Enhanced Drug Delivery to the Skin Using Liposomes.

BACKGROUND: Enhancing drug delivery to the skin has importance in many therapeutic strategies. In particular, the outcome in vascularized composite allotransplantation mainly depends on systemic immunosuppression to prevent and treat episodes of transplant rejection. However, the side effects of systemic immunosuppression may introduce substantial risk to the patient and are weighed against the expected benefits. Successful enhancement of delivery of immunosuppressive agents to the most immunogenic tissues would allow for a reduction in systemic doses, thereby minimizing side effects. Nanoparticle-assisted transport by low temperature-sensitive liposomes (LTSLs) has shown some benefit in anticancer therapy. Our goal was to test whether delivery of a marker agent to the skin could be selectively enhanced. METHODS: In an in vivo model, LTSLs containing doxorubicin (dox) as a marker were administered intravenously to rats that were exposed locally to mild hyperthermia. Skin samples of the hyperthermia treated hind limb were compared with skin of the contralateral normothermia hind limb. Tissue content of dox was quantified both via high-performance liquid chromatography and via histology in skin and liver. RESULTS: The concentration of dox in hyperthermia-treated skin was significantly elevated over both normothermic skin and liver. (P < 0.02). CONCLUSIONS: We show here that delivery of therapeutics to the skin can be targeted and enhanced using LTSLs. Targeting drug delivery with this method may reduce the systemic toxicity seen in a systemic free-drug administration. Development of more hydrophilic immunosuppressants in the future would increase the applicability of this system in the treatment of rejection reactions in vascularized composite allotransplantation. The treatment of other skin condition might be another potential application.

Automated measurement of microcirculatory blood flow velocity in pulmonary metastases of rats.

Because the lung is a major target organ of metastatic disease, animal models to study the physiology of pulmonary metastases are of great importance. However, very few methods exist to date to investigate lung metastases in a dynamic fashion at the microcirculatory level, due to the difficulty to access the lung with a microscope. Here, an intravital microscopy method is presented to functionally image and quantify the microcirculation of superficial pulmonary metastases in rats, using a closed-chest pulmonary window and automated analysis of blood flow velocity and direction. The utility of this method is demonstrated to measure increases in blood flow velocity in response to pharmacological intervention, and to image the well-known tortuous vasculature of solid tumors. This is the first demonstration of intravital microscopy on pulmonary metastases in a closed-chest model. Because of its minimized invasiveness, as well as due to its relative ease and practicality, this technology has the potential to experience widespread use in laboratories that specialize on pulmonary tumor research.

Bioburden after Staphylococcus aureus inoculation in type 1 diabetic rats undergoing internal fixation.

SUMMARY: Fracture stabilization in the diabetic patient is associated with higher complication rates, particularly infection and impaired wound healing, which can lead to major tissue damage, osteomyelitis, and higher amputation rates. With an increasing prevalence of diabetes and an aging population, the risks of infection of internal fixation devices are expected to grow. Although numerous retrospective clinical studies have identified a relationship between diabetes and infection, currently there are few animal models that have been used to investigate postoperative surgical-site infections associated with internal fixator implantation and diabetes. The authors therefore refined the protocol for inducing hyperglycemia and compared the bacterial burden in controls to pharmacologically induced type 1 diabetic rats after undergoing internal fracture plate fixation and Staphylococcus aureus surgical-site inoculation. Using an initial series of streptozotocin doses, followed by optional additional doses to reach a target blood glucose range of 300 to 600 mg/dl, the authors reliably induced diabetes in 100 percent of the rats (n = 16), in which a narrow hyperglycemic range was maintained 14 days after onset of diabetes (mean ± SEM, 466 ± 16 mg/dl; coefficient of variation, 0.15). With respect to their primary endpoint, the authors quantified a significantly higher infectious burden in inoculated diabetic animals (median, 3.2 × 10 colony-forming units/mg dry tissue) compared with inoculated nondiabetic animals (7.2 × 10 colony-forming units/mg dry tissue). These data support the authors' hypothesis that uncontrolled diabetes adversely affects the immune system's ability to clear Staphylococcus aureus associated with internal hardware.

Anti-hypotensive treatment and endothelin blockade synergistically antagonize exercise fatigue in rats under simulated high altitude.

