Occupational Fall Risk Assessment Tool for older workers.

BACKGROUND: No easy-to-use fall risk assessment tools have been devised to assess occupational fall risk in older workers. AIMS: To develop an Occupational Fall Risk Assessment Tool (OFRAT) and report its predictive validity and reliability in older workers. METHODS: The baseline fall risk assessment was completed by 1113 participants aged ≥60 years who worked ≥4 days/month in Saitama, Japan. Participants were followed up for falls during occupational activities for 1 year, and 30 participants were assessed twice for test-retest reliability. The following assessment measures were summed to form the OFRAT risk score: older age, male sex, history of falls, physical work participation, diabetes, use of medications increasing fall risk, reduced vision, poor hearing, executive dysfunction and slow stepping. The scores were then classified into four grades (0-2 points: very low, 3 points: low, 4 points: moderate and ≥5 points: high). RESULTS: During follow-up, 112 participants fell 214 times during work. The negative binomial regression model showed that participants with higher grades had a higher incidence rate ratio [95% confidence interval] for falls than those with very low grades (low: 1.64 [1.08-2.47], moderate: 4.23 [2.82-6.34] and high: 6.12 [3.83-9.76]). The intraclass correlation coefficient for risk score was 0.86 [0.72-0.93], and the weighted kappa coefficient for grade assessment was 0.74 [0.52-0.95]. CONCLUSIONS: The OFRAT is a valid and reliable tool for estimating the occupational fall risk in older workers. It may assist occupational physicians implement strategies to prevent falls in this group.

Trajectory of criterion symptoms of major depression under newly started antidepressant treatment: sleep disturbances and anergia linger on while suicidal ideas and psychomotor symptoms disappear early.

OBJECTIVE: In modern psychiatry, depression is diagnosed with the diagnostic criteria; however, the trajectory of each of the criterion symptoms is unknown. This study aims to examine this. METHODS: We made repeated assessments of the nine diagnostic criterion symptoms with the Patient Health Questionnaire-9 (PHQ-9) among 2011 participants of a 25-week pragmatic randomised controlled trial of sertraline and/or mirtazapine for hitherto untreated major depressive episodes. The changes from baseline were estimated with the mixed-effects model with repeated measures. The time to disappearance of each symptom was modeled using the Kaplan-Meier survival analysis. RESULTS: The total score on PHQ-9 was 18.5 (SD = 3.9, n = 2011) at baseline, which decreased to 15.3 (5.2, n = 2011) at week 1, to 11.5 (5.9, n = 1953) at week 3, to 7.8 (6.0, n = 1927) at week 9, and to 6.0 (5.9, n = 1910) at week 25. Suicidal ideas, psychomotor symptoms decreased rapidly, while anergia and sleep disturbance also decreased but only slowly. The survival analyses confirmed the primary analyses. CONCLUSIONS: Upon initiation of antidepressant treatment, patients with newly treated major depressive episodes can expect their suicidal ideas and psychomotor symptoms to disappear first but sleep disturbances and anergia to linger on.

Initial severity of major depression and efficacy of new generation antidepressants: individual participant data meta-analysis.

OBJECTIVE: The role of baseline severity as effect modifier in various psychiatric disorders is a topic of controversy and of clinical import. This study aims to examine whether baseline severity modifies the efficacy of various antidepressants for major depression through individual participant data (IPD) meta-analysis. METHOD: We identified all placebo-controlled, double-blind randomised trials of new generation antidepressants in the acute phase treatment of major depression conducted in Japan and requested their IPD through the public-private partnerships (PPPs) between the relevant academic societies and the pharmaceutical companies. The effect modification by baseline depression severity was examined through six increasingly complex competing mixed-effects models for repeated measures. RESULTS: We identified eleven eligible trials and obtained IPD from six, which compared duloxetine, escitalopram, mirtazapine, paroxetine or bupropion against placebo (total n = 2464). The best-fitting model revealed that the interaction between baseline severity and treatment was not statistically significant (coefficient = -0.04, 95% confidence interval: -0.16 to 0.08, P = 0.49). Several sensitivity analyses confirmed the robustness of the findings. CONCLUSION: We may expect as much benefit from antidepressant treatments for mild, moderate or severe major depression. Clinical practice guidelines will need to take these findings into consideration.

