Citations

AbstractMutations in the LRRK2 kinase are the most common cause of familial Parkinson’s disease, and variants increase risk for the sporadic form of the disease. LRRK2 phosphorylates multiple RAB GTPases including RAB8A and RAB10. Phosphorylated RAB10 is recruited to centrosome-localized RILPL1, which may interfere with ciliogenesis in a disease-relevant context. Our previous studies indicate that the centrosomal accumulation of phosphorylated RAB8A causes centrosomal cohesion deficits in dividing cells, including in peripheral patient-derived cells. Here, we show that both RAB8 and RAB10 contribute to the centrosomal cohesion deficits. Pathogenic LRRK2 causes the centrosomal accumulation not only of phosho-RAB8 but also of phospho-RAB10, and the effects on centrosomal cohesion are dependent on RAB8, RAB10 and RILPL1. Conversely, the pathogenic LRRK2-mediated ciliogenesis defects correlate with the centrosomal accumulation of both phospho-RAB8 and phospho-RAB10. LRRK2-mediated centrosomal cohesion and ciliogenesis alterations are observed in patient-derived peripheral cells, as well as in primary astrocytes from mutant LRRK2 mice, and are reverted upon LRRK2 kinase inhibition. These data suggest that the LRRK2-mediated centrosomal cohesion and ciliogenesis defects are distinct cellular readouts of the same underlying phospho-RAB8/RAB10/RILPL1 nexus and highlight the possibility that either centrosomal cohesion and/or ciliogenesis alterations may serve as cellular biomarkers for LRRK2-related PD.

This paper presents the diagnostic criteria for hemodynamic orthostatic dizziness/vertigo to be included in the International Classification of Vestibular Disorders (ICVD). The aim of defining diagnostic criteria of hemodynamic orthostatic dizziness/vertigo is to help clinicians to understand the terminology related to orthostatic dizziness/vertigo and to distinguish orthostatic dizziness/vertigo due to global brain hypoperfusion from that caused by other etiologies. Diagnosis of hemodynamic orthostatic dizziness/vertigo requires: A) five or more episodes of dizziness, unsteadiness or vertigo triggered by arising or present during upright position, which subsides by sitting or lying down; B) orthostatic hypotension, postural tachycardia syndrome or syncope documented on standing or during head-up tilt test; and C) not better accounted for by another disease or disorder. Probable hemodynamic orthostatic dizziness/vertigo is defined as follows: A) five or more episodes of dizziness, unsteadiness or vertigo triggered by arising or present during upright position, which subsides by sitting or lying down; B) at least one of the following accompanying symptoms: generalized weakness/tiredness, difficulty in thinking/concentrating, blurred vision, and tachycardia/palpitations; and C) not better accounted for by another disease or disorder. These diagnostic criteria have been derived by expert consensus from an extensive review of 90 years of research on hemodynamic orthostatic dizziness/vertigo, postural hypotension or tachycardia, and autonomic dizziness. Measurements of orthostatic blood pressure and heart rate are important for the screening and documentation of orthostatic hypotension or postural tachycardia syndrome to establish the diagnosis of hemodynamic orthostatic dizziness/vertigo.

Abstract The plant homeodomain 6 gene (PHF6) is frequently mutated in human T-cell acute lymphoblastic leukemia (T-ALL); however, its specific functional role in leukemia development remains to be established. Here, we show that loss of PHF6 is an early mutational event in leukemia transformation. Mechanistically, genetic inactivation of Phf6 in the hematopoietic system enhances hematopoietic stem cell (HSC) long-term self-renewal and hematopoietic recovery after chemotherapy by rendering Phf6 knockout HSCs more quiescent and less prone to stress-induced activation. Consistent with a leukemia-initiating tumor suppressor role, inactivation of Phf6 in hematopoietic progenitors lowers the threshold for the development of NOTCH1-induced T-ALL. Moreover, loss of Phf6 in leukemia lymphoblasts activates a leukemia stem cell transcriptional program and drives enhanced T-ALL leukemia-initiating cell activity. These results implicate Phf6 in the control of HSC homeostasis and long-term self-renewal and support a role for PHF6 loss as a driver of leukemia-initiating cell activity in T-ALL. Significance: Phf6 controls HSC homeostasis, leukemia initiation, and T-ALL leukemia-initiating cell self-renewal. These results substantiate a role for PHF6 mutations as early events and drivers of leukemia stem cell activity in the pathogenesis of T-ALL. This article is highlighted in the In This Issue feature, p. 305

