bluuebunny/crossref_metadata_2025 huggingface dataset:
CAMKK2 Promotes Prostate Cancer Independently of AMPK via Increased Lipogenesis
Authors: Penfold Lucy , Woods Angela , Muckett Phillip , Nikitin Alexander Yu. , Kent Tera R. , Zhang Shuai , Graham Rebecca , Pollard Alice , Carling David
Published: September 2018

New targets are required for treating prostate cancer, particularly castrate-resistant disease. Previous studies reported that calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2) expression is increased in human prostate cancer. Here, we show that Camkk2 deletion or pharmacologic inhibition protects against prostate cancer development in a preclinical mouse model that lacks expression of prostate-specific Pten. In contrast, deletion of AMP-activated protein kinase (Ampk) β1 resulted in earlier onset of adenocarcinoma development. These findings suggest for the first time that Camkk2 and Ampk have opposing effects in prostate cancer progression. Loss of CAMKK2 in vivo or in human prostate cancer cells reduced the expression of two key lipogenic enzymes, acetyl-CoA carboxylase and fatty acid synthase. This reduction was mediated via a posttranscriptional mechanism, potentially involving a decrease in protein translation. Moreover, either deletion of CAMKK2 or activation of AMPK reduced cell growth in human prostate cancer cells by inhibiting de novo lipogenesis. Activation of AMPK in a panel of human prostate cancer cells inhibited cell proliferation, migration, and invasion as well as androgen-receptor signaling. These findings demonstrate that CAMKK2 and AMPK have opposing effects on lipogenesis, providing a potential mechanism for their contrasting effects on prostate cancer progression in vivo. They also suggest that inhibition of CAMKK2 combined with activation of AMPK would offer an efficacious therapeutic strategy in treatment of prostate cancer.

Significance:

These findings show that CAMKK2 and its downstream target AMPK have opposing effects on prostate cancer development and raise the possibility of a new combined therapeutic approach that inhibits CAMKK2 and activates AMPK.
Immunotherapy Targeting HPV16/18 Generates Potent Immune Responses in HPV-Associated Head and Neck Cancer
Authors: Aggarwal Charu , Cohen Roger B. , Morrow Matthew P. , Kraynyak Kimberly A. , Sylvester Albert J. , Knoblock Dawson M. , Bauml Joshua M. , Weinstein Gregory S. , Lin Alexander , Boyer Jean , Sakata Lindsay , Tan Sophie , Anton Aubrey , Dickerson Kelsie , Mangrolia Drishty , Vang Russell , Dallas Michael , Oyola Sandra , Duff Susan , Esser Mark , Kumar Rakesh , Weiner David , Csiki Ildiko , Bagarazzi Mark L.
Published: September 2018

Purpose:

Clinical responses with programmed death (PD-1) receptor–directed antibodies occur in about 20% of patients with advanced head and neck squamous cell cancer (HNSCCa). Viral neoantigens, such as the E6/E7 proteins of HPV16/18, are attractive targets for therapeutic immunization and offer an immune activation strategy that may be complementary to PD-1 inhibition.

Patients and Methods:

We report phase Ib/II safety, tolerability, and immunogenicity results of immunotherapy with MEDI0457 (DNA immunotherapy targeting HPV16/18 E6/E7 with IL12 encoding plasmids) delivered by electroporation with CELLECTRA constant current device. Twenty-two patients with locally advanced, p16+ HNSCCa received MEDI0457.

Results:

MEDI0457 was associated with mild injection site reactions, but no treatment-related grade 3–5 adverse events (AE) were noted. Eighteen of 21 evaluable patients showed elevated antigen-specific T-cell activity by IFNγ ELISpot, and persistent cellular responses surpassing 100 spot-forming units (SFUs)/106 peripheral blood mononuclear cells (PBMCs) were noted out to 1 year. Induction of HPV-specific CD8+ T cells was observed. MEDI0457 shifted the CD8+/FoxP3+ ratio in 4 of 5 post immunotherapy tumor samples and increased the number of perforin+ immune infiltrates in all 5 patients. One patient developed metastatic disease and was treated with anti–PD-1 therapy with a rapid and durable complete response. Flow-cytometric analyses revealed induction of HPV16-specific PD-1+ CD8+ T cells that were not found prior to MEDI0547 (0% vs. 1.8%).

