In this article the authors advocate for a culturally responsible dual-factor model for the delivery of mental health services in the schools. This case is made because too many children are not ...receiving the mental health care they need in order to succeed in school and life. This is especially true for Black, Indigenous, children of color, and other minoritized youth. This transformative approach will require a dramatic change in how school psychological services are currently being delivered. The culturally responsible dual-factor model places a much greater emphasis on psychological well-being (as opposed to psychopathology), unwavering attention to rectifying discriminatory disparities in school mental health practices, an emphasis on population-based over individually focused mental health services, and a commitment to ensuring access for all children-not just those who are receiving special education services or 504 accommodations. This model is proactive and prevention oriented and focuses on equity. The case is presented that we continue to have a mental health crisis in today's youth with an increase in anxiety and depression. The authors conclude the article with implications for school psychology training, public policy and advocacy, and school-based practice.
Impact Statement
The culturally responsible dual-factor mental health framework is a transformative approach to school mental health services that is needed to address the nation's mental health crisis. It is needed because traditional approaches, models, and practices have been too narrow and, thus, continue to fail for diverse and minoritized children, families, and schools. A culturally responsible dual-factor mental health approach expands traditional approaches by emphasizing well-being, cultural strengths of minoritized communities, accessibility of services, and systems and structures (e.g., racism) that contribute to discrimination and disparities in mental health services.
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BFBNIB, NUK, PILJ, SAZU, UL, UM, UPUK
Opioids are commonly prescribed for the treatment of chronic pain. Approximately 50% of adults who are prescribed opioids for pain co-use cannabis with their opioid treatment. Morphine is primarily ...metabolized by UDP-glucuronosyltransferase (UGT) 2B7 to an inactive metabolite, morphine-3-glucuronide (M3G), and an active metabolite, morphine-6-glucuronide (M6G). Previous studies have shown that major cannabis constituents including Δ
-tetrahydrocannabinol (THC) and cannabidiol (CBD) inhibit major UGT enzymes. To examine whether cannabinoids or their major metabolites inhibit morphine glucuronidation by UGT2B7, in vitro assays and mechanistic static modeling were performed with these cannabinoids and their major metabolites including 11-hydroxy-Δ
-tetrahydrocannabinol (11-OH-THC), 11-nor-9-carboxy-Δ
-tetrahydrocannabinol (11-COOH-THC), 7-hydroxy-cannabidiol (7-OH-CBD), and 7-carboxy-cannabidiol (7-COOH-CBD). In vitro assays with rUGT-overexpressing microsomes and human liver microsomes showed that THC and CBD and their metabolites inhibited UGT2B7-mediated morphine metabolism, with CBD and THC exhibiting the most potent K
values (0.16 µM and 0.37 µM, respectively). Only 7-COOH-CBD exhibited no inhibitory activity against UGT2B7-mediated morphine metabolism. Static mechanistic modeling predicted an in vivo drug-drug interaction between morphine and THC after inhaled cannabis, and between THC, CBD, and 7-OH-CBD after oral consumption of cannabis. These data suggest that the co-use of these agents may lead to adverse drug events in humans.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Benzodiazepines (BZDs) such as oxazepam are commonly prescribed depressant drugs known for their anxiolytic, hypnotic, muscle relaxant, and anticonvulsant effects and are frequently used in ...conjunction with other illicit drugs including cannabis. Oxazepam is metabolized in an enantiomeric-specific manner by glucuronidation, with S-oxazepam metabolized primarily by UGT2B15 and R-oxazepam glucuronidation mediated by both UGT 1A9 and 2B7. The goal of the present study was to evaluate the potential inhibitory effects of major cannabinoids, Δ
-tetrahydrocannabinol (THC) and cannabidiol (CBD), and major THC metabolites, 11-hydroxy-Δ
-tetrahydrocannabinol (11-OH-THC) and 11-nor-9-carboxy-Δ
