Medical students value-adding to general practice.

BACKGROUND AND OBJECTIVES: Medical students can make valuable contributions to patient care during clinical placements. The aim of this study was to investigate student perceptions of the value of general practice placements for their learning, and their sense of contribution during their placements. METHOD: The study used a qualitative design to gather in-depth student perspectives on learning and contributions, using focus groups of final-year medical students on general practice placement. RESULTS: Thirteen students participated in one of three focus groups. Students reported valuable learning affordances in general practice and identified contributions to improved workflow, rapport-building, patient education, encouraging clinician reflection and shared learning between general practitioner and student. DISCUSSION: Student perspectives of value-adding on general practice placements, and a deeper understanding of these learning environments, may enable general practice supervisors to facilitate placements that maximise these benefits.

Don't Shoot Yourself in the Foot: Reconstruction of a Through-and-Through Gunshot Wound of the Foot.

A 69-year-old man presented with an accidental, self-inflicted, through-and-through left foot gunshot wound. An entry wound on the dorsum of the foot was noted, with a larger exit wound on the plantar aspect. X-ray revealed comminuted fractures of the second, third, fourth, and fifth metatarsals with numerous foreign bodies. Immediate excisional debridement was performed, and negative-pressure wound therapy was applied. A second look was performed 48 hours later. Five days after initial debridement, a Kirschner wire was utilized for fixation of the second metatarsal fracture, and an external fixator applied to the fifth metatarsal due to extensive bone loss. A free gracilis muscle flap was used to fill the defect, with plans for a vascularized bone graft at a later date. The flap was tunneled through the wound to the plantar aspect of the foot, with an overlying split-thickness skin graft. The patient's postoperative course was uncomplicated, and secondary bone grafting was not required. The gracilis flap was used to reconstruct the bony and soft tissue defects, and secondary muscle fibrosis appeared to provide adequate skeletal support. The patient was full weight-bearing by 4 months and has since returned to his preoperative activities, baseline gait, and regular footwear. The free gracilis muscle flap may serve as a valuable reconstructive option for through-and-through gunshot wounds to the foot, restoring both contour and function, while eliminating the need for secondary bone grafting.

Intracellular-signaling tumor-regression modeling of the pro-apoptotic receptor agonists dulanermin and conatumumab.

Dulanermin (rhApo2L/TRAIL) and conatumumab bind to transmembrane death receptors and trigger the extrinsic cellular apoptotic pathway through a caspase-signaling cascade resulting in cell death. Tumor size time series data from rodent tumor xenograft (COLO205) studies following administration of either of these two pro-apoptotic receptor agonists (PARAs) were combined to develop a intracellular-signaling tumor-regression model that includes two levels of signaling: upstream signals unique to each compound (representing initiator caspases), and a common downstream apoptosis signal (representing executioner caspases) shared by the two agents. Pharmacokinetic (PK) models for each drug were developed based on plasma concentration data following intravenous and/or intraperitoneal administration of the compounds and were used in the subsequent intracellular-signaling tumor-regression modeling. A model relating the PK of the two PARAs to their respective and common downstream signals, and to the resulting tumor burden was developed using mouse xenograft tumor size measurements from 448 experiments that included a wide range of dose sizes and dosing schedules. Incorporation of a pro-survival signal--consistent with the hypothesis that PARAs may also result in the upregulation of pro-survival factors that can lead to a reduction in effectiveness of PARAs with treatment--resulted in improved predictions of tumor volume data, especially for data from the long-term dosing experiments.

Plasma pharmacokinetics and oral bioavailability of 3,4,5,6-tetrahydrouridine, a cytidine deaminase inhibitor, in mice.

Cytidine analogues such as cytosine arabinoside, gemcitabine, decitabine, 5-azacytidine, 5-fluoro-2'-deoxycytidine and 5-chloro-2'-deoxycytidine undergo rapid catabolism by cytidine deaminase (CD). 3,4,5,6-tetrahydrouridine (THU) is a potent CD inhibitor that has been applied preclinically and clinically as a modulator of cytidine analogue metabolism. However, THU pharmacokinetics has not been fully characterized, which has impaired the optimal preclinical evaluation and clinical use of THU. Therefore, we characterized the THU pharmacokinetics and bioavailability in mice. Mice were dosed with THU iv (100 mg/kg) or po (30, 100, or 300 mg/kg). Plasma and urine THU concentrations were quantitated with a validated LC-MS/MS assay. Plasma pharmacokinetic parameters were calculated compartmentally and non-compartmentally. THU, at 100 mg/kg iv had a 73 min terminal half-life and produced plasma THU concentrations >1 microg/ml, the concentration shown to effectively block deamination, for 4 h. Clearance was 9.1 ml/min/kg, and the distribution volume was 0.95 l/kg. Renal excretion accounted for 36-55% of the THU dose. A three-compartment model fit the iv THU data best. THU, at 100 mg/kg po, produced a concentration versus time profile with a plateau of approximately 10 mug/ml from 0.5-3 h, followed by a decline with an 85 min half-life. The oral bioavailability of THU was approximately 20%. The 20% oral bioavailability of THU is sufficient to produce and sustain, for several hours, plasma concentrations that inhibit CD. This suggests the feasibility of using THU to decrease elimination and first-pass metabolism of cytidine analogues by CD. THU pharmacokinetics are now being evaluated in humans.