UW Neurological Surgery Recent PubMed Publications

Assessing drug efficacy against Plasmodium falciparum liver stages in vivo.

JCI Insight. 2018 01 11;3(1):

Authors: Flannery EL, Foquet L, Chuenchob V, Fishbaugher M, Billman Z, Navarro MJ, Betz W, Olsen TM, Lee J, Camargo N, Nguyen T, Schafer C, Sack BK, Wilson EM, Saunders J, Bial J, Campo B, Charman SA, Murphy SC, Phillips MA, Kappe SH, Mikolajczak SA

Abstract
Malaria eradication necessitates new tools to fight the evolving and complex Plasmodium pathogens. These tools include prophylactic drugs that eliminate Plasmodium liver stages and consequently prevent clinical disease, decrease transmission, and reduce the propensity for resistance development. Currently, the identification of these drugs relies on in vitro P. falciparum liver stage assays or in vivo causal prophylaxis assays using rodent malaria parasites; there is no method to directly test in vivo liver stage activity of candidate antimalarials against the human malaria-causing parasite P. falciparum. Here, we use a liver-chimeric humanized mouse (FRG huHep) to demonstrate in vivo P. falciparum liver stage development and describe the efficacy of clinically used and candidate antimalarials with prophylactic activity. We show that daily administration of atovaquone-proguanil (ATQ-PG; ATQ, 30 mg/kg, and PG, 10 mg/kg) protects 5 of 5 mice from liver stage infection, consistent with the use in humans as a causal prophylactic drug. Single-dose primaquine (60 mg/kg) has similar activity to that observed in humans, demonstrating the activity of this drug (and its active metabolites) in FRG huHep mice. We also show that DSM265, a selective Plasmodial dihydroorotate dehydrogenase inhibitor with causal prophylactic activity in humans, reduces liver stage burden in FRG huHep mice. Finally, we measured liver stage-to-blood stage transition of the parasite, the ultimate readout of prophylactic activity and measurement of infective capacity of parasites in the liver, to show that ATQ-PG reduces blood stage patency to below the limit of quantitation by quantitative PCR (qPCR). The FRG huHep model, thus, provides a platform for preclinical evaluation of drug candidates for liver stage causal prophylactic activity, pharmacokinetic/pharmacodynamics studies, and biological studies to investigate the mechanism of action of liver stage active antimalarials.

PMID: 29321371 [PubMed - indexed for MEDLINE]

Stromal cells from perinatal and adult sources modulate the inflammatory immune response in vitro by decreasing Th1 cell proliferation and cytokine secretion.

Stem Cells Transl Med. 2020 01;9(1):61-73

Authors: Khoury O, Atala A, Murphy SV

Abstract
Many immune-mediated conditions are associated with a dysregulated imbalance toward a Th1 response leading to disease onset, severity, and damage. Many of the therapies such as immunomodulators or anti-TNF-α antibodies often fall short in preventing disease progression and ameliorating disease conditions. Thus, new therapies that can target inflammatory environments would have a major impact in preventing the progression of inflammatory diseases. We investigated the role of human stromal cells derived from the amniotic fluid (AFSCs), the placenta (PLSCs), and bone marrow-derived mesenchymal stromal cells (BM-MSCs) in modulating the inflammatory response of in vitro-stimulated circulating blood-derived immune cells. Immune cells were isolated from the blood of healthy individuals and stimulated in vitro with antigens to activate inflammatory responses to stimuli. AFSC, BM-MSCs, and PLSCs were cocultured with stimulated leukocytes, neutrophils, or lymphocytes. Inflammatory cytokine production, neutrophil migration, enzymatic degranulation, T cell proliferation, and subsets were evaluated. Coculture of all three stromal cell types decreased the gene expression of inflammatory cytokines and enzymes such as IL-1β, IFN-γ, TNF-α, neutrophil elastase, and the transcription factor NF-κB in lipopolysaccharide-stimulated leukocytes. With isolated phytohemagglutinin-stimulated peripheral blood mononuclear cells, cells coculture leads to a decrease in lymphocyte proliferation. This effect correlated with decreased numbers of Th1 lymphocytes and decreased secreted levels of IFN-γ.

PMID: 31638323 [PubMed - indexed for MEDLINE]

Impact of an educational intervention on eye gaze behaviour in retinal image interpretation by consultant and trainee ophthalmologists.

