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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.

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. 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

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.

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.

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.

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.

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.

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.

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.

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.

UV-sensitive syndrome (UV SS) is a genodermatosis characterized by cutaneous photosensitivity without skin carcinoma. Despite mild clinical features, cells from individuals with UV SS, like Cockayne syndrome cells, are very UV sensitive and are deficient in transcription-coupled nucleotide-excision repair (TC-NER), which removes DNA damage in actively transcribed genes. Three of the seven known UV SS cases carry mutations in the Cockayne syndrome genes ERCC8 or ERCC6 (also known as CSA and CSB, respectively). The remaining four individuals with UV SS, one of whom is described for the first time here, formed a separate UV SS-A complementation group; however, the responsible gene was unknown. Using exome sequencing, we determine that mutations in the UVSSA gene (formerly known as KIAA1530) cause UV SS-A. The UVSSA protein interacts with TC-NER machinery and stabilizes the ERCC6 complex; it also facilitates ubiquitination of RNA polymerase IIo stalled at DNA damage sites. Our findings provide mechanistic insights into the processing of stalled RNA polymerase and explain the different clinical features across these TC-NERg-deficient disorders., Nature Genetics, 44(5), pp.586-592; 2012

Comparisons of the clinical manifestations with gene mutations in patients with xeroderma pigmentosum group A (XPA) have suggested that those with mutations closer to the C-terminal coding region of the XPA gene have milder neurological and cutaneous symptoms. Here we report on four middle-aged, newly diagnosed Japanese XPA patients whose unusually mild symptoms, especially those affecting the skin, implicate a reduced association of a subtle defect in the C-terminus of XPA protein with skin lesions. All patients had a heterozygous G → C transversion at the splice acceptor site of XPA intron 3. We identified previously unreported heterozygous mutations in exon 6: a single-base insertion (690insT) in one patient and a four-base insertion (779insTT and 780insTT) in the other patients. These mutations led to the frameshift that created new premature termination codons, resulting in the production of truncated XPA proteins. They were longer than any previously reported truncated XPA protein, suggesting that the minimal cutaneous symptoms in these patients are due to a higher residual level of XPA protein activity and that the subtle defect in the C-terminus of XPA protein is more closely related to neurological impairment than to cutaneous abnormalities.

Cholinergic modulation of spontaneous GABAergic currents (mIPSC) was studied using whole-cell patch methods in mouse accessory olfactory bulb slices. Carbachol (above 100 microM) administration produced an increase in the mIPSC frequency in mitral cells, but did not affect the responses of mitral cells to GABA. The carbachol effect persisted in the presence of combined ionotropic and metabotropic glutamatergic receptor antagonists. The carbachol effect was reduced by the muscarinic receptor type-1 and -4 (M1 and M4) antagonist pirenzepine (10 microM), but not by the M2 and M4 antagonist himbacine (10 microM). The KCNQ/Kv7 potassium channel openers retigabine (80 microM) and diclofenac (300 microM) blocked the carbachol action, while the KCNQ potassium channel blocker XE-911 (20 microM) increased the mIPSC frequency. XE-911's action persisted in the presence of glutamate receptor blockers. In the presence of carbachol, mIPSCs were abolished by Ni (200 microM), while being insensitive to the calcium channel blocker nimodipine (30 microM), suggesting a role for R-type calcium channels in the GABA release. These results suggest that carbachol closed KCNQ channels by stimulating M1 receptors on granule cell dendrites, and the resulting depolarized and unstable membrane promoted calcium influx, thus increasing the GABA release. The possible role of acetylcholine in facilitating formation of a pheromone memory in mice is also discussed.

