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rHuPH20 is a novel drug delivery enzyme that is locally degrading hyaluronan to transiently increase bulk fluid flow. rHuPH20 improves the subcutaneous (SC) absorption profiles of fluids and co-injected drugs and biologics. Formulation with rHuPH20 permits delivery of volumes that substantially exceed the typically tolerable SC limits and achieves bioavailability of protein therapeutics that approximate that of IV administration. In support of this novel drug delivery permeation enhancer and to characterize the preclinical safety profile, rHuPH20 was evaluated for acute, subacute and chronic toxicity in the Cynomolgus monkey. IV or SC injections of 30 mg/kg (3,600,000 U/kg) rHuPH20 dosed acutely, and 5 mg/kg (600,000 U/kg) dosed once daily for 7 days, elicited no adverse findings, as anticipated from the short t½, low systemic exposure and bioavailability of ≤5% following SC dosing. A 9-month study in monkeys dosed SC once weekly at 0.02, 0.2, and 2 mg/kg/dose (2,400, 24,000, 240,000 U/kg/dose) found no systemic toxicity. Minimal perivascular lymphoplasmacytic infiltration was observed at the injection sites in the mid- and high-dose, showing substantial improvement after a 4-week recovery. The finding was likely a local response of monkeys to the injection of a human protein and therefore considered non-adverse. The NOAEL was 2 mg/kg. Very low levels of plasma hyaluronidase activity were detectable at the high-dose only (for ≤6 months in males, for 9 months in females). Loss of plasma hyaluronidase activity correlated with increased levels of hyaluronidase neutralizing activity. Collectively, these studies establish that high SC doses of rHuPH20 resulted in very low systemic exposure and no systemic toxicity, which is consistent with rHuPH20’s activity as a locally-acting, transiently-active, fully reversible permeation-enhancing excipient. [ABSTRACT FROM AUTHOR]

Modification of the implant surface with the Arg-Gly-Asp tripeptide (RGD) putatively facilitates osteoblast attachment for improved implant fixation in the laboratory. We compared the histomorphometric and mechanical performance of titanium implants coated with RGD using a novel interface of self-assembled monolayers of phosphonates (RGD/SAMP) and implants coated with RGD using the more conventional thiolate-gold interface (RGD/thiolate-gold). We hypothesized RGD/SAMP-coated implants would show greater bone ongrowth and implant fixation than RGD/thiolate-gold-coated ones. We implanted an RGD/SAMP-coated implant in one femur and an RGD/thiolate-gold-coated in the contralateral femur of 60 rats. At 2, 4, and 8 weeks after implantation, 10 rats were sacrificed for histologic evaluation and another 10 for biomechanical testing. Bone-implant ongrowth and implant force-to-failure of the two implants were similar at all times. Although RGD/SAMP-coated implants did not show superior bone ongrowth and implant fixation, RGD/SAMP-coated implants have at least equally good histomorphometric and mechanical in vivo performance as RGD/thiolate-gold-coated ones. Additional in vivo characterization of self-assembled monolayer films of phosphonates as interface to bond RGD to titanium is needed to explore its full potential and seems justified based on the results of this study. [ABSTRACT FROM AUTHOR]

The effect and time course of free fatty acid (FFA) elevation on insulin-mediated vasodilation (IMV) and the relationship of FFA elevation to changes in insulin-mediated glucose uptake was studied. Two groups of lean insulin-sensitive subjects underwent euglycemic-hyperinsulinemic (40 mU x m(-2) x min(-1)) clamp studies with and without superimposed FFA elevation on 2 occasions approximately 4 weeks apart. Groups differed only by duration of FFA elevation, either short (2-4 h, n = 12) or long (8 h, n = 7). On both occasions, rates of whole-body glucose uptake were measured, and changes in leg blood flow (LBF) and femoral vein nitric oxide nitrite plus nitrate (NOx) flux in response to the clamps were determined. Short FFA infusion did not have any significant effect on the parameters of interest. In contrast, long FFA infusion decreased rates of whole-body glucose uptake from 47.7 +/-2.8 to 32.2 +/- 0.6 micromol x kg(-1) x min(-1) (P < 0.01), insulin-mediated increases in LBF from 66 +/- 8 to 37 +/- 7% (P < 0.05), and insulin-induced increases in NOx flux from 25 +/- 9 to 5 +/- 9% (P < 0.05). Importantly, throughout all groups, FFA-induced changes in whole-body glucose uptake correlated significantly with FFA-induced changes in insulin-mediated increases in LBF (r = 0.706, P < 0.001), which indicates coupling of metabolic and vascular effects. In a different protocol, short FFA elevation blunted the LBF response to NG-monomethyl-L-arginine (L-NMMA), which is an inhibitor of NO synthase. LBF in response to L-NMMA decreased by 17.3 +/- 2.4 and 9.0 +/- 1.4% in the groups without and with FFA elevation, respectively (P < 0.05), which indicates that FFA elevation interferes with shear stress-induced NO production. Thus, impairment of shear stress-induced vasodilation and IMV by FFA elevation occurs with different time courses, and impairment of IMV occurs only if glucose metabolism is concomitantly reduced. These findings suggest that NO production in response to the different stimuli may be mediated via different signaling pathways. FFA-induced reduction in NO production may contribute to the higher incidence of hypertension and macrovascular disease in insulin-resistant patients. [ABSTRACT FROM AUTHOR]

In defining the contemporary role of the specialist nurse it is necessary to challenge the concept of nursing as merely a combination of skills and knowledge. Nursing must be demonstrated and defined in the context of client care and include the broader notions of professional development and competence. This qualitative study sought to identify the competency standards for nurse specialists in critical care and to articulate the differences between entry-to-practice standards and the advanced practice of specialist nurses. Over 800 hours of specialist critical care nursing practice were observed and grouped into 'domains' or major themes of specialist practice using a constant comparison qualitative technique. These domains were further refined to describe attributes of the registered nurses which resulted in effective and/or superior performance (competency standards) and to provide examples of performance (performance criteria) which met the defined standard. Constant comparison of the emerging domains, competency standards and performance criteria to observations of specialist critical care practice, ensured the results provided a true reflection of the specialist nursing role. Data analysis resulted in 20 competency standards grouped into six domains: professional practice, reflective practice, enabling, clinical problem solving, teamwork, and leadership. Each of these domains is comprised of between two and seven competency standards. Each standard is further divided into component parts or 'elements' and the elements are illustrated with performance criteria. The competency standards are currently being used in several Australian critical care educational programmes and are the foundation for an emerging critical care credentialling process. They have been viewed with interest by a variety of non-critical care specialty groups and may form a common precursor from which further specialist nursing practice assessment will evolve. [ABSTRACT FROM AUTHOR]

Information from the 1979 to 1986 waves of the Panel Study of Income Dynamics is merged with data on respondents' tract and metropolitan area of residence to examine patterns and determinants of residential mobility between central cities and suburbs. Consistent with the life-cycle model of residential mobility, mobility in both directions declines with age, but on balance the presence of young children deters moving to the suburbs. Among blacks, education increases the probability of moving from cities to suburbs, while high income retains blacks and whites in suburbs. Consistent with the place stratification model, blacks are substantially less likely than whites to move from cities to suburbs, and substantially more likely to move from suburbs to cities, even after standardizing for racial differences in sociodemographic characteristics. High levels of violent crime and unemployment in cities relative to suburbs also tend to spur city-to-suburb mobility or inhibit suburb-to-city moves. [ABSTRACT FROM AUTHOR]