Access to Pediatric Type 1 Diabetes Care in Montana

Introduction: Management of Type 1 Diabetes (T1D) requires significant family effort and specialty support. We aimed to understand how living in a rural state impacts families’ experiences during and after diagnosis.https://knowledgeconnection.mainehealth.org/lambrew-retreat-2023/1013/thumbnail.jp

Inflammatory Regulation of CNS Barriers After Traumatic Brain Injury: A Tale Directed by Interleukin-1

Several barriers separate the central nervous system (CNS) from the rest of the body. These barriers are essential for regulating the movement of fluid, ions, molecules, and immune cells into and out of the brain parenchyma. Each CNS barrier is unique and highly dynamic. Endothelial cells, epithelial cells, pericytes, astrocytes, and other cellular constituents each have intricate functions that are essential to sustain the brain’s health. Along with damaging neurons, a traumatic brain injury (TBI) also directly insults the CNS barrier-forming cells. Disruption to the barriers first occurs by physical damage to the cells, called the primary injury. Subsequently, during the secondary injury cascade, a further array of molecular and biochemical changes occurs at the barriers. These changes are focused on rebuilding and remodeling, as well as movement of immune cells and waste into and out of the brain. Secondary injury cascades further damage the CNS barriers. Inflammation is central to healthy remodeling of CNS barriers. However, inflammation, as a secondary pathology, also plays a role in the chronic disruption of the barriers’ functions after TBI. The goal of this paper is to review the different barriers of the brain, including (1) the blood-brain barrier, (2) the blood-cerebrospinal fluid barrier, (3) the meningeal barrier, (4) the blood-retina barrier, and (5) the brain-lesion border. We then detail the changes at these barriers due to both primary and secondary injury following TBI and indicate areas open for future research and discoveries. Finally, we describe the unique function of the pro-inflammatory cytokine interleukin-1 as a central actor in the inflammatory regulation of CNS barrier function and dysfunction after a TBI

Measurement of Endogenous versus Exogenous Formaldehyde-Induced DNA-Protein Crosslinks in Animal Tissues by Stable Isotope Labeling and Ultrasensitive Mass Spectrometry

DNA-protein crosslinks (DPCs) arise from a wide range of endogenous and exogenous chemicals, such as chemotherapeutic drugs and formaldehyde. Importantly, recent identification of aldehydes as endogenous genotoxins in Fanconi anemia has provided new insight into disease causation. Due to their bulky nature, DPCs pose severe threats to genome stability, but previous methods to measure formaldehyde-induced DPCs were incapable of discriminating between endogenous and exogenous sources of chemical. In this study, we developed methods that provide accurate and distinct measurements of both exogenous and endogenous DPCs in a structurally-specific manner. We exposed experimental animals to stable isotope-labeled formaldehyde ([13CD2]-formaldehyde) by inhalation and performed ultrasensitive mass spectrometry to measure endogenous (unlabeled) and exogenous (13CD2-labeled) DPCs. We found that exogenous DPCs readily accumulated in nasal respiratory tissues, but were absent in tissues distant to the site of contact. This observation together with the finding that endogenous formaldehyde-induced DPCs were present in all tissues examined suggests that endogenous DPCs may be responsible for increased risks of bone marrow toxicity and leukemia. Furthermore, the slow rate of DPC repair provided evidence for persistence of DPCs. In conclusion, our method for measuring endogenous and exogenous DPCs presents a new perspective for the potential health risks inflicted by endogenous formaldehyde, and may inform improved disease prevention and treatment strategies

A composition-independent quantitative determination of the water content in silicate glasses and silicate melt inclusions by confocal Raman spectroscopy

