Translating Research Into Practice: Speeding the Adoption of Innovative Health Care Programs

Looks at case studies of four innovative clinical programs to determine key factors influencing the diffusion and adoption of innovations in health care

Preventing Leader Derailment—A Strategic Imperative for Public Health Agencies

Public health leaders, such as those who serve as state health officials (SHOs), routinely face challenges that are uncertain and complex. Those who reflect on the challenges they face and use those reflections to improve themselves and their teams develop into more effective leaders. Not addressing challenges can lead to the risk of premature “derailment.” In this column, we review research from the Center for Creative Leadership (CCL), a global authority in leadership development, which explores the underlying dynamics of derailment. We also share insights gained from ongoing research into SHO success discussed in prior Management Moment columns.1 , 2 Finally, we offer several thoughts on strategies for preventing derailment among senior public health leaders

Histamine stimulates the proliferation of small and large cholangiocytes by activation of both IP3/Ca2+ and cAMP-dependent signaling mechanisms

Although large cholangiocytes exert their functions by activation of cyclic adenosine 3',5'-monophosphate (cAMP), Ca(2+)-dependent signaling regulates the function of small cholangiocytes. Histamine interacts with four receptors, H1-H4HRs. H1HR acts by Gαq activating IP(3)/Ca(2+), whereas H2HR activates Gα(s) stimulating cAMP. We hypothesize that histamine increases biliary growth by activating H1HR on small and H2HR on large cholangiocytes. The expression of H1-H4HRs was evaluated in liver sections, isolated and cultured (normal rat intrahepatic cholangiocyte culture (NRIC)) cholangiocytes. In vivo, normal rats were treated with histamine or H1-H4HR agonists for 1 week. We evaluated: (1) intrahepatic bile duct mass (IBDM); (2) the effects of histamine, H1HR or H2HR agonists on NRIC proliferation, IP(3) and cAMP levels and PKCα and protein kinase A (PKA) phosphorylation; and (3) PKCα silencing on H1HR-stimulated NRIC proliferation. Small and large cholangiocytes express H1-H4HRs. Histamine and the H1HR agonist increased small IBDM, whereas histamine and the H2HR agonist increased large IBDM. H1HR agonists stimulated IP(3) levels, as well as PKCα phosphorylation and NRIC proliferation, whereas H2HR agonists increased cAMP levels, as well as PKA phosphorylation and NRIC proliferation. The H1HR agonist did not increase proliferation in PKCα siRNA-transfected NRICs. The activation of differential signaling mechanisms targeting small and large cholangiocytes is important for repopulation of the biliary epithelium during pathologies affecting different-sized bile ducts

High-Resolution Surveys Along the Hot Spot–Affected Galapagos Spreading Center: 1. Distribution of Hydrothermal Activity

The spatial density of hydrothermal activity along most mid-ocean ridges is a robust linear function of spreading rate (or magmatic budget), but extreme crustal properties may alter this relationship. In 2005–2006 we tested the effect of thickened crust on hydrothermal activity using high-resolution mapping of plumes overlying the hot spot–affected Galapagos Spreading Center from 95o to 89o42\u27W (~560 km of ridge crest). Plume mapping discovered only two active, high-temperature vent fields, subsequently confirmed by camera tows, though strong plume evidence indicated minor venting from at least six other locations. Total plume incidence (ph), the fraction of ridge crest overlain by significant plumes, was 0.11 ± 0.014, about half that expected for a non–hot spot mid-ocean ridge with a similar magmatic budget. Plume distributions on the Galapagos Spreading Center were uncorrelated with abrupt variations in the depth of the along-axis melt lens, so these variations are apparently not controlled by hydrothermal cooling differences. We also found no statistical difference (for a significance level of 0.05) in plume incidence between where the seismically imaged melt lens is shallow (2 ± 0.56 km, ph = 0.108 ± 0.045) and where it is deep (3.4 ± 0.7 km, ph = 0.121 ± 0.015). The Galapagos Spreading Center thus joins mid-ocean ridges near the Iceland (Reykjanes Ridge), St. Paul-Amsterdam (South East Indian Ridge), and Ascension (Mid- Atlantic Ridge) hot spots as locations of anomalously scarce high-temperature venting. This scarcity implies that convective cooling along hot spot–affected ridge sections occurs primarily by undetected diffuse flow or is permanently or episodically reduced compared to normal mid-ocean ridges

Identification of novel small molecule inhibitors of adenovirus gene transfer using a high throughput screening approach

Due to many favourable attributes adenoviruses (Ads) are the most extensively used vectors for clinical gene therapy applications. However, following intravascular administration, the safety and efficacy of Ad vectors are hampered by the strong hepatic tropism and induction of a potent immune response. Such effects are determined by a range of complex interactions including those with neutralising antibodies, blood cells and factors, as well as binding to native cellular receptors (coxsackie adenovirus receptor (CAR), integrins). Once in the bloodstream, coagulation factor X (FX) has a pivotal role in determining Ad liver transduction and viral immune recognition. Due to difficulties in generating a vector devoid of multiple receptor binding motifs, we hypothesised that a small molecule inhibitor would be of value. Here, a pharmacological approach was implemented to block adenovirus transduction pathways. We developed a high throughput screening (HTS) platform to identify the small molecule inhibitors of FX-mediated Ad5 gene transfer. Using an in vitro fluorescence and cell-based HTS, we evaluated 10,240 small molecules. Following sequential rounds of screening, three compounds, T5424837, T5550585 and T5660138 were identified that ablated FX-mediated Ad5 transduction with low micromolar potency. The candidate molecules possessed common structural features and formed part of the one pharmacophore model. Focused, mini-libraries were generated with structurally related molecules and in vitro screening revealed novel hits with similar or improved efficacy. The compounds did not interfere with Ad5:FX engagement but acted at a subsequent step by blocking efficient intracellular transport of the virus. In vivo, T5660138 and its closely related analogue T5660136 significantly reduced Ad5 liver transgene expression at 48 h post-intravenous administration of a high viral dose (1 × 10<sup>11</sup> vp/mouse). Therefore, this study identifies novel and potent small molecule inhibitors of the Ad5 transduction which may have applications in the Ad gene therapy setting