Interpretable inference on the mixed effect model with the Box-Cox transformation.

We derived results for inference on parameters of the marginal model of the mixed effect model with the Box-Cox transformation based on the asymptotic theory approach. We also provided a robust variance estimator of the maximum likelihood estimator of the parameters of this model in consideration of the model misspecifications. Using these results, we developed an inference procedure for the difference of the model median between treatment groups at the specified occasion in the context of mixed effects models for repeated measures analysis for randomized clinical trials, which provided interpretable estimates of the treatment effect. From simulation studies, it was shown that our proposed method controlled type I error of the statistical test for the model median difference in almost all the situations and had moderate or high performance for power compared with the existing methods. We illustrated our method with cluster of differentiation 4 (CD4) data in an AIDS clinical trial, where the interpretability of the analysis results based on our proposed method is demonstrated. Copyright © 2017 John Wiley & Sons, Ltd.

Inference of median difference based on the Box-Cox model in randomized clinical trials.

In randomized clinical trials, many medical and biological measurements are not normally distributed and are often skewed. The Box-Cox transformation is a powerful procedure for comparing two treatment groups for skewed continuous variables in terms of a statistical test. However, it is difficult to directly estimate and interpret the location difference between the two groups on the original scale of the measurement. We propose a helpful method that infers the difference of the treatment effect on the original scale in a more easily interpretable form. We also provide statistical analysis packages that consistently include an estimate of the treatment effect, covariance adjustments, standard errors, and statistical hypothesis tests. The simulation study that focuses on randomized parallel group clinical trials with two treatment groups indicates that the performance of the proposed method is equivalent to or better than that of the existing non-parametric approaches in terms of the type-I error rate and power. We illustrate our method with cluster of differentiation 4 data in an acquired immune deficiency syndrome clinical trial.

microRNA-mediated keratinocyte hyperproliferation in psoriasis vulgaris.

BACKGROUND: Psoriasis is a chronic inflammatory skin disease characterized by intense proliferation and abnormal differentiation of keratinocytes, although the pathogenesis is still not completely clarified. OBJECTIVES: We investigated the mechanism of keratinocyte proliferation seen in psoriasis, focusing on microRNA (miRNA). MATERIALS AND METHODS: miRNAs were extracted from tissues and sera of psoriasis, atopic dermatitis and healthy control. To determine pathogenic miRNAs, we performed miRNA polymerase chain reaction (PCR) array analysis. The results were confirmed with quantitative real-time PCR, in situ hybridization, immunohistochemistry, transient transfection of siRNA and inhibitor in cultured keratinocytes and Western blotting. RESULTS: PCR array analysis using tissue miRNA demonstrated miR-424 level was markedly decreased in psoriasis skin in vivo. Protein expression of mitogen-activated protein kinase kinase 1 (MEK1) or cyclin E1, predicted target genes of miR-424, was increased in psoriatic skin, although their mRNA levels were not. The transfection of specific inhibitor of miR-424 in normal human keratinocytes led to upregulation of MEK1 or cyclin E1 protein, and resulted in increased cell proliferation. On the other hand, cell number was significantly decreased when cells were transfected with siRNA for MEK1 or cyclin E1. Furthermore, we first investigated serum miRNA levels in psoriasis. Although not significant, serum miR-424 concentration tended to be decreased in patients with psoriasis compared with healthy controls. CONCLUSIONS: Decreased miR-424 expression and subsequently increased MEK1 or cyclin E1 may play a key role in the pathogenesis of psoriasis. Investigation of the regulatory mechanisms of keratinocyte proliferation by miRNA may lead to new treatments and a disease activity marker.

Expression of the anti-apoptotic factors Bcl-2 and survivin in canine vascular tumours.

