Kinetic modelling of haemodialysis removal of myoglobin in rhabdomyolysis patients.

An extended two compartment model is proposed to describe the dynamics of myoglobin in rhabdomyolysis patients undergoing dialysis. Before using clinical data to estimate the model's unknown parameters, structural identifiability analysis was performed to determine the parameters uniqueness given certain clinical observations. A Taylor series expansion method was implemented which found that the model was structurally globally/uniquely identifiable for both on- and off-dialysis phases. The fitted model was then used in a predictive capacity showing that the use of Theralite high cut-off (HCO) or HCO 1100 dialyser gave a significant reduction in myoglobin renal exposure compared to standard haemodialysis (HD).

Pharmacological profile of UK-74,505, a novel and selective PAF antagonist with potent and prolonged oral activity.

UK-74505, a novel 1,4-dihydropyridine PAF antagonist, exhibited highly selective, time-dependent inhibition of PAF-induced aggregation of rabbit washed platelets (IC50 = 26.3 +/- 0.88 and 1.12 +/- 0.04 nM after 0.25 and 60 min preincubation, respectively), which became irreversible within 15 min, whereas inhibition by WEB-2086 was both independent of preincubation time (IC50 = 145.7 +/- 24.7 nM) and competitive (KI = 27.5 +/- 7.7 nM; Schild slope = 0.98 +/- 0.04). The selective inhibition of specific [3H]PAF binding by UK-74,505 exhibited a slower onset, the IC50 obtained without preincubation (14.7 +/- 2.6 nM) decreasing 2-fold at 45 min. UK-74,505 was 450-fold weaker as an antagonist of [3H]nitrendipine binding to bovine brain membranes and KCl-induced contraction of rat aorta. UK-74,505 was 10-30-fold more potent than WEB-2086 in vivo as an inhibitor of PAF-induced hypotension in rats (ED50 = 35 +/- 5.8 micrograms/kg, i.v.), cutaneous vascular permeability in guinea pigs (ED50 = 0.37 +/- 0.08 mg/kg, p.o.) and lethality in mice, with oral ED50 values of 0.26 +/- 0.03 and 1.33 +/- 0.19 mg/kg at 2 and 8 h, respectively. These data demonstrate that UK-74,505 is a potent, selective, long-acting irreversible PAF antagonist.

UK-74,505, a novel and selective PAF antagonist, exhibits potent and long lasting activity in vivo.

UK-74,505, a potent and selective PAF antagonist in vitro, has been shown to be extremely active given orally or intravenously to various species. In anaesthetised guinea pigs UK-74,505 at 30 & 100 micrograms/kg i.v. inhibited bronchoconstrictor responses to aerosolised PAF without affecting blood pressure or heart rate. The increased cutaneous vascular permeability to intradermal PAF in rats was inhibited by UK-74,505 with an ED50 of 280 +/- 5 micrograms/kg p.o. In conscious dogs, complete inhibition of PAF-induced whole blood aggregation ex-vivo occurred for at least 14 hours after an oral dose of 75 micrograms/kg. It is concluded that UK-74,505 is an effective, orally active PAF antagonist of long duration with the potential for once daily dosing.

Chronic exercise stress in mice depresses splenic T lymphocyte mitogenesis in vitro.

This study investigated changes in functional response to splenic T lymphocytes of mitogens following acute and chronic exposure to endurance exercise. Splenic T cell response in vitro to concanavalin A (Con A) and the total number of lymphocytes per spleen were compared between mice assigned to the following treatment conditions: (a) exercise training (EX) by treadmill running (28 m/min, 8 degrees slope for 30 min, 5 times per week for 4 weeks preceded by 2 weeks of endurance build-up), (b) exercise training as above followed by a single, acute bout of exercise to exhaustion (EX + AC) (35 m/min, 8 degrees slope, 30 min to 2 h duration) (c) exposure to the novel environment for 6 weeks without exercise (control), and exposure to the novel environment as in (c) followed by a single, acute bout of exercise to exhaustion. Treadmill running for 6 weeks significantly enhanced succinate dehydrogenase activity in skeletal muscle compared to the sedentary, control condition, and was broadly interpreted as indicative of a training effect. EX mice had significantly reduced splenic lymphocyte proliferative responses to optimal and supraoptimal concentrations of Con A compared with control animals. Incorporation of [3H]thymidine into splenic lymphocytes from EX + AC mice was the most markedly depressed. Total number of lymphocytes per spleen was significantly lower in EX compared with control mice. These results suggests that chronic exercise challenge in mice is associated with T lymphocyte hyporesponsiveness in the secondary lymphoid organs, such as the spleen.

