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.

Venous thromboembolism risk in patients receiving neoadjuvant chemotherapy for bladder cancer.

INTRODUCTION: There is limited evidence to inform thromboprophylaxis use for patients receiving neoadjuvant chemotherapy prior to surgery in bladder cancer. We sought to determine the incidence of venous thromboembolism (VTE) in patients receiving neoadjuvant chemotherapy and cystectomy. We also assessed if the Khorana score was associated with VTE risk. METHODS: A retrospective cohort study was performed on consecutive patients who received a radical cystectomy for bladder cancer at The Ottawa Hospital between January 2016 and August 2020. Demographic information, chemotherapy data, operative characteristics, VTE and bleeding outcomes were collected from the start of treatment to 90 days postoperative. A Khorana score was calculated for each patient who received neoadjuvant chemotherapy. The primary outcome for this study was the incidence of VTE from the time the patient started treatment with neoadjuvant chemotherapy until 90 days post-cystectomy. Secondary outcomes included risk factors for VTE during neoadjuvant chemotherapy. RESULTS: Among 181 radical cystectomy cases during the study period, 123 had muscle-invasive disease and 72 (39.8%) received neoadjuvant chemotherapy. Eighteen (25.0%) patients who received neoadjuvant chemotherapy and radical cystectomy developed a VTE from the start of chemotherapy to 90 days postoperative. Thirteen of the 18 VTEs (72%) occurred while the patient was receiving chemotherapy. In multivariable analysis, the only factor associated with a significantly increased risk of VTE was treatment with neoadjuvant chemotherapy (Relative risk (RR) 3.05, 95% confidence interval [CI] 1.16-8.02; P = 0.02). A higher Khorana score was not associated with an increased risk of VTE in patients who received neoadjuvant chemotherapy (RR = 0.33, 95% CI 0.08-1.28, P = 0.11). One (1.4%) patient had a major bleeding event during neoadjuvant chemotherapy. CONCLUSIONS: Patients receiving neoadjuvant chemotherapy and radical cystectomy are at very high-risk of VTE. Prospective studies that assess the benefits and harms of pharmacologic thromboprophylaxis in this population are needed.

Dopamine and Huntington's disease.

Huntington's disease (HD) is an incurable, inherited, progressive neurodegenerative disorder that is defined by a combination of motor, cognitive and psychiatric features. Pre-clinical and clinical studies have demonstrated an important role for the dopamine (DA) system in HD with dopaminergic dysfunction at the level of both DA release and DA receptors. It is, therefore, not surprising that the drug treatments most commonly used in HD are anti-dopaminergic agents. Their use is based primarily on the belief that the characteristic motor impairments are a result of overactivation of the central dopaminergic pathways. While this is a useful starting place, it is clear that the behavior of the central dopaminergic pathways is not fully understood in this condition and may change as a function of disease stage. In addition, how abnormalities in dopaminergic systems may underlie some of the non-motor features of HD has also been poorly investigated and this is especially important given the greater burden these place on the patients' and families' quality of life. In this review, we discuss what is known about central dopaminergic pathways in HD and how this informs us about the mechanisms of action of the dopaminergic therapies used to treat it. By doing so, we will highlight some of the paradoxes that exist and how solving them may reveal new insights for improved treatment of this currently incurable condition, including the possibility that such drugs may even have effects on disease progression and pathogenesis.