Health Informatics J. 2019 Oct 19;:1460458219881337

Authors: Shirley K, Williams M, McLaughlin L, Parker N, Bond R

Abstract
This study uses eye-tracking technology to assess the differences in gaze behaviours between ophthalmologists of different experience levels while interpreting retinal images of diabetic retinopathy. The differences in gaze behaviours before and after a teaching intervention which introduced a suggested search strategy is also investigated. A total of 9 trainees and 10 consultant ophthalmologists interpreted six retinal images. They were then shown a 5-min tutorial that demonstrated a search strategy. This was followed by six further retinal image interpretations. Participants completed questionnaires indicating clinical signs seen, appropriate retinopathy grade, and confidence. Eye movements were tracked during each interpretation.Overall, trainees compared to consultants demonstrated more uncertain and unstructured gaze behaviours. Trainee eye gaze metrics included: longer interpretation time, 36.5 s (SD = 6.2 vs. 31.4 s) (SD = 4.2) (p = 0.024), higher visit count, 17.38 visits (SD = 5.13) versus 12.18 visits(SD = 2.64) (p = 0.01), higher proportion of fixation, 57.0 per cent (SD = 5) versus 50.5 per cent (SD = 5) (p = 0.05) and shorter time to first fixation, 0.232 s (SD = 0.10) versus 0.821 s (SD = 0.77) (p = 0.001), respectively. The teaching intervention resulted in more focused gaze patterns in both groups. Pre-intervention and post-intervention mean proportion fixation on areas of interest were 38.6 per cent (SD = 6.8) and 51.8 per cent (SD = 13.9) for the trainee group, respectively, and 39.9 per cent (SD = 4.1) and 50.9 per cent (SD = 9.3) for the consultant group (p = 0.01).Consultants used more systematic and efficient approaches than trainees during interpretation. After the introduction of a suggested search strategy, trainees showed trends towards consultant eye gaze behaviours. Eye tracking gives an interesting insight into the thought processes of physicians carrying out complex tasks. The implication is that eye tracking may have future use in teaching and assessment. Its use in objectively assessing different teaching strategies could be a valuable tool for medical education.

PMID: 31630618 [PubMed - as supplied by publisher]

CA 19-9 Response: A Surrogate to Predict Survival in Patients With Metastatic Pancreatic Adenocarcinoma.

Am J Clin Oncol. 2019 12;42(12):898-902

Authors: Diaz CL, Cinar P, Hwang J, Ko AH, Tempero MA

Abstract
OBJECTIVE: The objective of this study was to determine the features of carbohydrate antigen (CA) 19-9 decline that correlates best with survival benefit in patients with metastatic pancreatic cancer.
METHODS: This is a retrospective study of 225 patients with metastatic pancreatic cancer receiving first-line therapy. Analysis was performed by the Kaplan-Meier method and Cox-proportional hazards ratios. CA 19-9 decline was grouped into quartiles within different CA 19-9 baseline groups. Time to nadir and CA 19-9 decline at month-2 (M2) of therapy were evaluated for patients with a baseline level ≥1000 U/mL.
RESULTS: No significant trend in survival was observed across baseline CA 19-9 levels. The greatest survival benefit was seen with a ≥75% decline to nadir. Among those with a ≥75% decline and baseline ≥1000 U/mL, 43 of 57 patients had a >50% decline at M2 of therapy and additional survival benefit was observed with a slower decline to nadir. Small sample sizes limited analysis of other baseline groups. CA 19-9 decline at M2 was not predictive.
CONCLUSIONS: In patients with a CA 19-9 ≥1000 U/mL, serial CA 19-9 levels may be considered as a surrogate for serial imaging to evaluate treatment response, with a ≥75% decline indicating the greatest survival benefit. Survival was improved further in the setting of a slower decline to nadir with the highest benefit seen in patients with a nadir occurring at 4 months or longer.

PMID: 31634155 [PubMed - indexed for MEDLINE]

Commentary: Local Control and Toxicity of Multilevel Spine Stereotactic Body Radiotherapy.

Neurosurgery. 2020 02 01;86(2):E173-E174

Authors: Dunne EM, Liu M, Hofstetter C, Saigal R, Lo SS

PMID: 31628748 [PubMed - indexed for MEDLINE]

Direct Pulp Capping: Which is the Most Effective Biomaterial? A Retrospective Clinical Study.

