Thin film growth of CaAgAs by molecular beam epitaxy.

We have grown thin films of CaAgAs by molecular beam epitaxy, which was theoretically proposed to be a topological insulator. The temperature dependence of resistivity and the carrier concentration at 4 K were similar to the reported results of bulk samples. However, the magnetoresistance exhibited a steep increase at low magnetic fields, a behavior not observed for bulk samples. This steep increase of resistivity is ascribable to the weak antilocalization effect and provides clues to the nature of the topological surface state of CaAgAs.

Si-based Mach-Zehnder wavelength/mode multi/demultiplexer for a WDM/MDM transmission system.

We propose and experimentally demonstrate a low-loss and low-crosstalk Mach-Zehnder mode/wavelength multi/demultiplexer for WDM/MDM transmission based on a Si-photonics platform. A broadband 3-dB mode divider, which is also newly devised here, makes it possible to compose a Mach-Zehnder filter for "mode" and "wavelength" simultaneously. Transmission characteristics of fabricated 3-dB mode dividers are in excellent agreement with theoretical results. Mach-Zehnder filters using the 3-dB mode divider with a free spectral range (FSR) of 20 and 1 nm are also fabricated and the modal crosstalk is less than -24 dB in the 40-nm wavelength range for the MZ filter with an FSR of 20 nm. The tuning of the peak wavelength position by the TiN heater is also demonstrated.

Prospective predictors of exacerbation status in severe asthma over a 3-year follow-up.

BACKGROUND: A predisposition to exacerbations is being recognized as a distinct phenotype with "previous exacerbations" representing the strongest clinical factor associated with future exacerbation. Thus, to identify additional novel biomarkers associated with asthma exacerbations, "past exacerbation status" must be included as a confounding factor. OBJECTIVE: This study aimed to characterize the clinical and biomarker features associated with asthma exacerbations in severe asthma. METHODS: We evaluated clinical parameters from 105 severe asthmatics yearly for 3 years, as well as their exacerbation status. We classified the subjects into 3 groups: (i) consistent non-exacerbators (CNE, subjects who did not experience any exacerbation over the 3-year period); (ii) consistent frequent exacerbators (CFE, subjects with frequent exacerbation, defined as those who had 2 or more exacerbations within 1 year, throughout the 3-year period); and (iii) intermittent exacerbators (IE). We conducted multivariate analysis for comparisons among the groups for multiple factors, including several Th2-related biomarkers, in addition to the "past exacerbation status." RESULTS: Thirty-nine subjects were classified as CNE, 15 as CFE, and 51 as IE. Frequent exacerbations in the previous year predicted exacerbations for the following year (P < .001). Among the several Th2-related biomarkers, only FeNO was associated with exacerbation status. When we analysed the data after the second visit, the impact of FeNO on predicting future exacerbation remained significant, even after considering the exacerbation status during the first year (P < .05). CONCLUSIONS AND CLINICAL RELEVANCE: Measurement of FeNO has a significant potential to predict future asthma exacerbation, which is independent of the "past exacerbation history."

IgE sensitization to food allergens and airborne allergens in relation to biomarkers of type 2 inflammation in asthma.

BACKGROUND: We have recently reported that sensitization to food allergens and sensitization to airborne allergens had independent associations with increased fraction of exhaled nitric oxide (FeNO) and blood eosinophils in middle-aged adults and in young subjects with asthma. OBJECTIVE: To investigate the relation between IgE sensitization and several type 2 inflammation biomarkers in adult asthmatics. METHODS: FeNO, urinary eosinophil-derived neurotoxin (U-EDN), serum eosinophil cationic protein (S-ECP) and periostin were measured in 396 asthmatics, aged 17-76 years, from the Swedish GA2LEN study. Sensitization to airborne allergens was examined with skin prick tests (≥3 mm wheal) and sensitization to food allergens with measurement of specific IgE (≥0.35 kU/L). RESULTS: Asthmatics sensitized to food allergens had higher FeNO, 22.3 ppb (18.6, 26.7) vs 16.1 ppb (14.2, 18.2) (P = .005), S-ECP, 17.7 mg/L (14.8, 21.1) vs 12.8 mg/L (10.9, 14.9) (P = .01), and periostin, 73.7 (67.5, 80.3) ng/mL vs 59.9 (55.8, 64.2) ng/mL (P = .003), than non-sensitized subjects. Periostin levels in this group were also significantly higher than in the group sensitized only to airborne allergens (P = .01). Sensitization to food allergens related independently to FeNO (P = .02), S-ECP (P = .006) and periostin (P = .004), whereas sensitization only to airborne allergens related only to FeNO (P = .02) after adjustments for age, sex, height, weight and smoking history. FeNO correlated weakly with S-ECP (r = .17, P < .001), periostin (r = .19, P < .001) and U-EDN (0.16, P < .001). S-ECP also correlated weakly with U-EDN (r = .12, P = .02). None of the correlations between the remaining pairs of markers of type 2 inflammation were significant. CONCLUSIONS & CLINICAL RELEVANCE: Sensitization to food allergens related to several local and systemic type 2 inflammation markers, such as FeNO, S-ECP and periostin. Assessing the profile of allergic sensitization, including to food allergens, might improve the understanding and interpretation of inflammatory markers and potentially improve asthma management.

