Aflatoxins are well recognized as a cause of liver cancer, but they have additional important toxic effects. In farm and laboratory animals, chronic exposure to aflatoxins compromises immunity and ...interferes with protein metabolism and multiple micronutrients that are critical to health. These effects have not been widely studied in humans, but the available information indicates that at least some of the effects observed in animals also occur in humans. The prevalence and level of human exposure to aflatoxins on a global scale have been reviewed, and the resulting conclusion was that approximately 4.5 billion persons living in developing countries are chronically exposed to largely uncontrolled amounts of the toxin. A limited amount of information shows that, at least in those locations where it has been studied, the existing aflatoxin exposure results in changes in nutrition and immunity. The aflatoxin exposure and the toxic affects of aflatoxins on immunity and nutrition combine to negatively affect health factors (including HIV infection) that account for >40% of the burden of disease in developing countries where a short lifespan is prevalent. Food systems and economics render developed-country approaches to the management of aflatoxins impractical in developing-country settings, but the strategy of using food additives to protect farm animals from the toxin may also provide effective and economical new approaches to protecting human populations.
Abstract
Background
The objective of this review was to merge current treatment guidelines and best practice recommendations for management of neuropathic pain into a comprehensive algorithm for ...primary physicians. The algorithm covers assessment, multidisciplinary conservative care, nonopioid pharmacological management, interventional therapies, neurostimulation, low-dose opioid treatment, and targeted drug delivery therapy.
Methods
Available literature was identified through a search of the US National Library of Medicine’s Medline database, PubMed.gov. References from identified published articles also were reviewed for relevant citations.
Results
The algorithm provides a comprehensive treatment pathway from assessment to the provision of first- through sixth-line therapies for primary care physicians. Clear indicators for progression of therapy from firstline to sixth-line are provided. Multidisciplinary conservative care and nonopioid medications (tricyclic antidepressants, serotonin norepinephrine reuptake inhibitors, gabapentanoids, topicals, and transdermal substances) are recommended as firstline therapy; combination therapy (firstline medications) and tramadol and tapentadol are recommended as secondline; serotonin-specific reuptake inhibitors/anticonvulsants/NMDA antagonists and interventional therapies as third-line; neurostimulation as a fourth-line treatment; low-dose opioids (no greater than 90 morphine equivalent units) are fifth-line; and finally, targeted drug delivery is the last-line therapy for patients with refractory pain.
Conclusions
The presented treatment algorithm provides clear-cut tools for the assessment and treatment of neuropathic pain based on international guidelines, published data, and best practice recommendations. It defines the benefits and limitations of the current treatments at our disposal. Additionally, it provides an easy-to-follow visual guide of the recommended steps in the algorithm for primary care and family practitioners to utilize.
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•Cancer cell invasion through organotypic multi-ECM environments shows diverse modes.•In our model, invasion modes are indolent, dispersed, collective and multimodal.•ECM adhesion and ...remodeling establishes such modes and allows intermodal transitions.
The metastasis of malignant epithelial tumors begins with the egress of transformed cells from the confines of their basement membrane (BM) to their surrounding collagen-rich stroma. Invasion can be morphologically diverse: when breast cancer cells are separately cultured within BM-like matrix, collagen I (Coll I), or a combination of both, they exhibit collective-, dispersed mesenchymal-, and a mixed collective-dispersed (multimodal)- invasion, respectively. In this paper, we asked how distinct these invasive modes are with respect to the cellular and microenvironmental cues that drive them. A rigorous computational exploration of invasion was performed within an experimentally motivated Cellular Potts-based modeling environment. The model comprised of adhesive interactions between cancer cells, BM- and Coll I-like extracellular matrix (ECM), and reaction–diffusion-based remodeling of ECM. The model outputs were parameters cognate to dispersed- and collective- invasion. A clustering analysis of the output distribution curated through a careful examination of subsumed phenotypes suggested at least four distinct invasive states: dispersed, papillary-collective, bulk-collective, and multimodal, in addition to an indolent/non-invasive state. Mapping input values to specific output clusters suggested that each of these invasive states are specified by distinct input signatures of proliferation, adhesion and ECM remodeling. In addition, specific input perturbations allowed transitions between the clusters and revealed the variation in the robustness between the invasive states. Our systems-level approach proffers quantitative insights into how the diversity in ECM microenvironments may steer invasion into diverse phenotypic modes during early dissemination of breast cancer and contributes to tumor heterogeneity.