Conclusions:

These data demonstrate that MEDI0457 can generate durable HPV16/18 antigen-specific peripheral and tumor immune responses. This approach may be used as a complementary strategy to PD-1/PD-L1 inhibition in HPV-associated HNSCCa to improve therapeutic outcomes.
A High-Throughput Immune-Oncology Screen Identifies EGFR Inhibitors as Potent Enhancers of Antigen-Specific Cytotoxic T-lymphocyte Tumor Cell Killing
Authors: Lizotte Patrick H. , Hong Ruey-Long , Luster Troy A. , Cavanaugh Megan E. , Taus Luke J. , Wang Stephen , Dhaneshwar Abha , Mayman Naomi , Yang Aaron , Kulkarni Meghana , Badalucco Lauren , Fitzpatrick Erica , Kao Hsiang-Fong , Kuraguchi Mari , Bittinger Mark , Kirschmeier Paul T. , Gray Nathanael S. , Barbie David A. , Jänne Pasi A.
Published: September 2018

We developed a screening assay in which luciferized ID8 expressing OVA was cocultured with transgenic CD8+ T cells specifically recognizing the model antigen in an H-2b–restricted manner. The assay was screened with a small-molecule library to identify compounds that inhibit or enhance T cell–mediated killing of tumor cells. Erlotinib, an EGFR inhibitor, was the top compound that enhanced T-cell killing of tumor cells. Subsequent experiments with erlotinib and additional EGFR inhibitors validated the screen results. EGFR inhibitors increased both basal and IFNγ-induced MHC class-I presentation, which enhanced recognition and lysis of tumor cell targets by CD8+ cytotoxic T lymphocytes. The ID8 cell line was also transduced to constitutively express Cas9, and a pooled CRISPR screen, utilizing the same target tumor cell/T-cell assay, identified single-guide (sg)RNAs targeting EGFR that sensitized tumor cells to T cell–mediated killing. Combination of PD-1 blockade with EGFR inhibition showed significant synergistic efficacy in a syngeneic model, further validating EGFR inhibitors as immunomodulatory agents that enhance checkpoint blockade. This assay can be screened in high-throughput with small-molecule libraries and genome-wide CRISPR/Cas9 libraries to identify both compounds and target genes, respectively, that enhance or inhibit T-cell recognition and killing of tumor cells. Retrospective analyses of squamous-cell head and neck cancer (SCCHN) patients treated with the combination of afatinib and pembrolizumab demonstrated a rate of clinical activity exceeding that of each single agent. Prospective clinical trials evaluating the combination of an EGFR inhibitor and PD-1 blockade should be conducted.
The Relationship between Cytokines and Verbal Memory in Individuals with Schizophrenia and Their Unaffected Siblings
Authors: Rebouças Diego B. , Rabelo-da-Ponte Francisco Diego , Massuda Rafael , Czepielewski Leticia S. , Gama Clarissa S.
Published: September 2018

Background: Verbal memory impairment may be considered an endophenotype in schizophrenia (SZ), also affecting the siblings of SZ subjects. Furthermore, the immune-inflammatory system response has an important modulatory effect on brain processes, especially on memory circuits. Objective: Investigating the relationship between TNF-α and IL-6 and memory performance in patients with SZ, their unaffected siblings (SB) and healthy controls (HC). Methods: 35 subjects with SZ, 36 SB, and 47 HC underwent a neurocognitive assessment for verbal memory by means of the revised Hopkins Verbal Learning Test (HVLT-R) in addition to serum cytokines analyses. Results: SZ patients performed worse in HVLT-R than SB and HC, but SB and HC were not different. Regarding the biomarker levels, we found significant results of TNF-α for both groups. However, we did not find differences between groups after multiple-comparisons analysis. There were no significant correlations between episodic verbal memory, TNF-α, and IL-6. Conclusion: The results are compatible with the hypothesis that deficits in verbal memory of individuals with SZ could be secondary to inadequate functioning of cognitive processing areas, such as proactive cognitive control.
Cardiac Shock Wave Therapy Attenuates Cardiomyocyte Apoptosis after Acute Myocardial Infarction in Rats
Authors: Zhang Yunhe , Shen Tao , Liu Bing , Dai Dapeng , Cai Jianping , Zhao Cong , Du Ling , Jia Na , He Qing
Published: September 2018

