Changes in the composition of molecular species of covalently bound and free ceramides [EOS], and their correlation with disease severity in atopic dermatitis.

Ceramides are major constituents of stratum corneum (SC) intercellular lipids involved in skin barrier function. The ratio of molecular species of ceramides and their correlation with disease severity was examined in patients with atopic dermatitis (AD). Thirty-eight patients with AD and 32 healthy controls (HCs) were assessed for transepidermal water loss, SC collection and clinical assessment. The ceramide content of different molecular species in the samples was quantified using high-performance liquid chromatography coupled with tandem mass spectrometry. Unsaturated acyl chains of both covalently bound and free ceramides [EOS] were higher in AD lesional skin than those in AD non-lesional or normal HC skin. The proportion of unsaturated acyl chains (C30:1, C32:1 and C34:1) was higher than other ceramide molecular species among covalently bound and free ceramides [EOS] in patients with AD. The proportion of unsaturated acyl chains in covalently bound ceramides was positively correlated with transepidermal water loss (r = 0.600) when considering the total number of non-lesional and lesional skin. Additionally, thymus and activation-regulated chemokine (TARC) showed a positive correlation with unsaturated acyl chains proportion in AD non-lesional (r = 0.676) and lesional (r = 0.503) skin. Our study is the first to show the increase in unsaturated acyl chains of both covalently bound and free ceramides [EOS] in lesional and non-lesional skin in AD for each molecular species. This increase is associated with dryness and impaired barrier function, which correlates with TARC levels, a marker for the degree of type 2 inflammation. We speculate that type 2 inflammation exacerbation leads to abnormal epidermal lipid metabolism in the skin of patients with AD.

Nemolizumab plus topical agents in patients with atopic dermatitis (AD) and moderate-to-severe pruritus provide improvement in pruritus and signs of AD for up to 68 weeks: results from two phase III, long-term studies.

BACKGROUND: Interleukin (IL)-31 affects the inflammatory response, is involved in epidermal barrier disruption in atopic dermatitis (AD) and plays a key role in pruritus. Nemolizumab, a humanized monoclonal antibody against IL-31 receptor A, reduced pruritus in patients with AD after a 16-week administration period. OBJECTIVES: To examine the long-term effectiveness and safety of nemolizumab in patients aged ≥ 13 years with AD and inadequately controlled moderate-to-severe pruritus. METHODS: In two long-term phase III studies, nemolizumab 60 mg every 4 weeks (Q4W) was administered subcutaneously, concomitantly with topical treatments. Study-JP01 patients received double-blind nemolizumab or placebo for 16 weeks, and then entered a 52-week extension period in which all patients received nemolizumab (nemolizumab/nemolizumab and placebo/nemolizumab groups). Study-JP02 patients received nemolizumab for 52 weeks. Both studies included an 8-week follow-up period. RESULTS: Study-JP01 nemolizumab/nemolizumab and placebo/nemolizumab, and Study-JP02 nemolizumab groups comprised 143, 72 and 88 patients, respectively. In the nemolizumab/nemolizumab group, there were clinically meaningful improvements from the start of treatment to week 68 in the pruritus visual analogue scale (66% decrease) and Eczema Area and Severity Index (78% decrease). Quality of life (QoL) indicators improved after the first nemolizumab dose; improvements were maintained during the follow-up period. The long-term safety profile was consistent with previous studies, with no unexpected late-onset adverse events. CONCLUSIONS: Nemolizumab 60 mg Q4W with concomitant topical treatments in patients with AD and inadequately controlled moderate-to-severe pruritus produced a continuous improvement in pruritus, signs of AD, and QoL for up to 68 weeks, with a favourable safety profile.

Efficacy and safety of dupilumab in Japanese adults with moderate-to-severe atopic dermatitis: a subanalysis of three clinical trials.

