•There is growing concern that increased use of medical and recreational cannabis may result in increased exposure to contaminants on the cannabis, such as pesticides.•We curate the key events at the ...molecular, cellular, and tissue levels that result in developmental neurotoxicity with concomitant prenatal exposure to cannabinoids and organophosphate pesticides.•This adverse outcome pathway underscores the need to elucidate the potential developmental neurotoxicity that may result from prenatal exposure to pesticide-contaminated cannabis.
There is growing concern that increased use of medical and recreational cannabis may result in increased exposure to contaminants on the cannabis, such as pesticides. Several states are moving towards implementing robust regulation of the sales, cultivation, and manufacture of cannabis products. However, there are challenges with creating health-protective regulations in an industry that, to date, has been largely unregulated. The focus of this publication is a theoretical examination of what may happen when women are exposed pre-conceptually or during pregnancy to cannabis contaminated with pesticides. We propose an adverse outcome pathway of concomitant prenatal exposure to cannabinoids and the organophosphate pesticide chlorpyrifos by curating what we consider to be the key events at the molecular, cellular, and tissue levels that result in developmental neurotoxicity. The implications of this adverse outcome pathway underscore the need to elucidate the potential developmental neurotoxicity that may result from prenatal exposure to pesticide-contaminated cannabis.
Increasing prevalence of methicillin-resistant Staphylococcus aureus (MRSA) worldwide with limited therapeutic options is a growing public health concern. Natural products have been shown to possess ...antibacterial actions against MRSA. Flavonoids from natural products have been shown to possess antibacterial actions against MRSA by antagonizing its resistance mechanisms. Diosmin and diosmetin are natural flavonoids found in a variety of citrus fruits. The aim of this study was to investigate whether diosmin and diosmetin could inhibit the growth of MRSA and the in vitro enzymatic activity of a newly discovered MRSA drug target, pyruvate kinase (PK). By using a panel of MRSA strains with known resistant mechanisms, neither diosmin nor diosmetin was shown to possess direct antibacterial activities against all tested MRSA strains. However, in checkerboard assay, we found that diosmetin together with erythromycin, could synergistically inhibit the growth of ABC-pump overexpressed MRSA-RN4220/pUL5054, and time kill assay also showed that the antibacterial activities of diosmetin with erythromycin were bactericidal. Diosmetin was further shown to significantly suppress the MRSA PK activities in a dose dependent manner. In conclusion, the inhibition of MRSA PK by diosmetin could lead to a deficiency of ATP and affect the bacterial efflux pump which might contribute to the antibacterial actions of diosmetin against MRSA.
Plasma cells (PC) are found in the CNS of multiple sclerosis (MS) patients, yet their source and role in MS remains unclear. We find that some PC in the CNS of mice with experimental autoimmune ...encephalomyelitis (EAE) originate in the gut and produce immunoglobulin A (IgA). Moreover, we show that IgA+ PC are dramatically reduced in the gut during EAE, and likewise, a reduction in IgA-bound fecal bacteria is seen in MS patients during disease relapse. Removal of plasmablast (PB) plus PC resulted in exacerbated EAE that was normalized by the introduction of gut-derived IgA+ PC. Furthermore, mice with an over-abundance of IgA+ PB and/or PC were specifically resistant to the effector stage of EAE, and expression of interleukin (IL)-10 by PB plus PC was necessary and sufficient to confer resistance. Our data show that IgA+ PB and/or PC mobilized from the gut play an unexpected role in suppressing neuroinflammation.
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•Gut-derived IgA+ plasma cells (PC) access extra-intestinal tissues in the steady state•Gut-derived IgA+ PC access the CNS during EAE and attenuate disease•IgA+ PC attenuate EAE in an IL-10-dependent manner•An IgA-promoting protist and BAFF overexpression both confer resistance to EAE
Immune cells can travel from the gut to the brain to suppress neuroinflammation in a mouse model of multiple sclerosis.
Objective Pre‐eclampsia involves a maternal inflammatory response that differs from both normal pregnancy and normotensive intrauterine growth restriction (IUGR). Our objective was to examine ...neutrophil Toll‐like receptor (TLR), cryopyrin, nuclear factor‐κB (NF‐κB) subunit and interleukin‐1β (IL‐1β), and inflammatory cytokine profiles in women with pre‐eclampsia or normotensive IUGR, as well as in normal pregnancy and non‐pregnancy controls.
Design and method A case–control study was performed. We examined the messenger RNA (mRNA) and protein expressions of TLR4 and TLR2, mRNA levels of cryopyrin, IL‐1β, NF‐κB subunits p50 and p65, as well as maternal serum inflammatory cytokine profiles (IL‐2, IL‐6, tumour necrosis factor‐α TNF‐α, interferon‐γ IFN‐γ and IL‐10) in women with and without pre‐eclampsia using real‐time reverse transcription polymerase chain reactions, flow cytometry and multiplex immunoassays.