Background Whether the association of blood pressure ( BP ) during sleep (nocturnal BP ) with cognition differs by race is unknown. Methods and Results Participants in the GENOA (Genetic Epidemiology Network of Arteriopathy) Study underwent ambulatory BP measurements, brain magnetic resonance imaging, and cognitive function testing (the Rey Auditory Verbal Learning Test, the Digit Symbol Substitution Task, and the Trail Making Test Part B) between 2000 and 2007. We examined multivariable linear regression models of the nocturnal BP ‐cognition association. Among 755 participants (mean age, 63 years; 64% women; 42% self‐identified black race; 76% taking antihypertensive medication), mean nocturnal systolic BP ( SBP )/diastolic BP was 126/69 mm Hg, daytime SBP / diastolic BP level was 139/82 mm Hg, and mean reduction in SBP from day to night (dipping) was 9%. Among the entire sample, a race interaction was observed in Digit Symbol Substitution Task and Trail Making Test Part B (both P <0.15). Race‐stratified analyses showed that a 1‐ SD increase in nocturnal SBP levels was associated with poorer Digit Symbol Substitution Task and log‐transformed Trail Making Test Part B scores (unstandardized regression coefficient [95% confidence interval ]: −1.98 [−3.28 to −0.69] and 0.06 [0.004–0.12]; both P< 0.05) in black but not white individuals. Additional adjustments for white matter hyperintensity volumes or brain atrophy, measured via brain magnetic resonance imaging, did not change the results. Results were similar when nocturnal SBP dipping was assessed as the exposure, yet daytime SBP levels yielded no association with cognition. Conclusions Nocturnal SBP measurements may be useful in assessing the potential risk for lower cognitive function in middle‐aged and older adults, particularly in black individuals.

OBJECTIVESurgery for brain aneurysms is technically demanding. In recent years, the process to learn the technical skills necessary for these challenging procedures has been affected by a decrease in the number of surgical cases available and progressive restrictions on resident training hours. To overcome these limitations, surgical simulators such as cadaver heads and human placenta models have been developed. However, the effectiveness of these models in improving technical skills is unknown. This study assessed concurrent and predictive validity of brain aneurysm surgery simulation in a human placenta model compared with a “live” human brain cadaveric model.METHODSTwo human cadaver heads and 30 human placentas were used. Twelve neurosurgeons participated in the concurrent validity part of this study, each operating on 1 human cadaver head aneurysm model and 1 human placenta model. Simulators were evaluated regarding their ability to simulate different surgical steps encountered during real surgery. The time to complete the entire aneurysm task in each simulator was analyzed. The predictive validity component of the study involved 9 neurosurgical residents divided into 3 groups to perform simulation exercises, each lasting 6 weeks. The training for the 3 groups consisted of educational video only (3 residents), human cadaver only (3 residents), and human placenta only (3 residents). All residents had equivalent microsurgical experience with superficial brain tumor surgery. After completing their practice training, residents in each of the 3 simulation groups performed surgery for an unruptured middle cerebral artery (MCA) aneurysm, and their performance was assessed by an experienced vascular neurosurgeon who watched the operative videos.RESULTSAll human cadaver heads and human placentas were suitable to simulate brain aneurysm surgery. In the concurrent validity portion of the experiment, the placenta model required a longer time (p < 0.001) than cadavers to complete the task. The placenta model was considered more effective than the cadaver model in simulating sylvian fissure splitting, bipolar coagulation of oozing microvessels, and aneurysm neck and dome dissection. Both models were equally effective in simulating neck aneurysm clipping, while the cadaver model was considered superior for simulation of intraoperative rupture and for reproduction of real anatomy during simulation. In the predictive validity portion of the experiment, residents were evaluated for 4 tasks: sylvian fissure dissection, microvessel bipolar coagulation, aneurysm dissection, and aneurysm clipping. Residents trained in the human placenta simulator consistently had the highest overall performance scores when compared with those who had trained in the cadaver model and those who had simply watched operative videos (p < 0.001).CONCLUSIONSThe human placenta biological simulator provides excellent simulation for some critical tasks of aneurysm surgery such as splitting of the sylvian fissure, dissection of the aneurysm neck and dome, and bipolar coagulation of surrounding microvessels. When performing surgery for an unruptured MCA aneurysm, residents who had trained in the human placenta model performed better than residents trained with other simulation scenarios/models. In this age of reduced exposure to aneurysm surgery and restrictions on resident working hours, the placenta model is a valid simulation for microneurosurgery with striking similarities with real surgery.

Abstract T-cell immunophenotype of acute lymphoblastic leukemia (T-ALL) is an uncommon aggressive leukemia that can present with leukemic and/or lymphomatous manifestations. Molecular studies are enhancing our understanding of the pathogenesis of T-ALL, and the discovery of activating mutations of NOTCH1 and FBXW7 in a majority of patients has been a seminal observation. The use of pediatric intensive combination chemotherapy regimens in adolescents and young adults has significantly improved the outcome of patients with T-ALL. The use of nelarabine for relapsed and refractory T-ALL results in responses in a substantial minority of patients. Allogeneic hematopoietic cell transplantation (HCT) still plays a key role in patients with high-risk or relapsed/refractory disease. γ-Secretase inhibitors hold promise for the treatment of patients with NOTCH1 mutations, and the results of clinical trials with these agents are eagerly awaited. It is recommended that younger patients receive a pediatric-intensive regimen. Older and unfit patients can receive suitable multiagent chemotherapy and be allocated to HCT based on their response, risk factors, and comorbidities. Although advances in the treatment of T-ALL have lagged behind those of B-cell ALL, it is hoped that the molecular revolution will enhance our understanding of the pathogenesis and treatment of this aggressive lymphoid malignancy.

For influenza hemagglutination inhibition (HAI) assays, species selection of red blood cells (RBCs) is critical to determine antibody titers to influenza viruses reliably. We compared pandemic influenza virus A/H1N1 (pdH1N1) HAI titers using turkey or guinea pig RBCs. Turkey RBCs appear to be the more appropriate species choice for influenza A/pH1N1 HAI assays.