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von Hippel-Lindau (VHL) disease is an autosomal dominant hereditary cancer disorder caused by a germline mutation in the VHL tumor suppressor gene. Loss of the wild-type allele results in VHL deficiency and the potential formation of cerebellar hemangioblastomas, which resemble embryonic hemangioblast proliferation and differentiation processes. Multiple, microscopic, VHL-deficient precursors, termed developmentally arrested structural elements (DASEs), consistently involve the cerebellar molecular layer in VHL patients, indicating the tumor site of origin. Unlike hemangioblastomas, however, cerebellar DASEs do not express brachyury, a mesodermal marker for hemangioblasts. In this study, neuronal progenitors occupying the molecular layer were investigated as tumor cells of origin. By immunohistochemistry, cerebellar DASEs and hemangioblastomas lacked immunoreactivity with antibody ZIC1 (Zic family member 1), a granule cell progenitor marker with concordance from oligonucleotide RNA expression array analyses. Rather, cerebellar DASEs and hemangioblastomas were immunoreactive with antibody PAX2 (paired box 2), a marker of basket/stellate cell progenitors. VHL cerebellar cortices also revealed PAX2-positive cells in Purkinje and molecular layers, resembling the histological and molecular development of basket/stellate cells in postnatal non-VHL mouse and human cerebella. These data suggest that VHL deficiency can result in the developmental arrest of basket/stellate cells in the human cerebellum and that these PAX2-positive, initiated cells await another insult or signal to form DASEs and eventually, tumors.

This brief report describes factors that impact the effectiveness of Medicare’s Annual Wellness Visit (AWV). Patients who participated in an AWV at a large accountable care organization were contacted monthly via phone for up to 1 year to discuss their health promotion efforts. Data from visit narratives and secondary review of AWV documentation by researchers indicate that improved efforts are needed to ensure personalization of recommendations and support patient health promotion efforts. Enhancement of the AWV process, workflow redesign, and development of strategies to provide ongoing support between AWVs are vital to improve AWV outcomes.

Military spouses experience unique stressors due to service member deployments and frequent relocations. Our purpose is to examine how military spouses use social networking groups, such as Facebook, and determine how this use was related to perceived social support and well-being. We found more frequent Facebook use was associated with decreased well-being compared with those who reported using Facebook less frequently. Practitioners may enhance the care provided to military spouses by inquiring about their circumstances, social media use, and helping them to identify social support services that may mitigate stress and improve well-being.

Background and Purpose: In large artery occlusion stroke, both intravenous (IV) tPA (tissue-type plasminogen activator) and endovascular stroke treatment (EST) are standard-of-care. It is unknown how often tPA causes distal embolization, in which a procedurally accessible large artery occlusion is converted to a more distal and potentially inaccessible occlusion. Methods: We analyzed data from a decentralized stroke telemedicine program in an integrated healthcare delivery system covering 21 hospitals, with 2 high-volume EST centers. We captured all cases sent for EST and examined the relationship between IV tPA administration and the rate of distal embolization, the rate of target recanalization (modified Treatment in Cerebral Infarction scale 2b/3), clinical improvement before EST, and short-term and long-term clinical outcomes. Results: Distal embolization before EST was quite common (63/314 [20.1%]) and occurred more often after IV tPA before EST (57/229 [24.9%]) than among those not receiving IV tPA (6/85 [7.1%]; P P Conclusions: IV tPA administration before EST for large artery occlusion is associated with distal embolization, which in turn may reduce the chance that EST can be attempted and recanalization achieved. At the same time, some IV tPA-treated patients show symptomatic improvement and complete recanalization. Because IV tPA is associated with both distal embolization and improved long-term clinical outcome, there is a need for prospective clinical trials testing the net benefit or harm of IV tPA before EST.

Preclinical models that reliably recapitulate the immunosuppressive properties of human gliomas are essential to assess immune-based therapies. GL261 murine glioma cells are widely used as a syngeneic animal model of glioma, however, it has become common practice to transfect these cells with luciferase for fluorescent tumor tracking. The aim of this study was to compare the survival of mice injected with fluorescent or non-fluorescent GL261 cells and characterize the differences in their tumor microenvironment. Mice were intracranially implanted with GL261, GL261 Red-FLuc or GL261-Luc2 cells at varying doses. Cytokine profiles were evaluated by proteome microarray and Kaplan–Meier survival analysis was used to determine survival differences. Median survival for mice implanted with 5 × 104 GL261 cells was 18 to 21 days. The GL261 Red-FLuc implanted mice cells did not reach median survival at any tumor dose. Mice injected with 3 × 105 GL261-Luc2 cells reached median survival at 23 days. However, median survival was significantly prolonged to 37 days in mice implanted with 5 × 104 GL261-Luc2 cells. Additionally, proteomic analyses revealed significantly elevated inflammatory cytokines in the supernatants of the GL261 Red-FLuc cells and GL261-Luc2 cells. Our data suggest that GL261 Red-FLuc and GL261-Luc2 murine models elicit an anti-tumor immune response by increasing pro-inflammatory modulators.

