Phase 1 study of crisaborole in Japanese healthy volunteers and patients with atopic dermatitis

Crisaborole ointment, 2%, is a non-steroidal phosphodiesterase 4 inhibitor for the treatment of mild to moderate atopic dermatitis (AD). This parallel-cohort, phase 1 study was conducted to investigate skin irritation potential and safety of crisaborole in healthy Japanese adults (cohort 1) and the safety and pharmacokinetic profile of crisaborole and metabolites AN7602 and AN8323 in Japanese adults with mild to moderate AD (cohort 2). In cohort 1, 20 healthy volunteers received single applications of crisaborole and vehicle simultaneously on separate locations under 48-h occlusion. In cohort 2, 12 patients with mild to moderate AD received crisaborole (n = 10) or vehicle (n = 2) twice daily for 8 days. Skin irritation and safety were assessed in cohort 1. Pharmacokinetics and safety were assessed in cohort 2. Skin irritation index (scale 0–400) was 40.0 for crisaborole and 5.0 for vehicle. No treatment-emergent adverse events (TEAE) were reported in cohort 1. The most common TEAE in the crisaborole group in cohort 2 were application site irritation (n = 7) and application site pain (n = 4). Crisaborole was rapidly absorbed, with limited systemic exposure between days 1 and 8 that was comparable with that seen in US-based participants in previous trials. Crisaborole had higher skin irritation than vehicle under occlusion in healthy Japanese adults and had an acceptable safety profile in Japanese adults with mild to moderate AD.     

Contemporary Use of Venoarterial Extracorporeal Membrane Oxygenation: Insights from the Multicenter RESCUE Registry

BackgroundVenoarterial extracorporeal membrane oxygenation (VA-ECMO) is increasingly used as a life-saving therapy for patients with cardiovascular collapse, but identifying patients unlikely to benefit remains a challenge.Methods and ResultsWe created the RESCUE registry, a retrospective, observational registry of adult patients treated with VA-ECMO between January 2007 and June 2017 at 3 high-volume centers (Columbia University, Duke University, and Washington University) to describe short-term patient outcomes. In 723 patients treated with VA-ECMO, the most common indications for deployment were postcardiotomy shock (31%), cardiomyopathy (including acute heart failure) (26%), and myocardial infarction (17%). Patients frequently suffered in-hospital complications, including acute renal dysfunction (45%), major bleeding (41%), and infection (33%). Only 40% of patients (n = 290) survived to discharge, with a minority receiving durable cardiac support (left ventricular assist device [n = 48] or heart transplantation [n = 7]). Multivariable regression analysis identified risk factors for mortality on ECMO as older age (odds ratio [OR], 1.26; 95% confidence interval [CI], 1.12–1.42) and female sex (OR, 1.44; 95% CI, 1.02–2.02) and risk factors for mortality after decannulation as higher body mass index (OR 1.17; 95% CI, 1.01-1.35) and major bleeding while on ECMO support (OR, 1.92; 95% CI, 1.23–2.99).ConclusionsDespite contemporary care at high-volume centers, patients treated with VA-ECMO continue to have significant in-hospital morbidity and mortality. The optimization of outcomes will require refinements in patient selection and improvement of care delivery.     

Introduction of bifunctional alcohol/acetaldehyde dehydrogenase gene (adhE) in Fructobacillus fructosus settled its fructophilic characteristics

Fructophilic lactic acid bacteria (FLAB) are unique in the sense that they prefer D-fructose over D-glucose as main carbon source. If D-glucose is metabolised, electron acceptors are required and significant levels of acetate are produced. These bacteria are found in environments rich in D-fructose, such as flowers, fruits and the gastrointestinal tract of insects feeding on fructose-rich diets. Fructobacillus spp. are representatives of this unique group, and their fructophilic characteristics are well conserved. In this study, the bifunctional alcohol/acetaldehyde dehydrogenase gene (adhE) from Leuconostoc mesenteroides NRIC 1541^T was cloned into a plasmid and transferred to Fructobacillus fructosus NRIC 1058^T. Differences in biochemical characteristics between the parental strain (NRIC 1058^T) and the transformants were compared. Strain 1-11, transformed with the adhE gene, did not show any fructophilic characteristics, and the strain grew well on D-glucose without external electron acceptors. Accumulation of acetic acid, which was originally seen in the parental strain, was replaced with ethanol in the transformed strain. Furthermore, in silico analyses revealed that strain NRIC 1058^T lacked the sugar transporters/permeases and enzymes required for conversion of metabolic intermediates. This may be the reason for poor carbohydrate metabolic properties recorded for FLAB.     

Application of interdental distraction osteogenesis to unilateral cleft lip and palate patients

Distraction osteogenesis is widely used for the treatment of craniofacial deformities. In patients with cleft lip and palate, distraction osteogenesis can be employed to repair the alveolar cleft. In this report, we describe the management of three cases of unilateral cleft lip and palate by interdental distraction osteogenesis. Interdental distraction osteogenesis of the maxillary bone was performed to reduce the width of the alveolar cleft in these patients in conjunction with orthodontic treatment. Tooth-tooth type distraction devices were fabricated and delivered at the same time as osteotomy. Distraction was continued until the midline of the dentition coincided with the facial midline, and until the width of the alveolar cleft was reduced to the width of lateral incisor or had closed. One month after distraction was complete, orthodontic treatment with an edgewise appliance was initiated, and neighboring teeth were moved into the newly created bone. A favorable treatment outcome was achieved in all three cases.     

Relationship between large tubules and dentin caries in human deciduous tooth

The purpose of this study was to elucidate the relationship between large tubules and dentin caries by using human deciduous incisors that showed various levels of attrition but no macroscopical lesions resulting from caries. The teeth were cut longitudinally in the mesio-distal direction and the exposed surfaces observed with a high-resolution field emission scanning electron microscope. The inside of each large tubule showed dense collagen fibers running parallel to its long axis and small spherical bodies of aggregated crystals, but no marked attrition. In teeth where attrition had exposed dentin at the incisal edge, oral bacteria had infiltrated the large tubules. Furthermore, in teeth with advanced attrition, it was difficult to distinguish between the large tubules and the surrounding dentin matrix, and numerous bacteria were observed in both areas. These findings support the hypothesis that large tubules play a role in the pathway of caries formation in coronal dentin when incisal dentin is exposed by attrition. This suggests that early treatment of exposed dentin surfaces might be effective in preventing dental caries.     

Role of insulin receptor substrate‐1 for diethylnitrosamine plus high‐fat diet‐induced hepatic tumorigenesis in mice

We investigated the role of insulin receptor substrate (Irs)‐1 for diethylnitrosamine (DEN) plus high‐fat (HF) diet‐induced hepatic tumorigenesis in mice. We gave DEN by intraperitoneal injection at the dose of 80 mg/kg to 18‐week‐old wild‐type (WT) and Irs1‐knockout (Irs1^−/−) mice, which were fed a HF diet from 8 weeks‐of‐age until they were killed (52 weeks). The Irs1^−/− mice showed significantly lower plasma alanine aminotransferase levels, triglyceride contents in the liver and also lower expression levels of the genes encoding inflammatory cytokines than the WT mice. The incidence of DEN plus HF diet‐induced hepatic tumors was 71.4% in the WT mice, whereas it was just 14.3% in the Irs1^−/− mice. The present study showed that Irs1 played an important role in DEN plus HF diet‐induced hepatic tumorigenesis.