Hypoxia-stimulated membrane trafficking requires T-plastin.

AIM: Traffic between the plasma membrane and the endomembrane compartments is an essential feature of eukaryotic cells. The secretory pathway sends cargoes from biosynthetic compartments to the plasma membrane. This is counterbalanced by a retrograde endocytic route and is essential for cell homoeostasis. Cells need to adapt rapidly to environmental challenges such as the reduction of pO2 which, however, has not been analysed in relation to membrane trafficking in detail. Therefore, we determined changes in the plasma membrane trafficking in normoxia, hypoxia, and after reoxygenation. METHODS: Membrane trafficking was analysed by using the bulk membrane endocytosis marker FM 1-43, the newly developed membrane probe mCLING, wheat germ agglutinin as well as fluorescently labelled cholera toxin subunit B. Additionally, the uptake of specific membrane proteins was determined. In parallel, a non-biased SILAC screen was performed to analyse the abundance of membrane proteins in normoxia and hypoxia. RESULTS: Membrane trafficking was increased in hypoxia and quickly reversed upon reoxygenation. This effect was independent of the hypoxia-inducible factor (HIF) system. Using SILAC technology, we identified that the actin-bundling protein T-plastin is recruited to the plasma membrane in hypoxia. By the use of T-plastin knockdown cells, we could show that T-plastin mediates the hypoxia-induced membrane trafficking, which was associated with an increased actin density in the cells as determined by electron microscopy. CONCLUSION: Membrane trafficking is highly dynamic upon hypoxia. This phenotype is quickly reversible upon reoxygenation, which suggests that this mechanism participates in the cellular adaptation to hypoxia.

The expanding fireball of Nova Delphini 2013.

A classical nova occurs when material accreting onto the surface of a white dwarf in a close binary system ignites in a thermonuclear runaway. Complex structures observed in the ejecta at late stages could result from interactions with the companion during the common-envelope phase. Alternatively, the explosion could be intrinsically bipolar, resulting from a localized ignition on the surface of the white dwarf or as a consequence of rotational distortion. Studying the structure of novae during the earliest phases is challenging because of the high spatial resolution needed to measure their small sizes. Here we report near-infrared interferometric measurements of the angular size of Nova Delphini 2013, starting one day after the explosion and continuing with extensive time coverage during the first 43 days. Changes in the apparent expansion rate can be explained by an explosion model consisting of an optically thick core surrounded by a diffuse envelope. The optical depth of the ejected material changes as it expands. We detect an ellipticity in the light distribution, suggesting a prolate or bipolar structure that develops as early as the second day. Combining the angular expansion rate with radial velocity measurements, we derive a geometric distance to the nova of 4.54 ± 0.59 kiloparsecs from the Sun.

Imaging the surface of Altair.

Spatially resolving the surfaces of nearby stars promises to advance our knowledge of stellar physics. Using optical long-baseline interferometry, we constructed a near-infrared image of the rapidly rotating hot star Altair with a resolution of <1 milliarcsecond. The image clearly reveals the strong effect of gravity darkening on the highly distorted stellar photosphere. Standard models for a uniformly rotating star cannot explain our findings, which appear to result from differential rotation, alternative gravity-darkening laws, or both.

Intracranial meningioma and ionizing radiation in medical and occupational settings.

In a population-based case-control study of 200 cases and 400 controls in western Washington State, the authors assessed associations between meningioma and ionizing radiation in medical and occupational settings. No significant associations were observed for diagnostic studies or occupational settings, but associations were observed for radiation therapy to head or neck (odds ratio 3.7, 95% CI 1.5 to 9.5), especially for neoplastic conditions. Only four patients (2%) had meningiomas that followed high-dose cranial radiation.

Statin therapy and risk of dementia in the elderly: a community-based prospective cohort study.

