Slowly cycling Rho kinase-dependent actomyosin cross-bridge slippage explains intrinsic high compliance of detrusor smooth muscle

Biological soft tissues are viscoelastic because they display timeindependent pseudoelasticity and time-dependent viscosity. However, there is evidence that the bladder may also display plasticity, defined as an increase in strain that is unrecoverable unless work is done by the muscle. In the present study, an electronic lever was used to induce controlled changes in stress and strain to determine whether rabbit detrusor smooth muscle (rDSM) is best described as viscoelastic or viscoelastic plastic. Using sequential ramp loading and unloading cycles, stress-strain and stiffness-stress analyses revealed that rDSM displayed reversible viscoelasticity, and that the viscous component was responsible for establishing a high stiffness at low stresses that increased only modestly with increasing stress compared with the large increase produced when the viscosity was absent and only pseudoelasticity governed tissue behavior. The study also revealed that rDSM underwent softening correlating with plastic deformation and creep that was reversed slowly when tissues were incubated in a Ca2+ -containing solution. Together, the data support a model of DSM as a viscoelastic-plastic material, with the plasticity resulting from motor protein activation. This model explains the mechanism of intrinsic bladder compliance as slipping cross bridges, predicts that wall tension is dependent not only on vesicle pressure and radius but also on actomyosin cross-bridge activity, and identifies a novel molecular target for compliance regulation, both physiologically and therapeutically

Cancer Molecular Analysis Project: Weaving a rich cancer research tapestry

AbstractThe Cancer Molecular Analysis Project (CMAP) of the NCI is integrating diverse cancer research data to elucidate fundamental etiologic processes, enable development of novel therapeutic approaches, and facilitate the bridging of basic and clinical science

Antimicrobial Resistance in Neisseria gonorrhoeae: Proceedings of the STAR Sexually Transmitted Infection-Clinical Trial Group Programmatic Meeting.

The goal of the Sexually Transmitted Infection Clinical Trial Group's Antimicrobial Resistance (AMR) in Neisseria gonorrhoeae (NG) meeting was to assemble experts from academia, government, nonprofit and industry to discuss the current state of research, gaps and challenges in research and technology and priorities and new directions to address the continued emergence of multidrug-resistant NG infections. Topics discussed at the meeting, which will be the focus of this article, include AMR NG global surveillance initiatives, the use of whole genome sequencing and bioinformatics to understand mutations associated with AMR, mechanisms of AMR, and novel antibiotics, vaccines and other methods to treat AMR NG. Key points highlighted during the meeting include: (i) US and International surveillance programs to understand AMR in NG; (ii) the US National Strategy for combating antimicrobial-resistant bacteria; (iii) surveillance needs, challenges, and novel technologies; (iv) plasmid-mediated and chromosomally mediated mechanisms of AMR in NG; (v) novel therapeutic (eg, sialic acid analogs, factor H [FH]/Fc fusion molecule, monoclonal antibodies, topoisomerase inhibitors, fluoroketolides, LpxC inhibitors) and preventative (eg, peptide mimic) strategies to combat infection. The way forward will require renewed political will, new funding initiatives, and collaborations across academic and commercial research and public health programs

Brief of Corporate Law Professors as Amici Curie in Support of Respondents

The Supreme Court has looked to the rights of corporate shareholders in determining the rights of union members and non-members to control political spending, and vice versa. The Court sometimes assumes that if shareholders disapprove of corporate political expression, they can easily sell their shares or exercise control over corporate spending. This assumption is mistaken. Because of how capital is saved and invested, most individual shareholders cannot obtain full information about corporate political activities, even after the fact, nor can they prevent their savings from being used to speak in ways with which they disagree. Individual shareholders have no “opt out” rights or practical ability to avoid subsidizing corporate political expression with which they disagree. Nor do individuals have the practical option to refrain from putting their savings into equity investments, as doing so would impose damaging economic penalties and ignore conventional financial guidance for individual investors

The Association Between Money and Opinion in Academic Emergency Medicine

Objectives: Financial conflicts of interest have come under increasing scrutiny in medicine, but their impact has not been quantified. Our objective was to use the results of a national survey of academic emergency medicine (EM) faculty to determine if an association between money and personal opinion exists.Methods: We conducted a web-based survey of EM faculty. Opinion questions were analyzed with regard to whether the respondent had either 1) received research grant money or 2) received money from industry as a speaker, consultant, or advisor. Responses were unweighted, and tests of differences in proportions were made using Chi-squared tests, with p<0.05 set for significance.Results: We received responses from 430 members; 98 (23%) received research grants from industry, while 145 (34%) reported fee-for-service money. Respondents with research money were more likely to be comfortable accepting gifts (40% vs. 29%) and acting as paid consultants (50% vs. 37%). They had a more favorable attitude with regard to societal interactions with industry and felt that industry-sponsored lectures could be fair and unbiased (52% vs. 29%). Faculty with fee-for-service money mirrored those with research money. They were also more likely to believe that industry-sponsored research produces fair and unbiased results (61% vs. 45%) and less likely to believe that honoraria biased speakers (49% vs. 69%).Conclusion: Accepting money for either service or research identified a distinct population defined by their opinions. Faculty engaged in industry-sponsored research benefitted socially (collaborations), academically (publications), and financially from the relationship. [West J Emerg Med. 2010; 11(2):126-132.

