A Case Study: Community-Based Managed Care Program for Alzheimer’s and Other Related Dementias

A shift from long-term senior care to community living for those living with memory disorders has necessitated an increase in comprehensive care management programs to address their diverse needs. Increased life expectancy comes with challenges as many older Americans with memory disorders are living with co-occurring chronic health conditions that directly affect their quality of life. As the fifth leading cause of death worldwide and rapidly increasing, dementia is slated to become a global health crisis by the year 2035, with cases in the United States reaching 14 million by the year 2060. To help combat this issue, Presbyterian SeniorCare Network created a memory-care specific managed care program called Dementia360 to alleviate the burden of caregiving and increase the overall quality of life for memory-impaired individuals and their caregivers. Dementia360 addresses care quality, access, and cost relating to the provision and sustainment of dementia care. This approach focuses on targeting public health-related challenges by drawing upon the Triple Aim framework developed by the Institute for Healthcare Improvement. This essay aims to describe the managed care components of Dementia360 to examine its model compared to others previously studied. Overall, Dementia360 has created a framework incorporating best practices, thus strengthening the program’s predicted success of achievable disease management

Hyaluronan and self-assembling peptides as building blocks to reconstruct the extracellular environment in skin tissue

Funding for this study was provided by the Portuguese Foundation for Science and Technology (FCT, grant PTDC/EBB-BIO/114523/2009). D. S. Ferreira gratefully acknowledges FCT for a PhD scholarship (SFRH/BD/44977/2008

Biomimetic self-assembly of tetrapeptides into fibrillar networks and organogels

The self-assembly features of a family of tetrapeptides inspired in silk structure are presented. An exhaustive study of the influence of the terminal alkyl chain length in this process is undertaken. Scanning electron microscopy (SEM), wide-angle X-ray diffraction (WAXD), FTIR spectroscopy and circular dichroism are used for the structural analysis. These compounds, as in the natural model, self-assemble into antiparallel ?-sheet structures that further organize to form fibrillar aggregates. Furthermore, some of them are capable of forming a crowded network that entraps the solvent leading to physical gels with different microscopic morphologies. A model for the assembly process is propose

Molecularly Engineered Self-Assembling Membranes for Cell-Mediated Degradation

The use of peptide engineering to develop self-assembling membranes that are responsive to cellular enzyme activities is reported. The membranes are obtained by combining hyaluronan (HA) and a rationally designed peptide amphiphile (PA) containing a proteolytic domain (GPQGIWGQ octapeptide) sensitive to matrix metalloproteinase-1 (MMP-1). Insertion of an octapeptide in a typical PA structure does not disturb its self-assembly into fibrillar nanostructures neither the ability to form membranes with HA. In vitro enzymatic degradation with hyaluronidase and MMP-1 shows that membranes containing the MMP-1 substrate exhibit enhanced enzymatic degradation, compared with control membranes (absence of MMP-1 cleavable peptide or containing a MMP-1 insensitive sequence), being completely degraded after 7 days. Cell viability and proliferation is minimally affected by the enzymatically cleavable functionality of the membrane, but the presence of MMP-1 cleavable sequence does stimulate the secretion of MMP-1 by fibroblasts and interfere with matrix deposition, particularly the deposition of collagen. By showing cell-responsiveness to biochemical signals presented on self-assembling membranes, this study highlights the ability of modulating certain cellular activities through matrix engineering. This concept can be further explored to understand the cellular remodeling process and as a strategy to develop artificial matrices with more biomimetic degradation for tissue engineering applications.This work was funded by the European Regional Development Fund (ERDF) through the Operational Competitiveness Programme "COMPETE" (FCOMP-01-0124-FEDER-014758) and national funds through the Portuguese Foundation for Science and Technology (FCT) under the project PTDC/EBB-BIO/114523/2009. The authors also thank a start-up grant provided by the School of Engineering and Materials Science at QMUL. D.S.F. gratefully acknowledges FCT for the PhD scholarship (SFRH/BD/44977/2008)

Aqueous Self-Sorting in Extended Supramolecular Aggregates

Self-organization and self-sorting processes are responsible for the regulation and control of the vast majority of biological processes that eventually sustain life on our planet. Attempts to unveil the complexity of these systems have been devoted to the investigation of the binding processes between artificial molecules, complexes or aggregates within multicomponent mixtures, which has facilitated the emergence of the field of self-sorting in the last decade. Since, artificial systems involving discrete supramolecular structures, extended supramolecular aggregates or gel-phase materials in organic solvents or—to a lesser extent—in water have been investigated. In this review, we have collected diverse strategies employed in recent years to construct extended supramolecular aggregates in water upon self-sorting of small synthetic molecules. We have made particular emphasis on co-assembly processes in binary mixtures leading to supramolecular structures of remarkable complexity and the influence of different external variables such as solvent and concentration to direct recognition or discrimination processes between these species. The comprehension of such recognition phenomena will be crucial for the organization and evolution of complex matter

Development of a novel bioavailable inhibitor of the calmodulin-regulated protein kinase MLCK: A lead compound that attenuates vascular leak

AbstractTissue barriers involving epithelial and endothelial cell layers are critical to homeostasis, regulating passage of water, macromolecules, cells and certain classes of small molecules via two distinct cellular mechanisms, transcellular or paracellular. Endothelial or epithelial barrier dysfunction is a key component of pathophysiology in diverse diseases and injuries that have a broad impact on survival and quality of life. However, effective and safe small molecule therapeutics for these disorders are lacking. Success in development would therefore fill a major unmet medical need across multiple disease areas. Myosin light chain kinase (MLCK), a highly specialized calcium/calmodulin (CaM) regulated protein kinase, modulates barrier function through its regulation of intracellular contractile processes. MLCK levels and activity are increased in various animal models of disease and in human clinical disease samples. Our prior work with a genetic knockout (KO) mouse strain for the long form of MLCK, MLCK210, has identified MLCK as a drug discovery target for endothelial and epithelial barrier dysfunction. We describe here the development of a selective, bioavailable, stable inhibitor of MLCK that attenuates barrier dysfunction in mice comparable to that seen with the MLCK KO mice. The inhibitor compound 6 is stable in human microsomal metabolic stability assays and can be synthesized in a high-yielding and facile synthetic process. These results provide a foundation for and demonstrate the feasibility of future medicinal chemistry refinement studies directed toward the development of novel therapies for disorders involving barrier dysfunction

Modulation of Fluorescence through Coassembly of Molecules in Organic Nanostructures

This paper describes the fluorescence of bimolecular coassemblies that form one-dimensional nanostructures. One molecule is a fluorescent peptide amphiphile containing its branched stilbene chromophore covalently linked to the hydrophilic end of the amphiphile, and the second molecule is a shorter, nonfluorescent peptide amphiphile of complementary charge. Using circular dichroism we observe that mixing both molecules results in coassemblies that exhibit a β-sheet signature in the peptide region indicative of these types of nanostructures. The nature of the coassembly is dependent on the molar ratio of each component, and the changing CD spectra suggest the formation of domains along the length of the nanofibers with decreasing concentrations of the fluorescent component. In coassemblies with dilute concentrations of the fluorophore, we observe an increase in fluorescence intensity and quantum yield, as well as chiral transfer to the achiral segment of the fluorescent peptide amphiphile. The coassemblies studied containing a fluorescent component at a low molar ratio exhibit fluorescence resonance energy transfer to fluorescent acceptors in solution. When the nonfluorescent peptide amphiphile component is designed to bind the important bioactive polysaccharide heparin, a selective transfer of energy is observed between fluorescein-tagged heparin and the coassemblies in both dilute solution and in macroscopic gels