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Jeremy WD McGowan,1 Qingmei Shao,1 Parminder JS Vig,1,2 Gene L Bidwell III1,2 1Department of Neurology, 2Department of Biochemistry, University of Mississippi Medical Center, Jackson, MS, USA Abstract: Bypassing the blood–brain barrier is one of the primary considerations when designing compounds intended to function in the central nervous system (CNS). Intranasal (IN) administration of otherwise blood–brain barrier impermeable molecules can result in high CNS concentrations and low systemic accumulation, indicating that IN administration may be a useful method of delivering therapeutics to the CNS. Elastin-like polypeptide (ELP) is a large, non-immunogenic, highly manipulable biopolymer with extensive evidence supporting its use as a carrier with the ability to improve drug pharmacokinetics and drug targeting. The ability of ELP to reach the CNS via IN administration has been shown previously. Previous studies have also identified the ability of cell penetrating peptides (CPPs) to increase the uptake of molecules in some instances, including via the IN route. Here, we compared and contrasted the biodistribution of ELPs with or without addition of the CPPs Tat or SynB1 via both the IN and intravenous routes. Administration of ELP via the IN route led to significant accumulation in the brain, especially in the olfactory bulbs. When injected intravenously,

Background: Tumor extirpation of nonmelanoma skin cancer (NMSC) adjacent to the alar groove, using Mohs micrographic surgery (MMS), may risk causing internal nasal valve (INV) collapse, resulting in reduced airflow during inspiration. There are many surgical options described in the literature to repair INV collapse as a postoperative corrective procedure, but few exist as an intra-operative preventative procedure., Objective: The authors present 2 distinct methods to prevent and treat INV collapse during the repair of a perialar surgical defect caused by MMS., Methods: A 3-point stitch method or a modified suspension suture technique was used to prevent INV collapse during the repair of MMS defects overlying the alar groove, for nonmelanoma skin cancers. The 3-point stitch was used with a complex repair. The modified suspension suture was used with flap reconstruction., Results: The 3-point stitch and the modified suspension suture are simple, single-stage surgical solutions for perialar defects with collapse of the INV caused by loss of subcutaneous tissue during MMS. Once executed, patients experienced immediate subjective airflow improvement which was also supported by clinical examination. Patients were followed at 1 week and at 3 months postoperatively. Thirty-four of 35 patients reported good functional and cosmetic results and were satisfied with the final outcome., Conclusion: The 3-point stitch and the modified suspension suture techniques are easy and simple methods that can be incorporated into reconstruction after MMS for defects of variable depth covering any multisubunit perialar region to prevent or correct INV collapse.

Fluorescent labeling is a well-established process for examining the fate of labeled molecules under a variety of experimental conditions both in vitro and in vivo. Fluorescent probes are particularly useful in determining the bio-distribution of administered large molecules, where the addition of a small-molecule fluorescent label is unlikely to affect the kinetics or bio-distribution of the compound. A variety of methods exist to examine bio-distribution that vary significantly in the amount of effort required and whether the resulting measurements are fully quantitative, but using multiple methods in conjunction can provide a rapid and effective system for analyzing bio-distributions. Ex vivo whole-organ imaging is a method that can be used to quickly compare the relative concentrations of fluorescent molecules within tissues and between multiple types of tissues or treatment groups. Using an imaging platform designed for live-animal or whole-organ imaging, fluorescence within intact tissues can be determined without further processing, saving time and labor while providing an accurate picture of the overall bio-distribution. This process is ideal in experiments attempting to determine the tissue specificity of a compound or for the comparison of multiple different compounds. Quantitative tissue histology on the other hand requires extensive further processing of tissues in order to create a quantitative measure of the labeled compounds. To accurately assess bio-distribution, all tissues of interest must be sliced, scanned, and analyzed relative to standard curves in order to make comparisons between tissues or groups. Quantitative tissue histology is the gold standard for determining absolute compound concentrations within tissues. Here, we describe how both methods can be used together effectively to assess the ability of different administration methods and compound modifications to target and deliver fluorescently labeled molecules to the central nervous system 1 .

