Golden Ratio Flap Designed Using the Golden Ratio Rectangle.

Background: Rotation flaps are arcuate repairs that redistribute tension vectors and recruit adjacent and/or distant tissue laxity. The incision curve could be a logarithmic spiral curve to reduce the length of an incision. We propose a rotation flap-the golden ratio flap-designed using a golden rectangle. Methods: The flap incision is an arc though the major square which is beside the minor square of a golden rectangle. The defect is attached to the line of another minor square and diagonal to the major square. The bottom line runs from the incision end to the tangent point of the circle or the oval, and the perpendicular height line runs from the bottom line to the cross point of the flap incision. These parameters were analyzed retrospectively for four superficial sarcomas that were treated using a rotation flap with an incision approximating the logarithmic spiral curve. Results: The ratio of height to bottom of the golden ratio flap design was highly similar to the preoperative flap design in the four cases assessed. With the new design, the ratio of bottom to the defect diameter (minor axis in the oval defect) was 1.3, and for the height, it was 1.4. Conclusions: The golden ratio flap, designed using the golden rectangle, is reproducible. The parameters of height and bottom approximate the flap shape, or the length and width, respectively. For clinical applications, step-by-step guidance for drawing the new flap are also proposed.

THOC4 regulates energy homeostasis by stabilizing TFEB mRNA during prolonged starvation.

TFEB, a basic helix-loop-helix transcription factor, is a master regulator of autophagy, lysosome biogenesis and lipid catabolism. Compared to posttranslational regulation of TFEB, the regulation of TFEB mRNA stability remains relatively uncharacterized. In this study, we identified the mRNA-binding protein THOC4 as a novel regulator of TFEB. In mammalian cells, siRNA-mediated knockdown of THOC4 decreased the level of TFEB protein to a greater extent than other bHLH transcription factors. THOC4 bound to TFEB mRNA and stabilized it after transcription by maintaining poly(A) tail length. We further found that this mode of regulation was conserved in Caenorhabditiselegans and was essential for TFEB-mediated lipid breakdown, which becomes over-represented during prolonged starvation. Taken together, our findings reveal the presence of an additional layer of TFEB regulation by THOC4 and provide novel insights into the function of TFEB in mediating autophagy and lipid metabolism.

LC3 lipidation is essential for TFEB activation during the lysosomal damage response to kidney injury.

Sensing and clearance of dysfunctional lysosomes is critical for cellular homeostasis. Here we show that transcription factor EB (TFEB)-a master transcriptional regulator of lysosomal biogenesis and autophagy-is activated during the lysosomal damage response, and its activation is dependent on the function of the ATG conjugation system, which mediates LC3 lipidation. In addition, lysosomal damage triggers LC3 recruitment on lysosomes, where lipidated LC3 interacts with the lysosomal calcium channel TRPML1, facilitating calcium efflux essential for TFEB activation. Furthermore, we demonstrate the presence and importance of this TFEB activation mechanism in kidneys in a mouse model of oxalate nephropathy accompanying lysosomal damage. A proximal tubule-specific TFEB-knockout mouse exhibited progression of kidney injury induced by oxalate crystals. Together, our results reveal unexpected mechanisms of TFEB activation by LC3 lipidation and their physiological relevance during the lysosomal damage response.

Ubiquitination of exposed glycoproteins by SCFFBXO27 directs damaged lysosomes for autophagy.

Ubiquitination functions as a signal to recruit autophagic machinery to damaged organelles and induce their clearance. Here, we report the characterization of FBXO27, a glycoprotein-specific F-box protein that is part of the SCF (SKP1/CUL1/F-box protein) ubiquitin ligase complex, and demonstrate that SCFFBXO27 ubiquitinates glycoproteins in damaged lysosomes to regulate autophagic machinery recruitment. Unlike F-box proteins in other SCF complexes, FBXO27 is subject to N-myristoylation, which localizes it to membranes, allowing it to accumulate rapidly around damaged lysosomes. We also screened for proteins that are ubiquitinated upon lysosomal damage, and identified two SNARE proteins, VAMP3 and VAMP7, and five lysosomal proteins, LAMP1, LAMP2, GNS, PSAP, and TMEM192. Ubiquitination of all glycoproteins identified in this screen increased upon FBXO27 overexpression. We found that the lysosomal protein LAMP2, which is ubiquitinated preferentially on lysosomal damage, enhances autophagic machinery recruitment to damaged lysosomes. Thus, we propose that SCFFBXO27 ubiquitinates glycoproteins exposed upon lysosomal damage to induce lysophagy.

