Biomedical subjects
D Grainger
Publications and source records attributed to D Grainger.
Tissue-engineered bone biomimetic to regenerate calvarial critical-sized defects in athymic rats.
A tissue-engineered bone biomimetic device was developed to regenerate calvaria critical-sized defects (CSDs) in athymic rats. Well-documented evidence clearly confirms that left untreated, CSDs will not spontaneously regenerate bone. To accomplish regeneration, four candidate treatments were assessed: porous poly(D,L-lactide) and type I collagen (PLC), PLC and human osteoblast precursor cells (OPCs) at 2 x 10(5) (PLC/OPCs), PLC and 50 microg of recombinant human bone morphogenetic protein-2 (PLC/rhBMP-2), and PLC/OPCs/rhBMP-2 (the bone biomimetic device). The hypotheses for this study were PLC/OPCs/rhBMP-2 would promote more new bone formation in CSDs than the other treatments and the amount of bone formation would be time dependent. To test the hypotheses, outcomes from treatments were measured at 2 and 4 weeks postoperatively by radiomorphometry for percent radiopacity and by histomorphometry for square millimeters of new bone formation. Data were analyzed by analysis of variance and Fisher's protected least significant difference for multiple comparisons with p < or = 0.05. At 2 and 4 weeks, radiomorphometric data revealed PLC/rhBMP-2 and PLC/OPCs/rhBMP-2 promoted significantly more radiopacity than either PLC or PLC/OPCs. Histomorphometry data at 2 and 4 weeks indicated significantly more new bone formation for PLC/rhBMP-2, PLC/OPCs/rhBMP-2, and PLC/OPCs compared to PLC. By 4 weeks, PLC/OPCs/rhBMP-2 and PLC/rhBMP-2 had regenerated the CSDs with more new bone than the other treatments; the quantity of bone at 4 weeks for these treatments was greater than at 2 weeks.
Effects of methyltestosterone on insulin secretion and sensitivity in women.
The frequent coexistence of hyperandrogenism and insulin resistance is well established; however, whether a cause and effect relationship exists remains to be established. In this study we tested the hypothesis that short-term androgen administered to women would induce insulin resistance. To test this hypothesis, regularly menstruating, nonobese women were studied before and during methyltestosterone administration (5 mg tid for 10-12 days) by the hyperglycemic (n=8) and euglycemic, hyperinsulinemic (n=7) clamp techniques. Short-term methyltestosterone administration had no significant effects on the fasting levels of glucose, insulin, c-peptide, glucagon, or glucose turnover. During the hyperglycemic clamp studies, the mean glucose level during the final hour was 203+/-2 and 201+/-1 mg/dL in the methyltestosterone and control studies, respectively. The insulin response to this hyperglycemic challenge was slightly but not significantly greater during methyltestosterone treatment (first phase 59+/-8 vs. 50+/-8 microU/mL in controls; second phase 74+/-9 vs. 67+/-9 microU/mL in controls; total insulin response 133+/-16 vs. 117+/-15 microU/mL in controls). In spite of this, glucose uptake was reduced from the control study value of 10.96+/-1.11 to 7.3+/-0.70 mg/kg/min by methyltestosterone (P < 0.05). The ratio of glucose uptake per unit of insulin was also significantly reduced from a control study value of 14.3+/-1.4 to 9.4+/-1.3 mg/kg/min per microU/mL x 100 during methyltestosterone administration. In the euglycemic hyperinsulinemic clamp studies, insulin was infused at rates of 0.25 and 1.0 mU/kg/min to achieve insulin levels of approximately 25 and 68 microU/mL, respectively. During low-dose insulin infusion, rates of endogenous hepatic glucose production were equivalently suppressed from basal values of 2.37+/-0.29 and 2.40+/-0.27 mg/kg/min to 0.88+/-0.25 and 0.77+/-0.26 mg/kg/min in the methyltestesterone and control studies respectively. Whole body glucose uptake during low-dose insulin infusion was minimally affected. During the high-dose insulin infusion, endogenous hepatic glucose production was nearly totally suppressed in both groups. However, whole body glucose uptake was reduced from the control value of 6.11+/-0.49 mg/kg/min to 4.93+/-0.44 mg/kg/min during methyltestosterone administration (P < 0.05). Our data demonstrate that androgen excess leads to the development of insulin resistance during both hyperglycemic and euglycemic hyperinsulinemia. These findings provide direct evidence for a relationship between hyperandrogenemia and insulin resistance, and its associated risk factors for cardiovascular disease.
