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As people have regularly worn facial masks due to the coronavirus disease 2019 (COVID-19) pandemic, mask-wear-related adverse effects on the skin have been recognized. The aim of this study was to explore skin changes, their seasonal variations in the general population caused by commonly used masks and a possible mechanism underlying negative effects of mask-wearing.Eighteen Japanese females participated in the study during summer and winter in Japan. Skin characteristics were measured in the non-mask-wearing preauricular area and the mask-wearing cheek and perioral areas.Trans-epidermal water loss (TEWL) on the cheek area tended to be increased in winter, which was positively correlated with skin scaliness on the same area. Ceramide (CER) content and composition in the mask-covered stratum corneum (SC) were slightly changed between summer and winter, and CER [NP]/[NS] ratio was negatively correlated with the TEWL on the perioral skin in winter. Skin hydration and sebum secretion were higher on the cheek compared to the perioral area in summer. Skin redness was particularly high on the cheek in winter.Mask-wear-related skin changes were season- and facial site-specific, and alterations in SC CER may play a role in barrier-related skin problems caused by mask use.

Vitiligo is a common but puzzling skin disorder characterized by the selective loss of epidermal melanocytes due to unknown mechanisms. Here, we show patients with vitiligo have disruptions of basement membrane zone (BMZ) architecture including branched, fragmented, and multilayered lamina densa with increased numbers of dermal fibroblasts and overexpression of MMP2 in those cells. Extracts of vitiliginous skin showed increased MMP2 protein expression, with a large portion of the MMP2 proteins in the active form. Intradermal injection of MMP2-overexpressing fibroblasts in K14-SCF transgenic mice induced a vitiligo-like skin appearance and disappearance of melanocytes, which were reversed by coadministration of MMP2 inhibitors. These results suggest that disorganization of the BMZ driven by MMP2 overexpression in dermal fibroblasts may cause the impaired melanocyte inhabitation observed in vitiligo.

In this report, we describe a case of penile strangulation via metal rings. A 65-year-old Japanese man was transferred to the emergency room of our hospital for, dysuria and penile pain following penile incarceration with metal rings. Five metal rings approximately 30 mm in diameter were incarcerated to the penile root. Physical examination, revealed marked penile swelling distal to the rings. Various methods including the use of a ring cutter, were attempted to relieve the penial strangulation. However, these techniques failed, prompting referral to a rescue team. We started cutting the rings with an air cutter. After, 90 minutes, the rings were successfully removed. This study highlights the benefit of early cooperation with the rescue team in managing patients with mechanical penile strangulation.

Background Hyaluronan (HA) has a unique hydration capacity that contributes to firmness and bounciness of the skin. Epidermal HA declines with skin aging, which may lead to clinical signs of aging including skin wrinkles and loss of hydration and elasticity. Recently, we developed a new cosmetic agent 1-ethyl-β-N-acetylglucosaminide (β-NAG2), which enhances HA production in cultured human keratinocytes. The aim of this study was to explore antiaging potential of β-NAG2 in reconstructed human epidermal models and human clinical trial. Materials and methods The amount of HA in β-NAG2-treated epidermal models by topical application was analyzed by enzyme-linked immunosorbent assay (ELISA)-like assay. A randomized, double-blind and placebo-controlled study was conducted in Japanese females (n = 33) by topically treating each side of the face with a lotion formulated with β-NAG2 or placebo for 8 weeks. Results Topically applied β-NAG2 dose dependently increased HA production in epidermal models. Treatment with β-NAG2-formulated lotion significantly improved skin hydration and elasticity and reduced skin wrinkling in crow's foot areas when compared to the placebo formulation. Conclusion Topically applied β-NAG2 promoted epidermal HA production in vitro and showed antiwrinkle activity in vivo accompanying the improvement in skin hydration and elasticity. Our study provides a novel strategy for antiwrinkle care through β-NAG2-induced epidermal HA production.

Background It is well known that solar radiation accelerates skin photoaging. To evaluate subclinical photodamage in the skin especially from the early phase of ultraviolet (UV)-induced damage, we have focused on ultraweak photon emission (UPE), also called biophotons. Our previous study reported that the amount of long-lasting UPE induced by UV, predominantly from lipid peroxidation, is a valuable indicator to assess cutaneous photodamage even at a suberythemal dose, although it was only applied to evaluate acute UV damage. The aim of this study was to further investigate whether long-lasting UPE could also be a useful marker to assess subclinical chronic sun damage in the course of skin photoaging. Materials and methods Forty-three Japanese females in their 20s were recruited and were divided into two groups according to their history of sun exposure based on a questionnaire (high- and low-sun-exposure groups). Several skin properties on the cheek and outer forearm were measured in addition to UV-induced UPE. Results Among the skin properties measured, water content, average skin roughness, and the lateral packing of lipids in the stratum corneum were significantly deteriorated in the high-sun-exposure group as were changes in some skin photoaging scores such as pigmented spots and wrinkles. In addition, those skin properties were correlated with the UPE signals, suggesting the possible impact of oxidative stress on chronic skin damage. Conclusion Subtle oxidative stress detected by long-lasting UPE may contribute to subclinical cutaneous damage at the beginning phase of chronic sun exposure, which potentially enhances skin photoaging over a lifetime.

