Chronic Alcohol Intake Compromises Lung Immunity by Altering Immunometabolism in Humans and Mouse Models.

Chronic alcohol consumption disrupts lung immunity and host defense mechanisms, rendering individuals with alcohol use disorder more susceptible to developing inflammatory lung conditions with poor prognoses. Here, we focused on investigating the molecular and cellular effects of alcohol ingestion on lung immunity in male and female subjects using population-based human lung transcriptomics analysis and an experimental mouse model of chronic alcohol drinking using the NIAAA alcohol feeding model. Flow cytometry and transcriptomics analyses in lungs revealed a sexually dimorphic effect of chronic alcohol drinking on lung immunity of both human and mouse. The male lungs were more sensitive to chronic alcohol drinking-induced dysregulation of lung immunity compared to the females. Furthermore, comparative transcriptomics analysis using lungs and liver samples from matched human and mouse subjects exhibited that lungs were more sensitive than the liver to the effects of alcohol in down-regulating immune-related genes and pathways. Furthermore, the transcriptomics analysis provided evidence that immunometabolic change is a central driver in lung alteration by downregulating the immune pathways and upregulating metabolic pathways. Chronic alcohol consumption resulted in reduced mTOR signaling and decreased immune cell populations. mTOR signaling axis may serve as an upstream regulator of alcohol-induced dysregulation in lung immunity.

Lactational transfer of sulforaphane-N-acetylcysteine in vivo and in human breast milk.

Sulforaphane (SFN) is a bioactive phytonutrient found in cruciferous vegetables. There is a lack of detailed information on the lactational transfer of SFN and SFN metabolites, and potential pharmacological effects on breastfeeding infants. We carried out two maternal supplementation studies in a mouse model, wherein lactating dams received either vehicle, 300 or 600 ppm SFN from postnatal day (PND) 1 to 5, or in a second experiment, vehicle or 600 ppm SFN from PND 1 to 14. The parent compound was only detectable in milk and plasma from dams receiving 600 ppm SFN for five days. The predominant metabolite SFN-N-acetylcysteine (SFN-NAC) was readily detected in milk from dams receiving 300 and 600 ppm SFN for five days or 600 ppm for 14 days. Maternal SFN-NAC plasma levels were elevated in both 600 ppm groups. Maternal hepatic and pulmonary expression of NRF2-related genes, Nqo1, Gsta2, Gstm1, and Gstp1, were significantly increased, generally following a dose-response; however, offspring induction varied. PND5 neonates in the 600-ppm group exhibited significantly elevated expression of Nqo1, Gsta2, and Gstp1 in liver, and Gstm1 and Gstp1 in lung. Findings support maternal dietary supplementation with SFN induces NRF2-related gene expression in neonates via lactational transfer of SFN-NAC. However, NQO1 enzyme activity was not significantly elevated, highlighting the need to optimize dosing strategy. Additionally, in a pilot investigation of lactating women consuming a typical diet, without any purified SFN supplementation, 7 out of 8 breast milk samples showed SFN-NAC above the limit of quantification (LOQ). Notably, the one sample below the LOQ was collected from the only participant who reported no consumption of cruciferous vegetables in the past 24 h. The parent compound was not detected in any of the human breast milk samples. Overall, these data indicate lactational transfer of SFN-NAC at dietary relevant levels. Future studies are needed to evaluate pharmacokinetics and pharmacodynamics of lactational transfer for potential preventive or therapeutic effects in breastfeeding children.

Face-to-face bullying in and outside of schools and cyberbullying are associated with suicidality in Kenyan high school students: a public health issue.

