Diffusion of Botulinum Toxins

Background: It is generally agreed that diffusion of botulinum toxin occurs, but the extent of the spread and its clinical importance are disputed. Many factors have been suggested to play a role but which have the most clinical relevance is a subject of much discussion. Methods: This review discusses the variables affecting diffusion, including protein composition and molecular size as well as injection factors (e.g., volume, dose, injection method). It also discusses data on diffusion from comparative studies in animal models and human clinical trials that illustrate differences between the available botulinum toxin products (onabotulinumtoxinA, abobotulinumtoxinA, incobotulinumtoxinA, and rimabotulinumtoxinB). Results: Neither molecular weight nor the presence of complexing proteins appears to affect diffusion; however, injection volume, concentration, and dose all play roles and are modifiable. Both animal and human studies show that botulinum toxin products are not interchangeable, and that some products are associated with greater diffusion and higher rates of diffusion-related adverse events than others. Discussion: Each of the botulinum toxins is a unique pharmacologic entity. A working knowledge of the different serotypes is essential to avoid unwanted diffusion-related adverse events. In addition, clinicians should be aware that the factors influencing diffusion may range from properties intrinsic to the drug to accurate muscle selection as well as dilution, volume, and dose injected

Chemical Abundances of the Leo II Dwarf Galaxy

We use previously-published moderate-resolution spectra in combination with stellar atmosphere models to derive the first measured chemical abundance ratios in the Leo II dSph galaxy. We find that for spectra with SNR > 24, we are able to measure abundances from weak Ti, Fe and Mg lines located near the calcium infrared triplet (CaT). We also quantify and discuss discrepancies between the metallicities measured from Fe I lines and those estimated from the CaT features. We find that while the most metal-poor ([Fe/H] <-2.0]) Leo II stars have Ca and Ti abundance ratios similar to those of Galactic globular clusters, the more metal-rich stars show a gradual decline of Ti, Mg and Ca abundance ratio with increasing metallicity. Finding these trends in this distant and apparently dynamically stable dSph galaxy supports the hypothesis that the slow chemical enrichment histories of the dSph galaxies is universal, independent of any interaction with the Milky Way. Combining our spectroscopic abundances with published broadband photometry and updated isochrones, we are able to approximate stellar ages for our bright RGB stars to a relative precision of 2-3 Gyr. While the derived age-metallicity relationship of Leo II hints at some amount of slow enrichment, the data are still statistically consistent with no enrichment over the history of Leo II.Comment: Accepted to A

Planning and Development Strategies for Holy Trinity, Alabama

This report was written at the behest of and with the support of the Missionary Servants of the Most Holy Trinity for the School of City and Regional Planning course, CP 6052 second-year masters studio. The course is comprised of 16 Masters in City and Regional Planning candidates (MCRP) at the Georgia Institute of Technology in Atlanta, Ga.The Missionary Servants of the Most Holy Trinity (MSMHT) own and oversee parcels of rural land in Russell County, Alabama. The Missionary Servants are currently exploring and assessing how best to develop and utilize these major land holdings. By developing the land, members hope to provide services to their constituents, meet and help the needs of the larger community, and ensure a reliable source of income to fund Mission activities, all while promoting the principles of the Catholic Church as enunciated by MSMHT founder Father Thomas Judge, “Be good, do good, and be a power for good.” Towards this goal, the Missionary Servants have sought out the services and expertise of the School of City and Regional Planning Department of the Georgia Institute of Technology. MSMHT looked to Professor Michael Dobbins and professional planner Ray White for advice and guidance on how to best develop the land. The School subsequently formed a graduate level studio planning course around the project. Over the course of the Fall 2011 academic term, graduate students in the studio con­ducted site visits, interviewed stakeholders, solicited advice and guidance from subject-matter experts, examined the underlying data, engaged in quantitative analysis, created projections, generated maps and spatial analyses, and assessed various ideas and project proposals. Hundreds of hours were devoted to this project, with Professor Dobbins and Mr. White providing overall coordination, management, and expert guidance. The final report is presented here. It takes the form of a land management evaluation and pro­posal. The report is broken down into four major sections. The first section, “Description of Holy Trin­ity and Environs,” provides the background and context for the property located at the Holy Trinity site. Items in this section include a discussion of pertinent economic, housing, and demographic issues. This section addresses the composition of the land and environment, examines the social, cultural and busi­ness forces in the surrounding community and region, and provides an overview of the Church’s activi­ties in the area. The second section focuses on “Land Management.” This part of the report assesses current and potential revenue streams and amounts for the Mission. It also identifies and explores opportunities for Holy Trinity to partner with various businesses, investors, community and nonprofit organizations, and local and regional government offices and consortiums in furthering the goals of development, commu­nity service, and environmental preservation. The third section is devoted to “Development.” This portion analyzes and assesses various de­velopment possibilities for the property. It focuses on four potential scenarios for the land, consisting of agriculture industry, service provision, a town center concept, and/or environmental preservation. It also addresses land development from a functions perspective, examining how certain projects and pro­grams could realize the interests and meet some of the goals of the Mission and the larger community. Issues of infrastructure, design, policy and legal mechanisms, and recommendations are also contained in this section. A timeline for project planning and implementation accompanies these three sections. The re­port concludes with final land management recommendations, addresses long-term planning efforts, and furnishes contact and resource information.Michael Dobbins and Raymond Whit

Melanocortin receptor accessory proteins in adrenal disease and obesity.

