A922 Sequential measurement of 1 hour creatinine clearance (1-CRCL) in critically ill patients at risk of acute kidney injury (AKI)

Meeting abstrac

Activation of mGlu3 Receptors Stimulates the Production of GDNF in Striatal Neurons

Metabotropic glutamate (mGlu) receptors have been considered potential targets for the therapy of experimental parkinsonism. One hypothetical advantage associated with the use of mGlu receptor ligands is the lack of the adverse effects typically induced by ionotropic glutamate receptor antagonists, such as sedation, ataxia, and severe learning impairment. Low doses of the mGlu2/3 metabotropic glutamate receptor agonist, LY379268 (0.25–3 mg/kg, i.p.) increased glial cell line-derived neurotrophic factor (GDNF) mRNA and protein levels in the mouse brain, as assessed by in situ hybridization, real-time PCR, immunoblotting, and immunohistochemistry. This increase was prominent in the striatum, but was also observed in the cerebral cortex. GDNF mRNA levels peaked at 3 h and declined afterwards, whereas GDNF protein levels progressively increased from 24 to 72 h following LY379268 injection. The action of LY379268 was abrogated by the mGlu2/3 receptor antagonist, LY341495 (1 mg/kg, i.p.), and was lost in mGlu3 receptor knockout mice, but not in mGlu2 receptor knockout mice. In pure cultures of striatal neurons, the increase in GDNF induced by LY379268 required the activation of the mitogen-activated protein kinase and phosphatidylinositol-3-kinase pathways, as shown by the use of specific inhibitors of the two pathways. Both in vivo and in vitro studies led to the conclusion that neurons were the only source of GDNF in response to mGlu3 receptor activation. Remarkably, acute or repeated injections of LY379268 at doses that enhanced striatal GDNF levels (0.25 or 3 mg/kg, i.p.) were highly protective against nigro-striatal damage induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in mice, as assessed by stereological counting of tyrosine hydroxylase-positive neurons in the pars compacta of the substantia nigra. We speculate that selective mGlu3 receptor agonists or enhancers are potential candidates as neuroprotective agents in Parkinson's disease, and their use might circumvent the limitations associated with the administration of exogenous GDNF

Effects of tranexamic acid on death, disability, vascular occlusive events and other morbidities in patients with acute traumatic brain injury (CRASH-3): a randomised, placebo-controlled trial

Background Tranexamic acid reduces surgical bleeding and decreases mortality in patients with traumatic extracranial bleeding. Intracranial bleeding is common after traumatic brain injury (TBI) and can cause brain herniation and death. We aimed to assess the effects of tranexamic acid in patients with TBI. Methods This randomised, placebo-controlled trial was done in 175 hospitals in 29 countries. Adults with TBI who were within 3 h of injury, had a Glasgow Coma Scale (GCS) score of 12 or lower or any intracranial bleeding on CT scan, and no major extracranial bleeding were eligible. The time window for eligibility was originally 8 h but in 2016 the protocol was changed to limit recruitment to patients within 3 h of injury. This change was made blind to the trial data, in response to external evidence suggesting that delayed treatment is unlikely to be effective. We randomly assigned (1:1) patients to receive tranexamic acid (loading dose 1 g over 10 min then infusion of 1 g over 8 h) or matching placebo. Patients were assigned by selecting a numbered treatment pack from a box containing eight packs that were identical apart from the pack number. Patients, caregivers, and those assessing outcomes were masked to allocation. The primary outcome was head injury-related death in hospital within 28 days of injury in patients treated within 3 h of injury. We prespecified a sensitivity analysis that excluded patients with a GCS score of 3 and those with bilateral unreactive pupils at baseline. All analyses were done by intention to treat. This trial was registered with ISRCTN (ISRCTN15088122), ClinicalTrials.gov (NCT01402882), EudraCT (2011-003669-14), and the Pan African Clinical Trial Registry (PACTR20121000441277). Results Between July 20, 2012, and Jan 31, 2019, we randomly allocated 12 737 patients with TBI to receive tranexamic acid (6406 [50·3%] or placebo [6331 [49·7%], of whom 9202 (72·2%) patients were treated within 3 h of injury. Among patients treated within 3 h of injury, the risk of head injury-related death was 18·5% in the tranexamic acid group versus 19·8% in the placebo group (855 vs 892 events; risk ratio [RR] 0·94 [95% CI 0·86-1·02]). In the prespecified sensitivity analysis that excluded patients with a GCS score of 3 or bilateral unreactive pupils at baseline, the risk of head injury-related death was 12·5% in the tranexamic acid group versus 14·0% in the placebo group (485 vs 525 events; RR 0·89 [95% CI 0·80-1·00]). The risk of head injury-related death reduced with tranexamic acid in patients with mild-to-moderate head injury (RR 0·78 [95% CI 0·64-0·95]) but not in patients with severe head injury (0·99 [95% CI 0·91-1·07]; p value for heterogeneity 0·030). Early treatment was more effective than was later treatment in patients with mild and moderate head injury (p=0·005) but time to treatment had no obvious effect in patients with severe head injury (p=0·73). The risk of vascular occlusive events was similar in the tranexamic acid and placebo groups (RR 0·98 (0·74-1·28). The risk of seizures was also similar between groups (1·09 [95% CI 0·90-1·33]). Interpretation Our results show that tranexamic acid is safe in patients with TBI and that treatment within 3 h of injury reduces head injury-related death. Patients should be treated as soon as possible after injury. Funding National Institute for Health Research Health Technology Assessment, JP Moulton Charitable Trust, Department of Health and Social Care, Department for International Development, Global Challenges Research Fund, Medical Research Council, and Wellcome Trust (Joint Global Health Trials scheme)