BACKGROUND: Dupilumab, a human monoclonal antibody, blocks the shared receptor unit for interleukin-4 and interleukin-13. International phase II and III studies have evaluated the efficacy and safety of dupilumab in adults with moderate-to-severe atopic dermatitis (AD), but the effects of dupilumab in Japanese patients have not been reported. OBJECTIVES: To evaluate the efficacy and safety of dupilumab in Japanese patients with moderate-to-severe AD. METHODS: We analysed the efficacy and safety of dupilumab in the Japanese cohorts of a 16-week, phase IIb dose-finding trial (AD-1021; NCT01859988); a 16-week, phase III, placebo-controlled monotherapy trial (LIBERTY AD SOLO 1; NCT02277743) and a 52-week, phase III, placebo-controlled study of dupilumab with topical corticosteroids (LIBERTY AD CHRONOS; NCT02260986). RESULTS: Twenty-seven, 106 and 117 Japanese patients were enrolled in AD-1021, SOLO 1 and CHRONOS, respectively. Baseline disease severity was numerically higher in the Japanese cohort than in the overall study population. Generally, dupilumab significantly improved signs and symptoms of AD, including pruritus and patient quality of life, compared with placebo in the Japanese cohort, consistent with the overall study population. The combined safety profile of dupilumab in the Japanese cohort was similar to that in the total study populations; dupilumab was associated with an increased incidence of injection-site reactions and conjunctivitis compared with placebo. Dupilumab was associated with rapid reduction in thymus and activation-regulated chemokine and gradual IgE reductions. CONCLUSIONS: Dupilumab alone or with topical corticosteroids improved signs and symptoms of AD, had an acceptable safety profile, and suppressed biomarkers of type 2 inflammation compared with placebo in Japanese adult patients with moderate-to-severe AD. What's already known about this topic? Differences in atopic dermatitis (AD) pathology have been reported between Asian and Western populations, in which distinct helper T-cell activation profiles have been observed. International clinical studies in adults with moderate-to-severe AD have evaluated the efficacy and safety of dupilumab, which blocks interleukin-4 and interleukin-13, key molecules in type 2 inflammation. The effects of dupilumab in Japanese patients specifically have not yet been reported. What does this study add? Dupilumab alone or with topical corticosteroids improved signs and symptoms of AD and had an acceptable safety profile compared with placebo in Japanese patients with moderate-to-severe AD. The effects were comparable with those observed in the overall study population. Reported immunological differences in AD pathology in Asian patients may be secondary to type 2 immune activation.

Examining the accuracy of visual diagnosis of tinea pedis and tinea unguium in aged care facilities.

OBJECTIVE: The aim of this study was to examine the accuracy of visual diagnosis of tinea pedis (Athlete's foot) and tinea unguium (fungal nail infection), as well as to provide information on skin abnormalities that could help identify these diseases in aged care facilities (long-term care facilities (LTCFs) and nursing homes). METHOD: A multicentre, cross-sectional observational study was conducted in a LTCF and two nursing homes. A dermatologist observed the skin abnormalities in the participants' interdigital and plantar areas, to screen for tinea pedis, and in the participants' toenails, to screen for tinea unguium. If abnormalities were noted, samples such as scales or toenails were collected and examined using direct microscopy. The accuracy of the macroscopic observation for each skin abnormality was examined. RESULTS: A total of 173 residents were recruited. The accuracy of clinical diagnosis using macroscopic observation was relatively low. The sensitivities and specificities for clinical diagnosis were 0.37 and 0.95 for tinea pedis in the interdigital areas, 0.47 and 0.94 for tinea pedis in the plantar areas, and 0.80 and 0.61 for tinea unguium in toenails, respectively. Scales in the plantar areas and discoloration of the toenails were more frequently observed in residents with tinea pedis and tinea unguium than in those without them. CONCLUSION: Several skin abnormalities were observed in the residents recruited in this study, but there was insufficient correlation with tinea pedis and tinea unguium to be used for screening.

High-accuracy imputation for HLA class I and II genes based on high-resolution SNP data of population-specific references.