Introduction Registered Nurses (RNs) who are reported by their employer, or interface with the criminal justice system due to substance use, will typically appear before a board of nursing. In some states, this appearance becomes a legal record with documentation available to the public. Objective The purpose of this study is to qualitatively analyze the court documents of RNs whose licenses were placed on probationary, suspended, or revoked statuses by the Indiana State Board of Nursing (ISBN). Methods A descriptive content analysis was conducted on 236 court documents associated with 51 RNs. The study presents the typical paths of RNs appearing before the ISBN. Results From the qualitative data, five themes emerged: (a) critical junctures experienced by RNs during the disciplinary process; (b) emerging groups who appear before the ISBN; (c) individual contexts versus standardized discipline; (d) deliberate diversion, deceit, and deception; and (e) significant threat to public safety and quality health care. Conclusion Understanding regulatory oversight of substance use in RNs in Indiana offers potential directions for targeted interventions. These include identifying periods of vulnerability and understanding the dynamics of appearances before the ISBN across time.

Support for successful aging in place requires an understanding of the factors that impede or support health promotion behaviors. Nurse-led monthly follow-up calls between annual wellness visits (AWV) offer the opportunity to both provide support and collect data which can inform development of effective health promotion strategies. The aim of this research was to provide ongoing support for health promotion efforts and explore factors playing a role in meeting AWV recommendations. A total of 144 visit summaries for 47 Medicare beneficiaries (65+) who had completed an AWV within the last year were analyzed using a thematic approach. Themes were organized into 7 categories with findings indicating the complexity of factors which influence health promotion behaviors. The importance of ensuring personalization of health promotion recommendations using data collected during the AWV and provision of ongoing support between visits may enhance health outcomes.

Mutations in EPAS1, encoding hypoxia-inducible factor-2α (HIF-2α), were previously identified in a syndrome of multiple paragangliomas, somatostatinoma, and polycythemia. HIF-2α, when dimerized with HIF-1β, acts as an angiogenic transcription factor. Patients referred to the NIH for new, recurrent, and/or metastatic paraganglioma or pheochromocytoma were confirmed for EPAS1 gain-of-function mutation; imaging was evaluated for vascular malformations. We evaluated the Epas1A529V transgenic syndrome mouse model, corresponding to the mutation initially detected in the patients (EPAS1A530V), for vascular malformations via intravital 2-photon microscopy of meningeal vessels, terminal vascular perfusion with Microfil silicate polymer and subsequent intact ex vivo 14T MRI and micro-CT, and histologic sectioning and staining of the brain and identified pathologies. Further, we evaluated retinas from corresponding developmental time points (P7, P14, and P21) and the adult dura via immunofluorescent labeling of vessels and confocal imaging. We identified a spectrum of vascular malformations in all 9 syndromic patients and in all our tested mutant mice. Patient vessels had higher variant allele frequency than adjacent normal tissue. Veins of the murine retina and intracranial dura failed to regress normally at the expected developmental time points. These findings add vascular malformation as a new clinical feature of EPAS1 gain-of-function syndrome., We discovered vascular malformations due to failure of developmental vascular regression in patients with EPAS1 gain-of-function mutation syndrome and the corresponding transgenic mouse model.

Systolic and diastolic hypertension independently predict the risk of adverse cardiovascular events. It remains unclear how systolic pressure, diastolic pressure, and other patient characteristics influence the initial diagnosis of hypertension. Here, we use a cohort of 146,816 adults in a large healthcare system to examine how elevated systolic and/or diastolic blood pressure measurements influence initial diagnosis of hypertension and how other patient characteristics influence the diagnosis. Thirty-four percent of the cohort were diagnosed with hypertension within 1 year. In multivariable logistic regression of the diagnosis of hypertension, controlling for covariates, isolated systolic hypertensive measures (odds ratio [OR] 0.42 [95% confidence interval {CI} 0.41 to 0.43]) and isolated diastolic hypertensive measures (OR 0.32 [95% CI 0.31 to 0.33]) were less likely to lead to hypertension diagnosis when compared with combined hypertensive measures. Higher levels of systolic blood pressure had a greater impact on hypertension diagnosis (OR 1.77 [95% CI 1.75 to 1.79] per Z-score) than did higher levels of diastolic blood pressure (OR 1.34 [95% CI 1.32 to 1.36] per Z-score). Older age, non-white race/ethnicity, and medical comorbidities all predicted the establishment of a diagnosis of hypertension. Isolated systolic and isolated diastolic hypertension are underdiagnosed in clinical practice, and several patient-centered factors also strongly influence whether a diagnosis is made. In conclusion, our findings uncover a care gap that can be closed with increased attention to the independent influence of systolic and diastolic hypertension and the various patient-centered factors that may impact hypertension diagnosis.

Introduction: Recurrence of Cushing’s disease (CD) caused by benign pituitary microadenomas are challenging clinical problems. Mechanisms underlying adenoma formation and recurrence remain unknown. PMAIP1 gene codes for Noxa, a Bcl-2 homology 3 (BH3) pro-apoptotic protein frequently downregulated in malignant human tumors.1-6 The role of dysregulated apoptosis remains largely unknown in benign tumors and in CD. We hypothesized that altered expression of Noxa protein is a pro-survival adaptation employed by CD adenomas. Methods: Syngeneic human pituitary adenoma and adjacent normal gland pairs (n=2), and an additional CD adenoma were analyzed with RNAseq. 10 CD, 1 growth hormone (GH) and 1 non-functioning adenoma (NFPA) underwent immunohistochemical (IHC) analysis for Noxa expression, which was graded by a neuropathologist as 0=none, 1=light, 2=medium, 3=strong. Staining grade represents relative protein expression. Results: Compared to adjacent normal pituitary tissue, we found that adenomas (n = 3) had a 3.76 fold increase in PMAIP1 mRNA. However, there was attenuated Noxa IHC staining in adenomas compared to normal pituitary in 8 of 10 CD patients (2:3, respectively), but similar staining in 2 of 10 CD patients (2:2 and 2-3:2-3). In GH and NFPA, we found similar patterns of Noxa suppression in the adenomas compared to the normal gland. Conclusion: Despite elevated PMAIP1 (Noxa) gene expression in adenomas compared to adjacent normal gland in CD, protein expression was reduced in adenomas. This downregulation of Noxa protein expression may contribute to reduced apoptosis of tumor cells. These findings suggest that CD adenomas gain pro-survival advantage by downregulating Noxa protein at post-transcriptional or post-translational level. References 1. Escobar, D. et al. Cell Death Dis.6, 1-14 (2015).2. Brinkmann, K. et al. Cell Rep.3, 881-891 (2013).3. Liu, Y. L. et al. Oncotarget5, 11237-11251 (2014).4. Dengler, M. A. et al. Cell Death Dis.5, 1-10 (2014).5. Liang, L. et al. J. Oral Pathol. Med.48, 52-59 (2019).6. Tahir, S. K. et al. Cancer Res.67, 1176-1183 (2007).

