Modification of the in vivo four-point loading model for studying mechanically induced bone adaptation

We modified the noninvasive, in vivo technique for strain application in the tibiae of rats (Turner et al,, Bone 12:73-79, 1991), The original model applies four-point bending to right tibiae via an open-loop, stepper-motor-driven spring linkage, Depending on the magnitude of applied load, the model produces new bone formation at periosteal (Ps) or endocortical surfaces (Ec.S). Due to the spring linkage, however, the range of frequencies at which loads can be applied is limited. The modified system replaces this design with an electromagnetic vibrator. A load transducer in series with the loading points allows calibration, the loaders' position to be adjusted, and cyclic loading completed under load central as a closed servo-loop. Two experiments were conducted to validate the modified system: (1) a strain gauge was applied to the lateral surface of the right tibia of 5 adult female rats and strains measured at applied loads from 10 to 60 N; and (2) the bone formation response was determined in 28 adult female Sprague-Dawley rats. Loading was applied as a haversine wave with a frequency of 2 Hz for 18 sec, every second day for 10 days. Peak bending loads mere applied at 33, 40, 52, and 64 N, and a sham-loading group tr as included at 64 N, Strains in the tibiae were linear between 10 and 60 N, and the average peak strain at the Ps.S at 60 N was 2664 +/- 250 microstrain, consistent with the results of Turner's group. Lamellar bone formation was stimulated at the Ec.S by applied bending, but not by sham loading. Bending strains above a loading threshold of 40 N increased Ec Lamellar hone formation rate, bone forming surface, and mineral apposition rate with a dose response similar to that reported by Turner et al, (J Bone Miner Res 9:87-97, 1994). We conclude that the modified loading system offers precision for applied loads of between 0 and 70 N, versatility in the selection of loading rates up to 20 Hz, and a reproducible bone formation response in the rat tibia, Adjustment of the loader also enables study of mechanical usage in murine tibia, an advantage with respect to the increasing variety of transgenic strains available in bone and mineral research. (Bone 23:307-310; 1998) (C) 1998 by Elsevier Science Inc. All rights reserved.

Carboplatin pharmacokinetics following a single-dose infusion in sulphur-crested cockatoos (Cacatua galerita)

Objective To determine the pharmacokinetics of carboplatin in sulphur-crested cockatoos, so that its use in clinical studies in birds can be considered. Design A pharmacokinetic study of carboplatin, following a single intravenous (IV) or intraosseus (10) infusion over 3 min, was performed in six healthy sulphur-crested cockatoos (Cacatua galerita). Procedure Birds were anaesthetised and a jugular vein cannulated for blood collection. Carboplatin (5 mg/kg) was infused over 3 min by the IV route in four birds via the contralateral jugular vein, and by the 10 route in two birds via the ulna. Serial blood samples were collected for 96 h after initiation of the infusion. Tissue samples from 11 organs were obtained at necropsy, 96 h after carboplatin administration. Total Pt and filterable Pt in plasma and tissue Pt concentrations were assayed by inductively coupled plasma-mass spectrometry. A noncompartmental pharmacokinetic analysis was performed on the plasma data. Results The mean +/- SD for the C-max of filterable Pt was 27.3 +/- 4.06 mg/L and in all six birds occurred at the end of the 3 min infusion, thenceforth declining exponentially over the next 6 h to an average concentration of 0.128 +/- 0.065 mg/L. The terminal half-life (T-1/2) was 1.0 +/- 0.17 h, the systemic clearance (CI) was 5.50 +/- 1.06 mL/min/kg and the volume of distribution (Vss) was 0.378 +/- 0.073 L/kg. The extrapolated area under the curve (AUC(0-x)) was 0.903 +/- 0.127 mg/mL.min; the area extrapolated past the last (6 h) data point to infinite time averaged only 1.25% of the total AUC(0-x). The kidneys had the greatest accumulation of Pt (7.04 +/- 3.006 mug/g), followed by the liver (3.08 +/- 1.785 mug/g DM). Conclusions and clinical relevance Carboplatin infusion in sulphur-crested cockatoos produced mild, transient alimentary tract signs and the Pt plasma concentration was similar whether carboplatin was given intravenously or intraosseously. Filterable plasma Pt concentrations for carboplatin persisted longer than for cisplatin, due mostly to the difference in systemic clearance between these drugs in sulphur-crested cockatoos. The distribution of tissue Pt after carboplatin administration was similar to that reported for cisplatin in sulphur-crested cockatoos. Despite anatomical, physiological and biochemical differences among animal species, the pharmacokinetic disposition of filterable Pt in the sulphur-crested cockatoo shares some features with the kinetics reported previously in other animals and human beings.

