Synthesis and characterization of dendrimer-stabilized nanoparticles

It has been posited that different synthetic conditions, such as use of amine-terminated rather than hydroxyl-terminated PAMAM dendrimers, may result in the production of different species of nanoparticles, namely dendrimer stabilized nanoparticles (DSNs) rather than dendrimer encapsulated nanoparticles (DENs). Although DENs have been well studied, DSNs have received little attention because they are larger, less uniformly synthesized, and probably catalytically inactive. Nonetheless, we believe that an understanding of these nanoparticle systems requires knowledge of all possible species being formed. Moreover, we hope that better synthetic control of DSNs may allow for new applications. To this end, we have optimized literature procedures to form gold DSNs smaller than 2 nm. Two techniques, aqueous-organic extraction and transmission electron microscopy staining, were explored for their utility in differentiating the two species (DENs and DSNs). UV-Vis absorption spectroscopy indicates that extraction serves as a useful qualitative method for identifying the presence of a significant proportion of DSNs in a solution of nanoparticles. If reproducibility can be established, we believe this technique could be made quantitative. Perfection of a washing step to remove excess thiols would allow for corroboration of current evidence using transmission electron microscopy (TEM) images. Attempts to stain the dendrimer for TEM using uranyl acetate and phosphotungstic acid were unable to match the quality of currently published data, although some progress was made in removing prohibitive stain contamination. We outline several experimental changes that may result in this technique yet proving useful.Chemistr

Curriculum and Instructional Methods for Drug Information, Literature Evaluation, and Biostatistics: Survey of U.S. Pharmacy Schools

BACKGROUND: The drug information curriculum in US colleges of pharmacy continues to evolve. The American College of Clinical Pharmacy (ACCP) Drug Information Practice and Research Network (DI PRN) published an opinion paper with specific recommendations regarding drug information education in 2009. Adoption of these recommendations has not been evaluated. OBJECTIVE: To assess which recommendations made in the ACCP DI PRN opinion paper are included in US pharmacy school curricula and characterize faculty qualifications, educational methods, and recent changes in drug information education. METHODS: An electronic survey was designed using the ACCP DI PRN opinion paper and the Accreditation Council for Pharmacy Education standards and guidelines for accreditation of PharmD programs in the US. Survey questions addressed curricular content within the following categories: drug information, literature evaluation, and biostatistics. A letter including the online survey link was sent via email to the dean of each US college/school of pharmacy (N = 128). Recipients were instructed to forward the email to the individual at their institution who was the most knowledgeable about the content and methodology used for didactic drug information education. RESULTS: Sixty-four responses were included in the final analysis. Of the 19 ACCP DI PRN minimum core concepts, 9 (47%) were included in curricula of all responding institutions; 14 of 19 (74%) were included in curricula for all but 1 institution. In contrast, 5 of 16 concepts (31%) were not formally taught by a number of institutions. Many respondents noted an increased focus on evidence-based medicine, medication safety, and informatics. CONCLUSIONS: Although a survey of drug information curricula documented substantial inclusion of the essential concepts presented in the ACCP DI PRN opinion paper, room for improvement remains in drug information curricula in US colleges of pharmacy

Original article Sirt1-deficient mice exhibit an altered cartilage phenotype

tObjective: We previously demonstrated that Sirt1 regulates apoptosis in cartilage in vitro. Here weattempt to examine in vivo cartilage homeostasis, using Sirt1 total body knockout (KO) mice.Method: Articular cartilage was harvested from hind paws of 1-week and 3-week-old mice carrying wildtype (WT) or null Sirt1 gene. Knees of Sirt1 haploinsufficient mice also were examined, at 6 months. Jointcartilage was processed for histologic examination or biochemical analyses of chondrocyte cultures.Results: We found that articular cartilage tissue sections from Sirt1 KO mice up to 3 weeks of age exhibitedlow levels of type 2 collagen, aggrecan, and glycosaminoglycan content. In contrast, protein levels of MMP-13 were elevated in the Sirt1 KO mice, leading to a potential increase of cartilage breakdown, alreadyshown in the heterozygous mice. Additional results showed elevated chondrocyte apoptosis in Sirt1 KOmice, as compared to WT controls. In addition to these observations, PTP1b (protein tyrosine phosphataseb) was elevated in the Sirt1 KO mice, in line with previous reports.Conclusion: The findings from this animal model demonstrated that Sirt1 KO mice presented an alteredcartilage phenotype, with an elevated apoptotic process and a potential degradative cartilage process

