Obese rats with deficient leptin signaling exhibit heightened sensitivity to olfactory food cues.

The Zucker rat is used as a model of genetic obesity, and while Zucker rats have been well studied for their reduced sensitivity to leptin signaling and subsequent weight gain, little work has examined their responses to environmental signals that are associated with "hedonic" feeding. This study evaluated the effects of a high-fat food olfactory cue (bacon) in stimulating nose-poke food-seeking behavior on first exposure (novel) and after a period of access for consumption (familiar) in lean and obese Zucker rats at either 4 or 12 months of age, and under ad-lib fed (unrestricted; U) or chronically food-restricted (70% of ad-lib; R) conditions. Baseline nose-poke levels were comparable amongst all groups.

The effect of cone opsin mutations on retinal structure and the integrity of the photoreceptor mosaic.

Purpose: To evaluate retinal structure and photoreceptor mosaic integrity in subjects with OPN1LW and OPN1MW mutations.

Methods: Eleven subjects were recruited, eight of whom have been previously described. Cone and rod density was measured using images of the photoreceptor mosaic obtained from an adaptive optics scanning light ophthalmoscope (AOSLO).

Assessing retinal structure in complete congenital stationary night blindness and Oguchi disease.

Purpose: To examine retinal structure and changes in photoreceptor intensity after dark adaptation in patients with complete congenital stationary night blindness and Oguchi disease.

Design: Prospective, observational case series.

Methods: We recruited 3 patients with complete congenital stationary night blindness caused by mutations in GRM6, 2 brothers with Oguchi disease caused by mutations in GRK1, and 1 normal control.

Preclinical characterization of ABT-348, a kinase inhibitor targeting the aurora, vascular endothelial growth factor receptor/platelet-derived growth factor receptor, and Src kinase families.

ABT-348 [1-(4-(4-amino-7-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)thieno[3,2-c]pyridin-3-yl)phenyl)-3-(3-fluorophenyl)urea] is a novel ATP-competitive multitargeted kinase inhibitor with nanomolar potency (IC(50)) for inhibiting binding and cellular autophosphorylation of Aurora B (7 and 13 nM), C (1 and 13 nM), and A (120 and 189 nM). Cellular activity against Aurora B is reflected by inhibition of phosphorylation of histone H3, induction of polyploidy, and inhibition of proliferation of a variety of leukemia, lymphoma, and solid tumor cell lines (IC(50) = 0.3-21 nM).

Retroperitoneal extra-adrenal ganglioneuroma involving the infrahepatic inferior vena cava, celiac axis and superior mesenteric artery: A case report.

Introduction: Ganglioneuromas are rare benign neoplasms arising from the sympathetic neuroendocrine system. These tumors usually occur in the abdomen and tend to grow around major blood vessels making often their complete excision challenging and demanding.

Presentation Of Case: The authors present the challenging surgical management of a sizable retroperitoneal extra-adrenal ganglioneuroma involving the infrahepatic inferior vena cava, portal triad, celiac axis and superior mesenteric artery in a 23-year-old female patient.

Exploration of diverse hinge-binding scaffolds for selective Aurora kinase inhibitors.

Four hinge-binding scaffolds have been explored for novel selective Aurora kinase inhibitors. The structure activity relationship, selectivity and pharmacokinetic profiles have been evaluated.

Dopamine-related frontostriatal abnormalities in obesity and binge-eating disorder: emerging evidence for developmental psychopathology.

Obesity and binge-eating disorder (BED) frequently arise in adolescence, which is a critical developmental time period where self-regulatory processes are formed. Indeed, both obesity and BED are thought to arise partly due to deficits in self-regulatory processes (i.e.

Pyrazole diaminopyrimidines as dual inhibitors of KDR and Aurora B kinases.

In an effort to identify kinase inhibitors with dual KDR/Aurora B activity and improved aqueous solubility compared to the Abbott dual inhibitor ABT-348, a series of novel pyrazole pyrimidines structurally related to kinase inhibitor AS703569 were prepared. SAR work provided analogs with significant cellular activity, measureable aqueous solubility and moderate antitumor activity in a mouse tumor model after weekly ip dosing. Unfortunately these compounds were pan-kinase inhibitors that suffered from narrow therapeutic indices which prohibited their use as antitumor agents.