Materials (Basel). 2019 Oct 16;12(20):

Authors: Paula A, Carrilho E, Laranjo M, Abrantes AM, Casalta-Lopes J, Botelho MF, Marto CM, Ferreira MM

Abstract
(1) Background: Recently, tricalcium silicate cements, such as Biodentine™, have emerged. This biomaterial has a calcium hydroxide base and characteristics like mineral aggregate trioxide cements, but has tightening times that are substantially more suitable for their application and other clinical advantages. (2) Methods: A retrospective clinical study was conducted with 20 patients, which included a clinical evaluation of the presence or absence of pulp inflammation compatible symptoms, radiographic evaluation of the periapical tissues, and structural alterations of the coronary restoration that supports pulp capping therapies with Biodentine™ and WhiteProRoot®MTA. (3) Results: This clinical study revealed similar success rates between mineral trioxide cement and tricalcium silicates cements at 6 months, with 100% and 95% success rates, respectively. There were no statistically significant differences between both biomaterials and between these and the various clinical circumstances, namely the absolute isolation of the operating field, exposure size, the aetiology of exposure, and even the type of restorative material used. (4) Conclusions: Biodentine™ demonstrated a therapeutic effect on the formation of a dentin bridge accompanied by slight inflammatory signs, with a high clinical success rate, indicating the possibility of its effective and safe use in dental pulp direct capping in humans, similar to the gold standard material.

PMID: 31623190 [PubMed]

Cytotoxic effects of a chlorhexidine mouthwash and of an enzymatic mouthwash on human gingival fibroblasts.

Odontology. 2020 Apr;108(2):260-270

Authors: Coelho AS, Laranjo M, Gonçalves AC, Paula A, Paulo S, Abrantes AM, Caramelo F, Ferreira MM, Silva MJ, Carrilho E, Botelho MF

Abstract
The aim of this study was to evaluate the cytotoxic effects of an enzymatic mouthwash and of a chlorhexidine mouthwash on human gingival fibroblasts. The metabolic activity of the fibroblasts exposed to each mouthwash was assessed by the MTT assay and the protein content was assessed by the SRB assay. The flow cytometry was used to evaluate the cell cycle and the types of cell death. The oxidative status was evaluated through the DCF and the DHE probes and the intracellular GSH concentration and the mitochondrial membrane potential through JC-1. The cytotoxicity of both mouthwashes was found to be dependent on the exposure time and on the concentration. However, the cytotoxicity of the enzymatic mouthwash was found to be lower than that of the chlorhexidine mouthwash. A trend towards increased oxidative stress was observed for both mouthwashes. After exposing the fibroblasts to the mouthwashes, a G2/M phase block was observed and cell death occurred predominantly by necrosis. The effects of chlorhexidine on fibroblasts were identified at lower concentrations than those used in clinical practice. Therefore, the use of chlorhexidine as an antiseptic in surgical and postoperative situations should be limited. In order to clarify the clinical significance of the enzymatic mouthwash cytotoxicity new clinical studies will be necessary.

PMID: 31624978 [PubMed - indexed for MEDLINE]

Chemoprophylaxis vaccination: Phase 1 study to explore stage-specific immunity to Plasmodium falciparum in U.S. adults.

Clin Infect Dis. 2019 Oct 17;:

Authors: Healy SA, Murphy SC, Hume JCC, Shelton L, Kuntz S, Van Voorhis WC, Moodie Z, Metch B, Wang R, Silver-Brace T, Fishbaugher M, Kennedy M, Finney OC, Chaturvedi R, Hobbs CV, Warner-Lubin M, Talley AK, Wong-Madden S, Stuart K, Wald A, Kappe SH, Kublin JG, Duffy PE