Comparison of the prognostic value of tumour and patient related factors in patients undergoing potentially curative surgery for colon cancer

<b>Aim</b>: To comprehensively compare the prognostic value of tumour and patient-related factors in patients undergoing curative surgery for colon cancer. <b>Methods</b>: From a database of 287 patients who underwent elective resection between 1997-2005, tumour factors including stage and host factors including systemic inflammatory response (modified Glasgow Prognostic Score (mGPS)) were identified. <b>Results</b>: Median follow-up was 65 months. Over this time period 125 patients died, 80 from cancer. On multivariate analysis of all significant patient and tumour related factors, Dukes stage (P<0.01), vascular invasion (P<0.01), and the mGPS (P<0.01) were independently associated with cancer-survival. Of the patient-related factors, age (P<0.01), haemoglobin (P<0.01), white-cell (P<0.01), neutrophil (P<0.01) and platelet (P<0.01) counts and alkaline phosphatase (P<0.01) were most significantly associated with the mGPS. <b>Conclusion</b>: In addition to tumour-related factors such as Dukes stage and vascular invasion, the pre-operative mGPS should be included to guide prognosis in patients undergoing curative resection for colon cancer

Original article Sirt1-deficient mice exhibit an altered cartilage phenotype

tObjective: We previously demonstrated that Sirt1 regulates apoptosis in cartilage in vitro. Here weattempt to examine in vivo cartilage homeostasis, using Sirt1 total body knockout (KO) mice.Method: Articular cartilage was harvested from hind paws of 1-week and 3-week-old mice carrying wildtype (WT) or null Sirt1 gene. Knees of Sirt1 haploinsufficient mice also were examined, at 6 months. Jointcartilage was processed for histologic examination or biochemical analyses of chondrocyte cultures.Results: We found that articular cartilage tissue sections from Sirt1 KO mice up to 3 weeks of age exhibitedlow levels of type 2 collagen, aggrecan, and glycosaminoglycan content. In contrast, protein levels of MMP-13 were elevated in the Sirt1 KO mice, leading to a potential increase of cartilage breakdown, alreadyshown in the heterozygous mice. Additional results showed elevated chondrocyte apoptosis in Sirt1 KOmice, as compared to WT controls. In addition to these observations, PTP1b (protein tyrosine phosphataseb) was elevated in the Sirt1 KO mice, in line with previous reports.Conclusion: The findings from this animal model demonstrated that Sirt1 KO mice presented an alteredcartilage phenotype, with an elevated apoptotic process and a potential degradative cartilage process

Lessons Learned From all For them: Best Practices For a Cross-Collaboration approach to Hpv Vaccination in Public Schools

The Community Preventive Services Task Force endorses vaccination programs in schools to increase access to vaccinations. However, implementing a school-based approach requires substantial coordination, planning, and resources. All for Them (AFT) is a multilevel, multicomponent approach to increase HPV vaccination among adolescents attending public schools in medically underserved areas in Texas. AFT comprised a social marketing campaign, school-based vaccination clinics, and school nurse continuing education. Process evaluation metrics and key informant interviews to understand experiences with AFT program implementation informed lessons learned. Lessons emerged in six domains: strong champion, school-level support, tailored and cost-effective marketing approaches, mobile provider collaboration, community presence, and crisis management. Strong support at district and school levels is vital for gaining principal and school nurse buy-in. Social marketing strategies are integral to program implementation and should be adjusted to maximize their effectiveness in motivating parents to vaccinate children against HPV, which also can be achieved through increased community presence of the project team. Preparing contingency plans and flexibility within the program can facilitate appropriate responses to provider restrictions in mobile clinics or in the event of unforeseen crises. These important lessons can offer useful guidelines for the development of prospective school-based vaccination programs

