Multivitamin use and breast cancer outcomes in women with early-stage breast cancer: the Life After Cancer Epidemiology study

Little is known about the relation of multivitamin use to breast cancer outcomes. 2,236 women diagnosed from 1997 to 2000 with early-stage breast cancer (Stage I ≥ 1 cm, II, or IIIA) were enrolled about 2 years post-diagnosis, primarily from the Kaiser Permanente Northern California Cancer Registry (83%). Multivitamin use pre-diagnosis and post-diagnosis was assessed via mailed questionnaire. Outcomes were ascertained yearly by self-report and verified by medical record review. Delayed-entry Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI), adjusting for sociodemographic, tumor, and lifestyle factors. Overall, 54 and 72% of the cohort reported using multivitamins pre- and post-diagnosis, respectively. A total of 380 recurrences, 212 breast cancer deaths, and 396 total deaths were confirmed. Compared to never use, multivitamin use after diagnosis was not associated with any outcome (recurrence HR = 0.92; 95% CI: 0.71, 1.20; total mortality HR = 0.92; 95% CI: 0.71, 1.19). Compared to never use, persistent use of multivitamins from pre- to post-diagnosis was associated with a non-significant decreased risk of recurrence (HR = 0.76; 95% CI: 0.54, 1.06) and total mortality (HR = 0.79; 95% CI: 0.56, 1.12). The protective associations were limited to women who had been treated by radiation only (P for trend = 0.048 and 0.083 for recurrence and total mortality, respectively) and both radiation and chemotherapy (P for trend = 0.015 and 0.095 for recurrence and total mortality, respectively). In stratified analyses, women who consistently used multivitamins before and after diagnosis and ate more fruits/vegetables (P for trend = 0.008) and were more physically active (P for trend = 0.034) had better overall survival. Multivitamin use along with practice of other health-promoting behaviors may be beneficial in improving breast cancer outcomes in select groups of survivors.     

Enhanced cerebellar myelination with concomitant iron elevation and ultrastructural irregularities following prenatal exposure to ambient particulate matter in the mouse

Abstract

Accumulating evidence indicates the developing central nervous system (CNS) is a target of air pollution toxicity. Epidemiological reports increasingly demonstrate that exposure to the particulate matter (PM) fraction of air pollution during neurodevelopment is associated with an increased risk of neurodevelopmental disorders (NDDs) such as autism spectrum disorder (ASD). These observations are supported by animal studies demonstrating prenatal exposure to concentrated ambient PM induces neuropathologies characteristic of ASD, including ventriculomegaly and aberrant corpus callosum (CC) myelination. Given the role of the CC and cerebellum in ASD etiology, this study tested whether prenatal exposure to concentrated ambient particles (CAPs) produced pathological features in offspring CC and cerebella consistent with ASD. Analysis of cerebellar myelin density revealed male-specific hypermyelination in CAPs-exposed offspring at postnatal days (PNDs) 11–15 without alteration of cerebellar area. Atomic absorption spectroscopy (AAS) revealed elevated iron (Fe) in the cerebellum of CAPs-exposed female offspring at PNDs 11–15, which connects with previously observed elevated Fe in the female CC. The presence of Fe inclusions, along with aluminum (Al) and silicon (Si) inclusions, were confirmed at nanoscale resolution in the CC along with ultrastructural myelin sheath damage. Furthermore, RNAseq and gene ontology (GO) enrichment analyses revealed cerebellar gene expression was significantly affected by sex and prenatal CAPs exposure with significant enrichment in inflammation and transmembrane transport processes that could underlie observed myelin and metal pathologies. Overall, this study highlights the ability of PM exposure to disrupt myelinogenesis and elucidates novel molecular targets of PM-induced developmental neurotoxicity.     

Biofuels and North American Agriculture – Implications for the Health and Safety of North American Producers

ABSTRACT

This decade has provided North American agricultural producers with opportunity to not only produce fiber and food, but also fuel and other industrial products. The drivers incenting this development could be sustained well into the future, therefore workforce safety and health implications are likely to persist for some time. Within production agriculture, the ‘feedstock growth and harvest cycle’ and ‘transport’ sectors possess the changing exposures experienced by workers. The Conference explored the following exposures: distiller's grains and bio-processing byproducts, spent catalyst, solvent brine, microbial agents, genetically modified organisms, discharge effluent, H2O dilutes, change in cropping patterns and resultant use of different seeding and harvest technologies, pests (whether target or non-target), and rural traffic resulting from concentrated movement of massive quantities of biomass and grain. Other issues of a more general public health nature such as watershed implications, other environmental impacts, emissions, uneven economic development potential, public safety issues associated with transport of both fuel and other industrial products, and rural emergency medical service need were explored. And, agronomic impacts were noted, including tillage change, potassium buildup in soil, nutrient depletion, sedimentation and erosion of tillable soil, and local esthetics. It was concluded that rural venues for formation and exploration of public policy need to be created.     

