The effect of coronal plane angulation on patient reported outcome measures of operatively treated distal femur fractures: A multi-center prospective evaluation.

OBJECTIVES: The goal of this trial was to determine whether coronal plane angulation affects functional and clinical outcomes after the fixation of distal femur fractures. DESIGN: Multicenter, randomized controlled trial SETTING: 20 academic trauma centers PATIENTS/PARTICIPANTS: 156 patients with distal femur fractures were enrolled. 123 patients were followed 12 months. There was clinical outcome data available for 105 patients at 3 months, 95 patients at 6 months and 81 patients at one year. INTERVENTION: Lateral locked plating or retrograde intramedullary nailing MAIN OUTCOME MEASUREMENTS: Radiographic alignment, functional scoring including SMFA, Bother Index, and EQ-5D. Clinical scoring of walking ability, need for ambulatory support and ability to manage stairs. RESULTS: At 3 months, there was no difference between groups (varus, neutral or valgus) with respect to any of the clinical functional outcome scores measured. At 6 months, compared to those with neutral alignment, patients with varus angulation had a worse Stair Climbing score (4.33 vs. 2.91, p = 0.05). At 12 months, the average patient with neutral or valgus alignment needed less ambulatory support than the average patient in varus. Walking distance ability was no different between the groups at any time point. With respect to the validated patient-based outcome scores, we found no statistical difference in in the SMFA, Bother, or EQ-5D between patients with valgus or varus mal-alignment and those with neutral alignment at any time point (p > 0.05). Regardless of coronal angulation, the SMFA trended towards lower (improved) scores over time, while EQ-5D scores for patients with varus angulation did not improve over time. CONCLUSIONS: Valgus angulation and neutral angulation may be better tolerated in terms of clinical outcomes like stair climbing and need for ambulatory support than varus angulation, though patient reported outcome measures like the SMFA, Bother Index and EQ-5D show no statistical significance. Most patients with distal femur fractures tend to improve during the first year after injury but many remain significantly affected at 12 months post injury.

Advances in inhaled technologies: understanding the therapeutic challenge, predicting clinical performance, and designing the optimal inhaled product.

Inhaled medicines are designed mainly to provide safe and efficacious treatment of respiratory diseases, offering the potential advantages of targeted drug delivery such as reduced onset time and increased therapeutic ratio. However, as a flipside of targeted drug delivery, drug levels in the relevant effect compartment cannot be easily assessed. In combination with technical challenges associated with aerosolizing and administering an inhaled medicine, this renders inhalation product development demanding in the regulatory aspect as well. Emerging technologies that could address some of these challenges include (i) mechanistic pharmacokinetic/pharmacodynamic (PK/PD) modeling, which in combination with experimental techniques such as positron emission tomography could provide information on local target engagement; (ii) patient-feedback features in combination with electronic monitoring, which may improve patient adherence as well as patient handling; and (iii) controlled-release formulations and nanotechnology-based formulations with high drug load, which may expand the scope of development of compounds and targets suitable for inhalation product development.

Missed opportunities for identifying primary HIV within genitourinary medical/HIV services.

To assess the ability of three genitourinary medical centres to clinically identify primary HIV infection (PHI). Cases of recently acquired HIV infection, identified using the Health Protection Agency (HPA) avidity assay on all HIV diagnoses from January to August 2009, were investigated by case-note review. Sixty-four individuals were identified as PHI using the HPA avidity assay. Of 64 individuals, 31 (48%) were identified clinically. Imperial College identified 8/26 (31%), Guys and St Thomas' 15/27 (56%) and Brighton 8/11 (73%). Clinical suspicion of PHI was associated with reported unprotected anal intercourse (P = 0.017), seroconversion symptoms (P = 0.0004), a negative HIV test within six months (P = 0.024) and avidity assay result availability (P = 0.0169). Seventy percent of PHI cases missed had a documented risk factor. Thirty-five percent of those clinically identified with PHI were documented as informed of the associated enhanced infectivity. Suspicion of PHI was low despite documented risk factors and recent HIV-negative antibody tests. Counselling to prevent onward transmission was suboptimal.