Deep intronic mutation in OFD1, identified by targeted genomic next-generation sequencing, causes a severe form of X-linked retinitis pigmentosa (RP23).

X-linked retinitis pigmentosa (XLRP) is genetically heterogeneous with two causative genes identified, RPGR and RP2. We previously mapped a locus for a severe form of XLRP, RP23, to a 10.71 Mb interval on Xp22.

Developmental macular disorders: phenotypes and underlying molecular genetic basis.

The developmental macular disorders form part of a heterogeneous group of retinal conditions that are an important cause of visual impairment in children. The macular abnormality is present from birth and is usually non-progressive but visual loss may occur as a result of complications such as choroidal neovascularisation. To date, most of the causative genes have not been identified but with the advent of next generation sequencing, it is likely that the genetic basis of these disorders will soon be elucidated.

A 2-year prospective randomized controlled trial of intravitreal bevacizumab or laser therapy (BOLT) in the management of diabetic macular edema: 24-month data: report 3.

Objective: To report the 2-year outcomes of the BOLT study, a prospective randomized controlled trial evaluating intravitreous bevacizumab and modified Early Treatment Diabetic Retinopathy Study (ETDRS) macular laser therapy (MLT) in patients with persistent clinically significant macular edema (CSME).

Methods: In a 2-year, single-center, randomized controlled trial, 80 patients with center-involving CSME and visual acuity of 20/40 to 20/320 were randomized to receive either bevacizumab or MLT.

Primary Outcome: difference in ETDRS best-corrected visual acuity (BCVA) between arms.

Thienopyridine ureas as dual inhibitors of the VEGF and Aurora kinase families.

In an effort to identify multi-targeted kinase inhibitors with a novel spectrum of kinase activity, a screen of Abbott proprietary KDR inhibitors against a broad panel of kinases was conducted and revealed a series of thienopyridine ureas with promising activity against the Aurora kinases. Modification of the diphenyl urea and C7 moiety of these compounds provided potent inhibitors with good pharmacokinetic profiles that were efficacious in mouse tumor models after oral dosing. Compound 2 (ABT-348) of this series is currently undergoing Phase I clinical trials in solid and hematological cancer populations.

Leber congenital amaurosis associated with AIPL1: challenges in ascribing disease causation, clinical findings, and implications for gene therapy.

Leber Congenital Amaurosis (LCA) and Early Childhood Onset Severe Retinal Dystrophy are clinically and genetically heterogeneous retinal disorders characterised by visual impairment and nystagmus from birth or early infancy. We investigated the prevalence of sequence variants in AIPL1 in a large cohort of such patients (n = 392) and probed the likelihood of disease-causation of the identified variants, subsequently undertaking a detailed assessment of the phenotype of patients with disease-causing mutations. Genomic DNA samples were screened for known variants in the AIPL1 gene using a microarray LCA chip, with 153 of these cases then being directly sequenced.

Parallel factor analysis of ovarian autofluorescence as a cancer diagnostic.

Background And Objectives: Endogenous fluorescence from certain amino acids, structural proteins, and enzymatic co-factors in tissue is altered by carcinogenesis. We evaluate the potential of these changes in fluorescence to predict a diagnosis of malignancy and to estimate the risk of developing ovarian cancer.

Study Design/materials And Methods: Ovarian biopsies were interrogated over 270-550 nm excitation and fluorescence was collected from 290 to 700 nm.

X-linked megalocornea caused by mutations in CHRDL1 identifies an essential role for ventroptin in anterior segment development.

X-linked megalocornea (MGC1) is an ocular anterior segment disorder characterized by an increased cornea diameter and deep anterior chamber evident at birth and later onset of mosaic corneal degeneration (shagreen), arcus juvenilis, and presenile cataracts. We identified copy-number variation, frameshift, missense, splice-site and nonsense mutations in the Chordin-like 1 gene (CHRDL1) on Xq23 as the cause of the condition in seven MGC1 families. CHRDL1 encodes ventroptin, a bone morphogenic protein antagonist with a proposed role in specification of topographic retinotectal projections.