To investigate whether anti-apoptotic factors play a role in the malignant growth of canine haemangiosarcomas (HSAs), 83 HSAs and 22 haemangiomas were examined immunohistochemically for bcl-2 and survivin expression. Additionally, bcl-2 and survivin mRNA expression was quantified by semiquantitative real-time reverse transcription-polymerase chain reaction (RT-PCR). Immunolabelling for bcl-2 was observed in 50 of the 83 HSA samples (60.2%) but in none of the haemangiomas. The average survivin positive index was 24.7% in the HSAs and 0.6% in the haemangiomas. In contrast to the high average value for survivin mRNA expression, which was approximately six times that for the haemangiomas, no significant difference was observed between HSAs and haemangiomas for the average bcl-2 mRNA expression level. The discrepancy between bcl-2 mRNA and bcl-2 protein expression requires further investigation, but the results suggest that malignant proliferation in canine HSAs is associated with bcl-2 and survivin expression.

Triggering of the vascular permeability reaction by activation of the Hageman factor-prekallikrein system by house dust mite proteinase.

A 30-kilodalton (kDa) proteinase from the house dust mite Dermatophagoides farinae (Df-proteinase) was recently purified (Takahashi et al. (1990) Int. Arch. Allergy Appl. Immunol. 91, 80-85). In this paper we detailed the biological activities of the Df-proteinase. The activation of the kinin cascade by Df-proteinase was examined in vitro by using purified guinea pig Hageman factor (HF), prekallikrein (PK) and high-molecular-weight kininogen (HMWK) and the effect of this proteinase on endogenous human plasma proteinase inhibitors (serpins) and alpha 2-macroglobulin was tested. In addition, enhancement of the vascular permeability reaction in guinea pig skin by Df-proteinase was examined in vivo. These experiments showed that Df-proteinase could activate all the steps of the kinin-generating cascade, i.e., HF, PK and HMWK, and that Df-proteinase retained proteolytic activity even in the presence of an excess amount of endogenous proteinase inhibitors in plasma. We also found that the marked enhancement of the vascular permeability reaction was induced by Df-proteinase via the activation of the kinin-generating cascade without the release of histamine. From these results, we conclude that the proteinase of the house dust mite, Df-proteinase, has the potential to generate bradykinin and that the presence of this proteinase in biological systems would exacerbate inflammatory reactions in some pathological conditions.

Development of low-fluorescence thick photoresist for high-aspect-ratio microstructure in bio-application.

In this study, we propose and evaluate a novel low-auto-fluorescence photoresist (SJI photoresist) for bio-application, e.g., in gene analysis and cell assay. The spin-coated SJI photoresist has a wide thickness range of ten to several hundred micrometers, and photoresist microstructures with an aspect ratio of over 7 and micropatterns of less than 2 µm are successfully fabricated. The emission spectrum intensity of the SJI photoresist is found to be over 80% less than that of the widely used SU-8 photoresist. To evaluate the validity of using the proposed photoresist in bio-application for fluorescence observation, we demonstrate a chromosome extension device composed of the SJI photoresist. The normalized contrast ratio of the SJI photoresist exhibits a 50% improvement over that of the SU-8 photoresist; thus, the SJI photoresist is a versatile tool for bio-application.

Three-dimensional conformal radiation therapy for inoperable massive hepatocellular carcinoma in six dogs.

OBJECTIVES: To evaluate the activity and tolerability of three-dimensional conformal radiation therapy (3D-CRT) in dogs with massive hepatocellular carcinoma. MATERIALS AND METHODS: Six dogs with massive hepatocellular carcinoma that were ineligible for surgical resection or with owners who declined surgical resection, and underwent 3D-CRT were retrospectively reviewed. 6 to 10 Gy per fraction was prescribed at isocentre of planning target volume to a total dose of 18 to 42 Gy with 1 to 2 fractions per week for a total of 3 to 7 fractions. Follow-up examinations included physical examination, contrast-enhanced CT scan and blood analysis (complete blood count, electrolytes and serum biochemical panel). RESULTS: The median follow-up time after 3D-CRT was 534 (range, 281 to 1057) days. An objective response was observed in five of six cases. Radiation-induced liver disease developed in one dog but was asymptomatic and reversible. Toxicity was not noted in any other dog. CLINICAL SIGNIFICANCE: 3D-CRT appears to be a viable treatment option for dogs with inoperable massive hepatocellular carcinoma.