Background. Docetaxel (DOC) was the first regimen that increased the survival and became the standard-of-care in patients with metastatic castration-resistant prostate cancer (mCRPC). However, it is unclear whether switching to second-line chemotherapy or optimal sequencing of cabazitaxel (CBZ) ensures better clinical outcomes. We aimed to evaluate the efficacy of sequential therapy with DOC and CBZ and the effect of the number of prior DOC cycles on oncological outcomes in patients with mCRPC. Methods. We retrospectively included 46 mCRPC patients who received DOC followed by CBZ at quaternary hospitals in Japan between February 2015 and March 2019. Participants received intravenous DOC (40–75 mg/m2) every 3–4 weeks; CBZ (15–25 mg/m2) was administered every 3–4 weeks. Androgen-deprivation therapy and prednisolone 5 mg (twice daily) were administered throughout both regimens. The primary endpoints were overall (OS) and progression-free survival (PFS). The secondary endpoints were the rates of ≥30% and ≥50% reduction in prostate-specific antigen (PSA) levels at chemotherapy initiation. Results. Participants were divided into two groups according to DOC cycles (Groups A and B: ≤6 and ≥7 DOC cycles, respectively). The rates of ≥30% and ≥50% reduction in PSA levels were higher in Group B than in Group A, but there were no significant differences in both groups. Median OS in Groups A and B was 12.7 and 71.0 months, respectively P < 0.001 ; median PFS in Groups A and B was 3 and 12 months, respectively P < 0.001 . Conclusions. Administration of ≥7 cycles of DOC followed by CBZ may improve oncological outcomes in patients with mCRPC.

BACKGROUND Multi-contrast Jones matrix optical coherence tomography (JM-OCT) can provide quantitative depth-resolved local optical properties by improving the measurement algorithm. MATERIALS AND METHODS We examined the relationship between depth-resolved local optical properties of eye-corner skin measured by JM-OCT and corresponding wrinkle morphology of aged women (n = 21; age range, 71.7 ± 1.7 years). Wrinkle morphology was analyzed by measuring the surface topography of three-dimensional replicas. The same regions were measured three-dimensionally by JM-OCT, and the local optical properties at each depth were computed. RESULTS Birefringence (BR) and mean wrinkle depth correlated significantly at a depth of 88.2-138.6 µm from the skin surface, and attenuation coefficient (AC) and mean wrinkle depth correlated significantly at a depth of 12.6-18.9 µm and 189-459.9 μm from the skin surface, although a degree of polarization uniformity (DOPU) did not. Stepwise multiple regression analysis demonstrated that a significant regression equation (R2 = 0.649, P

Non-invasive acquisition of mRNA data from the skin can be extremely useful for understanding skin physiology and diseases. Inspired by the holocrine process, in which the sebaceous glands secrete cell contents into the sebum, we focused on the possible presence of mRNAs in skin surface lipids (SSLs). We found that measurable levels of human mRNAs exist in SSLs, where the sebum protects them from degradation by RNases. The AmpliSeq transcriptome analysis was modified to measure SSL-RNA levels, and our results revealed that the SSL-RNAs predominantly comprised mRNAs derived from sebaceous glands, the epidermis, and hair follicles. Analysis of SSL-RNAs non-invasively collected from patients with atopic dermatitis revealed increased expression of inflammation-related genes and decreased expression of terminal differentiation-related genes, consistent with the results of previous reports. Further, we found that lipid synthesis-related genes were downregulated in the sebaceous glands of patients with atopic dermatitis. These results indicate that the analysis of SSL-RNAs is a promising strategy to understand the pathophysiology of skin diseases.

Hyaluronan (HA), an essential component of the extracellular matrix of the skin, is synthesized by HA synthases (HAS1-3). To date, epidermal HA has been considered a major player in regulating cell proliferation and differentiation. However, a previous study reported that depletion of epidermal HA by Streptomyces hyaluronidase (St-HAase) has no influence on epidermal structure and function. In the present study, to further explore roles of epidermal HA, we examined effects of siRNA-mediated knockdown of HAS3, as well as conventional HA-depletion methods using St-HAase and 4-methylumbelliferone (4MU), on epidermal turnover and architecture in reconstructed skin or epidermal equivalents. Consistent with previous findings, HA depletion by St-HAase did not have a substantial influence on the epidermal architecture and turnover in skin equivalents. 4MU treatment resulted in reduced keratinocyte proliferation and epidermal thinning but did not seem to substantially decrease the abundance of extracellular HA. In contrast, siRNA-mediated knockdown of HAS3 in epidermal equivalents resulted in a significant reduction in epidermal HA content and thickness, accompanied by decreased keratinocyte proliferation and differentiation. These results suggest that HAS3-mediated HA production, rather than extracellularly deposited HA, may play a role in keratinocyte proliferation and differentiation, at least in the developing epidermis in reconstructed epidermal equivalents.

A 308 nm monochromatic excimer light (MEL) is widely used to treat patients with vitiligo. However, dose optimization still needs to be clarified. This study aimed to obtain objective evidence regarding various doses of MEL irradiation, induced cell level changes in vitro, and skin level alterations in vivo. Cultured human keratinocytes were irradiated with MEL using various doses. After irradiation at low doses, stem cell factor, endothelin-1, and glycoprotein nonmetastatic melanoma protein B, factors that activate and protect melanocytes, were found to be significantly elevated in keratinocytes. After irradiation using medium and high doses, inflammatory cytokines were induced. The amount of ATP released and the level of inflammasome activation, which are known to be related to interleukin-1β activation, were also increased. The back skin of guinea pigs and mice were irradiated with MEL at varying doses. After irradiation, an increase of epidermal melanin and epidermal melanocytes was confirmed, using the minimal erythemal dose or less. In rhododendrol-induced leukoderma guinea pigs, a much lower dose of MEL irradiation was effective, when compared with the effective dose for control guinea pigs. Our results suggest that a lower irradiation dose of MEL might be sufficient and more suitable for repigmentation in vitiligo treatment.

To accurately simulate human physiology and thermal comfort, certain human physiological and comfort models categorize the human body into multiple parts. Most of these body parts are normally clothed, which must be quantified in the simulation. However, existing databases of clothing evaporative resistance only characterize the evaporative resistance of the whole body and not those of individual body parts. This implies that each body part has the same level of clothing evaporative resistance. In this research, we measure the local clothing insulation and evaporative resistance. Here, we present the local thermal characteristic values as well as the values for the whole body.