Translational neuroimaging in drug addiction and obesity.

The use of translational noninvasive neuroimaging has revealed that drug addiction and obesity share striking similarities in functional impairment in discrete brain regions and neurotransmitter circuits. Imaging experiments in both humans and rodents (using complementary experimental designs) show similar abnormalities in brain glucose metabolism in the prefrontal cortex (involved in inhibitory control) and hippocampus (memory) as well as impairments in dopamine signaling in the striatum (involved in food and drug reward, goal orientation, motivation, and habit formation). In both species, many of these observations have been obtained through concurrent and parallel monitoring of both brain activity and behavioral manifestations during drug administration, food sensory (visual, olfactory) stimulation, and craving.

Unilateral vitelliform maculopathy: a comprehensive phenotype study with molecular screening of BEST1 and PRPH2.

Aim: To describe the clinical features of a case series of patients with unilateral vitelliform maculopathy and the results of screening BEST1 and PRPH2 for disease-causing mutations.

Design/methods: This was a retrospective case series study of six patients ascertained over a 2-year period. Ophthalmological examination, fundus photography, autofluorescence imaging, optical coherence tomography and detailed electrophysiological assessment were undertaken.

A new variant of Todani type I choledochal cyst. Imaging evaluation.

Background And Aim: Choledochal cysts are congenital segmental aneurysmal dilatations of any portion of bile ducts, most commonly of the main portion of the common bile duct. The classification system of choledochal cysts is based on the site of the cyst or dilatation and currently includes 5 major types. The purpose of our study is to describe the imaging findings of a new variant of choledochal cyst.

Posterior mediastinal Castleman's disease presented as hypervascular lipomatous tumor.

Castleman's disease (CD) is a rare lymphoproliferative disorder most often found in the chest. Herein we describe the imaging findings of a histologically proven case of CD involving the posterior mediastinum in a 41-year-old asymptomatic man presented as a well-defined hypervascular lipomatous tumor. To our knowledge less than 10 cases of posterior mediastinal CD have been reported so far and this is the first case of CD mimicking mediastinal lipomatous tumor.

PET imaging predicts future body weight and cocaine preference.

Deficits in dopamine D2/D3 receptor (D2R/D3R) binding availability using PET imaging have been reported in obese humans and rodents. Similar deficits have been reported in cocaine-addicts and cocaine-exposed primates. We found that D2R/D3R binding availability negatively correlated with measures of body weight at the time of scan (ventral striatum), at 1 (ventral striatum) and 2 months (dorsal and ventral striatum) post scan in rats.

Discovery of potent and selective thienopyrimidine inhibitors of Aurora kinases.

In an effort to discover Aurora kinase inhibitors, an HTS hit revealed an amide containing pyrrolopyrimidine compound. Replacement of the pyrrolopyrimidine residue with a thienopyrimidine moiety led to a series of potent and selective Aurora inhibitors.

D-cycloserine facilitates extinction of cocaine self-administration in C57 mice.

Introduction: Cocaine is a highly addictive drug of abuse for which there are currently no medications. In rats and mice d-cycloserine (DCS), a partial NMDA agonist, accelerates extinction of cocaine seeking behavior. Since cues delay extinction here, we evaluated the effects d-cycloserine in extinction with and without the presence of cues.

High-resolution optical coherence tomography imaging in KCNV2 retinopathy.

Aim: To report novel spectral domain optical coherence tomography (SD-OCT) findings and new mutational data in patients with 'cone dystrophy with supernormal rod electroretinogram', a recessive childhood onset retinal dystrophy consequent upon mutation in the KCNV2 gene.

Design/methods: This was a comparative case series study of 12 patients with clinical and/or electrophysiological findings in keeping with KCNV2 mutation. Clinical examination and electrophysiological testing results were reviewed.