Prototypic and arkypallidal neurons in the dopamine-intact external globus pallidus.

Studies in dopamine-depleted rats indicate that the external globus pallidus (GPe) contains two main types of GABAergic projection cell; so-called "prototypic" and "arkypallidal" neurons. Here, we used correlative anatomical and electrophysiological approaches in rats to determine whether and how this dichotomous organization applies to the dopamine-intact GPe. Prototypic neurons coexpressed the transcription factors Nkx2-1 and Lhx6, comprised approximately two-thirds of all GPe neurons, and were the major GPe cell type innervating the subthalamic nucleus (STN). In contrast, arkypallidal neurons expressed the transcription factor FoxP2, constituted just over one-fourth of GPe neurons, and innervated the striatum but not STN. In anesthetized dopamine-intact rats, molecularly identified prototypic neurons fired at relatively high rates and with high regularity, regardless of brain state (slow-wave activity or spontaneous activation). On average, arkypallidal neurons fired at lower rates and regularities than prototypic neurons, and the two cell types could be further distinguished by the temporal coupling of their firing to ongoing cortical oscillations. Complementing the activity differences observed in vivo, the autonomous firing of identified arkypallidal neurons in vitro was slower and more variable than that of prototypic neurons, which tallied with arkypallidal neurons displaying lower amplitudes of a "persistent" sodium current important for such pacemaking. Arkypallidal neurons also exhibited weaker driven and rebound firing compared with prototypic neurons. In conclusion, our data support the concept that a dichotomous functional organization, as actioned by arkypallidal and prototypic neurons with specialized molecular, structural, and physiological properties, is fundamental to the operations of the dopamine-intact GPe.

What dose of tranexamic acid is most effective and safe for adult patients undergoing cardiac surgery?

A best evidence topic in cardiac surgery was written according to a structured protocol. The question addressed was: what dose of tranexamic acid is most effective and safe for adult patients undergoing cardiac surgery? Altogether 586 papers were found using the reported search, of which 12 represented the best evidence to answer the clinical question. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers are tabulated. Current evidence shows clinical benefit of using high-dose tranexamic acid (>80 mg/kg total dose) as opposed to low-dose tranexamic acid (<50 mg/kg total dose) in cardiac surgery with cardiopulmonary bypass. Evidence from a large randomized controlled trial shows that patients receiving high-dose tranexamic acid lose less blood postoperatively than patients receiving low-dose tranexamic acid (590 vs 820 ml, P = 0.01). Patients receiving high-dose tranexamic acid also require fewer units of blood product transfusion (2.5 units vs 4.1 units; P = 0.02) and are less likely to undergo repeat surgery to achieve haemostasis. This effect is larger in those who are at high risk of bleeding. Several prospective studies comparing doses found no difference in clinical outcomes between high- and low-dose regimens, but excluded patients at high risk of bleeding. However, data from numerous observational studies demonstrate that tranexamic acid use is associated with an increased risk of postoperative seizure; one analysis showed tranexamic acid use to be a very strong independent predictor (odds ratio = 14.3, P < 0.001). There is also evidence that this risk of seizure is dose-dependent, with the greatest risk at higher doses of tranexamic acid. We conclude that, in general, patients with a high risk of bleeding should receive high-dose tranexamic acid, while those at low risk of bleeding should receive low-dose tranexamic acid with consideration given to potential dose-related seizure risk. We recommend the regimens of high-dose (30 mg kg(-1) bolus + 16 mg kg(-1) h(-1) + 2 mg kg(-1) priming) and low-dose (10 mg kg(-1) bolus + 1 mg kg(-1) h(-1) + 1 mg kg(-1) priming) tranexamic acid, as these are well established in terms of safety profile and have the strongest evidence for efficacy.

Distinct developmental origins manifest in the specialized encoding of movement by adult neurons of the external globus pallidus.

Transcriptional codes initiated during brain development are ultimately realized in adulthood as distinct cell types performing specialized roles in behavior. Focusing on the mouse external globus pallidus (GPe), we demonstrate that the potential contributions of two GABAergic GPe cell types to voluntary action are fated from early life to be distinct. Prototypic GPe neurons derive from the medial ganglionic eminence of the embryonic subpallium and express the transcription factor Nkx2-1. These neurons fire at high rates during alert rest, and encode movements through heterogeneous firing rate changes, with many neurons decreasing their activity. In contrast, arkypallidal GPe neurons originate from lateral/caudal ganglionic eminences, express the transcription factor FoxP2, fire at low rates during rest, and encode movements with robust increases in firing. We conclude that developmental diversity positions prototypic and arkypallidal neurons to fulfil distinct roles in behavior via their disparate regulation of GABA release onto different basal ganglia targets.