Regulation of hyaluronan (HA) synthesis and degradation is essential to maintenance of extracellular matrix homeostasis. We recently reported that HYBID (HYaluronan-Binding protein Involved in hyaluronan Depolymerization), also called KIAA1199, plays a key role in HA depolymerization in skin and arthritic synovial fibroblasts. However, regulation of HA metabolism mediated by HYBID and HA synthases (HASs) under stimulation with growth factors remains obscure. Here we report that TGF-β1, basic FGF, EGF, and PDGF-BB commonly enhance total amount of HA in skin fibroblasts through up-regulation of HAS expression, but molecular size of newly produced HA is dependent on HYBID expression levels. Stimulation of HAS1/2 expression and suppression of HYBID expression by TGF-β1 were abrogated by blockade of the MAPK and/or Smad signaling and the PI3K-Akt signaling, respectively. In normal human skin, expression of the TGF-β1 receptors correlated positively with HAS2 expression and inversely with HYBID expression. On the other hand, TGF-β1 up-regulated HAS1/2 expression but exerted only a slight suppressive effect on HYBID expression in synovial fibroblasts from the patients with osteoarthritis or rheumatoid arthritis, resulting in the production of lower molecular weight HA compared with normal skin and synovial fibroblasts. These data demonstrate that although TGF-β1, basic FGF, EGF, and PDGF-BB enhance HA production in skin fibroblasts, TGF-β1 most efficiently contributes to production of high molecular weight HA by HAS up-regulation and HYBID down-regulation and suggests that inefficient down-regulation of HYBID by TGF-β1 in arthritic synovial fibroblasts may be linked to accumulation of depolymerized HA in synovial fluids in arthritis patients.

Perospirone is a serotonin 5-HT(2A) and dopamine D(2) receptor antagonist which originated in Japan. It has been shown that perospirone is metabolized to ID-15036 mainly by CYP3A4 based on an in vitro study. To investigate the metabolism of perospirone in humans, the authors measured the concentration of perospirone and ID-15036 after a single oral dose of perospirone (8 mg) in 10 healthy male subjects, before and during coadministration of carbamazepine, known as a potent inducer of CYP3A4. Before carbamazepine coadministration, the peak plasma concentrations+/-SD of perospirone and ID-15036 were 4.0+/-4.3 and 11.7+/-7.1 ng/ml, respectively. During carbamazepine coadministration, the concentration of perospirone was decreased below the detection limit, and that of ID-15036 was 6.0+/-1.7 ng/ml. The concentrations of perospirone and ID-15036 were influenced significantly by the treatment with carbamazepine, and this was probably attributable to the induction of CYP3A4. This study provided an in vivo evidence of involvement of CYP3A4 in the metabolism of perospirone.

Background: Our previous study suggested a significant association between Ureaplasma urealyticum and nongonococcal urethritis (NGU). However, association of the serovars of U. urealyticum with NGU remains unclear. A polymerase chain reaction (PCR)-based assay can distinguish 4 serovars of Ureaplasma parvum from each other and categorize 10 serovars of U. urealyticum into 3 subtypes: subtype 1 (serovars 2, 5, 8, and 9), subtype 2 (serovars 4, 10, 12, and 13), and subtype 3 (serovars 7 and 11). Goal: The goal of this study was to determine which subtypes of U. urealyticum are associated with NGU as determined by PCR-based assay. Study: The prevalence of U. urealyticum subtypes in 106 ureaplasma-positive men with urethritis was compared with that in 30 ureaplasma-positive men without urethritis. Results: In men with nonchlamydial NGU and men with Mycoplasma genitalium-negative nonchlamydial NGU, only U. urealyticum subtype 1 (serovars 2, 5, 8, and 9) was detected significantly more often than in men without urethritis. Conclusion: This study suggests that subtype 1 of U. urealyticum (serovars 2, 5, 8, and 9) is associated with NGU independently of Chlamydia trachomatis or M. genitalium.