BACKGROUND: Childhood bullying has been classified as a major public health concern by WHO, with negative effects on the health education and social outcomes of both bullies and victims. There is no current Kenyan data on the prevalence of face-to-face bullying and cyberbullying co-occurring in the same cohort of youth and how they are associated with different aspects of suicidality and socio-demographic characteristics. This study aims to fill these gaps in the Kenyan situation so as to inform current policy and practice. METHODOLOGY: This cross-sectional study involved 2,652 students from ten secondary schools in Kenya, selected from three regions representing different levels of public funded schools and socioeconomic spaces. The outcome variable was derived from the questionnaire which asked students questions related to self-harm, suicide thoughts, plans, and attempts. Predictor variables were based on response on experience of bullying in school, out of school, at home, and cyberbullying. Other variables such as gender, age, family background, and class were also collected from the self-reported questions. Data were analyzed using SPSS version 25, with descriptive summary statistics and chi-square tests used to examine variables, and logistic regression analysis used to determine the associations between suicidality and experience of bullying. RESULTS: The mean age was 16.13 years. More than half of the participants were male, with the largest proportion living in rural areas. Face-to-face bullying was more prevalent than cyberbullying, with 82% of participants experiencing bullying and 68% experiencing it almost daily in the past six months. Both face-to-face bullying and cyberbullying were associated with suicidal thoughts, plans, and attempts. Predictors of suicidal attempts included being bullied outside of school and being a victim of group bullying, while being bullied every day and being bullied by adult men were predictors of suicidal attempts in cyberbullying. CONCLUSION: There is a high prevalence of face-to-face bullying both in and outside schools. There is also a high prevalence of cyberbullying. Both face-to-face and cyberbullying are associated with suicidality in Kenyan high school students.

The perceived impact of climate change on mental health and suicidality in Kenyan high school students.

BACKGROUND: Climate change has psychological impacts but most of the attention has been focused on the physical impact. This study was aimed at determining the association of climate change with adolescent mental health and suicidality as reported by Kenyan high school students. METHODS: This was a cross sectional study with a sample size of 2,652. The participants were high school students selected from 10 schools in 3 regions of Kenya. A questionnaire was used to assess climate change experiences, mental health problems, and suicidality of the youth. Data were analyzed descriptively and with logistic regression to determine various associations of the different variables and the predictors of the various scores of SDQ and suicidality at 95% CI. RESULTS: Significant differences were observed between gender and two of the threats of climate change - worry and being afraid as subjectively experienced by the participants. Females were more worried and afraid of climate change than males. On univariate and multivariate logistic regression, we found that various experiences of climate change were significantly associated with various scores of SDQ and much fewer of the experiences predicted SDQ scores. The same pattern was reflected in suicidality. CONCLUSION: Climate change appears to be associated with mental health concerns and suicidality according to Kenyan high school students' reports with gender differences in some associations.

The development of sniffing.

Sniffing is a commonly displayed behavior in rodents, yet how this important behavior adjusts throughout development to meet the sensory demands of the animals has remained largely unexplored. In this issue of Chemical Senses, Boulanger-Bertolus et al. investigates the ontogeny of odor-evoked sniffing through a longitudinal study of rats engaged in several olfactory paradigms from infancy to adulthood. The results of this study yield a cohesive picture of sniffing behavior across three developmental stages, while also providing direct comparisons within subjects between these timepoints. As we discuss herein, these results advance the field in relation to existing literature on the development of odor-evoked sniffing behavior in several important ways.

Maternal exposure to ultrafine particles enhances influenza infection during pregnancy.

BACKGROUND: Interactions between air pollution and infectious agents are increasingly recognized and critical to identify, especially to protect vulnerable populations. Pregnancy represents a vulnerable period for influenza infection and air pollution exposure, yet interactions during pregnancy remain unclear. Maternal exposure to ultrafine particles (UFPs, [Formula: see text] 100 nm diameter), a class of particulate matter ubiquitous in urban environments, elicits unique pulmonary immune responses. We hypothesized that UFP exposure during pregnancy would lead to aberrant immune responses to influenza enhancing infection severity. RESULTS: Building from our well-characterized C57Bl/6N mouse model employing daily gestational UFP exposure from gestational day (GD) 0.5-13.5, we carried out a pilot study wherein pregnant dams were subsequently infected with Influenza A/Puerto Rico/8/1934 (PR8) on GD14.5. Findings indicate that PR8 infection caused decreased weight gain in filtered air (FA) and UFP-exposed groups. Co-exposure to UFPs and viral infection led to pronounced elevation in PR8 viral titer and reduced pulmonary inflammation, signifying potential suppression of innate and adaptive immune defenses. Pulmonary expression of the pro-viral factor sphingosine kinase 1 (Sphk1) and pro-inflammatory cytokine interleukin-1ß (IL-1 [Formula: see text]) was significantly increased in pregnant mice exposed to UFPs and infected with PR8; expression correlated with higher viral titer. CONCLUSIONS: Results from our model provide initial insight into how maternal UFP exposure during pregnancy enhances respiratory viral infection risk. This model is an important first step in establishing future regulatory and clinical strategies for protecting pregnant women exposed to UFPs.