Argonaute proteins repress gene expression and defend against foreign nucleic acids using short RNAs or DNAs to specify the correct target RNA or DNA sequence. We have developed single-molecule ...methods to analyze target binding and cleavage mediated by the Argonaute:guide complex, RISC. We find that both eukaryotic and prokaryotic Argonaute proteins reshape the fundamental properties of RNA:RNA, RNA:DNA, and DNA:DNA hybridization—a small RNA or DNA bound to Argonaute as a guide no longer follows the well-established rules by which oligonucleotides find, bind, and dissociate from complementary nucleic acid sequences. Argonautes distinguish substrates from targets with similar complementarity. Mouse AGO2, for example, binds tighter to miRNA targets than its RNAi cleavage product, even though the cleaved product contains more base pairs. By re-writing the rules for nucleic acid hybridization, Argonautes allow oligonucleotides to serve as specificity determinants with thermodynamic and kinetic properties more typical of RNA-binding proteins than of RNA or DNA.
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•Argonaute changes the rate of target finding by pre-organizing a region of its guide•Seed pairing is required for rapid target finding and stable binding•AGO2 releases its cleaved products by destabilizing their interaction with the guide•RISC makes its guide behave more like an RNA-binding protein and less like free RNA
Argonaute proteins reshape how oligonucleotides find, bind, and dissociate from complementary nucleic acid sequences. By re-writing the rules, Argonautes allow oligonucleotides to serve as specificity determinants with thermodynamic and kinetic properties more typical of RNA-binding proteins.
Argonaute proteins loaded with microRNAs (miRNAs) or small interfering RNAs (siRNAs) form the RNA-induced silencing complex (RISC), which represses target RNA expression. Predicting the biological ...targets, specificity, and efficiency of both miRNAs and siRNAs has been hamstrung by an incomplete understanding of the sequence determinants of RISC binding and cleavage. We applied high-throughput methods to measure the association kinetics, equilibrium binding energies, and single-turnover cleavage rates of mouse AGO2 RISC. We find that RISC readily tolerates insertions of up to 7 nt in its target opposite the central region of the guide. Our data uncover specific guide:target mismatches that enhance the rate of target cleavage, suggesting novel siRNA design strategies. Using these data, we derive quantitative models for RISC binding and target cleavage and show that our in vitro measurements and models predict knockdown in an engineered cellular system.
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•Binding energies, association, and cleavage rates measured for >40,000 RISC targets•AGO2 tolerates large insertions in the target opposite the central region of the guide•Some guide:target mismatches enhance the single-turnover RISC cleavage rate•In vitro measured biochemical parameters explain knockdown in cells
By high-throughput, quantitative characterization of binding and cleavage for >40,000 distinct RISC targets, Becker et al. reveal principles of miRNA regulation and siRNA function. These data enable construction of quantitative models of binding and cleavage and are used to explain mRNA knockdown in cells.
Comparison of health related quality of life (HRQOL) of patients with systemic lupus erythematosus (SLE) with other common chronic illnesses.
Responses from self-administered Medical Outcomes Study ...Short Form-36 (SF-36) questionnaires from 90 patients with SLE, recorded in the lupus database at the University of Chicago Hospital, were analyzed. Comparative norms and domain scores for patients with other chronic diseases hypertension, congestive heart failure (CHF), adult onset diabetes mellitus, myocardial infarction, and depression were used and are based on the general US population. T tests were used to make comparisons.
Patients with SLE were younger than patients with most reference chronic conditions except for depression. Their Physical Component Scores and Mental Component Scores were 30 +/- 10.5 and 45.1 +/- 11, respectively. SLE patients fared significantly worse than age matched norms from the general US population for women (p = 0.0001) in all 8 domains. Their quality of life was significantly worse than for those with hypertension, diabetes, or myocardial infarction in all domains (p < 0.004). Patients with CHF were no worse than those with SLE in regard to physical function, role-physical, role-emotional, and vitality. CHF patients fared significantly better in mental health, bodily pain, social functioning, and general health, compared to patients with SLE. Patients with depression were significantly impaired in role-emotional and mental health domains (p = 0.0001) compared to SLE patients, but were no worse (role-physical, vitality, and social functioning) and even better (physical function, bodily pain, and general health) in some. General health of SLE patients was significantly lower than all comparative groups.
HRQOL of patients with SLE seems to be significantly worse and affects all health domains at an earlier age in comparison to patients with some other common chronic diseases.