Analysis of genomic mutation and immunohistochemistry of platelet-derived growth factor receptors in canine vascular tumours.

We examined whether mutation of the platelet-derived growth factor receptor protein tyrosine kinase (PDGFR)-α and PDGFR-ß genes contributes to their overexpression in canine vascular tumours. Genomic sequences of trans- or juxtamembrane regions of PDGFR-α and PDGFR-ß were analysed with immunohistochemical staining and polymerase chain reaction-direct sequencing using DNA from paraffin-embedded neoplastic tissues of 27 hemangiosarcomas (HSAs) and 20 hemangiomas (HAs). Immunohistochemically, 75% of the HA cases were positive for PDGFR-α and almost most of the HA cases were negative for PDGFR-ß. Of the HSA cases, 55.6% were negative for PDGFR-α and 63% were strongly positive for PDGFR-ß. Among the HA cases, 1 missense mutation was detected in PDGFR-α exon 18 and 1 in PDGFR-ß exon 17. Two HSA cases had missense mutations in exon 14 and 1 in exon 17 of PDGFR-ß. Thus, genomic mutation of trans- or juxtamembrane regions of PDGFRs was not the main mechanism driving the activation of receptors in HSA and HA.

Quantitative evaluation of irregular astigmatism by fourier series harmonic analysis of videokeratography data.

PURPOSE: To assess quantitatively corneal irregular astigmatism in association with best spectacle-corrected visual acuity. METHODS: Refractive powers on a mire ring measured with computerized videokeratography were decomposed, using the Fourier series harmonic analysis. Extracting spherical and regular astigmatic components, the remaining irregular astigmatic component was quantified on rings 2 through 9. A weighted average was calculated by using the Stiles-Crawford effect on the basis of the radius of each ring of each eye and was used as an index of the irregular astigmatic component. Data analyses were carried out in 108 eyes, including 53 normal eyes, 34 eyes with keratoconus, and 21 eyes that had undergone penetrating keratoplasty for keratoconus. Keratoconic eyes and eyes after keratoplasty were included in the study only if visual acuity, corrected with a hard contact lens, was 20/20 or better. Logarithm of best spectacle-corrected visual acuity, age, type of disease, refractive astigmatism, irregular astigmatic component, surface regularity index, and surface asymmetry index were analyzed. RESULTS: In results of multiple regression analysis, the irregular astigmatic component was significantly correlated with best spectacle-corrected visual acuity (r = -0.744; adjusted R2 = 0.549; P < 0.001), whereas other explanatory variables showed no correlation with best spectacle-corrected visual acuity. CONCLUSIONS: This model of the irregular astigmatic component seems to be an efficient, quantitative means of describing corneal irregular astigmatism.

Role of x-linked immunodeficiency (xid) and NK activity in rejection of human tumor xenotransplants in nude mice.

