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.     

Fecoflowmetric Analysis of Anorectal Motor Function in Postoperative Anal-Preserving Surgery Patients With Low Rectal Cancer Comparison With the Wexner Score and Anorectal Manometry

The aim of this study was to elucidate whether fecoflowmetry (FFM) could evaluate more detailed evacuative function than anorectal manometry by comparing between FFM or anorectal manometric findings and the clinical questionnaires and the types of surgical procedure in the patients who received anal-preserving surgery. Fifty-three patients who underwent anal-preserving surgery for low rectal cancer were enrolled. The relationships between FFM or the manometric findings and the clinical questionnaires and the types of procedure of anal-preserving surgery were evaluated. There were significant differences between FFM markers and the clinical questionnaire and the types of the surgical procedure, whereas no significant relationship was observed between the manometric findings and the clinical questionnaire and the types of the surgical procedure. FFM might be feasible and useful for the objective assessment of evacuative function and may be superior to manometry for patients undergoing anal-preserving surgery.Key words: Anorectal manometry, Anal-preserving surgery, Fecoflowmetry, Incontinence, Rectal cancerSphincter preservation has been one of the key issues of rectal cancer surgery. Low anterior resection (LAR)¹ and internal and external sphincter resection (ISR and ESR) are anal-preserving surgeries.^2,3 The aim of these procedures is to restore the normal process of defecation, along with its function, and to improve the quality of life of patients by avoiding permanent colostomy. However, anal-preserving surgery is often associated with evacuative dysfunction and various degrees of incontinence.^4–7Most studies that have assessed the evacuation function have used clinical questionnaires, which are subjective and may vary according to the patient perception.⁷ There are many factors that can affect the evacuative function, such as the stool consistency, rectal capacity, anal sphincters, pelvic floor muscles, and intra-abdominal pressure. Although manometry with or without the clinical score has also commonly been used, fecoflowmetry (FFM) has been reported to be more accurate and useful for assessing the postoperative anorectal motor function.^8–13 FFM was first introduced by Shafik and is a dynamic method for examining the anorectal motor activity that simulates the natural act of defecation.¹⁴ Some studies have shown its usefulness in postoperative patients with anorectal disease,^8–11 but only a few studies have been performed to examine the evacuative function following anal-preserving surgery.^12,13 The aim of this study was to evaluate the evacuative function in the postoperative period following anal-preserving surgery in patients with low rectal cancer using FFM, and to compare the results with the Wexner score and anorectal manometry.¹⁵     

Adjustment of the occlusal vertical dimension in the bite-raised guinea pig

In humans, the inappropriate occlusal vertical dimension (OVD) causes several orofacial disorders, such as bruxism and pain in the masticatory muscles and temporomandibular joint. However, it is still unclear how strictly the OVD is adjusted. To answer this question, we studied the temporal change of the OVD in bite-raised young guinea pigs. The OVD was raised by fixation of a bite-raising appliance to the lower incisors, and increased by either 3 or 1.5 mm at the first molars. After the space produced between the upper and lower molars was filled within 10 days due to eruption of the molars, the appliance was removed. In the bite-raised animals, the raised OVD was reduced until it attained that observed in the control animals, after which the OVD increased according to cranial growth. These results show that the OVD is developmentally changed and strictly controlled.     

Cadherin-related neuronal receptors in incisor development

Cadherins are cell adhesion molecules that are critical for tissue development. In this report, we identified members of the cadherin family cadherin-related neuronal receptors (CNRs) 1 and 5 expressed in rat incisors by the differential display method. Quantitative RT-PCR revealed that CNR1 mRNA is expressed in the secretory stage but reduced in the early-maturation stage, while CNR5 mRNA is expressed in both these stages. In situ hybridization showed that strong expression of CNR1 is strong in the secretory stage, but reduced in the early phase and diminished in the late phase of the early-maturation stage. CNR5 mRNA is expressed almost at the same levels in the secretory and in the early phase of the early-maturation stages but is absent in the late phase of the early-maturation stage. Both CNR1 and 5 mRNA are continuously expressed in odontoblasts. Immunohistology showed that CNR proteins are expressed in the secretory and early-maturation stages of ameloblasts, but no protein expression at the late-maturation stage was observed. CNR proteins were continuously expressed in odontoblasts. We found that recombinant CNR1 binds dental epithelial and mesenchymal cells through N-terminal domain EC1 in vitro. These results suggest that CNR1 and CNR5 may play an important role in enamel and dentin formation, probably through cell-cell and/or cell-matrix interactions.     

A mini-implant for orthodontic anchorage in a deep overbite case

This article describes the orthodontic treatment of a 19-year-old female patient with anterior crowding. There was a moderate arch length discrepancy in the lower dental arch, a significant deep overbite, and a "gummy smile." We inserted an orthodontic mini-implant as anchorage for the intrusion of the upper incisor segment, followed by alignment of the upper and lower dental arches with an edgewise appliance without tooth extraction. The overbite was corrected from +7.2 mm to +1.7 mm by upper incisor intrusion, and the gummy smile was improved. Good occlusion and facial esthetics were achieved, and these results have been maintained for two years after completion of the active treatment.     

Etiologies,risk factors,and outcomes of bacterial cholangitis after living donor liver transplantation

The interpretation of bacterial cholangitis after liver transplantation (LT) remains vague, because the presence of bacteria in bile, namely bacteriobilia, does not necessarily indicate an active infection. We investigated the association between post-LT bacterial cholangitis and a variety of short- and long-term outcomes. Two-hundred-seventy-four primary adult-to-adult living donor LT recipients from 2008 to 2016 were divided into three groups according the presence or absence of bacteriobilia and clinical symptoms: (1) no bacteriobilia (N group), (2) asymptomatic bacteriobilia (B group), and (3) cholangitis (C group). The number of patients was by group: N, 161; B, 64; and C, 49. Donor age ≥?45 years (p?=?0.012), choledochojejunostomy (p?<?0.001), and post-LT portal hypertension (p?=?0.023) were independent risk factors for developing cholangitis. Survival analysis revealed that the C group had significantly worse short- and long-term graft survival. The C group was associated with an increased incidence of early graft loss (EGL) (p?<?0.001). While the frequency of readmission for recurrent cholangitis was significantly higher in both the B and C groups (p?<?0.001), late graft loss (LGL) due to chronic cholangitis was only commonly observed in the C group (p?=?0.002). Post-LT cholangitis could result in not only EGL but also chronic cholangitis and associated LGL.