TUBB3 and KIF21A in neurodevelopment and disease

Neuronal migration and axon growth and guidance require precise control of microtubule dynamics and microtubule-based cargo transport. TUBB3 encodes the neuronal-specific β-tubulin isotype III, TUBB3, a component of neuronal microtubules expressed throughout the life of central and peripheral neurons. Human pathogenic TUBB3 missense variants result in altered TUBB3 function and cause errors either in the growth and guidance of cranial and, to a lesser extent, central axons, or in cortical neuronal migration and organization, and rarely in both. Moreover, human pathogenic missense variants in KIF21A, which encodes an anterograde kinesin motor protein that interacts directly with microtubules, alter KIF21A function and cause errors in cranial axon growth and guidance that can phenocopy TUBB3 variants. Here, we review reported TUBB3 and KIF21A variants, resulting phenotypes, and corresponding functional studies of both wildtype and mutant proteins. We summarize the evidence that, in vitro and in mouse models, loss-of-function and missense variants can alter microtubule dynamics and microtubule-kinesin interactions. Lastly, we highlight additional studies that might contribute to our understanding of the relationship between specific tubulin isotypes and specific kinesin motor proteins in health and disease

Not In Our Backyard: Spectroscopic Support for the CLASH z=11 Candidate MACS0647-JD

We report on our first set of spectroscopic Hubble Space Telescope observations of the z~11 candidate galaxy strongly lensed by the MACSJ0647.7+7015 galaxy cluster. The three lensed images are faint and we show that these early slitless grism observations are of sufficient depth to investigate whether this high-redshift candidate, identified by its strong photometric break at ~1.5 micron, could possibly be an emission line galaxy at a much lower redshift. While such an interloper would imply the existence of a rather peculiar object, we show here that such strong emission lines would clearly have been detected. Comparing realistic, two-dimensional simulations to these new observations we would expect the necessary emission lines to be detected at >5 sigma while we see no evidence for such lines in the dispersed data of any of the three lensed images. We therefore exclude that this object could be a low redshift emission line interloper, which significantly increases the likelihood of this candidate being a bona fide z~11 galaxy.Comment: 14 Pages. 6 Figures. 2nd revised version. Accepted. To appear in ApJ. Please contact [email protected] for comments on this pape

Traffic-Related Air Pollution and All-Cause Mortality during Tuberculosis Treatment in California.

BackgroundAmbient air pollution and tuberculosis (TB) have an impact on public health worldwide, yet associations between the two remain uncertain.ObjectiveWe determined the impact of residential traffic on mortality during treatment of active TB.MethodsFrom 2000-2012, we enrolled 32,875 patients in California with active TB and followed them throughout treatment. We obtained patient data from the California Tuberculosis Registry and calculated traffic volumes and traffic densities in 100- to 400-m radius buffers around residential addresses. We used Cox models to determine mortality hazard ratios, controlling for demographic, socioeconomic, and clinical potential confounders. We categorized traffic exposures as quintiles and determined trends using Wald tests.ResultsParticipants contributed 22,576 person-years at risk. There were 2,305 deaths during treatment for a crude mortality rate of 1,021 deaths per 10,000 person-years. Traffic volumes and traffic densities in all buffers around patient residences were associated with increased mortality during TB treatment, although the findings were not statistically significant in all buffers. As the buffer size decreased, fifth-quintile mortality hazards increased, and trends across quintiles of traffic exposure became more statistically significant. Increasing quintiles of nearest-road traffic volumes in the 100-m buffer were associated with 3%, 14%, 19%, and 28% increased risk of death during TB treatment [first quintile, referent; second quintile hazard ratio (HR)=1.03 [95% confidence interval (CI): 0.86, 1.25]; third quintile HR=1.14 (95% CI: 0.95, 1.37); fourth quintile HR=1.19 (95% CI: 0.99, 1.43); fifth quintile HR=1.28 (95% CI: 1.07, 1.53), respectively; p-trend=0.002].ConclusionsResidential proximity to road traffic volumes and traffic density were associated with increased all-cause mortality in patients undergoing treatment for active tuberculosis even after adjusting for multiple demographic, socioeconomic, and clinical factors, suggesting that TB patients are susceptible to the adverse health effects of traffic-related air pollution. https://doi.org/10.1289/EHP1699