In order to elucidate the factors influencing the takes of human tumor xenografts in nude mice, we compared the transplantability of human tumors in nude mice with additional genetic defects in the immune system. The nude mice strains tested were classified as follows by expression of the beige gene and the x-linked immunodeficiency (xid) gene: 1) high NK nude (C57BL/6N, nu/nu), 2) low NK nude (C57BL/6 bg/bg nu/nu), 3) high NK nude with B-cell defect (CBA/N nu/nu), and 4) low NK nude with B-cell defect (NIH(S)III). Takes of human tumor xenografts including gastric carcinoma, T-cell lymphoma and B-cell lymphoma were better in nude mice with xid (CBA/N and NIH(S) III nude mice) than in nude mice without xid (B6 and beige nude mice). In addition, among the nude mice with xid expression, the takes were slightly better in nude mice with a CBA/N background than in those with a NIH(S) background. Moreover, the xenotransplantation rate in (CBA/N x C57BL/6N)F1 male nude mice with xid expression was higher than in (C57BL/6N x CBA/N)F1 males without xid expression, but did not react the same level as that in CBA/N nude. On the other hand, introduction of the beige gene into nude mice minimally improved the takes of human tumor xenografts under limited experimental conditions (inoculation of 100 x 10(5) T-cell lymphoma and 1 x 10(5) gastric carcinoma cells) despite the reduction of NK activity. In xenotransplantation of human tumors directly from patients, the take rates of the tumors were also better in CBA/N nude mice than in BALB/cA nude mice. The results in the present report confirmed the effect of xid and CBA/N genetic background on human tumor xenografts in nude mice, suggesting the existence of serum factors, possibly present in serum IgM, mediating rejection of the xenografts.

Responsiveness of human lung cancer/nude mouse to antitumor agents in a model using clinically equivalent doses.

The responses of 14 lines of human lung cancer xenografts in BALB/c-nu/nu mice to eight known antitumor agents were investigated. These xenografts consisted of four small-cell carcinomas (SCLC) and ten non-small-cell carcinomas (four large cell, three squamous cell, and three adenocarcinomas; NSCLC). The doses used in the experiments were the maximum tolerated dose (MTD) in nude mice and the "rational dose" (RD), the latter considered to be pharmacokinetically equivalent to the clinical dose. When given at MTDs, all drugs except 5-fluorouracil (5-FU) and methotrexate (MTX) were extremely effective against NSCLC as well as SCLC. The response rates of drug-sensitive SCLC to mitomycin C (MMC), ACNU, and vinblastine (VLB) were 100%, and those to Adriamycin (ADR) and vincristine (VCR) were 75%. In addition, the response rates of even drug-resistant NSCLC to MMC and VLB were 70% and 90%, respectively. In contrast, the response rates of NSCLC to RDs of the drugs were reduced to less than 40% and corresponded well to the respective clinical rates. In SCLC, a good correlation of experimental and clinical response rates was observed with four drugs [cyclophosphamide (CPM), ACNU, VLB, and 5-FU]. As a result, we emphasize that a more reasonable prediction of the clinical effectiveness of antitumor agents can be made by a protocol using clinically equivalent doses.

Development of a multi-field fundus photographing system using a non-mydriatic camera for diabetic retinopathy.

A new fundus photographing system was developed for diabetic subjects with or without simple diabetic retinopathy using a non-mydriatic fundus camera. Eight internal fixation targets were incorporated in a non-mydriatic fundus camera (TRC-NW5S; TOPCON, Tokyo, Japan), interfaced with a 3CCD color camera. Nine 45 degrees fundus photographs were taken in 22 healthy volunteers and 16 diabetic subjects, and stored as digital images. Fundus images were reconstituted as collages on the monitor and printed out. The combined angle reached 94 degrees in collage, and the average times required for photographing with and without mydriasis were 3 min 26 s and 4 min 36 s, respectively. The concordance of fundus images between the first and second photographs of healthy volunteers with and without mydriasis was 95.4% (n = 22). The quality of the photographs, graded on a five-point scale (5, full) by three doctors, was 4.3 +/- 0.6 in the volunteers without mydriasis, 4.7 +/- 0.4 in the diabetics without mydriasis, and 4.8 +/- 0.3 in the volunteers with mydriasis. In retinas with diabetic retinopathy, the system was able to depict microaneurysms, hemorrhages, hard exudates and soft exudates. This new system was satisfactory for the screening and follow-up of diabetic retinopathy.

Anticancer activities of orally administered menogaril against human stomach and breast cancers implanted in nude mice.