Costs and cost-effectiveness of Shamiri, a brief, layperson-delivered intervention for Kenyan adolescents: a randomized controlled trial.

BACKGROUND: Low- and middle-income countries (LMICs) have the highest socio-economic burden of mental health disorders, yet the fewest resources for treatment. Recently, many intervention strategies, including the use of brief, scalable interventions, have emerged as ways of reducing the mental health treatment gap in LMICs. But how do decision makers prioritize and optimize the allocation of limited resources? One approach is through the evaluation of delivery costs alongside intervention effectiveness of various types of interventions. Here, we evaluate the cost-effectiveness of Shamiri, a group- and school-based intervention for adolescent depression and anxiety that is delivered by lay providers and that teaches growth mindset, gratitude, and value affirmation. METHODS: We estimated the cost-effectiveness of Shamiri using the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) guidelines for economic evaluations. Changes in depression and anxiety were estimated using the Patient Health Questionnaire (PHQ-8) and Generalized Anxiety Disorder questionnaire (GAD-7) at treatment termination and 7-month follow-up using two definitions of treatment benefit. Cost-effectiveness metrics included effectiveness-cost ratios and cost per number needed to treat. RESULTS: Base case cost assumptions estimated that delivering Shamiri cost $15.17 (in 2021 U.S. dollars) per student. A sensitivity analysis, which varied cost and clinical change definitions, estimated it cost between $48.28 and $172.72 to help 1 student in Shamiri, relative to the control, achieve reliable and clinically significant change in depression and anxiety by 7-month follow-up. CONCLUSIONS: Shamiri appears to be a low-cost intervention that can produce clinically meaningful reductions in depression and anxiety. Lay providers can deliver effective treatment for a fraction of the training time that is required to become a licensed mental health provider (10 days vs. multiple years), which is a strength from an economic perspective. Additionally, Shamiri produced reliable and clinically significant reductions in depression and anxiety after only four weekly sessions instead of the traditional 12-16 weekly sessions necessary for gold-standard cognitive behavioral therapy. The school setting, group format, and economic context of a LMIC influenced the cost per student; however, broader conclusions about the cost-effectiveness of Shamiri have yet to be determined due to limited economic evaluations of mental health programs in LMICs. TRIAL REGISTRATION: This study was registered prior to participant enrollment in the Pan-African Clinical Trials Registry (PACTR201906525818462), registered 20 Jun 2019, https://pactr.samrc.ac.za/Search.aspx .

Opioid-Induced Reductions in Amygdala Lateral Paracapsular GABA Neuron Circuit Activity.

Opioid use and withdrawal evokes behavioral adaptations such as drug seeking and anxiety, though the underlying neurocircuitry changes are unknown. The basolateral amygdala (BLA) regulates these behaviors through principal neuron activation. Excitatory BLA pyramidal neuron activity is controlled by feedforward inhibition provided, in part, by lateral paracapsular (LPC) GABAergic inhibitory neurons, residing along the BLA/external capsule border. LPC neurons express µ-opioid receptors (MORs) and are potential targets of opioids in the etiology of opioid-use disorders and anxiety-like behaviors. Here, we investigated the effects of opioid exposure on LPC neuron activity using immunohistochemical and electrophysiological approaches. We show that LPC neurons, and other nearby BLA GABA and non-GABA neurons, express MORs and δ-opioid receptors. Additionally, DAMGO, a selective MOR agonist, reduced GABA but not glutamate-mediated spontaneous postsynaptic currents in LPC neurons. Furthermore, in LPC neurons, abstinence from repeated morphine-exposure in vivo (10 mg/kg/day, 5 days, 2 days off) decrease the intrinsic membrane excitability, with a ~75% increase in afterhyperpolarization and ~40-50% enhanced adenylyl cyclase-dependent activity in LPC neurons. These data show that MORs in the BLA are a highly sensitive targets for opioid-induced inhibition and that repeated opioid exposure results in impaired LPC neuron excitability.

Reducing local synthesis of estrogen in the tubular striatum promotes attraction to same-sex odors in female mice.