Area-under-the-curve monitoring of prednisolone for dose optimization in a stable renal transplant population

Background: Renal transplant recipients were noted to appear cushingoid while on low doses of steroid as part of a triple therapy immunosuppression of cyclosporin A (CsA), prednisolone, and azathioprine. Methods: The study group comprised adult renal transplant recipients with stable graft function who had received their renal allograft a minimum of 1 year previously (43 studies undertaken in 22 men and 20 women) with median daily prednisone dose of 7 mg (range 3-10). The control group was healthy nontransplant subjects [median dose 10 mg (10-30)]. Prednisolone bioavailability was measured using a limited 6-hour area under the curve (AUC), with prednisolone measured using specific HPLC assay. Results: The median prednisolone AUC/mg dose for all transplant recipients was significantly greater than the control group by approximately 50% (316 nmol(.)h/L/mg prednisolone versus 218). AUC was significantly higher in female recipients (median 415 versus 297 for men) and in recipients receiving cyclospotin (348 versus 285). The highest AUC was in women on estrogen supplements who were receiving cyclosporin (median 595). A significantly higher proportion of patients on triple therapy had steroid side effects compared with those on steroid and azathioprine (17/27 versus 4/15), more women than men had side effects (14/16 versus 7/22), and the AUC/mg prednisone was greater in those with side effects than without (median 377 versus 288 nmol-h/L/mg). Discussion: The results are consistent with the hypothesis that CsA increases the bioavailability of prednisolone, most likely through inhibition of beta-glycoprotein. The increased exposure to steroid increased the side-effect profile of steroids in the majority of patients. Because the major contributor to AUC is the maximum postdose concentration, it may be possible to use single-point monitoring (2 hours postdose) for routine clinical studies.

Evaluation of random plasma cortisol and the low dose corticotropin test as indicators of adrenal secretory capacity in critically ill patients: A prospective study

It is unclear whether a random plasma cortisol measurement and the corticotropin (ACTH) test adequately reflect glucocorticoid secretory capacity in critical illness. This study aimed to determine whether these tests provide information representative of the 24 hour period. Plasma cortisol was measured hourly for 24 hours in 21 critically ill septic patients followed by a corticotropin test with 1 μ g dose administered intravenously. Serum and urine were analysed for ACTH and free cortisol respectively. Marked hourly variability in plasma cortisol was evident (coefficient of variation 8-30%) with no demonstrable circadian rhythm. The individual mean plasma cortisol concentrations ranged from 286 59 nmol/l to 796 &PLUSMN; 83 nmol/l. The 24 hour mean plasma cortisol was strongly correlated with both random plasma cortisol (r(2) 0.9, P< 0.0001) and the cortisol response to corticotropin (r(2) 0.72, P< 0.001). Only nine percent of patients increased their plasma cortisol by 250 nmol/l after corticotropin (euadrenal response). However, 35% of non-responders had spontaneous hourly rises > 250 nmol/l thus highlighting the limitations of a single point corticotropin test. Urinary free cortisol was elevated (865&PLUSMN; 937 nmol) in both corticotropin responders and non-responders suggesting elevated plasma free cortisol. No significant relationship was demonstrable between plasma cortisol and ACTH. We conclude that although random cortisol measurements and the low dose corticotropin tests reliably reflect the 24 hour mean cortisol in critical illness, they do not take into account the pulsatile nature of cortisol secretion. Consequently, there is the potential for erroneous conclusions about adrenal function based on a single measurement. We suggest that caution be exercised when drawing conclusions on the adequacy of adrenal function based on a single random plasma cortisol or the corticotropin test.

Column connection detail, Kangaroo Point House

Hand-made spotted gum column on edge of outdoor room.

West elevation, Cleveland Point House, Cleveland

Hand-drawn elevation.

Cottage, Cleveland Point House, Cleveland

Beach elevation of renovated existing cottage.

Lattice to boat house, Cleveland Point House, Cleveland

Lattice behind pull-down blind to boat house.

Beachfront elevation, Cleveland Point House, Cleveland

Timber framing to new bath house (centre), with existing buildings to either side.

Bath house, Cleveland Point House, Cleveland

New bath house under construction (centre), with existing buildings to either side.

Bath house, Cleveland Point House, Cleveland

Bath house under construction, as seen looking towards water from deck area.

Bath house, Cleveland Point House, Cleveland

As seen looking towards water from deck area.

Beachfront elevation, Cleveland Point House, Cleveland

New bath house (centre), with existing buildings to either side.

Boat house, Cleveland Point House, Cleveland

Existing boat house undergoing renovations.