Background Hyaluronan (HA) is an essential component of extracellular matrix in the skin, but its functions in the epidermis remain elusive. Objective We examined the interaction of increased HA production mediated by 1-ethyl-β-N-acetylglucosaminide (β-NAG2), a newly developed highly selective inducer of HA production which is intracellularly converted to UDP-N-acetylglucosamine, a substrate of HA, with epidermal proliferation and differentiation. Methods The amount, molecular size and epidermal tissue distribution of HA and expression of CD44, a cell surface receptor for HA, were analyzed in β-NAG2-treated organ cultured human skin, reconstructed human skin equivalents or cultured human skin keratinocytes. The relationship between HA and epidermal proliferation or differentiation was examined. Results β-NAG2 significantly increased HA production in the epidermis of skin explants or skin equivalents without affecting molecular size of HA (>2000 kDa) or CD44 mRNA expression. Histochemical experiments revealed that β-NAG2 enhances HA signals in the basal to granular layers of the epidermis of skin equivalents, accompanying increased epidermal stratification. Immunohistochemical experiments demonstrated that signals of Ki67, transglutaminase 1 and filaggrin are increased in β-NAG2-treated skin equivalents, and these observations were confirmed by the data showing that mRNA expression of PCNA, transglutaminase 1 (TGM1) and filaggrin (FLG) is significantly up-regulated by β-NAG2 in skin equivalents. Importantly, blockade of HA production by inhibiting conversion of β-NAG2 to UDP-NAG abolished β-NAG2-mediated up-regulation of PCNA, TGM1 and FLG mRNA expression in cultured keratinocytes. Conclusion These results suggest that increased epidermal HA production plays a key role in epidermal morphogenesis and homeostasis by accelerating keratinocyte proliferation and differentiation.

Autophagy is a membrane traffic system that provides sustainable degradation of cellular components for homeostasis, and is thus considered to promote health and longevity, though its activity declines with aging. The present findings show deterioration of autophagy in association with premature skin aging. Autophagy flux was successfully determined in skin tissues, which demonstrated significantly decreased autophagy in hyperpigmented skin such as that seen in senile lentigo. Furthermore, an exacerbated decline in autophagy was confirmed in xerotic hyperpigmentation areas, accompanied by severe dehydration and a barrier defect, which showed correlations with skin physiological conditions. The enhancement of autophagy in skin ex vivo ameliorated skin integrity, including pigmentation and epidermal differentiation. The present results indicate that the restoration of autophagy can contribute to improving premature skin aging by various intrinsic and extrinsic factors via the normalization of protein homeostasis.

Background Establishing a noninvasive method to estimate skin damage immediately after ultraviolet (UV) exposure is required to minimize the anticipated severe symptoms triggered by early phase UV-induced reactions in the skin. To develop a suitable method, we focused on ultraweak photon emission (UPE) immediately after UV exposure to characterize the relationship of UPE to skin photodamage caused by the UV exposure. Materials and methods Analysis of the correlation between UV-induced UPE and erythema formation characterized by skin redness was conducted in a clinical study. To clarify the source of UPE, time-dependent lipid oxidation was analyzed in human epidermal keratinocytes in vitro using a fluorescence indicator as well as the lipid hydroperoxide (LPO) assay. Results The average amount of UV-induced long-lasting UPE per second, especially from 1 to 3 minutes compared to other time periods after the UV radiation, increased in a dose-dependent manner and was highly correlated with the intensity of cutaneous redness 24 hours after UV exposure. In addition, cellular examinations elucidated that both the long-lasting UPE signals and the increased amounts of LPO 2 minutes after UV radiation were significantly suppressed by Trolox (a vitamin E derivative), which has been shown to inhibit UV-induced erythema formation in human skin. Conclusion Long-lasting UPE generated between 1 and 3 minutes immediately after UV exposure, which is associated with LPO production, is a valuable indicator to estimate and/or avoid severe cutaneous photodamage.

AIM To date, the optimal sequencing of life-prolonging therapies for patients with metastatic castration-resistant prostate cancer (mCRPC) remains unclear owing to a lack of prospective trials. This study aimed to evaluate the efficacy and safety of cabazitaxel (CBZ) treatment and examine the prognostic factors for oncological outcomes in patients with mCRPC who received CBZ after docetaxel (DOC). METHODS This multi-institutional retrospective study included 44 patients with mCRPC who received CBZ. All enrolled patients had histologically confirmed prostate cancer (PCa) with distant metastases and had received DOC before CBZ administration. The primary endpoint was the oncological outcomes, including the overall (OS) and progression-free survival (PFS). The secondary endpoints were adverse events due to CBZ and rates of ≥30% reduction in prostate-specific antigen (PSA) levels. RESULTS The median follow-up period was 9.2 months (range, 0.2-34 months). During this time, 34 patients (77%) died of PCa. The median OS and PFS were 12.2 (range, 0.2-34 months) and 1.4 months (range, 0.4-17 months), respectively. According to the PSA decline rate, patients who achieved a ≥30% reduction in PSA levels had significantly longer OS than those who showed a

Melanin in the epidermis is known to ultimately regulate human skin pigmentation. Recently, we exploited a phenotypic-based screening system composed of ex vivo human skin cultures to search for effective materials to regulate skin pigmentation. Since a previous study reported the potent inhibitory effect of metformin on melanogenesis, we evaluated several biguanide compounds. The unexpected effect of phenformin, once used as an oral anti-diabetic drug, on cutaneous darkening motivated us to investigate its underlying mechanism utilizing a chemical genetics approach, and especially to identify alternatives to phenformin because of its risk of severe lactic acidosis. Chemical pull-down assays with phenformin-immobilized beads were performed on lysates of human epidermal keratinocytes, and subsequent mass spectrometry identified 7-dehydrocholesterol reductase (DHCR7). Consistent with this, AY9944, an inhibitor of DHCR7, was found to decrease autophagic melanosome degradation in keratinocytes and to intensely darken skin in ex vivo cultures, suggesting the involvement of cholesterol biosynthesis in the metabolism of melanosomes. Thus, our results validated the combined utilization of the phenotypic screening system and chemical genetics as a new approach to develop promising materials for brightening/lightening and/or tanning technologies.