-tetrahydrocannabinol (11-COOH-THC), on the UGT-mediated metabolism of R- and S-oxazepam. The cannabinoids and metabolites were screened as inhibitors of R- and S-oxazepam glucuronidation in microsomes isolated from HEK293 cells overexpressing individual UGT enzymes (rUGTs). The IC
values were determined in human liver microsomes (HLM), human kidney microsomes (HKM), and rUGTs and utilized to estimate the nonspecific, binding-corrected K
(K
) values and predict the area under the concentration-time curve ratio (AUCR). The estimated K
values observed in HLM for S- and R-oxazepam glucuronidation by CBD, 11-OH-THC, and THC were in the micromolar range (0.82 to 3.7 µM), with the K
values observed for R-oxazepam glucuronidation approximately 2- to 5-fold lower as compared to those observed for S-oxazepam glucuronidation. The mechanistic static modeling predicted a potential clinically significant interaction between oral THC and CBD with oxazepam, with the AUCR values ranging from 1.25 to 3.45. These data suggest a pharmacokinetic drug-drug interaction when major cannabinoids like CBD or THC and oxazepam are concurrently administered.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Electronic cigarette (E-cigarettes) emissions present a potentially new hazard to neonates through inhalation, dermal and oral contact. Exposure to nicotine containing E-cigarettes may cause ...significant systemic absorption in neonates due to the potential for multi-route exposure. Systemic absorption of nicotine and constituents of E-cigarette emissions may adversely impact weight and lung development in the neonate. To address these questions we exposed neonatal mice to E-cigarette emissions and measured systemic cotinine levels and alveolar lung growth.
Neonatal mice were exposed to E-cigarettes for the first 10 days of life. E-cigarette cartridges contained either 1.8% nicotine in propylene glycol (PG) or PG vehicle alone. Daily weights, plasma and urine cotinine levels and lung growth using the alveolar mean linear intercept (MLI) method were measured at 10 days of life and compared to room air controls. Mice exposed to 1.8% nicotine/PG had a 13.3% decrease in total body weight compared to room air controls. Plasma cotinine levels were found to be elevated in neonatal mice exposed to 1.8% nicotine/PG E-cigarettes (mean 62.34± 3.3 ng/ml). After adjusting for sex and weight, the nicotine exposed mice were found to have modestly impaired lung growth by MLI compared to room air control mice (p<.054 trial 1; p<.006 trial 2). These studies indicate that exposure to E-cigarette emissions during the neonatal period can adversely impact weight gain. In addition exposure to nicotine containing E-cigarettes can cause detectable levels of systemic cotinine, diminished alveolar cell proliferation and a modest impairment in postnatal lung growth.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Bangladesh exhibits the second highest rate of smokeless tobacco (SLT) product usage in the world, and this has been associated with the high upper aerodigestive tract cancer incidence in this ...country. The goal of the present study was to examine the levels of the highly carcinogenic tobacco-specific nitrosamines (TSNAs) in Bangladeshi SLT products and compare these levels to that observed in SLT brands from southeast Asia and the USA. The levels of TSNAs and nicotine were determined by LC-MS/MS in twenty-eight SLT brands and several tobacco additives from Bangladesh, as well as several SLT brands from India, Pakistan and the USA. The levels of N-nitrosonornicotine (NNN), 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), N-nitrosoanatabine (NAT) and N-nitrosoanabasine (NAB) in Bangladeshi SLT brands ranged from 1.1-59, 0.15-34, 0.79-45, and 0.037-13 μg/g SLT powder, respectively. The mean levels of the highly carcinogenic TSNAs (NNN+NNK) were 7.4-, 2.4-, and 63-fold higher in Bangladeshi SLT products as compared to SLT brands from the USA, India and Pakistan, respectively; these trends were also observed for NAT and NAB. Similar mean levels of nicotine were observed in the Bangladeshi brands (31 mg/g powder) versus brands from the USA (25 mg/g powder) and India (20 mg/g powder); they were 3-fold higher than brands from Pakistan (10 mg/g powder). Gul SLT brands exhibited the highest pH and the highest levels of unprotonated nicotine. The high levels of TSNAs in Bangladeshi SLT brands may be an important factor contributing to the high rates of upper aerodigestive tract cancer in Bangladesh.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
