Activation of lactate receptor HCAR1 down-modulates neuronal activity in rodent and human brain tissue.

Lactate can be used by neurons as an energy substrate to support their activity. Evidence suggests that lactate also acts on a metabotropic receptor called HCAR1, first described in the adipose tissue. Whether HCAR1 also modulates neuronal circuits remains unclear. In this study, using qRT-PCR, we show that HCAR1 is present in the human brain of epileptic patients who underwent resective surgery. In brain slices from these patients, pharmacological HCAR1 activation using a non-metabolized agonist decreased the frequency of both spontaneous neuronal Ca <sup>2+</sup> spiking and excitatory post-synaptic currents (sEPSCs). In mouse brains, we found HCAR1 expression in different regions using a fluorescent reporter mouse line and in situ hybridization. In the dentate gyrus, HCAR1 is mainly present in mossy cells, key players in the hippocampal excitatory circuitry and known to be involved in temporal lobe epilepsy. By using whole-cell patch clamp recordings in mouse and rat slices, we found that HCAR1 activation causes a decrease in excitability, sEPSCs, and miniature EPSCs frequency of granule cells, the main output of mossy cells. Overall, we propose that lactate can be considered a neuromodulator decreasing synaptic activity in human and rodent brains, which makes HCAR1 an attractive target for the treatment of epilepsy

Increased blood product use among coronary artery bypass patients prescribed preoperative aspirin and clopidogrel

BACKGROUND: The administration of antiplatelet drugs before coronary artery bypass graft surgery (CABG) is associated with an increased risk of major hemorrhage and related surgical reexploration. Little is known about the relative effect of combined clopidogrel and aspirin on blood product use around the time of CABG. We evaluated the associated risk between the combined use of aspirin and clopidogrel and the transfusion of blood products perioperatively. METHODS: We retrospectively studied a cohort of 659 individuals who underwent a first CABG, without concomitant valvular or aortic surgery, at a single large Canadian cardiac surgical centre between January 2000 and April 2002. The four study exposure groups were those prescribed aspirin (n = 105), clopidogrel (n = 11), the combination of both (n = 46), or neither drug (n = 497), within 7 days prior to CABG. The primary study outcome was the excessive transfusion of blood products during CABG and up to the second post-operative day, defined as ≥ 2 units of packed red blood cells (PRBC), ≥ 2 units of fresh frozen plasma, ≥ 5 units of cryoprecipitate or ≥ 5 units of platelets. Secondary outcomes included the mean number of transfused units of each type of blood product. RESULTS: A greater mean number of units of PRBC were transfused among those who received clopidogrel alone (2.9) or in combination with aspirin (2.4), compared to those on aspirin alone (1.9) or neither antiplatelet drug (1.4) (P = 0.001). A similar trend was seen for the respective mean number of transfused units of platelets (3.6, 3.7, 1.3 and 1.0; P < 0.001) and fresh frozen plasma (2.5, 3.1, 2.3, 1.6; P = 0.01). Compared to non-users, the associated risk of excessive blood product transfusion was highest among recipients of aspirin and clopidogrel together (adjusted OR 2.2, 95% CI 1.1–4.3). No significant association was seen among lone users of aspirin (adjusted OR 1.0, 95% CI 0.6–1.6) or clopidogrel (adjusted OR 0.7, 95% CI 0.2–2.5), compared to non-users. CONCLUSIONS: While combined use of aspirin and clopidogrel shortly before CABG surgery may increase the associated risk of excess transfusion of blood products perioperatively, several study limitations prevent any confident conclusions from being drawn. Beyond challenging these findings, future research might focus on the value of both intraoperative monitoring of platelet function, and the effectiveness of antifibrinolytic agents, at reducing the risk of postoperative bleeding

Acoustic measures of low-frequency noise in extended high-frequency audiometry

A very high signal-to-noise ratio is required for equipment designed for extended high-frequency audiometry because listeners with almost no hearing ability in the extended high-frequency range may have normal hearing sensitivity in the lower frequencies. Two commercially available systems designed for pure-tone audiometry were evaluated both in the conventional and extended high-frequency range. Unwanted lower frequency signals greater than the noise floor occurred predominantly at presentation levels of approximately 110 dB SPL or higher. Test tones in the extended high-frequency range should be restricted to levels that are not associated with lower frequency noise

Effective surgical management of high-risk coronary patients using preoperative intra-aortic balloon counterpulsation therapy

The proportion of high-risk coronary patients submitted to surgical myocardial revascularization (CABG) is steadily increasing. High-risk patients utilize more hospital resources and have a higher procedural cost than low-moderate risk CABG patients. An efficient management is essential to improve outcome and reduce costs. This report entails three study periods. In an initial retrospective study coronary high-risk criteria were established. At least two of the following factors were required: redo CABG, unstable angina, left main stem stenosis greater than 70%, preoperative left ventricular ejection fraction < 0.30 and diffuse coronary artery disease. Poor preoperative cardiac performance was the major contributing factor for poor outcome. Intra-aortic balloon counterpulsation therapy (IABP) was introduced as preoperative therapy. During a second study period prospective randomized studies found preoperative IABP-therapy efficient, significantly improving both preoperative cardiac index (P < 0.0001), decreasing postoperative mortality (P < 0.0001) and morbidity, shorten intensive care unit stay as well as total hospital stay (P < 0.0001). Drug consumption was significantly reduced (P < 0.0001). Optimal timing was found to be 2 h prior to aortic cross-clamping and the therapy was found highly cost-beneficial with an average 36% reduction of the total procedural cost. During a third study period, well beyond any study protocol period, preoperative IABP therapy was again found highly effective with a close to 100% utilization rate in high-risk patients and continuous efficacy with excellent outcome, despite acceptance of sicker patients. During this post-study evaluation period 1/3 of the high-risk patients presented with 4 of the established risk factors. The use of preoperative IABP therapy is therefore highly recommended for high-risk coronary patients undergoing CABG