Statistical imputation of classical human leukocyte antigen (HLA) alleles is becoming an indispensable tool for fine-mappings of disease association signals from case-control genome-wide association studies. However, most currently available HLA imputation tools are based on European reference populations and are not suitable for direct application to non-European populations. Among the HLA imputation tools, The HIBAG R package is a flexible HLA imputation tool that is equipped with a wide range of population-based classifiers; moreover, HIBAG R enables individual researchers to build custom classifiers. Here, two data sets, each comprising data from healthy Japanese individuals of difference sample sizes, were used to build custom classifiers. HLA imputation accuracy in five HLA classes (HLA-A, HLA-B, HLA-DRB1, HLA-DQB1 and HLA-DPB1) increased from the 82.5-98.8% obtained with the original HIBAG references to 95.2-99.5% with our custom classifiers. A call threshold (CT) of 0.4 is recommended for our Japanese classifiers; in contrast, HIBAG references recommend a CT of 0.5. Finally, our classifiers could be used to identify the risk haplotypes for Japanese narcolepsy with cataplexy, HLA-DRB1*15:01 and HLA-DQB1*06:02, with 100% and 99.7% accuracy, respectively; therefore, these classifiers can be used to supplement the current lack of HLA genotyping data in widely available genome-wide association study data sets.

Clindamycin phosphate 1·2%-benzoyl peroxide 3·0% fixed-dose combination gel has an effective and acceptable safety and tolerability profile for the treatment of acne vulgaris in Japanese patients: a phase III, multicentre, randomised, single-blinded, active-controlled, parallel-group study.

BACKGROUND: A topical fixed-dose clindamycin phosphate 1·2% and benzoyl peroxide 3·0% combination gel (CLNP/BPO 3%) is known to be effective and safe in white people with acne. OBJECTIVES: To evaluate the efficacy and safety of CLNP/BPO 3·0% topically applied once or twice daily vs. CLNP twice daily in Japanese patients with acne. METHODS: Eight hundred patients were randomized to receive CLNP/BPO 3·0% once daily, CLNP/BPO 3·0% twice daily or CLNP twice daily for 12 weeks. Primary endpoints were absolute change in number of total lesions (TLs) from baseline to week 12 to demonstrate the superiority of CLNP/BPO 3·0% twice daily and noninferiority of CLNP/BPO 3·0% once daily vs. CLNP twice daily. Secondary endpoints were absolute and percentage changes in TLs, inflammatory lesions (ILs), noninflammatory lesions (non-ILs) and Investigator's Static Global Assessment (ISGA) score. Safety assessments included adverse events (AEs), laboratory tests, vital signs and local skin tolerability. RESULTS: Change in TL counts from baseline to week 12 for CLNP/BPO 3·0% twice daily was superior to CLNP twice daily (difference -11·0; P < 0·01); CLNP/BPO 3·0% once daily was not inferior to CLNP twice daily (difference -10·3; P < 0·01). Absolute and percentage reductions in TL, IL and non-IL counts and ISGA score were greater for CLNP/BPO 3·0% once or twice daily than for CLNP twice daily with significant differences seen from early on. Most AEs were mild or moderate. The incidence of adverse drug reactions was higher for CLNP/BPO 3·0% once (24·0%) or twice (35·1%) daily than for CLNP twice daily (9·0%). CONCLUSIONS: Compared with CLNP twice daily, CLNP/BPO 3·0% once daily was more effective and CLNP/BPO 3·0% twice daily at least as effective, with an early onset of action and an acceptable safety and tolerability profile in Japanese patients.

Screening for tinea unguium by Dermatophyte Test Strip.