A reduction in the post-ultraviolet (UV) DNA repair capacity is associated with aging. To clarify the mechanism of this change, we examined the DNA repair capacity of skin fibroblasts from healthy donors of different ages by the two methods: host cell reactivation (HCR) assay and ELISA of cyclobutane pyrimidine dimers and pyrimidine-pyrimidone (6-4) photoproducts. In HCR assay, cells from elderly donors exhibited significant declines in the ability to restore transfected reporter DNA damaged by UV light. In contrast, the ability to remove DNA damage declined little with age in ELISA. These results imply that the age-sensitive step took place after the damage excision in nucleotide excision repair (NER). The mRNA expression of DNA repair synthesis-related genes (DNA polymerase delta, replication factor C, and proliferating cell nuclear antigen) were markedly decreased in the cells from multiple elderly subjects compared with those from young subjects. Further, the protein level of DNA polymerase delta1, a catalytic subunit of the pivotal factor in repair synthesis, correlated with the mRNA level. These findings suggest that the reduced post-UV DNA repair capacity in aging results from an impairment in the latter step of NER by the decreased expression of factors in repair synthesis.

Of 150 clinical isolates of Neisseria gonorrhoeae recovered in 2001, we examined 55 clinical isolates of N. gonorrhoeae for which cefixime MICs were ≥0.125 μg/ml and randomly selected 15 isolates for which cefixime MICs were ≤0.06 μg/ml for analysis of alterations in the penicillin-binding protein 2 (PBP 2) gene. We found insertion of an extra codon (Asp-345a) in the transpeptidase domain of PBP 2, and this insertion occurred alone or in conjunction with other amino acid substitutions. We also found a mosaic PBP 2 that was composed of fragments of the PBP 2 proteins from Neisseria cinera and Neisseria perflava . This mosaic PBP 2 was significantly associated with decreased susceptibilities to penicillin and cephalosporins, especially oral cephalosporins. For most of the isolates with a mosaic PBP 2, the cefixime MICs were ≥0.5 μg/ml and the cefdinir MICs were ≥1 μg/ml. Analysis of chromosomal DNA restriction patterns by pulsed-field gel electrophoresis revealed that most isolates with the mosaic PBP 2 were genetically similar. The recombination events that generated the mosaic PBP 2 would likely have contributed to the decreased sensitivities to cephalosporins. Isolates with the mosaic PBP 2 appear to threaten the efficacy of the currently recommended regimen with cefixime. The emergence of such strains may be the result of the in vivo generation of clones in which interspecies recombination occurred between the penA genes of N. gonorrhoeae and commensal Neisseria species.

Purpose We retrospectively evaluated the outcome of Hautmann neobladder reconstruction in terms of complications, lower urinary tract symptoms, and sexual function in a large group of patients who underwent radical cystectomy. Methods We reviewed the medical records of 118 patients (105 men and 13 women) who underwent radical cystectomy and Hautmann neobladder construction at the Gifu University Hospital or one of its affiliate hospitals between Jan 1993 and Dec 1999. The 118 patients were asked to complete a questionnaire regarding lower urinary tract symptoms and sexual activity, and the data was compiled. Results The mean follow-up period was 50.4 months (range, 6.8-88.2). Early complications comprised wound infection (in 17.8% of patients) and ileus (in 10.1% of patients). Late complications comprised ileus, pyelonephritis, stone, and stricture of the pouch-urethral anastomosis, each of which occurred in 3.4% of patients. Eighty-one (73 men and 8 women, 72.9%) of 90 surviving patients replied to the questionnaire. Seventy-seven (95.1%) of these patients reported spontaneous micturition, whereas 4 (4.9%) patients required intermittent self-catheterization. The mean total I-PSS was 11.6 points. Twenty-five percent of patients experienced interrupted voiding almost always; 38% of patients did not experience this at all. Approximately 26% of patients experienced weak urinary streams; 36% did not. Daytime continence was achieved in 97.3% of patients; nighttime incontinence was present in 61.3%. Preoperatively, 79.7% of the men were capable of sexual intercourse. Postoperatively, 63.6% of men who underwent radical cystectomy with the nerve-sparing procedure were capable of sexual intercourse, whereas only 14.8% of men who underwent radical cystectomy without the nerve-sparing procedure were. Conclusions Morbidity rates were acceptable and functional outcome was excellent in this rather large group of patients who underwent Hautmann neobladder construction. Some problems have not been fully overcome, however, i.e., nocturnal incontinence and sexual dysfunction.