We examined the relationship between depth-resolved local optical properties of eye-corner skin measured by multifunctional Jones matrix optical coherence tomography (JM-OCT) and corresponding wrinkle morphology of aged women (n=21; age range, 71.7±1.7). Wrinkle morphology parameters were analyzed by measuring surface topography of three-dimensional silicone replicas. The same regions were measured three-dimensionally by JM-OCT and the means of several optical properties were computed at each depth. Optical properties include birefringence (BR), attenuation coefficient (AC), and degree-of-polarization uniformity (DOPU). BR and AC were correlated with mean wrinkle depth (WD), although DOPU was not. Significant correlations were found between WD and BR at 88.2 to 138.6 μm depth region from the skin surface (highest correlation at 113.4 μm), and between WD and AC at 12.6 to 18.9 μm and 189 to 459.9 μm depth regions from the skin surface (highest correlations at 18.9 μm and 415.8 μm). This suggests that the collagen structure of the papillary dermis and the microstructure and/or tissue density of the upper epidermis and reticular dermis may be associated with wrinkle morphology. Multiple regression analysis was used to examine the highest significant correlations of BR (113.4 μm) and AC (18.9 μm, 415.8 μm). A significant regression coefficient (R2=0.547, p = 0.001) was obtained, indicating that only BR and AC could sufficiently explain WD. Beta coefficients of BR (113.4 μm), AC (18.9 μm), and AC (415.8 μm) were −0.384, −0.369, and −0.354, respectively. This suggests that the upper epidermis, papillary dermis, and reticular dermis may contribute similarly to wrinkle formation.

An iridium-catalyzed reductive nucleophilic addition to secondary amides is reported. After the iridium-catalyzed reduction, the resulting imines can undergo the Strecker reaction, the Mannich reaction, allylation, and [3 + 2]-cycloaddition. The method shows high chemoselectivity in the presence of other functional groups such as methyl ester.

BACKGROUND Hyaluronan (HA) is an important constituent of extracellular matrix (ECM) in the skin, and HA degradation mediated by HYBID (KIAA1199) is suggested to be implicated in facial skin wrinkling in Japanese women. Ethnic difference in skin wrinkle formation is known between Caucasian and Japanese women, but no information is available for the relations of HA and HYBID expression levels with skin wrinkling in Caucasian women. METHODS The skin surface roughness at the eye corner of the Caucasian female subjects was measured, and the skin specimens biopsied from the same areas were subjected to microarray gene analysis, HA staining, and immunohistochemistry for HYBID. RESULTS Among the ECM genes and those related to ECM metabolism, only HYBID expression levels positively correlated with the skin roughness parameters. When the skin sample groups with high expression of HYBID or low expression of HYBID were compared, the HA staining intensity and the ratio of HYBID-immunoreactive cells to total cells in the superficial dermis were significantly reduced and increased in the high-HYBID-expression group compared with the low-HYBID-expression group, respectively. CONCLUSION Our data suggest that like Japanese women, HYBID-mediated reduction of HA in the superficial dermis is involved in the formation of wrinkles in Caucasian women.

Glycoprotein non-metastatic melanoma protein B (GPNMB) is a type I transmembrane glycoprotein that plays an important role in cancer metastasis and osteoblast differentiation. In the skin epidermis, GPNMB is mainly expressed in melanocytes and plays a critical role in melanosome formation. In our previous study, GPNMB was also found to be expressed in skin epidermal keratinocytes. In addition, decreased GPNMB expression was observed in the epidermis of lesional skin of patients with vitiligo. However, the exact role of keratinocyte-derived GPNMB and its effect on vitiligo is still unknown. In this study, we demonstrated that GPNMB expression was also decreased in rhododendrol-induced leukoderma, as seen in vitiligo. The extracellular soluble form of GPNMB (sGPNMB) was found to protect melanocytes from cytotoxicity and the impairment of melanogenesis induced by oxidative stress. Furthermore, the effect of rGPNMB was not altered by the knockdown of CD44, which is a well-known receptor of GPNMB, but accompanied by the suppressed phosphorylation of AKT but not ERK, p38, or JNK. In addition, we found that oxidative stress decreased both transcriptional GPNMB expression and sGPNMB protein expression in human keratinocytes. Our results suggest that GPNMB might provide novel insights into the mechanisms related to the pathogenesis of vitiligo and leukoderma.

A certain relationship between XPA gene mutations and the severity of symptoms has been observed in patients with xeroderma pigmentosum group A (XP-A). Patients with mutations within the DNA-binding domain usually exhibit severe symptoms, whereas splicing mutations in the same domain sometimes cause very mild symptoms. This inconsistency can be explained by a small amount of functional XPA protein produced from normally spliced transcripts. We herein report the case of an adult Japanese patient with XP-A with unusually mild symptoms. We identified a homozygous c.529G>A mutation in exon 4 of the XPA gene, which resulted in aberrant splicing with a 29-bp deletion in exon 4 causing a frameshift. Intact mRNA was observable, but a Western blot analysis failed to detect any normal XPA protein. We therefore evaluated the DNA repair capacity in normal cells in which the XPA expression was artificially diminished. The repair capacity was still present in cells with trace levels of the XPA protein. The repair capacity of the cells derived from our patient with mild symptoms was poor by comparison, but still significant compared with that of the cells derived from a patient with XP-A with severe symptoms. These results provide strong evidence that a trace level of XPA protein can still exert a relatively strong repair capacity, resulting in only a mild phenotype.

