Fernanda Carvalho Poyraz

BACKGROUND: Major ABO-incompatible platelet transfusions are associated with poor intracerebral hemorrhage (ICH) outcomes, yet drivers for this relationship remain unclear. Brain magnetic resonance imaging (MRI) ischemic lesions after ICH are neuroimaging biomarkers of secondary brain injury and are associated with poor outcomes. Given that ABO-incompatible platelet transfusions can induce immune complex formation, thrombo-inflammation, and endothelial barrier disruption, factors that could exacerbate cerebral ischemia, we explored whether major ABO-incompatible platelet transfusions are risk factors for ischemic lesions on brain MRI after ICH. METHODS: Adult patients admitted to a tertiary-care academic center between 2009 and 2016 who received a single-platelet transfusion within 24 hours of admission after an ICH, had available donor/recipient ABO data, and brain MRI during the hospitalization were analyzed. Adjusted regression models evaluated relationships between major ABO-incompatible platelet units and MRI ischemic lesions. RESULTS: A total of 40 patients were included in the study. The mean age was 67.1 (SD, 14.1), and 37.5% were female. Twenty percent of patients received a major ABO-incompatible platelet unit. Major ABO-incompatible platelet transfusions were associated with increased odds of MRI ischemic lesions after adjusting for ICH severity (adjusted odds ratio, 9.2 [95% CI, 1.3–62.7]). CONCLUSIONS: Our exploratory findings suggest that major ABO-incompatible platelet transfusions may contribute to secondary brain injury after ICH. Further work is needed to assess whether avoiding major ABO-incompatible platelet transfusions can prevent secondary brain injury burden and improve ICH outcomes.

Background: Anemia is associated with poor intracerebral hemorrhage (ICH) outcomes, yet the relationship of red blood cell (RBC) transfusions to ICH complications and functional outcomes remains unclear. We investigated the impact of RBC transfusion on hospital thromboembolic and infectious complications and outcomes in patients with ICH. Methods and Results: Consecutive patients with spontaneous ICH enrolled in a single‐center, prospective cohort study from 2009 to 2018 were assessed. Primary analyses assessed relationships of RBC transfusions on incident thromboembolic and infectious complications occurring after the transfusion. Secondary analyses assessed relationships of RBC transfusions with mortality and poor discharge modified Rankin Scale score 4 to 6. Multivariable logistic regression models adjusted for baseline demographics and medical disease severity (Acute Physiology and Chronic Health Evaluation II), and ICH severity (ICH score).Of 587 patients with ICH analyzed, 88 (15%) received at least one RBC transfusion. Patients receiving RBC transfusions had worse medical and ICH severity. Though patients receiving RBC transfusions had more complications at any point during the hospitalization (64.8% versus 35.9%), we found no association between RBC transfusion and incident complications in our regression models (adjusted odds ratio [aOR], 0.71 [95% CI, 0.42–1.20]). After adjusting for disease severity and other relevant covariates, we found no significant association between RBC transfusion and mortality (aOR, 0.87 [95% CI, 0.45–1.66]) or poor discharge modified Rankin Scale score (aOR, 2.45 [95% CI, 0.80–7.61]). Conclusions: In our cohort with ICH, RBC transfusions were expectedly given to patients with higher medical and ICH severity. Taking disease severity and timing of transfusions into account, RBC transfusion was not associated with incident hospital complications or poor clinical ICH outcomes.

Background: Hemoglobin concentration and diffusion-weighted imaging (DWI) ischemic lesions are separately known to be associated with poor intracerebral hemorrhage (ICH) outcomes. While hemoglobin concentrations have known relationships with ischemic stroke, it is unclear whether hemoglobin concentration is associated with DWI ischemic lesions after ICH. We sought to investigate the hypothesis that hemoglobin concentrations would associate with DWI lesions after ICH and further investigated their relationships with clinical outcomes. Methods: Supratentorial ICH patients enrolled between 2010 and 2016 to a prospective, multicenter, observational cohort study (ERICH study [Ethnic/Racial Variations of Intracerebral Hemorrhage]) were assessed. Patients from this study with baseline, admission hemoglobin, and hospitalization magnetic resonance imaging were analyzed. Hemoglobin was examined as the primary exposure variable defined as a continuous variable (g/dL). Magnetic resonance imaging DWI ischemic lesion presence was assessed as the primary radiographic outcome. Primary analyses assessed relationships of hemoglobin with DWI lesions. Secondary analyses assessed relationships of DWI lesions with poor 3-month outcomes (modified Rankin Scale score, 4–6). These analyses were performed using separate multivariable logistic regression models adjusting for relevant covariates. Results: Of 917 patients with ICH analyzed, mean baseline hemoglobin was 13.8 g/dL (±1.9), 60% were deep ICH, and DWI lesions were identified in 27% of the cohort. In our primary analyses, increased hemoglobin, defined as a continuous variable, was associated with DWI lesions (adjusted odds ratio, 1.21 per 1 g/dL change in hemoglobin [95% CI, 1.07–1.37]) after adjusting for sex, race, ICH severity, time to magnetic resonance imaging, and acute blood pressure change. In secondary analyses, DWI lesions were associated with poor 3-month outcomes (adjusted odds ratio, 1.83 [95% CI, 1.24–2.69]) after adjusting for similar covariates. Conclusions: We identified novel relationships between higher baseline hemoglobin concentrations and DWI ischemic lesions in patients with ICH. Further studies are required to clarify the role of hemoglobin concentration on both cerebral small vessel disease pathophysiology and ICH outcomes.