Importin alpha subtypes determine differential transcription factor localization in embryonic stem cells maintenance.

We recently demonstrated that the expression of the importin α subtype is switched from α2 to α1 during neural differentiation in mouse embryonic stem cells (ESCs) and that this switching has a major impact on cell differentiation. In this study, we report a cell-fate determination mechanism in which importin α2 negatively regulates the nuclear import of certain transcription factors to maintain ESC properties. The nuclear import of Oct6 and Brn2 was inhibited via the formation of a transport-incompetent complex of the cargo bound to a nuclear localization signal binding site in importin α2. Unless this dominant-negative effect was downregulated upon ESC differentiation, inappropriate cell death was induced. We propose that although certain transcription factors are necessary for differentiation in ESCs, these factors are retained in the cytoplasm by importin α2, thereby preventing transcription factor activity in the nucleus until the cells undergo differentiation.

Evaluating the interaction between the therapy and the treatment in clinical trials by the propensity score weighting method.

In clinical trials for antihypertensive drugs, a combination therapy trial and a monotherapy trial are often conducted simultaneously. In this situation, it can be a clinical concern to know the difference of the safety or efficacy of the new drug between the two therapies, in other words, to investigate the interaction between the therapy (monotherapy or combination therapy) and the treatment (test or control). However, because patients are often registered in either of these trials on the basis of their background characteristics, specific patients may be selected to participate in the monotherapy trial or combination therapy trial and not chosen at random, whereas the treatment is assigned randomly in each trial after registration. If this fact is not considered, the statistical analysis of the interaction may be biased. In this paper, we aim to evaluate the interaction between the two aforementioned factors by adjusting for covariates that may affect registration in the two trials. For this purpose, we apply the propensity score weighting method to suit the problem. The propensity score in this case is decomposed into the usual propensity score for the registration and the assignment probability for the random treatment assignment on the basis of their two-stage structure. We also discuss the augmented estimator known as the doubly robust estimator. In addition, we apply this method to data of a clinical trial for an antihypertensive drug that was conducted in Japan and conduct a simulation study to evaluate the performance of our proposed method.

[Investigation of the factors that contribute to the onset of insomnia in hypertensive patients by using a post-marketing surveillance database].

Many factors contribute to the onset of insomnia. However, few studies have identified the factors related to the onset of insomnia in hypertensive patients. We conducted a pharmacoepidemiologic study to examine the incidence of insomnia in hypertensive patients by using a post-marketing surveillance database. The insomnia onset was defined as the time of first prescription of hypnotics. The insomnia incidence rate in hypertensive patients under antihypertensive therapy was 0.77/100 person-years. The median insomnia onset date was 5 weeks. The insomnia type in 50.2% of the patients was difficulty in initiating sleep. We assessed the factors contributing to insomnia by using a nested case-control design. We selected 10 time-matched controls for every case. The hypotensive effect induced by antihypertensive therapy on the case group was lesser than that on the control group (p<0.01). The odds ratios (ORs) were estimated using multivariate conditional logistic regression. The factors contributing to insomnia onset were α blockers (OR, 2.38; 95% confidence interval [CI], 1.14-4.98), ß blockers (OR, 1.54; 95% CI, 0.99-2.39), and calcium channel blockers (OR, 0.62; 95% CI, 0.43-0.90) compared with angiotensin-converting enzyme inhibitors; female sex (OR, 1.76; 95% CI, 1.27-2.44); complication of gastric/duodenal disorders (OR, 2.35; 95% CI, 1.14-4.86) or musculoskeletal system/connective tissue disorders (OR, 2.43; 95% CI, 1.23-4.79); and concomitant antihypertensive therapy (OR, 0.44; 95% CI, 0.31-0.63). This study identified the potential factors that may help to predict insomnia onset in hypertensive patients under antihypertensive therapy.

