Species-dependent posttranscriptional regulation of NOS1 by FMRP in the developing cerebral cortex.

Fragile X syndrome (FXS), the leading monogenic cause of intellectual disability and autism, results from loss of function of the RNA-binding protein FMRP. Here, we show that FMRP regulates translation of neuronal nitric oxide synthase 1 (NOS1) in the developing human neocortex. Whereas NOS1 mRNA is widely expressed, NOS1 protein is transiently coexpressed with FMRP during early synaptogenesis in layer- and region-specific pyramidal neurons. These include midfetal layer 5 subcortically projecting neurons arranged into alternating columns in the prospective Broca's area and orofacial motor cortex. Human NOS1 translation is activated by FMRP via interactions with coding region binding motifs absent from mouse Nos1 mRNA, which is expressed in mouse pyramidal neurons, but not efficiently translated. Correspondingly, neocortical NOS1 protein levels are severely reduced in developing human FXS cases, but not FMRP-deficient mice. Thus, alterations in FMRP posttranscriptional regulation of NOS1 in developing neocortical circuits may contribute to cognitive dysfunction in FXS.

Comparative neural correlates of DBS and MRgFUS lesioning for tremor control in essential tremor.

BACKGROUND: Given high rates of early complications and non-reversibility, refined targeting is necessitated for magnetic resonance-guided focused ultrasound (MRgFUS) thalamotomy for essential tremor (ET). Selection of lesion location can be informed by considering optimal stimulation area from deep brain stimulation (DBS). METHODS: 118 patients with ET who received DBS (39) or MRgFUS (79) of the ventral intermediate nucleus (VIM) underwent stimulation/lesion mapping, probabilistic mapping of clinical efficacy and normative structural connectivity analysis. The efficacy maps were compared, which depict the relationship between stimulation/lesion location and clinical outcome. RESULTS: Efficacy maps overlap around the VIM ventral border and encompass the dentato-rubro-thalamic tract. While the MRgFUS map extends inferiorly into the posterior subthalamic area, the DBS map spreads inside the VIM antero-superiorly. CONCLUSION: Comparing the efficacy maps of DBS and MRgFUS suggests a potential alternative location for lesioning, more antero-superiorly. This may reduce complications, without sacrificing efficacy, and individualise targeting. TRIAL REGISTRATION NUMBER: NCT02252380.

Ipsilateral and axial tremor response to focused ultrasound thalamotomy for essential tremor: clinical outcomes and probabilistic mapping.

BACKGROUND: MR-guided focused ultrasound (MRgFUS) thalamotomy has been shown to be a safe and effective treatment for essential tremor (ET). OBJECTIVE: To investigate the effects of MRgFUS in patients with ET with an emphasis on ipsilateral-hand and axial tremor subscores. METHODS: Tremor scores and adverse effects of 100 patients treated between 2012 and 2018 were assessed at 1 week, 3, 12, and 24 months. A subgroup analysis of ipsilateral-hand tremor responders (defined as patients with ≥30% improvement at any time point) and non-responders was performed. Correlations and predictive factors for improvement were analysed. Weighted probabilistic maps of improvement were generated. RESULTS: Significant improvement in axial, contralateral-hand and total tremor scores was observed at all study visits from baseline (p<0.0001). There was no significant improvement in ipsilateral subscores. A subset of patients (n=20) exhibited group-level ipsilateral-hand improvement that remained significant through all follow-ups (p<0.001). Multivariate regression analysis revealed that higher baseline scores predict better improvement in ipsilateral-hand and axial tremor. Probabilistic maps demonstrated that the lesion hotspot for axial improvement was situated more medially than that for contralateral improvement. CONCLUSION: MRgFUS significantly improved axial, contralateral-hand and total tremor scores. In a subset of patients, a consistent group-level treatment effect was observed for ipsilateral-hand tremor. While ipsilateral improvement seemed to be less directly related to lesion location, a spatial relationship between lesion location and axial and contralateral improvement was observed that proved consistent with the somatotopic organisation of the ventral intermediate nucleus. TRIAL REGISTRATION NUMBERS: NCT01932463, NCT01827904, and NCT02252380.

Microelectrode Recording and Radiofrequency Thalamotomy following Focused Ultrasound Thalamotomy.