Purpose of Review: Vascular endothelial growth factors (VEGFs) influence renal function through angiogenesis, with VEGF-A being the most potent inducer of vascular formation. In the normal glomerulus, tight homeostatic balance is maintained between the levels of VEGF-A isoforms produced by podocyte cells, and the VEGF receptors (VEGFRs) expressed by glomerular endothelial, mesangial, and podocyte cells. Renal disease occurs when this homeostatic balance is lost, manifesting in the abnormal autocrine and paracrine VEGF-A/VEGFR signaling, ultrastructural glomerular and tubular damage, and impaired filtration., Recent Findings: Preclinical disease models of ischemic renal injury, including acute ischemia/reperfusion, thrombotic microangiopathy, and chronic renovascular disease, treated with exogenous VEGF supplementation demonstrated therapeutic efficacy. These results suggest a therapeutic VEGF-A paracrine effect on endothelial cells in the context of acute or chronic obstructive ischemia. Conversely, renal dysfunction in diabetic nephropathy appears to occur through an upregulated VEGF autocrine effect on podocyte cells, which is exacerbated by hyperglycemia. Therefore, VEGF supplementation therapy may be contraindicated for treatment of diabetic nephropathy, but specific results will depend on dose and on the specific site of VEGF delivery. A drug delivery system that demonstrates cell specificity for glomerular or peritubular capillaries could be employed to restore balance to VEGF-A/VEGFR2 signaling, and by doing so, prevent the progression to end-stage renal disease., Summary: The review discusses the preclinical data available for VEGF supplementation therapy in models of renal disease.

Therapeutic peptides represent a largely untapped resource in medicine today, especially in the central nervous system. Despite their ease of design and remarkably high target specificity, it is difficult to deliver them beyond the blood-brain barrier or into the required intracellular compartments. In addition, the instability of these peptides in vivo precludes their use to combat the symptoms of numerous neurological disorders including Alzheimer's disease and spinocerebellar ataxia. In this review, we aim to characterize recent advances in the delivery of therapeutic peptides to the central nervous system past the blood-brain barrier and discuss the advantages and disadvantages of the examined methods as well as explore new potential directions.

Mosquito feeding patterns identify vertebrate species potentially involved in the amplification of West Nile virus. In New York, northern cardinals (Cardinalis cardinalis) were the predominant hosts in most habitats. Crow (Corvus sp.) blood meals were most frequently identified from sewage treatment plant and storm water catch basin habitats.

Background: Although melanoma accounts for only 4% to 5% of all skin cancers in the United States, it causes most skin cancer-related deaths. We describe a unique group of African-American patients with multiple primary acral lentiginous melanomas (ALMs)., Objective: The purpose of this study was to review the case histories and management of a cohort of patients in the Mohs practice of our dermatologic surgeon with multiple primary ALM., Methods: This is a case series of patients with multiple ALM identified by chart review from 2000 to 2005. A thorough review of the literature was performed., Results: Four patients, all African-American, were identified with multiple ALM. All patients were managed with excision or Mohs micrographic surgery utilizing permanent sections. None of the patients with ALM had melanomas at nonacral sites or other types of skin cancer. Several had acral melanosis. Information in the literature on patients with multiple primary acral melanomas was insufficient., Conclusion: Patients with multiple acral melanomas have not, to our knowledge, been reported thus far. It can be extrapolated from current literature, however, that appropriate management of these patients, including staging work and surgical intervention, is to be determined by the individual characteristics of the melanoma and the patient's concomitant risk factors, if any.

The balloon-cell nevus was first described over 100 years ago. Since then, balloon-cell changes of melanocytes have been noted in numerous tumors, including melanoma, blue nevus, and Spitz nevus. Whether these changes reflect cellular deterioration or proliferative changes is a matter of debate. We report a case in which balloon-cell changes were found within proliferative nodules occurring in a large congenital melanocytic nevus.

We report a case of vitiligo arising one year after human immunodeficiency virus (HIV) seropositivity but before clinical onset of acquired immunodeficiency syndrome (AIDS). To our knowledge, this specific time sequence has not been described. Generalization of such lesions began during a period of medical noncompliance, increasing viral load, rising CD8+ count, and markedly decreased CD4+ count. These findings suggest new mechanisms of autoimmune and infectious pathogenesis.

Unlabelled: We describe a patient with pyoderma gangrenosum (PG) whose lesions responded to etanercept therapy. This disease has been recognized for diverse underlying pathology and associated immune disturbances. Although the role of cytokines in pathogenesis is not fully understood, tumor necrosis factor alpha (TNF-alpha) may facilitate induction and maintenance of the disease. This is supported by the successful use of infliximab, a recombinant anti-TNF-alpha monoclonal antibody, in cases of PG associated with inflammatory bowel disease (IBD). Etanercept is a divalent recombinant fusion protein that binds soluble TNF-alpha. To our knowledge, the utility of etanercept for PG has not been reported. A patient with recalcitrant and widespread PG that was unresponsive to systemic corticosteroids was treated with etanercept. Rapid and complete clearing of the skin lesions was observed, and steroid taper to 5 mg/day was sustained for two months. Treatment was well-tolerated with no adverse reactions reported., Conclusions: Etanercept therapy offered rapid and complete resolution of all PG lesions. Such response supports the use of etanercept as a steroid-sparing agent in recalcitrant disease and suggests the role of TNF-alpha in pathogenesis of PG.