Outcome of periprosthetic distal femoral fractures following knee arthroplasty.

INTRODUCTION: The majority of periprosthetic fractures around the knee occur at the supracondylar region of the distal femur. Fixation of distal femoral fractures in osteoporotic bone with short segment remains a challenge, especially after total knee arthroplasty (TKA). Internal fixation of these fractures using locking plates has become popular. The purpose of this study was to evaluate a consecutive series of periprosthetic supracondylar femoral fractures treated with locked periarticular plate fixation with regard to surgical procedure, complications and clinical outcome. MATERIALS AND METHODS: From two academic trauma centres, 55 consecutive periprosthetic distal femoral fractures (Arbeitsgemeinschaft für Osteosynthesefragen/Orthopaedic Trauma Association, AO/OTA 33) were retrospectively identified as having been treated with locked plate fixation. Of these, 36 fractures in 35 patients (86.1% female) met the inclusion criteria. Patients had an average age of 73.2 years (range 54-95 years). Fixation constructs for plate length and working length were delineated. Nonunion, infection and implant failure were used as complication variables. Demographics were assessed. Outcome was addressed radiographically and clinically according to Kristensen et al.(1) by range of motion and pain. RESULTS: Twenty-five of 36 fractures (69.4%) healed after the index procedure. Eight of 36 fractures (22.2%) developed a nonunion with three fractures (8.3%) leading to hardware failure. Nine of the 36 patients (25%) were radiographically diagnosed with notching of the anterior femoral cortex. Regarding technical aspects, distance from the anterior flange of the femoral component to fracture was significantly shorter in patients with compared to without anterior notching (t=3.68, p=0.02). Patients who underwent submuscular plate insertion compared to an extensive lateral approach had a reduced nonunion risk (χ(2)=0.05). No difference in infection rate was found for submuscular procedures compared with open procedures (χ(2)=0.85). Range of motion was reduced in most of the patients and 13.5% had a persistent loss of extension of 5°. More than 77% of the patients reported no or only mild pain during the last office visit. Range of motion loss did not influence pain. Successful treatment according to Cain et al.(2) was achieved in 83%. Using Kristensen's(1) criteria, 56% of the knees had acceptable flexion. CONCLUSION: Operative fixation of periprosthetic distal femoral fractures after TKA continues to be challenging. Notching of the anterior femoral cortex should be avoided. Loss of reduction and high failure rates still occur with locked plating and may be related to underlying factors. Indirect reduction and submuscular plate insertion technique reduce nonunion risk.

Is the grass any greener? Canada to United States of America nurse migration.

AIM: Little or no attempt has been made to determine why nurses leave Canada, remain outside of Canada, or under what circumstances might return to Canada. The purpose of this study was to gain an understanding of Canadian-educated registered nurses working in the USA. DATA SOURCES: Data for this study include the 1996, 2000 and 2004 USA National Sample Survey of Registered Nurses and reports from the same time period from the Canadian Institute for Health Information. FINDINGS: This research demonstrates that full-time work opportunities and the potential for ongoing education are key factors that contribute to the migration of Canadian nurses to the USA. In addition, Canada appears to be losing baccalaureate-prepared nurses to the USA. DISCUSSION: These findings underscore how health care policy decisions such as workforce retention strategies can have a direct influence on the nursing workforce. Policy emphasis should be on providing incentives for Canadian-educated nurses to stay in Canada, and obtain full-time work while continuing to develop professionally. CONCLUSION: Findings from this study provide policy leaders with important information regarding employment options of interest to migrating nurses. STUDY LIMITATIONS: This study describes and contrasts nurses in the data set, thus providing information on the context of nurse migration from Canada to the USA. Data utilized in this study are cross-sectional in nature, thus the opportunity to follow individual nurses over time was not possible.

Lessons about sleepiness and driving from the Selby rail disaster case: R v Gary Neil Hart.

