Signaling from blood vessels to CNS axons through nitric oxide

Brain function is usually perceived as being performed by neurons with the support of glial cells, the network of blood vessels situated nearby serving simply to provide nutrient and to dispose of metabolic waste. Revising this view, we find from experiments on a rodent central white matter tract (the optic nerve) in vitro that microvascular endothelial cells signal persistently to axons using nitric oxide (NO) derived from the endothelial NO synthase (eNOS). The endogenous NO acts to stimulate guanylyl cyclase-coupled NO receptors in the axons, leading to a raised cGMP level which then causes membrane depolarization, apparently by directly engaging hyperpolarization-activated cyclic nucleotide-gated ion channels. The tonic depolarization and associated endogenous NO-dependent cGMP generation was absent in optic nerves from mice lacking eNOS, although such nerves responded to exogenous NO, with raised cGMP generation in the axons and associated depolarization. In addition to the tonic activity, exposure of optic nerves to bradykinin, a classical stimulator of eNOS in endothelial cells, elicited reversible NO- and cGMP-dependent depolarization through activation of bradykinin B-2 receptors, to which eNOS is physically complexed. No contribution of other NO synthase isoforms to either the action of bradykinin or the continuous ambient NO level could be detected. The results suggest that microvascular endothelial cells participate in signal processing in the brain and can do so by generating both tonic and phasic NO signals

Merkel cell carcinoma: a review.

Merkel cell carcinoma (MCC) is a rare neuroendocrine tumor of unknown origin that usually presents in the elderly population. A novel polyomavirus has been associated with a large percentage of tumors. Immune response plays an important role in pathogenesis of MCC. This article reviews the history, pathogenesis, presentation, and treatment of MCC. Future treatments also are discussed briefly

Cutaneous Manifestations of Nutritional Deficiencies in the Context of Food Deserts of United States.

Food deserts exist due to a multitude of factors ranging from socioeconomic status, racial disparities, geography, cost, and healthful food access. Given the vast biological function of vitamins and minerals, the clinical presentation for nutritional deficiencies ranges from benign to life-threatening. Often, the first indicators of underlying nutritional deficiencies are cutaneous manifestations. The first patient case is a 36-year-old female at 25 weeks gestation with a pruritic and painful rash that began in the genital region and spread centrifugally to her legs. The second patient case is a 42-year-old male with a pruritic rash that began at his abdomen and progressed to his thighs. The third patient case is a 48-year-old female with scattered lower extremity ecchymoses in different healing stages and scattered perifollicular erythema with corkscrew hairs. All three patients were found to have nutritional deficiencies and lived in identified food deserts. Deficiencies of zinc, vitamin A, thiamine, pyridoxine, and vitamin C and their subsequent cutaneous manifestations have scarce documentation within food deserts. These cases provide further insight into nutritional deficiencies and offer an opportunity for providers to identify patients at risk. To promote wellness, patients suffering from food insecurity must be identified efficiently and connected with essential resources

Morphometrical features of left atrial appendage in the AF patients subjected to left atrial appendage closure

Background: This study aimed to evaluate the morphometrical features of left atrial appendage (LAA) in patients with atrial fibrillation, subjected to left atrial appendage percutaneous closure (LARIAT) for stroke prevention. Materials and methods: Computed tomography (CT) scans of 51 patients with atrial fibrillation subjected to LARIAT procedure were comparatively evaluated with 50 patients with sinus rhythm (control group). Three-dimensional (3D) reconstructions were created using volume-rendering for evaluation. Results: No differences were found in LAA types of distribution (cauliflower: 25.5 vs. 34.0%, chicken wing: 45.1 vs. 46.0%, windsock: 29.4 vs. 20.0%, all p>0.05) between groups. However, the study group was characterized by LAAs with a lower number of lobes. The LAA orifice anteroposterior and transverse diameters (19.3±4.12 vs. 17.2±4.0mm, p=0.01 and 25.1±5.1 vs. 20.5±4.4mm, p=0.001), orifice area (387.2±133.9 vs. 327.1±128.3mm2, p=0.02) and orifice perimeter (70.2±12.5 vs. 61.2±11.6mm, p=0.04) was significantly larger in atrial fibrillation patients. More oval LAA orifices was found in atrial fibrillation group (94.0 vs. 70.4%, p=0.001). No statistically significant differences were found in LAA body length (47.4±15.4 vs. 43.7±10.9mm, p=0.17), body width (24.7±5.6 vs. 24.4±5.8mm, p=0.81), and chamber depth (17.7±3.5 vs. 16.5±3.8mm, p=0.11). Calculated LAA ejection fraction was significantly lower in study group compared to healthy patients (16.4±14.9 vs. 48.2±12.9%, p=0.001). Conclusions: Important morphometrical differences in LAA orifice have been found, which was significantly larger and more oval in patients with atrial fibrillation compared to healthy controls. Although no difference in LAA body type and size was observed; the LAA ejection fraction was significantly lower in atrial fibrillation rhythm patients