Background/Aims: Researches have showed that cardiac shock wave therapy (CSWT) could improve left ventricular function and attenuate LV remodeling of the ischemic heart. Apoptosis plays an important role in myocardial infarction and determines heart function and prognosis. However, it is still not clear whether CSWT is sufficient to attenuate acute myocardial infarction (AMI) induced cardiomyocyte apoptosis in vivo. In this study, we used a rat model to examine whether CSWT could attenuate cardiomyocyte apoptosis after AMI and to explore potential mechanisms. Methods: We generated an AMI rat model to investigate the function and possible regulatory mechanisms of CSWT. All rats were randomly divided into four groups: the sham-operated only group, sham-operated with SW treatment group, AMI only group, and AMI treated with SW treatment group.The rats were treated with a left anterior descending coronary artery ligation for 12h and then treated with or without CSWT (800 shots at 0.1 mJ/ mm2). Cytochrome c release was measured to analyze mitochondrial function and integrity. The apoptotic cell rate was determined by TUNEL assay. Western blot was used to analyze the cell apoptosis-, inflammation-, and survival-related signaling pathways. Results: First, the methodology of CSWT in the rat model of AMI was established. Second, CSWT attenuated the cardiomyocyte apoptosis rate in the infarct border zone. Third, CSWT suppressed the expression of apoptosis and inflammation molecules after AMI. Fourth, CSWT inhibited activation of the JNK pathway, which indicated inhibition of the cell inflammatory pathways and promotion of cardiomyocyte survival after AMI. Conclusion: These results indicate that CSWT exerts a protective effect against AMI-induced cardiomyocyte apoptosis, potentially by attenuating cytochrome c release from the mitochondria and inhibiting of the mitochondrial-dependent intrinsic apoptotic pathway. We also demonstrate that CSWT suppresses the JNK pathway and cardiomyocyte inflammation, which may also decrease cardiomyocyte apoptosis in vivo.
Parkin Modulates ERRα/eNOS Signaling Pathway in Endothelial Cells
Authors: Xia Weiwei , Yin Jie , Zhang Shuping , Guo Chuchu , Li Yuanyuan , Zhang Yue , Zhang Aihua , Jia Zhanjun , Chen Hongbing
Published: September 2018

Background/Aims: Although a number of reports documented the important role of parkin in mitophagy, emerging evidence also indicated additional functions of parkin besides mitophagy. The present study was undertaken to investigate the role of parkin in the regulation of ERRα/eNOS pathway in endothelial cells (ECs). Methods: Mouse aortic endothelial cells (MAECs) and cardiac muscle HL-1 cells were transfected with parkin plasmid or siRNA. ERRα inhibitor XCT-790, autophagy inhibitor 3-MA and Bafilomycin A1, and caspase inhibitor Z-VAD-FMK were used to block autophagy or apoptosis. Western blotting was performed to examine the protein levels. Flow cytometry was applied to determine the cell apoptosis and ROS production. Mitochondrial membrane potential was measured using JC-1 and TMRM. Immunoprecipitation was performed to confirm the parkin effect on ERRα ubiquitination. Results: Overexpression of parkin resulted in a significant reduction of total-eNOS and p-eNOS in parallel with the downregulation of ERRα (a regulator of eNOS) protein and the enhancement of ERRα ubiquitination. To test the role of ERRα in regulating eNOS in this experimental setting, we treated ECs with ERRα inhibitor and found a decrement of total-eNOS and p-eNOS. On the contrary, overexpression of ERRα increased the levels of total-eNOS and p-eNOS. Meanwhile, parkin overexpression induced mitochondrial dysfunction and cell apoptosis in both ECs and HL-1 cells. Finally, we confirmed that the parkin effect on the regulation of eNOS was independent of the autophagy and apoptosis. Conclusion: These findings suggested that parkin overexpression downregulated eNOS possibly through the ubiquitination of ERRα in endothelial cells.
КЛІНІЧНИЙ РОЗБІР ХВОРОГО ЯК ОДИН ІЗ ГОЛОВНИХ ЕТАПІВ ПРАКТИЧНОЇ ПІДГОТОВКИ СТУДЕНТІВ-ВИПУСКНИКІВ НА КАФЕДРІ ТЕРАПЕВТИЧНОЇ СТОМАТОЛОГІЇ ВДНЗУ “УМСА”
Authors: Nikolishyna E. V. , Bojcnenko O. M.
Published: September 2018