BACKGROUND: Pre-operative detection of corticotropin (ACTH) secreting microadenomas causing Cushing's disease (CD) improves surgical outcomes. Current best magnetic resonance imaging fails to detect up to 40% of these microadenomas. (18)F-fluorodeoxyglucose ((18)F-FDG) positron emission tomography (PET) is specific, but not sensitive in detecting corticotropinomas. Theoretically, secretagogue stimulation with corticotropin releasing hormone (CRH) could improve detection of adenomas with (18)F-FDG PET. Previous attempts with simultaneous CRH stimulation have failed to demonstrate increased (18)F-FDG uptake in corticotropinomas. We hypothesized that CRH stimulation leads to a delayed elevation in glucose uptake in corticotropinomas. METHODS: Clinical data was analyzed for efficacy of CRH in improving (18)FDG-PET detection of corticotropinomas in CD. Glucose transporter 1 (GLUT1) immunoreactivity was performed on surgical specimens. Ex-vivo, viable cells from these tumors were tested for secretagogue effects (colorimetric glucose uptake), and for fate of intracellular glucose (glycolysis stress analysis). Validation of ex-vivo findings was performed with AtT-20 cells. RESULTS: CRH increased glucose uptake in human-derived corticotroph tumor cells and AtT-20, but not in normal murine or human corticotrophs (p

With a wide spectrum of severity, osteogenesis imperfecta (OI) is a connective tissue disease resulting in bone fragility. Approximately 25,000–50,000 Americans are afflicted with OI; 50% of these cases are classified as type I. Type I does not discriminate regarding ethnicity, race, or sex. The disease symptoms change across the life span and vary among patients; therefore, diagnosis is often missed. The aim of this article is to briefly explain etiology, clinical manifestations, common assessment findings, and recommended health promotion activities to recognize individuals with OI type I, thereby facilitating an early diagnosis and appropriate referrals.

Background The etiology of cervical dystonia is unknown. Cholinergic abnormalities have been identified in dystonia animal models and human imaging studies. Some animal models have cholinergic neuronal loss in the striatum and increased acetylcholinesterase activity in the pedunculopontine nucleus. Objectives The objective of this study was to determine the presence of cholinergic abnormalities in the putamen and pedunculopontine nucleus in cervical dystonia human brain donors. Methods Formalin-fixed brain tissues were obtained from 8 cervical dystonia and 7 age-matched control brains (controls). Pedunculopontine nucleus was available in only 6 cervical dystonia and 5 controls. Neurodegeneration was evaluated pathologically in the putamen, pedunculopontine nucleus, and other regions. Cholinergic neurons were detected using choline acetyltransferase immunohistochemistry in the putamen and pedunculopontine nucleus. Putaminal cholinergic neurons were quantified. A total of 6 cervical dystonia patients and 6 age-matched healthy controls underwent diffusion tensor imaging to determine if there were white matter microstructural abnormalities around the pedunculopontine nucleus. Results Decreased or absent choline acetyltransferase staining was identified in all 6 pedunculopontine nucleus samples in cervical dystonia. In contrast, strong choline acetyltransferase staining was present in 4 of 5 pedunculopontine nucleus controls. There were no differences in pedunculopontine nucleus diffusion tensor imaging between cervical dystonia and healthy controls. There was no difference in numbers of putaminal cholinergic neurons between cervical dystonia and controls. Conclusions Our findings suggest that pedunculopontine nucleus choline acetyltransferase deficiency represents a functional cholinergic deficit in cervical dystonia. Structural lesions and confounding neurodegenerative processes were excluded by absence of neuronal loss, gliosis, diffusion tensor imaging abnormalities, and beta-amyloid, tau, and alpha-synuclein pathologies. © 2018 International Parkinson and Movement Disorder Society.

This review discusses the relationship between animal-assisted interventions (AAI) and behavioral and psychological symptoms of dementia (BPSD). A systematic search was conducted within CINAHL, Web of Science CAB Abstracts, PubMed, Abstracts in Social Gerontology, Google Scholar, and PsycINFO for primary research articles. A total of 32 studies were included in the final review. Variation was noted in study designs and in study setting. Twenty-seven of 32 studies used dogs as the intervention. Agitation/aggression showed a significant decrease in nine of 15 studies. Eleven of 12 studies demonstrated increased social interaction with AAI. Mood had mixed results in nine studies. Quality of life was increased in three of four studies. Resident activity and nutritional intake were each increased in two studies. Animal assisted activities/interventions showed a strong positive effect on social behaviors, physical activity, and dietary intake in dementia patients and a positive effect on agitation/aggression and quality of life.