Setting A single tertiary maternity hospital in Vancouver, Canada.
Population Women with early‐onset pre‐eclampsia (<34 weeks of gestation, n = 25), women with late‐onset pre‐eclampsia (≥34+0 weeks of gestation, n = 25), women with normotensive IUGR (n = 25), women with normal pregnancy (n = 75) and non‐pregnancy (n = 25) controls.
Results Women with pre‐eclampsia (as a single combined group of early‐ and late‐onset, and particularly in women with early‐onset pre‐eclampsia) had increased TLR2 and TLR4 mRNA and protein expressions elevated cryopyrin, NF‐κB subunit, and IL‐1β mRNA expression, and TNF‐α:IL‐10 and IL‐6:IL‐10 ratios compared with other groups.
Conclusions These data suggest that TLRs and cryopyrin may modulate the innate immune response of the maternal syndrome of pre‐eclampsia, and might also trigger the differential inflammatory response existing between early onset pre‐eclampsia and normotensive IUGR.
Clonal proliferation in myeloproliferative neoplasms (MPN) is driven by somatic mutations in JAK2, CALR or MPL, but the contribution of inherited factors is poorly characterized. Using a three-stage ...genome-wide association study of 3,437 MPN cases and 10,083 controls, we identify two SNPs with genome-wide significance in JAK2(V617F)-negative MPN: rs12339666 (JAK2; meta-analysis P=1.27 × 10(-10)) and rs2201862 (MECOM; meta-analysis P=1.96 × 10(-9)). Two additional SNPs, rs2736100 (TERT) and rs9376092 (HBS1L/MYB), achieve genome-wide significance when including JAK2(V617F)-positive cases. rs9376092 has a stronger effect in JAK2(V617F)-negative cases with CALR and/or MPL mutations (Breslow-Day P=4.5 × 10(-7)), whereas in JAK2(V617F)-positive cases rs9376092 associates with essential thrombocythemia (ET) rather than polycythemia vera (allelic χ(2) P=7.3 × 10(-7)). Reduced MYB expression, previously linked to development of an ET-like disease in model systems, associates with rs9376092 in normal myeloid cells. These findings demonstrate that multiple germline variants predispose to MPN and link constitutional differences in MYB expression to disease phenotype.
ABSTRACT
We define a new morphology metric called ‘patchiness’ (P) that is sensitive to deviations from the average of a resolved distribution, does not require the galaxy centre to be defined, and ...can be used on the spatially resolved distribution of any galaxy property. While the patchiness metric has a broad range of applications, we demonstrate its utility by investigating the distribution of dust in the interstellar medium (ISM) of 310 star-forming galaxies at spectroscopic redshifts 1.36 < z < 2.66 observed by the MOSFIRE Deep Evolution Field survey. The stellar continuum reddening distribution, derived from high-resolution multiwaveband CANDELS/3D-HST imaging, is quantified using the patchiness, Gini, and M20 coefficients. We find that the reddening maps of high-mass galaxies, which are dustier and more metal-rich on average, tend to exhibit patchier distributions (high P) with the reddest components concentrated within a single region (low M20). Our results support a picture where dust is uniformly distributed in low-mass galaxies (≲1010 M⊙), implying efficient mixing of dust throughout the ISM. On the other hand, the dust distribution is patchier in high-mass galaxies (≳1010 M⊙). Dust is concentrated near regions of active star formation and dust mixing time-scales are expected to be longer in high-mass galaxies, such that the outskirt regions of these physically larger galaxies remain relatively unenriched. This study presents direct evidence for patchy dust distributions on scales of a few kpc in high-redshift galaxies, which previously has only been suggested as a possible explanation for the observed differences between nebular and stellar continuum reddening, star formation rate indicators, and dust attenuation curves.
MEK1 and MEK2 are closely related, dual-specificity tyrosine/threonine protein kinases found in the Ras/Raf/MEK/ERK mitogen-activated protein kinase (MAPK) signaling pathway. Approximately 30% of all ...human cancers have a constitutively activated MAPK pathway, and constitutive activation of MEK1 results in cellular transformation. Here we present the X-ray structures of human MEK1 and MEK2, each determined as a ternary complex with MgATP and an inhibitor to a resolution of 2.4 A and 3.2 A, respectively. The structures reveal that MEK1 and MEK2 each have a unique inhibitor-binding pocket adjacent to the MgATP-binding site. The presence of the potent inhibitor induces several conformational changes in the unphosphorylated MEK1 and MEK2 enzymes that lock them into a closed but catalytically inactive species. Thus, the structures reported here reveal a novel, noncompetitive mechanism for protein kinase inhibition.