Recent climatic changes have enhanced plant growth in northern mid-latitudes and high latitudes. However, a comprehensive analysis of the impact of global climatic changes on vegetation productivity ...has not before been expressed in the context of variable limiting factors to plant growth. We present a global investigation of vegetation responses to climatic changes by analyzing 18 years (1982 to 1999) of both climatic data and satellite observations of vegetation activity. Our results indicate that global changes in climate have eased several critical climatic constraints to plant growth, such that net primary production increased 6% (3.4 petagrams of carbon over 18 years) globally. The largest increase was in tropical ecosystems. Amazon rain forests accounted for 42% of the global increase in net primary production, owing mainly to decreased cloud cover and the resulting increase in solar radiation.
Describes the morphological features of a coccidia species from the endangered South Island takahē. Source: National Library of New Zealand Te Puna Matauranga o Aotearoa, licensed by the Department ...of Internal Affairs for re-use under the Creative Commons Attribution 3.0 New Zealand Licence.
As complete absence of germ cells leads to sterile males in zebrafish, we explored the relationship between primordial germ cell (PGC) number and sexual development. Our results revealed dimorphic ...proliferation of PGCs in the early zebrafish larvae, marking the beginning of sexual differentiation. We applied morpholino-based gene knockdown and cell transplantation strategies to demonstrate that a threshold number of PGCs is required for the stability of ovarian fate. Using histology and transcriptomic analyses, we determined that zebrafish gonads are in a meiotic ovarian stage at 14 days postfertilization and identified signaling pathways supporting meiotic oocyte differentiation and eventual female fate. The development of PGC-depleted gonads appears to be restrained and delayed, suggesting that PGC number may directly regulate the variability and length of gonadal transformation and testicular differentiation in zebrafish. We propose that gonadal transformation may function as a developmental buffering mechanism to ensure the reproductive outcome.
Objectives
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that leads to a variety of negative health outcomes resulting from inflammation in various organ systems. Although ...treatment continues to advance, fatigue remains one of the most salient, poorly understood and addressed patient complaints. Understanding the mechanisms of fatigue can help guide the development of interventions to improve health outcomes. The aim of this research was to evaluate the contribution of six variables (disease activity, insomnia, depression, stress, pain and physical health) to fatigue in SLE without concomitant fibromyalgia (FM).
Methods
A total of 116 ethnically diverse, primarily female participants (91%) with SLE, receiving care at university medical centers, completed assessments of disease activity and quality of life outcomes (FACIT-FT, Insomnia Severity Index, Perceived Stress Scale (PSS-4), Pain Inventory, Depression-PHQ-9, and LupusPRO-physical function). All patients met the American College of Rheumatology classification criteria for SLE and did not have a known diagnosis of FM. Multivariate linear and stepwise regression analyses were conducted with fatigue (FACIT-FT) as the dependent variable, and the above six variables as independent variables.
Results
Mean (SD) age was 39.80 (13.87) years; 50% were African American, 21% Caucasian, 13% Hispanic, 9% Asian and 8% other. Mean (SD) FACIT-FT was 20.09 (12.76). Collectively, these six variables explained 57% of the variance in fatigue. In the multivariate model, depression, stress and pain were significantly and independently associated with fatigue, but not disease activity, sleep or physical health. Stress had the largest effect on fatigue (β 0.77, 95% CI 0.17–1.38, p = 0.01), followed by depression (β 0.66, 95% CI 0.21–1.10, p = 0.005). On stepwise regression analysis, only stress, depression and pain were retained in the model, and collectively explained 56% of the variance in fatigue. All three remained independent correlates of fatigue, with the largest contribution being stress (β 0.84, 95% CI 0.27–1.42, p = 0.005), followed by depression (β 0.79, 95% CI 0.44–1.14, p < 0.001) with fatigue.
Conclusion
Stress, depression and pain are the largest independent contributors to fatigue among patients with SLE, without concurrent FM. Disease activity, sleep and physical health were not associated with fatigue. The evaluation of stress, depression and pain needs to be incorporated during assessments and clinical trials of individuals with SLE, especially within fatigue. This stress-depression-fatigue model requires further validation in longitudinal studies and clinical trials.
Significance and innovation:
• Disease activity, sleep, pain, stress, depression, and physical health have been reported individually to be associated with fatigue in lupus. This analysis evaluated the role of each and all of these six variables collectively in fatigue among patients with SLE without a known diagnosis of FM.
• Disease activity, sleep and physical health were not significantly related to fatigue, but depression, stress and pain were.
• The results emphasize the need to evaluate and treat fatigue in individuals with SLE utilizing a biopsychosocial approach, particularly in the realm of clinical trials. Behavioral medicine interventions are shown to be most effective for the treatment of depression, stress and pain.
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