Brain-derived 17ß-estradiol (E2) confers rapid effects on neural activity. The tubular striatum (TuS, also called the olfactory tubercle) is both capable of local E2 synthesis due to its abundant expression of aromatase and is a critical locus for odor-guided motivated behavior and odor hedonics. TuS neurons also contain mRNA for estrogen receptors α, ß, and the G protein-coupled estrogen receptor. We demonstrate here that mRNA for estrogen receptors appears to be expressed upon TuS dopamine 1 receptor-expressing neurons, suggesting that E2 may play a neuromodulatory role in circuits which are important for motivated behavior. Therefore, we reasoned that E2 in the TuS may influence attraction to urinary odors which are highly attractive. Using whole-body plethysmography, we examined odor-evoked high-frequency sniffing as a measure of odor attaction. Bilateral infusion of the aromatase inhibitor letrozole into the TuS of gonadectomized female adult mice induced a resistance to habituation over successive trials in their investigatory sniffing for female mouse urinary odors, indicative of an enhanced attraction. All males displayed resistance to habituation for female urinary odors, indicative of enhanced attraction that is independent from E2 manipulation. Letrozole's effects were not due to group differences in basal respiration, nor changes in the ability to detect or discriminate between odors (both monomolecular odorants and urinary odors). Therefore, de novo E2 synthesis in the TuS impacts females' but not males' attraction to female urinary odors, suggesting a sex-specific influence of E2 in odor hedonics.

In Utero Ultrafine Particulate Exposure Yields Sex- and Dose-Specific Responses to Neonatal Respiratory Syncytial Virus Infection.

Exposure to particulate matter (PM) is associated with lower respiratory tract infections. The role of ultrafine particles (UFPs, ≤0.1 µm) in respiratory disease is not fully elucidated, especially in models of immunologically immature populations. To characterize the effects of maternal UFP exposure on neonatal infection, we exposed time-mated C57Bl/6n mice to filtered air or UFPs at a low dose (LD, ∼55 µg/m3) and high dose (HD, ∼275 µg/m3) throughout gestation. At 5 days of age, offspring were infected with a respiratory syncytial virus (RSV) strain known to mimic infant infection or sham control. Offspring body weights were significantly reduced in response to infection in the LD RSV group, particularly females. Pulmonary gene expression analysis demonstrated significantly increased levels of oxidative stress- and inflammation-related genes in HD-exposed male offspring in sham and RSV-infected groups. In males, the highest grade of inflammation was observed in the HD RSV group, whereas in females, the LD RSV group showed the most marked inflammation. Overall, findings highlight neonatal responses are dependent on offspring sex and maternal UFP dose. Importantly, infant RSV pathology may be enhanced following even low dose UFP exposure signifying the importance of preventing maternal exposure.

Photochemical Synthesis and Spectroscopy of Covalent PAH Dimers.

Laser photochemistry of pressed-pellet samples of polycyclic aromatic hydrocarbons (PAHs) produces covalently bonded dimers and some higher polymers. This chemistry was discovered initially via laser desorption time-of-flight mass spectrometry experiments, which produced masses (m/z) of 2M-2 and 2M-4 (where M is the monomer parent mass). Dimers are believed to be formed from photochemical dehydrogenation and radical polymerization chemistry in the desorption plume. Replication of these ablation conditions at higher throughput allowed PAH dimers of pyrene, perylene, and coronene to be produced and collected in milligram quantities. Differential sublimation provided purification of the dimers and elimination of residual monomers. The purified dimers were investigated with UV-visible, IR, and Raman spectroscopy, complemented by computational studies using density functional theory at the CAM-B3LYP/def2-TZV level. Calculations and predicted spectra were calibrated by comparison with the corresponding monomers and used to determine the lowest energy dimer structures. Infrared and Raman spectroscopy provided few distinctive signatures, but UV-visible spectra detected new transitions for each dimer. The comparison of simulated and experimental spectra allows determination of the most prevalent structures for the PAH dimers. The work presented here provides interesting insights into the spectroscopy of extended aromatic systems and a new strategy for the photochemical synthesis of large PAH dimers.

Long-Term Disability Outcomes for Patients With Ischemic Stroke Presenting With Visual Deficits.

