The Quest for Moral Leaders: Essays on Leadership Ethics

The quest for moral leaders is both a personal quest that takes place in the hearts and minds of leaders and a pursuit by individuals, groups, organizations, communities and societies for leaders who are both ethical and effective. The contributors to this volume, all top scholars in leadership studies and ethics, provide a nuanced discussion of the complex ethical relationships that lie at the core of leadership.https://scholarship.richmond.edu/bookshelf/1018/thumbnail.jp

Pharmacotherapy of retinal disease with visual cycle modulators

Introduction: Pharmacotherapy with visual cycle modulators (VCMs) is under investigation for retinitis pigmentosa (RP), Leber congenital amaurosis (LCA), Stargardt macular dystrophy (SMD) and nonexudative age-related macular degeneration (AMD), all blinding diseases that lack effective treatment options. Areas covered: The authors review investigational VCMs, including oral retinoids, 9-cis-retinyl-acetate (zuretinol) and 9-cis-β-carotene, which restore 11-cis-retinal levels in RP and LCA caused by LRAT and RPE65 gene mutations, and may improve visual acuity and visual fields. Therapies for SMD aiming to decrease accumulation of toxic Vitamin A dimers and lipofuscin in the retina and retinal pigment epithelium (RPE) include C20-D3-vitamin A (ALK-001), isotretinoin, VM200, emixustat, and A1120. Mouse models of SMD show promising data for these treatments, though proof of efficacy in humans is currently lacking. Fenretinide and emixustat are investigational VCMs for dry AMD, though neither has been shown to reduce geographic atrophy or improve vision in human trials. A1120 prevents retinol transport into the RPE and may spare the side effects typically seen in VCMs (nyctalopia and chromatopsia) per mouse studies. Expert opinion: Oral VCMs may be feasible treatment options for degenerative retinal diseases based on pre-clinical and some early clinical studies. Further trials are warranted to assess their efficacy and safety in humans

GASTRIC METASTASES ORIGINATING FROM OCCULT BREAST LOBULAR CARCINOMA: DIAGNOSTIC AND THERAPEUTIC PROBLEMS

BACKGROUND: Breast cancer is the most frequent malignant tumour to metastasize into the gastrointestinal tract in female and is second only to malignant melanoma. Nevertheless gastrointestinal metastases arising from breast cancer are quite rare. The upper gastrointestinal tract is more frequently involved and lobular infiltrating carcinoma has a greater predilection compared to the ductal type. CASE PRESENTATION: The authors describe the case of a 70 years old woman with a preoperative diagnosis of gastric undifferentiated medullary--type carcinoma, which was the first manifestation of an occult breast carcinoma. The primary site of carcinoma was identified with the use of a panel of selected immunohistochemical markers. CONCLUSION: Our goal in this case report is to increase the awareness of surgeons and clinicians to rule out the possibility of mammary origin in circumstance of gastric cancer occurring in female, even in patients without a previous or concurrent history of breast carcinoma. Although not a particularly common event, it is, nevertheless, reported in the literature. The differentiation between primary gastric carcinoma and metastatic breast carcinoma is essential for planning the correct therapeutic approach, in order to avoid the patient unnecessary surgery

Muscular Strength and Body Composition Comparison Between the Charlotte-Mecklenburg Fire and Police Departments

Firefighters and police have different physical job requirements and selection processes. Firefighters have on-duty exercise time and police do not. This could affect body composition and strength. The purpose of this investigation was to compare body composition and bench press strength between firefighters and police officers in the Charlotte-Mecklenburg departments. Current 2006 fitness records were analyzed to compare firefighters and police (N = 2330). Variables included: gender, age, body mass, percent body-fat, fat mass, lean mass, bench press strength, bench press/lean mass, bench press/body mass, and percent that were obese. Significant (p ≤ 0.05) differences were found between male firefighters and police in age (37.7 vs. 36.9 yrs), body mass (91.5 vs. 93.2 kg), percent body-fat (17.8% vs.18.5%), fat mass (16.9 vs. 18.0 kg), bench press strength (93.4 vs. 96.3 kg), bench press/body mass (1.03 vs.1.05) and percent that were obese (10% vs.17%), respectively. Significant differences between female firefighters and police were found in age (42.4 vs. 37.4 yrs), body mass (77.5 vs. 71.8 kg), lean mass (54.4 vs. 51.2 kg), bench press strength (52.3 vs. 43.9 kg), bench press/lean mass (0.99 vs. 0.86) and bench press/body mass (0.69 vs. 0.62), respectively. Male police were younger, weighed more, had higher percent body fat, higher percent of obesity, and had greater upper body strength than firefighters. Female police were younger, weighed less, had less lean mass and less upper body strength than their firefighter counterparts. Contributing factors might include pre-employment selection, recruit training, in-service physical fitness testing, and counseling provided by departments