BACKGROUND: The direct microscopy, fungal culture and histopathology that are necessary for the definitive diagnosis of tinea unguium are disadvantageous in that detection sensitivity is affected by the level of skill of the person who performs the testing, and the procedures take a long time. OBJECTIVES: The Dermatophyte Test Strip, which was developed recently, can simply and easily detect filamentous fungi in samples in a short time, and there are expectations for its use as a method for tinea unguium screening. With this in mind, we examined the detection capacity of the Dermatophyte Test Strip for tinea unguium. METHODS: The presence or absence of fungal elements was judged by direct microscopy and Dermatophyte Test Strip in 165 nail samples obtained from residents in nursing homes for the elderly. Moreover, the minimum sample amount required for positive determination was estimated using 32 samples that showed positive results by Dermatophyte Test Strip. RESULTS: The Dermatophyte Test Strip showed 98% sensitivity, 78% specificity, 84·8% positive predictive value, 97% negative predictive value and a positive and negative concordance rate of 89·1%. The minimum sample amount required for positive determination was 0·002-0·722 mg. CONCLUSIONS: The Dermatophyte Test Strip showed very high sensitivity and negative predictive value, and was considered a potentially useful method for tinea unguium screening. Positive determination was considered to be possible with a sample amount of about 1 mg.

A case of lupus erythematosus profundus with multiple arc-shaped erythematous plaques on the scalp and a review of the literature.

A 26-year-old Japanese female presented to us with a 2-year history of multiple arc-shaped erythematous lesions on her scalp and the right side of her forehead. Histopathological examination of two of the lesions showed lobular and septal panniculitis with deposits of IgG in the basement membrane zone. We diagnosed the case as lupus erythematosus profundus, and successfully treated her with 20 mg/day prednisolone. To our knowledge, there has been only one previously reported case of lupus erythematosus profundus with annular-shaped erythematous lesions and six cases with linear configuration.

Phase I trial of combination chemotherapy with docetaxel, cisplatin and S-1 (TPS) in patients with locally advanced or recurrent/metastatic head and neck cancer.

BACKGROUND: we investigated the maximum tolerated dose (MTD) of combination therapy with docetaxel, cisplatin, and S-1 (TPS) in patients with locally advanced or recurrent/metastatic head and neck cancer (HNC). PATIENTS AND METHODS: treatment consisted of docetaxel (Taxotere) at doses of 50, 60, and 70 mg/m(2); cisplatin at 70 mg·m(2)/day on day 1; and S-1 twice daily on days 1-14 at doses of 40, 60, and 80 mg·m(2)/day, repeated every 3 or 4 weeks. RESULTS: forty patients were enrolled. MTD was not reached until level 4. Subjects at expanded dose were limited to patients with locally advanced disease. Two dose-limiting toxic effects (DLTs) were observed at dose level 5 (TPS: 70/70/80 mg·m(2)/day, every 3 weeks), namely one grade 3 infection and one grade 3 hyperbilirubinemia, establishing this as the MTD. Of 12 patients treated at dose level 6 (TPS: 70/70/60 mg·m(2)/day, every 3 weeks), 2 DLTs were seen. Six achieved a complete response and 22 a partial response, giving a response rate of 70%. CONCLUSIONS: TPS was well tolerated. The recommended phase II dose as induction chemotherapy for locally advanced HNC was determined as 70/70/60 mg·m(2)/day every 3 weeks. Antitumor activity was highly promising and warrants further investigation.

Calcitonin receptor bindings in the hen hypothalamus before and after oviposition.

To demonstrate the presence of a receptor for calcitonin (CT) in the hen hypothalamus and to determine when CT acts on this tissue during the oviposition cycle, bindings of (125)I labeled CT in the plasma membrane fraction of the hen hypothalamus were measured by radioligand binding assay. The specific CT binding component in the plasma membrane fraction of the hypothalamus containing the preoptic area (HPOA) possessed properties of a receptor: binding specificity to CT, saturable binding, high affinity, and limited capacity. As for the median eminence area, no specific binding component was found in the present study. Therefore, the binding component for CT in the plasma membrane fraction of HPOA is likely to be a receptor for CT. In laying hens, the binding affinity of CT receptor increased at 30 min before oviposition and the binding capacity was decreased at 30 min before oviposition but not changed in nonlaying hens during a 24-h period. These results suggest that the action of CT on the hen HPOA may increase 30 min before oviposition.