BACKGROUND: Ischemic strokes in both the anterior and posterior circulation can lead to visual deficits, which can affect functional ability. Thrombolytic therapies are often withheld to patients with visual deficits because of either being missed on initial evaluation or because of the misconception that their deficits are not as severe or as disabling. Alternatively, delays in patient arrival for emergent evaluation lead to missed opportunities for acute stroke treatment. This retrospective study aims to explore the differences in perceived long-term disability for patients with stroke who present with visual deficits vs those who do not as a manifestation of their acute stroke syndrome. In addition, we explore the differences in treatment effect with thrombolytics and further analyze if the region of ischemia causing the deficit leads to differences in disability outcomes. METHODS: We conducted a retrospective analysis of patients with visual deficits as evidenced by an abnormal score on NIHSS categories related to vision (gaze palsy, visual fields, or extinction/inattention). Patients with Acute Ischemic Stroke were reviewed from the Houston Methodist Hospital Outcomes-based Prospective Endpoints in Stroke (HOPES) Registry from 2016-2021 for visual deficits. In total, 155 patient charts with visual deficits and 155 patient charts without a documented visual deficit were reviewed for ischemic stroke location (anterior vs posterior circulation), NIHSS scores, and thrombolytic therapies. The outcome variable was categorized using mRS, as mRS between 0 and 3 while mRS 4 to 6 was considered as poor functional outcome at 90 days. The independent variable was the vision group. A multivariable logistic regression model was constructed adjusting for demographics and comorbidities on the binary outcome. RESULTS: Multivariable logistic model after adjusting for demographics and comorbidities showed that patients with acute ischemic stroke with vision defects were 4 times more likely to have poor functional outcomes at 90 days, with most of these patients (14% vs 6%; P < 0.05) suffering from severe disability compared with patients in the control group (i.e., patients with acute ischemic stroke without vision defects) (OR = 4.05; 95% CI [2.28-7.19]; P < 0.001). The application of thrombolytics and the location of ischemia (ACS vs PCS) did not result in a significant change in disability outcomes in patients with visual defects in this limited sample size. CONCLUSIONS: The results of this study indicated that a large population of patients with ischemic stroke experience visual deficits and are, therefore, at an increased likelihood of worse functional outcome. This reveals the necessity for rehabilitation techniques that specifically target visual deficits to speed up the recovery process of these patients. Further studies with larger sample size are needed to assess whether the location of ischemic event and the application of thrombolytic treatments plays a role in the disability outcomes of these patients.

In utero ultrafine particulate matter exposure causes offspring pulmonary immunosuppression.

Early life exposure to fine particulate matter (PM) in air is associated with infant respiratory disease and childhood asthma, but limited epidemiological data exist concerning the impacts of ultrafine particles (UFPs) on the etiology of childhood respiratory disease. Specifically, the role of UFPs in amplifying Th2- and/or Th17-driven inflammation (asthma promotion) or suppressing effector T cells (increased susceptibility to respiratory infection) remains unclear. Using a mouse model of in utero UFP exposure, we determined early immunological responses to house dust mite (HDM) allergen in offspring challenged from 0 to 4 wk of age. Two mice strains were exposed throughout gestation: C57BL/6 (sensitive to oxidative stress) and BALB/C (sensitive to allergen exposure). Offspring exposed to UFPs in utero exhibited reduced inflammatory response to HDM. Compared with filtered air (FA)-exposed/HDM-challenged mice, UFP-exposed offspring had lower white blood cell counts in bronchoalveolar lavage fluid and less pronounced peribronchiolar inflammation in both strains, albeit more apparent in C57BL/6 mice. In the C57BL/6 strain, offspring exposed in utero to FA and challenged with HDM exhibited a robust response in inflammatory cytokines IL-13 and Il-17. In contrast, this response was lost in offspring exposed in utero to UFPs. Circulating IL-10 was significantly up-regulated in C57BL/6 offspring exposed to UFPs, suggesting increased regulatory T cell expression and suppressed Th2/Th17 response. Our results reveal that in utero UFP exposure at a level close to the WHO recommended PM guideline suppresses an early immune response to HDM allergen, likely predisposing neonates to respiratory infection and altering long-term pulmonary health.

Adverse organogenesis and predisposed long-term metabolic syndrome from prenatal exposure to fine particulate matter.