Cognitive Aging in Zebrafish

BACKGROUND: Age-related impairments in cognitive functions represent a growing clinical and social issue. Genetic and behavioral characterization of animal models can provide critical information on the intrinsic and environmental factors that determine the deterioration or preservation of cognitive abilities throughout life. METHODOLOGY/PRINCIPAL FINDINGS: Behavior of wild-type, mutant and gamma-irradiated zebrafish (Danio rerio) was documented using image-analysis technique. Conditioned responses to spatial, visual and temporal cues were investigated in young, middle-aged and old animals. The results demonstrate that zebrafish aging is associated with changes in cognitive responses to emotionally positive and negative experiences, reduced generalization of adaptive associations, increased stereotypic and reduced exploratory behavior and altered temporal entrainment. Genetic upregulation of cholinergic transmission attenuates cognitive decline in middle-aged achesb55/+ mutants, compared to wild-type siblings. In contrast, the genotoxic stress of gamma-irradiation accelerates the onset of cognitive impairment in young zebrafish. CONCLUSIONS/SIGNIFICANCE: These findings would allow the use of powerful molecular biological resources accumulated in the zebrafish field to address the mechanisms of cognitive senescence, and promote the search for therapeutic strategies which may attenuate age-related cognitive decline

The Redox Enzyme p66Shc Contributes to Diabetes and Ischemia-Induced Delay in Cutaneous Wound Healing

OBJECTIVE: The redox enzyme p66Shc produces hydrogen peroxide and triggers proapoptotic signals. Genetic deletion of p66Shc prolongs life span and protects against oxidative stress. In the present study, we evaluated the role of p66Shc in an animal model of diabetic wound healing. RESEARCH DESIGN AND METHODS: Skin wounds were created in wild-type (WT) and p66Shc(-/-) control and streptozotocin-induced diabetic mice with or without hind limb ischemia. Wounds were assessed for collagen content, thickness and vascularity of granulation tissue, apoptosis, reepithelialization, and expression of c-myc and beta-catenin. Response to hind limb ischemia was also evaluated. RESULTS: Diabetes delayed wound healing in WT mice with reduced granulation tissue thickness and vascularity, increased apoptosis, epithelial expression of c-myc, and nuclear localization of beta-catenin. These nonhealing features were worsened by hind limb ischemia. Diabetes induced p66Shc expression and activation; wound healing was significantly faster in p66Shc(-/-) than in WT diabetic mice, with or without hind limb ischemia, at 1 and 3 months of diabetes duration and in both SV129 and C57BL/6 genetic backgrounds. Deletion of p66Shc reversed nonhealing features, with increased collagen content and granulation tissue thickness, and reduced apoptosis and expression of c-myc and beta-catenin. p66Shc deletion improved response to hind limb ischemia in diabetic mice in terms of tissue damage, capillary density, and perfusion. Migration of p66Shc(-/-) dermal fibroblasts in vitro was significantly faster than WT fibroblasts under both high glucose and hypoxia. CONCLUSIONS: p66Shc is involved in the delayed wound-healing process in the setting of diabetes and ischemia. Thus, p66Shc may represent a potential therapeutic target against this disabling diabetes complication

Binary-induced magnetic activity? Time-series echelle spectroscopy and photometry of HD123351 = CZ CVn

We present a first and detailed study of the bright and active K0IV-III star HD 123351. The star is found to be a single-lined spectroscopic binary with a period of 147.8919+-0.0003 days and a large eccentricity of e=0.8086+-0.0001. The rms of the orbital solution is just 47 m/s, making it the most precise orbit ever obtained for an active binary system. The rotation period is constrained from long-term photometry to be 58.32+-0.01 days. It shows that HD 123351 is a very asynchronous rotator, rotating five times slower than the expected pseudo-synchronous value. Two spotted regions persisted throughout the 12 years of our observations. Four years of Halpha, CaII H&K and HeI D3 monitoring identifies the same main periodicity as the photometry but dynamic spectra also indicate that there is an intermittent dependence on the orbital period, in particular for Ca ii H&K in 2008. Line-profile inversions of a pair of Zeeman sensitive/insensitive iron lines yield an average surface magnetic-flux density of 542+-72 G. The time series for 2008 is modulated by the stellar rotation as well as the orbital motion, such that the magnetic flux is generally weaker during times of periastron and that the chromospheric emissions vary in anti-phase with the magnetic flux. We also identify a broad and asymmetric lithium line profile and measure an abundance of log n(Li) = 1.70+-0.05. The star's position in the H-R diagram indicates a mass of 1.2+-0.1 Msun and an age of 6-7 Gyr. We interpret the anti-phase relation of the magnetic flux with the chromospheric emissions as evidence that there are two magnetic fields present at the same time, a localized surface magnetic field associated with spots and a global field that is oriented towards the (low-mass) secondary component