Randomized controlled study on the prevention of osteoporotic fractures (OF study): a phase IV clinical study of 15-mg menatetrenone capsules.

An open-label study with blinded evaluation was performed to compare the preventive effect of a calcium supplement alone (monotherapy) or calcium supplement plus menatetrenone (combined therapy) on fracture in osteoporotic postmenopausal women aged 50 years or older. Patients were randomized to receive monotherapy (n = 2,193) or combined therapy (n = 2,185). Before randomization, the subjects were stratified into a subgroup without vertebral fractures (n = 2,986; no-fracture subgroup) and a subgroup with at least one vertebral fracture (n = 1,392; fracture subgroup). The incidence rate of new vertebral fractures during 36 months of treatment (primary endpoint) did not differ significantly between either subgroup of the two treatment groups. Although the cumulative 48-month incidence rate of new clinical fractures (secondary endpoint) was lower in the combined therapy group, the difference was not significant. There was a lower risk of new vertebral fractures in patients with at least five baseline fractures who received combined therapy. Also, the loss of height was less with combined therapy than with monotherapy among patients 75 years of age or older at enrollment, those whose last menstrual period occurred 30 years or more before enrollment, and those with at least five vertebral fractures at enrollment. Adverse events and adverse reactions were more frequent in the combined therapy group. In conclusion, menatetrenone therapy was not effective for preventing vertebral fractures in the full analysis set of this study, but the results suggested that it may prevent vertebral fractures in patients with more advanced osteoporosis.

Assessing the effects of non-steroidal anti-inflammatory drugs on antihypertensive drug therapy using post-marketing surveillance database.

BACKGROUND: Antihypertensive and non-steroidal anti-inflammatory drugs (NSAIDs) are used to treat many common diseases. However, it has been suspected that interactions between these drugs exist. Here, we assessed the interactions between non-selective NSAIDs and several classes of antihypertensive drugs. METHODS: The study design was a cohort study using "The Antihypertensive Drug Database," which is a collection of data accumulated from Drug Use Investigations. Subjects newly starting antihypertensive drug therapy were identified in the database. We compared the "User" group, who were co-administered NSAIDs, with the "Non-user" group, who were not. The outcome measure was the change in systolic blood pressure from the baseline after 2 months of treatment. We estimated the non-adjusted and adjusted differences in the change in systolic blood pressure between the "User" and "Non-user" groups. RESULTS: Data were collected for a total of 1,204 subjects, of whom 364 were prescribed beta blockers, 60 were prescribed diuretics, 628 were prescribed angiotensin-converting enzyme inhibitors, and 152 were prescribed calcium channel blockers. The adjusted difference in the change in systolic blood pressure between the User (n = 301) and Non-user (n = 903) groups was 2.88 mmHg (95% confidence interval: 0.89, 4.87); thus, systolic blood pressure in the Non-User group decreased further from the baseline than that in the User group. In subjects administered beta blockers, diuretics, angiotensin-converting enzyme inhibitors, and calcium channel blockers, the corresponding differences were 0.37 mmHg (-3.24, 3.98), 6.11 mmHg (-3.16, 15.37), 3.85 mmHg (1.16, 6.66), and 3.50 mmHg (-2.03, 9.02). CONCLUSION: The effectiveness of antihypertensive drugs was attenuated by the co-administration of NSAIDs. The differences in the effects of NSAIDs varied with different classes of antihypertensive drugs.

Design of the Japan Nurses' Health Study: a prospective occupational cohort study of women's health in Japan.