Background: The objective of this study was to evaluate factors associated with intraventricular hemorrhage (IVH) expansion and its association with long-term outcomes. Methods: We performed a post hoc analysis of the international, multi-center CLEAR III trial (Clot Lysis: Evaluating Accelerated Resolution of Intraventricular Hemorrhage) which enrolled IVH patients between September 1, 2009, and January 31, 2015. The exposure was IVH expansion, defined as >1 mL increase in volume between baseline and stability computed tomography scans, before treatment randomization. We assessed factors associated with IVH expansion and secondarily assessed the relationship of IVH expansion with clinical outcomes: composite of death or major disability (modified Rankin Scale score, >3), and mortality alone at 6 months. The relationship of IVH expansion on ventriculoperitoneal shunt placement was additionally explored. Multivariable logistic regression was used for all analyses. Results: Of 500 IVH patients analyzed, the mean age was 59 (±11) years old, 44% were female and 135 (27%) had IVH expansion. In multivariable regression models, factors associated with IVH expansion were baseline parenchymal intracerebral hemorrhage (ICH) volume (adjusted odds ratio [OR], 1.04 per 1 mL increase [95% CI, 1.01–1.08]), presence of parenchymal hematoma expansion: >33% (adjusted OR, 6.63 [95% CI, 3.92–11.24]), time to stability head CT (adjusted OR, 0.71 per 1 hour increase [95% CI, 0.54–0.94]), and thalamic hematoma location (adjusted OR, 1.68 [95% CI, 1.01–2.79]) while additionally adjusting for age, sex, and race. In secondary analyses, IVH expansion was associated with higher odds of poor 6-month outcomes (adjusted OR, 1.84 [95% CI, 1.12–3.02]) but not mortality (OR, 1.40 [95% CI, 0.78–2.50]) after adjusting for baseline ICH volume, thalamic ICH location, age, anticoagulant use, Glasgow Coma Scale score, any withdrawal of care order, and treatment randomization arm. However, there were no relationships of IVH expansion on subsequent ventriculoperitoneal shunt placement (adjusted OR, 1.02 [95% CI, 0.58–1.80]) after adjusting for similar covariates. Conclusions: In a clinical trial cohort of patients with large IVH, acute hematoma characteristics, specifically larger parenchymal volume, hematoma expansion, and thalamic ICH location were associated with IVH expansion. Given that IVH expansion resulted in poor functional outcomes, exploration of treatment approaches to optimize hemostasis and prevent IVH expansion, particularly in patients with thalamic ICH, require further study. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT00784134.

Altered dopamine D2 receptor (D2R) binding in the striatum has been associated with abnormal motivation in neuropsychiatric disorders, including schizophrenia. Here, we tested whether motivational deficits observed in mice with upregulated D2Rs (D2R-OE_devmice) are reversed by decreasing function of the striatopallidal “no-go” pathway. To this end, we expressed the G_αi-coupled designer receptor hM4D in adult striatopallidal neurons and activated the receptor with clozapine-N-oxide (CNO). Using a head-mounted miniature microscope we confirmed with calcium imaging in awake mice that hM4D activation by CNO inhibits striatopallidal function measured as disinhibited downstream activity in the globus pallidus. Mice were then tested in three operant tasks that address motivated behavior, the progressive ratio task, the progressive hold-down task, and outcome devaluation. Decreasing striatopallidal function in the dorsomedial striatum or nucleus accumbens core enhanced motivation in D2R-OE_devmice and control littermates. This effect was due to increased response initiation but came at the cost of goal-directed efficiency. Moreover, response vigor and the sensitivity to changes in reward value were not altered. Chronic activation of hM4D by administering CNO for 2 weeks in drinking water did not affect motivation due to a tolerance effect. However, the acute effect of CNO on motivation was reinstated after discontinuing chronic treatment for 48 h. Used as a therapeutic approach, striatopallidal inhibition should consider the risk of impairing goal-directed efficiency and behavioral desensitization.SIGNIFICANCE STATEMENTMotivation involves a directional component that allows subjects to efficiently select the behavior that will lead to an optimal outcome and an activational component that initiates and maintains the vigor and persistence of actions. Striatal output pathways modulate motivated behavior, but it remains unknown how these pathways regulate specific components of motivation. Here, we found that the indirect pathway controls response initiation without affecting response vigor or the sensitivity to changes in the reward outcome. A specific enhancement in the activational component of motivation, however, can come at the cost of goal-directed efficiency when a sustained response is required to obtain the goal. These data should inform treatment strategies for brain disorders with impaired motivation such as schizophrenia and Parkinson's disease.

LeuT is a bacterial sodium/leucine symporter, related to human neurotransmitters targeted by antidepressant drugs. Now spin labeling and EPR analysis on the dynamics in the extracellular vestibule of LeuT reveal the conformational changes caused by Na+ and Leu binding that drive the transport cycle. Crystallographic, computational and functional analyses of LeuT have revealed details of the molecular architecture of Na+-coupled transporters and the mechanistic nature of ion/substrate coupling, but the conformational changes that support a functional transport cycle have yet to be described fully. We have used site-directed spin labeling and electron paramagnetic resonance (EPR) analysis to capture the dynamics of LeuT in the region of the extracellular vestibule associated with the binding of Na+ and leucine. The results outline the Na+-dependent formation of a dynamic outward-facing intermediate that exposes the primary substrate binding site and the conformational changes that occlude this binding site upon subsequent binding of the leucine substrate. Furthermore, the binding of the transport inhibitors tryptophan, clomipramine and octyl-glucoside is shown to induce structural changes that distinguish the resulting inhibited conformation from the Na+/leucine-bound state.