Chronic GLP-1 receptor activation by exendin-4 induces expansion of pancreatic duct glands in rats and accelerates formation of dysplastic lesions and chronic pancreatitis in the Kras(G12D) mouse model.

Pancreatic duct glands (PDGs) have been hypothesized to give rise to pancreatic intraepithelial neoplasia (PanIN). Treatment with the glucagon-like peptide (GLP)-1 analog, exendin-4, for 12 weeks induced the expansion of PDGs with mucinous metaplasia and columnar cell atypia resembling low-grade PanIN in rats. In the pancreata of Pdx1-Cre; LSL-Kras(G12D) mice, exendin-4 led to acceleration of the disruption of exocrine architecture and chronic pancreatitis with mucinous metaplasia and increased formation of murine PanIN lesions. PDGs and PanIN lesions in rodent and human pancreata express the GLP-1 receptor. Exendin-4 induced proproliferative signaling pathways in human pancreatic duct cells, cAMP-protein kinase A and mitogen-activated protein kinase phosphorylation of cAMP-responsive element-binding protein, and increased cyclin D1 expression. These GLP-1 effects were more pronounced in the presence of an activating mutation of Kras and were inhibited by metformin. These data reveal that GLP-1 mimetic therapy may induce focal proliferation in the exocrine pancreas and, in the context of exocrine dysplasia, may accelerate formation of neoplastic PanIN lesions and exacerbate chronic pancreatitis

MC2^2: Multi-wavelength and dynamical analysis of the merging galaxy cluster ZwCl 0008.8+5215: An older and less massive Bullet Cluster

We analyze a rich dataset including Subaru/SuprimeCam, HST/ACS and WFC3, Keck/DEIMOS, Chandra/ACIS-I, and JVLA/C and D array for the merging galaxy cluster ZwCl 0008.8+5215. With a joint Subaru/HST weak gravitational lensing analysis, we identify two dominant subclusters and estimate the masses to be M$_{200}=\text{5.7}^{+\text{2.8}}_{-\text{1.8}}\times\text{10}^{\text{14}}\,\text{M}_{\odot}$ and 1.2$^{+\text{1.4}}_{-\text{0.6}}\times10^{14}$ M$_{\odot}$. We estimate the projected separation between the two subclusters to be 924$^{+\text{243}}_{-\text{206}}$ kpc. We perform a clustering analysis on confirmed cluster member galaxies and estimate the line of sight velocity difference between the two subclusters to be 92$\pm$164 km s$^{-\text{1}}$. We further motivate, discuss, and analyze the merger scenario through an analysis of the 42 ks of Chandra/ACIS-I and JVLA/C and D polarization data. The X-ray surface brightness profile reveals a remnant core reminiscent of the Bullet Cluster. The X-ray luminosity in the 0.5-7.0 keV band is 1.7$\pm$0.1$\times$10$^{\text{44}}$ erg s$^{-\text{1}}$ and the X-ray temperature is 4.90$\pm$0.13 keV. The radio relics are polarized up to 40$\%$. We implement a Monte Carlo dynamical analysis and estimate the merger velocity at pericenter to be 1800$^{+\text{400}}_{-\text{300}}$ km s$^{-\text{1}}$. ZwCl 0008.8+5215 is a low-mass version of the Bullet Cluster and therefore may prove useful in testing alternative models of dark matter. We do not find significant offsets between dark matter and galaxies, as the uncertainties are large with the current lensing data. Furthermore, in the east, the BCG is offset from other luminous cluster galaxies, which poses a puzzle for defining dark matter -- galaxy offsets.Comment: 22 pages, 19 figures, accepted for publication in the Astrophysical Journal on March 13, 201

The rise and fall of star-formation in z∼0.2\bf z\sim0.2 merging galaxy clusters

CIZA J2242.8+5301 (`Sausage') and 1RXS J0603.3+4213 (`Toothbrush') are two low-redshift ($z\sim0.2$), massive ($\sim2\times10^{15}M_\odot$), post-core passage merging clusters, which host shock waves traced by diffuse radio emission. To study their star-formation properties, we uniformly survey the `Sausage' and `Toothbrush' clusters in broad and narrow band filters and select a sample of $201$ and $463$ line emitters, down to a rest-frame equivalent width ($13${\AA}). We robustly separate between H$\alpha$ and higher redshift emitters using a combination of optical multi-band (B, g, V, r, i, z) and spectroscopic data. We build H$\alpha$ luminosity functions for the entire cluster region, near the shock fronts, and away from the shock fronts and find striking differences between the two clusters. In the dynamically younger, $1$ Gyr old `Sausage' cluster we find numerous ($59$) H$\alpha$ emitters above a star-formation rate (SFR) of $0.17$ M_{\sun} yr$^{-1}$ surprisingly located in close proximity to the shock fronts, embedded in very hot intra-cluster medium plasma. The SFR density for the cluster population is at least at the level of typical galaxies at $z\sim2$. Down to the same star-formation rate, the possibly dynamically more evolved `Toothbrush' cluster has only $9$ H$\alpha$ galaxies. The cluster H$\alpha$ galaxies fall on the SFR-stellar mass relation $z\sim0.2$ for the field. However, the `Sausage' cluster has an H$\alpha$ emitter density $>20$ times that of blank fields. If the shock passes through gas-rich cluster galaxies, the compressed gas could collapse into dense clouds and excite star-formation for a few $100$ Myr. This process ultimately leads to a rapid consumption of the molecular gas, accelerating the transformation of gas-rich field spirals into cluster S0s or ellipticals.Comment: Accepted for publication in MNRAS after minor referee report. 21 pages, 15 figures, 5 table

