Drug interactions may be important risk factors for methotrexate neurotoxicity, particularly in pediatric leukemia patients

Purpose: Methotrexate administration is associated with frequent adverse neurological events during treatment for childhood acute lymphoblastic leukemia. Here, we present evidence to support the role of common drug interactions and low vitamin B12 levels in potentiating methotrexate neurotoxicity. Methods: We review the published evidence and highlight key potential drug interactions as well as present clinical evidence of severe methotrexate neurotoxicity in conjunction with nitrous oxide anesthesia and measurements of vitamin B12 levels among pediatric leukemia patients during therapy. Results: We describe a very plausible mechanism for methotrexate neurotoxicity in pediatric leukemia patients involving reduction in methionine and consequential disruption of myelin production. We provide evidence that a number of commonly prescribed drugs in pediatric leukemia management interact with the same folate biosynthetic pathways and/or reduce functional vitamin B12 levels and hence are likely to increase the toxicity of methotrexate in these patients. We also present a brief case study supporting out hypothesis that nitrous oxide contributes to methotrexate neurotoxicity and a nutritional study, showing that patients. Conclusions: Use of nitrous oxide in pediatric leukemia patients at the same time as methotrexate use should be avoided especially as many suitable alternative anesthetic agents exist. Clinicians should consider monitoring levels of vitamin B12 in patients suspected of having methotrexate- induced neurotoxic effects

Reply: Methotrexate neurotoxicity due to drug interactions: an inadequate folinic acid effect

No abstract available

Field-calibrated model of melt, refreezing, and runoff for polar ice caps : Application to Devon Ice Cap

Acknowledgments R.M.M. was supported by the Scottish Alliance for Geoscience, Environment and Society (SAGES). The field data collection contributed to the validation of the European Space Agency Cryosat mission and was supported by the Natural Sciences and Engineering Research Council, Canada, the Meteorological Service of Canada (CRYSYS program), the Polar Continental Shelf Project (an agency of Natural Resources Canada), and by UK Natural Environment Research Council consortium grant NER/O/S/2003/00620. Support for D.O.B. was provided by the Canadian Circumpolar Institute and the Climate Change Geoscience Program, Earth Sciences Sector, Natural Resources Canada (ESS contribution 20130371). Thanks are also due to the Nunavut Research Institute and the communities of Resolute Bay and Grise Fjord for permission to conduct fieldwork on Devon Ice Cap. M.J. Sharp, A. Gardner, F. Cawkwell, R. Bingham, S. Williamson, L. Colgan, J. Davis, B. Danielson, J. Sekerka, L. Gray, and J. Zheng are thanked for logistical support and field assistance during the data collection. We thank Ruzica Dadic, two other anonymous reviewers, and the Editor, Bryn Hubbard, for their helpful comments on an earlier version of this paper and which resulted in significant improvements.Peer reviewedPublisher PD

Are neighbourhood characteristics associated with depressive symptoms? A review of evidence

A review of published observational studies of neighbourhoods and depression/depressive symptoms was conducted to inform future directions for the field. Forty-five English-language cross-sectional and longitudinal studies that analysed the effect of at least one neighbourhood-level variable on either depression or depressive symptoms were analysed. Of the 45 studies, 37 reported associations of at least one neighbourhood characteristic with depression/depressive symptoms. Seven of the 10 longitudinal studies reported associations of at least one neighbourhood characteristic with incident depression. Socioeconomic composition was the most common neighbourhood characteristic investigated. The associations of depressive symptoms/depression with structural features (socioeconomic and racial composition, stability and built environment) were less consistent than with social processes (disorder, social interactions, violence). Among the structural features, measures of the built environment were the most consistently associated with depression but the number of studies was small. The extent to which these associations reflect causal processes remains to be determined. The large variability in studies across neighbourhood definitions and measures, adjustment variables and study populations makes it difficult to draw more than a few general qualitative conclusions. Improving the quality of observational work through improved measurement of neighbourhood attributes, more sophisticated consideration of spatial scale, longitudinal designs and evaluation of natural experiments will strengthen inferences regarding causal effects of area attributes on depressionhttp://deepblue.lib.umich.edu/bitstream/2027.42/61831/1/Are neighborhood characteristics associated with depressive symptoms.pd

Neighborhood stressors and social support as predictors of depressive symptoms in the Chicago Community Adult Health Study

There is a growing interest in understanding the effects of specific neighborhood conditions on psychological wellbeing. We examined cross-sectional associations of neighborhood stressors (perceived violence and disorder, physical decay and disorder) and social support (residential stability, family structure, social cohesion, reciprocal exchange, social ties) with depressive symptoms in 3105 adults in Chicago. Subjects lived in 343 neighborhood clusters, areas of about two census tracts. Depressive symptoms were assessed with an 11-item version of the Center for Epidemiologic Studies-Depression (CES-D) scale. Neighborhood variables were measured using rater assessments, surveys, and the US census. We used two-level gender-stratified models to estimate associations of neighborhood conditions with depressive symptoms after adjusting for individual-level covariates. Most social support variables were associated with lower levels of depressive symptoms in women but not men, while stressors were moderately associated with higher levels in all subjects. Adjusting concurrently for stressors and social support did not change results. This suggests both neighborhood stressors and social support are associated with depressive symptoms.http://deepblue.lib.umich.edu/bitstream/2027.42/78331/1/MairDiezRoux2010_HealthPlace.pd

Understanding Polarizing Community Perspectives on Harm Reduction Strategies: Challenges to Addressing the Opioid Crisis in Appalachian Pennsylvania