Magnetic resonance imaging-guided focused ultrasound (MRgFUS) is a novel method for stereotactic brain lesioning and has primarily been applied for thalamotomies to treat essential tremor (ET). The electrophysiological properties of previously MRgFUS-sonicated thalamic neurons have not yet been described. We report on an ET patient who underwent an MRgFUS thalamotomy but experienced tremor recurrence. We expanded the MRgFUS-induced thalamic cavity using radiofrequency (RF), with good effect on the tremor but transient sensorimotor deficits and permanent ataxia. This is the first report of a patient undergoing RF thalamotomy after an unsuccessful MRgFUS thalamotomy. As we used microelectrode recording to guide the RF thalamotomy, we could also study for the first time the electrophysiological properties of previously sonicated thalamic neurons bordering the MRgFUS-induced cavity. These neurons displayed electrophysiological characteristics identical to those recorded from nonsonicated thalamic cells in ET patients. Hence, our findings support the widespread assumption that sonication below the necrotic threshold does not permanently alter neuronal function.

Multimodal MRI for MRgFUS in essential tremor: post-treatment radiological markers of clinical outcome.

BACKGROUND: MRI-guided focused ultrasound (MRgFUS) thalamotomy is a promising non-invasive treatment option for medication-resistant essential tremor. However, it has been associated with variable efficacy and a relatively high incidence of adverse effects. OBJECTIVES: To assess the evolution of radiological findings after MRgFUS thalamotomy and to evaluate their significance for clinical outcomes. METHODS: Ninety-four patients who underwent MRgFUS between 2012 and 2017 were retrospectively evaluated. Lesion characteristics were assessed on routine MRI sequences, as well as with tractography. Relationships between imaging appearance, extent of white matter tract lesioning (59/94, on a 4-point scale) and clinical outcome were investigated. Recurrence was defined as >33% loss of tremor suppression at 3 months relative to day 7. RESULTS: Acute lesions demonstrated blood products, surrounding oedema and peripheral diffusion restriction. The extent of dentatorubrothalamic tract (DRTT) lesioning was significantly associated with clinical improvement at 1 year (t=4.32, p=0.001). Lesion size decreased over time (180.8±91.5 mm3 at day 1 vs 19.5±19.3 mm3 at 1-year post-treatment). Higher post-treatment oedema (t=3.59, p<0.001) was associated with larger lesions at 3 months. Patients with larger lesions at day 1 demonstrated reduced rates of tremor recurrence (t=2.67, p=0.019); however, lesions over 170 mm3 trended towards greater incidence of adverse effects (sensitivity=0.60, specificity=0.63). Lesion encroachment on the medial lemniscus (Sn=1.00, Sp=0.32) and pyramidal tract (Sn=1.00, Sp=0.12) were also associated with increased adverse effects incidence. CONCLUSION: Lesion size at day 1 predicts symptom recurrence, with fewer recurrences seen with larger lesions. Greater DRTT lesioning is associated with treatment efficacy. These findings may have implications for lesion targeting and extent. TRIAL REGISTRATION NUMBER: NCT02252380.

Echo-Focusing in Transcranial Focused Ultrasound Thalamotomy for Essential Tremor: A Feasibility Study.

BACKGROUND: Transcranial magnetic resonance-guided focused ultrasound (TcMRgFUS) systems currently employ computed tomography (CT)-based aberration corrections, which may provide suboptimal trans-skull focusing. OBJECTIVES: The objective of this study was to evaluate a contrast agent microbubble imaging-based transcranial focusing method, echo-focusing (EF), during TcMRgFUS for essential tremor. METHODS: A clinical trial of TcMRgFUS thalamotomy using EF for the treatment of essential tremor was conducted (NCT03935581; funded by InSightec [Tirat Carmel, Israel]). Patients (n = 12) were injected with Definity (Lantheus Medical Imaging, North Billerica, MA) microbubbles, and EF was performed using a research feature add-on to a commercial TcMRgFUS system (ExAblate Neuro, InSightec). Subablative thermal sonications carried out using (1) EF and (2) CT-based aberration corrections were compared via magnetic resonance thermometry, and the optimal focusing method for each patient was employed for TcMRgFUS thalamotomy. RESULTS: EF aberration corrections provided increased sonication efficiency, decreased focal size, and equivalent targeting accuracy relative to CT-based focusing. EF aberration corrections were employed successfully for lesion formation in all 12 patients, 3 of whom had previously undergone unsuccessful TcMRgFUS thalamotomy via CT-based focusing. There were no adverse events related directly to the EF procedure. CONCLUSIONS: EF is feasible and appears safe during TcMRgFUS thalamotomy for essential tremor and improves on the trans-skull focal quality provided by existing CT-based focusing methods. © 2020 International Parkinson and Movement Disorder Society.