Economic evaluation of insulin lispro versus neutral (regular) insulin therapy using a willingness-to-pay approach.
This willingness-to-pay (WTP) analysis is the first study of its kind undertaken in Australia to support an application for listing of a new drug on the Australian national formulary. The technique offers the advantage of being able to summarise diverse outcomes of therapy in a single unit of measure. Willingness to pay is used to value benefits in cost-benefit analysis (CBA), and CBA represents an absolute decision rule. An open-ended question with a bid-up approach was used to minimise bias and elicit the maximum amount patients would be willing to pay for insulin lispro. The WTP study incorporated scenarios describing the outcomes from insulin lispro and neutral (regular) insulin, the results from a formal metaanalysis and a description of the injection characteristics of the therapies. A sample of 83 patients with type I or II diabetes mellitus were surveyed using an open questionnaire to determine their maximum willingness to pay for the therapy they preferred. Overall, 92% of patients preferred insulin lispro (referred to as insulin A) and 8% preferred neutral insulin (referred to as insulin B). The incremental benefit per patient was calculated as 452.16 Australian dollars ($A) per year. Insulin lispro was listed on the Australian national formulary at a 36% premium over neutral insulin, so the additional cost per patient would be $A70.32 per year. Therefore, costs were exceeded by the benefits and insulin lispro was deemed to offer a net benefit. A multivariate analysis indicated that those patients who were middle-aged had the strongest preference for insulin lispro.
Distribution of platelet-derived growth factor (PDGF) A chain mRNA, protein, and PDGF-alpha receptor in rapidly forming human bone.
Platelet-derived growth factors (PDGFs) are potent bone cell mitogens which stimulate the proliferation of osteoblastic cells, may also be involved in the regulation of osteoclastic bone resorption, and indirectly induce vascular endothelial cell proliferation and angiogenesis. In view of the established relationship between angiogenesis and osteogenesis, the production of PDGFs by both osteoblastic and vascular endothelial cells suggests that they may play a role in bone formation during skeletal development. We have used two human models of rapid bone formation, heterotopic bone and osteophytic bone, to investigate the expression of PDGF-A mRNA and protein and the PDGF-alpha receptor protein in vivo using in situ hybridization and immunohistochemistry. PDGF-A mRNA and protein were widely distributed throughout heterotopic and osteophytic bone. Within the cartilaginous tissue PDGF-A mRNA and protein were most strongly expressed by mature chondrocytes with decreased expression in the hypertrophic zone and almost no staining in the mineralizing and mineralized zones. PDGF mRNA and protein were also expressed in cells of small blood vessels within fibrous and cartilaginous tissue. In contrast, PDGF-alpha receptor expression was restricted to a minority of hypertrophic chondrocytes and sites of vascular invasion. Within the bone and fibrous tissue the growth factor and the receptor were widely distributed, being detected on most cells at sites of bone formation or in remodeling sites; no receptor was detected on osteoclasts. These data demonstrate the widespread expression of PDGF-A and its receptor in forming human bone and indicate that this growth factor may exert autocrine and paracrine effects to regulate osteogenesis during skeletal development.
Who bears the costs of antidepressants in Australia?
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Progesterone administration induced impairment of insulin suppression of hepatic glucose production.