The Japan Nurses' Health Study (JNHS) is a prospective occupational cohort study investigating the effects of lifestyle and healthcare practices on women's health. It was initiated in 2001, with a six-year entry period and a proposed ten-year follow-up. Participants comprise female registered nurses, licensed practical nurses, public health nurses, and midwives, aged 25 yr or over at the baseline survey. Participants were recruited in cooperation with the Japanese Nursing Association and the Japan Menopause Society. A self-administered baseline questionnaire was distributed, requesting demographic information, lifestyle factors, pharmaceutical drug use, physical condition, reproductive health, and disease history. A total of 49,914 women from all 47 prefectures in Japan responded to the baseline survey. Among them, approximately 18,000 agreed to be followed-up, and returned signed informed-consent sheets, together with their completed baseline questionnaires. Changes in lifestyle, healthcare, incidence of disease, and health outcomes over time will now be studied. The cohort receives annual JNHS newsletters and biennial follow-up questionnaires by mail.

Prevalence of diseases and statistical power of the Japan Nurses' Health Study.

The Japan Nurses' Health Study (JNHS) is a long-term, large-scale cohort study investigating the effects of various lifestyle factors and healthcare habits on the health of Japanese women. Based on currently limited statistical data regarding the incidence of disease among Japanese women, our initial sample size was tentatively set at 50,000 during the design phase. The actual number of women who agreed to participate in follow-up surveys was approximately 18,000. Taking into account the actual sample size and new information on disease frequency obtained during the baseline component, we established the prevalence of past diagnoses of target diseases, predicted their incidence, and calculated the statistical power for JNHS follow-up surveys. For all diseases except ovarian cancer, the prevalence of a past diagnosis increased markedly with age, and incidence rates could be predicted based on the degree of increase in prevalence between two adjacent 5-yr age groups. The predicted incidence rate for uterine myoma, hypercholesterolemia, and hypertension was > or =3.0 (per 1,000 women, per year), while the rate of thyroid disease, hepatitis, gallstone disease, and benign breast tumor was predicted to be > or =1.0. For these diseases, the statistical power to detect risk factors with a relative risk of 1.5 or more within ten years, was 70% or higher.

[Discharge curve among psychiatric patients after admission and risk factors associated with long stay based on "patient survey"].

The "Reform Vision of Mental Health Services" (2004) announced the basic policy for the transition from hospital based to community based care, and set up numerical objectives, such as the average proportion remaining hospitalized in the first year after admission and the incidence rate of discharge among psychiatric patients hospitalized for more than one year. Using data from the "Patient Survey" performed in 2002 by the Ministry of Health, Labour and Welfare, we estimated discharge curves for each mental disorder during the first year after admission and assessed the effects of variables, i.e., diagnosis, sex, age, hospital type, and residential area, on remaining hospitalized after one year from admission and the incidence rate of discharge among psychiatric patients hospitalized for more than one year. The estimated number of discharged psychiatric patients was 27,974 in September, 2002, and 86% of them were discharged less than one year after admission. The incidence rate of discharge (per 100 person-year) in the first year was 314.8, but the rate after the second year sharply decreased to 19.9. Patients with dementia, mental retardation, and schizophrenia tended to stay for a long period in hospital, and proportions remaining hospitalized after one year from admission were 27.0%, 16.4%, and 14.6% respectively. Based on multivariate analysis using the weighted Poisson regression model, risk factors associated with an increased chance of remaining hospitalized after the first year included a long length of continuous hospitalization, diagnoses of dementia, mental retardation, and schizophrenia, male, older age, and being in a mental hospital. On the other hand, as to the incidence rate of discharge after one year, a long length of continuous hospitalization and being in a mental hospital were related with a long stay, but other variables were slightly different. Being female, patients aged 45-54 years old, and diagnoses of epilepsy and schizophrenia were associated with a long stay. These results clarify the present situation of discharge among psychiatric inpatients and indicate the important variables associated with discharge to prevent new long hospital-stay cases in Japan.

The relationship between depression and sleep disturbances: a Japanese nationwide general population survey.

