A model of corrective gene transfer in X-linked ichthyosis

Single gene recessive genetic skin disorders offer attractive prototypes for the development of therapeutic cutaneous gene delivery. We have utilized X-linked ichthyosis (XLI), characterized by loss of function of the steroid sulfatase arylsulfatase C (STS), to develop a model of corrective gene delivery to human skin in vivo. A new retroviral expression vector was produced and utilized to effect STS gene transfer to primary keratinocytes from XLI patients. Transduction was associated with restoration of full-length STS protein expression as well as steroid sulfatase enzymatic activity in proportion to the number of proviral integrations in XLI cells. Transduced and uncorrected XLI keratinocytes, along with normal controls, were then grafted onto immunodeficient mice to regenerate full thickness human epidermis. Unmodified XLI keratinocytes regenerated a hyperkeratotic epidermis lacking STS expression with defective skin barrier function, effectively recapitulating the human disease in vivo. Transduced XLI keratinocytes from the same patients, however, regenerated epidermis histologically indistinguishable from that formed by keratinocytes from patients with normal skin. Transduced XLI epidermis demonstrated STS expression in vivo by immunostaining as well as a normalization of histologic appearance at 5 weeks post-grafting. In addition, transduced XLI epidermis demonstrated a return of barrier function parameters to normal. These findings demonstrate corrective gene delivery in human XLI patient skin tissue at both molecular and functional levels and provide a model of human cutaneous gene therapy.      

Prevalence of Deficient Retro-Aortic Rim and Its Effects on Outcomes in Device Closure of Atrial Septal Defects

Deficient retro-aortic rim is of concern as a risk factor for aortic erosion after device closure of atrial septal defects (ASD). However, its prevalence and contribution to technical failure and adverse outcomes have not been delineated. A single-center retrospective cohort study of children and adults undergoing cardiac catheterization for device occlusion of ASD from 1 January 1999 to 1 April 2012 was performed. Risk factors for technical failure and early adverse outcome were assessed using multivariate logistic regression. During the study period, 445 consecutive subjects with a median age of 5.9 years (range, 0.8–80 years) underwent catheterization. Of the subjects with reviewable echocardiograms, 60 % had deficient retro-aortic rim. No attempt at device closure was made for 3.6 % of the subjects. Of the remaining 429 subjects, 96 % underwent successful device occlusion. Major early adverse events occurred in 1.2 % (95 % confidence interval 0.4–2.7 %) of the cases, all of them either device embolization or malposition. Deficient retro-aortic rim was not a risk factor for composite outcome of technical failure or early major adverse event. No deaths, late reinterventions, or erosion events occurred during 2,395 total person-years (median, 5.8 years) of follow-up evaluation. Deficient retro-aortic rim was associated with increased risk of device impingement on the aorta, but no association was seen between device impingement or deficient retro-aortic rim and the development of new/progressive aortic insufficiency. Deficient retro-aortic rim is highly prevalent but did not increase the risk of adverse outcomes. Its contribution to the risk of aortic erosion could not be addressed by this study.     

Effect of inpatient psychiatry training on internal medicine residents. Results of a survey

Forty-two residents in internal medicine completed an attitudinal survey at the beginning and end of a 2-month inpatient psychiatry rotation. Residents noted a significant increase in their confidence regarding the management of various psychiatric problems and personality problems, the conducting of supportive counseling, the making of psychiatric referrals, the usefulness of psychotherapy, and the ability to discuss emotionally difficult subjects with patients. The rotation was perceived as being worthwhile and enjoyable. Areas of uncertainty that remained included concern regarding the time demands, the perception that psychiatric patients are anxiety-provoking and difficult to treat, and that psychiatric knowledge was an extension of common sense.     

The Natural History of Human Papillomavirus (HPV) Atypia of the Cervix

This study examines the natural history of human papilloma virus (HPV) atypia of the cervix in 259 untreated patients who were followed for 3 to 74 months (median 18 months). Progression to cervical intraepithelial neoplasia (CIN) occurred in 41 patients (15.8%)--all but 3 progressions occurred within the first 24 months of follow-up. In no patient did invasive cancer develop during this study. Persistence occurred in 39.4% and regression in 44.8% patients. An increasing number of regressions were noted with the passage of time. Progression to histologically confirmed CIN which occurred in 23 of 46 (50%) patients in whom both the cytological and colposcopic assessment at the first visit suggested CIN did so significantly more frequently than when either the cytology or colposcopy alone suggested CIN (11 progressions in 83 patients--13.3%, p less than .00001) or when neither cytology nor colposcopy suggested CIN (7 progressions in 119 patients--5.9%, p less than .000001). We recommend that patients with both cytological and colposcopic features suggestive of CIN should be treated even though HPV atypia only is reported on biopsy. Those who are not treated should be followed closely until regression occurs and consideration should be given to treating those patients in whom the abnormality persists longer than 2 years.     

Design and Objectives of the Evaluation of Oral Xemilofiban in Controlling Thrombotic Events (EXCITE) Study

Clinical trials have demonstrated the efficacy of glycoprotein (GP) IIb/IIIa antagonists in preventing the thrombotic end points of death, myocardial infarction, and urgent revascularization when they are administered at the time of percutaneous coronary revascularization (PTCR). It has been postulated that prolongation of receptor blockade beyond acute intervention would extend the clinical benefit of these agents. The Evaluation of Oral Xemilofiban in Controlling Thrombotic Events (EXCITE) study was a multicenter, international, randomized placebo-controlled trial of the oral GP IIb/IIIa antagonist Xemilofiban administered prior to and after PTCR. The study was designed to assess the efficacy and safety of continuing oral xemilofiban for 6 months to prevent these primary thrombotic end points. More than 7,200 patients were randomized in 29 countries to receive placebo or one of two doses of xemilofiban. Stenting was performed at the discretion of the operator. All patients received aspirin and periprocedural heparin; all stented patients received continuous xemilofiban, or ticlopidine for 2–4 weeks followed by xemilofiban-placebo. Most patients were also evaluated 1 month after conclusion of the study drug treatment. Clinical data from up to 6 months of drug treatment and 1 month posttreatment were used to evaluate the acute and long-term efficacy and safety of xemilofiban. Secondary end points included the need for any revascularization, repeat hospitalization for unstable angina, and nonhemorrhagic stroke. The cumulative incidence of bleeding events and effects of xemilofiban in stented and nonstented patients were evaluated. The efficacy of continuing xemilofiban and aspirin therapy as the sole antithrombotic medications following stent deployment was assessed against a ticlopidine and aspirin control group. The incremental clinical benefit of long-term receptor blockade over acute receptor antagonism was evaluated.