Magnetic Resonance-Guided Focused Ultrasound Thalamotomy to Treat Essential Tremor in Nonagenarians.

Essential tremor (ET) is a disabling movement disorder that is most prevalent among the elderly. While deep brain stimulation surgery targeting the ventral intermediate nucleus of the thalamus is commonly used to treat ET, the most elderly patients or those with multiple medical comorbidities may not qualify as surgical candidates. Magnetic resonance-guided focused ultrasound (MRgFUS) constitutes a less invasive modality that may be used to perform thalamotomy without the need for a burr hole craniotomy. Here, we report on 2 patients over the age of 90 years who benefited significantly from MRgFUS thalamotomy to relieve their symptoms and improve their quality of life. The procedure was well tolerated and performed safely in both patients. We conclude that age should not be a limiting factor in the treatment of patients with MRgFUS.

Stitching a solution to the addiction epidemic: A longitudinal addiction curricular thread across four years of medical training.

BACKGROUND: Despite the enormous burden and public health impact, addiction continues to be one of the most under-treated chronic diseases primarily because of the lack of adequately trained work force of medical providers. To address this issue, medical schools should greatly expand education on addiction. Methods: The six-step Kern model of curriculum development was used as a framework to create an addiction curriculum which includes didactic activities, workshop exercises, practice-based learning activities, clinical simulations, and clinical experiences. Results: The authors and other members of the addiction thread committee conducted a comprehensive needs assessment, developed curriculum goals and objectives, and worked with course and clerkship directors to develop and enhance educational strategies and implement a longitudinal curricular thread woven across all four years of medical school curriculum. Conclusion: Development and implementation of a comprehensive addiction curriculum is feasible, and this model could lay the ground work for implementation at other institutions.

Internet of Measurement Things Architecture: Proof of Concept with Scope of Accreditation.

Many industries, such as manufacturing, aviation, and power generation, employ sensitive measurement devices to be calibrated by certified experts. The diversity and sophistication of measurement devices and their calibration needs require networked and automated solutions. Internet of Measurement Things (IoMT) is an architectural framework that is based on the Industrial Internet of Things for the calibration industry. This architecture involves a layered model with a cloud-centric middle layer. In this article, the realization of this conceptual architecture is described. The applicability of the IoMT architecture in the calibration industry is shown through an editor application for Scope of Accreditation. The cloud side of the implementation is deployed to Microsoft Azure. The editor itself is created as a cloud service, and IoT Hub is used to collect data from calibration laboratories. By adapting the IoMT architecture to a commonly used cloud platform, considerable progress is achieved to encompass Metrology data and serve the majority of the stakeholders.

The Use of Mobile Devices to Enhance Engagement and Integration with Curricular Content.

This perspective describes the processes, pilot designs, and deployment strategies that the Yale School of Medicine (YSM) employed when integrating iPads into the undergraduate pre-clinical medical curriculum. We also explore the multiplier effect this technology inspired in expanding the program into our clerkship curriculum with the iPad Mini and how integrating mobile technology into our existing E-systems afforded us opportunities to enter the e-book and augmented reality technology spaces. Our hope is that this perspective provides a framework that may guide other institutions researching their own technological innovations.

A prospective trial of magnetic resonance-guided focused ultrasound thalamotomy for essential tremor: Results at the 2-year follow-up.

