Identification of a subset of trace amine-associated receptors and ligands as potential modulators of insulin secretion.

The worldwide prevalence of diabetes has reached 8.5% among adults, and this is characterised by elevated glucose concentrations and failing insulin secretion. Furthermore, most people with type 2 diabetes are either obese or overweight, with the associated dyslipidaemia contributing to the development of insulin resistance and increased cardiovascular risk. Here we incubated INS-1 pancreatic ß-cells for 72 h in RPMI-1640 media, or media supplemented with 28 mM glucose, 200 µM palmitic acid, and 200 µM oleic acid as a cellular model of diabetic glucolipotoxicity. Illumina HiSeq gene expression analysis showed the trace amine-associated receptor (TAAR) family to be among the most highly downregulated by glucolipotoxicity. Importantly, MetaCore integrated knowledge database, from Clarivate Analytics, indicated potential TAAR impact on insulin secretion through adenylyl cyclase signalling pathways. We therefore investigated the effect of TAAR ligands on cAMP signalling and insulin secretion, and found that only the branch of the TAAR family tree that is activated by isopentylamine, 2-phenylethylamine, p-tyramine, and agmatine significantly increased intracellular cAMP and resulted in increased insulin secretion from INS-1 cells and primary mouse islets under normal conditions. Crucially however, this enhancement was not evident when the receptor family was downregulated by glucolipotoxic conditions. This data indicates that a subset of TAARs are regulators of insulin secretion in pancreatic ß-cells, and that their downregulation contributes to glucolipotoxic inhibition of insulin secretion. As such they may be potential targets for treatment of type 2 diabetes.

In vitro effects of a kaolin-coated hemostatic dressing on anticoagulated blood.

BACKGROUND: The use of kaolin-coated dressings has become common and have efficacy in normal patients, but their increased use will inevitably include use on bleeding patients taking anticoagulants. We hypothesize that kaolin coating material (KCM) will improve clotting regardless of anticoagulation medication. METHODS: A prospective study was performed on blood from patients who were on a vitamin K antagonist (VKA), unfractionated heparin (UH), an antiplatelet (AP) agent, a Xa inhibitor (Xa), or a direct thrombin inhibitor (DTI). None were on more than one type of anticoagulation medication. Viscoelastic testing was performed with and without KCM. All p values were adjusted for multiple comparisons. RESULTS: The addition of KCM significantly decreased the time for initial clot formation (CT) in all groups. The mean CT for controls was decreased from 692 to 190.8 s (p < 0.0001). KCM decreased the initial clot formation time by about 1.5 times in those on DTI (p = 0.043) and 2.5 times in those taking AP medication (p < 0.001). The most profound effect was seen in those on UH (no KCM 1,602 s vs. KCM 440 s; p < 0.001), VKA (no KCM 1,152 s vs. 232 s; p < 0.01), and Xa (no KCM 1,342 s vs. 287 s; p < 0.001). Analysis of other clot formation parameters revealed that KCM significantly improved the clot formation kinetics (CFT) only in patients taking Xa (p = 0.03). KCM improved maximum clot strength in patients on Xa inhibitors (p = 0.05). Patients on UH had a larger effect size with an increase in clot strength from 24.35 mm to 43.35 mm whereas those on Xa had an increase of 38.7 mm to 49.85 mm. CONCLUSION: In this in vitro analysis, the addition of KCM to the blood of patients taking any of these anticoagulation medications significantly improved the time to initial clot formation, indicating that kaolin-based hemostatic dressings will be effective in initiating clot formation in patients on anticoagulants. LEVEL OF EVIDENCE: Therapeutic, level IV.

Drastic Genome Reduction in an Herbivore's Pectinolytic Symbiont.

Pectin, an integral component of the plant cell wall, is a recalcitrant substrate against enzymatic challenges by most animals. In characterizing the source of a leaf beetle's (Cassida rubiginosa) pectin-degrading phenotype, we demonstrate its dependency on an extracellular bacterium housed in specialized organs connected to the foregut. Despite possessing the smallest genome (0.27 Mb) of any organism not subsisting within a host cell, the symbiont nonetheless retained a functional pectinolytic metabolism targeting the polysaccharide's two most abundant classes: homogalacturonan and rhamnogalacturonan I. Comparative transcriptomics revealed pectinase expression to be enriched in the symbiotic organs, consistent with enzymatic buildup in these structures following immunostaining with pectinase-targeting antibodies. Symbiont elimination results in a drastically reduced host survivorship and a diminished capacity to degrade pectin. Collectively, our findings highlight symbiosis as a strategy for an herbivore to metabolize one of nature's most complex polysaccharides and a universal component of plant tissues.

Cannabis Use Has Negligible Effects Following Severe Traumatic Injury.

Nearly half of all states have legalized medical marijuana or recreational-use marijuana. As more states move toward legalization, the effects on injured patients must be evaluated. This study sought to determine effects of cannabis positivity at the time of severe injury on hospital outcomes compared with individuals negative for illicit substances and those who were users of other illicit substances. A Level I trauma center performed a retrospective chart review covering subjects over a 2-year period with toxicology performed and an Injury Severity Score (ISS) of more than 16. These individuals were divided into the negative and positive toxicology groups, further divided into the marijuana-only, other drugs-only, and mixed-use groups. Differences in presenting characteristics, hospital length of stay, intensive care unit (ICU) stays, ventilator days, and death were compared. A total of 8,441 subjects presented during the study period; 2,134 (25%) of these had toxicology performed; 843 (40%) had an ISS of more than 16, with 347 having negative tests (NEG); 70 (8.3%) substance users tested positive only for marijuana (MO), 323 (38.3%) for other drugs-only, excluding marijuana (OD), and 103 (12.2%) subjects showed positivity for mixed-use (MU). The ISS was similar for all groups. No differences were identified in Glasgow Coma Scale (GCS), ventilator days, blood administration, or ICU/hospital length of stay when comparing the MO group with the NEG group. Significant differences occurred between the OD group and the NEG/MO/MU groups for GCS, ICU length of stay, and hospital charges. Cannabis users suffering from severe injury demonstrated no detrimental outcomes in this study compared with nondrug users.