Relationship between Eustachian tube dysfunction and otitis media with effusion in radiotherapy patients.

OBJECTIVE: This study evaluated the relationship between radiation and Eustachian tube dysfunction, and examined the radiation dose required to induce otitis media with effusion. METHODS: The function of 36 Eustachian tubes in 18 patients with head and neck cancer were examined sonotubometrically before, during, and 1, 2 and 3 months after, intensity-modulated radiotherapy. Patients with an increase of 5 dB or less in sound pressure level (dB) during swallowing were categorised as being in the dysfunction group. Additionally, radiation dose distributions were assessed in all Eustachian tubes using three dose-volume histogram parameters. RESULTS: Twenty-two of 25 normally functioning Eustachian tubes before radiotherapy (88.0 per cent) shifted to the dysfunction group after therapy. All ears that developed otitis media with effusion belonged to the dysfunction group. The radiation dose threshold evaluation revealed that ears with otitis media with effusion received significantly higher doses to the Eustachian tubes. CONCLUSION: The results indicate a relationship between radiation dose and Eustachian tube dysfunction and otitis media with effusion.

Pancreatoduodenectomy with portal vein resection for distal cholangiocarcinoma.

BACKGROUND: Little is known about the value of portal vein (PV) resection in distal cholangiocarcinoma. The aim of this study was to evaluate the clinical significance of PV resection in distal cholangiocarcinoma. METHODS: Patients who underwent pancreatoduodenectomy (PD) for distal cholangiocarcinoma between 2001 and 2010 at one of 31 hospitals in Japan were reviewed retrospectively with special attention to PV resection. Short- and long-term outcomes were evaluated. RESULTS: In the study interval, 453 consecutive patients with distal cholangiocarcinoma underwent PD, of whom 31 (6·8 per cent) had combined PV resection. The duration of surgery (510 versus 427 min; P = 0·005) and incidence of blood transfusion (48 versus 30·7 per cent; P = 0·042) were greater in patients who had PV resection than in those who did not. Postoperative morbidity and mortality were no different in the two groups. Several indices of tumour progression, including high T classification, lymphatic invasion, perineural invasion, pancreatic invasion and lymph node metastasis, were more common in patients who had PV resection. Consequently, the incidence of R1/2 resection was higher in this group (32 versus 11·8 per cent; P = 0·004). Survival among the 31 patients with PV resection was worse than that for the 422 patients without PV resection (15 versus 42·4 per cent at 5 years; P < 0·001). Multivariable analyses revealed that age, blood loss, histological grade, perineural invasion, pancreatic invasion, lymph node metastasis and surgical margin were independent risk factors for overall survival. PV resection was not an independent risk factor. CONCLUSION: PV invasion in distal cholangiocarcinoma is associated with locally advanced disease and several negative prognostic factors. Survival for patients who have PV resection is poor even after curative resection.

Serum periostin relates to type-2 inflammation and lung function in asthma: Data from the large population-based cohort Swedish GA(2)LEN.