OBJECTIVE: Magnetic resonance guided focused ultrasound (MRgFUS) has recently been investigated as a new treatment modality for essential tremor (ET), but the durability of the procedure has not yet been evaluated. This study reports results at a 2- year follow-up after MRgFUS thalamotomy for ET. METHODS: A total of 76 patients with moderate-to-severe ET, who had not responded to at least two trials of medical therapy, were enrolled in the original randomized study of unilateral thalamotomy and evaluated using the clinical rating scale for tremor. Sixty-seven of the patients continued in the open-label extension phase of the study with monitoring for 2 years. Nine patients were excluded by 2 years, for example, because of alternative therapy such as deep brain stimulation (n = 3) or inadequate thermal lesioning (n = 1). However, all patients in each follow-up period were analyzed. RESULTS: Mean hand tremor score at baseline (19.8 ± 4.9; 76 patients) improved by 55% at 6 months (8.6 ± 4.5; 75 patients). The improvement in tremor score from baseline was durable at 1 year (53%; 8.9 ± 4.8; 70 patients) and at 2 years (56%; 8.8 ± 5.0; 67 patients). Similarly, the disability score at baseline (16.4 ± 4.5; 76 patients) improved by 64% at 6 months (5.4 ± 4.7; 75 patients). This improvement was also sustained at 1 year (5.4 ± 5.3; 70 patients) and at 2 years (6.5 ± 5.0; 67 patients). Paresthesias and gait disturbances were the most common adverse effects at 1 year-each observed in 10 patients with an additional 5 patients experiencing neurological adverse effects. None of the adverse events worsened over the period of follow-up, and 2 of these resolved. There were no new delayed complications at 2 years. INTERPRETATION: Tremor suppression after MRgFUS thalamotomy for ET is stably maintained at 2 years. Latent or delayed complications do not develop after treatment. Ann Neurol 2018;83:107-114.

Focused ultrasound thalamotomy location determines clinical benefits in patients with essential tremor.

Magnetic resonance guided focused ultrasound (MRgFUS) thalamotomy is a novel and minimally invasive ablative treatment for essential tremor. The size and location of therapeutic lesions producing the optimal clinical benefits while minimizing adverse effects are not known. We examined these relationships in patients with essential tremor undergoing MRgFUS. We studied 66 patients with essential tremor who underwent MRgFUS between 2012 and 2017. We assessed the Clinical Rating Scale for Tremor (CRST) scores at 3 months after the procedure and tracked the adverse effects (sensory, motor, speech, gait, and dysmetria) 1 day (acute) and 3 months after the procedure. Clinical data associated with the postoperative Day 1 lesions were used to correlate the size and location of lesions with tremor benefit and acute adverse effects. Diffusion-weighted imaging was used to assess whether acute adverse effects were related to lesions encroaching on nearby major white matter tracts (medial lemniscus, pyramidal, and dentato-rubro-thalamic). The area of optimal tremor response at 3 months after the procedure was identified at the posterior portion of the ventral intermediate nucleus. Lesions extending beyond the posterior region of the ventral intermediate nucleus and lateral to the lateral thalamic border were associated with increased risk of acute adverse sensory and motor effects, respectively. Acute adverse effects on gait and dysmetria occurred with lesions inferolateral to the thalamus. Lesions inferolateral to the thalamus or medial to the ventral intermediate nucleus were also associated with acute adverse speech effects. Diffusion-weighted imaging revealed that lesions associated with adverse sensory and gait/dysmetria effects compromised the medial lemniscus and dentato-rubro-thalamic tracts, respectively. Lesions associated with adverse motor and speech effects encroached on the pyramidal tract. Lesions larger than 170 mm3 were associated with an increased risk of acute adverse effects. Tremor improvement and acute adverse effects of MRgFUS for essential tremor are highly dependent on the location and size of lesions. These novel findings could refine current MRgFUS treatment planning and targeting, thereby improving clinical outcomes in patients.

Loss of TrkB Signaling in Parvalbumin-Expressing Basket Cells Results in Network Activity Disruption and Abnormal Behavior.

The GABAergic system is regulated by the brain-derived neurotrophic factor (BDNF)/Tropomyosin-related kinase B (TrkB) pathway, but the cell-intrinsic role of TrkB signaling in parvalbumin cortical interneuron development and function is unclear. We performed conditional ablation of the TrkB receptor in parvalbumin-expressing (PV) interneurons to study whether postnatal loss of TrkB in parvalbumin cells affects their survival, connectivity, spontaneous and evoked neuronal activity and behavior. Using in vivo recordings of local field potentials, we found reduced gamma oscillations in the sensory cortex of PVcre+; TrkBF/F conditional knockout mice (TrkB cKO), along with increased firing of putative excitatory neurons. There was a significant downregulation in parvalbumin neuron number in cerebral and cerebellar cortices of TrkB cKO mice. In addition, inhibitory synaptic connections between basket cells and pyramidal neurons were profoundly reduced in the neocortex of TrkB cKO mice and there was a loss of cortical volume. TrkB cKO mice also showed profound hyperactivity, stereotypies, motor deficits and learning/memory defects. Our findings demonstrate that the targeting and/or synapse formation of PV-expressing basket cells with principal excitatory neurons require TrkB signaling in parvalbumin cells. Disruption of this signaling has major consequences for parvalbumin interneuron connectivity, network dynamics, cognitive and motor behavior.