Three human hyaluronan synthase genes ( HAS1 , HAS2 , and HAS3 ) have been cloned, but the functional differences between these HAS genes remains obscure. The purpose of this study was to examine which of the HAS genes are selectively regulated in epidermis. We examined the relation of changes between hyaluronan production and HAS gene expression when cytokines were added to cultured human keratinocytes. Interferon-γ increased hyaluronan production whereas transforming growth factor β decreased it. Both cytokines affected preferentially high-molecular-mass (> 10 6 Da) hyaluronan production. Consistent with the change in hyaluronan synthesis, we found that interferon-γ markedly upregulated HAS3 mRNA whereas transforming growth factor β downregulated HAS3 transcript levels. The expression of HAS1 mRNA was not significantly affected by either cytokine, and HAS2 mRNA expression was undetectable under either basal or cytokine-stimulated conditions by northern blot using total RNA. Furthermore, in situ mRNA hybridization showed that mouse epidermal keratinocytes abundantly expressed HAS3 mRNA from the basal to the granular cell layers, suggesting that HAS3 functions in epidermis. These findings suggest that HAS3 gene expression plays a crucial role in the regulation of hyaluronan synthesis in the epidermis.

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.

The aim of this study was to investigate risk factors affecting 5- and 10-year survival in autotransplantation of third molars with complete root formation at dental clinics. Participating dentists were requested to provide information on transplantations performed between 1 January 1990 and 31 December 2009. After data screening and elimination, 183 teeth in 171 men aged 20-72 years (mean, 44.8 years) and 205 teeth in 189 women aged 20-74 years (mean, 42.0 years) were included in the study. A single-factor analysis using the log-rank test revealed that the following factors had a significant influence (p

OBJECTIVE This prospective and randomized clinical study was initiated to compare the efficacy and safety of combined androgen blockade with combination with UFT in patients with untreated prostate cancer. METHODS A total of 142 patients were entered in this study between April 1990 and December 1992. All patients received bilateral orchiectomy and 200 mg/day of diethylstilbestrol diphosphate. Of these patients, 70 patients were administered an additional 400 mg/day of UFT after randomization. Either treatment was continued for at least 1 year or until objective progression occurred if the initial response was equal to or better than no change. The endpoints of this study were progression-free survival, cancer-specific survival and change of QOL scores. RESULTS A total of 136 patients were evaluable and 131 patients (96.3%) could be followed up with a median follow-up period of 1469 days. Both groups showed similar initial treatment response at 12 weeks, adverse effect and change of quality of life score during the first year after initiation of the treatment. There was a significantly longer progression-free survival and better but not significant cancer-specific survival in the endocrine chemotherapy group. The patients with earlier stage and initial serum prostate-specific antigen values

The effects of 3-week treatment with a typical antipsychotic drug chlorpromazine and three atypical antipsychotic drugs (risperidone, olanzapine and perospirone) on the binding to dopamine D2 and serotonin 5-HT2A receptors were examined in the rat stratum and frontal cortex, respectively. Subchronic treatment with chlorpromazine (10 mg/kg) and perospirone (1 mg/kg) significantly increased D2 receptors, while no increase was observed with lower dose of chlorpromazine (5 mg/kg), perospirone (0.1 mg/kg), risperidone (0.25, 0.5 mg/kg) or olanzapine (1, 2 mg/kg). On the other hand, 3-week administration of chlorpromazine (5, 10 mg/kg) and olanzapine (1, 2 mg/kg) significantly decreased 5-HT2A receptors, but risperidone (0.25, 0.5 mg/kg) or perospirone (0.1, 1 mg/kg) had no effect. The measurement of in vivo drug occupation for D2 and 5-HT2A receptors using N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) suggested that high occupation of 5-HT2A receptors with lower D2 receptor occupancy might be involved in the absence of up-regulation of D2 receptors after subchronic treatment with some atypical antipsychotic drugs.