Designing a Patient Safety Undergraduate Medical Curriculum: The Telluride Interdisciplinary Roundtable Experience

Purpose: Patient safety has emerged as a global concern in the provision of quality health care, and yet, to date, few medical schools have created and/or implemented patient safety curricula. The purpose of this article is to introduce readers to one model of a patient safety undergraduate medical curriculum, as designed by a group of experts attending an annual interdisciplinary roundtable assembled for this purpose. Summary: The Annual Telluride Interdisciplinary Roundtable met in 2005 and 2006 to design what it considered to be a comprehensive patient safety curriculum for medical students. Invited members included stakeholders from a variety of fields, including health care providers, senior health care administration, students, residents, patient advocacy leaders, and curriculum development/assessment experts. The group developed a list of general curricular principles, followed by 11 specific elements felt to be essential to an effective patient safety curriculum for undergraduate medical education students. It also identified a number of challenges to implementing such a curriculum. Conclusions: A patient safety curriculum, developed by a group of experts for an undergraduate medical education population, was successfully developed over a two-year period of time. Future meetings of the Telluride Roundtable group have centered on evaluation and refinement of these curricular elements as pilots occur in a number of medical schools, and new curricular ideas continue to be developed. Continued interprofessional dialogue and collaborative research will enable the development and implementation of a standardized longitudinal patient safety student curriculum.     

Ca2+ sparks promote myogenic tone in retinal arterioles

Background and Purpose

Ca²⁺ imaging reveals subcellular Ca²⁺ sparks and global Ca²⁺ waves/oscillations in vascular smooth muscle. It is well established that Ca²⁺ sparks can relax arteries, but we have previously reported that sparks can summate to generate Ca²⁺ waves/oscillations in unpressurized retinal arterioles, leading to constriction. We have extended these studies to test the functional significance of Ca²⁺ sparks in the generation of myogenic tone in pressurized arterioles.

Experimental Approach

Isolated retinal arterioles (25–40 μm external diameter) were pressurized to 70 mmHg, leading to active constriction. Ca²⁺ signals were imaged from arteriolar smooth muscle in the same vessels using Fluo4 and confocal laser microscopy.

Key Results

Tone development was associated with an increased frequency of Ca²⁺ sparks and oscillations. Vasomotion was observed in 40% of arterioles and was associated with synchronization of Ca²⁺ oscillations, quantifiable as an increased cross-correlation coefficient. Inhibition of Ca²⁺ sparks with ryanodine, tetracaine, cyclopiazonic acid or nimodipine, or following removal of extracellular Ca²⁺, resulted in arteriolar relaxation. Cyclopiazonic acid-induced dilatation was associated with decreased Ca²⁺ sparks and oscillations but with a sustained rise in the mean global cytoplasmic [Ca²⁺] ([Ca²⁺]_c), as measured using Fura2 and microfluorimetry.

Conclusions and Implications

This study provides direct evidence that Ca²⁺ sparks can play an excitatory role in pressurized arterioles, promoting myogenic tone. This contrasts with the generally accepted model in which sparks promote relaxation of vascular smooth muscle. Changes in vessel tone in the presence of cyclopiazonic acid correlated more closely with changes in spark and oscillation frequency than global [Ca²⁺]_c, underlining the importance of frequency-modulated signalling in vascular smooth muscle.     

Metabotropic glutamate receptor 5 positive allosteric modulators are neuroprotective in a mouse model of Huntington's disease

Background and Purpose

Huntington''s disease (HD) is an autosomal dominant neurodegenerative disorder caused by a polyglutamine expansion in the huntingtin protein. We have previously demonstrated that the cell signalling of the metabotropic glutamate receptor 5 (mGluR5) is altered in a mouse model of HD. Although mGluR5-dependent protective pathways are more activated in HD neurons, intracellular Ca²⁺ release is also more pronounced, which could contribute to excitotoxicity. In the present study, we aim to investigate whether mGluR5 positive allosteric modulators (PAMs) could activate protective pathways without triggering high levels of Ca²⁺ release and be neuroprotective in HD.

Experimental Approach

We performed a neuronal cell death assay to determine which drugs are neuroprotective, Western blot and Ca²⁺ release experiments to investigate the molecular mechanisms involved in this neuroprotection, and object recognition task to determine whether the tested drugs could ameliorate HD memory deficit.

Key Results

We find that mGluR5 PAMs can protect striatal neurons from the excitotoxic neuronal cell death promoted by elevated concentrations of glutamate and NMDA. mGluR5 PAMs are capable of activating Akt without triggering increased intracellular Ca²⁺ concentration ([Ca²⁺]_i); and Akt blockage leads to loss of PAM-mediated neuroprotection. Importantly, PAMs'' potential as drugs that may be used to treat neurodegenerative diseases is highlighted by the neuroprotection exerted by mGluR5 PAMs on striatal neurons from a mouse model of HD, BACHD. Moreover, mGluR5 PAMs can activate neuroprotective pathways more robustly in BACHD mice and ameliorate HD memory deficit.

Conclusions and Implications

mGluR5 PAMs are potential drugs that may be used to treat neurodegenerative diseases, especially HD.     

The endogenous lectin of human platelets is an alpha-granule component

Platelets from patients with several bleeding disorders (congenital afibrinogenemia, Glanzmann's thrombasthenia, gray platelet syndrome, and Hermansky-Pudlak syndrome) were evaluated for both platelet-bound and platelet-free hemagglutination activities. Thrombin and A23187 activated afibrinogenemic, Hermansky-Pudlak, and thrombasthenic platelets had normal platelet-bound hemagglutination activity. Gray platelets activated by the same agents had deficient platelet-bound hemagglutination activity. In contrast, thrombin-activated afibrinogenemic, gray, and thrombasthenic platelets lacked platelet- free hemagglutination activity. Only thrombin-activated Hermansky- Pudlak platelets had a normal level of platelet-free hemagglutination activity. On the basis of these results and the distinguishing characteristics of the defective platelets, it is concluded that the alpha-granules are the origin of the enhanced hemagglutination activity. Furthermore, it is suggested that the insufficiency of the platelet-bound agglutinin may be the cause of the inability of gray platelets to aggregate normally in response to thrombin.