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Needham D.,Duke University | Park J.-Y.,DUMC | Park J.-Y.,Jefferson Lab | Wright A.M.,Amgen Inc. | Tong J.,Duke University
Faraday Discussions | Year: 2012

This paper describes how we have used material science, physical chemistry, and some luck, to design a new thermal-sensitive liposome (the low temperature sensitive liposome (LTSL)) that responds at clinically attainable hyperthermic temperatures releasing its drug in a matter of seconds as it passes through the microvasculature of a warmed tumor. The LTSL is composed of a judicial combination of three component lipids, each with a specific function and each affecting specific material properties, including a sharp thermal transition and a rapid on-set of membrane permeability to small ions, drugs and small dextran polymers. Experimentally, the paper describes how bilayer-concentration changes involving the lysolipid and the presence or absence of DSPE-PEG2000 affect both the lipid transition temperature and the drug release. While the inclusion of 4 mol% DSPE-PEG2000 raises the transition temperature peak (Tm) by about 1 °C, the inclusion of 5.0, 9.7, 12.7 and 18.0 mol% MSPC slightly lowered this peak back to 41.7°C, while not further broadening the peak breadth. As for drug release, in the absence of MSPC, the encapsulated doxorubicin-citrate is hardly released at all. Increasing the composition of MSPC in the lipid mixture (5.0, 7.4, 8.5 and 9.3 mol% MSPC) shows faster and faster initial doxorubicin release rates, with 8.5 and 9.3 mol% MSPC formulations giving 80% of encapsulated drug released in 4 and 3 min, respectively. The Thermodox® formulation (9.7 mol% MSPC) gives 60% released in the first 20 s. The presence of PEG-lipid is found to be essential in order for the lysolipid-induced permeability to reach these very fast times. From drug and dextran release experiments, and estimates of the molecular and pore size, the conclusions are that: in order to induce lasting nanopores in lipid bilayers ∼10 nm diameter, they initially require the presence (from the solid phase structure) of grain boundary defects at the DPPC transition and the permeabilizing component(s) can either be a pore forming lysolipid/surfactant plus a PEG-lipid, or can be generated by a PEG-surfactant incorporated at ∼4-5 mol%. The final discussion is centered around the postulated defect structures that result in membrane leakage and the permeability of doxorubicin and H+ ions. This journal is © The Royal Society of Chemistry.

Mentz R.J.,Duke University | Fiuzat M.,DUMC | Wojdyla D.M.,Duke Clinical Research Institute | Chiswell K.,Duke Clinical Research Institute | And 3 more authors.
European Journal of Heart Failure | Year: 2012

Aims: Chronic obstructive pulmonary disease (COPD) is common in heart failure (HF) patients, yet the population is poorly characterized and associated with conflicting outcomes data. We aimed to evaluate the clinical characteristics and outcomes of HF patients with systolic dysfunction and COPD in a large acute HF registry. Methods and results: OPTIMIZE-HF (Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure) was a performance-improvement registry of patients hospitalized with HF (n 48 612), which included a pre-specified subgroup of patients (n 5,701) with 60-to 90-day follow-up. We performed a retrospective analysis of the clinical characteristics and outcomes (length of stay, and in-hospital and 60-day mortality) of patients with systolic dysfunction according to baseline COPD status. COPD was present in 25 of the patients. These patients had more co-morbidities compared with patients without COPD. They were less likely to receive a beta-blocker or angiotensin-converting enzyme inhibitor during hospitalization and at discharge (P < 0.001). COPD was associated with an increased median length of stay [5 days (interquartile range 38) vs. 4 days (interquartile range 37), P < 0.0001] and increased in-hospital all-cause and non-cardiovascular (CV) mortality, with rates of 4.5 vs. 3.7 (P 0.01) and 1.0 vs. 0.6 (P 0.01), respectively, for the two endpoints, but similar 60-day mortality (6.2 vs. 6.0, P 0.28). After risk adjustment, the in-hospital non-CV mortality remained increased (odds ratio 1.65, 95 confidence interval 1.122.41; P 0.01). Conclusion: The presence of COPD in HF patients with systolic dysfunction is associated with an increased burden of co-morbidities, lower use of evidence-based HF medications, longer hospitalizations, and increased in-hospital non-CV mortality, but similar post-discharge mortality. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2012.