Rapid ascent to high altitude causes illness and fatigue, and there is a demand for effective acute treatments to alleviate such effects. We hypothesized that increased oxygen delivery to the tissue using a combination of a hypertensive agent and an endothelin receptor A antagonist drugs would limit exercise-induced fatigue at simulated high altitude. Our data showed that the combination of 0.1 mg/kg ambrisentan with either 20 mg/kg ephedrine or 10 mg/kg methylphenidate significantly improved exercise duration in rats at simulated altitude of 4,267 m, whereas the individual compounds did not. In normoxic, anesthetized rats, ephedrine alone and in combination with ambrisentan increased heart rate, peripheral blood flow, carotid and pulmonary arterial pressures, breathing rate, and vastus lateralis muscle oxygenation, but under inspired hypoxia, only the combination treatment significantly enhanced muscle oxygenation. Our results suggest that sympathomimetic agents combined with endothelin-A receptor blockers offset altitude-induced fatigue in rats by synergistically increasing the delivery rate of oxygen to hypoxic muscle by concomitantly augmenting perfusion pressure and improving capillary conductance in the skeletal muscle. Our findings might therefore serve as a basis to develop an effective treatment to prevent high-altitude illness and fatigue in humans.

Factors associated with transfer of hand injuries to a level 1 trauma center: a descriptive analysis of 1147 cases.

BACKGROUND: The transfer of patients with hand injuries involves a commitment of substantial resources, emphasizing the importance of understanding factors that may influence referral patterns. Anecdotal experience suggests that the likelihood of transfer increases during nights and weekends. This study aimed to analyze patterns of hand trauma transfers to Duke University Medical Center with respect to timing and patient insurance status. METHODS: The authors performed a retrospective chart review and analysis of 1147 consecutive patient transfers from 2005 to 2010 at a single level 1 university trauma center. Data categories included timing of transfer, patient demographics, insurance status, diagnosis, and procedures performed. Statistical analysis was performed using SAS software (SAS Institute Inc., Cary, N.C.). RESULTS: Of the patient sample, 39.8 percent was female, 30 percent were African American, and 57.3 percent were white. Contrary to our expectations, transfers were more likely during the day (p = 0.0001). Likewise, patients were more likely to present on weekdays than on weekends (p = .001). Although uninsured patients were not disproportionately represented overall, they were more frequently transferred at night (p = 0.0001), despite having the same complexity of injuries as privately insured patients. Conversely, patients with private insurance were less likely to be transferred at night (p = 0.0001). CONCLUSIONS: Similar to studies in other surgical specialties, this analysis demonstrates significant associations between insurance status and hand injury transfer patterns. The current climate, including declining numbers of surgeons willing to provide emergency hand care, diminishing reimbursements, and an expanding uninsured patient population, threatens to exacerbate these concerning trends in trauma patient management.

Vascularized fibula-based physis transfer for pediatric proximal humerus reconstruction.

UNLABELLED: Free vascularized fibular transfer has become a standard procedure in upper extremity reconstruction after resection of osteogenic tumors. The authors present two rare pediatric cases of high-grade osteosarcoma resection of the proximal humerus. A free vascularized fibula autograft including the physis based on the anterior tibial artery and vein was used for reconstruction in a delayed (case 1) and immediate (case 2) approach. The main focus of the article is to describe the surgical technique, which is also presented in a series of intraoperative videos. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, V.

Automated measurement of blood flow velocity and direction and hemoglobin oxygen saturation in the rat lung using intravital microscopy.

Intravital microscopy of the pulmonary microcirculation in research animals is of great scientific interest for its utility in identifying regional changes in pulmonary microcirculatory blood flow. Although feasibility studies have been reported, the pulmonary window can be further refined into a practical tool for pharmaceutical research and drug development. We have established a method to visualize and quantify dynamic changes in three key features of lung function: microvascular red blood cell velocity, flow direction, and hemoglobin saturation. These physiological parameters were measured in an acute closed-chest pulmonary window, which allows real-time images to be captured by fluorescence and multispectral absorption microscopy; images were subsequently quantified using computerized analysis. We validated the model by quantifying changes in microcirculatory blood flow and hemoglobin saturation in two ways: 1) after changes in inspired oxygen content and 2) after pharmacological reduction of pulmonary blood flow via treatment with the ß1 adrenergic receptor blocker metoprolol. This robust and relatively simple system facilitates pulmonary intravital microscopy in laboratory rats for pharmacological and physiological research.

Acute carpal tunnel syndrome secondary to iatrogenic hemorrhage. A case report.

Carpal tunnel syndrome is a common compression neuropathy of the median nerve. Acute carpal tunnel syndrome (aCTS) is rare, associated with a variety of conditions. In this case report we present a patient who developed aCTS and volar forearm compartment syndrome after a radial artery line placement, while receiving intravenous heparin. The patient underwent immediate forearm fasciotomy and surgical release for restoration of nerve function, which resulted in improved hand function and mild residual median nerve neuropathy. There is controversy whether to discontinue or not anticoagulation in a patient with aCTS. In our patient, heparin therapy was restarted on the second postoperative day.