Potential role of the CD38/cADPR signaling pathway as an underlying mechanism of the effects of medetomidine on insulin and glucose homeostasis

ObjectiveTo investigate the CD38/cADPR signaling pathway as possible underlying mechanism of the effects of medetomidine on insulin and glucose homeostasis.AnimalsThirty–two C57BL/6 mice of both sexes.MethodsWild–type (WT) and CD38–knockout (CD38^?/?) mice received medetomidine (50 μg kg^?1) or a similar volume of 0.9% NaCl (control) by intraperitoneal (IP) injection (each group n = 8). The mice were euthanized 45 minutes later with sodium pentobarbital IP and blood was sampled via cardiac puncture. Insulin and glucose concentrations were measured by radioimmunoassay and by the oxygen rate method, respectively. Data were analyzed with anova and Bonferroni post hoc (5% significance) and are shown as mean ± SD.ResultsPlasma insulin and glucose concentrations were similar between WT and CD38^?/? mice under control conditions. As compared to controls, medetomidine administration produced a statistically significant decrease in plasma insulin concentrations in the WT mice whereas the decrease in the CD38^?/? mice was not statistically significant. Correspondingly, medetomidine caused a significantly greater increase in plasma glucose concentrations in the WT than in the CD38^?/? mice.ConclusionThe CD38/cADPR signaling pathway may be one underlying mechanism of the glucose and insulin effects of the alpha–2 adrenergic receptor agonist medetomidine and likely other drugs of its’ class.     

A neoproterozoic snowball earth

Negative carbon isotope anomalies in carbonate rocks bracketing Neoproterozoic glacial deposits in Namibia, combined with estimates of thermal subsidence history, suggest that biological productivity in the surface ocean collapsed for millions of years. This collapse can be explained by a global glaciation (that is, a snowball Earth), which ended abruptly when subaerial volcanic outgassing raised atmospheric carbon dioxide to about 350 times the modern level. The rapid termination would have resulted in a warming of the snowball Earth to extreme greenhouse conditions. The transfer of atmospheric carbon dioxide to the ocean would result in the rapid precipitation of calcium carbonate in warm surface waters, producing the cap carbonate rocks observed globally.     

Herbicides inhibiting branched-chain amino acid biosynthesis

Herbicides inhibiting branched-chain amino acid biosynthesis represent a signal advance in crop protection chemistry, with implications for both practical weed control and basic agricultural science. In practical terms, at least 20 different active ingredients are currently marketed or are in development, and more may be expected. They offer selectivity in virtually every major crop, unprecedented low use rates, and inherently selective toxicity to plants. In scientific terms, the research behind these compounds shows modern agricultural chemistry at its best. Synthesis has been integrated with other disciplines to understand and rapidly optimize properties. In the process, basic knowledge has been gained in chemistry, biochemistry, and strategies for finding new agrochemicals. This issue provides the first unified, interdisciplinary overview of the three major classes of inhibitors–sulfonylureas, imidazolinones, and triazolopyrimidines. The following introductory note explores some implications of this research.     

Use of a soluble epoxide hydrolase inhibitor as an adjunctive analgesic in a horse with laminitis

HistoryA 4‐year old, 500 kg Thoroughbred female horse diagnosed with bilateral forelimb laminitis and cellulitis on the left forelimb became severely painful and refractory to non‐steroidal anti‐inflammatory therapy (flunixin meglumine on days 1, 2, 3 and 4; and phenylbutazone on days 5, 6 and 7) alone or in combination with gabapentin (days 6 and 7).Physical examinationPain scores assessed independently by three individuals with a visual analog scale (VAS; 0 = no pain and 10 = worst possible pain) were 8.5 on day 6, and it increased to 9.5 on day 7. Non‐invasive blood pressure monitoring revealed severe hypertension.ManagementAs euthanasia was being considered for humane reasons, a decision was made to add an experimental new drug, trans‐4‐{4‐[3‐(4‐Trifluoromethoxy‐phenyl)‐ureido]‐cyclohexyloxy}‐benzoic acid (t‐TUCB), which is a soluble epoxide hydrolase (sEH) inhibitor, to the treatment protocol. Dose and frequency of administration were selected based on the drug potency against equine sEH to produce plasma concentrations within the range of 30 nmol L^?1 and 2.5 μmol L^?1. Pain scores decreased sharply and remarkably following t‐TUCB administration and blood pressure progressively decreased to physiologic normal values. Plasma concentrations of t‐TUCB, measured daily, were within the expected range, whereas phenylbutazone and gabapentin plasma levels were below the suggested efficacious concentrations.Follow upNo adverse effects were detected on clinical and laboratory examinations during and after t‐TUCB administration. No new episodes of laminitis have been noted up to the time of writing (120 days following treatment).ConclusionsInhibition of sEH with t‐TUCB was associated with a significant improvement in pain scores in one horse with laminitis whose pain was refractory to the standard of care therapy. No adverse effects were noticed. Future studies evaluating the analgesic and protective effects of these compounds in painful inflammatory diseases in animals are warranted.     

Bryophyllum pinnatum poisoning of cattle

SUMMARY Two adult cattle died within 48 h of being fed a large amount of Bryophyllum pinnatum plants collected from a house garden. Clinical signs became apparent the day after feeding and included hypersalivation, ataxia, severe cardiac arrhythmia and laboured respiration. The main necropsy findings were acute rumenitis, reduction of bronchiolar lumens and emphysema.