OBJECTIVE: To assess whether P administration impairs insulin-mediated glucose uptake. DESIGN: Two-step euglycemic hyperinsulinemic clamp studies. SETTING: Rats studied with (n = 11) or without (n = 10) P treatment. PARTICIPANTS: Conscious, unstressed, oophorectomized female rats. MAIN OUTCOME MEASURES: Plasma glucose and insulin levels and the rates of glucose turnover results. RESULTS: Fasting glucose (115 +/- 5 versus 109 +/- 4 mg/dL; conversion factor to SI units 0.05551) and insulin (1.67 +/- 0.24 versus 1.51 +/- 0.22 ng/mL; conversion factor to SI units 174.5) levels were not significantly different in the control and P treated groups, respectively. However, the basal rate of glucose turnover was significantly higher in P-treated rats (8.38 +/- 0.50 versus 6.59 +/- 0.35 mg/kg per minute in controls. During low-dose insulin infusion (2 mU/kg per minute), there was no difference in glucose or insulin levels, or the rate of glucose utilization; however, residual hepatic glucose production was significantly greater in the P group (5.34 +/- 0.68 versus 2.57 +/- 1.00 mg/kg per minute) in controls. At high-dose insulin infusion (10 mU/kg per minute), hepatic glucose production was completely suppressed in both groups; there was no difference in insulin sensitivity as assessed by the glucose utilization rate or the ratio of glucose uptake to insulin level. CONCLUSIONS: Chronic P therapy does not alter insulin-mediated glucose utilization in peripheral tissues but does reduce the ability of insulin to suppress endogenous hepatic glucose production.
Influence of basal androgen levels in euandrogenic women on glucose homeostasis.
OBJECTIVE: To evaluate possible relationships between insulin action and the normal variations of serum androgens in euandrogenic women. DESIGN: Prospective evaluation of insulin action in normal nonobese women using hyperglycemic and euglycemic hyperinsulinemic clamp techniques, correlating insulin action to serum testosterone (T), free T, androstenedione (A), and dehydroepiandrosterone sulfate (DHEAS). Statistical analysis used Spearman's rank correlation. SETTING: Yale University Clinical Research Center. PARTICIPANTS: Nonobese females with normal oral glucose tolerance tests, on no medications known to affect glucose metabolism, having the following range of serum androgen levels: T, 0.69 to 3.12 nmol/L; free T, 0.17 to 1.25 nmol/L; A, 2.48 to 11.31 nmol/L; DHEAS, 0.68 to 10.61 mumol/L. Total number of patients studied: hyperglycemic clamps, n = 58; euglycemic hyperinsulinemic clamps, n = 43. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Pancreatic insulin secretion in response to hyperglycemia and insulin action as assessed by insulin-mediated glucose utilization using the euglycemic, hyperinsulinemic clamp technique. RESULTS: We identified no significant correlation between serum androgens and either glucose uptake or insulin-mediated glucose utilization. Glucose-stimulated insulin release was negatively correlated with serum T and free T throughout the normal range of these hormones. CONCLUSION: We conclude that, within the normal range, variations of serum androgens are not correlated with changes in the response to insulin. It seems unlikely, therefore, that modest increases of serum androgens within the normal range are responsible for inducing insulin resistance.
Prediction of hip fracture in elderly women: a prospective study.