OBJECTIVE: To assess the association between statin therapy and risk of Alzheimer disease (AD) in a prospective cohort study with documented statin exposure and incident dementia. METHODS: This is a prospective, cohort study of statin use and incident dementia and probable AD. A cohort of 2,356 cognitively intact persons, aged 65 and older, were randomly selected from a health maintenance organization (HMO), and were assessed biennially for dementia. Statin use was identified using the HMO pharmacy database. A proportional hazards model with statin use as a time-dependent covariate was used to assess the statin-dementia/AD association. RESULTS: Among 312 participants with incident dementia, 168 had probable AD. The unadjusted hazard ratios (HRs) with statin use were 1.33 (95% CI 0.95 to 1.85) for all-cause dementia and 0.90 (CI 0.54 to 1.51) for probable AD. Adjusted corresponding HRs were 1.19 (CI 0.82 to 1.75) and 0.82 (CI 0.46 to 1.46). A subgroup analysis of participants with at least one APOE-epsilon4 allele who entered the study before age 80 produced an adjusted HR of 0.33 (CI 0.10 to 1.04). CONCLUSION: Employing time-dependent proportional hazards modeling, the authors found no significant association between statin use and incident dementia or probable AD. In contrast, when the data were analyzed, inappropriately, as a case-control study, the authors found an OR of 0.55 for probable AD, falsely indicating a protective effect of statins. Study design and analytic methods may explain the discrepancy between the current null findings and earlier findings.

Prognosis in amyotrophic lateral sclerosis: a population-based study.

BACKGROUND: Accurate information on prognosis of ALS is useful to patients, families, and clinicians. METHODS: In a population-based study of ALS in western Washington, the authors assembled a cohort of 180 patients with incident ALS between 1990 and 1994. Information on potential prognostic factors was collected during an in-person interview. Patients also completed the Medical Outcomes Study Short Form 36 (SF-36). Vital status through December 1999 was known for all patients. RESULTS: Median survival was 32 months from onset of symptoms and 19 months from diagnosis. The 5-year survival after diagnosis was 7%. Older age and female sex were strongly associated with poor survival. In multivariable Cox proportional hazards regression models, factors significantly and independently associated with a worse prognosis included older age, any bulbar features at onset, shorter time from symptom onset to diagnosis, lack of a marital partner, and residence in King County. Recursive partitioning identified age, time from symptom onset to diagnosis, and marital status as the strongest predictors of survival. Good summary scores for physical health on the SF-36, but not for mental health, were significantly associated with longer survival than poor scores. CONCLUSION: These findings are consistent with other population-based studies of ALS and confirm its pernicious nature. Older age, female sex, any bulbar features at onset, short time from symptom onset to diagnosis, lack of a marital partner, and disease severity are key prognostic factors. Serial measurement of severity would likely improve predictions.

History of head trauma and risk of intracranial meningioma: population-based case-control study.

A population-based case-control study in western Washington state was performed to assess the relation between head trauma and meningioma. Based on 200 case and 400 control subjects, head trauma was associated with an increased risk of meningioma (odds ratio = 1.83; 95% CI = 1.28, 2.62), especially head traumas occurring 10 to 19 years before reference date (odds ratio = 4.33; 95% CI = 2.06, 9.10). A dose-response relationship was present for number, but not severity, of head traumas. Whether the associations observed in this study are causal remains unclear.

Brain SPECT: a controlled, blinded assessment of intra-reader and inter-reader agreement.

A detailed assessment of intra- and inter-reader variation in the interpretation of brain SPECT scans has been performed. A random sample was selected from scans performed at a community/teaching hospital in Seattle. Scans were interpreted independently by three experienced readers who were blinded to all patient information. Forty-eight scans were interpreted twice by each reader, for a total of 288 readings. Readers recorded detailed assessments of individual lesions and overall impressions using a standardized reporting form. Intra-observer agreement as reflected in per cent agreement for severity scores ranged from 65% to 100%. Intra-observer agreement on the 'overall impression' was very good for Alzheimer's pattern (kappa=0.73-1.00), and fair to good for the 'heterogeneous pattern' (kappa=0.30-0.63). Inter-observer agreement, as reflected in per cent agreement, ranged from 29% to 100%. Inter-observer agreement about the 'overall impression' was fair to moderate for Alzheimer's pattern (kappa=0.24-0.54) and was poor for the descriptors 'heterogeneous' and 'normal'. It is concluded that brain SPECT has great potential value in many important conditions. This study demonstrates a need for further work in the areas of pattern definition and reduction of observer variation.

Air sampling at the chest and ear as representative of the breathing zone.