Twelve tips for incorporating and teaching sexual and gender minority health in medical school curricula.

The World Health Organization has identified many barriers to improving the health of lesbian, gay, bisexual, and transgender (LGBT) patients, including challenges to incorporating and teaching about healthcare for such patients, which we call "sexual and gender minority" (SGM) health content. These challenges include structural and logistical barriers to incorporating SGM health content into undergraduate medical curricula, as well as lack of support in identifying high-quality pedagogical methods for teaching this material. Here, we provide twelve tips for incorporating and teaching SGM health curricular content in undergraduate medical education, including resources and strategies to support individual educators. Based on our success in developing and implementing this content, we believe that our approach can be effectively used by individual educators aiming to incorporate SGM health curricular material into their teaching, and to support individuals or groups championing the inclusion of a SGM health topical sequence in medical curricula.

Principles and Practices for Developing an Integrated Medical School Curricular Sequence About Sexual and Gender Minority Health.

Problem: Sexual and gender minority patients face well-documented health disparities. One strategy to help overcome disparities is preparing medical trainees to competently provide care for sexual and gender minority patients. The Association of American Medical Colleges has identified professional competencies that medical students should develop to meet sexual and gender minority health needs. However, challenges in the medical education environment may hinder the adoption and implementation of curricular interventions to foster these competencies. Intervention: Our medical education community engaged in curriculum evaluation and subsequently developed a sexual and gender minority topical sequence to promote student development of these competencies. This process was guided by explicit principles and curriculum development practices. Context: This work began at the Yale University School of Medicine in 2014, shortly after the Association of American Medical Colleges published sexual and gender minority health competencies and amidst the development and implementation of a new curriculum at the institution. Impact: We identified core principles and practices to guide the development of an integrated sexual and gender minority health sequence. This process resulted in successful creation of an integrated curricular sequence. At this time, 9 new or enhanced curricular components have been adopted through our process-5 in preclinical, 3 in the clinical, and 1 in the elective, curricula-in addition to the 13 preexisting components that have been updated as appropriate. Feedback about the process from students and faculty has been overwhelmingly positive. Evaluation of curricular components and their effectiveness as an integrated sequence is ongoing. Lessons Learned: Core principles consisted of including a wide range of stakeholders to build consensus, establishing complementary student and faculty roles, using the "language of collaboration" rather than the "language of demand," presenting sexual and gender minority content in an intersectional manner whenever possible, and balancing sexual and gender minority components across the curriculum. Key practices included mapping curriculum to identify gaps; developing curriculum "pitches"; identifying early and potential later "adopters" among faculty; focusing on faculty ownership of curriculum to facilitate institutionalization; and performing ongoing tracking, assessment, and revision of curriculum.

Magnetic resonance-guided focused ultrasound thalamotomy for treatment of essential tremor: A 2-year outcome study.

BACKGROUND: Magnetic resonance-guided focused ultrasound is an emerging, minimally invasive thermoablation technique for medically refractory essential tremor. Beyond the initial year, data regarding efficacy and potential predictors of efficacy are still preliminary. OBJECTIVES: The objective of this study was to assess the outcome at 2 years and the association between lesion volume and outcome 1 year after treatment. METHODS: We reviewed data from 37 patients who underwent unilateral magnetic resonance-guided focused ultrasound thalamotomy, with primary outcome being dominant tremor subscore of the Clinical Rating Scale for Tremor. We used multivariable linear regression to model initial lesion volume with 1-year outcome, adjusting for other clinically relevant variables. RESULTS: Although we detected a trend in loss of clinical benefit within the first year, the dominant tremor score at 2 years continued to be significantly improved (43.4%, 95% confidence interval 27.8%-59.0%) from baseline. Secondarily, initial lesion volume is significantly associated with 1-year outcome. CONCLUSION: Our findings show that magnetic resonance-guided focused ultrasound thalamotomy results in sustained tremor reduction for medically refractory essential tremor even in the long term, and we highlight areas for improvement.