Мета роботи – проаналізувати роль клінічного розбору хворого як одного із головних етапів практичної підготовки студентів-випускників на кафедрі терапевтичної стоматології ВДНЗУ “УМСА”.Основна частина. Терапевтична стоматологія є основою практичної консервативної стоматології. Без глибоких знань аспектів діагностичного процесу неможливе розкриття закономірностей порушення функцій зубощелепного апарату, пошук механізмів їх відновлення, попередження хвороб та їх лікування. Для формування уміння логічно мислити, на основі отриманих знань та результатів обстеження хворого, ефективним методом навчання є вибіркове проведення клінічного розбору тематичних хворих. Під час проведення клінічного розбору хворого досвідчений викладач має змогу робити акценти та звернути увагу студентів на наявність причинно-наслідкових зв’язків між скаргами та анамнезом у зіставленні з об’єктивною картиною захворювання. Особлива увага студентів, які навчаються на кафедрі терапевтичної стоматології, звертається на побудову логічного зв’язку між отриманою інформацією і зіставленням з додатковими лабораторними та інструментальними дослідженнями в пошуку недостатніх ланцюжків для отримання розуміння всієї повноти патології.Висновки. Майбутній медик повинен володіти різноманітними видами професійної діяльності, компетентно і відповідально вирішувати професійні завдання. Саме, шляхом щоденного проведення, практично спрямований вид аудиторної роботи – клінічний розбір хворих дозволяє якісно сформувати основи клінічного мислення у майбутнього лікаря.
ДОСВІД ЗАПРОВАДЖЕННЯ ТРЕНІНГІВ З ОВОЛОДІННЯ ПРАКТИЧНИМИ НАВИЧКАМИ КОМУНІКАЦІЙ ІЗ ПАЦІЄНТАМИ НА БАЗІ ОКРЕМИХ ЗАКЛАДІВ ОХОРОНИ ЗДОРОВ’Я ІВАНО-ФРАНКІВСЬКОЇ ОБЛАСТІ
Authors: Yavorskyy A. M.
Published: September 2018

Мета роботи – проаналізувати досвід запровадження тренінгів з оволодіння практичними навичками комунікацій із пацієнтами в окремих закладах охорони здоров’я Івано-Франківської області.Основна частина. На базі стаціонарних закладів охорони Івано-Франківської області провели медико-соціальне дослідження рівня і причин незадоволеності пацієнтів отриманим медичним обслуговуванням. Опитано 553 пацієнтів. Встановлено, що серед понад 50 вивчених різноманітних чинників найбільший вплив на задоволеність пацієнтів медичним обслуговуванням мали інформаційно-деонтологічні чинники, спровоковані неналежним ставленням з боку медичного персоналу, усуненням пацієнтів від процесу прийняття рішення щодо призначених їм методів медичних втручань, недостатнім обговоренням з хворими можливих наслідків захворювання, неналежним інформуванням пацієнтів про їх права і обов’язки тощо. Розроблено і впроваджено на базі двох центральних районних, однієї центральної міської та обласної клінічної лікарень Івано-Франківської області короткотривалі навчальні тренінги для лікарів з оволодіння практичними навичками комунікацій із пацієнтами. До їх проведення залучались юрисконсульти лікарень, психологи та спеціально підготовані тренери з числа заступників керівників закладів охорони здоров’я. Результати повторного опитування 445 пацієнтів у цих закладах охорони здоров’я довели ефективність такої форми навчання і доцільність охоплення нею усіх медичних працівників. Висновок.Оволодіння практичними навичками комунікацій із пацієнтами – важлива і необхідна складова програм інформальної освіти у рамках безперервного професійного розвитку усіх фахівців у сфері охорони здоров’я.
Coupling Between Interleukin-1R1 and Necrosome Complex Involves in Hemin-Induced Neuronal Necroptosis After Intracranial Hemorrhage
Authors: Chu Xiang , Wu Xiaofeng , Feng Hua , Zhao Hengli , Tan Yan , Wang Liting , Ran Haiying , Yi Liang , Peng Yan , Tong Haipeng , Liu Rui , Bai Wei , Shi Huiwen , Li Lei , Huo Danqun
Published: September 2018

Background and Purpose—

Accumulated evidence suggests that hemin—a breakdown product of hemoglobin—plays a pivotal role in the inflammatory injuries that result after hemorrhagic stroke through the Toll Like Receptor 2-Toll Like Receptor 4 signal pathway. However, the mechanism of how hemin triggers neuronal necroptosis directly after intracranial hemorrhage (ICH) is still an area of active research. As animal model and preclinical studies have shown, the recombinant interleukin-1 receptor antagonist (IL-1RA) improves clinical outcomes after stroke. As such, we have chosen to investigate the mechanism of how IL-1RA exerts protective effect in hemin-induced neuronal necroptosis after ICH.