The main reasons for loss of autotransplanted teeth are different from those involved in natural teeth loss. The aim of this study was to investigate which procedures were employed to treat spaces vacated when autotransplanted teeth were lost. Participating dentists were requested to provide information on transplantations they had undertaken. A total of 614 teeth in 552 patients (37 dentists) ranging in age from 17 to 79 years (mean age: 44.1 years) were examined. A total of 102 transplanted teeth were lost during the observation period. Procedures for treatment of spaces vacated were not influenced by main reason for transplanted tooth loss. The procedure used to treat depended on the original prosthodontic treatment of the transplanted teeth. For single crowns, the spaces were left empty (33.9%) or replaced by bridge work (30.5%), implants (20.3%), or dentures (10.2%). For single crowns in the upper and lower second molar regions, the spaces were usually left empty (upper 100%, lower 71.4%), while for those in the upper and lower first molar regions, the spaces were often replaced by bridge work (upper 41.7%, lower 50.0%). For bridge abutments, spaces were replaced by dentures (42.9%), implants (33.3%), or left empty (14.3%), and in the lower second molar region, they were mostly replaced by implants (5 cases, 41.7%). For most denture abutment cases, the spaces were replaced by dentures (88.9%). During the survival period of the transplanted teeth, the masticatory burden on the other teeth is reduced and the adjacent teeth are supported by the transplanted tooth. Even if transplanted teeth are eventually lost, traditional procedures can be performed to fill the vacated space.

Hepatocellular carcinoma (HCC) and inflammatory pseudotumor of the liver (IPL) are often difficult to differentiate before surgery. To date, colocalization of IPL and HCC has not been reported. We experienced a case of necrotic HCC surrounded by IPL-like tissue. The raised levels of alpha-fetoprotein and PIVKA-II declined to within the normal ranges after resection of the tumor. The IPL-like nodule most likely developed as a process of an inflammatory reaction such as abscess formation after the spontaneous destruction of the HCC. Our case is a warning that the presence of a 'pseudotumor' does not rule out the possible simultaneous presence of carcinoma.

Yasushi Yoshioka, Yoshito Takahashi \ Ken Matsuoka, Kenzo Nakamura, Jun Koizumi, Mineo Kojima and Yasunori Machida 1 Division of Biological Science, Graduate School of Science, Nagoya University, Chikusa-ku, Nagoya, 464-01 Japan 2 Laboratory of Biochemistry, Faculty of Agriculture, Nagoya University, Chikusa-ku, Nagoya, 464-01 Japan 3 Department of Applied Biology, Shinshu University, Tsuneta 3-15-1, Ueda, Nagano, 386 Japan

Cockayne syndrome (CS) is a genetic disorder characterized by developmental abnormalities and photodermatosis resulting from the lack of transcription-coupled nucleotide excision repair, which is responsible for the removal of photodamage from actively transcribed genes. To date, all identified causative mutations for CS have been in the two known CS-associated genes, ERCC8 (CSA) and ERCC6 (CSB). For the rare combined xeroderma pigmentosum (XP) and CS phenotype, all identified mutations are in three of the XP-associated genes, ERCC3 (XPB), ERCC2 (XPD), and ERCC5 (XPG). In a previous report, we identified several CS cases who did not have mutations in any of these genes. In this paper, we describe three CS individuals deficient in ERCC1 or ERCC4 (XPF). Remarkably, one of these individuals with XP complementation group F (XP-F) had clinical features of three different DNA-repair disorders--CS, XP, and Fanconi anemia (FA). Our results, together with those from Bogliolo et al., who describe XPF alterations resulting in FA alone, indicate a multifunctional role for XPF.