Studies of plasma membrane function in human hypertension.

Considerable evidence has emerged in recent years to suggest that the cell plasma membrane handles univalent and divalent cations abnormally in patients with untreated essential hypertension. Many of the phenomena originally discovered in patients with the established disease have now been found to occur in the genetically hypertension-prone offspring of hypertensive patients when their blood pressure is normal. The studies described in this thesis were designed to investigate the mechanisms which might explain these disturbances of membrane function. The first experiments were performed to investigate whether a circulating blood-borne factor might be present in excess in hypertensive patients and their relatives and by exposing cells from subjects with normal blood pressure and no family history to serum from patients and their offspring, the object was to try and reproduce the findings in hypertension. These studies were negative. Because of many reports of an overactive sympathetic nervous system in hypertension leucocytes were exposed to noradrenaline and this was found to influence sodium transport in cells from control subjects suggesting that at least some of the phenomena described in hypertension might be related to autonomic dysfunction. An alternative hypothesis to explain these abnormalities is that there is a genetically predetermined disturbance of the physicochemical structure of the plasma membrane which alters its function. The abnormality might well lie within the lipid fraction of the cell membrane. Attempts to alter this were undertaken using changes in dietary fat intake. These lowered blood pressure slightly and indeed altered sodium influx. The final series of experiments involved detailed examination of one fraction of plasma membrane phospholipids which is highly metabolically active, namely the phosphoinositides, and indeed using red cells it was possible to demonstrate that these lipids are overactive in the early stages of hypertension. These findings suggest that the plasma membrane is structurally abnormal in hypertension, the abnormality may reside in the phospho- inositide lipids and may possibly be susceptible to dietary manipulation

Affectionate communication received from spouses predicts stress hormone levels in healthy adults

Recent research on the communication of affection has illuminated its implications for mental and physical health. In particular, affectionate communication has been shown to covary with healthy hormonal variation and accelerated recovery from stress. The present study focuses on the association between marital affection and hormonal markers of stress regulation, including cortisol, dehydroepiandrosterone-sulfate (DHEA-S), and their ratio. Twenty healthy adults and their spouses provided independent reports of their propensity for verbal, nonverbal, and support-based expressions of affection prior to providing saliva samples that were assayed for cortisol and DHEA-S. As hypothesized, spouses’ reports of verbal, nonverbal, and supportive affection significantly predicted participants’ waking cortisol levels, cortisol change, and cortisol:DHEA-S ratio. Participants’ own reports of affection were predictive of cortisol:DHEA-S ratio for verbal affection behaviors only, and were not predictive of participants’ waking cortisol, cortisol change, or DHEA-S. In addition, spouses’ reports of verbal, nonverbal, and supportive affection predicted participants’ evening cortisol levels. Results illustrate that affectionate communication from one’s spouse is related to hormonal stress regulation and suggest the possibility that interventions designed to increase affectionate behavior in romantic relationships may have stress-ameliorating physiological effects