The immune-regulatory compound histamine is involved in the metabolism of the essential skin component hyaluronan (HA). We previously reported that histamine up-regulates the expression of HYBID (hyaluronan-binding protein involved in hyaluronan depolymerization, also called CEMIP or KIAA1199), which plays a key role in HA degradation. However, no information is available about histamine's effects on HA synthase (HAS) expression, the molecular sizes of HA species produced, and histamine receptors and their signaling pathways in skin fibroblasts. Moreover, histamine's effects on photoaged skin remain elusive. Here, we show that histamine increases HA degradation by up-regulating HYBID and down-regulating HAS2 in human skin fibroblasts in a dose- and time-dependent manner and thereby decreases the total amounts and sizes of newly produced HA. Histamine H1 blocker abrogated the histamine effects on HYBID up-regulation, HAS2 suppression, and HA degradation. Histamine H1 agonist exhibited effects on HA levels, composition, and breakdown similar to those of histamine. Of note, blockade of protein kinase Cδ or PI3K-Akt signaling abolished histamine-mediated HYBID stimulation and HAS2 suppression, respectively. Immunohistochemical experiments revealed a significant ∼2-fold increase in tryptase-positive mast cells in photoaged skin, where HYBID and HAS2 expression levels were increased and decreased, respectively, compared with photoprotected skin. These results indicate that histamine controls HA metabolism by up-regulating HYBID and down-regulating HAS2 via distinct signaling pathways downstream of histamine receptor H1. They further suggest that histamine may contribute to photoaged skin damage by skewing HA metabolism toward degradation.

The antimicrobial susceptibility patterns of bacterial pathogens isolated from patients with complicated urinary tract infections were analyzed using national surveillance data. The data consisted of 881 bacterial strains from eight clinically relevant species. The data were collected for the third national surveillance project from January 2015 to March 2016 by the Japanese Society of Chemotherapy, the Japanese Association for Infectious Disease, and the Japanese Society of Clinical Microbiology. Surveillance was undertaken with the cooperation of 41 medical institutions throughout Japan. Fluoroquinolone required a MIC90 of 2–64 mg/L to inhibit the 325 Escherichia coli strains tested and the proportion of levofloxacin resistant E. coli strains increased to 38.5% from 29.6% in 2011 and 28.6% in 2008. The proportion of levofloxacin resistant strains of Pseudomonas aeruginosa and Enterococcus faecalis decreased from previous reports and the proportion of multidrug-resistant P. aeruginosa and carbapenem-resistant Enterobacteriaceae remained low. Among methicillin-resistant Staphylococcus aureus (MRSA) strains, strains with reduced susceptibility to vancomycin (minimum inhibitory concentration, 2 μg/mL) increased to 14.7% from 5.5%. Bacterial strains that produced extended-spectrum β-lactamase included E. coli (79 of 325 strains, 24.3%), Klebsiella pneumoniae (9 of 177 strains, 7.7%), and Proteus mirabilis (6 of 55 strains, 10.9%). The proportion of extended-spectrum β-lactamase producing E. coli and K. pneumoniae strains increased from previous surveillance reports.

The content and distribution of melanin in the epidermis determines the wide variety of skin colors associated with ethnic/racial diversity. Although it was previously reported that qualitative changes in keratinocyte-derived exosomes regulate melanocyte pigmentation in vitro, their practical involvement, especially in skin color development in vivo, has remained unclear. To address this unexplained scientific concern, the correlation of epidermal exosomes isolated from human skin tissues with melanosomal protein expression levels was demonstrated in this study for the first time. After confirming the quantitative effect of human keratinocyte-derived exosomes on human melanocyte activation, even in the absence of ultraviolet B (UV-B) exposure, the impact of exosomes secreted from UV-B-irradiated keratinocytes on melanogenesis was consistently detected, which suggests their constitutive role in regulating cutaneous pigmentation. Additionally, both a specific exosome secretion inducer and a suppressor were consistently found to significantly control melanin synthesis in a co-culture system composed of keratinocytes and melanocytes as well as in an ex vivo skin culture system. These results suggest that quantitative changes, in addition to already known qualitative changes, in exosomes secreted from human epidermal keratinocytes homeostatically regulate melanogenic activity in a paracrine manner, which leads to skin color determination.

We report a case of a staghorn stone containing ammonium acid urate that was effectively treated with drug therapy alone. A 46-year-old man had recurring urinary tract stones. He had no previous episode of urinary tract stones that required hospitalization and operation. He received only drug therapy for hyperuricemia in another hospital. Ultrasonography and computed tomography revealed a left staghorn stone measuring 37×34 mm. The kidney-ureter-bladder radiograph did not show any stones. His urine was acidic, and we estimated that the left staghorn stone consisted of urate. Oral administration of sodium hydrogen carbonate was initiated to alkalize the urine, and treatment with transurethral lithotripsy (TUL) was scheduled. Before the TUL, analysis of an excreted stone sample revealed that it consisted of ammonium acid urate. The staghorn stone was completely removed in 10 months after the first medical examination. At present, the patient is free of urinary tract stones.

Rhododendrol is a phenolic compound that shows a tyrosinase-dependent toxicity for melanocytes and occasionally induces a vitiligo-like skin depigmentation. The post-tyrosinase mechanisms determining melanocyte death or survival, however, are far from clear. Here, we find that rhododendrol treatment leads to a reduction in the levels of cellular glutathione but also induces a cellular antioxidant response that eventually increases glutathione levels. We further find that rhododendrol toxicity is enhanced when glutathione levels are experimentally reduced and alleviated when glutathione levels are increased. Hence, it appears that the size of the preexisting glutathione pool along with the capacity to supply glutathione via the antioxidant response determines whether melanocytes survive or die after rhododendrol exposure. It is conceivable, therefore, that rhododendrol-induced leukoderma depends on the capacity to maintain appropriate glutathione levels and that enhancement of glutathione levels may preserve a patient's melanocytes and potentially help in repigmentation.

A thermoregulation model, joint system thermoregulation model (JOS-3), was developed based on JOS-2. JOS-3 consists of 83 nodes, and human physiological responses and body temperatures are calculated using the backward difference method. In JOS-3, brown adipose tissue activity, aging effects, and heat gain by shortwave solar radiation at the skin, are installed to predict human physiological responses, considering personal characteristics in transient and non-uniform thermal environments. In addition, methods to determine shivering thermogenesis, sweating distribution, and basal metabolic rate were modified from those used in JOS-2. We coded JOS-3 in Python-3 and published the JOS-3 package. This model was validated by comparing its results with those of human subject tests conducted under stable and transient conditions. It was confirmed that JOS-3 has a higher accuracy for heat production in young and older subjects and mean skin temperature in older subjects than JOS-2 under cold environmental conditions. Moreover, JOS-3 was simulated in nine transient conditions. Consequently, the root mean-squared error (RMSE) of the rectal and mean skin temperatures between the predicted and experimental values were 0.12–0.38 and 0.58–0.83 °C, respectively.

