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.     

Parallel enlargement of Marinesco bodies and nuclei and progressive deposition of p62 in pigmented neurons of the substantia nigra

Marinesco bodies (MBs) are spherical nuclear inclusions found in pigmented neurons of the substantia nigra. Although MBs are abundant in senescent brains, how they are related to aging processes remains unclear. Here, we performed a morphometric analysis of midbrain pigmented neurons to identify the possible influence of MBs on nuclear size. The transected area of the nucleus (nuclear area) was larger in the presence of MBs and was correlated with the area of MB (MB area) in all tested brains. The MB-associated nuclear enlargement was significant even after MB areas were subtracted from nuclear areas. Moreover, higher MB immunoreactivity of p62 was detected in the nucleoplasm of the enlarged MB-associated nuclei. This study on human brains is the first quantitative approach demonstrating MB-associated nuclear enlargement and progressive accumulation of small nucleoplasmic materials. Although cellular hypertrophy is usually considered to be an indication of the upregulation of cellular function, this might not always be the case. These findings suggest that an age-related decline of ubiquitin-proteasome and autophagy system activity and stagnation of undegradable materials are one of the candidate mechanisms to explain the age-related decline of neural activity in the substantia nigra.     

Pyoderma gangrenosum in an ulcerative colitis patient during treatment with vedolizumab responded favorably to adsorptive granulocyte and monocyte apheresis

Pyoderma gangrenosum (PG) is an extra-intestinal skin lesion in inflammatory bowel disease (IBD) as is erythema nodosum. Vedolizumab (VED) is a monoclonal antibody that targets α4β7 integrin and has an intestinal selective mechanism. Despite good therapeutic effects on colitis, the effect on extra-intestinal manifestations (EIMs) remains unclear. Here we report a case of ulcerative colitis complicated by PG during treatment with VED, which was successfully treated with prednisolone in combination with adsorptive granulocyte and monocyte apheresis (GMA). The patient was a 50-year-old woman with a past medical history of extensive ulcerative colitis managed by golimumab (GLM). She developed flare symptoms due to loss of response to GLM, and treatment was switched to VED. Her gastrointestinal symptoms were improved with VED treatment with less frequent bowel movements. However, infiltrative erythema with pain appeared on the right lower leg and right knee, and expanded and gradually ulcerated. Her skin lesions were treated with corticosteroid, but showed poor improvement. Therefore, granulocyte and monocyte apheresis (GMA) treatment was administered in combination with prednisolone. After 3 months, the ulcer gradually improved, and at the time of this writing, the eruptions were nearly replaced by epithelial tissue. This case study showed that patients with UC and EIMS may respond well to combination therapy of VED and GMA. GMA has a very favorable safety profile. On the other hand, the causal connection between VED and PG is still unclear. We believe that a combination therapy involving VED and GMA in IBD patients with EIMs warrants consideration.     

Actinomycosis originating in the submandibular gland: Report of a case

We report herein a very rare case of actinomycosis originating in the submandibular gland in which malignancy was suspected. A 56-year-old man visited our clinic with a chief complaint of painless mass in the right submandibular region. From the imaging diagnosis, we suspected malignant tumor in the submandibular gland. Under general anesthesia, right radical neck dissection and excision of the submandibular gland with the above mass were carried out. Histopathological diagnosis of actinomycosis in the submandibular gland was made. Because the focus exists within the gland, we consider this case as a primary submandibular gland actinomycosis. Two years postoperatively, the tumor has not recurred. On diagnosis, it is necessary to differentiate this disease with other benign or malignant tumors.     

High temperature characteristics and solidification microstructures of dental metallic materials part I: silver-palladium-copper-gold alloy

Ag-Pd-Cu-Au alloy was subjected to a Thermo-Mechanical Analyzer to investigate high temperature properties up to its liquidus temperature. Microstructural examination and elemental analysis with EPMA were also conducted in the solid/liquid mixture region. The following conclusions were obtained. (1) The solidus temperature was 838.3 +/- 2.52 degrees C and 957.7 +/- 1.53 degrees C for the liquidus point. (2) Thermal expansion coefficients were 1.39 +/- 0.08% at the solidus, 2.338 +/- 0.13% at the liquidus, and the melting expansion coefficient was 0.932 +/- 0.058%. (3) The expansion during melting was controlled by a small amount of pressure such as 1/100 of the air pressure, therefore the fit accuracy of castings is suggested not to be influenced by the solidification shrinkage. (4) Although the softening heat treatment and casting exhibited an influence on thermal expansion behavior, casting temperature in addition to post-casting plastic deformation did not show an effect on the thermal expansion. (5) The yield strength at 750 degrees C was reduced down to about 1/400 of that at room temperature, and the modulus of elasticity was about 1/100 of the room temperature value.     

Effect of wax melting range and investment liquid concentration on the accuracy of a three-quarter crown casting.

STATEMENT OF PROBLEM: Dental casting accuracy is influenced by the setting expansion of investment materials. Although setting expansion can help compensate for casting shrinkage, it cannot be fully realized under a confined wax pattern. Exactly how soft a wax pattern should be to ensure optimum setting expansion has not been determined. PURPOSE: In this study, the relationship between wax characteristics and the casting accuracy of a three-quarter crown was investigated. MATERIAL AND METHODS: Four different wax materials were used: paraffin 135 with a softening temperature of 37.5 degrees C (P38), paraffin 1080 with a softening temperature of 63.5 degrees C, Shofu Red with a softening temperature of 41.5 degrees C, and Shofu Hard with a softening temperature of 51 degrees C. Two mixtures of phosphate-bonded investment were prepared: one with 100% special liquid and another with 75% special liquid plus 25% distilled water. For both, the liquid/powder ratio was 16:100. A type IV gold alloy was cast into a three-quarter crown mold. The discrepancy at 6 locations (1 lingual, 1 mesial, 1 distal, and 3 facial) was measured with a traveling microscope. Five readings were collected. Means and standard deviations were calculated for all data. A 2-way analysis of variance followed by the Student-Newman-Keuls test for multiple comparisons was used to identify significant differences between groups at the 95% confidence level. RESULTS: For the gingival measurement sites (lingual, mesial, and distal), there was no significant difference in cast adaptation when Shofu Hard and paraffin 1080 waxes were used. However, the results with these 2 waxes were different than with Shofu Red and P38. For the 3 facial measurement sites, significantly different measurements were found for each wax; P38 demonstrated the best results. Casting shrinkage was smaller with the use of 100% special liquid. CONCLUSION: Within the limitations of this study, casting shrinkage was affected by the type of wax used and was sensitive to the site at which dimensional measurements were performed. The higher the softening temperature, the larger the casting shrinkage.