BACKGROUND: Periostin has been suggested as a novel, phenotype-specific biomarker for asthma driven by type 2 inflammation. However, large studies examining relationships between circulating periostin and patient characteristics are lacking and the suitability of periostin as a biomarker in asthma remains unclear. AIM: To examine circulating periostin in healthy controls and subjects with asthma from the general population with different severity and treatment profiles, both with and without chronic rhinosinusitis (CRS), in relation to other biomarkers and clinical characteristics. METHODS: Serum periostin was examined by ELISA in 1100 subjects aged 17-76 from the Swedish Global Allergy and Asthma European Network (GA(2)LEN) study, which included 463 asthmatics with/without chronic rhinosinusitis (CRS), 98 individuals with CRS only, and 206 healthy controls. Clinical tests included measurement of lung function, Fraction of exhaled NO (FeNO), IgE, urinary eosinophil-derived neurotoxin (U-EDN), and serum eosinophil cationic protein (S-ECP), as well as completion of questionnaires regarding respiratory symptoms, medication, and quality of life. RESULTS: Although median periostin values showed no differences when comparing disease groups with healthy controls, multiple regression analyses revealed that periostin was positively associated with higher FeNO, U-EDN, and total IgE. In patients with asthma, an inverse relationship with lung function was also observed. Current smoking was associated with decreased periostin levels, whereas increased age and lower body mass index (BMI) related to higher periostin levels in subjects both with and without asthma. CONCLUSION: We confirm associations between periostin and markers of type 2 inflammation, as well as lung function, and identify novel constitutional factors of importance to the use of periostin as a phenotype-specific biomarker in asthma.

IL4Rα and ADAM33 as genetic markers in asthma exacerbations and type-2 inflammatory endotype.

BACKGROUND: Genetic markers of susceptibility to asthma exacerbations in adults remain unclear. OBJECTIVE: To identify genetic markers of asthma exacerbations, particularly in patients with type-2 inflammatory endotype. METHODS: In this observational study of patients enrolled in the Kinki Hokuriku Airway disease Conference multicenter study, frequency of exacerbations requiring systemic corticosteroids during 2 years after enrolment and associated risk factors was determined. For genetic marker analysis, interleukin-4 receptor α (IL4RA) rs8832 and a disintegrin and metalloprotease 33 (ADAM33) S_2 (rs528557), T_1 (rs2280091), T_2 (rs2280090), and V_4 (rs2787094) variants were included. Elevated serum periostin levels at enrolment (≥95 ng/mL, defined as type-2 inflammatory endotype) were considered in the analysis. RESULTS: Among 217 patients who were successfully followed up for 2 years after enrolment, 60 patients showed at least one asthma exacerbation during the 2 years. Airflow limitation (%FEV1 <80%) and recent exacerbations but not genetic variants were identified as risk markers of exacerbations. A total of 27 patients showed type-2 inflammatory endotype (serum periostin ≥95 ng/mL at enrolment) and subsequent exacerbations; risk factors in these patients were airflow limitation (odds ratio, 6.51; 95% confidence interval (CI): 2.37-18.6; P=.0003), GG genotype of IL4RA rs8832 (odds ratio, 4.01; 95% CI: 1.47-11.0; P=.007), and A allele of ADAM33 T_2 (odds ratio, 2.81; 95% CI: 1.05-7.67; P=.04) by multivariate analysis. In addition, GG genotype of IL4RA rs8832 was associated with type-2 endotype, whereas A allele of ADAM33 T_2 was associated with mixed type of eosinophilic/type-2 and neutrophilic inflammations. CONCLUSIONS AND CLINICAL RELEVANCE: IL4RA and ADAM33 variants may be risk markers of asthma exacerbations in type-2 inflammatory endotype. Precise endotyping may facilitate the identification of genetic risk markers of asthma exacerbations.

Population of the temperate mosquito, Culex pipiens, decreases in response to habitat climatological changes in future.