Melanocortin receptor accessory proteins (MRAPs) are regulators of the melanocortin receptor family. MRAP is an essential accessory factor for the functional expression of the MC2R/ACTH receptor. The importance of MRAP in adrenal gland physiology is demonstrated by the clinical condition familial glucocorticoid deficiency type 2. The role of its paralog melanocortin-2-receptor accessory protein 2 (MRAP2), which is predominantly expressed in the hypothalamus including the paraventricular nucleus, has recently been linked to mammalian obesity. Whole body deletion and targeted brain specific deletion of the Mrap2 gene result in severe obesity in mice. Interestingly, Mrap2 complete knockout (KO) mice have increased body weight without detectable changes to food intake or energy expenditure. Rare heterozygous variants of MRAP2 have been found in humans with severe, early-onset obesity. In vitro data have shown that Mrap2 interaction with the melanocortin-4-receptor (Mc4r) affects receptor signaling. However, the mechanism by which Mrap2 regulates body weight in vivo is not fully understood and differences between the phenotypes of Mrap2 and Mc4r KO mice may point toward Mc4r independent mechanisms

Involvement of the Cytokine MIF in the Snail Host Immune Response to the Parasite Schistosoma mansoni

We have identified and characterized a Macrophage Migration Inhibitory Factor (MIF) family member in the Lophotrochozoan invertebrate, Biomphalaria glabrata, the snail intermediate host of the human blood fluke Schistosoma mansoni. In mammals, MIF is a widely expressed pleiotropic cytokine with potent pro-inflammatory properties that controls cell functions such as gene expression, proliferation or apoptosis. Here we show that the MIF protein from B. glabrata (BgMIF) is expressed in circulating immune defense cells (hemocytes) of the snail as well as in the B. glabrata embryonic (Bge) cell line that has hemocyte-like features. Recombinant BgMIF (rBgMIF) induced cell proliferation and inhibited NO-dependent p53-mediated apoptosis in Bge cells. Moreover, knock-down of BgMIF expression in Bge cells interfered with the in vitro encapsulation of S. mansoni sporocysts. Furthermore, the in vivo knock-down of BgMIF prevented the changes in circulating hemocyte populations that occur in response to an infection by S. mansoni miracidia and led to a significant increase in the parasite burden of the snails. These results provide the first functional evidence that a MIF ortholog is involved in an invertebrate immune response towards a parasitic infection and highlight the importance of cytokines in invertebrate-parasite interactions

MIF homologues from a filarial nematode parasite synergize with IL-4 to induce alternative activation of host macrophages

Macrophage migration inhibitory factor (MIF) is a highly conserved cytokine considered to exert wide-ranging, proinflammatory effects on the immune system. Recently, members of this gene family have been discovered in a number of invertebrate species, including parasitic helminths. However, chronic helminth infections are typically associated with a Th2-dominated, counter-inflammatory phenotype, in which alternatively activated macrophages (AAMs) are prominent. To resolve this apparent paradox, we have analyzed the activity of two helminth MIF homologues from the filarial nematode Brugia malayi, in comparison with the canonical MIF from the mouse. We report that murine MIF (mMIF) and Brugia MIF proteins induce broadly similar effects on bone marrow-derived mouse macrophages, eliciting a measured release of proinflammatory cytokines. In parallel, MIF was found to induce up-regulation of IL-4R on macrophages, which when treated in vitro with MIF in combination with IL-4, expressed markers of alternative activation [arginase, resistin-like molecule α (RELM-α) or found in inflammatory zone 1, Ym-1, murine macrophage mannose receptor] and differentiated into functional AAMs with in vitro-suppressive ability. Consistent with this finding, repeated in vivo administration of Brugia MIF induced expression of alternative macrophage activation markers. As mMIF did not induce RELM-α or Ym-1 in vivo, alternative activation may require components of the adaptive immune response to Brugia MIF, such as the production of IL-4. Hence, MIF may accentuate macrophage activation according to the polarity of the environment, thus promoting AAM differentiation in the presence of IL-4-inducing parasitic helminths