In April 2003, near the town of Selby in North Yorkshire, England, a motor vehicle went off the road to cause a train collision, killing 10 and injuring more than 70 people. The driver of the vehicle, Gary Neil Hart, had allegedly fallen asleep while driving, and was charged and subsequently convicted of causing death by dangerous driving. Evidence from an expert witness was led by the prosecution to establish that Hart had in fact fallen asleep, and that prior to falling asleep, he knew (or ought to have known) that he was at risk of falling asleep but nevertheless continued to drive. The issue of whether and to what extent individuals are aware that they are about to fall asleep has significant implications for criminal prosecutions. Generally, the definition of a criminal offense includes a mental element such as intent or knowledge. Therefore, it is imperative that issues such as whether in every individual there is forewarning of sleep and the degree to which individuals are able to self-assess their ability to continue driving under conditions of extreme sleepiness must be resolved. Sleepiness is now regarded as the largest identifiable and preventable cause of accidents in all modes of transportation. Litigation for such accidents is likely to increase, and therefore it is of great importance that further research be undertaken to examine the process of falling asleep, especially the subjective experiences immediately preceding sleep.

Building health services research capacity in nursing: views from members of nursing's leadership [interview by Candice Cook Bowman and Deborah Gardner].

BACKGROUND: Despite a short history that dates back to the 1960s, health services research (HSR) has become an important force in shaping the delivery system in the current health care environment. Nursing has been noticeably absent from this endeavor, and if it does not increase its presence, it risks missing an important opportunity to influence future directions of health care delivery. PURPOSE: Our purpose was to evaluate the state of nursing's HSR contributions and to consider ways to increase its capacity in this arena. METHOD: An interview with four members from nursing's leadership was conducted. DISCUSSION: Nurses can increase the capacity by becoming better collaborators with those who are currently contributing to HSR, both nurses and members of other healthcare disciplines. Also, by reshaping undergraduate and graduate curricula and creating mentorships, nursing can increase its involvement through an informed workforce. CONCLUSIONS: Solutions that were offered in this discussion are presented.

Surgical treatment of olecranon fractures.

Fractures of the olecranon are common injuries with no single accepted treatment. Numerous clinical factors and biomechanical studies guide the surgeon in determining a treatment plan. The goals of surgical management include anatomical reduction and stable fixation, which allow early range of motion of the elbow joint. Numerous fixation methods have been described and include screw fixation, cerclage wiring, modified tension-band wiring, and plate fixation. The surgical technique depends on a combination of patient factors, the fracture pattern, and the mechanical stability of the fixation construct. Postoperative rehabilitation includes early active range-of-motion exercises and follows clinical and radiographic healing. Complications are related to the fracture, choice of implant, and surgical technique.

Percutaneous stabilization of U-shaped sacral fractures using iliosacral screws: technique and early results.

PURPOSE: To present the technique and early results of percutaneous stabilization of U-shaped sacral fractures with attention to neurologic recovery and maintenance of fracture reduction of the sacrum. DESIGN: Retrospective clinical study. SETTING: Level I trauma center. PATIENTS: During a thirty-eight-month period, 442 patients with pelvic ring disruptions were treated at a Level I trauma center. Thirteen (2.9 percent) of these patients had displaced U-shaped sacral fractures treated with percutaneous stabilization. INTERVENTION: Fracture stabilization was accomplished using fluoroscopically guided iliosacral screws inserted percutaneously with the patient positioned supine. Neurodiagnostic monitoring was not used during screw insertions. This technique was limited to patients with sacral kyphotic deformities, which allowed in situ fixation. Sacral neurologic decompression was not performed. MAIN OUTCOME MEASUREMENTS: Fracture healing and the stability of fixation were assessed on inlet and outlet radiographs and a lateral sacral view. Detailed neurologic examinations were performed at injury and at follow-up. RESULTS: The sacral fractures were classified based on plain pelvic radiographs and computed tomography scans and included one Type 1, eight Type 2, and four Type 3 fracture patterns. Twenty-five fully threaded cancellous 7.0-millimeter cannulated screws were used. Eleven patients had bilateral screw fixations; one patient had unilateral double screw fixation; and one patient had unilateral single screw fixation. Operative time for screw insertion averaged forty-eight minutes, with 2.1 minutes of fluoroscopy per screw. Accurate screw insertions without neuroforaminal or sacral spinal canal violations were confirmed in all patients with postoperative pelvic plain radiographs and computed tomography scans. A paradoxical inlet view of the upper sacral segments on the injury anteroposterior pelvis was seen in twelve of thirteen patients (92.3 percent), and the diagnosis was confirmed with the lateral sacral view in all thirteen (100 percent) patients. Preoperatively, sacral kyphosis averaged 29 degrees, whereas postoperative sacral kyphosis averaged 28 degrees. Screw disengagement occurred without a change in position of the sacral fracture in the only patient treated with a single unilateral screw. All fractures healed clinically and radiographically. Of the nine patients with preoperative neurologic abnormalities, two (22 percent) patients had residual neurologic deficits. Both patients had associated multiple level lumbar burst fractures, which required decompression and instrumented stabilization. CONCLUSIONS: These sacral fractures are rare and occur after significant spinal axial loading. A paradoxic inlet view of the upper sacrum on the anteroposterior plain pelvic radiograph heralds the diagnosis. Delayed diagnosis is avoided by a high clinical suspicion, early lateral sacral radiographs, and pelvic computed tomography scans. Surgical stabilization may assist in early mobilization of the patient from recumbency and prevents progressive deformity with associated nerve root injury. Percutaneous fixation diminishes potential blood loss and operative times, yet still allows subsequent sacral decompression of the local neural elements using open techniques when necessary. Early percutaneous iliosacral screw fixation is effective treatment for these injuries.