Predictions of the temporal distribution of vector mosquitoes are an important issue for human health because the response of mosquito populations to climate change could have implications for the risk of vector-borne diseases. To elucidate the effects of climate change on mosquito populations inhabiting temperate regions, we developed a Physiology-based Climate-driven Mosquito Population model for temperate regions. For accurately reproducing the temporal patterns observed in mosquito populations, the key factors were identified by implementing the combinations of factors into the model. We focused on three factors: the effect of diapause, the positive effect of rainfall on larval carrying capacity, and the negative effect of rainfall as the washout mortality on aquatic stages. For each model, parameters were calibrated using weekly observation data of a Culex pipiens adult population collected in Tokyo, Japan. Based on its likelihood value, the model incorporating diapause, constant carrying capacity, and washout mortality was the best to replicate the observed data. By using the selected model and applying global climate model data, our results indicated that the mosquito population would decrease and adults' active season would be shortened under future climate conditions. We found that incorporating the washout effect in the model settings or not caused a difference in the temporal patterns in the projected mosquito populations. This suggested that water resources in mosquito habitats in temperate regions should be considered for predicting the risk of vector-borne diseases in such regions.

Utility of serum periostin and free IgE levels in evaluating responsiveness to omalizumab in patients with severe asthma.

BACKGROUND: Omalizumab, a humanized anti-IgE monoclonal antibody, has demonstrated efficacy in patients with severe allergic asthma. However, treatment responses vary widely among individuals. Despite a lack of data, free serum IgE levels following omalizumab treatment have been proposed as a marker of treatment responsiveness. METHODS: In this prospective, observational study, we assessed the utility of biomarkers of type 2 inflammation in predicting omalizumab treatment responses, as determined by the absence of asthma exacerbation during the first year of treatment. Free serum IgE levels were monitored for 2 years to examine their association with baseline biomarker levels and the number of exacerbations. RESULTS: We enrolled thirty patients who had been treated with omalizumab for at least 1 year, of whom 27 were treated for 2 years. Baseline serum periostin levels and blood eosinophil counts were significantly higher in patients without exacerbations during the first year of treatment than in patients with exacerbations. Baseline serum periostin levels, but not eosinophil counts, were negatively associated with free serum IgE levels after 16 or 32 weeks of treatment. Reduced free serum IgE levels during treatment from those at baseline were associated with reduced exacerbation numbers at 2 years. In 14 patients who continued to have exacerbations during the first year of treatment, exacerbation numbers gradually and significantly decreased over the 2-year study period, with concurrent significant reductions in free serum IgE levels. CONCLUSION: Baseline serum periostin levels and serum free IgE levels during treatment follow-up may be useful in evaluating responses to omalizumab treatment.

Influenza 2014-2015 among pregnant Japanese women: primiparous vs multiparous women.

This study was performed to determine whether multiparous pregnant women are prone to influenza. A questionnaire survey was conducted at 19 centres located throughout Japan, targeting all 6,694 postpartum women within 7 days after birth before leaving the hospital. All women gave birth during the study period between March 1, 2015, and July 31, 2015. Data regarding vaccination and influenza infection in or after October 2014, age, previous experience of childbirth, and number and ages of cohabitants were collected. Seventy-eight percent (n = 51,97) of women given questionnaires responded. Of these, 2,661 (51 %) and 364 (7.0 %) women reported having been vaccinated and having contracted influenza respectively. Multiparous women had a higher risk of influenza regardless of vaccination status (8.9 % [121/1362] vs 5.7 % [74/1299], relative risk [95 % confidence interval], 1.80 [1.36 to 2.38] for vaccinated and 9.3 % [112/1198] vs 4.3 % [57/1328], 2.18 [1.60 to 2.97] for unvaccinated women) compared to primiparous women. The risk of influenza increased with increasing number of cohabitants: 4.8 % (100/2089), 7.5 %, (121/1618), 9.0 %, (71/785), and 10.4 % (58/557) for women with 1, 2, 3, and ≥4 cohabitants respectively. Family size is a risk factor for influenza infection in pregnancy.

Elevation of serum squamous cell carcinoma antigen 2 in patients with psoriasis: associations with disease severity and response to the treatment.

