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Cindy V Leiton,1,2 Elyssa Chen,2 Alissa Cutrone,3 Kristy Conn,2 Kennelia Mellanson,4 Dania M Malik,5 Michael Klingener,6 Ryan Lamm,7 Michael Cutrone,8 John Petrie IV,9 Joher Sheikh,10 Adriana DiBua,11 Betsy Cohen,12 Thomas F Floyd13–15 1Department of Pathology, Stony Brook University, Stony Brook, NY, USA; 2Department of Anesthesiology, Stony Brook University, Stony Brook, NY, USA; 3Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA; 4Department of Pharmacological Sciences, Stony Brook University, Stony Brook, NY, USA; 5Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, PA, USA; 6Department of Genetics, Stony Brook University, Stony Brook, NY, USA; 7Department of General Surgery, Thomas Jefferson University Hospital, Philadelphia, PA, USA; 8Department of Anesthesiology, Duke University Medical Center, Durham, NC, USA; 9Department of Biochemistry & Molecular Biology, Bloomberg School of Public health, Johns Hopkins University, Baltimore, MD, USA; 10Department of Physiology and Biophysics, Georgetown University, Washington, DC, USA; 11Department of Chemistry, Hofstra University, Hempstead, NY, USA; 12Computer Science Department, Swarthmore College, Swarthmore, PA, USA; 13Department of Anesthesiology and Pain Management, University of Texas Southwestern, Dallas, TX, USA; 14Department of Cardiothoracic Surgery, University of Texas Southwestern, Dallas, TX, USA; 15Department of Radiology, University of Texas Southwestern, Dallas, TX, USA Background: The brain is extensively vascularized, uses ~20% of the body’s oxygen, and is highly sensitive to changes in oxygen. While synaptic plasticity and memory are impaired in healthy individuals by exposure to mild hypoxia, aged individuals appear to be even more sensitive. Aging is associated with progressive failure in pulmonary and cardiovascular systems, exposing the aged to both chronic and superimposed acute hypoxia. The HIF proteins, the “master regulators” of the cellular response to hypoxia, are robustly expressed in neurons and astrocytes. Astrocytes support neurons and synaptic plasticity via complex metabolic and trophic mechanisms. The activity of HIF proteins in the brain is diminished with aging, and the increased exposure to chronic and acute hypoxia with aging combined with diminished HIF activity may impair synaptic plasticity. Purpose: Herein, we test the hypothesis that astrocyte HIF supports synaptic plasticity and learning upon hypoxia. Materials and Methods: An Astrocyte-specific HIF loss-of-function model was employed, where knock-out of HIF-1α or HIF-2α in GFAP expressing cells was accomplished by cre-mediated recombination. Animals were tested for behavioral (open field and rotarod), learning (passive avoidance paradigm), and electrophysiological (long term potentiation) responses to mild hypoxic challenge. Results: In an astrocyte-specific HIF loss-of-function model followed by mild hypoxia, we identified that the depletion of HIF-2α resulted in an impaired passive avoidance learning performance. This was accompanied by an attenuated response to induction in long-term potentiation (LTP), suggesting that the hippocampal circuitry was perturbed upon hypoxic exposure following HIF-2α loss in astrocytes, and not due to hippocampal cell death. We investigated HIF-regulated trophic and metabolic target genes and found that they were not regulated by HIF-2α, suggesting that these specific targets may not be involved in mediating the phenotypes observed. Conclusion: Together, these results point to a role for HIF-2α in the astrocyte’s regulatory role in synaptic plasticity and learning under hypoxia and suggest that even mild, acute hypoxic challenges can impair cognitive performance in the aged population who harbor impaired HIF function. Keywords: astrocyte, hypoxia, HIF, learning, LTP, tripartite synapse, memory, glia, cognitive function

The incidence of prepubertal melanoma is not raising in children, unlike adolescent and adult (24). Its incidence therefore remains so low that no center is able to do statistics only based on its cases. Over the past 40 years in five Italian Pediatric Dermatology centers 15 cases of melanoma in children aged under 12 years were observed, 4 of which associated with large or multiple congenital melanocytic nevi. The latter, including two cutaneous melanomas arising on congenital melanocytic nevi and 2 meningoencephalic melanomas, started early - average age at diagnosis 18 months - and had poor prognosis quoad vitam. The 11 melanomas arising on normal skin - 8 cases - or associated with small congenital - 1 case - or acquired - 2 cases - melanocytic nevi started at a later age - average age 9.2 years - and had a good prognosis despite average thickness of 2 mm and lymph node involvement in 3/11 cases. These two categories of prepubertal melanoma, though so different from each other, shared the same nodular or ulcerative non specific, often amelanotic clinical appearance. Therefore, they were different and more difficult to be diagnosed as compared with pigmented and usually initially superficial spreading adult melanoma.

Objective Juvenile localized scleroderma is a chronic progressive fibrotic disorder of the skin that causes permanent disability and aesthetic damage. This study was undertaken to assess the safety and efficacy of methotrexate (MTX) in the treatment of juvenile localized scleroderma. Methods In this double-blind study, patients with active juvenile localized scleroderma were randomized (2:1) to receive oral MTX (15 mg/m 2, maximum 20 mg) or placebo once weekly, for 12 months or until treatment failure. Both groups received oral prednisone (1 mg/kg/day, maximum 50 mg) for the first 3 months. A target lesion was evaluated clinically, with infrared thermography and using a computerized scoring system with skin score rate (SSR) evaluation. Response to treatment was defined as the absence of new lesions, SSR â1, and a decrease in lesion temperature of at least 10% compared to baseline. Treatment failure was defined as the occurrence of new lesions, SSR >1, or increased lesion temperature. All analyses were done on the intent-to-treat population. Results Of the 85 patients screened, 70 (ages 6-17 years) were randomized (46 to the MTX group, 24 to the placebo group). The mean disease duration was 2.3 years. After an initial response in all patients, disease relapsed in 15 MTX-treated patients (32.6%) and 17 placebo-treated patients (70.8%) (P ;lt& 0.005). New lesions appeared in 3 MTX-treated patients (6.5%) versus 4 placebo-treated patients (16.7%). The mean SSR decreased from 1 to 0.79 in the MTX group and increased from 1 to 1.1 in the placebo group, and the mean target lesion temperature decreased by 44.4% in the MTX group versus 12.1% in the placebo group. Twenty-six patients in the MTX group (56.5%) and 11 patients in the placebo group (45.8%) developed mild side effects related to treatment. None of the side effects were severe enough to necessitate treatment discontinuation. Conclusion Our findings indicate that MTX is efficacious in the treatment of juvenile localized scleroderma and is well tolerated. Copyright © 2011 by the American College of Rheumatology.

We present a study aimed at exploring whether a humanoid robot may improve the effectiveness of educational interventions targeting children with autism spectrum disorders (ASD). Preliminary results with three preschool children with ASD indicate that interacting with a humanoid robot may facilitate engagement and goal achievement in educational activities.