A new approach was developed to measure the water content of silicate glasses using Raman spectroscopy, which is independent of the glass matrix composition and structure. Contrary to previous studies, the compositional range of our studied silicate glasses was not restricted to rhyolites, but included andesitic, basaltic and phonolitic glasses. We used 21 glasses with known water contents for calibration. To reduce the uncertainties caused by the baseline removal and correct for the influence of the glass composition on the spectra, we developed the following strategy: (1) application of a frequency-dependent intensity correction of the Raman spectra; (2) normalization of the water peak using the broad T-O and T-O-T vibration band at 850-1250cm−1 wavenumbers (instead of the low wavenumber T-O-T broad band, which appeared to be highly sensitive to the FeO content and the degree of polymerization of the melt); (3) normalization of the integrated Si-O band area by the total number of tetrahedral cations and the position of the band maximum. The calibration line shows a ±0.4wt% uncertainty at one relative standard deviation in the range of 0.8-9.5wt% water and a wide range of natural melt compositions. This method provides a simple, quick, broadly available and cost-effective way for a quantitative determination of the water content of silicate glasses. Application to silicate melt inclusions yielded data in good agreement with SIMS dat

Gut Microbiome Phenotypes Driven by Host Genetics Affect Arsenic Metabolism

Large individual differences in susceptibility to arsenic-induced diseases are well-documented and frequently associated with different patterns of arsenic metabolism. In this context, the role of the gut microbiome in directly metabolizing arsenic and triggering systemic responses in diverse organs raises the possibility that gut microbiome phenotypes affect the spectrum of metabolized arsenic species. However, it remains unclear how host genetics and the gut microbiome interact to affect the biotransformation of arsenic. Using an integrated approach combining 16S rRNA gene sequencing and HPLC-ICP-MS arsenic speciation, we demonstrate that IL-10 gene knockout leads to a significant taxonomic change of the gut microbiome, which in turn substantially affects arsenic metabolism.National Institute of Environmental Health Sciences (P30 ES010126)National Institute of Environmental Health Sciences (NIEHS grant P30 ES002109)University of Georgia. College of Public Health (internal grant)University of Georgia (Faculty Research Grant (FRG)

Gut Microbiome Perturbations Induced by Bacterial Infection Affect Arsenic Biotransformation

Exposure to arsenic affects large human populations worldwide and has been associated with a long list of human diseases, including skin, bladder, lung, and liver cancers, diabetes, and cardiovascular disorders. In addition, there are large individual differences in susceptibility to arsenic-induced diseases, which are frequently associated with different patterns of arsenic metabolism. Several underlying mechanisms, such as genetic polymorphisms and epigenetics, have been proposed, as these factors closely impact the individuals’ capacity to metabolize arsenic. In this context, the role of the gut microbiome in directly metabolizing arsenic and triggering systemic responses in diverse organs raises the possibility that perturbations of the gut microbial communities affect the spectrum of metabolized arsenic species and subsequent toxicological effects. In this study, we used an animal model with an altered gut microbiome induced by bacterial infection, 16S rRNA gene sequencing, and inductively coupled plasma mass spectrometry-based arsenic speciation to examine the effect of gut microbiome perturbations on the biotransformation of arsenic. Metagenomics sequencing revealed that bacterial infection significantly perturbed the gut microbiome composition in C57BL/6 mice, which in turn resulted in altered spectra of arsenic metabolites in urine, with inorganic arsenic species and methylated and thiolated arsenic being perturbed. These data clearly illustrated that gut microbiome phenotypes significantly affected arsenic metabolic reactions, including reduction, methylation, and thiolation. These findings improve our understanding of how infectious diseases and environmental exposure interact and may also provide novel insight regarding the gut microbiome composition as a new risk factor of individual susceptibility to environmental chemicals.National Institute of Environmental Health Sciences (Massachusetts Institute of Technology. Center for Environmental Health Sciences Grant P30 ES002109)National Institute of Environmental Health Sciences (University of North Carolina. Center for Environmental Health and Susceptibility Grant P30 ES010126

Epigenetic Alterations in Liver of C57BL/6J Mice after Short-Term Inhalational Exposure to 1,3-Butadiene