To investigate the association between cannabis smoking and lung cancer risk, data on 2,159 lung cancer cases and 2,985 controls were pooled from 6 case‐control studies in the US, Canada, UK, and New ...Zealand within the International Lung Cancer Consortium. Study‐specific associations between cannabis smoking and lung cancer were estimated using unconditional logistic regression adjusting for sociodemographic factors, tobacco smoking status and pack‐years; odds‐ratio estimates were pooled using random effects models. Subgroup analyses were done for sex, histology and tobacco smoking status. The shapes of dose‐response associations were examined using restricted cubic spline regression. The overall pooled OR for habitual versus nonhabitual or never users was 0.96 (95% CI: 0.66–1.38). Compared to nonhabitual or never users, the summary OR was 0.88 (95%CI: 0.63–1.24) for individuals who smoked 1 or more joint‐equivalents of cannabis per day and 0.94 (95%CI: 0.67–1.32) for those consumed at least 10 joint‐years. For adenocarcinoma cases the ORs were 1.73 (95%CI: 0.75–4.00) and 1.74 (95%CI: 0.85–3.55), respectively. However, no association was found for the squamous cell carcinoma based on small numbers. Weak associations between cannabis smoking and lung cancer were observed in never tobacco smokers. Spline modeling indicated a weak positive monotonic association between cumulative cannabis use and lung cancer, but precision was low at high exposure levels. Results from our pooled analyses provide little evidence for an increased risk of lung cancer among habitual or long‐term cannabis smokers, although the possibility of potential adverse effect for heavy consumption cannot be excluded.
What's new?
Due to the potential adverse effect of cannabis smoking and its popularity, an investigation of its association with lung cancer risk is essential to help support appropriate regulations as well as health and social policy responses. The analysis presented here included the largest data set on cannabis and lung cancer risk to date. Its non‐linear dose‐response was examined using restricted cubic spline regression, a first in this line of work. Results provide little evidence for an increased risk of lung cancer among habitual or long‐term cannabis smokers, although the possibility of potential adverse effect for heavy consumption cannot be excluded.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
OBJECTIVEExemestane (EXE) is a potent third-generation aromatase inhibitor used as endocrine therapy in breast cancer treatment and prevention. Characterization of its metabolic pathway is ...incomplete, with ambiguity existing in the identity of enzymes driving the production of its key metabolite, 17β-dihydroexemestane (17β-DHE). The impact of genetic variation on EXE metabolism is also unknown. This study aims to describe cytosolic reductase involvement in hepatic EXE metabolism and to assess the impact of functional polymorphisms on metabolite production.
MATERIALS AND METHODSPhase I metabolites were identified in incubations of EXE with pooled human liver cytosol or recombinant protein for AKR1Cs and CBR1. Kinetic parameters characterizing EXE reduction were measured for purified wild-type enzymes, and nonsynonymous variants occurring at greater than 1% minor allele frequency using UPLC/MS/MS.
RESULTSHuman liver cytosol, CBR1, AKR1C1, AKR1C2, AKR1C3, and AKR1C4 reduce EXE to active primary metabolite 17β-DHE. The formation of a novel metabolite, 17α-DHE, was catalyzed by recombinant AKR1C4 and CBR1 in addition to hepatic cytosol. Variants AKR1C3 Arg258Cys and AKR1C4 Gly135Glu had significantly decreased affinity for EXE relative to their respective wild types. Five common AKR1C3 polymorphisms were associated with decreased rates of catalysis, whereas AKR1C4 Gly135Glu increased the velocity of EXE reduction.
CONCLUSIONAKR1Cs and CBR1 catalyze EXE reduction in vitro. These results imply that cytosolic ketosteroid reductases may participate in the EXE metabolic pathway in vivo. In addition, several common variants were associated with altered enzymatic activity, suggesting that functional polymorphisms could play an important role in overall EXE metabolism and activity by altering the extent and duration of 17β-DHE exposure.
