TGF-beta and phorbol esters inhibit mitogenesis utilizing parallel protein kinase C-dependent pathways.

Transforming growth factor (TGF)-beta mediates matrix production in both mesangial and vascular smooth muscle cells. Both TGF-beta and phorbol-12-myristate-13-acetate (PMA) exert both positive and negative effects on mitogenesis in these as well as other cell types. Phorbol esters act through stimulation of protein kinase C (PKC) and are among the most potent tumor promoters known. The present study was conducted to determine if the growth inhibitory effect of TGF-beta parallels that of the phorbol esters and whether this effect of TGF-beta is dependent on activation of PKC. We show that, in vascular smooth muscle cells stimulated to divide by the addition of the serum component basic fibroblast growth factor (bFGF), TGF-beta1 inhibits mitogenesis in a dose-dependent manner, by a maximum of 79% when applied at a concentration of 1 ng/ml. Furthermore, the inhibitory effect on mitogenesis of either TGF-beta1 or PMA, when added four hours after bFGF, are 71% and 84% respectively. Both TGF-beta1 and PMA cause translocation of celllular PKC with similar time courses, while neither PKC-alpha nor PKC-betaII are increased in quantity in response to TGF-beta1. In addition, down-regulation of PKC by 24 hours incubation with PMA abolishes TGF-beta's inhibitory effect in bFGF-stimulated cells. We conclude that (i) the signaling pathway utilized by TGF-beta resulting in inhibition of mitogenesis parallels that of PMA, and (ii) the inhibitory effect of TGF-beta1 on bFGF-induced mitogenesis is partially due to activation of PKC. These data suggest that TGF-beta may be an endogenous activator of the growth-inhibitory pathway of PKC, and, since cellular differentiated functions generally occur when the cells are proliferation-inhibited, PKC may be a modulator of extracellular matrix deposition.

Sleep fragmentation in patients from a nursing home.

Institutionalized elderly persons are said to have very disturbed sleep, yet few studies have collected empirical data on the sleep of these patients. We recorded sleep in 200 patients (131 females and 69 males; mean age = 81.9 years, SD = 8.6) in a skilled nursing facility. A modified Respitrace-Medilog portable recording system was used. In recordings averaging 15.4 hours, the patients were asleep for 7 hours, 58 minutes and awake for 7 hours, 28 minutes. To obtain that amount of sleep, the patients spent an extended time in bed during the day, for they averaged no more than 39.5 minutes of sleep per hour in any hour of the night, and 50% woke up at least 2 to 3 times per hour. In summary, although nursing home patients slept on average only one hour longer than independently living elderly, they had to spend substantially more time in bed to obtain the same amount of sleep.