Abstract
BACKGROUND: Chemoprophylaxis vaccination with sporozoites (CVac) with chloroquine induces protection against homologous P. falciparum sporozoite (PfSPZ) challenge, but whether blood-stage parasite exposure is required for protection remains unclear. Chloroquine suppresses and clears blood-stage parasitemia, while other antimalarial drugs such as primaquine act against liver-stage parasites. Here, we evaluate CVac regimens using chloroquine or primaquine as the partner drug to discern whether blood stage parasite exposure impacts protection against homologous controlled human malaria infection.
METHODS: In a phase 1, randomized, partial double-blind, placebo-controlled study of 36 malaria-naïve adults, all CVac subjects received chloroquine prophylaxis and bites from 12-15 P. falciparum-infected mosquitoes (CVac-chloroquine arm) at 3 monthly iterations, and some received post-exposure primaquine (CVac-primaquine/chloroquine arm). Drug control subjects received primaquine, chloroquine, and uninfected mosquito bites. After chloroquine washout, subjects, including treatment-naïve infectivity controls, underwent homologous PfSPZ controlled human malaria infection and were monitored for parasitemia for 21 days.
RESULTS: No serious adverse events occurred. During CVac, all but one subject in the study remained blood smear-negative while only one subject (primaquine/chloroquine arm) remained PCR-negative. Upon challenge, compared to infectivity controls, 3/3 chloroquine arm subjects displayed delayed patent parasitemia (p=0.01) but not sterile protection, while 3/11 primaquine/chloroquine subjects remained blood smear negative.
CONCLUSIONS: CVac-primaquine/chloroquine is safe and induces sterile immunity to P. falciparum in some recipients, but a single 45 mg dose of primaquine post-exposure does not completely prevent blood-stage parasitemia. Unlike previous studies, CVac-chloroquine did not produce sterile immunity.
CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov identifier NCT01500980.

PMID: 31621832 [PubMed - as supplied by publisher]

Do patient characteristics moderate the effect of extended-release naltrexone (XR-NTX) for opioid use disorder?

J Subst Abuse Treat. 2018 02;85:61-65

Authors: Friedmann PD, Wilson D, Nunes EV, Hoskinson R, Lee JD, Gordon M, Murphy SM, Bonnie RJ, Chen DT, Boney TY, O'Brien CP

Abstract
BACKGROUND: Extended release naltrexone (XR-NTX) injected intramuscularly monthly has been shown to reduce relapse in persons with opioid use disorder. Baseline factors, including patients' demographics, comorbidities and lifestyle, may help identify patients who will benefit most or least from XR-NTX treatment.
METHODS: Potential moderators of XR-NTX's effect were examined in the largest North American randomized open-label effectiveness trial of XR-NTX. Relapse status (Yes/No) at 6-month follow-up was regressed on treatment group (XR-NTX, N=153; or Treatment-as-Usual [TAU], N=155), baseline covariates, and their two-way interaction to identify moderator effects. Baseline covariates included age, gender, summary scores for depression, suicidal thoughts, drug abuse risk, substance use, medical, psychiatric and employment status, socialization, legal and family/social issues, history of abuse and quality of life measures.
RESULTS: Alcohol use to intoxication in the 30days before randomization was a significant moderator: during the treatment phase, those who reported being recently intoxicated before randomization to XR-NTX relapsed to opioids at a rate (56%) similar to TAU (58%), while those without alcohol intoxication in the prior 30days had a lower rate of opioid relapse (41% vs. 65%, respectively, P<0.04).
CONCLUSIONS: XR-NTX appeared to work equally well across subgroups with diverse demographic, addiction, mental health and environmental characteristics, with the possible exception of working better among those without recent alcohol intoxication. These findings should be reassuring to practitioners increasingly using XR-NTX as medical addiction therapy in diverse and often vulnerable populations.

PMID: 28236511 [PubMed - indexed for MEDLINE]

Quantitative Volumetric Imaging and Clinical Outcome Characterization of Symptomatic Concussion in 10- to 14-Year-Old Adolescent Athletes.

J Head Trauma Rehabil. 2018 Nov/Dec;33(6):E1-E10

Authors: Mac Donald CL, Barber J, Wright J, Coppel D, De Lacy N, Ottinger S, Peck S, Panks C, Zalewski K, Sun S, Temkin N

Abstract
OBJECTIVE: Prior work suggests that younger athletes may be more vulnerable to postconcussive syndrome. We investigated measures of clinical outcome and quantitative volumetric imaging in 10- to 14-year-old adolescent athletes to better understand the impact of concussion on this younger population.
SETTING: Outpatient clinics.
PARTICIPANTS: Ten- to 14-year-old symptomatic pediatric sports concussion patients and typically developing active controls.
DESIGN: Prospective, observational multiclinic study.
MAIN MEASURES: Demographics, magnetic resonance imaging, clinical assessments (neurocognitive function, postconcussive symptoms, mental health symptoms, quality of life).
RESULTS: Neuropsychological performance was comparable between groups while symptoms of mental health were discriminating and comprised the top regression model describing factors related to overall health behavior impairment. Concussion patients had smaller total brain volume as well as total intracranial volume in comparison with controls even though there was no difference on measures of natural development (age, height, weight, education, gender, and handedness).
CONCLUSIONS: Findings indicate that 10- to 14-year-old concussion patients symptomatic at 1 month more likely exhibit mental health symptoms impairing health behavior than cognitive dysfunction. There may be a vulnerability for those with smaller brain volumes at the time of the exposure. The study provides new data to support further investigation into risk factors for prolonged symptoms in this younger athlete population.