Stargardt macular dystrophy and evolving therapies

Introduction: Stargardt macular dystrophy (STGD1) is a hereditary retinal degeneration that lacks effective treatment options. Gene therapy, stem cell therapy, and pharmacotherapy with visual cycle modulators (VCMs) and complement inhibitors are discussed as potential treatments. Areas covered: Investigational therapies for STGD1 aim to reduce toxic bisretinoids and lipofuscin in the retina and retinal pigment epithelium (RPE). These agents include C20-D3-vitamin A (ALK-001), isotretinoin, VM200, emixustat, and A1120. Avacincaptad pegol is a C5 complement inhibitor that may reduce inflammation-related RPE damage. Animal models of STGD1 show promising data for these treatments, though proof of efficacy in humans is lacking. Fenretinide and emixustat are VCMs for dry AMD and STGD1 that failed to halt geographic atrophy progression or improve vision in trials for AMD. A1120 prevents retinol transport into RPE and may spare side effects typically seen with VCMs (nyctalopia and chromatopsia). Stem cell transplantation suggests potential biologic plausibility in a phase I/II trial. Gene therapy aims to augment the mutated ABCA4 gene, though results of a phase I/II trial are pending. Expert opinion: Stem cell transplantation, ABCA4 gene therapy, VCMs, and complement inhibitors offer biologically plausible treatment mechanisms for treatment of STGD1. Further trials are warranted to assess efficacy and safety in humans

Novel self-assembling cyclic peptides with reversible supramolecular nanostructures

Self-assembly peptides (SAPs) are an important class of hydrogels used in nanomedicine for tissue repair and neural regeneration. Due to their unique properties, SAPs may be used in a wide range of applications but some limitations, such as low bioavailability and rapid hydrolysis degradation, need to be overcome. Here, we describe the synthesis and characterization of two novel cyclic SAPs without the use of d/l-alternating amino acids, showing a reversible transition of their supramolecular nanostructures, from nanotubes/nanofibers into nanovesicles/nanospheres. The investigation, characterization and optimization are performed using atomic force microscopy (AFM), attenuated total reflectance-Fourier transform infrared (ATR-FTIR) spectroscopy, Raman analysis, circular dichroism (CD), and rheology measurements. Also, in vitro cell viability assays show negligible toxicity of the representative optimized cyclic SAP towards human neural stem cells (hNSCs). Our results suggest that linear SAP theoretical background can be applied to develop cyclic SAPs, with important implications in the scalable fabrication of inter-changeable nanostructures, as well as for biomedical applications, including tissue regeneration, drug-delivery, drug-design, sensing, imaging, and size selectivity

Gelation as arrested phase separation in short-ranged attractive colloid-polymer mixtures

We present further evidence that gelation is an arrested phase separation in attractive colloid-polymer mixtures, based on a method combining confocal microscopy experiments with numerical simulations recently established in {\bf Nature 453, 499 (2008)}. Our results are independent of the form of the interparticle attractive potential, and therefore should apply broadly to any attractive particle system with short-ranged, isotropic attractions. We also give additional characterization of the gel states in terms of their structure, inhomogeneous character and local density.Comment: 6 figures, to be published in J. Phys. Condens. Matter, special issue for EPS Liquids Conference 200

Identification of a Novel Pseudo-Natural Product Type IV IDO1 Inhibitor Chemotype

Natural product (NP)-inspired design principles provide invaluable guidance for bioactive compound discovery. Pseudo-natural products (PNPs) are de novo combinations of NP fragments to target biologically relevant chemical space not covered by NPs. We describe the design and synthesis of apoxidoles, a novel pseudo-NP class, whereby indole- and tetrahydropyridine fragments are linked in monopodal connectivity not found in nature. Apoxidoles are efficiently accessible by an enantioselective [4+2] annulation reaction. Biological evaluation revealed that apoxidoles define a new potent type IV inhibitor chemotype of indoleamine 2,3-dioxygenase 1 (IDO1), a heme-containing enzyme considered a target for the treatment of neurodegeneration, autoimmunity and cancer. Apoxidoles target apo-IDO1, prevent heme binding and induce unique amino acid positioning as revealed by crystal structure analysis. Novel type IV apo-IDO1 inhibitors are in high demand, and apoxidoles may provide new opportunities for chemical biology and medicinal chemistry research