OBJECTIVEThe most frequent procedural complication of the endovascular treatment of intracranial aneurysms is a thromboembolic event (TEE); in a subset of patients, such events will cause permanent neurological disability. In patients with unruptured aneurysms, increasing evidence supports the use of periprocedural antiplatelet therapy to prevent TEEs. The object of this study was to evaluate whether patients with ruptured aneurysms and subarachnoid hemorrhage would also benefit from periprocedural antiplatelet therapy.METHODSThe authors reviewed a prospective registry of 169 patients with endovascularly treated intracranial aneurysms to delineate angiographic features associated with periprocedural TEEs. They then performed a controlled before-and-after study in 79 patients with ruptured aneurysms who were deemed to be at high risk for TEEs (for example, patients with at least 1 angiographic feature associated with TEEs) to evaluate whether selective aspirin administration would reduce the rate of periprocedural thromboembolism without increasing major hemorrhagic complications.RESULTSSix angiographic features were associated with periprocedural TEEs in the study cohort: wide aneurysm neck, coil or loop protrusion, small parent artery diameter, an incorporated branch, intraprocedural thrombus formation, and intracranial parent vessel atherosclerosis. Aspirin administration to high-risk patients significantly decreased the rate of periprocedural TEEs, from 53.8% in the control group to 10.6% in the aspirin-treated group (p = 0.001). The reduction in TEEs in the aspirin-treated group continued to be statistically significant even when adjusted for age, sex, cardiovascular risk factors (smoking, diabetes, hypertension, dyslipidemia, coronary artery disease), and factors associated with TEEs in other large studies (wide aneurysm neck, aneurysm size ≥ 10 mm), with an adjusted OR of 0.16 (95% CI 0.03–0.8). There were no major systemic hemorrhagic complications, and aspirin did not increase the risk of aneurysm rebleeding, symptomatic intracranial hemorrhage, or major external ventricular drain (EVD)–associated hemorrhage (p = 0.3), though there was an increase in asymptomatic, minor (< 1 cm) EVD-associated hemorrhage in the aspirin-treated group (p = 0.02).CONCLUSIONSThe study findings suggest that for ruptured aneurysm patients with high-risk features, antiplatelet therapy can significantly reduce the rate of periprocedural TEE without increasing major systemic or intracranial hemorrhages.

Objective Patients with intracerebral hemorrhage (ICH) may elaborate varying degrees of perihematomal edema (PHE), requiring closer monitoring and a higher intensity of treatment. Here, we explore whether the soluble form of CD163, a scavenger receptor responsible for hemoglobin sequestration, can serve as a prognostic biomarker of PHE development and poor outcome after ICH. Methods Our study cohort was comprised of 51 primary age- and sex-matched ICH patients with moderate-sized, hypertensive deep hemorrhages. Patients were part of a prospective ICH registry cataloguing admission data along with functional outcomes. We measured sCD163 levels in serial serum and cerebrospinal fluid (CSF) samples obtained at prespecified timepoints. Descriptive statistics, including a generalized estimating equation for longitudinal data, were used to analyze sCD163 in relation to ICH outcomes. Results Acute serum sCD163 (

OBJECTIVETo study peritumoral brain edema (PTBE), it is necessary to create a model that accurately simulates vasogenic brain edema (VBE) without introducing a complicated tumor environment. PTBE associated with brain tumors is predominantly a result of vascular endothelial growth factor (VEGF) secreted by brain tumors, and VEGF infusion alone can lead to histological blood-brain barrier (BBB) breakdown in the absence of tumor. VBE is intimately linked to BBB breakdown. The authors sought to establish a model for VBE with chronic infusion of VEGF that can be validated by serial in-vivo MRI and histological findings.METHODSMale Fischer rats (n = 182) underwent stereotactic striatal implantation of MRI-safe brain cannulas for chronic infusion of VEGF (2–20 µg/ml). Following a preinfusion phase (4–6 days), the rats were exposed to VEGF or control rat serum albumin (1.5 µl/hr) for as long as 144 hours. Serial MRI was performed during infusion on a high-field (9.4-T) machine at 12–24, 24–36, 48–72, and 120–144 hours. Rat brains were then collected and histological analysis was performed.RESULTSControl animals and animals infused with 2 µg/ml of VEGF experienced no neurological deficits, seizure activity, or abnormal behavior. Animals treated with VEGF demonstrated a significantly larger volume (42.90 ± 3.842 mm3) of T2 hyper-attenuation at 144 hours when compared with the volume (8.585 ± 1.664 mm3) in control animals (mean difference 34.31 ± 4.187 mm3, p < 0.0001, 95% CI 25.74–42.89 mm3). Postcontrast T1 enhancement in the juxtacanalicular region indicating BBB breakdown was observed in rats undergoing infusion with VEGF. At the later time periods (120–144 hrs) the volume of T1 enhancement (34.97 ± 8.99 mm3) was significantly less compared with the region of edema (p < 0.0001). Histologically, no evidence of necrosis or inflammation was observed with VEGF or control infusion. Immunohistochemical analysis demonstrated astrocyte activation, vascular remodeling, and increased claudin-5 expression in juxtacanalicular regions. Aquaporin-4 expression was increased in both control and VEGF animals in the juxtacanalicular regions.CONCLUSIONSThe results of this study show that chronic brain infusion of VEGF creates a reliable model of VBE. This model lacks necrosis and inflammation that are characteristic of previous models of VBE. The model allows for a precise investigation into the mechanism of VBE formation. The authors also anticipate that this model will allow for investigation into the mechanism of glucocorticoid action in abrogating VBE, and to test novel therapeutic strategies targeting PTBE.

