The action of ryanodine upon sarcoplasmic reticulum (SR) Ca2+ handling is controversial with evidence for both activation and inhibition of SR Ca2+ release. In this study, the role of the intraluminal SR Ca2+ load was probed as a potential regulator of ryanodine-mediated effects upon SR Ca2+ release. Through dual-wavelength spectroscopy of Ca2+:antipyrylazo III difference absorbance, the intraluminal Ca2+ dependence of ryanodine and Ca(2+)-induced Ca2+ release (CICR) from skeletal SR vesicles was examined. Ryanodine addition after initiation of Ca2+ uptake (a) increased the intraluminal Ca2+ sensitivity of CICR and (b) stimulated spontaneous Ca2+ release with a delayed onset. These ryanodine effects were inversely proportional to the intraluminal Ca2+ load. Ryanodine also inhibited subsequent CICR after reaccumulation of Ca2+ released from the initial CICR. These results provide evidence that ryanodine inhibits transitions between low and high affinity Ca2+ binding states of an intraluminal Ca2+ compartment, possibly calsequestrin. Conformational transitions of calsequestrin may be reciprocally coupled to transitions between open and closed states of the Ca2+ release channel.

Adenosine Triphosphate↗

PubMed1992

Calcium-activated neutral protease effects upon skeletal muscle sarcoplasmic reticulum protein structure and calcium release.

In this study, the effects of Ca(2+)-activated neutral protease (CANP) upon skeletal muscle heavy sarcoplasmic reticulum (HSR) structure and function were investigated. CANP was immunolocalized to the 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonic acid detergent-insoluble fraction of purified HSR membranes. Ca2+ activation of the endogenous membrane-bound CANP produced a characteristic partial fragmentation of the HSR 565-kDa Ca2+ release channel. Similarly, the major substrate for both micromolar and millimolar Ca(2+)-sensitive isoforms of exogenous CANP was the Ca2+ release channel with proteolysis of a 88-kDa HSR protein also observed. Ca2+ release channel proteolysis was initiated at a single cleavage site with coincidental production of 410- and 150-kDa peptide fragments. Appearance of 160- and 137-kDa limiting peptides accompanied secondary proteolysis of the primary 410- and 150-kDa fragments, respectively. Despite extensive proteolysis of the Ca2+ release channel, CANP did not dramatically alter the Ca2+ handling and ryanodine binding properties of HSR membranes. The association of CANP with isolated HSR membranes suggests that, in vivo, this protease may modify an additional property of the Ca2+ release channel. This may be related to the CANP-susceptible structural association of the Ca2+ release channel with dihydropyridine receptors at T-tubule/sarcoplasmic reticulum junctions.

Adenosine Triphosphate↗

PubMed1992

MD-patient communication key to reducing asthma's toll, seminar told.

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Adolescent↗

PubMed1992

Regulation of calcium transport in pancreatic acinar plasma membranes from guinea pig.

The regulation of the guinea-pig pancreatic acinar plasma membrane Ca2+ pump by protein kinase A, protein kinase C and calmodulin was investigated. The results were compared with the effects of these regulators on the high affinity Ca(2+)-ATPase found in this membrane preparation. The catalytic subunit of cyclic AMP-dependent protein kinase stimulated Ca2+ transport 2-fold, but had no effect on Ca(2+)-dependent ATPase activity. Purified protein kinase C, the phorbol ester 12-O-tetradecanoyl phorbol-13-acetate and diacylglycerol derivative, 1-stearoyl-2-arachidonoyl-sn-glycerol, failed to stimulate the Ca(2+)-uptake but augmented the Ca(2+)-dependent ATPase activity. Exogenously added calmodulin failed to stimulate either activity. In addition, two antagonists of calmodulin activity, trifluoperazine and compound 48/80 produced a concentration-dependent inhibition of Ca(2+)-transport. These data suggest the presence of endogenous calmodulin within guinea-pig pancreatic acinar plasma membranes. Both calmodulin antagonists failed to influence the Ca(2+)-dependent ATPase activity. The ability of boiled extracts from guinea-pig pancreatic acinar plasma membranes to stimulate the Ca(2+)-ATPase activity in calmodulin-depleted erythrocyte plasma membranes confirmed the presence of endogenous calmodulin. Our results imply a role for calmodulin and cAMP-dependent protein kinase, but not protein kinase C, in the regulation of Ca2+ efflux from pancreatic acinar cells. These results also provide further evidence suggesting that the high affinity Ca(2+)-ATPase does not catalyze the plasma membrane Ca(2+)-transport activity observed in pancreatic acini.