PMID: 29385018 [PubMed - indexed for MEDLINE]

Phosphoproteomic and Kinomic Signature of Clinically Aggressive Grade I (1.5) Meningiomas Reveals RB1 Signaling as a Novel Mediator and Biomarker.

Clin Cancer Res. 2020 01 01;26(1):193-205

Authors: Parada CA, Osbun JW, Busald T, Karasozen Y, Kaur S, Shi M, Barber J, Adidharma W, Cimino PJ, Pan C, Gonzalez-Cuyar LF, Rostomily R, Born DE, Zhang J, Ferreira M

Abstract
PURPOSE: Most World Health Organization (WHO) grade I meningiomas carry a favorable prognosis. Some become clinically aggressive with recurrence, invasion, and resistance to conventional therapies (grade 1.5; recurrent/progressive WHO grade I tumors requiring further treatment within 10 years). We aimed to identify biomarker signatures in grade 1.5 meningiomas where histopathology and genetic evaluation has fallen short.
EXPERIMENTAL DESIGN: Mass spectrometry (MS)-based phosphoproteomics and peptide chip array kinomics were used to compare grade I and 1.5 tumors. Ingenuity Pathway Analysis (IPA) identified alterations in signaling pathways with validation by Western blot analysis. The selected biomarker was evaluated in an independent cohort of 140 samples (79/140 genotyped for meningioma mutations) by tissue microarray and correlated with clinical variables.
RESULTS: The MS-based phosphoproteomics revealed differential Ser/Thr phosphorylation in 32 phosphopeptides. The kinomic profiling by peptide chip array identified 10 phosphopeptides, including a 360% increase in phosphorylation of RB1, in the 1.5 group. IPA of the combined datasets and Western blot validation revealed regulation of AKT and cell-cycle checkpoint cascades. RB1 hyperphosphorylation at the S780 site distinguished grade 1.5 meningiomas in an independent cohort of 140 samples and was associated with decreased progression/recurrence-free survival. Mutations in NF2, TRAF7, SMO, KLF4, and AKT1 E17K did not predict RB1 S780 staining or progression in grade 1.5 meningiomas.
CONCLUSIONS: RB1 S780 staining distinguishes grade 1.5 meningiomas, independent of histology, subtype, WHO grade, or genotype. This promising biomarker for risk stratification of histologically bland WHO grade I meningiomas provides insight into the pathways of oncogenesis driving these outlying clinically aggressive tumors.

PMID: 31615938 [PubMed - indexed for MEDLINE]

Long noncoding RNA LINC00319 regulates ROMO1 expression and promotes bladder cancer progression via miR-4492/ROMO1 axis.

J Cell Physiol. 2020 04;235(4):3768-3775

Authors: Yang Y, Zhang F, Huang H, Xie Z, Huang W, Xie H, Wang F

Abstract
Growing reports indicate that long noncoding RNA (lncRNA) are involved in the regulation of various biological processes of cancer cells. LINC00319 is an ill investigated lncRNA and has been shown to regulate lung cancer, nasopharyngeal carcinoma and ovarian cancer. Nevertheless, its roles in bladder cancer (BCa) remain unclear. In our research, LINC00319 was shown to be an upregulated lncRNA in BCa tissues. LINC00319 expression is negatively correlated with the patient's prognosis. Silencing of LINC00319 suppressed BCa proliferation and invasiveness. In addition, the data indicated LINC00319 was a sponge for miR-4492 and miR-4492 suppressed ROMO1 expression in BCa. Furthermore, our results illustrated miR-4492/ROMO1 axis regulates proliferation, migration, and invasion and LINC00319 exerts oncogenic roles through modulating miR-4492/ROMO1 axis. In sum, this study suggested that LINC00319 acts as oncogenic roles in BCa progression.

PMID: 31608995 [PubMed - indexed for MEDLINE]

Advancing BSNs by 2020: Innovative Educational Progression for Success.