INTRODUCTION Despite multi-model therapies that include maximal surgical resection, radiation, chemotherapy, and tumor treating fields, the median survival of Glioblastoma (GBM) patients is around 15 months. WASP-family verprolin homologous protein 1 (WAVE1) is a downstream effector that receives signals from small GTPases to regulate the actin cytoskeleton. WAVE1’s interaction with arp2/3 modulates critical roles, such as cell motility and morphologic changes. Expression of WAVE1 has been implicated in leukemia, ovarian, and prostate cancer. In this study, we tested the role of WAVE1 in GBM tumor biology. METHODS Expression of WAVE1 in normal brain and GBM tumor specimens was assessed by immunohistochemistry (IHC). The relevance of targeting WAVE1 for GBM therapy was evaluated in vitro by western blot, proliferation assay, cell cycle analysis, apoptosis assay, migration assay, and neurosphere formation assay using scrambled and target specific WAVE1-siRNA in patient-derived primary GBM neurospheres (GBMNS). RESULTS IHC data shows that the expression of WAVE1 is higher in GBM tumor samples than in low-grade gliomas and normal brain tissues. WAVE1 expression is upregulated in GBMNS compared to normal human astrocytes. WAVE1 knockdown significantly decreased the proliferation, migration, and self-renewal of GBMNS without affecting its cell cycle progression. Furthermore, WAVE1 depletion did not show any alterations in the apoptotic cell population, indicating that WAVE1 knockdown has a cytostatic effect on GBMNS. CONCLUSION Expression of WAVE1 positively correlates with GBM, and its knockdown imparts antitumor efficacy through cytostasis.

Background and Purpose— Large artery occlusion (LAO) in ischemic stroke requires recognition and triage to an endovascular stroke treatment center. Noninvasive LAO detection is needed to improve triage. Methods— Prospective study to test whether noninvasive cerebral oximetry can detect anterior circulation LAO in acute stroke. Interhemispheric ΔBrSO 2 in LAO was compared with controls. Results— In LAO stroke, mean interhemispheric ΔBrSO 2 was −8.3±5.8% (n=19), compared with 0.4±5.8% in small artery stroke (n=17), 0.4±6.0% in hemorrhagic stroke (n=14), and 0.2±7.5% in subjects without stroke (n=19) ( P 2 in most LAO subjects (16/19). Discrimination of LAO at a −3% ΔBrSO 2 cut had 84% sensitivity and 70% specificity. Addition of the G-FAST clinical score (gaze–face–arm–speech– time) to the BrSO 2 measure had 84% sensitivity and 90% specificity. Conclusions— Noninvasive cerebral oximetry may help detect LAO in ischemic stroke, particularly when combined with a simple clinical scoring system.

Preclinical models that reliably recapitulate the immunosuppressive properties of human gliomas are essential to assess immune-based therapies. Intracranially injected GL261 cells are widely used as an immunocompetent animal model of glioma, but it is common practice to transfect these with luciferase to facilitate tumor monitoring during treatment. Our group has previously shown that the luciferase-expressing GL261 Red-FLuc cells create an inflammatory response when implanted intracranially. Now, we additionally explore the inflammatory response of GL261-Luc2 cells and demonstrate a similar host immune response occurs with this model as well. In our in vivo evaluation, C57BL/6 mice underwent stereotaxic, intracranial implantation with GL261, GL261 Red-FLuc or GL261-Luc2 cells at doses of 5x104cells/5mL or 3x105cells/5uL.MRIs were performed to monitor relative tumor growth. To assess intrinsic differences between cell lines, in vitro cytokine profiles were evaluated by proteome microarray. Kaplan-Meier survival analyses demonstrated median survival for mice implanted with GL261 cells at 5x104cells was 18 to 21 days. The GL261-Red FLuc implanted mice cells did not reach median survival at either tumor dose with greater than 60% of mice termed long-term survivors. Finally, mice injected with GL261-Luc2 cells at 3x105cells reached median survival at 23 days, but median survival was significantly prolonged for mice implanted with GL261-Luc2 at a dose of 5x104cells (37 days, with 40% becoming long-term survivors) compared to GL261 implanted mice. MRIs reveal differences in tumor growth that correspond with the differences in median survival between groups. In addition, proteomic analyses revealed significantly elevated inflammatory cytokines such as IFN-gamma, IL-7 and TNF-alpha in the supernatants of the GL261 Red-FLuc cells and GL261-Luc2 cells. Further immune characterization is ongoing. Our data suggests that GL261 Red-FLuc and GL261-Luc2 murine models elicit an anti-tumor immune response by increasing pro-inflammatory modulators which stimulate the tumoricidal function of immune cells in the tumor microenvironment.