MC2^2: Subaru and Hubble Space Telescope Weak-Lensing Analysis of the Double Radio Relic Galaxy Cluster PLCK G287.0+32.9

The second most significant detection of the Planck Sunyaev Zel'dovich survey, PLCK~G287.0+32.9 ($z=0.385$) boasts two similarly bright radio relics and a radio halo. One radio relic is located $\sim 400$ kpc northwest of the X-ray peak and the other $\sim 2.8$ Mpc to the southeast. This large difference suggests that a complex merging scenario is required. A key missing puzzle for the merging scenario reconstruction is the underlying dark matter distribution in high resolution. We present a joint Subaru Telescope and {\it Hubble Space Telescope} weak-lensing analysis of the cluster. Our analysis shows that the mass distribution features four significant substructures. Of the substructures, a primary cluster of mass $M_{200\text{c}}=1.59^{+0.25}_{-0.22}\times 10^{15} \ h^{-1}_{70} \ \text{M}_{\odot}$dominates the weak-lensing signal. This cluster is likely to be undergoing a merger with one (or more) subcluster whose mass is approximately a factor of 10 lower. One candidate is the subcluster of mass$M_{200\text{c}}=1.16^{+0.15}_{-0.13}\times 10^{14} \ h^{-1}_{70} \ \text{M}_{\odot}$located$\sim 400$kpc to the southeast. The location of this subcluster suggests that its interaction with the primary cluster could be the source of the NW radio relic. Another subcluster is detected$\sim 2$Mpc to the SE of the X-ray peak with mass$M_{200\text{c}}=1.68^{+0.22}_{-0.20}\times 10^{14} \ h^{-1}_{70} \ \text{M}_{\odot}$. This SE subcluster is in the vicinity of the SE radio relic and may have created the SE radio relic during a past merger with the primary cluster. The fourth subcluster,$M_{200\text{c}}=1.87^{+0.24}_{-0.22}\times 10^{14} \ h^{-1}_{70} \ \text{M}_{\odot}$, is northwest of the X-ray peak and beyond the NW radio relic.Comment: 19 pages, 14 figures; Accepted to Ap

Experimental Spinal Fusion With Recombinant Human Bone Morphogenetic Protein-2 Without Decortication of Osseous Elements

Study Design. L4-L5 intertransverse process fusions were produced with 58 μg, 230 μg, or 920 μg of recombinant human bone morphogenetic protein-2 in 20 dogs. Eleven had traditional decortication of posterior elements before insertion of the implant. Nine were left undecorticated. All animals were evaluated 3 months after surgery. Objectives. To determine whether decortication is a prerequisite for successful fusion in the presence of osteoinductive proteins such as bone morphogenetic protein-2. Summary of Background Data. Recombinant osteoinductive proteins can induce de novo bone in ectopic soft-tissue sites in the absence of bone marrow elements. Traditional methods for achieving spinal fusion rely on exposure of bone marrow through decortication to facilitate osteogenesis. It is hypothesized that the presence of an implanted osteoinductive protein obviates the need for exposure and release of host inductive factors. Methods. Recombinant human bone morphogenetic protein-2-induced intertransverse process fusions were performed with and without decortication. Fusion sites were evaluated by computed tomography imaging, high-resolution radiography, manual testing, mechanical testing, and histologic analysis. Results. One hundred percent of decorticated spines and 89% of undecorticated spines were clinically fused by 3 months. Ninety-one percent of decorticated spines and 78% of undecorticated specimens exhibited bilateral transverse process osseous bridging. The only spines that failed to achieve solid bilateral arthrodesis were in the lowest dose group. With the higher two doses, there was histologic evidence of osseous continuity between the fusion mass and undecorticated transverse processes. Conclusions. There were no statistical differences in clinical and radiographic fusion rates between decorticated and undecorticated sites. With higher doses of recombinant human bone morphogenetic protein-2, there was little histologic distinction between fusions in decorticated versus undecorticated spines