Methods—

Our ICH model was induced by hemin injection in C57BL/6 mice and IL-1R1
−/−
mice. In addition, we used primary cultured neurons to assess hemin-induced cell death. Co-immunoprecipitation, immunoblot, immunofluorescent staining, neurological deficit scores, and brain water content were used to study the mechanisms of IL-1R1 modulation in neuronal necroptosis both in vitro and in vivo.

Results—

Free hemin could mediate neuronal necroptosis directly by assembling necrosome complex and then to trigger cell death. This phenomenon was driven by IL-1R1 as IL-1R1 can form a complex with necrosome. After treatment with IL-1RA, both the expression and translocation of the necrosome decreased while disruption of the interaction between IL-1R1 and RIP1/RIP3 (receptor interacting protein 1/3) increased neuron survival. In addition, the IL-1R1–deficient mice demonstrated lower levels of necrosome components, including RIP1, RIP3, and MLKL (mixed lineage kinase domain-like protein), compared with control groups after hemin treatment. In addition, the neurological deficit scores, brain water content, and inflammatory response were all also reduced in the IL-1R1–deficient mice.

Conclusions—

Functional inhibition of the interaction between IL-1R1 and the necrosome complex improves neuron survival and promotes the recovery of neurological function in experimental ICH. Targeting IL-1R1/RIP1/RIP3 assembly could be a promising therapeutic strategy for patients with ICH.
Mechanical Thrombectomy in Patients With Milder Strokes and Large Vessel Occlusions
Authors: Nagel Simon , Bouslama Mehdi , Krause Lars U. , Küpper Clemens , Messer Mirko , Petersen Martina , Lowens Stephan , Herzberg Moritz , Ringleb Peter A. , Möhlenbruch Markus A. , Tiedt Steffen , Lima Fabricio O. , Haussen Diogo C. , Smith Wade S. , Lev Michael H. , Nogueira Raul G.
Published: September 2018

Background and Purpose—

We aimed to describe the safety and efficacy of immediate mechanical thrombectomy (MT) in patients with large vessel occlusions and low National Institutes of Health Stroke Scale (NIHSS) versus best medical management.

Methods—

Patients from prospectively collected databases of 6 international comprehensive stroke centers with large vessel occlusions (distal intracranial internal carotid, middle cerebral artery-M1 and M2 segments, or basilar artery with or without tandem occlusions) and NIHSS 0 to 5 were identified and divided into 2 groups for analysis: immediate MT or initial best medical management which included rescue MT after neurological deterioration (best medical management-MT). Uni- and multivariate analyses and patient-level matching for age, baseline NIHSS, and occlusion site were performed to compare baseline and outcome variables across the 2 groups. The primary outcome was defined as good outcome (modified Rankin Scale score, 0–2) at day 90. Safety outcome was symptomatic intracranial hemorrhage as defined by the ECASS (European Cooperative Acute Stroke Study) II and mortality at day 90.

Results—

Compared with best medical management-MT (n=220), patients with immediate MT (n=80) were younger (65.3±13.5 versus 69.5±14.1;
P
=0.021), had more often atrial fibrillation (44.8% versus 28.2%;
P
=0.012), higher baseline NIHSS (4, 0–5 versus 3, 0–5;
P
=0.005), higher Alberta Stroke Program Early CT Score (10, 7–10 versus 10, 5–10;
P
=0.023), more middle cerebral artery-M1, and less middle cerebral artery-M2 (41.3% versus 21.9% and 28.8% versus 49.3%;
P
=0.016) occlusions. The adjusted odds ratio for good outcome was 3.1 (95% CI, 1.4–6.9) favoring immediate MT. In the matched analysis, there was a 14.4% absolute difference in good outcome (84.4% versus 70.1%;
P
=0.03) at day 90 favoring immediate MT. There were no safety concerns.