Introduction: Intracerebral hemorrhage (ICH) affects approximately 2 million individuals per year. Incidence of ICH is roughly equal in men and women, but few studies have examined the influence of sex on long-term outcomes after ICH and secondary injury. Previous studies have shown that women in the post-partum period and post-menopausal women are especially susceptible to poor functional outcomes after ICH. Matrix metalloproteinases (MMPs) promote vessel rupture during ICH and may lead to poorer outcomes in female patients due to blood-brain barrier breakdown. We hypothesized that MMP isoform levels would be predictive of injury severity, secondary injury and long-term functional outcomes after ICH in males and females. Methods and Results: Patients from our prospectively collected ICH database were included. We included patients with deep hypertensive ICH, and excluded secondary ICH. Baseline clinical, radiographic and laboratory data were collected. Neurologic deterioration was defined as increase in NIHSS score and/or reduction in GCS score. Functional outcomes were assessed by modified Rankin Scale (mRS) and EuroQol at 90 DPI. Discharge disposition was recorded. With a total of 55 patients (n = 39 male, 16 female) we demonstrated a significantly higher risk of IVH (p = 0.012) and neurologic deterioration (p = 0.005) in females compared to males. We found that MMP levels in serum reliably predict injury severity in males, and secondary injury in females. Using multiplex ELISA we demonstrated that serum MMP-2 levels are negatively correlated with IVH severity (p = 0.028) in females. Additionally, serum levels of MMP-3 (p= 0.011) in males and MMP-10 (p= 0.044) in females predicted long-term functional outcomes in a sex-specific manner. Conclusion: Our work demonstrates the importance of studying sex-specific factors in ICH outcomes. We have found that there is a potential use of serum MMP expression as a sex-specific diagnostic tool for physicians treating patients after ICH. To our knowledge, this is the first sex-specific study to examine serum MMP levels and their correlation with clinicoradiologic measures after ICH. Further research to confirm these findings is necessary.

Introduction: The imaging characteristics of ischemic lesions seen on MRI aid in the interpretation of the lesion pathogenesis. Early ischemic lesions are seen on diffusion weighted imaging (DWI) with low apparent diffusion coefficient (ADC), later evolve on T2-FLAIR, develop elevated ADC, then disappear on DWI. Chronic white matter lesions (WML) seen on T2-FLAIR but not DWI may or may not be of ischemic origin. Here we present an MRI targeted pathology approach to better describe in-vivo MRI based on cellular changes. Methods: The brain of a patient was obtained for pathological evaluation early after stroke recurrence. As part of clinical care and study procedures, 3T MRI was obtained at baseline (within 2-hours), multiple follow-up visits, and during second admission. Radiological-pathological methods previously validated in trauma was employed. Whole brain 7T MRI was performed after formalin fixation, and MRI targeted pathology was performed, co-localizing three lesions of different ages based on history and presumed imaging characteristics; i) acute, ii) subacute, and iii) chronic vs WML. Homologous contralateral tissue was used as control. Results: Lesions seen in-vivo were observed in post mortem MRI, and reconfirmed in histology. An example of in-vivo and post-mortem MRI, along with corresponding tissue sections and H&E are shown in figure. Qualitative delineation of the boundaries of the chronic lesion on H&E was challenging. A large number of small vessels with enlarged perivascular spaces dominated. The subacute lesion, was characterized by loss of white mater, infiltration of macrophages, and astrocytosis. The acute lesion had a text-book appearance. Conclusion: Dramatic differences are seen in the volume fraction of free water, which likely a major contributor to the appearance on DWI/ADC and T2 FLAIR. Work continues with immunohistochemistry to better delineate the boundaries of the lesions and cellular morphology relevant to in-vivo MRI.

Dementia is a disease primarily affecting older adults in their ability to carry out daily activities. Frontotemporal dementia (FTD), a leading cause of early-onset dementia, can present in the fourth and fifth decade by progressive changes in personality, affect, and behavior. The atypical presentation of FTD may resemble a midlife crisis, depression, schizophrenia, or a traumatic brain injury among its causes. The etiology of FTD is unknown, although genetic links have been suggested, thus treatment focuses on behavioral and symptom management. Early diagnosis of FTD is needed to better support the emotional and financial burdens of family and caregivers.

Background: Infection with HIV predisposes patients to a myriad of neurologic disorders, including cerebrovascular disease. The pathophysiology is likely multifactorial, with proposed mechanisms including infectious vasculitis, HIV-induced endothelial dysfunction and adverse effects of combination antiretroviral therapy (cART). Epidemiologic data on clinically evident cerebral vasculopathy in HIV-infected adults is scarce, even though stroke hospitalizations are rising in this patient population. Methods: A total of 6,298 HIV-infected adults (San Francisco General Hospital, 2000-2013) were screened to generate a cohort of patients with dedicated neuroimaging of the intra- and extracranial cerebral vasculature. We extracted information regarding the extent of HIV disease (including serial viral load and CD4 counts), cardiovascular disease risk factors and exposure to cART (cross-referenced with pharmacy records) and performed multivariate logistic regression analysis to identify predictors of vasculopathy. Results: Of 144 patients, 55 patients (38.2%) had radiographic evidence of cerebral vasculopathy. Twenty (13.9%) had a vasculopathy characterized by vessel dolichoectasia and intracranial aneurysm formation. Thirty-five patients (24.3%) had intra- and or extracranial stenosis/occlusion. cART use (OR 2.27, 95% CI 1.03-5) and tobacco abuse (OR 2.35, 95% CI 1.04-5.25) were independently associated with the development of any vasculopathy, whereas cART use was also an independent risk factor for the stenosis/occlusion subtype specifically (OR 2.87, 95% CI 1.11-7.45). Conclusions: There was a high frequency of cerebral arterial disease in this neuroimaging cohort of HIV/AIDS patients. A history of cART use and a history of tobacco abuse were independent risk factors for vasculopathy, though these findings should be confirmed with large-scale prospective studies.