Regulation of bleomycin-induced DNA breakage and chromatin structure in lung endothelial cells by integrins and poly(ADP-ribose) polymerase.

Activation of endothelial cell integrins inhibits DNA breakage by diverse agents, including the DNA-damaging agent bleomycin. DNA breaks activate nuclear poly(ADP-ribose) polymerase (PARP), which regulates chromatin structure and DNA repair. We determined the role of PARP in suppression of bleomycin genotoxicity by integrins using wild-type and PARP knockout mouse lung endothelial cells (MLEC), and the PARP inhibitor, 3-aminobenzamide (3AB). Activation of beta1 integrins by antibody clustering enhanced the sensitivity of wild-type nuclei to digestion with micrococcal nuclease and deoxyribonuclease I, indicating that chromatin structure was altered. 3AB blocked this effect. Knockout and 3AB-treated wild-type MLEC were hypersensitive to deoxyribonuclease I compared with wild-type cells, demonstrating that PARP regulates chromatin structure. Integrin clustering reduced the hypersensitivity of knockout cells, suggesting additional, PARP-independent mechanisms that inhibit nuclease interaction with chromatin. Bleomycin caused DNA breakage in wild-type and knockout MLEC. Breaks were eliminated after 60 min incubation of wild-type cells in drug-free medium, whereas 3AB or PARP knockout inhibited DNA repair. Integrin clustering protected wild-type cells from DNA breakage, and 3AB and PARP knockout inhibited this protection. Bleomycin caused large increases in PARP activity in wild-type but not knockout MLEC, and integrin clustering inhibited the activation of PARP. The results indicate that the antigenotoxic effects of integrin activation require PARP and that integrins alter chromatin structure by PARP-dependent and -independent mechanisms.

Duration of action of inhaled vs. Intravenous beta(2)-adrenoceptor agonists in an anaesthetized guinea-pig model.

We compared the duration of action of the short-acting alpha(2)-adrenoceptor agonist salbutamol and the long-acting alpha(2)-adrenoceptor agonists salmeterol and formoterol when administered iv or by inhalation in a histamine-induced bronchoconstriction model in the guinea-pig. Following aerosol dosing, maximal bronchoprotector effects were seen for salbutamol, salmeterol and formoterol at concentrations of 1 mg/ml, 100 microg/ml and 30 microg/ml respectively, giving a potency order of formoterol > salmeterol > salbutamol. All displayed similar maximum effects in this system. A maximal concentration of salbutamol showed bronchoprotection at 1 h but not at 3 h post-dosing whereas maximal concentrations of formoterol and salmeterol showed protection up to 5 h post-aqueous-aerosol dosing, giving a duration order of salmeterol > formoterol > salbutamol. All three alpha(2)-adrenoceptor agonists showed dose-dependent bronchoprotection and duration of action following intravenous administration; salbutamol and salmeterol were equipotent and both were less potent than formoterol. Bronchoprotection obtained with sub-maximal concentrations of all three alpha(2)-adrenoceptor agonists faded within 30 min following iv administration, but this could be extended by increasing the doses. These results demonstrate that the route of administration is important in determining the duration of action of alpha(2)-adrenoceptor agonists in the lung. Furthermore, such findings lend support to the suggestion that the physico-chemical characteristics of salmeterol govern its duration of action rather than sustained binding of this agonist to a alpha(2)-adrenoceptor exo-site.