Nurs Educ Perspect. 2020 Sep/Oct;41(5):E24-E25

Authors: Roberts MS, Gapp DK, Burns-Coral M, Greaves VD, Williams ML

Abstract
As we approach 2020, with limited time to meet the Institute of Medicine goal of 80 percent baccalaureate in nursing by 2020, there is a need for additional innovative academic progression models with seamless progression to obtain a BSN. A community college and university created a new model for educational progression that resulted in the Associates Degree in Nursing/Bachelor of Science in Nursing Collaborative Program, the first of its kind in this state. The program utilizes the ADN traditional curriculum during the fall/winter semesters, completing the BSN-based curriculum in the spring/summer semesters at the university.

PMID: 31609824 [PubMed - indexed for MEDLINE]

Commentary: Postoperative Stereotactic Body Radiotherapy for Spinal Metastases and the Impact of Epidural Disease Grade.

Neurosurgery. 2020 01 01;86(1):E91-E92

Authors: Vellayappan B, Kumar N, Foote M, Hofstetter CP, Saigal R, Chao ST, Lo SS

PMID: 31595964 [PubMed - indexed for MEDLINE]

A Genome-Wide Knockout Screen in Human Macrophages Identified Host Factors Modulating Salmonella Infection.

mBio. 2019 10 08;10(5):

Authors: Yeung ATY, Choi YH, Lee AHY, Hale C, Ponstingl H, Pickard D, Goulding D, Thomas M, Gill E, Kim JK, Bradley A, Hancock REW, Dougan G

Abstract
A genome-scale CRISPR knockout library screen of THP-1 human macrophages was performed to identify loss-of-function mutations conferring resistance to Salmonella uptake. The screen identified 183 candidate genes, from which 14 representative genes involved in actin dynamics (ACTR3, ARPC4, CAPZB, TOR3A, CYFIP2, CTTN, and NHLRC2), glycosaminoglycan metabolism (B3GNT1), receptor signaling (PDGFB and CD27), lipid raft formation (CLTCL1), calcium transport (ATP2A2 and ITPR3), and cholesterol metabolism (HMGCR) were analyzed further. For some of these pathways, known chemical inhibitors could replicate the Salmonella resistance phenotype, indicating their potential as targets for host-directed therapy. The screen indicated a role for the relatively uncharacterized gene NHLRC2 in both Salmonella invasion and macrophage differentiation. Upon differentiation, NHLRC2 mutant macrophages were hyperinflammatory and did not exhibit characteristics typical of macrophages, including atypical morphology and inability to interact and phagocytose bacteria/particles. Immunoprecipitation confirmed an interaction of NHLRC2 with FRYL, EIF2AK2, and KLHL13.IMPORTANCE Salmonella exploits macrophages to gain access to the lymphatic system and bloodstream to lead to local and potentially systemic infections. With an increasing number of antibiotic-resistant isolates identified in humans, Salmonella infections have become major threats to public health. Therefore, there is an urgent need to identify alternative approaches to anti-infective therapy, including host-directed therapies. In this study, we used a simple genome-wide screen to identify 183 candidate host factors in macrophages that can confer resistance to Salmonella infection. These factors may be potential therapeutic targets against Salmonella infections.

PMID: 31594818 [PubMed - indexed for MEDLINE]

International multicentre validation of the arteriovenous malformation-related intracerebral haemorrhage (AVICH) score.

J Neurol Neurosurg Psychiatry. 2018 11;89(11):1163-1166

Authors: Neidert MC, Lawton MT, Kim LJ, Nerva JD, Kurisu K, Ikawa F, Konczalla J, Dinc N, Seifert V, Habdank-Kolaczkowski J, Hatano T, Hayase M, Podlesek D, Schackert G, Wanet T, Gläsker S, Griessenauer CJ, Ogilvy CS, Kneist A, Sure U, Seifert B, Regli L, Bozinov O, Burkhardt JK