OBJECTIVE: Among the existing epidemiologic studies that have examined the relationship between depression and sleep disturbances, there are few nationwide studies that have been conducted on subjects representing the general population. The present study was therefore conducted to clarify the relationship between depression and sleep disturbances, in particular the relationship between depression and both sleep duration and subjective sleep sufficiency, using a large sample representative of the general population. METHOD: The survey was conducted in June 2000, using self-administered questionnaires, targeting a population that was selected randomly from among 300 communities throughout Japan. Among the respondents, data from 24,686 individuals aged 20 years or older were analyzed. The Center for Epidemiologic Studies Depression Scale was used to assess the presence of depression. Sleep status, including sleep duration, subjective sleep sufficiency, and the presence or absence of insomnia symptoms, was evaluated. RESULTS: Those whose sleep duration was less than 6 hours and those whose sleep duration was 8 hours or more tended to be more depressed than those whose sleep duration was between 6 and 8 hours. Thus, sleep duration exhibited a U-shaped association with symptoms of depression. As subjective sleep sufficiency decreased, symptoms of depression increased, indicating a linear inverse-proportional relationship. CONCLUSION: The fact that sleep duration and subjective sleep sufficiency exhibited different relationships with symptoms of depression indicates that these 2 sleep parameters each have their own significance with regard to depression. These findings may be useful in the medical management of mental diseases.

A pilot study to build a database on seven anti-hypertensive drugs.

PURPOSE: In Japan, all patients are able to see freely any clinics or hospitals. So clinical data of all patients have been stored at clinics, hospitals and medical institutes respectively. These patients' clinical course data stocks have not been combined with one another. There is no large-scale database, which has been available and has played its role in complementing spontaneous adverse drug reaction (ADR) reporting system. We tried to build an original database using anti-hypertensive drugs' data from Drug Use Investigation conducted for the Japanese Drug Re-examination application by every pharmaceutical manufacturer in conformity with Japanese Pharmaceutical Affairs Law and Related Regulation. METHODS: The 43 565 case data of seven anti-hypertensive drugs (one Ca-antagonist, one alpha-blocker, two beta-blockers, three ACE inhibitors) were kindly offered from seven manufacturers who were members of RAD-AR Council, Japan. After examining the data items and categories, they were standardized into common codes based on Japanese Drug Category Classification (JDCC), International Classification of Diseases 9 (ICD-9) and Japanese Adverse Drug Reaction Terminology (J-ART). As each manufacturer had a different coding method in accordance to manufacturer's own practice of data management, the original forms were divided into several datasets. The data processing and statistical analysis were conducted using Statistical Analysis System (SAS). RESULTS: (1) Technology and know-how to combine data coded by different methods were established for building a database that had never been tried in Japan. (2) The following are the by-products of the study: a) Onset of ADR concentrated in the early stage but onset of some disorders prevailed equally throughout the investigation period. b) Although the number of collected cases of anti-hypertensive drugs was 43 565, total number of administrated anti-hypertensive drugs reached to 70 714 because additional anti-hypertensive drugs were often used with subject drugs. CONCLUSION: There is no large-scale database of patients' clinical course in Japan. However, since the Japanese Drug Re-examination System started in 1979, almost eight million cases of Drug Use Investigation on about 700 drugs have been collected with enormous human power and huge expenditure for Japanese Drug Re-examination application by pharmaceutical manufacturers. New and more appropriate information will be detected by the database, built using Drug Use Investigation data that were collected only for the Japanese Drug Re-examination application.

Risk of adverse reproductive outcomes associated with proximity to municipal solid waste incinerators with high dioxin emission levels in Japan.