UCN-01 and camptothecin induce DNA double-strand breaks in p53 mutant tumor cells, but not in normal or p53 negative epithelial cells.

Previous research has shown synergistic growth inhibition between UCN-01 and camptothecin (CPT) in tumor cells with mutant p53 versus tumor cells with wild-type p53. To determine the possible role of p53 in this drug combination, we tested the hypothesis that the synergistic growth inhibition is due to the absence of p53, and can result from the induction of DNA double-strand breaks (DSBs). Experiments were performed with the use of normal human mammary epithelial cells (HMEC); HMEC transfected with HPV16 E6 protein which inactivates p53 (HE6), or p53-mutant MDA-MB-231 tumor cells. CPT, UCN-01, or a 1:1 combination of both, in either HMEC or HE6 cells did not induce DSBs. In contrast, simultaneous treatment of MDA-MB-231 cells with both UCN-01 and CPT induced significant levels of DSBs while treatment with either drug alone did not. While UCN-01 was surprisingly potent against HMEC, the growth inhibition was only additive between UCN-01 and CPT against these cells. HE6 cells were much less sensitive than HMEC to UCN-01 and slightly less sensitive to the combined treatment with UCN-01 and CPT. The drug combination was synergistic against HE6 cells, due to their lower sensitivity to UCN-01. Unlike what was observed previously in MDA-MB-231 cells, UCN-01 did not abrogate CPT-induced inhibition of DNA synthesis in either HMEC or HE6 cells. These data indicate that synergistic growth inhibition by UCN-01 and CPT against p53 mutant MDA-MB-231 tumor cells may be due to induction of DSBs however the loss of p53 function alone does not sensitize normal cells to the combination of both drugs.

Enhancement of camptothecin-induced cytotoxicity with UCN-01 in breast cancer cells: abrogation of S/G(2) arrest.

PURPOSE: To determine the ability of UCN-01 to abrogate the cell cycle arrest induced by camptothecin (CPT) in tumor cells that lack p53 function, and therefore enhance the cytotoxicity of CPT in these cells in relation to normal cells with wild-type p53. METHODS: The responses of MDA-MB-231 and GI 101A breast cancer cells were compared to those of normal bovine endothelial cells. Cytotoxicity was assessed by the MTT assay, and the resulting data were modeled using median-effect analysis. Inhibition of DNA synthesis was determined by loss of [(3)H]thymidine incorporation, and cell cycle status was determined by flow cytometric analysis of propidium-iodide-stained nuclei. RESULTS: UCN-01, a specific inhibitor of protein kinase C (PKC) presently in clinical trials, abrogated CPT-induced activation of S and G(2) checkpoints in human MDA-MB-231 and GI 101A breast carcinoma cells, both of which are mutants for the p53 gene. This abrogation occurred with the use of sublethal doses (100 nM) of UCN-01 and correlated with the enhancement of CPT-induced cytotoxicity. Median-effect analysis showed that synergistic cytotoxic interactions existed between CPT and UCN-01 against these tumor cells. In normal cells, however, abrogation of the S phase arrest caused accumulation in G(0)/G(1) phase, perhaps by the presence of wild-type p53 activity, with no change in CPT-induced cytotoxicity. CONCLUSION: We have shown previously that the cytotoxicity of CPT is correlated with cell cycle response in normal and tumor cells. Low doses of CPT arrest cells in the G(2)/M phase and inhibit DNA synthesis, but higher doses cause arrest of cells in S phase. Thus modulation of events at the S and G(2) checkpoints may provide an opportunity to enhance CPT-induced cytotoxicity in tumor cells. The results of this study indicate that UCN-01 enhances the progression of tumor cells through S phase thus greatly increasing CPT-induced cytotoxicity. Normal cells, however, are able to arrest in G(0)/G(1) and thus avoid the increased toxicity induced by CPT. Our findings suggest potential usefulness of combining UCN-01 in topoisomerase I inhibitor-based drug therapy for the treatment of breast cancer with a dysfunctional p53 gene.