Finlen Copeland C.A.,DUMC | Davis W.A.,DUMC | Snyder L.D.,DUMC | Banks M.,Duke Clinical Research Institute | And 4 more authors.
Journal of Heart and Lung Transplantation | Year: 2011

Background: The optimal approach to cytomegalovirus (CMV) prevention after lung transplantation is controversial. We recently completed a prospective, randomized, placebo-controlled study of CMV prevention in lung transplantation that demonstrated the short-term efficacy and safety of extending valganciclovir prophylaxis to 12 months vs 3 months of therapy. In the current analysis, we monitored a single-center subset of patients enrolled in the CMV prevention trial to determine if extended prophylaxis conferred a sustained long-term benefit and to assess its hematologic safety. Methods: The sub-analysis included 38 randomized patients from Duke University Medical Center. All patients underwent consistent serial serum CMV monitoring and surveillance bronchoscopies. CMV was defined by viremia (< 500 CMV DNA copies/ml) or pneumonitis. The safety assessment included a review of all complete blood counts obtained from transplant onward. Results: During a mean follow-up of 3.9 years in each group, extended-course compared with short-course prophylaxis provided a sustained protective benefit with a lifetime CMV incidence of 12% vs 55%, respectively (hazard ratio, 0.13; 95% confidence interval, 0.030.61; p = 0.009), an effect that persisted after adjustment for clinical risk factors. Patients in each group underwent a comparable number of peripheral blood draws and bronchoscopies. Post-transplant white blood cell, neutrophil, and platelet counts were similar between each treatment group during the course of follow-up. Conclusion: Extending valganciclovir prophylaxis to 12 months provides a durable long-term CMV protective benefit compared with short-course therapy, without increasing adverse hematologic effects. © 2011 International Society for Heart and Lung Transplantation. All rights reserved.

Watters T.S.,Duke University | Cardona D.M.,DUMC | Menon K.S.,Duke University | Vinson E.N.,Duke University | And 2 more authors.
American Journal of Clinical Pathology | Year: 2010

It is estimated that 35% of total hip arthroplasties (THAs) involve a second-generation metal-on-metal (MOM) prosthesis. A novel complication has appeared in a subset of patients with MOM THAs that is described as an aseptic, lymphocyte-dominated vasculitis-associated lesion (ALVAL). The clinical features of ALVAL are nonspecific, but patients complain of pain and may develop "pseudotumors." It is hypothesized that metal ions are released from the prosthesis and form haptens with native proteins that elicit a type IV hypersensitivity response in the local soft tissues. Histopathologic descriptions of ALVAL are similar to those of failed arthroplasty in general, with the addition of a dense perivascular inflammatory infiltrate that is the hallmark of ALVAL. We report 3 cases of ALVAL with clinical, radiographic, and histologic findings. Accurate assessment is crucial because an intraoperative diagnosis of chronic inflammation suggestive of ALVAL will necessitate a replacement of the prosthetic component surfaces. © American Society for Clinical Pathology.

Easley M.E.,Duke University | Adams Jr. S.B.,DUMC | Hembree W.C.,DUMC | DeOrio J.K.,Duke University
Journal of Bone and Joint Surgery - Series A | Year: 2011

▶ Most published reports related to total ankle arthroplasty have a fair to poor-quality level of evidence. ▶ Comparative studies with a fair to good-quality level of evidence suggest that total ankle arthroplasty provides equal pain relief and possibly improved function compared with ankle arthrodesis. ▶ On the basis of the current literature, survivorship of total ankle arthroplasty implants, when measured as the retention of metal components, ranges from 70% to 98% at three to six years and from 80% to 95% at eight to twelve years. ▶ Several investigators have argued that, in the evolution of total ankle arthroplasty, some obligatory reoperation without removal of the metal implants is anticipated; examples of reoperation include relief of osseous or softtissue impingement, improvement of alignment or stability of the foot and ankle, bone-grafting for cystic lesions, and/or polyethylene exchange. ▶ A successful return to low-impact, recreational sporting activities is possible after total ankle arthroplasty. Copyright © 2011 by The Journal of Bone and Joint Surgery, Incorporated.