Tracer gas concentrations were measured on a 60%-sized mannequin holding a pure sulfur hexafluoride source in its hands at waist height while it stood in a wind tunnel. Samplers were placed at the mannequin's mouth, in front of the ear, and at three chest locations at lapel level. Simultaneous 15-min time-weighted average samples were taken by drawing air into different sampling bags with sampling pumps. For the factorial study design, test conditions included cross-draft velocities of 10, 22, 47, and 80 ft/min; three mannequin orientations (facing to, side to, and back to cross-draft), and rotating speed through an 80 degrees arc (fast, slow, and no movement). Each study condition was tested twice. Concentrations at all sampling locations when the mannequin faced to the front and side were less than a tenth of the levels measured at the nose (Cnose) when the mannequin faced downstream. Higher velocities significantly increased concentration at the Back orientation and generally reduced it at the Side and Facing orientations. Concentrations at the nose were different from concentrations at other sites. For 34 of 36 samples the mean chest concentration (Cchest,) was higher than the Cnose (geometric mean three times higher). The ratio of ear (Cear) and Cnose varied with orientation. At the Back orientation, Cear, was lower than Cnose, whereas Cear was higher than Cnose at the Side and Facing to flow orientations. Velocity affected the ratios of concentrations. At the Back orientation, the chest sampler provided lower overestimates of Cnose, at higher velocities than at lower values. Mannequin movement, done only at the Back orientation, proved important only for the ear location. Results showed significant and substantial differences between concentrations at the nose and lapel. However, these findings should be interpreted with caution because a very dense tracer gas and an unheated, nonbreathing mannequin were used. In more realistic conditions, the findings probably would show far smaller differences in concentrations at different sampling sites.

Using census data and birth certificates to reconstruct the early-life socioeconomic environment and the relation to the development of Alzheimer's disease.

The early-life environment and its effect on growth and maturation of children and adolescents are associated with several adult chronic diseases, including Alzheimer's disease. Because it is not feasible to collect information prospectively over the average life span, methods to reconstruct the early-life environment of the aged are necessary to evaluate these associations. In a community-based case-control study conducted in the United States, we collected U.S. census records and birth certificates to reconstruct the early-life socioeconomic environment of each elderly subject. Information was found on 82% of the available Alzheimer's disease cases (239 of 292) and 87% of the available controls (245 of 282). We investigated risk of Alzheimer's disease associated with father's occupation, parental age, household size, sibship size, and birth order. Subjects whose fathers were unskilled manual workers or laborers were at higher risk for Alzheimer's disease (odds ratio = 1.80, 95% confidence interval = 1.19--2.73). The risk of Alzheimer's disease was increased with increasing number of people in the household. We also evaluated whether subjects with the apolipoprotein epsilon 4 allele (APOE epsilon 4), a strong genetic risk factor that is not a necessary cause or a sufficient cause by itself for the development of Alzheimer's disease, were at higher risk than subjects who did not carry this allele. Among subjects with the APOE epsilon 4 allele whose fathers held lower-socioeconomic level occupations, the odds of developing Alzheimer's disease were higher (odds ratio = 2.35, 95% confidence interval = 1.07--5.16) compared with subjects without the allele (odds ratio = 1.40, 95% confidence interval = 0.78--2.52). Subjects carrying the APOE epsilon 4 allele alone have a threefold increased risk of Alzheimer's disease (odds ratio = 3.17, 95% confidence interval = 1.99--5.04). Compared with subjects with neither risk factor, subjects with both the genetic and the environmental risk factors (household size of seven or more and father's occupation being manual) had a relatively high risk of Alzheimer's disease (odds ratio = 14.8, 95% confidence interval = 4.9--46). The data suggest that APOE epsilon 4 may modify the associations between father's occupation, other early-life environmental factors, and development of Alzheimer's disease in late life.

Dietary soy isoflavone intake in older Japanese American women.

OBJECTIVE: In a sample of older Japanese American women, we aimed to: (1) describe the most commonly consumed soy foods, (2) estimate dietary soy isoflavone intake, (3) describe characteristics associated with dietary soy isoflavone intake, and (4) compare our estimates with previously published estimates in other Japanese samples. DESIGN: A 14-item soy food-frequency questionnaire was administered to older Japanese American women and responses were converted to quantitative estimates of soy isoflavones (genistein plus daidzein). Multiple regression was used to examine characteristics associated with dietary soy isoflavone intake, including self-reported lifestyle and cultural factors and dietary intake of various foods ascertained from a semi-quantitative food-frequency questionnaire. To compare our estimates with other samples, a review of the literature was conducted. SETTING/SUBJECTS: Data are from 274 women aged 65+ years, recruited from a longitudinal cohort study of Japanese Americans in King County, Washington State. RESULTS: The soy foods most commonly consumed were tofu (soybean curd), miso (fermented soybean paste) and aburaage (fried thin soybean curd). The mean intake of dietary soy isoflavones was 10.2 (standard deviation (SD), 12.4) mg day(-1), approximately a quarter to a half that of previously published estimates in Japanese samples. Dietary soy isoflavone intake was positively associated with speaking Japanese, the consumption of traditional Japanese dishes (kamaboko, manju and mochi), low-fat/non-fat milk and yellow/red vegetables, vitamin E supplement use, and walking several blocks each day. Dietary soy isoflavone intake was negatively associated with the consumption of butter. CONCLUSIONS: The estimated dietary soy isoflavone intake in Japanese American women living in King County, Washington State was about a quarter to a half that of women living in Japan. Dietary soy isoflavone intake was associated with speaking Japanese and healthy lifestyle and dietary habits.