We studied a relationship between in vitro sensitivity of the tumors to anti-cancerous drugs and histopathological effectiveness of an intra-arterial infusion chemotherapy in 15 patients with bladder cancers. The in vitro sensitivity test was performed by measuring intra-cellular ATP contents (ATP assay). The intra-arterial chemotherapy were performed by injecting methotrexate (MTX), adriamycin (ADM) and eisplatin (CDDP) from the internal iliac artery. When the intra-cellular ATP contents of the tumor cells treated with an anti-cancerous drug decreased to less than 50% of the untreated tumor cells, the tumor was evaluated as sensitive to the drug. The effectiveness of the chemotherapy were histopathologically evaluated by a pathologist according to the response criteria for bladder cancer treatment. When the histopathological responses of higher than grade 2 were observed in the tumor, the chemotherapy was evaluated as effective. In 8 of 9 tumors sensitive to ADM, chemotherapy were effective histopathologically and in all 6 tumors resistant to ADM, histopathological response of the chemotherapies were poor. The overall coincidence ratio between sensitivity to ADM and the histopathological effectiveness of the chemotherapy was 93%, showing statistically significant correlation. In 7 of 12 tumors sensitive to CDDP, the chemotherapies were effective and in 2 of 3 tumors resistant to CDDP, the chemotherapies were ineffective. Although the overall coincidence ratio between the sensitivities to CDDP and chemotherapeutic effectiveness was 60%, there was no significant correlation between them. In 7 of 8 tumors sensitive to both of ADM and CDDP, the chemotherapies were effective and in 6 of 7 tumors resistant to at least one of them, the chemotherapies were ineffective. (ABSTRACT TRUNCATED AT 250 WORDS)

Out of 110 strains of Staphylococcus aureus isolated from 1985 to 1990, isolation rate of methicillin-resistant S. aureus (MRSA) was investigated. Nineteen strains of 59 S. aureus from outpatients and 20 strains of 51 S. aureus from inpatients were determined as MRSA. Isolation frequency of MRSA from inpatients was increasing in the recent two years. Coagulase type, enterotoxin type and production of toxic shock syndrome toxin-1 (TSST-1) were examined in 22 strains of MRSA. Coagulase type II (86%), enterotoxin type C (68%) and TSST-1 positive strain was most dominant. Susceptibility of MRSA to 4 antimicrobial agents were measured, MRSA were sensitive to vancomycin (VCM), arbekacin (ABK) and minocycline, but resistant to flomoxef. Thirty-four patients from whom MRSA was isolated including 20 patients from urine, 13 from pus and 1 from blood, were analyzed clinically. Pyuria was not recognized in some cases in whom MRSA was isolated from their urine. Concomitant polymicrobial infection was frequently noted in those patients with MRSA in their urinary tract. These facts show that the pathogenic role of MRSA in the urinary tract infection was not significant. On the other hand, when MRSA was isolated from pus or blood, serious infections could be caused by MRSA, especially in compromised host. Regarding the treatment in these cases, administration of VCM or ABK was though to be necessary.

This study was conducted by the Japanese Society of Chemotherapy and is the first nationwide study on bacterial pathogens isolated from patients with urinary tract infections at 28 hospitals throughout Japan between January 2008 and June 2008. A total of 688 bacterial strains were isolated from adult patients with urinary tract infections. The strains investigated in this study are as follows: Enterococcus faecalis (n = 140), Escherichia coli (n = 255), Klebsiella pneumoniae (n = 93), Proteus mirabilis (n = 42), Serratia marcescens (n = 44), and Pseudomonas aeruginosa (n = 114). The minimum inhibitory concentrations of 39 antibacterial agents used for these strains were determined according to the Clinical and Laboratory Standards Institute (CLSI) manual. All Enterococcus faecalis strains were susceptible to ampicillin and vancomycin. Although a majority of the E. faecalis strains were susceptible to linezolid, 11 strains (7.8%) were found to be intermediately resistant. The proportions of fluoroquinolone-resistant Enterococcus faecalis, Escherichia coli, Proteus mirabilis, and S. marcescens strains were 35.7%, 29.3%, 18.3%, and 15.2%, respectively. The proportions of E. coli, P. mirabilis, K. pneumoniae, and S. marcescens strains producing extended-spectrum β-lactamase were 5.1%, 11.9%, 0%, and 0%, respectively. The proportions of Pseudomonas aeruginosa strains resistant to carbapenems, aminoglycosides, and fluoroquinolones were 9.2%, 4.4%, and 34.8%, respectively, and among them, 2 strains (1.8%) were found to be multidrug resistant. These data present important information for the proper treatment of urinary tract infections and will serve as a useful reference for periodic surveillance studies in the future.