How to Obtain Contact Hours by Reading This Article Instructions 1.2 contact hours will be awarded by Villanova University College of Nursing upon successful completion of this activity. A contact hour is a unit of measurement that denotes 60 minutes of an organized learning activity. This is a learner-based activity. Villanova University College of Nursing does not require submission of your answers to the quiz. A contact hour certificate will be awarded once you register, pay the registration fee, and complete the evaluation form online at http://goo.gl/gMfXaf . To obtain contact hours you must: 1. Read the article, “Familism and Health Care Provision to Hispanic Older Adults” found on pages 21–29, carefully noting any tables and other illustrative materials that are included to enhance your knowledge and understanding of the content. Be sure to keep track of the amount of time (number of minutes) you spend reading the article and completing the quiz. 2. Read and answer each question on the quiz. After completing all of the questions, compare your answers to those provided within this issue. If you have incorrect answers, return to the article for further study. 3. Go to the Villanova website listed above to register for contact hour credit. You will be asked to provide your name; contact information; and a VISA, MasterCard, or Discover card number for payment of the $20.00 fee. Once you complete the online evaluation, a certificate will be automatically generated. This activity is valid for continuing education credit until December 31, 2018. Contact Hours This activity is co-provided by Villanova University College of Nursing and SLACK Incorporated. Villanova University College of Nursing is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's Commission on Accreditation. Activity Objectives 1. Explain familism and its potential effect on health care provision to Hispanic older adults. 2. Describe cultural considerations with decision making and caregiving within Hispanic families. Disclosure Statement Neither the planners nor the authors have any conflicts of interest to disclose. The Hispanic older adult population's rapid growth calls for an awareness of values that can affect the rendering and receipt of care. Familism, or familismo , a traditional Hispanic value, places importance of family over the self and can potentially affect health care perceptions and practices for Hispanic older adults. The current article discusses familism, which is upheld by some Hispanic older adults, and the potential for underuse of health care services. The traditional feminine role, marianismo , and masculine role, machismo , are considered, as well as implications for how decision making may be made by family members rather than the patient. Clinical implications for the provision of health care to Hispanic older adults are provided, along with the importance of considering acculturation and ethnic heterogeneity. Health care management strategies that reflect recognition and respect of familism, yet emphasize optimization of adherence and self-care, are described. [ Journal of Gerontological Nursing, 42 (1), 21–29.]

Immunocompetent murine models of glioma, such as GL261, are essential to assess immune therapy efficacy. The GL261 cell line expressing firefly luciferase (GL261RFluc), has been used to enable non-invasive tumor monitoring in preclinical studies. However, it is unclear if the GL261 and GL261RFluc cells are equivalent, particularly when applied to tumor immunology. C57BL/6 mice (n=20 per group, repeated once) underwent stereotaxic, intracranial implantation with GL261 or GL261RFLuc cells at 5x10^4cells/5uL and were assessed for survival. GL261 and GL261RFluc cell lines were assessed by CFSE proliferation assay. TGF-Beta2 ELISA and proteome profiler immunoassay were performed on equivalent cell culture lysates for cytokine analysis. Mice were implanted with GL261 or GL261RFluc cell lines, sacrificed at day 10, and brains were either disassociated, FACS stained, and sorted for immune cell surface antigens (n=4 each group) or formalin-fixed and paraffin embedded for immunohistochemistry (IHC, n=6 each group). Median survival for GL261 implanted mice was 20.9 ± 1.3 days with all animals progressing to a moribund state, while median survival was not reached for animals implanted with GL261RFluc cells (P=0.001). Quantitative IHC analyses of brains implanted with GL261RFluc cells showed significant increases in CD4 and CD8 cells but decrease in FoxP3 positive cells. Proliferation assays were equivalent. TGF-Beta2 ELISA showed significantly elevated levels in the GL261RFLuc cells. Proteomic profiler results demonstrated differential cytokine expression greater than 2-fold for over 25% of cytokines evaluated. The detected increases in chemoattractants CCL2 and CCL5 were particularly pronounced in GL261RFLuc cells. FACS analysis showed a trend of increased PD-L1 positive cells in brains implanted with GL261 cells, but this did not reach significance. GL261RFluc cells create an inflammatory immune microenvironment when implanted intracranially in C57BL/6 mice compared to GL261 cells. These findings suggest that investigators should avoid GL261RFluc cells when evaluating immune therapeutics in a C57BL/6 background.

Intracerebral hemorrhage affects approximately 2 million individuals per year. While the incidence is roughly equal in men and women, few studies have examined the influence of sex on secondary injury and associated long-term functional outcomes. Matrix metalloproteinases (MMPs) promote vessel rupture and worsen outcomes by potentiating blood-brain barrier breakdown after injury. We hypothesized that different MMP isoform levels would be predictive of injury severity, secondary injury, and long-term functional outcomes in males and females, respectively.We examined the levels of MMP isoforms in serum samples from a prospective patient biobank (n = 55). Baseline clinical, radiographic, and laboratory data were also analyzed.We found that MMP-1 (P = .036), MMP-2 (P = .014), MMP-3 (P .001), and MMP-9 (P = .02) levels gradually increased over time in male patients until 10 DPI. In female patients, we found a different pattern of activation: MMP-8 (P = .02) was the only isoform that significantly changed with time, which reached a peak at 3-5 days postinjury. Several MMP isoforms correlated with markers of secondary injury in female patients (all P .05). Additionally, serum levels of MMP-3 (P = .011) in males and MMP-10 (P = .044) in females were significantly associated with long-term functional outcomes in a sex-specific manner.This is the first sex-specific study to examine serum MMP levels and their correlation with clinicoradiologic measures after intracerebral hemorrhage, and identifies potential biomarkers of secondary injury and long-term outcomes in both sexes.