DNA double-strand breaks in mouse kidney cells with age.

A Biojector device fitted with a CO2 cartridge was used to prepare single cell suspensions from kidneys of 12-month- (middle-aged) and 24-month-old (old) C57B1/6 mice. Microgel electrophoresis of DNA from these cells revealed a modest but significant 7.3% increase (P = 0.04) in DNA double-strand breaks in old mice. This increase is equivalent to the DNA damage induced by 0.1 Gray of X-rays (5 double-strand breaks) in kidney cells of 10-month-old mice, as determined by a standard calibration curve. Greater DNA damage with aging was also positively correlated with higher levels of pathology in the kidneys.

Reliability of cognitive tests used in Alzheimer's disease.

Assessment of cognitive status is a key component of monitoring Alzheimer's patients during the course of their illness. The reliability of a cognitive test is a measure of its reproducibility under replicate conditions. In the classical setting, reliability is defined in three ways: the ratio of the variance of the true scores to the variance of the observed scores; the correlation of observed scores on two parallel forms of the test, and the square of the correlation between the observed score and the true score. In the classical case of independence of true scores and measurement errors, the three definitions are equivalent. Estimation of reliability through analysis of variance techniques and construction of confidence intervals is accomplished when the true scores and errors are normally distributed. This paper examines a non-parametric, probabilistic estimate of reliability as the probability that, given a parallel test, the second set of scores has the same ranking as the first set. In the classical case there is a monotonic relationship between this measure and the reliability. This measure is also linked to Kendall's tau. The performance of the probabilistic measure is compared with the traditional measures in a variety of models, including those with bounded scales, and those with skewed distributions. The ideas are extended to the case of the reliability of change scores and to biased estimators of true scores. In this context truncation models and Bayes estimates of true scores are considered.

Early-life risk factors and the development of Alzheimer's disease.

OBJECTIVE: To investigate the association of early-life factors with AD. BACKGROUND: The early-life environment and its effect on growth and maturation of children and adolescents are linked to many adult chronic diseases (heart disease, stroke, hypertension, and diabetes mellitus), and these effects are also linked to maternal reproduction. AD may have an early-life link. The areas of the brain that show the earliest signs of AD are the same areas of the brain that take the longest to mature during childhood and adolescence. A poor-quality childhood or adolescent environment could prevent the brain from reaching complete levels of maturation. Lower levels of brain maturation may put people at higher risk for AD. METHODS: In a community-based case-control study (393 cases, 377 controls), we investigated the association of early-life factors and AD. Early-life variables include mother's age at patient's birth, birth order, number of siblings, and area of residence before age 18 years. Patient education level and apolipoprotein E (APOE) genotypes were also included in the analysis. RESULTS: Area of residence before age 18 years and number of siblings are associated with subsequent development of AD. For each additional child in the family the risk of AD increases by 8% (OR = 1.08, 95% CI = 1.01 to 1.15). More controls compared with cases grew up in the suburbs (OR = 0.45, 95% CI = 0.25 to 0.82). APOE epsilon 4 and the patient's education level did not confound or modify the associations. CONCLUSIONS: The early-life childhood and adolescent environment is associated with the risk of AD.

Cross-sectional versus longitudinal estimates of cognitive change in nondemented older people: a CERAD study. Consortium to Establish a Registry for Alzheimer's Disease.