Changes in prostaglandin F2α receptor bindings in the hen oviduct uterus before and after oviposition.

The specific binding component for prostaglandin F(2α) (PGF(2α)) that exists in the plasma membrane fraction of the oviduct uterus myometrium of laying hens was shown to possess receptor properties for PGF(2α), such as binding specificity to PGF(2α), binding saturation, high affinity, and limited capacity. The value of the equilibrium dissociation constant (K(d)) for the receptor was not different between laying hens and nonlaying hens, but the value of the maximum binding capacity (B(max)) was smaller in laying hens than in nonlaying hens. During an oviposition cycle, the K(d) value did not show a significant change, but the B(max) value decreased at 3 and 0.5 h before oviposition and 2 h after oviposition. Neither the K(d) nor B(max) value changed in nonlaying hens during a 24-h period. An intravenous injection of PGF(2α) (5 µg/hen) decreased the B(max) value, but not the K(d) value, of the PGF(2α) receptor. It is thought from the results that PGF(2α) may act directly on the oviduct uterus myometrium at a fixed time before and after oviposition in laying hens.

Changes in angiotensin II receptor bindings in the hen neurohypophysis before and after oviposition.

The present study was performed to elucidate whether the angiotensin II (ANG II) receptor exists in the plasma membrane fraction of the neurohypophysis in hens, to estimate the time of action of ANG II on the neurohypophysis before and after oviposition, and to examine relationships between the action of ANG II on the neurohypophysis and those of estrogen and prostaglandin F(2α) (PGF(2α)) in relation to arginine vasotocin (AVT) release. The specific binding had a binding specificity to chicken ANG II (cANG II), reversibility, and saturation in the [(125)I]cANG II binding assay. Scatchard analysis revealed that the binding sites are of a single class. The equilibrium dissociation constant (K(d)) obtained by kinetic analysis and Scatchard analysis suggested a high affinity, and the maximum binding capacity (B(max)) obtained by Scatchard analysis suggested a limited capacity. These results suggest that an ANG II receptor exists in the neurohypophysis of hens. The K(d) and the B(max) value was significantly smaller in laying hens than in nonlaying hens, which suggests that bindings of the cANG II receptor change, depending on the difference in laying condition. Values of the K(d) and the B(max) decreased approximately 15 min before oviposition in laying hens, and decreased 1 h after an intramuscular injection of estradiol-17ß and 5 min after an intravenous injection of cANG II in nonlaying hens. The amount of specific binding of PGF(2α) receptor in the neurohypophysis also decreased and AVT concentration in blood increased after the cANG II injection. It seems likely that the action of cANG II in the neurohypophysis increases due to the effect of estrogen approximately 15 min before oviposition, and the cANG II action stimulates AVT release through the increase in the PGF(2α) action in this tissue.

Parathyroid hormone-related peptide directly increases adrenocorticotropic hormone secretion from the anterior pituitary in hens.

The presence of the receptor for parathyroid hormone-related peptide (PTHrP) and the effect of PTHrP on adrenocorticotropic hormone (ACTH) secretion in the hen anterior pituitary were examined. The plasma membrane fraction of the anterior pituitary was found to contain a specific chicken PTHrP (cPTHrP) binding component. The binding component had properties of a receptor, such as binding specificity to cPTHrP, reversibility, saturable binding, high affinity, and limited capacity; therefore, it was elucidated that the PTHrP receptor exists in the plasma membrane of the hen anterior pituitary. A third ventricular injection of cPTHrP in nonlaying hens caused a decrease in the chicken ACTH level of the anterior pituitary and an increase in the chicken ACTH level of blood plasma, with an increase in the binding affinity and a decrease in the binding capacity of PTHrP receptor in the anterior pituitary. The present study suggests that PTHrP may act directly on the anterior pituitary via its receptor binding and may enhance ACTH secretion from this tissue in hens.

Effect of estradiol-17ß on calcitonin receptor bindings in the hen neurohypophysis.