Conclusions—

Our retrospective, pilot analysis suggests that immediate thrombectomy in large vessel occlusions patients with low NIHSS on presentation may be safe and has the potential to result in improved outcomes. Randomized clinical trials are warranted to establish the optimal management for this patient population.
Progression From Paroxysmal to Sustained Atrial Fibrillation Is Associated With Increased Adverse Events
Authors: Ogawa Hisashi , An Yoshimori , Ikeda Syuhei , Aono Yuya , Doi Kosuke , Ishii Mitsuru , Iguchi Moritake , Masunaga Nobutoyo , Esato Masahiro , Tsuji Hikari , Wada Hiromichi , Hasegawa Koji , Abe Mitsuru , Lip Gregory Y.H. , Akao Masaharu ,   on behalf of the Fushimi AF Registry Investigators
Published: September 2018

Background and Purpose—

Atrial fibrillation (AF) is a common arrhythmic disorder among the elderly and sometimes progresses from paroxysmal to sustained (persistent or permanent) types. Clinical outcomes of patients with progression of AF were unknown. This study assessed the characteristics of patients with AF progression and the impact of AF progression on various clinical events.

Methods—

The Fushimi AF Registry is a community-based prospective survey of the patients with AF in Fushimi-ku, Kyoto. Analyses were performed on 4045 patients, which included 1974 paroxysmal AF (PAF; 48.8%) and 2071 sustained (persistent or permanent) AF (SAF; 51.2%) at baseline.

Results—

During the median follow-up period of 1105 days, progression of AF occurred in 252 patients with PAF (4.22 per 100 person-years). Multivariate Cox regression analysis demonstrated that progression of AF was significantly associated with an increased risk of ischemic stroke or systemic embolism (adjusted hazard ratio [HR], 4.10; 95% CI, 1.95–8.24;
P
<0.001 [versus PAF without progression]; adjusted HR, 2.20; 95% CI, 1.11–4.00;
P
=0.025 [versus SAF]) during progression period from paroxysmal to sustained forms. The risk after the progression was equivalent to SAF (adjusted HR, 1.54; 95% CI, 0.78–2.75;
P
=0.201 [versus SAF]). AF progression was significantly associated with a higher risk of hospitalization for heart failure (adjusted HR, 2.70; 95% CI, 1.55–4.52;
P
<0.001 [versus PAF without progression]; adjusted HR, 1.81; 95% CI, 1.08–2.88;
P
=0.026 [versus SAF]).

Conclusions—

Progression of AF was associated with increased risk of clinical adverse events during arrhythmia progression period from PAF to SAF among Japanese patients with AF. The risk of adverse events was transiently elevated during progression period from PAF to SAF and declined to the level equivalent to SAF after the progression.

Clinical Trial Registration—

URL:
http://www.umin.ac.jp/ctr/
. Unique identifier: UMIN000005834.
Persistently Elevated Microvascular Resistance Postrecanalization
Authors: Ng Felix C. , Coulton Bronwyn , Chambers Brian , Thijs Vincent
Published: September 2018

Background and Purpose—

Impaired microvascular reperfusion despite complete recanalization (no-reflow) represents a potential therapeutic target to improve outcomes after recanalization therapies. Although well documented in animal models, this phenomenon has not been demonstrated clinically. We investigated whether transcranial Doppler can detect acute microvascular changes postrecanalization as a biomarker of the no-reflow phenomenon in stroke patients.

Methods—

Consecutive patients with recanalized (Thrombolysis in Cerebral Infarction grade IIb/III) acute middle cerebral artery occlusion by thrombectomy at a Comprehensive Stroke Centre with a high-volume neurovascular laboratory were retrospectively identified. Sonographic measures of middle cerebral artery territory microvascular resistance (pulsatility index and resistive index) on days 1 to 3 follow-up transcranial Doppler were compared between patients and age/gender-matched controls.

Results—

In 53 patients, middle cerebral artery pulsatility index was significantly more likely to be asymmetrically increased on interside comparison (27.9% versus 4.9%;
P
=0.007) and abnormally elevated beyond normal reference ranges (46.7% versus 22.0%;
P
=0.016) in the symptomatic hemisphere. Middle cerebral artery pulsatility index elevation was associated with less hemorrhagic infarction (9.5% versus 45.8%;
P
=0.009) but worse functional outcome irrespective of infarct volume as assessed on 90-day modified Rankin Scale (score of ≤1, 18.2% versus 58.1%;
P
=0.035).