In recent years, the outdoor summer environment in Japan has become progressively warmer due to the severity of the heat island phenomenon. The danger of heat stroke and thermal comfort outdoors in summer are regarded as problems. In order to evaluate these problems, it is important to evaluate physiological exertion in the human body. The purpose of this research is to demonstrate the possibility of predicting physiological exertion in the human body with high accuracy in an outdoor environment during summer using the JOS-2 thermoregulation model developed by our research group. First, the Japanese metabolic rate in summer and autumn was measured for various activities, including sitting, standing, and walking. As a result, we found that the metabolic rate during sitting and standing was lower by about 10% in summer than in autumn. Next, using the obtained metabolic rate measurement as an input to the model, the experiment in an outdoor environment during summer was reproduced using JOS-2. The accuracy of the predicted mean skin temperature and local skin wettedness in an outdoor environment during summer was improved by choosing the appropriate input to the model.

We coupled a cardiovascular model with a thermoregulation model to predict human blood pressure in unsteady environmental conditions. Our cardiovascular model is a lumped parameter model and consists of 42 segments, which include the entire artery and vein system, divided into 18 segments; the heart, divided into 4 segments; and the pulmonary artery and vein. The vessel parameters were adjusted on the basis of local body blood volume and flow of the thermoregulation model in a thermoneutral environment. Blood pressure under unsteady environmental conditions is predicted by changing the heart rate and vessel resistance of the cardiovascular model which is controlled by blood flow that the thermoregulation model predicts. It is possible to predict the increase in blood pressure under cold environmental conditions and the increase in cardiac output under hot environmental conditions and when bathing. The model was validated by simulating bathing experiments. As the result, the model predicted the peak blood pressure later than the experimental data in a cold environment. To improve the accuracy of the model, it is necessary to consider a method for controlling the heart rate, vessel resistance, and gravity effects after a change in posture.

Hyaluronan (HA), an important constituent of extracellular matrix in the skin, has many biological activities such as hydration that contributes to firmness and bounciness of the skin. We have reported that reduction in HA in the papillary dermis and over-expression of HYBID (HYaluronan Binding protein Involved in hyaluronan Depolymerization, alias KIAA1199 or CEMIP), a key molecule for HA degradation in skin fibroblasts, are implicated in facial skin wrinkling in Japanese and Caucasian women. However, little or no information is available for substances which inhibit the HYBID-mediated HA degradation.Inhibition of Sanguisorba officinalis root extract and ziyuglycoside I, one of the components of Sanguisorba officinalis root extract, to the HYBID-mediated HA degradation was assessed by size-exclusion chromatography of HA depolymerized by stable transfectants of HYBID in HEK293 cells (HYBID/HEK293 cells) or normal human skin fibroblasts (Detroit 551 cells and NHDF-Ad cells). The HYBID mRNA and protein expression was examined by quantitative real-time PCR and immunoblotting in the skin fibroblasts treated with Sanguisorba officinalis root extract, and size distribution of newly produced HA was evaluated by preparing metabolically radiolabelled HA. A double-blind, randomized and placebo-controlled study was carried out in the 21 healthy Japanese women, who were topically treated with the formulation containing Sanguisorba officinalis root extract or the placebo on each side of the face including crow's foot area.Sanguisorba officinalis root extract, but not ziyuglycoside I, abolished HYBID-mediated HA degradation by HYBID/HEK293 cells. Sanguisorba officinalis root extract also inhibited HYBID-mediated HA degradation in skin fibroblasts by down-regulating HYBID mRNA and protein expression. Although control untreated skin fibroblasts produced polydispersed HA, the cells treated with Sanguisorba officinalis root extract produced only high-molecular-weight HA. Treatment with Sanguisorba officinalis root extract-formulated lotion significantly improved skin elasticity, and reduced skin wrinkling scores at the outer eye corner compared with the placebo formulation.Sanguisorba officinalis root extract showed an anti-HYBID-mediated HA degradation activity and anti-wrinkle activity on human facial skin, which is accompanied by the improvement in elasticity. Our study provides the possibility of a new strategy to inhibit HYBID-mediated HA degradation for anti-wrinkle care.OBJECTIFS: l'acide hyaluronique (AH), un composant important de la matrice extracellulaire de la peau, assure de nombreuses activités biologiques, telles que l'hydratation qui contribue à la fermeté et l’élasticité de la peau. Nous avons rapporté que la réduction d’AH dans le derme papillaire et une surexpression de la protéine de liaison de l’AH impliquée dans la dépolymérisation de l’AH (HYBID, alias KIAA1199 ou CEMIP), une molécule clé de la dégradation de l’AH des fibroblastes cutanés, sont impliquées dans la formation des rides au niveau de la peau du visage chez les femmes d'origine japonaise et caucasienne. Cependant, peu ou aucune information n'est disponible concernant les substances qui inhibent la dégradation de l’AH provoquée par la protéine HYBID. MÉTHODES: l'inhibition de l'extrait de racine de la pimprenelle (Sanguisorba officinalis) et du ziyuglycoside I, l'un des composants de l'extrait de racine de Sanguisorba officinalis, sur la dégradation de l’AH provoquée par la protéine HYBID a été évaluée à l'aide d'une chromatographie par exclusion stérique de l’AH dépolymérisé par des transfectants stables de la protéine HYBID dans les cellules HEK293 (cellules HYBID/HEK293) ou les fibroblastes cutanés humains normaux (lignée cellulaire Detroit 551 et cellules des fibroblastes du derme humain chez l'adulte). L'expression de l’ARNm et de la protéine HYBID a été examinée par PCR quantitative en temps réel et par immuno-empreinte des fibroblastes cutanés traités avec de l'extrait de racine de Sanguisorba officinalis, et l'attribution des tailles des nouveaux échantillons produits de l’AH a été évaluée par préparation d’AH radiomarqué métaboliquement. Une étude en double aveugle, randomisée et contrôlée par placebo a été menée auprès des 21 femmes japonaises en bonne santé, qui ont été traitées localement avec la formulation élaborée à partir d'extraits de racine de Sanguisorba officinalis ou un placebo, sur chaque côté du visage, notamment sur la zone à pattes d'oie. RÉSULTATS: l'extrait de racine de Sanguisorba officinalis a permis d'arrêter la dégradation de l’AH provoquée par la protéine HYBID par les cellules HYBID/HEK293, mais ce n’était pas le cas du ziyuglycoside I. L'extrait de racine de Sanguisorba officinalis a également inhibé la dégradation de l’AH provoquée par la protéine HYBID des fibroblastes cutanés en diminuant l'expression de l’ARNm et des protéines HYBID. Bien que les fibroblastes cutanés témoins non traités aient produit de l’AH polydispersé, les cellules traitées aux extraits de racine de Sanguisorba officinalis ont produit uniquement de l’AH de haut poids moléculaire. Le traitement par lotion formulée à partir d'extraits de racine de Sanguisorba officinalis a amélioré de manière significative l’élasticité de la peau et réduit les scores de vieillissement du coin extérieur de la peau autour des yeux, par rapport à la formulation placebo. CONCLUSION: l'extrait de racine de Sanguisorba officinalis a démontré une action anti-dégradation de l’AH provoquée par la protéine HYBID et une activité antirides au niveau de la peau du visage humain, s'accompagnant d'une amélioration de l’élasticité. Notre étude fournit la possibilité d'une nouvelle stratégie pour inhiber la dégradation de l’AH provoquée par la protéine HYBID dans le cadre des soins antirides.