BACKGROUND: Squamous cell carcinoma antigen (SCCA) belongs to the ovalbumin-serpin family and is a known tumour marker. Expression of SCCA is upregulated in the serum and skin of patients with psoriasis. OBJECTIVES: The aim of this study was to determine SCCA2 levels in association with disease severity and treatment efficacy in patients with psoriasis. MATERIALS AND METHODS: Patients with psoriasis (n = 123) and healthy controls (n = 25) were enrolled in this prospective cross-sectional study. Enzyme-linked immunosorbent assay (ELISA) analysis was performed to determine serum SCCA2 levels. SCCA2 expression in skin was evaluated using immunohistochemical analysis. Serum SCCA2 levels were compared with Psoriasis Area Severity Index (PASI) scores. The effect of treatment on serum SCCA2 levels was assessed using serial examinations. Induction of SCCA2 by several psoriatic cytokines in human keratinocytes was evaluated. RESULTS: The serum levels of SCCA2 were significantly higher in patients with psoriasis than healthy controls and correlated well with disease severity. Increased SCCA2 staining was observed in lesional skin but not in nonlesional skin of patients with psoriasis. In addition, SCCA2 expression levels in skin correlated with serum concentrations of SCCA2. SCCA2 significantly decreased according to improvement of PASI scores. Interleukin (IL)-17 and IL-22 synergistically increased the production of SCCA2 at both mRNA and protein levels in human keratinocytes. CONCLUSIONS: Significant elevation of SCCA2 is associated with disease severity and reflects treatment efficacy. SCCA2 may be a useful biomarker in psoriasis, reflecting T-helper 17-type inflammation - the main determinant of the severity of psoriasis.

MRI study of atherosclerotic plaque progression using ultrasmall superparamagnetic iron oxide in Watanabe heritable hyperlipidemic rabbits.

OBJECTIVE: The purpose of this study was to evaluate plaque progression by using MRI with ultrasmall superparamagnetic iron oxide (USPIO) and by histopathological studies. METHODS: We divided 12 Watanabe heritable hyperlipidemic (WHHL) rabbits into 4 groups based on their age (3, 9, 14 and 26 months) and injected them intravenously with 0.8 mmol (Fe) kg(-1) of USPIO (size, 32 nm; concentration, 15 mg dl(-1)). On the fifth post-injection day, they were again given an intravenous injection with 40 µmol kg(-1) of the same USPIO, and MR angiography (MRA) was performed. The signal-to-noise ratio (SNR) in regions of interest in the wall of the upper abdominal aorta was calculated on coronal images. Specimens from the same level of the aorta were subjected to iron staining and RAM-11 immunostaining and used for histopathological study. For statistical analysis of the MRA and histopathological findings, we used analysis of variance [Tukey's honest significant difference (HSD) test]. RESULTS: In 9-month-old rabbits, the SNR was significantly lower than in rabbits of the other ages (p < 0.01), and the area of RAM-11 (DAKO Corporation, Glostrup, Denmark) and iron uptake in the aortic wall was significantly larger (RAM-11, p < 0.01; iron, p < 0.05). These areas were the smallest in 3-month-old rabbits. CONCLUSION: Histopathologically, the number of macrophages was the greatest in 9-month-old rabbits. Our findings indicate that the SNR on MRI scans reflects the number of macrophages in the aortic wall of WHHL rabbits. ADVANCES IN KNOWLEDGE: USPIO-enhanced MRI visualized the accumulation of macrophages in early atherosclerotic plaques of WHHL rabbits in the course of natural progression.

The oncogenic role of the cochaperone Sgt1.

Sgt1/Sugt1, a cochaperone of Hsp90, is involved in several cellular activities including Cullin E3 ubiqutin ligase activity. The high level of Sgt1 expression in colorectal and gastric tumors suggests that Sgt1 is involved in tumorigenesis. Here, we report that Sgt1 is overexpressed in colon, breast and lung tumor tissues and in Ewing sarcoma and rhabdomyosarcoma xenografts. We also found that Sgt1 heterozygous knockout resulted in suppressed Hras-mediated transformation in vitro and tumor formation in p53(-/-) mouse embryonic fibroblast cells and significantly increased survival of p53(-/-) mice. Moreover, depletion of Sgt1 inhibited the growth of Ewing sarcoma and rhabdomyosarcoma cells and destabilized EWS-FLI1 and PAX3-FOXO1 oncogenic fusion proteins, respectively, which are required for cellular growth. Our results suggest that Sgt1 contributes to cancer development by stabilizing oncoproteins and that Sgt1 is a potential therapeutic target.

Periostin levels correlate with disease severity and chronicity in patients with atopic dermatitis.