Abstract
OBJECTIVE: The recently published arteriovenous malformation-related intracerebral haemorrhage (AVICH) score showed better outcome prediction for patients with arteriovenous malformation (AVM)-related intracerebral haemorrhage (ICH) than other AVM or ICH scores. Here we present the results of a multicentre, external validation of the AVICH score.
METHODS: All participating centres (n=11) provided anonymous data on 325 patients to form the Spetzler-Martin (SM) grade, the supplemented SM (sSM) grade, the ICH score and the AVICH score. Modified Rankin score (mRS) at last follow-up (mean 25.6 months) was dichotomized into favourable (mRS 0-2, n=210) and unfavourable (mRS 3-6;n=115). Univariate and AUROC analyses were performed to validate the AVICH score.
RESULTS: Except nidus structure and AVM size, all single parameters forming the SM, sSM, ICH and AVICH score and the scores itself were significantly different between both outcome groups in the univariate analysis. The AVICH score was confirmed to be the highest predictive outcome score with an AUROC of 0.765 compared with 0.705 for the ICH score and 0.682 for the sSM grade.
CONCLUSION: The multicentre-validated AVICH score predicts clinical outcome superior to pre-existing scores. We suggest the routine use of this score for future clinical outcome prediction and in clinical research.
TRIAL REGISTRATION NUMBER: NCT02920645.

PMID: 28986471 [PubMed - indexed for MEDLINE]

Nuclear Excluded Autism-Associated Phosphatase and Tensin Homolog Mutations Dysregulate Neuronal Growth.

Biol Psychiatry. 2018 08 15;84(4):265-277

Authors: Fricano-Kugler CJ, Getz SA, Williams MR, Zurawel AA, DeSpenza T, Frazel PW, Li M, O'Malley AJ, Moen EL, Luikart BW

Abstract
BACKGROUND: Phosphatase and tensin homolog (PTEN) negatively regulates downstream protein kinase B signaling, resulting in decreased cellular growth and proliferation. PTEN is mutated in a subset of children with autism spectrum disorder (ASD); however, the mechanism by which specific point mutations alter PTEN function is largely unknown. Here, we assessed how ASD-associated single-nucleotide variations in PTEN (ASD-PTEN) affect function.
METHODS: We used viral-mediated molecular substitution of human PTEN into Pten knockout mouse neurons and assessed neuronal morphology to determine the functional impact of ASD-PTEN. We employed molecular cloning to examine how PTEN's stability, subcellular localization, and catalytic activity affect neuronal growth.
RESULTS: We identified a set of ASD-PTEN mutations displaying altered lipid phosphatase function and subcellular localization. We demonstrated that wild-type PTEN can rescue the neuronal hypertrophy, while PTEN H93R, F241S, D252G, W274L, N276S, and D326N failed to rescue this hypertrophy. A subset of these mutations lacked nuclear localization, prompting us to examine the role of nuclear PTEN in regulating neuronal growth. We found that nuclear PTEN alone is sufficient to regulate soma size. Furthermore, forced localization of the D252G and W274L mutations into the nucleus partially restores regulation of soma size.
CONCLUSIONS: ASD-PTEN mutations display decreased stability, catalytic activity, and/or altered subcellular localization. Mutations lacking nuclear localization uncover a novel mechanism whereby lipid phosphatase activity in the nucleus can regulate mammalian target of rapamycin signaling and neuronal growth.

PMID: 29373119 [PubMed - indexed for MEDLINE]

Distinct Expression Patterns of Carbonic Anhydrase IX in Clear Cell, Microcystic, and Angiomatous Meningiomas.

J Neuropathol Exp Neurol. 2019 12 01;78(12):1081-1088

Authors: Chkheidze R, Cimino PJ, Hatanpaa KJ, White CL, Ferreira M, Piccirillo SGM, Li L, Rajaram S, Nyagilo JO, Burns DK, Raisanen JM, Cai C

Abstract
Clear cell, microcytic, and angiomatous meningiomas are 3 vasculature-rich variants with overlapping morphological features but different prognostic and treatment implications. Distinction between them is not always straightforward. We compared the expression patterns of the hypoxia marker carbonic anhydrase IX (CA-IX) in meningiomas with predominant clear cell (n = 15), microcystic (n = 9), or angiomatous (n = 11) morphologies, as well as 117 cases of other World Health Organization recognized histological meningioma variants. Immunostaining for SMARCE1 protein, whose loss-of-function has been associated with clear cell meningiomas, was performed on all clear cell meningiomas, and selected variants of meningiomas as controls. All clear cell meningiomas showed absence of CA-IX expression and loss of nuclear SMARCE1 expression. All microcystic and angiomatous meningiomas showed diffuse CA-IX immunoreactivity and retained nuclear SMARCE1 expression. In other meningioma variants, CA-IX was expressed in a hypoxia-restricted pattern and was highly associated with atypical features such as necrosis, small cell change, and focal clear cell change. In conclusion, CA-IX may serve as a useful diagnostic marker in differentiating clear cell, microcystic, and angiomatous meningiomas.