Introduction: Rural communities face barriers to opioid treatment and overdose prevention including concerns about stigma and lack of harm reduction services. Purpose: The aim of this study was to explore community perspectives and understanding of harm reduction approaches to opioid use and overdose in a high-risk Northern Appalachian case community in Pennsylvania. Methods: A small town approximately 10 miles from Pittsburgh was identified as the community with the greatest predicted probabilities of epidemic outbreak using posteriors from spatial models of hospitalizations for opioid use disorders. We interviewed 20 key stakeholders in the case community in using a semi-structured interview guide and analyzed the qualitative data using an inductive grounded theory approach. Results: Our findings illustrate how conflicting perspectives about opioid dependence lay the foundation for the polarizing community perspectives on addressing opioid use and overdose and general disagreement regarding the legitimacy of harm reduction approaches versus abstinence-based recovery plans. Community members shared varying perspectives on multiple aspects of the opioid epidemic, including appropriate strategies, treatment, and overdose prevention methods and how community leaders and organizations should respond. Implications: Opinions, coupled with a general lack of education regarding opioid use and harm reduction options, make it challenging for small communities with limited resources to create comprehensive plans to address the opioid crisis

Is neighborhood racial/ethnic composition associated with depressive symptoms? The multi-ethnic study of atherosclerosis.

The racial/ethnic composition of a neighborhood may be related to residents' depressive symptoms through differential levels of neighborhood social support and/or stressors. We used the Multi-Ethnic Study of Atherosclerosis to investigate cross-sectional associations of neighborhood racial/ethnic composition with the Center for Epidemiologic Studies-Depression (CES-D) scale in adults aged 45-84. The key exposure was a census-derived measure of the percentage of residents of the same racial/ethnic background in each participant's census tract. Two-level multilevel models were used to estimate associations of neighborhood racial/ethnic composition with CES-D scores after controlling for age, income, marital status, education and nativity. We found that living in a neighborhood with a higher percentage of residents of the same race/ethnicity was associated with increased CES-D scores in African American men (p < 0.05), and decreased CES-D scores in Hispanic men and women and Chinese women, although these differences were not statistically significant. Models were further adjusted for neighborhood-level covariates (social cohesion, safety, problems, aesthetic quality and socioeconomic factors) derived from survey responses and census data. Adjusting for other neighborhood characteristics strengthened protective associations amongst Hispanics, but did not change the significant associations in African American men. These results demonstrate heterogeneity in the associations of race/ethnic composition with mental health and the need for further exploration of which aspects of neighborhood environments may contribute to these associations.http://deepblue.lib.umich.edu/bitstream/2027.42/78333/1/MairDiezRoux2010_SocSciMedicine.pd

Cabbage and fermented vegetables : From death rate heterogeneity in countries to candidates for mitigation strategies of severe COVID-19

Large differences in COVID-19 death rates exist between countries and between regions of the same country. Some very low death rate countries such as Eastern Asia, Central Europe, or the Balkans have a common feature of eating large quantities of fermented foods. Although biases exist when examining ecological studies, fermented vegetables or cabbage have been associated with low death rates in European countries. SARS-CoV-2 binds to its receptor, the angiotensin-converting enzyme 2 (ACE2). As a result of SARS-CoV-2 binding, ACE2 downregulation enhances the angiotensin II receptor type 1 (AT(1)R) axis associated with oxidative stress. This leads to insulin resistance as well as lung and endothelial damage, two severe outcomes of COVID-19. The nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is the most potent antioxidant in humans and can block in particular the AT(1)R axis. Cabbage contains precursors of sulforaphane, the most active natural activator of Nrf2. Fermented vegetables contain many lactobacilli, which are also potent Nrf2 activators. Three examples are: kimchi in Korea, westernized foods, and the slum paradox. It is proposed that fermented cabbage is a proof-of-concept of dietary manipulations that may enhance Nrf2-associated antioxidant effects, helpful in mitigating COVID-19 severity.Peer reviewe

Nrf2-interacting nutrients and COVID-19 : time for research to develop adaptation strategies

There are large between- and within-country variations in COVID-19 death rates. Some very low death rate settings such as Eastern Asia, Central Europe, the Balkans and Africa have a common feature of eating large quantities of fermented foods whose intake is associated with the activation of the Nrf2 (Nuclear factor (erythroid-derived 2)-like 2) anti-oxidant transcription factor. There are many Nrf2-interacting nutrients (berberine, curcumin, epigallocatechin gallate, genistein, quercetin, resveratrol, sulforaphane) that all act similarly to reduce insulin resistance, endothelial damage, lung injury and cytokine storm. They also act on the same mechanisms (mTOR: Mammalian target of rapamycin, PPAR gamma:Peroxisome proliferator-activated receptor, NF kappa B: Nuclear factor kappa B, ERK: Extracellular signal-regulated kinases and eIF2 alpha:Elongation initiation factor 2 alpha). They may as a result be important in mitigating the severity of COVID-19, acting through the endoplasmic reticulum stress or ACE-Angiotensin-II-AT(1)R axis (AT(1)R) pathway. Many Nrf2-interacting nutrients are also interacting with TRPA1 and/or TRPV1. Interestingly, geographical areas with very low COVID-19 mortality are those with the lowest prevalence of obesity (Sub-Saharan Africa and Asia). It is tempting to propose that Nrf2-interacting foods and nutrients can re-balance insulin resistance and have a significant effect on COVID-19 severity. It is therefore possible that the intake of these foods may restore an optimal natural balance for the Nrf2 pathway and may be of interest in the mitigation of COVID-19 severity