BACKGROUND: Recent findings indicate that periostin, an extracellular matrix protein induced by T helper 2 cytokines, plays a critical role in the pathogenesis of atopic dermatitis (AD). OBJECTIVES: To determine whether serum periostin level is associated with clinical phenotype in adult patients with AD. METHODS: An enzyme-linked immunosorbent assay was performed to determine serum periostin levels in 257 adult patients with AD, 66 patients with psoriasis vulgaris (PV) as a disease control and 25 healthy controls. Serum periostin levels were analysed together with clinical characteristics and laboratory parameters, including thymus and activation-regulated chemokine (TARC), lactate dehydrogenase (LDH), blood eosinophil count and total IgE. Immunohistochemical analysis evaluated the expression of periostin in association with various clinical phenotypes of AD. The effect of treatment on serum periostin level was also assessed. RESULTS: Serum periostin was significantly higher in patients with AD than in patients with PV and healthy controls. Periostin level was found to be positively correlated with disease severity, TARC level, LDH level and eosinophil count, but not with IgE level. Higher serum periostin level was observed in patients with extrinsic AD compared with patients with intrinsic AD; the positive correlation of disease severity disappeared in patients with intrinsic AD. Robust expression of periostin was detected in the dermis of patients with AD with erythroderma, lichenification and, to a lesser extent, scaly erythema. Serial measurement of serum periostin revealed decreased levels of periostin after treatment for AD. CONCLUSIONS: Periostin may play a critical role in disease severity and chronicity in the pathogenesis of AD.

GLCCI1 variant accelerates pulmonary function decline in patients with asthma receiving inhaled corticosteroids.

BACKGROUND: In steroid-naive patients with asthma, several gene variants are associated with a short-term response to inhaled corticosteroid (ICS) treatment; this has mostly been observed in Caucasians. However, not many studies have been conducted for other ethnicities. Here, we aimed to determine the relationship between the annual decline in forced expiratory flow volume in one second (FEV1 ) and the variant of the glucocorticoid-induced transcript 1 gene (GLCCI1) in Japanese patients with asthma receiving long-term ICS treatment, taking into account the effect of high serum periostin levels, a known association factor of pulmonary function decline and a marker of refractory eosinophilic/Th2 inflammation. METHODS: In this study, 224 patients with asthma receiving ICS treatment for at least 4 years were enrolled. The effects of single-nucleotide polymorphisms (SNPs) in GLCCI1, stress-induced phosphoprotein 1 (STIP1), and T gene on the decline in FEV1 of 30 ml/year or greater were determined. RESULTS: Besides the known contributing factors, that is, the most intensive treatment step, ex-smoking, and high serum periostin levels (≥95 ng/ml), the GG genotype of GLCCI1 rs37973, and not other SNPs, was independently associated with a decline in FEV1 of 30 ml/year or greater. When patients were stratified according to their serum periostin levels, the GG genotype of rs37973 was significantly associated with blood eosinophilia (≥250/µl) in the high serum periostin group. CONCLUSIONS: A GLCCI1 variant is a risk factor of pulmonary function decline in Japanese patients with asthma receiving long-term ICS treatment. Thus, GLCCI1 may be associated with response to ICS across ethnicities.

Cell type-dependent agonist/antagonist activities of polybrominated diphenyl ethers.

There have been many concerns expressed regarding the possible adverse effects of thyroid hormone-disrupting chemicals including polychlorinated biphenyls and polybrominated diphenyl ethers (PBDEs), since thyroid hormones play crucial roles in normal vertebrate development. A vast amount of PBDEs have been used as flame retardants for the last two decades and our environment has been contaminated with them. Some PBDEs, especially hydroxylated PBDEs, reportedly show an affinity to the thyroid hormone receptor (TR) and act as thyroid hormone agonists, but in other studies they were reported to inhibit the actions of thyroid hormones. Therefore, in the present study, we investigated the binding affinities of PBDEs and their metabolites to TR and their ability to induce thyroid hormone-responsive transcription using luciferase reporter gene assays in two different cell lines, a pituitary cell line, MtT/E-2, and Chinese hamster ovary (CHO) cells. The binding assay showed that many of the examined PBDEs have significant affinity to TR. Interestingly, some of these PBDEs, such as 4'-OH-BDE-17 and 2'-OH-BDE-28, acted as agonists in the reporter gene assay in MtT/E-2 cells, while they acted as antagonists in CHO cells. Our results demonstrated that whether PBDEs and their metabolites are TR agonists or antagonists depends on the cell type used in the assay, which may suggest that the thyroid hormone-disrupting actions of PBDEs differ among target tissues or species.