Background Hyaluronan (HA) is an essential constituent of extracellular matrix in the skin. HA reduction in the dermis and overexpression of HYBID (KIAA1199), a key molecule for HA degradation in skin fibroblasts, are implicated in facial skin wrinkling. Aims We aimed to obtain anti-wrinkle agent(s) by screening for inhibition of HYBID-mediated HA degradation. Methods Various plant extracts were screened for inhibition of HA degradation in HYBID-stable transfectants in HEK293 (HYBID/HEK293). Inhibition of HA-degrading activity and HYBID mRNA and protein expression by Geranium thunbergii extract was studied in skin fibroblasts and HYBID/HEK293 cells. Size distribution of newly produced HA was evaluated by preparing metabolically radiolabeled HA in skin fibroblasts. A double-blind, randomized, and placebo-controlled study was performed in healthy Japanese women (n = 21) by topically treating each side of the face with a lotion formulated with G. thunbergii extract or placebo for 8 weeks. Results Among the plant extracts tested, only G. thunbergii extract abolished HA depolymerization in skin fibroblasts and HYBID/HEK293 cells by down-regulating HYBID mRNA and protein expression and by inhibiting HYBID-mediated HA-degrading activity. Although untreated skin fibroblasts produced polydispersed HA, G. thunbergii extract-treated cells produced high-molecular-weight HA. Treatment with G. thunbergii extract-formulated lotion significantly improved skin elasticity and reduced skin wrinkling scores at the outer eye corner compared with the placebo formulation. Conclusions Geranium thunbergii extract inhibited HYBID-mediated HA degradation in vitro and showed anti-wrinkle activity in vivo accompanying the improvement in skin elasticity. Our study provides a possible strategy for anti-wrinkle care through inhibition of HYBID-mediated HA degradation.

To investigate antimicrobial susceptibility patterns of various bacterial pathogens isolated from complicated urinary tract infection (UTI) cases, the Japanese Society of Chemotherapy, the Japanese Association of Infectious Disease, and the Japanese Society of Clinical Microbiology conducted the second nationwide surveillance from January to September 2011. With the cooperation of 42 medical institutions throughout Japan, 1036 strains belonging to 8 clinically relevant bacterial species were collected. Among methicillin-resistant Staphylococcus aureus (MRSA) strain, the vancomycin (VCM) MIC for 5.5% (3/55) of the strains was 2 μg/mL. Ampicillin, VCM, and linezolid were relatively active against 209 Enterococcus faecalis strains. The proportion of fluoroquinolone (FQ)-resistant strains was >20%. The MIC90 of FQs against the 382 Escherichia coli strains was 2-64 mg/L and the proportion resistant to FQs was approximately 30%. However, susceptibility of E. coli to sitafloxacin was still high (MIC90 = 2 mg/L). Fifty-eight (15.2%) of 382 E. coli, 6 (4.5%) of 132 Klebsiella pneumoniae, 1 (2.4%) of 41 Klebsiella oxytoca and 4 (6.8%) of 59 Proteus mirabilis strains were suspected of producing extended-spectrum beta-lactamase. Of 93 Pseudomonas aeruginosa strains, the proportions resistant to imipenem, amikacin, and ciprofloxacin were 21.5%, 4.3%, and 20.4%, respectively. Four strains (4.3%) were found to be multidrug-resistant. In complicated UTI cases, all of MRSA and E. faecalis were susceptible to all anti-MRSA agents. Sitafloxacin was active against other FQ-resistant E. coli strains. The isolation of extended-spectrum beta-lactamase-producing and multidrug-resistant strains increased.

Pelvic lymphoceles are an infrequent complication after pelvic surgery and develop shortly after the surgery in most cases. We experienced a case of delayed infection of a lymphocele 6 months after robot-assisted radical prostatectomy (RARP) and pelvic lymphadenectomy. In this case, antimicrobial chemotherapy and percutaneous drainage were effective, and there was no recurrence of the disease. Most urologists do not recognize that infected lymphoceles can develop a long time after surgery; thus, infected lymphoceles should be kept in mind in patients with nonspecific infectious symptoms, regardless of the length of time after surgery.