OBJECTIVE: To assess the relative importance of osteoporosis of the os calcis, cognisance, and mobility in the risk of subsequent fracture of the hip in elderly women. DESIGN: Prospective study of elderly women in residential care over two years. SETTING: 21 Private or 38 local authority residential homes for the elderly and 4 geriatric hospitals in Doncaster and Hull. SUBJECTS: 1414 Ambulant women aged over 69, in private or local authority residential care or geriatric care. Those who had had bilateral hip surgery were excluded. MAIN OUTCOME MEASURES: Broad band ultrasonic attenuation (BUA) index, Clifton assessment procedures for the elderly test (for cognisance), and mobility on a six point scale, and fracture of the hip in the subsequent two year period. RESULTS: 73 Women fractured their hip during the two years. Their mean age was not significantly different from that of the women who did not have a fracture (85.3 (SD 5.6) v 83.9 (6.3); p = 0.07), but their mean BUA index (40.3 (19.3) v 50.9 (22.2) db/MH2), and score for cognisance (median 19 (interquartile range 10.5-27.0) v 24 (17-30)) were significantly lower (both p less than 0.001). These variables had independent associations with fracture of the hip. Women with fractures had a significantly lower score for the psychomotor component of the cognisance test (4.5 (1-8) v 7 (2-10); p less than 0.0025 and were significantly more mobile (1(1-3) v 3 (1-6); p less than 0.02). Subdividing women according to high, medium, and low scores for BUA index and cognisance testing disclosed a high risk group (118 women) with low BUA index and cognisance score, whose incidence of fracture was 12.8%; in the group at lowest risk (136 women) with high BUA index and cognisance score, the incidence of fracture was only 1.5% (relative risk 8.4 (95% confidence interval -2.0 to 35.5]. Further analysis showed that those most at risk were, additionally, most mobile but that less mobile women with good cognisance had a low incidence of fractures, regardless of the BUA index, (1.2%, high index, v 0.9%, low index). CONCLUSIONS: Elderly women most at risk of sustaining hip fractures were those with low BUA index, low cognisance test score, and high mobility. Improving bone strength and cognisance in elderly women may reduce their incidence of hip fracture.
Surface modification for improved blood compatibility.
Several surface modification techniques are currently being used to improve the biocompatibility of blood-contacting devices. These include the immobilization of bioactive materials to prevent thrombus generation and platelet activation, the incorporation of hydrophilic grafts onto practical hydrophobic surfaces (polyurethanes) to reduce protein adsorption, and the concept of microdomain-phase separated surfaces to regulate cellular and protein adhesion.
Sensitivity to intravenous anaesthetics: a report of three cases.
Three patients with sensitivity to an intravenous anaesthetic-thiopentone, propanidid, and Althesin (alphadolone and alphaxalone)-are described. In the cases of thiopentone and Althesin the reaction was characterized by cardiovascular collapse, while bronchospasm also occurred with thiopentone. The reaction to propanidid was a direct skin sensitivity. All patients had a personal or family history of asthma and all had been previously exposed to the offending drug. A leucocyte challenge test showed an allergic response to thiopentone and Althesin in two patients but gave a negative result in the patient with the skin reaction. Allergic reactions can occur to all types of intravenous anaesthetics in a few patients.
Clinical outcomes with insulin lispro compared with human regular insulin: a meta-analysis.
We performed a meta-analysis to compare insulin lispro and human regular insulin across a range of outcomes common in modern diabetes management to establish a basis for subsequent economic evaluation. We included all identifiable head-to-head randomized controlled trials, pooling dichotomous and continuous outcomes using appropriate statistical methods. Measures associated with various aspects of glycemic control (preparandial and postprandial glycemic control, glucose excursion, and glycated hemoglobin) and with hypoglycemia were evaluated. Results showed significant differences in favor of insulin lispro in the outcomes associated with postprandial glycemic control without an increase in hypoglycemia. Outcomes associated with fasting glycemic control and overall long-term glycemic control were not significantly different between insulin lispro and human regular insulin. Alternative approaches to the meta-analysis were explored but did not alter the conclusions. Thus our meta-analysis supports the existence of significant differences between insulin lispro and human regular insulin in terms of important postprandial outcome measures in diabetes. In addition, there is a practical difference in injection timing relative to meals: human regular insulin should be administered 30 to 45 minutes before eating, whereas insulin lispro can be administered 15 minutes or less before eating. These differences should be the subject of an economic evaluation to assist in determining the place of insulin lispro in diabetes management.
Evaluation of nonthrombogenic polymers in a new rabbit A-A shunt model.
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