Animals↗

PubMed1992

[Nonoperative treatment of pancreatic pseudocyst in children].

3 children with pseudocyst of the pancreas resulting from blunt abdominal trauma are described (boys 6 and 8.5 years old, and a 6.5-year-old girl). Based on abdominal ultrasound and CT findings, nonoperative treatment was elected. There was spontaneous resolution in 1 and in the other 2 the pseudocyst was successfully drained. Previous reports and our own results indicate that it is safe to treat pancreatic pseudocysts in children after blunt abdominal trauma.

Abdominal Injuries↗

PubMed1992

Addiction can take many forms, experts warn MDs at conference.

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Adult↗

PubMed1992

Autocrine growth induced by kinase type oncogenes in myeloid cells requires AP-1 and NF-M, a myeloid specific, C/EBP-like factor.

The nuclear oncogenes v-myc or v-myb specifically transform avian myeloid cells. In both cases, the transformed cells remain dependent on chicken myelomonocytic growth factor (cMGF). This factor dependence can be relieved by expression of kinase-type oncogenes such as v-mil or v-erbB, leading to expression of cMGF and autocrine growth stimulation. In erythroid cells the same kinase-type oncogenes cause transformation but do not induce cMGF expression. Here we investigated the molecular mechanisms of the observed lineage specific oncogene collaboration. We found that kinase-type oncogenes and TPA activate the cMGF promoter via AP-1 like transcription factors. The activation of the cMGF promoter is, however, strictly dependent on the binding of nuclear proteins to both halves of an inverted repeat adjacent to the AP-1 binding site. These proteins are related to C/EBP. They are expressed exclusively in myeloid cells and were therefore termed NF-M. Our results indicate that the lineage specific cooperation of kinase type oncogenes with v-myb or v-myc in leukemia formation is based on the concerted action of AP-1 and NF-M on the cMGF promoter.

Animals↗

PubMed1992

Renal trauma with posttraumatic hypertension in a neonate.

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Female↗

PubMed1992

Giant cystic hygroma associated with venous aneurysm.

Complete excision of giant cystic hygroma requires meticulous dissection of the multilocular lymphatic cysts from the adjacent vascular and neural structures. The association of venous aneurysms with cystic hygroma is extremely rare. We report two infants with cystic hygroma in whom preoperative diagnosis of venous aneurysm was helpful in planning complete excision of the lymphatic lesions.

Aneurysm↗

PubMed1992

Inhalation toxicity of chromium from Whetlerite dust in rats.

The acute inhalation toxicity and metabolic fate of chromium and copper from Whetlerite dust in rats were investigated. Groups of male and female, Sprague-Dawley rats were exposed to Whetlerite dust and base carbon dust as outlined in the OECD Limit Test guidelines. At 14, 28 and 180 days post-exposure, rats were evaluated for gross pathological changes and tissues were collected for chromium and copper determination. Four deaths occurred during or post-exposure, but did not appear to be compound related. No gross pathological changes were observed at necropsy in either group. Organ chromium concentrations were below detection limits of 0.5 micrograms Cr/g dry tissue in both exposure groups. According to OECD guidelines, neither Whetlerite dust nor base carbon dust demonstrated an acute inhalation toxicity.

Administration, Inhalation↗

PubMed1992

Pharmacokinetic strategies for cyclosporin therapy in organ transplantation.

