Monohydroxylated metabolites of the K2 synthetic cannabinoid JWH-073 retain intermediate to high cannabinoid 1 receptor (CB1R) affinity and exhibit neutral antagonist to partial agonist activity

K2 and several similar purported "incense products" spiked with synthetic cannabinoids are abused as cannabis substitutes. We hypothesized that metabolism of JWH-073, a prevalent cannabinoid found in K2, contributes to toxicity associated with K2 use. Competition receptor binding studies and G-protein activation assays, both performed by employing mouse brain homogenates, were used to determine the affinity and intrinsic activity, respectively, of potential monohydroxylated (M1, M3-M5) and monocarboxylated (M6) metabolites at cannabinoid 1 receptors (CB1Rs). Surprisingly, M1, M4 and M5 retain nanomolar affinity for CB1Rs, while M3 displays micromolar affinity and M6 does not bind to CB1Rs. JWH-073 displays equivalent efficacy to that of the CB1R full agonist CP-55,940, while M1, M3, and M5 act as CB1R partial agonists, and M4 shows little or no intrinsic activity. Further in vitro investigation by Schild analysis revealed that M4 acts as a competitive neutral CB1R antagonist (K(b)～40nM). In agreement with in vitro studies, M4 also demonstrates CB1R antagonism in vivo by blunting cannabinoid-induced hypothermia in mice. Interestingly, M4 does not block agonist-mediated responses of other measures in the cannabinoid tetrad (e.g., locomotor suppression, catalepsy or analgesia). Finally, also as predicted by in vitro results, M1 exhibits agonist activity in vivo by inducing significant hypothermia and suppression of locomotor activity in mice. In conclusion, the present study indicates that further work examining the physiological effects of synthetic cannabinoid metabolism is warranted. Such a complex mix of metabolically produced CB1R ligands may contribute to the adverse effect profile of JWH-073-containing products.     

Improving internal medicine residents' falls assessment and evaluation: an interdisciplinary, multistrategy program

Falls are a major problem in older adults, and physicians receive inadequate training in falls evaluation. A multicomponent program (lecture, academic detailing, and case studies) was implemented to enhance medical residents' knowledge, skills, decisions, and interventions made about falls as part of a larger project to improve assessment and care of older adults. Electronic medical record (EMR) template modifications provided cues and reminders, decision support, and documentation into the visit note. Nursing staff and the EMR prompted residents to evaluate patients with a history of falls. Knowledge and confidence were assessed using a pre- and postintervention questionnaire, and an attending physician assessed skills by direct observation of the Timed Up and Go Test (TUG). Effect on clinical actions was assessed using the EMR database. Participation in training of faculty and staff was high. Over the 3-month intervention period, an attending physician reviewed the detailing sheet outlining important points of the training with 86% of residents, and 64% demonstrated a TUG to an attending physician. Of 895 older adults seen, 15% (134) had a positive screen for falls, of whom 92% (123) had an EMR falls template completed, and 42% (56) had a TUG performed. Of the patients evaluated with the TUG, 53% (29) failed. A review of charts for patients who failed the screen or TUG revealed that the majority had special circumstances limiting their participation, even after a physical therapy evaluation. Education and system changes facilitated improvements in resident knowledge, skill, self-efficacy, and clinical action in screening, evaluating, and managing falls in older adults.     

Silent cerebral infarcts occur despite regular blood transfusion therapy after first strokes in children with sickle cell disease

Children with sickle cell disease (SCD) and strokes receive blood transfusion therapy for secondary stroke prevention; despite this, approximately 20% experience second overt strokes. Given this rate of second overt strokes and the clinical significance of silent cerebral infarcts, we tested the hypothesis that silent cerebral infarcts occur among children with SCD being transfused for secondary stroke prevention. A prospective cohort enrolled children with SCD and overt strokes at 7 academic centers. Magnetic resonance imaging and magnetic resonance angiography of the brain were scheduled approximately every 1 to 2 years; studies were reviewed by a panel of neuroradiologists. Eligibility criteria included regularly scheduled blood transfusion therapy. Forty children were included; mean pretransfusion hemoglobin S concentration was 29%. Progressive cerebral infarcts occurred in 45% (18 of 40 children) while receiving chronic blood transfusion therapy; 7 had second overt strokes and 11 had new silent cerebral infarcts. Worsening cerebral vasculopathy was associated with new cerebral infarction (overt or silent; relative risk = 12.7; 95% confidence interval, 2.65-60.5, P = .001). Children with SCD and overt strokes receiving regular blood transfusion therapy experience silent cerebral infarcts at a higher rate than previously recognized. Additional therapies are needed for secondary stroke prevention in children with SCD.     

Soluble receptor for AGE (RAGE) is a novel independent predictor of all-cause and cardiovascular mortality in type 1 diabetes

Aims/hypothesis  

Activation of the receptor for AGE (RAGE) is implicated in the development and progression of vascular complications of diabetes. In this study, we explore factors and mortality outcomes associated with soluble RAGE (sRAGE) in a multicentre nationwide cohort of Finnish adults with type 1 diabetes.     

An assessment of MEG coherence imaging in the study of temporal lobe epilepsy

Purpose: This study examines whether magnetoencephalographic (MEG) coherence imaging is more sensitive than the standard single equivalent dipole (ECD) model in lateralizing the site of epileptogenicity in patients with drug‐resistant temporal lobe epilepsy (TLE). Methods: An archival review of ECD MEG analyses of 30 presurgical patients with TLE was undertaken with data extracted subsequently for coherence analysis by a blinded reviewer for comparison of accuracy of lateralization. Postoperative outcome was assessed by Engel classification. MEG coherence images were generated from 10 min of spontaneous brain activity and compared to surgically resected brain areas outlined on each subject’s magnetic resonance image (MRI). Coherence values were averaged independently for each hemisphere to ascertain the laterality of the epileptic network. Reliability between runs was established by calculating the correlation between epochs. Match rates compared the results of each of the two MEG analyses with optimal postoperative outcome. Key Findings: The ECD method provided an overall match rate of 50% (13/16 cases) for Engel class I outcomes, with 37% (11/30 cases) found to be indeterminate (i.e., no spikes identified on MEG). Coherence analysis provided an overall match rate of 77% (20/26 cases). Of 19 cases without evidence of mesial temporal sclerosis, coherence analysis correctly lateralized the side of TLE in 11 cases (58%). Sensitivity of the ECD method was 41% (indeterminate cases included) and that of the coherence method 73%, with a positive predictive value of 70% for an Engel class Ia outcome. Intrasubject coherence imaging reliability was consistent from run‐to‐run (correlation >0.90) using three 10‐min epochs. Significance: MEG coherence analysis has greater sensitivity than the ECD method for lateralizing TLE and demonstrates reliable stability from run‐to‐run. It, therefore, improves upon the capability of MEG in providing further information of use in clinical decision‐making where the laterality of TLE is questioned.