Background Hyaluronan (HA) metabolism in skin fibroblasts is mediated by HYBID (hyaluronan binding protein involved in hyaluronan depolymerization, alias CEMIP and KIAA1199) and the HA synthases HAS1 and HAS2. However, photoageing-dependent changes in HA and their molecular mechanisms, and the relationship between HA metabolism and clinical symptoms in photoaged skin remain elusive. Objectives We examined the amount, size and tissue distribution of HA and expression levels of HYBID, HAS1 and HAS2 in photoaged skin, and analysed their relationship with the degree of photoageing. Methods Photoageing-dependent changes of HA were investigated by studying skin biopsies isolated from photoprotected and photoexposed areas of the same donors, and the relationships between HA and photoageing symptoms such as skin wrinkling and sagging were examined. Results Skin biopsy specimens showed that the amount and size of HA are decreased in photoexposed skin compared with photoprotected skin, and this was accompanied by increased expression of HYBID and decreased expression of HAS1 and HAS2. Histologically, HA staining in the papillary dermis was decreased in photoexposed skin, showing reverse correlation with HYBID expression. HYBID expression in the photoexposed skin directly correlated with skin roughness and sagging parameters, and the reduced HA staining in the papillary dermis in the photoexposed skin positively correlated with these symptoms. Conclusions These data demonstrate that imbalance between HYBID-mediated HA degradation and HAS-mediated HA synthesis may contribute to enhanced HA catabolism in photoaged skin, and suggest that HYBID-mediated HA reduction in the papillary dermis is related to skin wrinkling and sagging of photoaged skin.

A unified total synthesis of stemoamide-type alkaloids is reported. Our synthetic approach features the chemoselective convergent assembly of five-membered building blocks via stemoamide as the common precursor to tetracyclic natural products. The synthesis consists of two successive coupling reactions of the three five-membered building blocks. The first coupling reaction is the vinylogous Michael addition/reduction sequence, which enables the gram-scale synthesis of stemoamide. The second coupling reaction is a chemoselective nucleophilic addition to stemoamide. While the lactone-selective nucleophilic addition to stemoamide affords saxorumamide and isosaxorumamide, the lactam-selective reductive nucleophilic addition leads to the formation of stemonine. Both chemoselective nucleophilic additions enable direct modification of stemoamide, resulting in highly concise and efficient total syntheses of the stemoamide-type alkaloids.

We report a case of ureteral carcinoma in which port site metastasis was found after a laparoscopic nephroureterectomy. The patient was a 77-year-old woman with a chiefcomplaint ofgross hematuria. A tumor was found in her left ureter by computed tomography (CT). The patient was diagnosed with a left ureter carcinoma with T2N0M0 or less. She underwent retroperitoneoscopic radical nephroureterectomy. The pathological diagnosis was an urothelial carcinoma, Grade 2, pT2Nx. She was carefully followed up without any adjuvant therapy. At 26 months postoperatively, a subcutaneous tumor was found at a port site without any disseminated disease or distant metastasis by CT and positron emission tomography-CT (PETCT). She underwent surgical resection ofthe subcutaneous tumor. Pathological diagnosis was port site metastatic urothelial carcinoma. She had no recurrence or metastasis at 24 months after the surgical resection without any adjuvant therapy.

The original definition of atypical antipsychotic drugs (APD) was drugs that are effective against positive symptoms in schizophrenia with no or little extrapyramidal symptoms (EPS). However, atypical APD have been reported to be more effective for cognitive dysfunction and negative symptoms in schizophrenia than typical APD, which expands the definition of 'atypicality'. This article provides a critical review of the pharmacology of atypical APD, especially from the viewpoint of receptor binding profiles and neurotransmitter regulations as well as neuroprotection and neurogenesis. A variety of serotonin (5-HT) receptors, such as 5-HT2A / 2C , 5-HT1A , 5-HT6 and 5-HT7 receptors, may contribute to the mechanisms of action of 'atypicality'. The dopaminergic modulations, including a low affinity for dopamine D2 receptors and a partial D2 receptor agonistic action, and glutamatergic regulations may also be involved in the pharmacological backgrounds of 'atypicality'. Atypical APD, but not typical APD, may facilitate cortical neuroprotection and hippocampal neurogenesis, which might be a part of the action mechanisms of atypical APD. The facilitation of cortical neuroprotection and hippocampal neurogenesis induced by atypical APD might be mediated by an increase in the Ser9 phosphorylation of glycogen synthase kinase-3β (GSK-3β). The stimulation of 5-HT1A receptors and/or the blockade of 5-HT2 receptors, which is characteristic of atypical APD, might increase Ser9 phosphorylation of GSK-3β. Moreover, atypical APD increase brain-derived neurotrophic factor (BDNF) levels. BDNF increases Ser9 phosphorylation of GSK-3β and has neuroprotective and neurogenic effects, as in the case of atypical APD. These findings suggest that GSK-3β might play a role in the action mechanisms of atypical APD, in both the 5-HT-dependent and BDNF-dependent mechanisms.

Rhododendrol, an inhibitor of melanin synthesis developed for lightening/whitening cosmetics, was recently reported to induce a depigmentary disorder principally at the sites of repeated chemical contact. Rhododendrol competitively inhibited mushroom tyrosinase and served as a good substrate, while it also showed cytotoxicity against cultured human melanocytes at high concentrations sufficient for inhibiting tyrosinase. The cytotoxicity was abolished by phenylthiourea, a chelator of the copper ions at the active site, and by specific knockdown of tyrosinase with siRNA. Hence, the cytotoxicity appeared to be triggered by the enzymatic conversion of rhododendrol to active product(s). No reactive oxygen species were detected in the treated melanocytes, but up-regulation of the CCAAT-enhancer-binding protein homologous protein gene responsible for apoptosis and/or autophagy and caspase-3 activation were found to be tyrosinase dependent. These results suggest that a tyrosinase-dependent accumulation of ER stress and/or activation of the apoptotic pathway may contribute to the melanocyte cytotoxicity.