The UDP-glucuronosyltransferase (UGT) 2B subfamily of enzymes plays an important role in the metabolism of numerous endogenous and exogenous compounds, including various carcinogens present in ...tobacco smoke. The goal of the present study was to examine the levels of expression of individual UGT2B genes in various tissues that are targets for tobacco carcinogenesis. Using MT-ATP6 as the experimentally validated housekeeping gene, the highest extrahepatic expression of UGT2B genes was observed in human tonsil, with UGT2B expression levels similar to that observed in human liver. UGT2B17 exhibited high relative expression in most tissues examined, including lung, most tissues of the aerodigestive tract, and pancreas. UGT2B7 expression was highest in pancreas but low or undetectable in most other tissues examined. UGT2B10 expression was high in both tonsil and tongue. There was wide variability between individuals in the magnitude of expression in each tissue site, and there were strong correlations between UGT2B expression levels in different individuals within many of the tissue sites, suggesting coordinated regulation of UGT2B gene expression in extrahepatic tissues. In the liver, UGTs 2B4, 2B7, 2B10, and 2B15 were significantly correlated with each other (all r(2) > 0.70, P < 0.0001). In all examined tissues of the aerodigestive tract, UGTs 2B10, 2B11, and 2B17 exhibited a strong correlation with each other (all r(2) > 0.75, P < 0.05). UGTs 2B7 and 2B10 exhibited a strong inverse correlation in the pancreas (r(2) = -0.95, P < 0.01). These data suggest that specific UGT2B enzymes important in tobacco carcinogen metabolism are expressed and coordinately regulated in various target sites for tobacco-related cancers.
Context: There is a paucity of data describing the impact of type of beverage (coffee versus energy drink), different rates of consumption and different temperature of beverages on the ...pharmacokinetic disposition of caffeine. Additionally, there is concern that inordinately high levels of caffeine may result from the rapid consumption of cold energy drinks. Objective: The objective of this study was to compare the pharmacokinetics of caffeine under various drink temperature, rate of consumption and vehicle (coffee versus energy drink) conditions. Materials: Five caffeine (dose = 160 mg) conditions were evaluated in an open-label, group-randomized, crossover fashion. After the administration of each caffeine dose, 10 serial plasma samples were harvested. Caffeine concentration was measured via liquid chromatography-mass spectrometry (LC-MS), and those concentrations were assessed by non-compartmental pharmacokinetic analysis. The calculated mean pharmacokinetic parameters were analyzed statistically by one-way repeated measures analysis of variance (RM ANOVA). If differences were found, each group was compared to the other by all pair-wise multiple comparison. Results: Twenty-four healthy subjects ranging in age from 18 to 30 completed the study. The mean caffeine concentration time profiles were similar with overlapping SDs at all measured time points. The ANOVA revealed significant differences in mean C
max
and V
d ss
/F, but no pair-wise comparisons reached statistical significance. No other differences in pharmacokinetic parameters were found. Discussion: The results of this study are consistent with previous caffeine pharmacokinetic studies and suggest that while rate of consumption, temperature of beverage and vehicle (coffee versus energy drink) may be associated with slightly different pharmacokinetic parameters, the overall impact of these variables is small. Conclusion: This study suggests that caffeine absorption and exposure from coffee and energy drink is similar irrespective of beverage temperature or rate of consumption.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Timed-pregnant C57BL/6J mice were exposed to 2.4% nicotine in propylene glycol (PG) or 0% nicotine /PG once a day from gestational day 15 until delivery. After delivery, offspring and mothers were ...exposed to E-cigarette vapors for an additional 14 days from postnatal day 2 through 16. Following their last exposure serum cotinine levels were measured in female juvenile mice. Male mice underwent behavioral testing at 14 weeks of age to assess sensorimotor, affective, and cognitive functional domains.
Adult male mice exposed to 2.4% nicotine/PG E-cigarette vapors had significantly more head dips in the zero maze test and higher levels of rearing activity in the open field test compared to 0% nicotine/PG exposed mice and untreated controls. In the water maze test after reversal training, the 2.4% nicotine/PG mice spent more than 25% of time in the new location whereas the other groups did not.
Adult male mice exhibited increased levels of activity in the zero maze and open field tests when exposed to E-cigarette vapor containing nicotine during late prenatal and early postnatal life. These findings indicate that nicotine exposure from E-cigarettes may cause persistent behavioral changes when exposure occurs during a period of rapid brain growth.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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