Exposure to fine particulate matter (PM) during pregnancy is associated with high risks of birth defects/fatality and adverse long-term postnatal health. However, limited mechanistic data are available to assess the detailed impacts of prenatal PM exposure. Here we evaluate fine PM exposure during pregnancy on prenatal/postnatal organogenesis in offspring and in predisposing metabolic syndrome for adult life. Between days 0 and 18 of gestation, two groups of adult female rats (n = 10 for each) were placed in a dual-exposure chamber device, one with clean ambient air (∼3 µg·m-3) and the other with ambient air in the presence of 100 to 200 µg·m-3 of ultrafine aerosols of ammonium sulfate. At birth (postnatal day 0, PND0), four males and four females were selected randomly from each litter to be nursed by dams, whereas tissues were collected from the remaining pups. At PND21, tissues were collected from two males and two females, whereas the remaining pups were fed either a high- or low-fat diet until PND105, when tissues were obtained for biochemical and physiological analyses. Maternal exposure to fine PM increased stillbirths; reduced gestation length and birth weight; increased concentrations of glucose and free fatty acids in plasma; enhanced lipid accumulation in the liver; and decreased endothelium-dependent relaxation of aorta. This lead to altered organogenesis and predisposed progeny to long-term metabolic defects in an age-, organ-, and sex-specific manner. Our results highlight the necessity to develop therapeutic strategies to remedy adverse health effects of maternal PM exposure on conceptus/postnatal growth and development.

Air pollution and children's health-a review of adverse effects associated with prenatal exposure from fine to ultrafine particulate matter.

BACKGROUND: Particulate matter (PM), a major component of ambient air pollution, accounts for a substantial burden of diseases and fatality worldwide. Maternal exposure to PM during pregnancy is particularly harmful to children's health since this is a phase of rapid human growth and development. METHOD: In this review, we synthesize the scientific evidence on adverse health outcomes in children following prenatal exposure to the smallest toxic components, fine (PM2.5) and ultrafine (PM0.1) PM. We highlight the established and emerging findings from epidemiologic studies and experimental models. RESULTS: Maternal exposure to fine and ultrafine PM directly and indirectly yields numerous adverse birth outcomes and impacts on children's respiratory systems, immune status, brain development, and cardiometabolic health. The biological mechanisms underlying adverse effects include direct placental translocation of ultrafine particles, placental and systemic maternal oxidative stress and inflammation elicited by both fine and ultrafine PM, epigenetic changes, and potential endocrine effects that influence long-term health. CONCLUSION: Policies to reduce maternal exposure and health consequences in children should be a high priority. PM2.5 levels are regulated, yet it is recognized that minority and low socioeconomic status groups experience disproportionate exposures. Moreover, PM0.1 levels are not routinely measured or currently regulated. Consequently, preventive strategies that inform neighborhood/regional planning and clinical/nutritional recommendations are needed to mitigate maternal exposure and ultimately protect children's health.

Recent testosterone drop-off and risk of cardiovascular events.

Low baseline testosterone level has been associated with the development of risk factors for cardiovascular disease such as insulin resistance and obesity. In addition to the absolute testosterone level, remarkable changes in testosterone level may have an acute effect on cardiovascular disease development and progression, which has been rarely investigated. In this study, we used a clinical dataset of 376 hypogonadal men whose testosterone levels were measured every six months for up to 11 years from a registry study in Germany, and conducted survival analyses to investigate the effect of testosterone changes since the last visit (time-varying) on the risk of cardiovascular events. Given the potential discrepancies in comorbidity conditions among patients with prior cardiovascular events and those without, all the analyses were stratified by patients' prior cardiovascular event status. We found the effects were not different among patients with prior cardiovascular events and those without. Regardless of patients' prior cardiovascular event status, patients with larger testosterone declines (≥3.12 nmol/L, 90th percentile) since the last visit were more likely to experience myocardial infarction. In conclusion, recent pronounced testosterone drop-offs may affect the risk of cardiovascular events among hypogonadal men. Future longitudinal studies are needed to confirm our exploratory study findings.

Serum miR-182 is a predictive biomarker for dichotomization of risk of hepatocellular carcinoma in rats.

