Mitogen- and stress-activated protein kinase-1 (MSK1) is directly activated by MAPK and SAPK2/p38, and may mediate activation of CREB

We have identified a novel mitogen- and stress-activated protein kinase (MSK1) that contains two protein kinase domains in a single polypeptide. MSK1 is activated in vitro by MAPK2/ERK2 or SAPK2/p38. Endogenous MSK1 is activated in 293 cells by either growth factor/phorbol ester stimulation, or by exposure to UV radiation, and oxidative and chemical stress. The activation of MSK1 by growth factors/phorbol esters is prevented by PD 98059, which suppresses activation of the MAPK cascade, while the activation of MSK1 by stress stimuli is prevented by SB 203580, a specific inhibitor of SAPK2/p38. In HeLa, PC12 and SK-N-MC cells, PD 98059 and SB 203580 are both required to suppress the activation of MSK1 by TNF, NGF and FGF, respectively, because these agonists activate both the MAPK/ERK and SAPK2/p38 cascades. MSK1 is localized in the nucleus of unstimulated or stimulated cells, and phosphorylates CREB at Ser133 with a Km value far lower than PKA, MAPKAP-K1(p90Rsk) and MAPKAP-K2. The effects of SB 203580, PD 98059 and Ro 318220 on agonist-induced activation of CREB and ATF1 in four cell-lines mirror the effects of these inhibitors on MSK1 activation, and exclude a role for MAPKAP-K1 and MAPKAP-K2/3 in this process. These findings, together with other observations, suggest that MSK1 may mediate the growth-factor and stress-induced activation of CREB.     

Genomic cloning and species-specific properties of the recombinant canine beta3-adrenoceptor

A molecular clone encoding a beta3-adrenoceptor was isolated from a canine genomic library. The cloned receptor exhibited a pharmacological profile similar to that of other species: in particular, high efficiency of the two selective beta3-adrenoceptor agonists, CL 316,243 (disodium(R,R)-5[2[[2-(chlorophenyl)-2hydroxyethyl]-amino]propyl]- 1,3-benzodioxole-2,2-dicarboxylate) and ICI 201651 ((R)4-(2-hydroxy-3-phenoxypropylaminoethoxy)-N-(2-methoxyethyl)phe noxy acetic acid) and a low affinity for the radioligand (-)-[3-(125)I]-iodocyanopindolol. Interestingly, CGP 12177A ((+/-)-4-(3-t-butylamino-2-hydroxypropoxy)benzimidazol-2-one), which is described as a partial agonist for the human receptor, was a full agonist for the canine receptor. After expression and stimulation of the canine beta3-adrenoceptor in stably transfected Chinese hamster ovary cells there was a very low accumulation of cAMP, suggesting weak coupling to Gs-protein and adenylyl cyclase. However, the response was much better in human embryonal kidney cells transfected with the canine beta3-adrenoceptor gene. The cloning of the canine beta3-adrenoceptor and the insights gained from its pharmacological characterization may allow the development of selective compounds for use in the treatment of obese dogs.     

Phase analysis in high-frequency oscillation

This year, 1998, marks the 75th anniversary of the general availability of insulin in the United Kingdom. To mark the occasion, Diabetic Medicine publishes this account of the early days of insulin therapy in one of Britain's district general hospitals, Hereford General Hospital. The authors describe the first tentative use of insulin and draw some interesting parallels with the issues which still concern the introduction of novel therapies in endocrinology today.     

Interactive effects of betaine, crude protein, and net energy in finishing pigs

Two experiments were conducted to determine the effect of betaine on growth and carcass characteristics of finishing pigs. In Exp. 1, 32 gilts were fed one of two diets: 1) a corn-soybean meal basal (B) diet or 2) B + .125% betaine diet. In Exp. 2, 122 gilts were allotted to one of eight dietary treatments in a 2 x 2 x 2 factorial arrangement with two levels of betaine (0 or .125%), crude protein (adequate [ACP] or inadequate [ICP]), and net energy (NE; 0 or 6% added fat). In Exp. 1, betaine did not affect (P > .10) growth performance or carcass traits other than an increased (P < .05) dressing percentage. In Exp. 2, betaine tended to decrease ADFI during the overall experimental period (P = .11). In the late finishing period (LF), betaine increased ADG in inadequate CP low-NE diets and adequate CP high-NE diets, but decreased ADG in inadequate CP high-NE and adequate CP low-NE diets (betaine x CP x NE, P < .04). Betaine increased (P < .04) carcass length and decreased (P < .01) color score for pork quality. Other carcass measurements were unaffected (P > .10) by betaine. Betaine decreased (P < .02) serum urea N (SUN) in fed pigs during the LF period. Betaine decreased fasting SUN and albumin in pigs fed the ACP diets, but it increased fasting SUN and albumin in pigs fed the ICP diets during the LF period (betaine x CP, P = .10). Betaine increased serum total protein in the low-NE diets, but not in the high-NE diets (betaine x NE, P < .08). The serum metabolite data suggest that betaine may affect protein status of pigs, and these effects may depend on the crude protein and energy content of the diet.     

Intensive care unit bedside documentation systems. Realizing cost savings and quality improvements

Automating intensive care unit (ICU) documentation saves time and assists in interpreting data and planning care. The current economic climate makes the cost of ICU computer systems prohibitive for many institutions. Any expenditure without a measurable return on investment will be scrutinized carefully. The literature describing ICU computer system benefits often is difficult to interpret. No two implementations, hospitals, or benefit study designs have been the same. Each implementation has many unique variables. These variables make study comparison and replication potentially impossible. The authors have concluded that replicating previous studies may not be relevant if the goal is to justify system cost. The objective is met by designing a study that evaluates changes in data management activities as well as issues unique to the study unit or institution. The purpose of this article is to review the findings of previous benefits studies related to ICU documentation systems and to suggest other measures to support cost justification for expensive bedside documentation systems.