Fish Intake Is Associated with Slower Cognitive Decline in Chinese Older Adults

Modifiable lifestyle changes, including dietary changes, could translate into a great reduction in the global burden of cognitive impairment and dementia. Few studies evaluated the benefits of fish intake for delaying cognitive decline, and no studies were conducted in a Chinese population, which may differ with respect to types, amounts, and correlates of fish consumption compared with Western populations. We hypothesized that higher consumption of fish would predict slower decline in cognitive function, independent of a wide range of potential confounders. This prospective cohort study comprised 1566 community-dwelling adults aged ≥55 y who completed a cognitive screening test at ≥2 waves of the China Health and Nutrition Survey in 1997, 2000, or 2004, with a mean follow-up of 5.3 y [age at entry (mean ± SD): 63 ± 6 y]. Diet was measured by 3-d 24-h recalls at baseline. Outcomes included repeated measures of global cognitive scores (baseline mean ± SD: 19 ± 6 points), composite cognitive Z-scores (standardized units), and standardized verbal memory scores (standardized units). Multivariable-adjusted linear mixed-effects models were used to evaluate the relation of fish intake with changes in cognitive scores. Age was found to significantly modify the association between fish consumption and cognitive change (P = 0.007). Among adults aged ≥65 y, compared with individuals who consumed <1 serving/wk (i.e., 100 g) fish, the mean annual rate of global cognitive decline was reduced by 0.35 point (95% CI: 0.13, 0.58) among those consuming ≥1 serving/wk, equivalent to the disparity associated with 1.6 y of age. Fish consumption was also associated with a slower decline in composite and verbal memory scores. No associations were observed among adults aged 55–64 y. Our findings suggest a potential role of fish consumption as a modifiable dietary factor to reduce the rate of cognitive decline in later life

Indicators of pulmonary exacerbation in cystic fibrosis: A Delphi survey of patients and health professionals

Background: There is uncertainty about the most important indicators of pulmonary exacerbations in CF. Methods: Two parallel Delphi surveys in 13 CF centres (UK and Ireland). Delphi 1: 31 adults with CF, ≥ one exacerbation over 12 months. Delphi 2: 38 CF health professionals. Rounds 1 and 2 participants rated their level of agreement with statements relating to indicators of exacerbation; Round 3 participants rated the importance of statements which were subsequently placed in rank order. Results: Objective measurements were of higher importance to health professionals. Feelings of increased debility were rated most important by adults with CF. Conclusions: There were clear differences in perspectives between the two groups as to the most important indicators of an exacerbation. This highlights that CF health professionals should take more cognisance of specific signs and symptoms reported by adults with CF, especially since these may be a precursor to an exacerbation

Cytochrome P4501A biomarker indication of the timeline of chronic exposure of Barrow’s goldeneyes to residual Exxon Valdez oil

Author Posting. © The Author(s), 2010. This is the author's version of the work. It is posted here by permission of Elsevier B.V. for personal use, not for redistribution. The definitive version was published in Marine Pollution Bulletin 62 (2011): 609-614, doi:10.1016/j.marpolbul.2010.11.015.We examined hepatic EROD activity, as an indicator of CYP1A induction, in Barrow's goldeneyes captured in areas oiled during the 1989 Exxon Valdez spill and those from nearby unoiled areas. We found that average EROD activity differed between areas during 2005, although the magnitude of the difference was reduced relative to a previous study from 1996/97, and we found that areas did not differ by 2009. Similarly, we found that the proportion of individuals captured from oiled areas with elevated EROD activity ( 2 times unoiled average) declined from 41% in winter 1996/97 to 10% in 2005 and 15% in 2009. This work adds to a body of literature describing the timelines over which vertebrates were exposed to residual Exxon Valdez oil and indicates that, for Barrow's goldeneyes in Prince William Sound, exposure persisted for many years with evidence of substantially reduced exposure by 2 decades after the spill.This research was supported primarily by the Exxon Valdez Oil Spill Trustee Council

