedict-Roth spirometer substituted for the reservoir bag. The movements of the spirometer were recorded to enable the oxygen consumption and respiratory pattern to be measured continuously before surgery commenced. Increasing concentrations of halothane produced progressive decreases in oxygen uptake and in the tidal and minute volumes, but an increase in the respiratory rate.

Automatic analysis of arrhythmias from a tape recorded electrocardiogram (e.c.g.) is described, and its application to the detection and comparison of these during halothane and enflurane anesthesia is discussed. The results confirm that the use of enflurane during oral surgery produces much greater cardiac stability than the use of halothane.