The present study was performed to elucidate whether estradiol-17ß (E2) would affect calcitonin (CT) receptor binding in the hen neurohypophysis. The equilibrium dissociation constant (K(d)) and the maximum binding capacity (B(max)) of the CT receptor in the plasma membrane fraction of the hen neurohypophysis were examined by Scatchard analysis of specific binding of (125)I-labeled chicken CT. A single i.m. injection of E2 into nonlaying hens caused a decrease in K(d) and B(max) values of the CT receptor. The K(d) and B(max) values of the CT receptor were smaller in laying hens than in nonlaying hens. The present study suggests that E2 may increase the action of CT on the neurohypophysis in hens.

Hemodynamic Analysis of Cerebral AVMs with 3D Phase-Contrast MR Imaging.

BACKGROUND AND PURPOSE: The hemodynamics associated with cerebral AVMs have a significant impact on their clinical presentation. This study aimed to evaluate the hemodynamic features of AVMs using 3D phase-contrast MR imaging with dual velocity-encodings. MATERIALS AND METHODS: Thirty-two patients with supratentorial AVMs who had not received any previous treatment and had undergone 3D phase-contrast MR imaging were included in this study. The nidus diameter and volume were measured for classification of AVMs (small, medium, or large). Flow parameters measured included apparent AVM inflow, AVM inflow index, apparent AVM outflow, AVM outflow index, and the apparent AVM inflow-to-outflow ratio. Correlation coefficients between the nidus volume and each flow were calculated. The flow parameters between small and other AVMs as well as between nonhemorrhagic and hemorrhagic AVMs were compared. RESULTS: Patients were divided into hemorrhagic (n = 8) and nonhemorrhagic (n = 24) groups. The correlation coefficient between the nidus volume and the apparent AVM inflow and outflow was .83. The apparent AVM inflow and outflow in small AVMs were significantly smaller than in medium AVMs (P < .001 for both groups). The apparent AVM inflow-to-outflow ratio was significantly larger in the hemorrhagic AVMs than in the nonhemorrhagic AVMs (P = .02). CONCLUSIONS: The apparent AVM inflow-to-outflow ratio was the only significant parameter that differed between nonhemorrhagic and hemorrhagic AVMs, suggesting that a poor drainage system may increase AVM pressure, potentially causing cerebral hemorrhage.

Pathogenesis of arteritis of SL/Ni mice. Possible lytic effect of anti-gp70 antibodies on vascular smooth muscle cells.

The SL/Ni strain of mice spontaneously develops a necrotizing polyarteritis (NPA) that is histologically quite similar to human polyarteritis nodosa. This NPA most frequently affected parametrial tissues and/or ovaries of females and small arterioles of the major salivary glands. Electron microscopic studies of early arterial lesions revealed massive budding of C-type particles from arterial smooth muscle cells just before or at the onset of arteritis. In addition, binding of mouse IgG and C3 to the plasma membrane of virus-producing smooth muscle cells was shown by immunoelectron microscopy. Antibody-bound muscle cells showed disintegration of their plasma membrane, but degeneration and necrosis of muscle cells were not associated with dense infiltration of neutrophils. SL/Ni mice had natural antibodies that bound specifically to a fibroblast cell line infected with an endogenous ecotropic murine leukemia virus (MuLV) recovered from a SL/Ni mouse. Most of the natural antibodies were cytotoxic in the presence of murine complement. Western blot immunoassays revealed that among 14 SL/Ni female mice tested, all of the 9 mice that were affected by arteritis had anti-gp70 antibodies, while the 3 anti-gp70- mice were not affected. The presence of anti-p30 or anti-p15 (anti-p12) antibodies, which were also detected in some SL/Ni mice, did not correlate with the development of arteritis. These results strongly support the hypothesis that NPA in SL/Ni mice is mediated by the lysis of arterial smooth muscle cells due to the deposition of cytotoxic natural antibodies directed to cell membrane-bound gp70 molecules of an endogenous ecotropic MuLV.