Serum periostin levels are correlated with progressive skin sclerosis in patients with systemic sclerosis.

BACKGROUND: Periostin, a matricellular protein, serves as a regulator of wound healing and fibrosis. The role of periostin in the pathogenesis of systemic sclerosis (SSc) is unknown. OBJECTIVE: To determine periostin levels in association with severity of skin fibrosis in patients with SSc. METHODS: Expression of periostin was immunohistochemically examined in skin obtained from patients with SSc and healthy controls. Enzyme-linked immunosorbent assay was performed to evaluate serum periostin levels in association with clinical characteristics in 56 patients with SSc [diffuse cutaneous SSc (dSSc), n=16; and limited cutaneous SSc (lSSc), n=40] and 66 healthy controls. RESULTS: Periostin was strongly expressed in the affected dermis from patients with SSc. Periostin was colocalized in α-smooth muscle actin-positive myofibroblasts and platelet endothelial cell adhesion molecule-1-positive endothelial cells in SSc dermis. Serum levels of periostin in patients with dSSc were markedly elevated compared with those in patients with lSSc and control subjects. Patients with lSSc had increased periostin levels compared with healthy controls. In addition, significantly higher levels of periostin were observed in patients with dSSc with disease duration ≤5 years compared with those with disease duration >5 years. Furthermore, the modified Rodnan total skin thickness score (MRSS) was positively correlated with periostin levels in patients with SSc. Serial analysis revealed a correlation between periostin and MRSS; namely, MRSS decreased in line with decreased periostin levels in some patients with dSSc as the disease progressed. CONCLUSION: An elevated periostin level in patients with SSc is associated with severity of skin sclerosis. Periostin may be a potential biomarker for progressive skin fibrosis in SSc.

A change of osteocalcin (OC) and tartrate resistant acid phosphatase 5b (TRACP-5b) with the menstrual cycle.

Bone metabolism markers associated with 4 menstrual cycle phases were evaluated in 14 healthy young females without menstrual disorder. Menstrual cycle phases were confirmed with basal body temperature for 3 months, luteinizing hormone kits, and sexual hormone concentrations of serum. The bone metabolism markers used were osteocalcin (OC), which was measured by immunoradiometric assay (IRMA), and tartrate resistant acid phosphatase 5b (TRACP-5b), which was measured by enzyme immunometric assay (EIA). The highest values of OC and TRACP-5b were observed in the ovulation phase, and TRACP-5b increased significantly when compared with levels in the menstrual phase (p<0.05). Furthermore, the changes in sex-hormone secretion involved in OC and TRACP-5b showed specific patterns during the menstrual cycle. In other words, TRACP-5b levels are influenced by sex hormones produced during the menstrual period and are based on the bone-formation status. Therefore, it is presumed that the TRACP-5b levels during ovulation play a central role in bone formation and bone metabolism.

Topical application of the antiapoptotic TAT-FNK protein prevents aminoglycoside-induced ototoxicity.

We previously demonstrated that an artificial protein, TAT-FNK, has antiapoptotic effects against cochlear hair cell (HC) damage caused by ototoxic agents when applied systemically. To examine the feasibility of topical protein therapy for inner ear disorders, we investigated whether gelatin sponge soaked with TAT-FNK and placed on the guinea pig round window membrane (RWM) could deliver the protein to the cochlea and attenuate aminoglycoside (AG)-induced cochlear damage in vivo. First, we found that the immunoreactivity of TAT-myc-FNK was distributed throughout the cochlea. The immunoreactivity was observed from 1-24 h after application. When Tat-FNK was applied 1 h before ototoxic insult (a combination of kanamycin sulfate and ethacrynic acid), auditory brainstem response threshold shifts and the extent of HC death were significantly attenuated. When cochlear organotypic cultures prepared from P5 rats were treated with kanamycin, TAT-FNK significantly reduced the extent of caspase-9 activation and HC death. These findings indicate that TAT-FNK topically applied on the RWM can enter the cochlea by diffusion and effectively prevent AG-induced apoptosis of cochlear HCs by suppressing the mitochondrial caspase-9 pathway.