The targets for saccadic eye movements in natural visual scenes are spatially extended objects, yet saccades land at a single position within them. To characterize the spatial transformation that determines the saccadic goal position within attended objects, we studied saccadic localization of large patterns of random dots. Saccades landed with a high degree of precision near the center-of-gravity of the patterns (average error < 10%; SDs around the center-of-gravity = 7-11% of target eccentricity). Predictions of landing position were improved by using a weighted center-of-gravity, in which the weight assigned to each dot was reduced by the presence of neighboring dots. Weighting based either on the eccentricity of dots or their position relative to the boundary of the pattern had no effect. The results can be accounted for by a spatial transformation in which the "local signs" of an initial array of detectors, weighted by the activity of each, are averaged to yield the saccadic goal. This model can account for accurate and precise saccadic localization of large targets, while preserving sensitivity to local pattern characteristics. Unlike models of recognition, the boundary of the object has the same status as the internal details.

High resolution x-ray lithographic studies of cells from chick embryo hearts dried by the CO2 critical point method have been made with soft x-ray radiation of different wavelengths. A marked difference in the relief replica in polymethyl methacrylate (PMMA) resulting from the differential absorption by the dried cells of carbon K alpha radiation at 4.48 nm and broad band synchrotron radiation (SR) with lambda is greater than 1.5 nm demonstrates the potential usefulness of the technique in making high resolution (approximately or equal to 10 nm) chemical identification of the constitutents which make up the various parts of the cell.

A systematic electron microscopic study was made of the structure of foveal cones of Macaca spp. Transverse sections of inner (IS) and outer segments (OS) were made in sequence, from the pigment epithelial zone (PEZ) to the outer limiting membrane (OLM). The smallest diameters of hundreds of cone sections were measured from electron micrographs with a Zeiss particle-size analyzer, and analyzed statistically. Some details are also included about Cebus photoreceptors. It is claimed in the literature that foveal cones are rod-like (cylindrical) and untapered. Our study shows the foveolar cone to be a tapered structure. There has been some confusion between the foveola, which is rod-free, and the fovea, which has a high concentration of cones, but is not rod-free. Within the fovea, as the ratio of cones to rods falls from infinity to 1, with distance from the central bouquet of cones, the cone center-to-center distances increase, the inner segment diameters increase, and the number of cones/sq mm decreases. The tapered calycal processes are more massive in M. irus than M. mulatta, and the lateral fins are better developed. Lateral fins are not present in the foveola. The cones are arranged in straight lines.

In the retina from an eye enucleated for choroidal melanoma apposed rod outer segments were seen by transmission electron microscopy to be fusing together in groups by the confluence of their plasma membranes and the formation of cytoplasmic bridges between adjacent outer segments. These fusions were seen in areas distant from the melanoma but where the retina was not normal in appearance.

This study presents the topography as seen by scanning electron microscopy of the rabbit retina in general and the photoreceptors in particular; and of large laser lesions in the retina.

Novel retinal irradiation techniques for laser damage studies are described; these are straightforward applications of the Fourier transform properties of an optical system. Interposing an appropriate diffracting screen between the laser source and the test eye enables one to simultaneously induce a number of discrete and precisely located retinal exposures with a known gradation of energy. Various kinds of diffracting objects are considered, and it is seen that transparent sinusoidal phase gratings offer the most promise for damage threshold studies. The method provides an objective measure of the ocular focal length at the time of the exposure. The production of arbitrary retinal irradiation patterns for more general research or clinical applications is possible with the extension of the technique by the use of simple holographic methods for forming the appropriate diffracting screens.

Scanning electron microscopic (SEM) observations of the rabbit retinal pigment epithelium (RPE) are reported both for normal tissue and for tissue subjected to laser radiation. In normal RPE, cells were observed to be closely packed and to have the characteristic hexagonal shape. The microvilli were abundant and of two types. Suprathreshold lesions were produced with 0.4 musec pulses of high-intensity yellow light (585 nm.) from a dye laser. In the lased RPE, cells were denuded of their microvilli, and a number of cells with single discrete holes were observed. Hypertrophied cells were always present. Within 5 days of irradiation groups of small proliferating RPE cells were found in the lesion area.