Thromboxane Modulates Endothelial Permeability

The study tests the role of thromboxane in modulating microvascular permeability in vitro. Cultured monolayers of bovine aortic endothelial cells were challenged with the thromboxane (Tx) mimic U46619. This led to disassembly of actin microfilaments, cell rounding, border retraction and interendotheHal gap formation. Pretreatment with the Tx receptor antagonist SQ 29,548 prevented the Tx mimic-induced cytoskeletal changes. The Tx mimic also altered endothelial cell barrier function. Increased permeability was indicated by the increased passage of labelled albumin across monolayers cultured on microcarriers, relative to untreated endothelial cells (p < 0.05). Furthermore, electron microscopy of endothelial cells cultured on the basement membrane of human placental amnion indicated increased permeability based on wide, interendotheHal gap formation and transit of the tracer horseradish peroxidase. Quantification of interendothelial gaps revealed an eleven-fold increase with the Tx mimic relative to untreated endothial cells (p < 0.05) and prevention by pretreatment with the Tx receptor antagonist (p < 0.05). These data indicate that Tx directly modulates the permeability of endothelial cell in vitro

Supporting the massive scale-up of antiretroviral therapy: the evolution of PEPFAR-supported treatment facilities in South Africa, 2005-2009

<p>Abstract</p> <p>Background</p> <p>South Africa has an estimated 1.5 million persons in need of antiretroviral therapy (ART). In 2004, the South African government began collaborating with the United States President's Emergency Plan for AIDS Relief (PEPFAR) to increase access to ART. We determined how PEPFAR treatment support changed from 2005-2009.</p> <p>Methods</p> <p>In order to describe the change in number and type of PEPFAR-supported ART facilities, we analyzed routinely collected program-monitoring data from 2005-2009. The collected data included the number, type and province of facilities as well as the number of patients receiving ART at each facility.</p> <p>Results</p> <p>The number of PEPFAR-supported facilities providing ART increased from 184 facilities in 2005 to 1,469 facilities in 2009. From 2005-2009 the number of PEPFAR-supported government facilities increased 10.1 fold from 54 to 546 while the number of PEPFAR-supported NGO facilities (including general practitioner and NGO facilities) increased 6.2 fold from 114 to 708. In 2009 the total number of persons treated at PEPFAR-supported NGO facilities was 43,577 versus 501,089 persons at PEPFAR-supported government facilities. Overall, the median number of patients receiving ART per site increased from 81 in 2005 to 136 in 2009.</p> <p>Conclusions</p> <p>To mitigate the gap between those needing and those receiving ART, more facilities were supported. The proportion of government facilities supported and the median number of persons treated at these facilities increased. This shift could potentially be sustainable as government sites reach more individuals and receive government funding. These results demonstrate that PEPFAR was able to support a massive scale-up of ART services in a short period of time.</p

Pharmacokinetics and pharmacodynamics of a human monoclonal anti‐FGF23 antibody (KRN23) in the first multiple ascending‐dose trial treating adults with X‐linked hypophosphatemia

In X-linked hypophosphatemia (XLH), serum fibroblast growth factor 23 (FGF23) is increased and results in reduced renal maximum threshold for phosphate reabsorption (TmP), reduced serum inorganic phosphorus (Pi), and inappropriately low normal serum 1,25 dihydroxyvitamin D (1,25[OH]2D) concentration, with subsequent development of rickets or osteomalacia. KRN23 is a recombinant human IgG1 monoclonal antibody that binds to FGF23 and blocks its activity. Up to 4 doses of KRN23 were administered subcutaneously every 28 days to 28 adults with XLH. Mean ± standard deviation KRN23 doses administered were 0.05, 0.10 ± 0.01, 0.28 ± 0.06, and 0.48 ± 0.16 mg/kg. The mean time to reach maximum serum KRN23 levels was 7.0 to 8.5 days. The mean KRN23 half-life was 16.4 days. The mean area under the concentration–time curve (AUCn) for each dosing interval increased proportionally with increases in KRN23 dose. The mean intersubject variability in AUCn ranged from 30% to 37%. The area under the effect concentration–time curve (AUECn) for change from baseline in TmP per glomerular filtration rate, serum Pi, 1,25(OH)2D, and bone markers for each dosing interval increased linearly with increases in KRN23 AUCn. Linear correlation between serum KRN23 concentrations and increase in serum Pi support KRN23 dose adjustments based on predose serum Pi concentration