The SPRED1 Variants Repository for Legius Syndrome

Legius syndrome (LS) is an autosomal dominant disorder caused by germline loss-of-function mutations in the sprouty-related, EVH1 domain containing 1 (SPRED1) gene. The phenotype of LS is multiple café au lait macules (CALM) with other commonly reported manifestations, including intertriginous freckling, lipomas, macrocephaly, and learning disabilities including ADHD and developmental delays. Since the earliest signs of LS and neurofibromatosis type 1 (NF1) syndrome are pigmentary findings, the two are indistinguishable and individuals with LS may meet the National Institutes of Health diagnostic criteria for NF1 syndrome. However, individuals are not known to have an increased risk for developing tumors (compared with NF1 patients). It is therefore important to fully characterize the phenotype differences between NF1 and LS because the prognoses of these two disorders differ greatly. We have developed a mutation database that characterizes the known variants in the SPRED1 gene in an effort to facilitate this process for testing and interpreting results. This database is free to the public and will be updated quarterly

Volumetric Measurements of Lung Nodules with Multi-Detector Row CT: Effect of Changes in Lung Volume

OBJECTIVE: To evaluate how changes in lung volume affect volumetric measurements of lung nodules using a multi-detector row CT. MATERIALS AND METHODS: Ten subjects with asthma or chronic bronchitis who had one or more lung nodules were included. For each subject, two sets of CT images were obtained at inspiration and at expiration. A total of 33 nodules (23 nodules > or =3 mm) were identified and their volume measured using a semiautomatic volume measurement program. Differences between nodule volume on inspiration and expiration were compared using the paired t-test. Percent differences, between on inspiration and expiration, in nodule attenuation, total lung volume, whole lung attenuation, and regional lung attenuation, were computed and compared with percent difference in nodule volume determined by linear correlation analysis. RESULTS: The difference in nodule volume observed between inspiration and expiration was significant (p or =3 mm. The volume of nodules was measured to be larger on expiration CT than on inspiration CT (28 out of 33 nodules; 19 out of 23 nodules > or =3 mm). A statistically significant correlation was found between the percent difference of lung nodule volume and lung volume or regional lung attenuation (p or =3 mm. CONCLUSION: Volumetric measurements of pulmonary nodules were significantly affected by changes in lung volume. The variability in this respiration-related measurement should be considered to determine whether growth has occurred in a lung nodule.Supported by in part NIH NHLBI, RO1 HL 69149 and by a grant from Electronics and Telecommunications Research Institute

Imaging of Acute Lung Injury

Acute lung injury (ALI) is the clinical syndrome associated with histopathologic diffuse alveolar damage. It is a common cause of acute respiratory symptoms and admission to the intensive care unit. Diagnosis of ALI is typically based on clinical and radiographic criteria; however, because these criteria can be nonspecific, diagnostic uncertainty is common. A multidisciplinary approach that synthesizes clinical, imaging, and pathologic data can ensure an accurate diagnosis. Radiologists must be aware of the radiographic and computed tomographic findings of ALI and its mimics. This article discusses the multidisciplinary diagnosis of ALI from the perspective of the imager

Phase 3 trials of ixekizumab in moderate-to-severe plaque psoriasis

BACKGROUND Two phase 3 trials (UNCOVER-2 and UNCOVER-3) showed that at 12 weeks of treatment, ixekizumab, a monoclonal antibody against interleukin-17A, was superior to placebo and etanercept in the treatment of moderate-to-severe psoriasis. We report the 60-week data from the UNCOVER-2 and UNCOVER-3 trials, as well as 12-week and 60-week data from a third phase 3 trial, UNCOVER-1. METHODS We randomly assigned 1296 patients in the UNCOVER-1 trial, 1224 patients in the UNCOVER-2 trial, and 1346 patients in the UNCOVER-3 trial to receive subcutaneous injections of placebo (placebo group), 80 mg of ixekizumab every 2 weeks after a starting dose of 160 mg (2-wk dosing group), or 80 mg of ixekizumab every 4 weeks after a starting dose of 160 mg (4-wk dosing group). Additional cohorts in the UNCOVER-2 and UNCOVER-3 trials were randomly assigned to receive 50 mg of etanercept twice weekly. At week 12 in the UNCOVER-3 trial, the patients entered a long-term extension period during which they received 80 mg of ixekizumab every 4 weeks through week 60; at week 12 in the UNCOVER-1 and UNCOVER-2 trials, the patients who had a response to ixekizumab (defined as a static Physicians Global Assessment [sPGA] score of 0 [clear] or 1 [minimal psoriasis]) were randomly reassigned to receive placebo, 80 mg of ixekizumab every 4 weeks, or 80 mg of ixekizumab every 12 weeks through week 60. Coprimary end points were the percentage of patients who had a score on the sPGA of 0 or 1 and a 75% or greater reduction from baseline in Psoriasis Area and Severity Index (PASI 75) at week 12. RESULTS In the UNCOVER-1 trial, at week 12, the patients had better responses to ixekizumab than to placebo; in the 2-wk dosing group, 81.8% had an sPGA score of 0 or 1 and 89.1% had a PASI 75 response; in the 4-wk dosing group, the respective rates were 76.4% and 82.6%; and in the placebo group, the rates were 3.2% and 3.9% (P<0.001 for all comparisons of ixekizumab with placebo). In the UNCOVER-1 and UNCOVER-2 trials, among the patients who were randomly reassigned at week 12 to receive 80 mg of ixekizumab every 4 weeks, 80 mg of ixekizumab every 12 weeks, or placebo, an sPGA score of 0 or 1 was maintained by 73.8%, 39.0%, and 7.0% of the patients, respectively. Patients in the UNCOVER-3 trial received continuous treatment of ixekizumab from weeks 0 through 60, and at week 60, at least 73% had an sPGA score of 0 or 1 and at least 80% had a PASI 75 response. Adverse events reported during ixekizumab use included neutropenia, candidal infections, and inflammatory bowel disease. CONCLUSIONS In three phase 3 trials involving patients with psoriasis, ixekizumab was effective through 60 weeks of treatment. As with any treatment, the benefits need to be weighed against the risks of adverse events. The efficacy and safety of ixekizumab beyond 60 weeks of treatment are not yet known