The Patient-Centered Medical Home care model emphasizes efficient, coordinated care distributed among interdisciplinary team members. One key function to care coordination is referral/test tracking. This study evaluated the referral practices in a nurse-managed Patient-Centered Medical Home primary care clinic. The major findings corroborate the need for a well-organized referral-tracking system that is centralized and contains safety nets to reduce the number of delayed or missed referrals.

Introduction: Intracerebral hemorrhage (ICH) dramatically remodels the blood-brain barrier (BBB). However, BBB remodeling may differ between ICH cases due to location (lobar or deep hemorrhage) as well as etiology (hypertension, trauma or amyloid-β). This study addresses whether serum levels of BBB remodeling proteins, including matrix metalloproteases (MMPs), transforming growth factor-β (TGF-β) and fibronectin (FN), are biomarkers of ICH etiology and outcomes. Hypothesis: We hypothesize that serum MMP, TGF-β and FN levels are predictive of ICH etiology, severity and functional outcomes. Methods: Patient data (n=37 lobar, n=42 deep ICH patients) were abstracted from prospective ICH databases detailing admission data, radiology, hospital course (ICH score, NIH stroke scale [NIHSS], Glasgow Coma Scale [GCS]), and functional outcomes (modified Rankin Scale [mRS], Euroqol). Serum samples were drawn from admission to 10 days post-injury. Levels of TGF-β isoforms, MMPs and FN were measured by multiplex ELISA (11 cytokines total) and divided into early ( Results: Early FN levels were lower in lobar than deep hemorrhages ( p=0.007 ). Levels of early MMP-8, -9 and -10, as well as levels of TGF-β1, TGF-β2 and TGF–β3 positively correlated with initial neurological deficits (NIHSS, p=0.005-0.039 ). Additionally, late MMP-8 levels negatively correlated with edema ( p=0.018 ). Furthermore, early MMP-1, TGF-β1 and TGF-β3 levels positively correlated with persistent neurologic deficits (mRS) at discharge and 90-days post-injury ( p=0.003-0.041 ). Finally, females had lower early levels of MMP-8, -9 and -10 than males ( p=0.019, 0.019, 0.019 ). Conclusion: BBB remodeling markers change with ICH location and patient sex, and are predictive of functional deficits and recovery. Specifically, these markers correlate with (1) the type and severity of initial injury, (2) the induction of secondary injury and (3) long-term functional recovery. This research improves our understanding of BBB responses to ICH, and may lead to novel biomarkers for ICH diagnosis and treatment.

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OBJECTIVEVon Hippel-Lindau disease (VHL) is a tumor predisposition syndrome characterized by CNS hemangioblastomas (HBs) and clear cell renal cell carcinomas (RCCs) due to hypoxia-inducible factor activation (pseudohypoxia). Because of the lack of effective medical therapies for VHL, HBs and RCCs account for significant morbidity and mortality, ultimately necessitating numerous neurological and renal surgeries. Propranolol is an FDA-approved pan-beta adrenergic antagonist with antitumor effects against infantile hemangiomas (IHs) and possibly VHL HBs. Here, the authors investigated the antitumor efficacy of propranolol against pseudohypoxia-driven VHL-HBs and VHL-RCCs.METHODSPatient-derived VHL-associated HBs (VHL-HBs) or 786-O-VHL−/− RCC cells were treated with clinically relevant concentrations of propranolol in vitro and assessed with viability assays, flow cytometry, quantitative real-time polymerase chain reaction, and western blotting. In vivo confirmation of propranolol antitumor activity was confirmed in athymic nude mice bearing 786-O xenograft tumors. Lastly, patients enrolled in a VHL natural history study (NCT00005902) were analyzed for incidental propranolol intake. Propranolol activity against VHL-HBs was assessed retrospectively with volumetric HB growth kinetic analysis.RESULTSPropranolol decreased HB and RCC viability in vitro with IC50 (half maximal inhibitory concentration) values of 50 µM and 200 µM, respectively. Similar to prior reports in infantile hemangiomas, propranolol induced apoptosis and paradoxically increased VEGF-A mRNA expression in patient-derived VHL-HBs and 786-O cells. While intracellular VEGF protein levels were not affected by propranolol treatment, propranolol decreased HIF expression in 786-O cells (7.6-fold reduction, p < 0.005). Propranolol attenuated tumor progression compared with control (33% volume reduction at 7 days, p < 0.005) in 786-O xenografted tumor-bearing mice. Three patients (harboring 25 growing CNS HBs) started propranolol therapy during the longitudinal VHL-HB study. HBs in these patients tended to grow slower (median growth rate 27.1 mm3/year vs 13.3 mm3/year) during propranolol treatment (p < 0.0004).CONCLUSIONSPropranolol decreases VHL-HB and VHL-related RCC viability in vitro likely by modulation of VEGF expression and by inducing apoptosis. Propranolol abrogates 786-O xenograft tumor progression in vivo, and retrospective clinical data suggest that propranolol curtails HB growth. These results suggest that propranolol may play a role in the treatment of VHL-related tumors.