Administration of pegylated recombinant human megakaryocyte growth and development factor to humans stimulates the production of functional platelets that show no evidence of in vivo activation

This report describes the effect of pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF) on platelet production and platelet function in humans. Subjects with advanced solid tumors received PEG-rHuMGDF daily for up to 10 days. There was no increase in circulating platelet count at doses of 0.03 or 0.1 microgram/kg/d by day 12 of study. At doses of 0.3 and 1.0 microgram/kg/d there was a threefold median increase (maximum 10-fold) in platelet count by day 16. The platelets produced in vivo in response to PEG-rHuMGDF showed unchanged aggregation and adenosine triphosphate (ATP)-release responses in in vitro assays. Tests included aggregation and release of ATP in response to adenosine diphosphate (ADP) (10, 5, 2.5, and 1.25 mumol/L), collagen (2 micrograms/mL), thrombin-receptor agonist peptide (TRAP, 10 mumol/L) and ristocetin (1.5 mg/mL). Administration of aspirin to an individual with platelet count of 1,771 x 10(3)/L resulted in the typical aspirin-induced ablation of the normal aggregation and ATP-release response to stimulation with arachidonic acid (0.5 mg/mL), collagen, and ADP (2.5 and 1.25 mumol/L). There was no change in the expression of the platelet-surface activation marker CD62P (P-selectin) nor induction of the fibrinogen binding site on glycoprotein IIb/IIIa as reported by the monoclonal antibody, D3GP3. An elevation of reticulated platelets was evident after 3 days of treatment with PEG-rHuMGDF and preceded the increase in circulating platelet count by 5 to 8 days; this reflected the production of new platelets in response to PEG-rHuMGDF. At later time points, the mean platelet volume (MPV) decreased in a manner inversely proportional to the platelet count. Levels of plasma glycocalicin, a measure of platelet turnover, rose 3 days after the initial increase in the peripheral platelet count. The level of plasma glycocalicin was proportional to the total platelet mass, suggesting that platelets generated in response to PEG-rHuMGDF were not more actively destroyed. Thus, the administration of PEG-rHuMGDF, to humans, increased the circulating platelet count and resulted in fully functional platelets, which showed no detectable increase in reactivity nor alteration in activation status.     

Stability and Trunnion Wear Potential in Large-diameter Metal-on-Metal Total Hips: A Finite Element Analysis

Background

Large-diameter femoral heads for metal-on-metal THA hold theoretical advantages of joint stability and low bearing surface wear. However, recent reports have indicated an unacceptably high rate of wear-associated failure with large-diameter bearings, possibly due in part to increased wear at the trunnion interface. Thus, the deleterious consequences of using large heads may outweigh their theoretical advantages.

Questions/purposes

We investigated (1) to what extent femoral head size influenced stability in THA for several dislocation-prone motions; and the biomechanics of wear at the trunnion interface by considering the relationship between (2) wear potential and head size and (3) wear potential and other factors, including cup orientation, type of hip motion, and assembly/impaction load.

Methods

Computational simulations were executed using a previously validated nonlinear contact finite element model. Stability was determined at 36 cup orientations for five distinct dislocation challenges. Wear at the trunnion interface was calculated for three separate cup orientations subjected to gait, stooping, and sit-to-stand motions. Seven head diameters were investigated: 32 to 56 mm, in 4-mm increments.

Results

Stability improved with increased diameter, although diminishing benefit was seen for sizes of greater than 40 mm. By contrast, contact stress and computed wear at the trunnion interface all increased unabatedly with increasing head size. Increased impaction forces resulted in only small decreases in trunnion wear generation.

Conclusions

These data suggest that the theoretical advantages of large-diameter femoral heads have a limit. Diameters of greater than 40 mm demonstrated only modest improvement in terms of joint stability yet incurred substantial increase in wear potential at the trunnion.

Clinical Relevance

Our model has potential to help investigators and designers of hip implants to better understand the optimization of trunnion design for long-term durability.     

The discard of deceased donor kidneys in the UK

It is essential to minimize the unnecessary discard of procured deceased donor kidneys, but information on discard rates and the extent to which discard can be avoided are limited. Analysis of the UK Transplant Registry revealed that the discard rate of procured deceased donor kidneys has increased from 5% in 2002‐3 to 12% in 2011‐12. A national offering system for hard‐to‐place kidneys was introduced in the UK in 2006 (the Declined Kidney Scheme), but just 13% of kidneys that were subsequently discarded until 2012 were offered through the scheme. In order to examine the appropriateness of discard, 20 consecutive discarded kidneys from 13 deceased donors were assessed to determine if surgeons agreed with the decision that they were not implantable. Donors had a median (range) age of 67 (31–80) yr. Kidneys had been offered to a median of 3 (1–12) centers before discard. Four (20%) of the discarded kidneys were thought to be usable, and nine (45%) were possibly usable. As a result of these findings, major changes to the UK deceased donor kidney offering system have been implemented, including simultaneous offering and broader entry criteria for hard‐to‐place kidneys. Organizational changes are necessary to improve utilization of deceased donor kidneys.