Place-based marketing and wine tourism: creating a point of difference and economic sustainability for small wineries

The purpose of this paper is to explore how small-scale wineries and wine regions create a point of difference and economic sustainability in a competitive marketplace through utilizing regional place branding and cellar door visitation. This research is based on qualitative, semi-structured, in-depth interviews with winery owners/managers and additional wine and tourism stakeholders in a single case study: The Central Otago wine region in the South Island of New Zealand. In total, 39 interviews were conducted in 2007 and 2010. Interviews were audio-recorded, transcribed verbatim, coded and categorized for analysis. Place marketing is a significant factor in the success of both regional and individual wine marketing initiatives, as it serves as a strategy of differentiation. Desirable regional attributes, as well as emotionally-appealing stories of the people and processes behind wine production, have been used deliberately by respondents in the marketing of Central Otago wine products and experiences. Respondents suggest that one of the most effective ways to facilitate a positive association between place and their product in the minds of consumers is through winery visitation, whereby visitors come to associate the region’s wines with the landscape and beauty of the area that they experience. Visitors also have the opportunity to experience the stories behind the wine, building emotional connections with the winery, and the region, which may ultimately lead to brand loyalty

The impact of receiving a diagnosis of Non-Epileptic Attack Disorder (NEAD): a systematic review

Background: Clinicians have reported observations of the immediate cessation of non-epileptic attacks after the diagnosis of NEAD is presented. Objective: The purpose of this systematic review was to examine the impact of receiving a diagnosis of NEAD. Search strategy: A literature search across the databases Medline, PsycINFO, EMBASE, and CINAHL, and additional hand searching, identified 6 original studies meeting criteria for the review. Selection Criteria: Included studies were original peer-reviewed articles investigating the impact of receiving a diagnosis of NEAD on adult populations with at least one outcome measured pre and post-diagnosis. Analysis: The studies were assessed for methodological quality, including biases. This assessment was developed to include criteria specific to research regarding NEAD and diagnosis. Results: Six identified studies, with a total of 153 NEAD participants, examined the impact of receiving a diagnosis on seizure frequency. Two of the six also examined the impact on health-related quality of life. The findings were inconsistent, with approximately half the participants experiencing seizure reduction or cessation post-diagnosis. Diagnosis appeared to have no significant impact on health-related quality of life. The overall evidence lacked quality, particularly in study design and statistical rigour. Conclusions: Mixed results and a lack of high quality evidence was found. Concerns are considered regarding the appropriateness of seizure frequency as the primary outcome measure and the use of epilepsy control groups. Indications for future research include: measuring more meaningful outcomes, using larger samples and power calculations, and ensuring consistent and standard methods for communicating the diagnosis and recording outcomes

Dynamic changes of the extracellular matrix after acute tako-tsubo cardiomyopathy

Funding Tenovus Scotland. Grant number G13/10.Peer reviewedPublisher PD

Effective Doses of Recombinant Human Bone Morphogenetic Protein-2 in Experimental Spinal Fusion

Study Design Nineteen dogs underwent L4-L5 intertransverse process fusions with either 58 μg, 115 μg, 230 μg, 460 μg, or 920 μg of recombinant human bone morphogenetic protein-2 carried by a polylactic acid polymer. A previous study (12 dogs) compared 2300 μg of recombinant human bone morphogenetic protein-2, autogenous iliac bone, and carrier alone in this model. All fusions subsequently were compared. Objectives To characterize the dose-response relationship of recombinant human bone morphogenetic protein-2 in a spinal fusion model. Summary of Background Data Recombinant osteoinductive morphogens, such as recombinant human bone morphogenetic protein-2, are effective in vertebrate diaphyseal defect and spinal fusion models. It is hypothesized that the quality of spinal fusion produced with recombinant human bone morphogenetic protein-2, above a threshold dose, does not change with increasing amounts of inductive protein. Methods After decortication of the posterior elements, the designated implants were placed along the intertransverse process space bilaterally. The fusion sites were evaluated after 3 months by computed tomography imaging, high-resolution radiography, manual testing, mechanical testing, and histologic analysis. Results As in the study using 2300 μg of recombinant human bone morphogenetic protein-2, implantation of 58–920 μg of recombinant human bone morphogenetic protein-2 successfully resulted in intertransverse process fusion in the dog by 3 months. This had not occurred in animals containing autograft or carrier alone. The cross-sectional area of the fusion mass and mechanical stiffness of the L4-L5 intersegment were not dose-dependent. Histologic findings varied but were not related to rhBMP-2 dose. Inflammatory reaction to the composite implant was proportional inversely to the volume of the fusion mass. Conclusions No mechanical, radiographic, or histologic differences in the quality of intertransverse process fusion resulted from a 40-fold variation in dose of recombinant human bone morphogenetic protein-2