The continuous renewal of human epidermis is sustained by stem cells contained in the epidermal basal layer and in hair follicles. Cultured keratinocyte stem cells, known as holoclones, generate sheets of epithelium used to restore severe skin, mucosal and corneal defects. Mutations in genes encoding the basement membrane component laminin 5 (LAM5) cause junctional epidermolysis bullosa (JEB), a devastating and often fatal skin adhesion disorder. Epidermal stem cells from an adult patient affected by LAM5-beta3-deficient JEB were transduced with a retroviral vector expressing LAMB3 cDNA (encoding LAM5-beta3), and used to prepare genetically corrected cultured epidermal grafts. Nine grafts were transplanted onto surgically prepared regions of the patient's legs. Engraftment was complete after 8 d. Synthesis and proper assembly of normal levels of functional LAM5 were observed, together with the development of a firmly adherent epidermis that remained stable for the duration of the follow-up (1 year) in the absence of blisters, infections, inflammation or immune response. Retroviral integration site analysis indicated that the regenerated epidermis is maintained by a defined repertoire of transduced stem cells. These data show that ex vivo gene therapy of JEB is feasible and leads to full functional correction of the disease.

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Objective-Hypercholesterolemia is an early risk factor for Alzheimer's disease. Low density lipoprotein (LDL) receptors may be involved in this disorder. Our objective was to determine the risk of mild cognitive impairment in a population of patients with heterozygous familial hypercholesterolemia, a condition involving LDL receptors dysfunction and life long hypercholesterolemia.Methods-Using a cohort study design, patients with (N=47) meeting inclusion criteria and comparison patients without familial hypercholesterolemia (N=70) were consecutively selected from academic specialty and primary care clinics respectively. All patients were older than 50 years. Those with disorders which could impact cognition, including history of stroke or transient ischemic attacks, were excluded from both groups. Thirteen standardized neuropsychological tests were performed in all subjects. Mutational analysis was performed in patients with familial hypercholesterolemia and brain imaging was obtained in those with familial hypercholesterolemia and mild cognitive impairment. All authors have full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. None of the authors report any conflicts of interest.None of the authors report any conflicts of interest.Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author ManuscriptAm J Med. Author manuscript; available in PMC 2011 March 1. Results-Patients with familial hypercholesterolemia showed a very high incidence of mild cognitive impairment compared to those without familial hypercholesterolemia (21.3% vs. 2.9%; p = 0.00). This diagnosis was unrelated to structural pathology or white matter disease. There were significant differences between the familial hypercholesterolemia and the no-familial hypercholesterolemia groups in several cognitive measures, all in the direction of worse performance for familial hypercholesterolemia patients, independent of apoE4 or apoE2 status.Conclusions-Because prior studies have shown that older patients with sporadic hypercholesterolemia do not show higher incidence of mild cognitive impairment, the findings presented here suggest that early exposure to elevated cholesterol or LDL receptors dysfunction may be risk factors for mild cognitive impairment.

Background and Purpose-We sought to explore the safety and efficacy of the new TREVO stent-like retriever in consecutive patients with acute stroke. Methods-We conducted a prospective, single-center study of 60 patients (mean age, 71.3 years; male 47%) with stroke lasting Ͻ8 hours in the anterior circulation (nϭ54) or Ͻ12 hours in the vertebrobasilar circulation (nϭ6) treated if CT perfusion/CT angiography confirmed a large artery occlusion, ruled out a malignant profile, or showed target mismatch if symptoms Ͼ4.5 hours. Successful recanalization (Thrombolysis In Cerebral Infarction 2b-3), good outcome (modified Rankin Scale score 0 -2) and mortality at Day 90, device-related complications, and symptomatic hemorrhage (parenchymal hematoma Type 1 or parenchymal hematoma Type 2 and National Institutes of Health Stroke Scale score increment Ն4 points) were prospectively assessed. Results-Median (interquartile range) National Institutes of Health Stroke Scale score on admission was 18 (12-22). The median (interquartile range) time from stroke onset to groin puncture was 210 (173-296) minutes. Successful revascularization was obtained in 44 (73.3%) of the cases when only the TREVO device was used and in 52 (86.7%) when other devices or additional intra-arterial tissue-type plasminogen activator were also required. The median time (interquartile range) of the procedure was 80 (45-114) minutes. Good outcome was achieved in 27 (45%) of the patients and the mortality rate was 28.3%. Seven patients (11.7%) presented a symptomatic intracranial hemorrhage. No other major complications were detected. Conclusions-The TREVO device was reasonably safe and effective in patients with severe stroke. These results support further investigation of the TREVO device in multicentric registries and randomized clinical trials. (Stroke.

Background and Purpose-The value of multimodal CT to assist thrombolysis has received little attention in stroke. Methods-We assessed prospectively the impact derived from the routine application of CT perfusion and CTA in patients with acute stroke treated consecutively with alteplase. The safety and efficacy of thrombolytic therapy were compared in 106 patients assisted with CT/CTA/CT perfusion (multimodal CT group) and 262 patients assisted without full multimodal brain imaging (control group) during a 5-year period (2005)(2006)(2007)(2008)(2009). Results-Good outcome (modified Rankin scale score Յ2) at 3 months was increased in the multimodal group compared with controls (adjusted OR, 2.88; 95% CI, 1.50 -5.52). Multimodal-assisted thrombolysis yielded superior benefits in patients treated beyond 3 hours (adjusted OR, 4.48; 95% CI, 1.68 -11.98) than treated within 3 hours (adjusted OR, 1.31; 95% CI, 0.80 -2.16; interaction test Pϭ0.043). Mortality (14% and 15%) and symptomatic hemorrhage (5% and 7%) were similar in both groups. Conclusions-Multimodal CT use in routine clinical practice may heighten the overall efficacy of thrombolytic therapy in acute ischemic stroke. The benefits seem greater in patients treated Ͼ3 hours after stroke onset, but further randomized clinical trials are needed to confirm these findings.

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