Conclusions—

Elevated microvascular resistance within the ischemic territory is commonly present after successful recanalization as measured by pulsatility index on transcranial Doppler and may be a readily available and clinically relevant biomarker of the no-reflow phenomenon.
Estimation of Ischemic Core Volume Using Computed Tomographic Perfusion
Authors: Sakai Yu , Delman Bradley N. , Fifi Johanna T. , Tuhrim Stanley , Wheelwright Danielle , Doshi Amish H. , Mocco J , Nael Kambiz
Published: September 2018

Background and Purpose—

Estimation of infarction based on computed tomographic perfusion (CTP) has been challenging, mainly because of noise associated with CTP data. The Bayesian method is a robust probabilistic method that minimizes effects of oscillation, tracer delay, and noise during residue function estimation compared with other deconvolution methods. This study compares CTP-estimated ischemic core volume calculated by the Bayesian method and by the commonly used block-circulant singular value deconvolution technique.

Methods—

Patients were included if they had (1) anterior circulation ischemic stroke, (2) baseline CTP, (3) successful recanalization defined by thrombolysis in cerebral infarction ≥IIb, and (4) minimum infarction volume of >5 mL on follow-up magnetic resonance imaging (MRI). CTP data were processed with circulant singular value deconvolution and Bayesian methods. Two established CTP methods for estimation of ischemic core volume were applied: cerebral blood flow (CBF) method (relative CBF, <30% within the region of delay >2 seconds) and cerebral blood volume method (<2 mL per 100 g within the region of relative mean transit time >145%). Final infarct volume was determined on MRI (fluid-attenuated inversion recovery images). CTP and MRI-derived ischemic core volumes were compared by univariate and Bland-Altman analysis.

Results—

Among 35 patients included, the mean/median (mL) difference for CTP-estimated ischemic core volume against MRI was −4/−7 for Bayesian CBF (
P
=0.770), 20/12 for Bayesian cerebral blood volume (
P
=0.041), 21/10 for circulant singular value deconvolution CBF (
P
=0.006), and 35/18 for circulant singular value deconvolution cerebral blood volume (
P
<0.001). Among all methods, Bayesian CBF provided the narrowest limits of agreement (−28 to 19 mL) in comparison with MRI.

Conclusions—

Despite existing variabilities between CTP postprocessing methods, Bayesian postprocessing increases accuracy and limits variability in CTP estimation of ischemic core.
Alberta Stroke Program Early CT Score Versus Computed Tomographic Perfusion to Predict Functional Outcome After Successful Reperfusion in Acute Ischemic Stroke
Authors: Demeestere Jelle , Scheldeman Lauranne , Cornelissen Sandra A. , Heye Sam , Wouters Anke , Dupont Patrick , Christensen Sören , Mlynash Michael , Albers Gregory W. , Lansberg Maarten , Lemmens Robin
Published: September 2018

Background and Purpose—

We aimed to compare the ability of conventional Alberta Stroke Program Early CT Score (ASPECTS), automated ASPECTS, and ischemic core volume on computed tomographic perfusion to predict clinical outcome in ischemic stroke because of large vessel occlusion ≤18 hours after symptom onset.

Methods—

We selected patients with acute ischemic stroke from the CRISP study (Computed Tomographic Perfusion to Predict Response to Recanalization in Ischemic Stroke Project) with successful reperfusion (modified treatment in cerebral ischemia score 2b or 3). We used e-ASPECTS software to calculate automated ASPECTS and RAPID software to estimate ischemic core volumes. We studied associations between these imaging characteristics and good outcome (modified Rankin Scale score, 0–2) or poor outcome (modified Rankin Scale score, 4–6) in univariable and multivariable analysis, after adjustment for relevant clinical confounders.

Results—

We included 156 patients. Conventional and automated ASPECTS was not associated with good or poor outcome in univariable analysis (
P
=nonsignificant for all). Automated ASPECTS was associated with good outcome in multivariable analysis (
P
=0.02) but not with poor outcome. Ischemic core volume was associated with good (
P
<0.01) and poor outcome (
P
=0.04) in univariable and multivariable analysis (
P
=0.03 and
P
=0.02, respectively). Computed tomographic perfusion predicted good outcome with an area under the curve of 0.62 (95% CI, 0.53–0.71) and optimal cutoff core volume of 15 mL.

