Phospholamban is the regulator of the Ca'+-ATPase in cardiac sarcoplasmic reticulum (SR), and it has been suggested to be an important determinant in the inotropic responses of the heart to 8-adrenergic stimulation. To determine the role of phospholamban in vivo, the gene coding for this protein was targeted in murine embryonic stem cells, and mice deficient in phospholamban were generated. The phospholamban-deficient mice showed no gross developmental abnormalities but exhibited enhanced myocardial performance without changes in heart rate. The time to peak pressure and the time to half-relaxation were significantly shorter in phospholamban-deficient mice compared with their wild-type homozygous littermates as assessed in work-performing mouse heart preparations under identical venous returns, afterloads, and heart rates. The first derivatives of intraventricular pressure (±dP/dt) were also significantly elevated, and this was associated with an increase in the affinity of the SR Ca +-ATPase for Ca`in the phospholamban-deficient hearts. Baseline levels of these parameters in the phospholamban-deficient hearts were equal to those observed in hearts of wild-type littermates maximally stimulated with the (-agonist isoproterenol. These findings indicate that phospholamban acts as a critical repressor of basal myocardial contractility and may be the key phosphoprotein in mediating the heart's contractile responses to f-adrenergic agonists. (Circ Res. 1994; 75:401-409.) Key Words * phospholamban * gene targeting . sarcoplasmic reticulum * cardiac contractility * l3-agonists C ardiac 8-adrenergic stimulation is associated with increases in the force of contraction and in the rates of rise and fall of force. These changes are mediated by increases in cAMP levels, which lead to phosphorylation of key regulatory proteins that may act as effectors of the adrenergic stimulation. One of these phosphoproteins is phospholamban, the regulator of the Ca`+-ATPase in cardiac sarcoplasmic reticulum (SR). Dephosphorylated phospholamban is an inhibitor of the Ca2`-ATPase activity, and phosphorylation relieves this inhibition.' The inhibition has been suggested to involve physical direct interaction between the two proteins,23 followed by conformational changes in the SR Ca2`-ATPase.

Phospholamban is the regulator of the cardiac sarcoplasmic reticulum (SR) Ca 2 ϩ -ATPase activity and an important modulator of basal contractility in the heart. To determine whether all the SR Ca 2 ϩ -ATPase enzymes are subject to regulation by phospholamban in vivo, transgenic mice were generated which overexpressed phospholamban in the heart, driven by the cardiac-specific ␣ -myosin heavy chain promoter. Quantitative immunoblotting revealed a twofold increase in the phospholamban protein levels in transgenic hearts compared to wild type littermate hearts. The transgenic mice showed no phenotypic alterations and no changes in heart/body weight, heart/lung weight, and cardiomyocyte size. Isolated unloaded cardiac myocytes from transgenic mice exhibited diminished shortening fraction (63%) and decreased rates of shortening (64%) and relengthening (55%) compared to wild type (

The benefits of bup-nx for opioid detoxification are supported and illustrate important ways in which clinical research can be conducted in community treatment programs.

The effectiveness of a motivational and skills training HIV/AIDS group intervention designed for men in substance abuse treatment was evaluated. Men in methadone maintenance (n=288) or outpatient psychosocial treatment (n=302) completed assessments at baseline, 2 weeks, 3- and 6-months post intervention. Participants were randomly assigned to attend either “Real Men Are Safe” (REMAS; five sessions containing information, motivational exercises and skills training), or HIV education (HIV-Ed; one session containing HIV prevention information). REMAS participants engaged in significantly fewer unprotected vaginal and anal sexual intercourse occasions (USO) during the 90 days prior to the 3- and 6-month follow-ups than HIV-Ed participants. Completing REMAS resulted in an even stronger effect: completers reduced their number of USO by 21% from baseline to 6-month follow-up. In contrast, HIV-Ed completers increased the number of USO by 2%. A motivational and skills training HIV prevention intervention designed for men was associated with greater sexual risk reduction over standard HIV education. Substance abuse treatment programs can therefore help reduce sexual risk among their clientele by providing a more intensive intervention than what is traditionally provided.

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