Modulation of cellular immunity in malnutrition: effect of interleukin 1 on suppressor T cell activity.

T-lymphocyte mitogenesis is impaired in protein-energy malnutrition. The effect of interleukin 1 (IL-1) on the augmentation of suppressor cell activity during concanavalin A-induced lymphocyte proliferation was measured using IL-1 and lymphocytes from protein malnourished and control rabbits. Addition of IL-1 to lymphocyte cultures from control donors enhanced the suppression of fresh lymphocytes to phytohaemagglutinin (PHA). Addition of IL-1 to lymphocyte cultures from malnourished donors abrograted the suppressor cell activity. Isoelectric focusing showed the presence of a protein band with a pI of about 7.0 in the IL-1 supernatants from protein malnourished and control donors. The results suggest that severe protein malnutrition alters the ability of T-lymphocytes to respond appropriately to IL-1 rather than simply affecting synthesis of this monokine.

Comparison of potency of alpha 2-adrenoceptor antagonists in vitro: evidence for heterogeneity of alpha 2-adrenoceptors.

A comparison has been made of affinity of alpha-adrenoceptor antagonists for alpha 2 binding sites in radioligand binding assays, and functional antagonist activity at pre- and postjunctional alpha 2-adrenoceptors in various in vitro preparations. The antagonists displaced [3H]-rauwolscine from rat brain and rabbit spleen membranes but there were substantial differences in rank order and absolute potency in the two tissues. pA2 values for yohimbine, phentolamine and Wy26703 against the selective alpha 2 agonist UK-14,304 were determined in the rat left atrium, rat and rabbit vas deferens and rabbit saphenous vein preparations. The pA2 values varied substantially between the tissues, differing by two orders of magnitude in the case of Wy26703. Yohimbine was more potent in rabbit preparations while Wy26703 was markedly more potent in all the rat preparations. Yohimbine and Wy26703 were compared in the dog saphenous vein preparation where pre- and postjunctional alpha 2 antagonist activity can be compared in the same tissue. As in the rabbit preparations, yohimbine was more potent than Wy26703 at both sites but the absolute potencies were different. It is concluded that alpha 2-adrenoceptors are a heterogeneous population, different subgroups being more apparent between species rather than between tissue types or location.

Monocyte factors modulate in vitro T-lymphocyte mitogenesis in protein malnutrition.

This study investigated changes in T-lymphocyte mitogenesis and immunoregulatory cytokines during protein malnutrition. In vitro T cell response to concanavalin A was compared among protein deprived (PD), energy restricted pair fed control (PF), and ad libitum control (C) rabbits. Cell cultures were supplemented with crude monocyte supernatants (CMS) from PD, PF or C animals at either 1% or 8% final concentration in culture. Prostaglandin E2 (PGE2) concentration of unstimulated or stimulated lymphocyte culture supernatants and CMS was determined. Lymphocyte cultures from PD, PF and C animals had enhanced 3H-thymidine incorporation when supplemented with C and/or PF derived CMS. Addition of 8% CMS from PD rabbits inhibited proliferation below levels observed in mitogen-only stimulated groups in all cultures. At the 1% concentration, inhibition was seen in PD and C derived cells cultures and modest enhancement was seen in PF cultures. PGE2 concentration in supernatants from stimulated and unstimulated lymphocyte cultures from PD rabbits were higher than in C and PF cell cultures. These results suggest (a) that under appropriate culture conditions lymphocytes from PD donors are capable of enhanced proliferation and (b) that depressed T cell mitogenesis observed in protein malnutrition may reflect alterations in immunoregulatory signals. The role of interleukin 1 (IL-1) and PGE2 in the modulation of this response is discussed.