Caring for people with disabilities often becomes an all-encompassing responsibility for one or more family members. To manage the multifaceted demands, caregivers must possess strong multitasking ...skills, including the ability to assist with daily life tasks; provide emotional support; help with financial affairs; mediate and advocate with health care providers. Maintaining balance within their own lives can become incredibly challenging for caregivers. More often than not, providing care for family members or loved ones occurs at the expense of the caregivers well-being. And for caregivers who themselves have disabilities, it further complicates matters.Multiple Dimensions of Caregiving and Disability addresses concerns that have been long familiar to the caregiver population and examines the current state of family care for individuals with disabilities. With a lifespan perspective, this concise reference reviews the literature on specific problems of caregivers and explores which care strategies are effective, promising, or lacking in available resources and support interventions. Contributors also explore the more fluid and subjective aspects of caregiving, such as feelings, spirituality, and family roles. Suggestions for future policy improvements, particularly within the public health sector, are discussed as well.Topics covered include: Family dynamics and caregiving for people with disabilities. Parent caregiving of children with disabilities. Race, ethnicity, socioeconomic status, and caregiving. Educational, training, and support programs for caregivers. Emerging technologies to aid caregivers. Developing partnerships between caregivers and health care providers. Multiple Dimensions of Caregiving and Disability is a must-have resource for researchers, scientist-practitioners, policy makers, and graduate students across such disciplines as clinical psychology, nursing, social work, public health, medicine, and social and education policy.
Summary Background We sought to improve outcome in patients with childhood acute myeloid leukaemia (AML) by applying risk-directed therapy that was based on genetic abnormalities of the leukaemic ...cells and measurements of minimal residual disease (MRD) done by flow cytometry during treatment. Methods From Oct 13, 2002, to June 19, 2008, 232 patients with de-novo AML (n=206), therapy-related or myelodysplasia-related AML (n=12), or mixed-lineage leukaemia (n=14) were enrolled at eight centres. 230 patients were assigned by block, non-blinded randomisation, stratified by cytogenetic or morphological subtype, to high-dose (18 g/m2 , n=113) or low-dose (2 g/m2 , n=117) cytarabine given with daunorubicin and etoposide (ADE; induction 1). The primary aim of the study was to compare the incidence of MRD positivity of the high-dose group and the low-dose group at day 22 of induction 1. Induction 2 consisted of ADE with or without gemtuzumab ozogamicin (GO anti-CD33 monoclonal antibody); consolidation therapy included three additional courses of chemotherapy or haematopoietic stem-cell transplantation (HSCT). Levels of MRD were used to allocate GO and to determine the timing of induction 2. Both MRD and genetic abnormalities at diagnosis were used to determine the final risk classification. Low-risk patients (n=68) received five courses of chemotherapy, whereas high-risk patients (n=79), and standard-risk patients (n=69) with matched sibling donors, were eligible for HSCT (done for 48 high-risk and eight standard-risk patients). All 230 randomised patients were analysed for the primary endpoint. Other analyses were limited to the 216 patients with AML, excluding those with mixed-lineage leukaemia. This trial is closed to accrual and is registered with ClinicalTrials.gov , number NCT00136084. Findings Complete remission was achieved in 80% (173 of 216 patients) after induction 1 and 94% (203 of 216) after induction 2. Induction failures included two deaths from toxic effects and ten cases of resistant leukaemia. The introduction of high-dose versus low-dose cytarabine did not significantly lower the rate of MRD-positivity after induction 1 (34% vs 42%, p=0·17). The 6-month cumulative incidence of grade 3 or higher infection was 79·3% (SE 4·0) for patients in the high-dose group and 75·5% (4·2) for the low-dose group. 3-year event-free survival and overall survival were 63·0% (SE 4·1) and 71·1% (3·8), respectively. 80% (155 of 193) of patients achieved MRD of less than 0·1% after induction 2, and the cumulative incidence of relapse for this group was 17% (SE 3). MRD of 1% or higher after induction 1 was the only significant independent adverse prognostic factor for both event-free (hazard ratio 2·41, 95% CI 1·36–4·26; p=0·003) and overall survival (2·11, 1·09–4·11; p=0·028). Interpretation Our findings suggest that the use of targeted chemotherapy and HSCT, in the context of a comprehensive risk-stratification strategy based on genetic features and MRD findings, can improve outcome in patients with childhood AML. Funding National Institutes of Health and American Lebanese Syrian Associated Charities (ALSAC).
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