BACKGROUND: Great public concern about health effects of dioxins emitted from municipal solid waste incinerators has increased in Japan. This paper investigates the association of adverse reproductive outcomes with maternal residential proximity to municipal solid waste incinerators. METHODS: The association of adverse reproductive outcomes with mothers living within 10 km from 63 municipal solid waste incinerators with high dioxin emission levels (above 80 ng international toxic equivalents TEQ/m3) in Japan was examined. The numbers of observed cases were compared with the expected numbers calculated from national rates adjusted regionally. Observed/expected ratios were tested for decline in risk or peak-decline in risk with distance up to 10 km. RESULTS: In the study area within 10 km from the 63 municipal solid waste incinerators in 1997-1998, 225,215 live births, 3,387 fetal deaths, and 835 infant deaths were confirmed. None of the reproductive outcomes studied here showed statistically significant excess within 2 km from the incinerators. However, a statistically significant peak-decline in risk with distance from the incinerators up to 10 km was found for infant deaths (p=0.023) and infant deaths with all congenital malformations combined (p=0.047), where a "peak" is detected around 1-2 km. CONCLUSION: Our study shows a peak-decline in risk with distance from the municipal solid waste incinerators for infant deaths and infant deaths with all congenital malformations combined. However, due to the lack of detailed exposure information to dioxins around the incinerators, the observed trend in risk should be interpreted cautiously and there is a need for further investigation to accumulate good evidence regarding the reproductive health effects of waste incinerator exposure.

[A study of where mentally disordered people receive medical care in Fukuoka Prefecture].

OBJECTIVE: To investigate the "secondary medical regions" where mentally disordered people receive out-patient and in-patient medical care in Fukuoka prefecture, and examine factors related receiving care in medical facilities outside of their secondary medical region of residence. METHODS: 16,129 out-patients on June 30, 2001 using "the public assistance system of outpatients' medical expenses" in line with the Law on Mental Health and Welfare for People with Mental Disorders were analyzed. 7513 in-patients with mental disorders in hospitals were also analyzed utilizing data from the "Patient Survey" by the Ministry of Health and Welfare in 1999. Whether they received out-patient care and in-patient medical care in their own region of residence or not was clarified for all of 13 secondary medical regions. Univariate and multivariate analyses with the multiple logistic regression model were employed to evaluate the relationship between the medical care outside their residential region and characteristics, such as the secondary medical region, gender, age, diagnosis, medical care insurance and so on. RESULTS: With out-patient care, patients in secondary medical regions with a small population size tended to receive care outside of their residential region. Other characteristics associated with a significantly an increased proportion receiving care outside of their region included; young age, receiving care in clinics, and medical care insurance as "public corporation staff mutual aid association" and "employees' insurance or government's managed health insurance". For in-patients care, patients in secondary medical regions with a small number of psychiatric beds per population showed a marked tendency to receive care outside of their residential region. A slight correlation was observed between population ant the proportion receiving care outside of their region. Young and diagnoses such as of "mental and behavioural disorders due to use of alcohol," "other mental or behavioural disorders" "neurotic, stress-related and somatoform disorders" or "mood [affective] disorders", were other characteristics associated with an increased proportion receiving care outside of their region. CONCLUSIONS: With the societal prejudice against mental disorders and regional differences in psychiatric medical facilities, it is of interest that this study indicated that mental disordered people receive medical care in a wide and relatively close area beyond their secondary medical region of residence.

Relationship between a high mortality rate and extreme heat during the summer of 1999 in Hokkaido Prefecture, Japan.

In order to describe the relationship between mortality rate and extreme heat during the summer of 1999 in Hokkaido, we calculated the monthly age-adjusted death rates, average monthly mean temperature and average monthly high temperature for the years 1995 to 1999 in Hokkaido. The materials were derived from Statistics and Information Department, Minister's Secretariat, Ministry of Health, Labour and Welfare of Japan, Statistical Bureau Management and Coordination Agency Government of Japan and the Japan Meteorological Agency. Trends in the monthly age-adjusted death rates and temperature changes in the same period were analyzed. The highest average monthly high temperature for August and September (28.8 degrees C and 23.8 degrees C, respectively) occurred in 1999; the similar trend was observed in the highest average monthly mean temperature. In August 1999, there were 14 days with highest temperatures of 30 degrees C and over. The age-adjusted rate in August 1999 was significantly higher compared with those for the years 1995 to 1998 (p<0.01). We concluded that an unusually hot spell in 1999 was followed by a high mortality rate in Hokkaido.