The receptor for advanced glycation end-products (RAGE) has increasingly been demonstrated to be an important modulator of inflammation in cases of pulmonary disease. Published reports involving tobacco smoke exposure have demonstrated increased expression of RAGE, its participation in proinflammatory signaling, and its role in irreversible pulmonary remodeling. The current research evaluated the in vivo effects of short-term secondhand smoke (SHS) exposure in RAGE knockout and control mice compared with identical animals exposed to room air only. Quantitative PCR, immunoblotting, and immunohistochemistry revealed elevated RAGE expression in controls after 4 wk of SHS exposure and an anticipated absence of RAGE expression in RAGE knockout mice regardless of smoke exposure. Ras activation, NF-κB activity, and cytokine elaboration were assessed to characterize the molecular basis of SHS-induced inflammation in the mouse lung. Furthermore, bronchoalveolar lavage fluid was procured from RAGE knockout and control animals for the assessment of inflammatory cells and molecules. As a general theme, inflammation coincident with leukocyte recruitment was induced by SHS exposure and significantly influenced by the availability of RAGE. These data reveal captivating information suggesting a role for RAGE signaling in lungs exposed to SHS. However, ongoing research is still warranted to fully explain roles for RAGE and other receptors in cells coping with involuntary smoke exposure for prolonged periods of time.

BackgroundReceptors for advanced glycation end-products (RAGE) are immunoglobulin-like pattern recognition receptors abundantly localized to lung epithelium. Our research demonstrated that primary tobacco smoke exposure increases RAGE expression and that RAGE partly mediates pro-inflammatory signaling during exposure. However, the degree to which RAGE influences developing lungs when gestating mice are exposed to secondhand smoke (SHS) has not been determined to date.MethodsTimed pregnant RAGE null and wild type control mice were exposed to 4 consecutive days of SHS from embryonic day (E) 14.5 through E18.5 using a state of the art nose-only smoke exposure system (Scireq, Montreal, Canada). RAGE expression was assessed using immunofluorescence, immunoblotting, and quantitative RT-PCR. TUNEL immunostaining and blotting for caspase-3 were performed to evaluate effects on cell turnover. Matrix abnormalities were discerned by quantifying collagen IV and MMP-9, a matrix metalloprotease capable of degrading basement membranes. Lastly, TNF-α and IL-1β levels were assessed in order to determine inflammatory status in the developing lung.ResultsPulmonary RAGE expression was elevated in both dams exposed to SHS and in fetuses gestating within mothers exposed to SHS. Fetal weight, a measure of organismal health, was decreased in SHS-exposed pups, but unchanged in SHS-exposed RAGE null mice. TUNEL assessments suggested a shift toward pulmonary cell apoptosis and matrix in SHS-exposed pups was diminished as revealed by decreased collagen IV and increased MMP-9 expression. Furthermore, SHS-exposed RAGE null mice expressed less TNF-α and IL-1β when compared to SHS-exposed controls.ConclusionsRAGE augmentation in developing pups exposed to maternal SHS weakens matrix deposition and influences lung inflammation.

From 2000 to 2014, drug overdose deaths increased 137% in the United States, and 61% of these deaths included some form of opiate. The vast majority of opiate-related drug fatalities include multiple drugs, although there is scant data quantitatively describing the exact drugs that contribute to deaths due to multiple drugs. In the present study, we sought to quantitatively identify the drugs that occur with opiates in accidental multidrug-related fatalities. We retrospectively explored fatal drug trends in four Michigan counties, with a focus on profiling drugs present concurrently with opiates. Blood and urine toxicology reports for mixed drug fatalities (N=180) were analyzed using frequent item analysis approaches to identify common analyte trends in opiate-related fatalities. Within our cohort, the most prevalent serum analytes included caffeine (n=147), morphine (n=90), alprazolam (n=69), gabapentin (n=46), and tetrahydrocannabinol (n=44). In 100% of cases where gabapentin was present (n=46), an opiate was also present in the serum or urine. The average gabapentin serum concentration was 13.56 μg/mL (SEM =0.33 μg/mL), with a range of 0.5-88.7 μg/mL. Gabapentin was found at very high frequency in accidental mixed drug fatalities. Gabapentin concentrations were generally within the normal therapeutic range (2-20 μg/mL). It is unknown whether a synergistic effect with opioids may contribute to central respiratory depression. Further research is warranted to determine any contributory role of gabapentin in these deaths. Confirmed interactions could have broad implications for future reporting by forensic pathologists as well as prescribing practices by clinicians.

This study sought to determine if there were any changes in opioid prescribing habits of providers at a single institution after the implementation of legislation to increase opioid prescribing regulations. Our study demonstrated a 39.5 percent decrease in overall morphine milligram equivalent (MME) prescribed the year after the laws took effect when compared with the year prior. It is clear that these laws have been effective in decreasing the number of opioids prescribed at discharge from Mercy Health Grand Rapids.Introduction: Opioid use disorder has become an epidemic with approximately 130 people dying every day in the United States due to prescription and illegal opioid overdoses. In December 2017, the Michigan legislature ratified a package of 10 acts to address a variety of problems through several layers of regulations including more restrictive prescribing rules, which took effect in June 2018. Objective: To evaluate the impact of legislation on the opioid prescribing habits of providers who discharged patients from a community-based academic teaching hospital.Design, setting, and participants: A retrospective cohort study was performed using data from a community-based academic teaching hospital with 303 beds, a medical ICU, labor and delivery unit, and a 42-room emergency department. All patients discharged from in-patient or observation status in the 12 months before and after June 1, 2018 were included.Main outcomes and measures: The primary outcome was MMEs of opioids prescribed at discharge before (June 1, 2017 to May 31, 2018) and after (June 1, 2018 to May 31, 2019) legislation. Medications included morphine, hydrocodone, oxycodone, fentanyl, methadone, hydromorphone, tramadol, codeine, and meperidine.Results: There were 17,227 patients discharged during the first 12-month period and 15,855 patients discharged in the second 12-month period. There were 14,064 new opioid prescriptions in total during these time periods. Total MME prescribed during the study period showed a 39.5 percent decrease from pre- (2,268,460 MME) to post-legislation (1,372,424 MME), while average MMEs/discharge significantly decreased (135.1 ± 321.2 vs. 87.6 ± 187.4; p 0.001). Total pill/patch count decreased by almost 40 percent. For patients who were prescribed opioids, average MME/discharge showed significant decline after legislation implementation (309.6 ± 427.1 vs. 212.2 ± 242.1; p 0.001). Average daily MME/patient prescribed an opioid remained similar between the time periods (52.4 ± 37.0 vs. 51.6 ± 35.0; p = 0.21). Significant reductions (p 0.05) were seen in MMEs for each individual medication with the exception of acetaminophen-codeine and methadone.Conclusions and relevance: Our results indicate that the legislation implemented in Michigan to regulate opioid prescriptions was associated with a reduction in opioids prescribed to patients discharged from a community-based academic teaching hospital.