The therapeutic effects of orally administered menogaril, a semisynthetic analog of the anthracycline antibiotic nogalamycin, were studied on a panel of human stomach and breast cancer xenografts. The maximum tolerated dose (200 mg/kg) of menogaril was administered 3 times every 4 days and its growth-inhibitory effects on subcutaneously implanted tumors in nude mice were evaluated. Menogaril significantly retarded the growth of 3 out of 7 stomach cancers, SC-2, SC-9 and 4-1ST, and 3 out of 4 breast cancers, H-31, MC-2 and MX-1, with overall response rates of 43 and 75% for stomach and breast cancers, respectively. Some of these relatively responsive cancers were also treated by daily oral administration for 5 consecutive days, but the anticancer effects of the intermittent administration seemed to be better. These results suggest that menogaril may be effective against stomach and breast cancers when orally administered.

Responsiveness of subcutaneous human glioma xenografts to various antitumor agents.

Responsiveness of seven human glioma xenografts to seven antitumor agents was investigated by an sc-iv system and the efficacies of these agents against human glioma were evaluated in terms of response rate. When their maximum tolerated doses were used, experimental response rates of nimustine (ACNU), vincristine (VCR), adriamycin (ADR) and vinblastine (VLB) were as high as 86-100%, while that of mitomycin (MMC) was 57%, and those of 5-fluorouracil (5-FU) and methotrexate (MTX) were 0%. On the other hand, when the doses pharmacokinetically equivalent to their clinical doses were employed, the response rate of ADR was the highest, followed by VCR and ACNU in this order. These results suggest that gliomas are significantly responsive to various antitumor agents in this sc-iv system.

Biochemical and immunohistochemical analysis of cathepsins B, H, L and D in human melanocytic tumours.

We carried out biochemical and immunohistochemical analyses of cathepsins B, H, L and D in human melanocytic tumours using monospecific antibodies against rat cathepsins. In Western blot analysis, anti-rat cathepsin antibodies reacted with the cathepsins from normal human tissues and human malignant melanoma. However, the molecular profiles of the cathepsins from human melanoma were slightly different from those of the rat cathepsins, suggesting a distinct intracellular processing mechanism for cathepsins in human melanoma. Although cathepsins B, H, L and D were expressed in primary and metastatic melanomas and pigmented naevi immunohistochemically, the intensity of staining in metastatic melanomas was stronger than in primary melanomas and pigmented naevi. These findings suggest that anti-rat cathepsin antibodies may be useful in biochemical and/or immunohistochemical analysis of human melanocytic tumours.

Interactions of human fibroblast interferon with chemotherapeutic agents and radiation against human gliomas in nude mice.

The growth inhibitory effects of the combination of beta-interferon (beta-IFN) and conventional anticancer drugs such as adriamycin (ADM) and ACNU were evaluated in nude mice receiving subcutaneous transplants of human glioblastoma. Next, the anticancer and radiation sensitizing effects of beta-IFN on human glioblastoma was also evaluated in nude mice model. After three weeks of combined treatment, tumour reduction rates (treated/control values) were evaluated by the Battelle's method. In conclusion, the growth inhibitory effect of IFN was most enhanced when IFN was administered following radiotherapy. Furthermore, the combined effect was enhanced in proportion to the dose of radiation.

Morphea profunda--a cutaneo-pulmonary variant with profuse sweating.

A 51-year-old Japanese male developed morphea profunda over a plaque of pigmented sweating skin on the left chest extending deeply into the lung. Eight years previously, he noted a brown pigmented spot on the left axilla which started to enlarge over the left chest in a band-like manner. Later, the involved skin hardened with profuse sweating. Chest X-ray examination and computer tomography revealed a thickening of the left chest wall and a nodular mass lesion in the left lower lung field. Biopsy specimens from lung, chest wall, and overlying skin revealed a granulomatous tissue in the parenchyma and a marked fibrosis extending from the deep dermis to the pleura. There were no findings suggestive of malignancy or chronic infectious disease. We assume that the process of morphea in this patient extended deeply from the skin to the lung.