Visit-to-Visit Variability in Blood Pressure Is Related to Late-Life Cognitive DeclineNovelty and Significance

The association between visit-to-visit variability of blood pressure (BP) and cognitive decline over time remains incompletely understood in a general population of older adults. We assessed the hypothesis that higher visit-to-visit variability in BP, but not mean BP, would be associated with faster decline in cognitive function among community-dwelling older adults. This prospective cohort study comprised 976 adults who had 3 or 4 visits with BP measurements as part of the China Health and Nutrition Survey from 1991, up to their first cognitive tests, and completed cognitive screening tests at 2 or more visits in 1997, 2000 or 2004. Visit-to visit BP variability was expressed as the standard deviation (SD), coefficient of variation or as the variation independent of mean BP across visits conducted at a mean interval of 3.2y. Mean (SD) age at the first cognitive test was 64 (6)y. Using multivariable-adjusted linear mixed-effects models, we found higher visit-to-visit variability in systolic BP, but not mean systolic BP, was associated with a faster decline of cognitive function (adjusted mean difference [95% CI] for high vs. low tertile of SD variability: standardized composite scores −0.038 standardized units (SU)/y [−0.066, −0.009] and verbal memory −0.041 SU/y [−0.075 to −0.008]). Higher visit-to-visit variability in diastolic BP was associated with a faster decline of cognitive function, independent of mean diastolic BP, among adults 55–64y but not those ≥ 65y. Our results suggest that higher long-term BP visit-to-visit variability is associated with a faster rate of cognitive decline among older adults

Impact of socioeconomic status on cancer incidence and stage at diagnosis: selected findings from the surveillance, epidemiology, and end results: National Longitudinal Mortality Study

BACKGROUND: Population-based cancer registry data from the Surveillance, Epidemiology, and End Results (SEER) Program at the National Cancer Institute (NCI) are mainly based on medical records and administrative information. Individual-level socioeconomic data are not routinely reported by cancer registries in the United States because they are not available in patient hospital records. The U.S. representative National Longitudinal Mortality Study (NLMS) data provide self-reported, detailed demographic and socioeconomic data from the Social and Economic Supplement to the Census Bureau's Current Population Survey (CPS). In 1999, the NCI initiated the SEER-NLMS study, linking the population-based SEER cancer registry data to NLMS data. The SEER-NLMS data provide a new unique research resource that is valuable for health disparity research on cancer burden. We describe the design, methods, and limitations of this data set. We also present findings on cancer-related health disparities according to individual-level socioeconomic status (SES) and demographic characteristics for all cancers combined and for cancers of the lung, breast, prostate, cervix, and melanoma. METHODS: Records of cancer patients diagnosed in 1973–2001 when residing 1 of 11 SEER registries were linked with 26 NLMS cohorts. The total number of SEER matched cancer patients that were also members of an NLMS cohort was 26,844. Of these 26,844 matched patients, 11,464 were included in the incidence analyses and 15,357 in the late-stage diagnosis analyses. Matched patients (used in the incidence analyses) and unmatched patients were compared by age group, sex, race, ethnicity, residence area, year of diagnosis, and cancer anatomic site. Cohort-based age-adjusted cancer incidence rates were computed. The impact of socioeconomic status on cancer incidence and stage of diagnosis was evaluated. RESULTS: Men and women with less than a high school education had elevated lung cancer rate ratios of 3.01 and 2.02, respectively, relative to their college educated counterparts. Those with family annual incomes less than $12,500 had incidence rates that were more than 1.7 times the lung cancer incidence rate of those with incomes$50,000 or higher. Lower income was also associated with a statistically significantly increased risk of distant-stage breast cancer among women and distant-stage prostate cancer among men. CONCLUSIONS: Socioeconomic patterns in incidence varied for specific cancers, while such patterns for stage were generally consistent across cancers, with late-stage diagnoses being associated with lower SES. These findings illustrate the potential for analyzing disparities in cancer outcomes according to a variety of individual-level socioeconomic, demographic, and health care characteristics, as well as by area measures available in the linked database