PMID: 31589317 [PubMed - indexed for MEDLINE]

Renal and pulmonary thrombotic microangiopathy triggered by proteasome-inhibitor therapy in patient with smoldering myeloma: A renal biopsy and autopsy case report.

Medicine (Baltimore). 2019 Sep;98(39):e17148

Authors: Cassol CA, Williams MPA, Caza TN, Rodriguez S

Abstract
RATIONALE: Thrombotic microangiopathy (TMA) is a group of clinical syndromes characterized by excessive platelet activation and endothelial injury that leads to acute or chronic microvascular obliteration by intimal mucoid and fibrous thickening, with or without associated thrombi. It frequently involves the kidney but may involve any organ or system at variable frequencies depending on the underlying etiology. Among its numerous causes, drug toxicities and complement regulation abnormalities stand out as some of the most common. A more recently described association is with monoclonal gammopathy. Lung involvement by TMA is infrequent, but has been described in Cobalamin C deficiency and post stem-cell transplantation TMA.
PATIENT CONCERNS: This is the case of a patient with smoldering myeloma who received proteasome-inhibitor therapy due to retinopathy and developed acute renal failure within one week of therapy initiation.
DIAGNOSES: A renal biopsy showed thrombotic microangiopathy. At the time, mild pulmonary hypertension was also noted and presumed to be idiopathic.
INTERVENTIONS: Given the known association of proteasome-inhibitor therapy with thrombotic microangiopathy, Bortezomib was discontinued and dialysis was initiated.
OUTCOMES: Drug withdrawal failed to prevent disease progression and development of end-stage renal disease, as well as severe pulmonary hypertension that eventually lead to the patient's death.
LESSONS: To our knowledge, this is the first reported case of pulmonary involvement by TMA associated with monoclonal gammopathy which appears to have been triggered by proteasome-inhibitor therapy. Clinicians should be aware of this possibility to allow for more prompt recognition of pulmonary hypertension as a potential manifestation of monoclonal gammopathy-associated TMA, especially in patients also receiving proteasome-inhibitors, so that treatment aiming to slow disease progression can be instituted.

PMID: 31574818 [PubMed - indexed for MEDLINE]

Proceedings of the Sixth Deep Brain Stimulation Think Tank Modulation of Brain Networks and Application of Advanced Neuroimaging, Neurophysiology, and Optogenetics.

Front Neurosci. 2019;13:936

Authors: Ramirez-Zamora A, Giordano J, Boyden ES, Gradinaru V, Gunduz A, Starr PA, Sheth SA, McIntyre CC, Fox MD, Vitek J, Vedam-Mai V, Akbar U, Almeida L, Bronte-Stewart HM, Mayberg HS, Pouratian N, Gittis AH, Singer AC, Creed MC, Lazaro-Munoz G, Richardson M, Rossi MA, Cendejas-Zaragoza L, D'Haese PF, Chiong W, Gilron R, Chizeck H, Ko A, Baker KB, Wagenaar J, Harel N, Deeb W, Foote KD, Okun MS

Abstract
The annual deep brain stimulation (DBS) Think Tank aims to create an opportunity for a multidisciplinary discussion in the field of neuromodulation to examine developments, opportunities and challenges in the field. The proceedings of the Sixth Annual Think Tank recapitulate progress in applications of neurotechnology, neurophysiology, and emerging techniques for the treatment of a range of psychiatric and neurological conditions including Parkinson's disease, essential tremor, Tourette syndrome, epilepsy, cognitive disorders, and addiction. Each section of this overview provides insight about the understanding of neuromodulation for specific disease and discusses current challenges and future directions. This year's report addresses key issues in implementing advanced neurophysiological techniques, evolving use of novel modulation techniques to deliver DBS, ans improved neuroimaging techniques. The proceedings also offer insights into the new era of brain network neuromodulation and connectomic DBS to define and target dysfunctional brain networks. The proceedings also focused on innovations in applications and understanding of adaptive DBS (closed-loop systems), the use and applications of optogenetics in the field of neurostimulation and the need to develop databases for DBS indications. Finally, updates on neuroethical, legal, social, and policy issues relevant to DBS research are discussed.

PMID: 31572109 [PubMed]