Treatment of a Patient With Task-Specific Writing Tremor Using Magnetic Resonance-Guided Focused Ultrasound.

Task-specific dystonia is characterized by abnormal repetitive movements or postures in a specific body part that is triggered and ends with a task, such as writing. Failing medications, surgery, specifically disruption of key nuclei in the thalamus, can provide excellent symptomatic relief. Transcranial magnetic resonance (MR)-guided focused ultrasound is an emerging incision-less thermoablation technique. We describe MR-guided focused ultrasound tandem ablation of the ventral intermediate and ventralis oralis posterior nuclei in a 60-year-old patient with writer's cramp. The clinical improvement was immediate with incremental benefit from the latter lesion, which was sustained at 6 months follow-up.

When patients hurt us.

In this thoughtful article, medical educators in various stages of their careers (resident, mid-career clinician-educators, medical school deans) reflect upon increasing reports of harassment and mistreatment of trainees by patients. In addition to providing a general overview of the limited literature on this topic, the authors describe their own experience collecting information on trainee mistreatment by patients at their institution. They explore the universal difficulty that educators face regarding how to best address this mistreatment and support both faculty and trainees. Given the current sociopolitical climate, there has never been a more urgent need to critically examine this issue. The authors call on the greater medical education community to join them in these important conversations.

Using learning analytics to evaluate a video-based lecture series.

BACKGROUND: The video-based lecture (VBL), an important component of the flipped classroom (FC) and massive open online course (MOOC) approaches to medical education, has primarily been evaluated through direct learner feedback. Evaluation may be enhanced through learner analytics (LA) - analysis of quantitative audience usage data generated by video-sharing platforms. METHODS AND RESULTS: We applied LA to an experimental series of ten VBLs on electroencephalography (EEG) interpretation, uploaded to YouTube in the model of a publicly accessible MOOC. Trends in view count; total percentage of video viewed and audience retention (AR) (percentage of viewers watching at a time point compared to the initial total) were examined. The pattern of average AR decline was characterized using regression analysis, revealing a uniform linear decline in viewership for each video, with no evidence of an optimal VBL length. Segments with transient increases in AR corresponded to those focused on core concepts, indicative of content requiring more detailed evaluation. We propose a model for applying LA at four levels: global, series, video, and feedback. DISCUSSION AND CONCLUSIONS: LA may be a useful tool in evaluating a VBL series. Our proposed model combines analytics data and learner self-report for comprehensive evaluation.

The role of endothelial HIF-1 αin the response to sublethal hypoxia in C57BL/6 mouse pups.

Chronic sublethal hypoxia, a complication of premature birth, is associated with cognitive and motor handicaps. Responsiveness to and recovery from this hypoxic environment is dependent on induction of HIF-1 α in the cells affected. Microvascular endothelial-glial and microvascular endothelial-neuronal precursor interactions have been found to be dynamic and reciprocal, involving autocrine and paracrine signaling, with response and recovery correlated with baseline levels and levels of induction of HIF-1 α.To ascertain the roles of endothelial HIF-1 α in the responses of brain microvascular endothelial cells (EC) and neuronal precursors to hypoxia, we examined the effects of the presence and absence of endothelial HIF-1 α expression in culture and in cells comprising the subventricular zone (SVZ) and dentate gyrus under normoxic and hypoxic conditions. We used C57BL/6 WT and EC HIF-1 α -deficient mice and brain microvascular ECs isolated from these mice in western blots, immunofluorescence, and behavioral studies to examine the roles of EC HIF-1 α behaviors of endothelial and neuronal precursor cells (NPCs) in SVZ and hippocampal tissues under normoxic and hypoxic conditions and behaviors of these mice in open field activity tests. Analyses of ECs and SVZ and dentate gyrus tissues revealed effects of the absence of endothelial HIF-1 α on proliferation and apoptosis as well as open field activity, with both ECs and neuronal cells exhibiting decreased proliferation, increased apoptosis, and pups exhibiting gender-specific differences in open field activities. Our studies demonstrate the autocrine and paracrine effects of EC HIF-1 α-modulating proliferative and apoptotic behaviors of EC and NPC in neurogenic regions of the brain and gender-specific behaviors in normoxic and hypoxic settings.