Antiangiogenic potential of camptothecin and topotecan.

PURPOSE: To determine the inhibitory nature of sublethal doses of camptothecin (CPT) and topotecan (TPT) treatments on normal human endothelial cells in vitro, as well as the in vivo antiangiogenic activity as compared to another antiangiogenic compound, TNP-470 and to a nonspecific cytotoxic agent, cisplatin. METHODS: Growth inhibition was determined by the crystal violet assay to measure relative cell numbers. (3)H-thymidine uptake was used to determine the inhibitory effect of CPT and TPT on DNA synthesis in vitro. Cell viability was determined using trypan blue exclusion assays. Cell cycle response to CPT was determined by flow cytometric analysis of propidium iodide-stained nuclei. In vivo inhibition of angiogenesis was determined by the disc angiogenesis system (DAS), where surgical sponge discs were placed subcutaneously in the rat dorsum and the ability of systemic treatment with liposomal CPT (LCPT), TPT, TNP-470 or cisplatin to inhibit vascular growth into the discs was evaluated. Quantitation of vascular growth was determined using toluidine blue staining of sectioned discs followed by digital image analysis. RESULTS: Treatment with 50 nM CPT or TPT inhibited human umbilical venular endothelial cell (HUVEC) growth as shown by crystal violet staining, but was not cytotoxic to the cells. This was evidenced by the fact that cell numbers did not increase or decrease with treatment, but remained static while cells were viable for over 96 h posttreatment. (3)H-thymidine uptake in HUVEC was inhibited as early as 5 min, reached a maximum inhibition at 24 h and lasted over 96 h posttreatment. Cell cycle analysis of CPT-treated HUVEC showed arrest in S-phase at 12 h with a concurrent decrease in population of cells in G(1). Accumulation of cells at the G(2)/M-phase was discernible at 24 h along with the S-phase inhibition. Treatment of rats with 1 mg/kg LCPT or TPT every other day for 14 days resulted in approximately 30% inhibition of vascular growth into the discs. This inhibition was similar to the inhibition seen with TNP-470, an established and potent angiogenic inhibitor. In contrast, cisplatin was not as effective in inhibiting vascular growth into the discs. CONCLUSIONS: In this work we showed that CPT and TPT inhibit human endothelial cell growth in vitro in a non-cytotoxic manner and that this inhibition lasts more than 96 h after drug removal. We also showed that LCPT and TPT, unlike a nonspecific cytotoxic agent, cisplatin, are as effective as TNP-470 in inhibiting angiogenic growth in the in vivo disc angiogenesis model. From this observation we propose that in addition to their proven tumoricidal activities, camptothecins may have an indirect in vivo antitumor effect mediated through the inhibition of angiogenesis.

Superior gluteal artery injury during iliosacral screw placement.

Percutaneous fixation of an unstable pelvic ring injury is becoming a popular method of pelvic stabilization. As posterior pelvic percutaneous techniques become more common, the possibility of iatrogenic complications increases. This case report describes an injury to the superior gluteal artery during percutaneous iliosacral screw insertion and the treatment of this potentially devastating injury.

A method to determine when active translocation of nonhuman primates is justified.

This article addresses translocation, or artificial dispersal, the movement of one or more organisms from one location to another, and focuses on the decisions to be made before translocation begins. Scientific, economic, or pragmatic reasons such as pest removal or conservation of biodiversity may account for undertaking translocation. When is translocation ethical, and how can that decision be determined? This article provides one quantitative and utilitarian method for evaluating these questions. Although this analysis may apply to any nonhuman species for which costs and benefits can be assessed, the examples in this article derive from the nonhuman primate literature.