Exploration of animal models leads to discoveries that can reveal candidate biomarkers for translation to human populations. Herein, a model of hepatocarcinogenesis and protection was used in which rats treated with aflatoxin (AFB1 ) daily for 28 days (200 µg/kg BW) developed tumors compared with rats completely protected from tumors by concurrent administration of the chemoprotective agent, 1-[2-cyano-3-,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole (CDDO-Im). Differential expression of miRNAs in tumors (AFB1 ) and nontumor (AFB1 + CDDO-Im) bearing livers and their levels in sera over the life-course of the animals was determined. miRNA transcriptome analysis identified 17 miRNAs significantly upregulated at greater than five-fold in the tumors. The ten most dysregulated miRNAs judged by fold-change and biological significance were selected for further study, including liver-specific miR-122-5p. Validation of sequencing results by real-time PCR confirmed the upregulation of the majority of these miRNAs in tumors, including miR-182, as well as miR-224-5p as the most dysregulated of these miRNAs (over 400-fold). The longitudinal analysis of levels of miR-182 in sera demonstrated significant and persistent increases (5.13-fold; 95% CI: 4.59-5.70). The increase in miR-182 was detected months before any clinical symptoms were present in the animals. By the terminal time point of the study, in addition to elevated levels of serum miR-182, serum miR-122-5p was also found to be increased (>1.5-fold) in animals that developed hepatocarcinomas. Thus, using the data from an unbiased discovery approach of the tissue findings, serum miR-182 was found to track across the complex, multistage process of hepatocarcinogenesis opening an opportunity for translation to human populations.

A systematic review of adherence to diabetes self-care behaviours: Evidence from low- and middle-income countries.

AIMS: To determine diabetes patient's adherence to five self-care behaviours (diet, exercise; medication, self-monitoring of blood glucose [SMBG] and foot care) in low- and middle-income countries. DESIGN: Systematic review. DATA SOURCES: We searched MEDLINE, CINAHL, PUBMED, SCOPUS, PsycINFO, EMBASE, Cochrane library and EMCARE for the period January 1990 - June 2017. REVIEW METHODS: Title, abstract and full text screening were done according to eligibility criteria. A narrative synthesis of the literature was conducted. RESULTS: A total of 7,109 studies were identified of which 27 met the review eligibility criteria and were included. All the studies used self-report of adherence to diabetes self-care. Studies reported adherence rates in two major forms: (a) mean number of days participants performed a recommended dietary behaviour/activity during the past week; and (b) proportions of participants adhering to a recommended self-care behaviour. Mean number of days per week participants adhered to a self-care behaviour ranged from 2.34.6 days per week for diet, 5.5-6.8 days per week for medication, 1.8-5.7 days per week for exercise, 0.2-2.2 days per week for SMBG and 2.2-4.3 days per week for foot care. Adherence rates ranged from 29.9%-91.7% for diet, 26.0%-97.0% for medication taking, 26.7%-69.0% for exercise, 13.0%-79.9% for self-monitoring of blood glucose and 17.0%-77.4% for foot care. CONCLUSION: Although most diabetes patients do not adhere to recommended self-care behaviours, adherence rates vary widely and were found to be high in some instances. IMPACT: Health services in low- and middle-income countries should monitor adherence to diabetes self-care behaviours rather than assume adherence and resources should be invested in improving adherence to the self-care behaviours. Large-scale accurate monitoring of adherence to diabetes self-care behaviour is needed and consideration should be given to choice of measurement tool for such exercise.

Development of broad-acting clays for the tight adsorption of benzo[a]pyrene and aldicarb.

People and animals can be unintentionally exposed to complex mixtures of hazardous chemicals that can threaten the safety of food and water supplies following natural and man-made disasters and emergencies. Our research has focused on the development of broad-acting adsorbents that will tightly bind environmental contaminants in the gastrointestinal tract and decrease their bioavailability to humans and animals during these events. In this study, benzo[a]pyrene (BaP) and aldicarb were used as representative chemicals due to their high toxicity and extensive distribution in the environment. Both chemicals have been commonly detected in water and sediments in the US, and their distribution and concentrations can be enhanced during disasters. To address this problem, we have amended and functionalized montmorillonite clays with the nutrients, L-carnitine and choline to enhance their attraction for lipophilic toxins, such as BaP and aldicarb. Based on equilibrium isothermal analyses, we have demonstrated a significantly increased binding capacity (Qmax) and affinity (Kd) for BaP and aldicarb compared to the parent clay. Adsorption isotherms also showed that talc bound strongly to BaP with the highest Qmax, which was twice that of activated carbon. Additionally, cultures of adult hydra with a metabolism activation package were used as an in vivo toxicity indicator to confirm the ability of test adsorbents to protect against toxicity at low inclusion levels. We anticipate that the optimal adsorbents developed can be delivered in food and flavored water, or administered by sachet or capsule during emergencies and disasters to decrease human and animals exposures to environmental toxins.