Background1,3-Butadiene (BD) is a high-volume industrial chemical and a known human carcinogen. The main mode of BD carcinogenicity is thought to involve formation of genotoxic epoxides.ObjectivesIn this study we tested the hypothesis that BD may be epigenotoxic (i.e., cause changes in DNA and histone methylation) and explored the possible molecular mechanisms for the epigenetic changes.Methods and ResultsWe administered BD (6.25 and 625 ppm) to C57BL/6J male mice by inhalation for 2 weeks (6 hr/day, 5 days a week) and then examined liver tissue from these mice for signs of toxicity using histopathology and gene expression analyses. We observed no changes in mice exposed to 6.25 ppm BD, but glycogen depletion and dysregulation of hepatotoxicity biomarker genes were observed in mice exposed to 625 ppm BD. We detected N-7-(2,3,4-trihydroxybut-1-yl)guanine (THB-Gua) adducts in liver DNA of exposed mice in a dose-responsive manner, and also observed extensive alterations in the cellular epigenome in the liver, including demethylation of global DNA and repetitive elements and a decrease in histone H3 and H4 lysine methylation. In addition, we observed down-regulation of DNA methyltransferase 1 (Dnmt1) and suppressor of variegation 3–9 homolog 1, a histone lysine methyltransferase (Suv39h1), and up-regulation of the histone demethylase Jumonji domain 2 (Jmjd2a), proteins responsible for the accurate maintenance of the epigenetic marks. Although the epigenetic effects were most pronounced in the 625-ppm exposure group, some effects were evident in mice exposed to 6.25 ppm BD.ConclusionsThis study demonstrates that exposure to BD leads to epigenetic alterations in the liver, which may be important contributors to the mode of BD carcinogenicity

Biomarkers of Exposure and Effect in Human Lymphoblastoid TK6 Cells Following [13C2]-Acetaldehyde Exposure

The dose-response relationship for biomarkers of exposure (N2-ethylidene-dG adducts) and effect (cell survival and micronucleus formation) was determined across 4.5 orders of magnitude (50nM–2mM) using [13C2]-acetaldehyde exposures to human lymphoblastoid TK6 cells for 12h. There was a clear increase in exogenous N 2-ethylidene-dG formation at exposure concentrations ≥ 1µM, whereas the endogenous adducts remained nearly constant across all exposure concentrations, with an average of 3.0 adducts/107 dG. Exogenous adducts were lower than endogenous adducts at concentrations ≤ 10µM and were greater than endogenous adducts at concentrations ≥ 250µM. When the endogenous and exogenous adducts were summed together, statistically significant increases in total adduct formation over the endogenous background occurred at 50µM. Cell survival and micronucleus formation were monitored across the exposure range and statistically significant decreases in cell survival and increases in micronucleus formation occurred at ≥ 1000µM. This research supports the hypothesis that endogenously produced reactive species, including acetaldehyde, are always present and constitute the majority of the observed biological effects following very low exposures to exogenous acetaldehyde. These data can replace default assumptions of linear extrapolation to very low doses of exogenous acetaldehyde for risk prediction

The endogenous exposome

The concept of the Exposome, is a compilation of diseases and one’s lifetime exposure to chemicals, whether the exposure comes from environmental, dietary, or occupational exposures; or endogenous chemicals that are formed from normal metabolism, inflammation, oxidative stress, lipid peroxidation, infections, and other natural metabolic processes such as alteration of the gut microbiome. In this review, we have focused on the Endogenous Exposome, the DNA damage that arises from the production of endogenous electrophilic molecules in our cells. It provides quantitative data on endogenous DNA damage and its relationship to mutagenesis, with emphasis on when exogenous chemical exposures that produce identical DNA adducts to those arising from normal metabolism cause significant increases in total identical DNA adducts. We have utilized stable isotope labeled chemical exposures of animals and cells, so that accurate relationships between endogenous and exogenous exposures can be determined. Advances in mass spectrometry have vastly increased both the sensitivity and accuracy of such studies. Furthermore, we have clear evidence of which sources of exposure drive low dose biology that results in mutations and disease. These data provide much needed information to impact quantitative risk assessments, in the hope of moving towards the use of science, rather than default assumptions