Comparison of activity of alpha-adrenoceptor agonists and antagonists in dog and rabbit saphenous vein.

The alpha adrenoceptors present on the saphenous vein of the dog and rabbit were characterised in vitro using the selective alpha 1 antagonist prazosin and the alpha 2 antagonists rauwolscine and yohimbine. In the dog saphenous vein, prazosin and rauwolscine competitively antagonised contractile responses to phenylephrine and UK-14,304 respectively. Noradrenaline was competitively blocked by prazosin only. In contrast, phenylephrine and methoxamine-induced responses in the rabbit saphenous vein were insensitive to prazosin and corynanthine. Rauwolscine competitively blocked responses to UK-14,304, noradrenaline and phenylephrine and pA2 values were similar against each agonist. Noradrenaline and UK-14,304 were equipotent agonists on the rabbit saphenous vein while in the dog vein noradrenaline has a lower potency than UK-14,304. These results suggest that the dog saphenous vein has a mixed population of alpha adrenoceptors, while the alpha adrenoceptors on the rabbit vein are homogeneous, with characteristics of the alpha 2 subtype.

Fever and survival in aged mice after endotoxin challenge.

Male C57BL/6 mice of 12, 19, and 24 months of age received injections of low (25 micrograms 100 g-1 body weight) or high (50 micrograms 100 g-1 body weight) doses of Salmonella typhosa endotoxin and were exposed to ambient temperatures below (24 degrees C) or within (30 degrees C) the thermoneutral zone. Old mice (19 and 24 months) developed initial fevers followed by hypothermia in response to endotoxin challenge at 24 degrees C, irrespective of dose; 12-month-old-mice became hypothermic at 24 degrees C following injection of the high dose of endotoxin only. At 30 degrees C, 12- and 19-month-old mice developed and maintained fever over 4 hr in response to endotoxin compared with the 24-month-old mice who were unable to maintain fevers. Logistic regression analysis showed that age, ambient temperature, and body temperature responses were significant predictors of survival outcome in endotoxin-treated mice; of these, age and ambient temperature had the strongest effects.

Body temperature responses of aged mice to ambient temperature and humidity stress.

Male C57BL/6 mice aged 6 to 7 months, 13 to 14 months, and 19 to 20 months were acutely exposed to four ambient temperature (15 degrees C, 20 degrees C, 30 degrees C, 35 degrees C) and two relative humidity (50% rh, 80% rh) conditions. Three-hour average rectal temperatures were compared across age groups and environmental conditions. At the two temperature extremes of 15 degrees C and 35 degrees C, there was a very marked age-associated hypothermia and hyperthermia, respectively. This hypothermic response was maintained by the 19 to 20-month-old mice during exposure to 20 degrees C and thermoneutrality (30 degrees C). At any given ambient temperature, relative humidity had no effect on thermoregulatory function in the oldest mice, whereas the 6 to 7-month- and 13 to 14-month-old mice were sensitive to the effects of humidity at 15 degrees C and 20 degrees C.

Calcite Dissolution: An in situ Study in the Panama Basin.

The results of an in situ study of calcite dissolution in the Panama Basin indicate that the rate of dissolution in the water column increases suddenly below a water depth of about 2800 meters. This coincides with the depth at which the calcium carbonate content of surface sediments begins to decrease rapidly or the sedimentary lysocline. Since this level of increased dissolution both in the water column and on the sea floor does not appear to be related to the transition from supersaturation to undersaturation with respect to carbonate, there may be a kinetic origin for the lysocline in this region.