Marked interindividual variations in cyclosporin (CsA) produce disparate clinical results in organ transplant recipients. In an attempt to eliminate marked deviations of insufficient or excessive CsA concentrations consequent to the administration of uniform drug doses, test dose pharmacokinetics were performed on each potential organ transplant candidate. An intravenous 3 mg/kg test dose delivered over 3 h proved to be readily performed, namely 53% perfect studies, and relatively reliable, namely 73% of observed concentrations within 10% of the predicted values. Furthermore, the use of CsA doses predicted by pretransplant studies reduces the incidence of delayed graft function, early rejection episodes and transplant loss. The oral test dose study predicted a suitable amount of CsA to achieve sufficient gastrointestinal absorption but was less accurate than the iv prediction method: namely, 40% of observed post-transplant concentrations were within 10% of the predicted target value. Furthermore, patients who received oral doses predicted by the test dose strategy showed no improvement in the incidence of acute rejection episodes between 7 and 60 days, and only modestly improved serum creatinine values. The lower accuracy of predictions from oral test dose studies may reflect the impact of non-linear oral (as opposed to iv) drug pharmacokinetics, of variable diet, and/or of altered postoperative gastrointestinal function.

Administration, Oral↗

PubMed1992

The ability of pretransplant test-dose pharmacokinetic profiles to reduce early adverse events after renal transplantation.

Pretransplant test-dose pharmacokinetic profiles were used to determine individual cyclosporine drug bioavailability and clearance rates in renal transplant patients. Assuming a linear relation between dose and area under the concentration curve (AUC), starting i.v. and p.o. CsA doses were computed from the test-dose results. Target values were 400 ng/ml steady-state concentration (Css) during continuous intravenous infusion, and 500 ng/ml average drug concentration (Cavss = AUC/dosing interval) after oral administration, based upon measurements with the specific monoclonal antibody 3H-tracer radioimmunoassay. The outcomes after dose individualization with a 1-(n = 32), 2-(n = 38), or 3-(n = 41) hr i.v. infusion test dose and a p.o. test dose (n = 111) were compared with 228 historical control patients who received a uniform protocol of CsA i.v. at 2.5 mg/kg/day and p.o. at 14 mg/kg/day. The observed Css after i.v. CsA was within 10% of the target concentration in 73% of recipients tested with the 3-hr protocol, a significantly greater fraction than achieved with either the uniform dose (14%), or the 1-(34%) and 2-(25%) hr protocols. Patients in the 3-hr protocol group showed reduced incidences of delayed graft function, early graft loss, and rejection episodes, and a lower mean serum creatinine value, particularly at 7 but also at 30 days posttransplantation. Administration of the predicted oral dose produced a peak concentration of greater than or equal to 700 ng/ml drug absorption in 60% of recipients at 3 days, 90% at 5 days, and 98% at 7 days. The test-dose method less effectively predicted the appropriate oral CsA dose to produce target Cssav and failed to reduce the 90-day rejection incidence. Despite its limitations with the more-complicated p.o. route, the test-dose method successfully predicts i.v. CsA doses, thereby reducing the incidence of early adverse events.

Administration, Oral↗

PubMed1992

Initial organ localisation of blood-borne Candida albicans in a rat model of disseminated candidosis.

The rat was evaluated as an experimental model for disseminated candidosis by quantitating blood clearance and initial organ localisation of 3H-leucine-labelled Candida albicans after intravenous injection into the tail or portal vein. Viable or formalin-killed blastoconidia or viable blastoconidia with germ tubes were injected into experimental animals. Blood and tissue samples were obtained up to 24 h after injection and processed for liquid scintillation counting (to determine the distribution of labelled yeasts) and quantitation of viable organisms. Yeasts were cleared rapidly after intravenous (i.v.) injection by either route, i.e., < 5% of the radioactivity was detected in the blood after 5 min. The liver and lung were the major organs that sequestered blood-borne yeasts 1 h after tail vein injection (42.5 SD 15% and 41.4 SD 6.4% of labelled yeasts injected, respectively). However, injections via the portal vein resulted in trapping of the yeasts predominantly by the liver. Recovery of radioactivity and viable yeasts from all organs except the kidneys decreased with time. Overall, the results indicated that the rat might serve as a reliable model for short-term studies on organ distribution and thus contribute to our understanding of tissue trophism in candidosis.

Animals↗