Tsalik E.L.,DUMC | Jaggers L.B.,DUMC
American Journal of the Medical Sciences | Year: 2010

Incidental lung nodules can be due to a variety of etiologies. Management is guided by the most likely or urgent pathology, which is frequently malignancy in an elderly smoker. We present the case of a 62-year-old, long-time smoker, with an incidental lung nodule. Pursuit of the underlying etiology revealed disseminated cryptococcal and Mycobacterium avium intracellulare infections, which are most often seen in patients with advanced human immunodeficiency virusacquired immunodeficiency syndrome or other immunocompromise. This patient was ultimately determined to have idiopathic CD4 lymphocytopenia, a rare and poorly understood acquired immunodeficiency syndrome. Furthermore, Cryptococcus neoformans is well known to cause asymptomatic meningitis in immunocompetent individuals but is very rarely asymptomatic in the immunosuppressed, as was the case with this patient.

Pfeiffer C.D.,DUMC | Garcia-Effron G.,Public Health Research Institute | Zaas A.K.,DUMC | Perfect J.R.,DUMC | And 2 more authors.
Journal of Clinical Microbiology | Year: 2010

For Candida species, a bimodal wild-type MIC distribution for echinocandins exists, but resistance to echinocandins is rare. We characterized isolates from patients with invasive candidiasis (IC) breaking through ≥3 doses of micafungin therapy during the first 28 months of its use at our center: MICs were determined and hot-spot regions within FKS genes were sequenced. Eleven of 12 breakthrough IC cases identified were in transplant recipients. The median duration of micafungin exposure prior to breakthrough was 33 days (range, 5 to 165). Seventeen breakthrough isolates were recovered: FKS hot-spot mutations were found in 5 C. glabrata and 2 C. tropicalis isolates; of these, 5 (including all C. glabrata isolates) had micafungin MICs of >2 μg/ml, but all demonstrated caspofungin MICs of >2 μg/ml. Five C. parapsilosis isolates had wild-type FKS sequences and caspofungin MICs of 0.5 to 1 μg/ml, but 4/5 had micafungin MICs of >2 μg/ml. The remaining isolates retained echinocandin MICs of ≤2 μg/ml and wild-type FKS gene sequences. Breakthrough IC on micafungin treatment occurred predominantly in severely immunosuppressed patients with heavy prior micafungin exposure. The majority of cases were due to C. glabrata with an FKS mutation or wild-type C. parapsilosis with elevated micafungin MICs. MIC testing with caspofungin identified all mutant strains. Whether the naturally occurring polymorphism within the C. parapsilosis FKS1 gene responsible for the bimodal wild-type MIC distribution is also responsible for micafungin MICs of >2 μg/ml and clinical breakthrough or an alternative mechanism contributes to the nonsusceptible echinocandin MICs in C. parapsilosis requires further study. Copyright © 2010, American Society for Microbiology. All Rights Reserved.

Dorth J.A.,DUMC | Prosnitz L.R.,DUMC | Broadwater G.,Duke University | Diehl L.F.,Duke University | And 3 more authors.
International Journal of Radiation Oncology Biology Physics | Year: 2012