Unanesthetized Rodents Demonstrate Insensitivity of QT Interval and Ventricular Refractory Period to Pacing Cycle Length

Aim: The cardiac electrophysiology of mice and rats has been analyzed extensively, often in the context of pathological manipulations. However, the effects of beating rate on the basic electrical properties of the rodent heart remain unclear. Due to technical challenges, reported electrophysiological studies in rodents are mainly from ex vivo preparations or under deep anesthesia, conditions that might be quite far from the normal physiological state. The aim of the current study was to characterize the ventricular rate-adaptation properties of unanesthetized rats and mice.Methods: An implanted device was chronically implanted in rodents for atrial or ventricular pacing studies. Following recovery from surgery, QT interval was evaluated in rodents exposed to atrial pacing at various frequencies. In addition, the frequency dependence of ventricular refractoriness was tested by conventional ventricular programmed stimulation protocols.Results: Our findings indicate total absence of conventional rate-adaptation properties for both QT interval and ventricular refractoriness. Using monophasic action potential recordings in isolated mice hearts we could confirm the previously reported shortening of the action potential duration at fast pacing rates. However, we found that this mild shortening did not result in similar decrease of ventricular refractory period.Conclusion: Our findings indicate that unanesthetized rodents exhibit flat QT interval and ventricular refractory period rate-dependence. This data argue against empirical use of QT interval correction methods in rodent studies. Our new methodology allowing atrial and ventricular pacing of unanesthetized freely moving rodents may facilitate more appropriate utility of these important animal models in the context of cardiac electrophysiology studies

Hepatic acute-phase proteins control innate immune responses during infection by promoting myeloid-derived suppressor cell function

Acute-phase proteins (APPs) are an evolutionarily conserved family of proteins produced mainly in the liver in response to infection and inflammation. Despite vast pro- and antiinflammatory properties ascribed to individual APPs, their collective function during infections remains poorly defined. Using a mouse model of polymicrobial sepsis, we show that abrogation of APP production by hepatocyte-specific gp130 deletion, the signaling receptor shared by IL-6 family cytokines, strongly increased mortality despite normal bacterial clearance. Hepatic gp130 signaling through STAT3 was required to control systemic inflammation. Notably, hepatic gp130–STAT3 activation was also essential for mobilization and tissue accumulation of myeloid-derived suppressor cells (MDSCs), a cell population mainly known for antiinflammatory properties in cancer. MDSCs were critical to regulate innate inflammation, and their adoptive transfer efficiently protected gp130-deficient mice from sepsis-associated mortality. The hepatic APPs serum amyloid A and Cxcl1/KC cooperatively promoted MDSC mobilization, accumulation, and survival, and reversed dysregulated inflammation and restored survival of gp130-deficient mice. Thus, gp130-dependent communication between the liver and MDSCs through APPs controls inflammatory responses during infection

Numerical approach to a model for quasistatic damage with spatial BV-regularization

We address a model for rate-independent, partial, isotropic damage in quasistatic small strain linear elasticity, featuring a damage variable with spatial BV-regularization. Discrete solutions are obtained using an alternate time-discrete scheme and the Variable-ADMM algorithm to solve the constrained nonsmooth optimization problem that determines the damage variable at each time step. We prove convergence of the method and show that discrete solutions approximate a semistable energetic solution of the rate-independent system. Moreover, we present our numerical results for two benchmark problems