OBJECTIVES: To investigate the effect of increasing age on cognition in nondemented older people. DESIGN: A cross-sectional and longitudinal analysis. PARTICIPANTS: A total of 454 control subjects for Alzheimer's cases from the cohort assembled by the Consortium to Establish a Registry for Alzheimer's Disease (CERAD). MEASUREMENT: The Mini-Mental State Examination (MMSE) to assess cognitive function. RESULTS: Cross-sectional estimates were derived by generalized linear models and longitudinal estimates by generalized estimating equations. The cross-sectional model indicated a small but significant decline in MMSE of -.4 points per 10 years. The longitudinal model indicated a small but significant increase in MMSE of about +.6 points per 10 years. Evidence of an early learning effect and nonrandom dropout exists. CONCLUSIONS: The question of "normal" aging can be approached by considering cross-sectional information and, usually separately, longitudinal information. This study does both using recently developed statistical methods. We conclude that there is a small but significant decline in scores on the MMSE with increasing population age. The effect can be masked in longitudinal cohorts by a learning effect (especially early in follow-up) and other factors associated with repeated testing.

Evaluation of a public-private certified nurse-midwife maternity program for indigent women.

OBJECTIVES: This study assessed the impact of a public-private certified nurse-midwife program on prenatal and delivery outcomes among medically indigent women. METHODS: A population-based quasi-experimental design was used to compare 1 intervention county with 2 nonintervention counties. RESULTS: The program significantly reduced the number of women who received no prenatal care and the risk of acquiring less than adequate prenatal care. Reductions in the proportion of infants born premature or with low birth-weights were of borderline significance. The use of induction and/or stimulation of labor was statistically elevated. CONCLUSIONS: These results suggest that the intervention program was instrumental in reducing some, but not all, negative prenatal and delivery outcomes.

Risk of amyotrophic lateral sclerosis and history of physical activity: a population-based case-control study.

OBJECTIVE: To assess in greater detail than previous studies the purported association between a history of physical activity and amyotrophic lateral sclerosis (ALS). METHODS: A population-based case-control study was used to identify risk factors for ALS. Case patients were from 3 counties of western Washington State who were newly diagnosed as having ALS by a neurologist. Two control subjects matched with each case patient for sex and age within 5 years were identified by random digit telephone dialing or random selection from Medicare eligibility lists. All subjects underwent an in-person structured interview including detailed information about physical activity before a reference date, which was the month and year the case patient was diagnosed as having ALS. Various measures of physical activity both at work and leisure time were evaluated using conditional logistic regression taking into account the matching for sex and age. RESULTS: One hundred seventy-four case patients and 348 control subjects participated in the study. Physical activity was not significantly different between case patients and controls--whether at work, leisure time or both combined, and whether during a person's lifetime (from 10 years before reference date back to age 15 years) or during specific decades before reference date. An exception was that case patients reported having participated in organized sports in high school slightly more frequently than control subjects (odds ratio, 1.52; 95% confidence interval, 1.03-2.25). CONCLUSION: A history of physical activity has little, if any, effect on the risk of ALS.

Behavioral changes following participation in a home health promotional program in King County, Washington.

This study examined behavioral changes in households after participation in a home environmental assessment. Home assessment visits by a trained coach, which involved a walk-through in the home with the home residents, were conducted in 36 homes. The walk-through included a list of recommended behavioral changes that the residents could make to reduce their exposures to home pollutants in areas such as dust control, moisture problems, indoor air, hazardous household products, and hobbies. Recruited households were surveyed 3 months after the home assessment to evaluate their implementation of the recommendations. Following the home visits, 31 of 36 households reported making at least one behavioral change, and 41% of the recommendations made by the volunteer coaches were implemented. In conclusion, this study found that the majority of the households who participated in the home assessment reported implementing at least one recommendation. This home health promotional method was effective in influencing behavioral changes.

Consortium to establish a registry for Alzheimer's disease: development, database structure, and selected findings.

The Consortium to Establish a Registry for Alzheimer's Disease (CERAD) was funded in 1986 by the National Institute on Aging to develop standardized assessments for patients with Alzheimer's disease (AD). Since that time, CERAD has developed and evaluated clinical and neuropsychological test batteries, a neuroimaging protocol, and an assessment of the neuropathological findings of the brains of these patients at autopsy. Approximately 1,200 carefully screened patients with AD and 450 control subjects were evaluated using these instruments at 24 major medical centers around the United States. Annual follow-up observations of these subjects were made for up to eight years. Autopsy examinations of the brain were done in over half of the deceased cases and the clinical diagnosis of AD was confirmed in 85 percent of them. This article outlines the procedures used for identifying the clinical sites, the entry and annual evaluations of patients and control subjects, the collection and analysis of data at a central Methodology and Data Management Center, and evaluation of the CERAD measures. We also present selected data from the 50 or so peer-reviewed papers published to date, with particular emphasis on findings from African-American patients with AD, and related policy implications.