Purpose: While consolidation radiation therapy (i.e., RT administered after chemotherapy) is routine treatment for patients with early-stage diffuse large B-cell lymphoma (DLBCL), the role of consolidation RT in stage III-IV DLBCL is controversial. Methods and Materials: Cases of patients with stage III-IV DLBCL treated from 1991 to 2009 at Duke University, who achieved a complete response to chemotherapy were reviewed. Clinical outcomes were calculated using the Kaplan-Meier method and were compared between patients who did and did not receive RT, using the log-rank test. A multivariate analysis was performed using Cox proportional hazards model. Results: Seventy-nine patients were identified. Chemotherapy (median, 6 cycles) consisted of anti-CD20 antibody rituximab combined with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP; 65%); cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP; 22%); or other (13%). Post-chemotherapy imaging consisted of positron emission tomography (PET)/computed tomography (CT) (73%); gallium with CT (14%); or CT only (13%). Consolidation RT (median, 25 Gy) was given to involved sites of disease in 38 (48%) patients. Receipt of consolidation RT was associated with improved in-field control (92% vs. 69%, respectively, p = 0.028) and event-free survival (85% vs. 65%, respectively, p = 0.014) but no difference in overall survival (85% vs. 78%, respectively, p = 0.15) when compared to patients who did not receive consolidation RT. On multivariate analysis, no RT was predictive of increased risk of in-field failure (hazard ratio [HR], 8.01, p = 0.014) and worse event-free survival (HR, 4.3, p = 0.014). Conclusions: Patients with stage III-IV DLBCL who achieve negative post-chemotherapy imaging have improved in-field control and event-free survival with low-dose consolidation RT. © 2012 Elsevier Inc.

Lipkin M.E.,DUMC | Preminger G.M.,DUMC
Current Opinion in Urology | Year: 2012

Purpose of Review: To discuss the risk of radiation exposure to patients with nephrolithiasis. To review the risk factors for increased radiation exposure to patients during percutaneous nephrolithotomy (PNL) from fluoroscopy. To review the techniques to reduce patient radiation doses during PNL. Recent Findings: Patients with nephrolithiasis are at risk for significant radiation exposure from diagnostic imaging. Fluoroscopy used during surgical treatment of nephrolithiasis also contributes to patient radiation exposure. On average, PNL with fluoroscopy exposes patients to more radiation than a noncontrast computed tomography of the abdomen and pelvis. Risk factors for increased radiation during PNL include obesity, larger stone size and increased access tracts. Following the principles of As Low As Reasonably Achievable, use of air instead of contrast for retrograde pyelogram and use of ultrasound all reduce radiation exposure during PNL. Summary: It is important to be aware of the amount of radiation patients with nephrolithiasis receive. These patients are at risk for multiple imaging studies and multiple procedures during their lifetime. Whenever possible, the techniques outlined in this review should be implemented to reduce the amount of radiation to which patients are exposed during PNL. © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Wang B.,DUMC | Rao Y.-H.,DUMC | Inoue M.,DUMC | Hao R.,DUMC | And 7 more authors.
Nature Communications | Year: 2014

Reversible acetylation of α-tubulin is an evolutionarily conserved modification in microtubule networks. Despite its prevalence, the physiological function and regulation of microtubule acetylation remain poorly understood. Here we report that macrophages challenged by bacterial lipopolysaccharides (LPS) undergo extensive microtubule acetylation. Suppression of LPS-induced microtubule acetylation by inactivating the tubulin acetyltransferase, MEC17, profoundly inhibits the induction of anti-inflammatory interleukin-10 (IL-10), a phenotype effectively reversed by an acetylation-mimicking α-tubulin mutant. Conversely, elevating microtubule acetylation by inhibiting the tubulin deacetylase, HDAC6, or stabilizing microtubules via Taxol stimulates IL-10 hyper-induction. Supporting the anti-inflammatory function of microtubule acetylation, HDAC6 inhibition significantly protects mice from LPS toxicity. In HDAC6-deficient macrophages challenged by LPS, p38 kinase signalling becomes selectively amplified, leading to SP1-dependent IL-10 transcription. Remarkably, the augmented p38 signalling is suppressed by MEC17 inactivation. Our findings identify reversible microtubule acetylation as a kinase signalling modulator and a key component in the inflammatory response. © 2014 Macmillan Publishers Limited. All rights reserved.

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