Conclusions—

Ischemic core volume assessed on computed tomographic perfusion is a predictor of clinical outcome among patients in whom endovascular reperfusion is achieved ≤18 hours after symptom onset. In this population, conventional or automated ASPECTS did not predict outcome.
Optimization of Prehospital Triage of Patients With Suspected Ischemic Stroke
Authors: Ali Ayman , Zachrison Kori S. , Eschenfeldt Patrick C. , Schwamm Lee H. , Hur Chin
Published: September 2018

Background and Purpose—

Prehospital routing algorithms for patients with suspected stroke because of large vessel occlusions should account for likelihood of benefit from endovascular therapy (EVT), risk of alteplase delays, and transport times. We built a mathematical model to give a real-time, location-based optimal emergency medical service routing location based on local resources, transport times, and patient characteristics.

Methods—

Using location, onset time, age, sex, and prehospital stroke severity, we calculated odds of a favorable outcome for a patient with suspected large vessel occlusions under 2 scenarios: direct to EVT-capable hospital versus transport to the nearest alteplase-capable hospital with transfer to EVT-capable hospital if appropriate. We project lifetime outcomes incorporating disability, quality of life utility, and cost. Multiple parameter sets of center-specific times (eg, door to alteplase) were randomly selected within a clinically plausible range to account for the model sensitivity to these estimates; for each iteration, the optimal strategy was defined as the most cost-effective outcome (threshold, $100 000 per quality-adjusted life-years gained). After 1000 simulations, the most frequently occurring optimal strategy was the final recommendation, with its strength measured as the proportion of runs for which it was optimal.

Results—

Routing recommendations were highly sensitive to small changes in model input parameters. Under many scenarios, the recommendations for direct transfer to the EVT site increased with increasing stroke severity and geographic proximity but did not vary substantially with respect to sex, age, or onset time.

Conclusions—

We present a mathematical decision model that determines ideal prehospital routing recommendations for patients with suspected stroke because of large vessel occlusions, with consideration of patient characteristics and location at onset. This model may be further refined by incorporating real-time data on traffic patterns and actual EVT and alteplase timeliness performance. Further studies are needed to verify model predictions.
Elevated Neutrophil and Presence of Intracranial Artery Stenosis Increase the Risk of Recurrent Stroke
Authors: Zhu Bihong , Liu Huihui , Pan Yuesong , Jing Jing , Li Hao , Zhao Xingquan , Liu Liping , Wang David , Johnston S. Claiborne , Wang Zhimin , Wang Yilong , Wang Yongjun ,   on behalf of the CHANCE Investigators
Published: September 2018

Background and Purpose—

The association of neutrophil and intracranial artery stenosis (ICAS) with the prognosis of stroke is uncertain. This study evaluated the relationship between neutrophil levels with and without ICAS and the prognosis of patients with minor stroke or transient ischemic attack.

Methods—

Data from the CHANCE trial (Clopidogrel in High-Risk Patients With Acute Nondisabling Cerebrovascular Events) was reviewed. Patients were divided into 4 groups according to the dichotomy of neutrophil counts and status of ICAS. The primary outcome was a new stroke (ischemic or hemorrhagic), and secondary outcomes included a new composite vascular event (stroke, myocardial infarction, or cardiovascular death) and ischemic stroke. Safety outcome was any hemorrhage at 90 days. The association between neutrophil counts with and without ICAS and risk of any outcome was analyzed by Cox regression models.

Results—

Of 1034 patients included in this subgroup analysis, 91 had recurrent strokes. Compared with the lower neutrophil levels without ICAS, higher neutrophil levels with ICAS significantly increased the risk of stroke recurrence (adjusted hazard ratio, 2.26; 95% CI, 1.19–4.31;
P
=0.01) and composite outcome (adjusted hazard ratio, 1.98; 95% CI, 1.06–3.67;
P
=0.03). However, there was no safety issue.

Conclusions—

Concomitant presence of higher neutrophil levels and ICAS was associated with the increased risk of stroke recurrence, and combined adverse outcome events in patients already had minor ischemic stroke or high-risk transient ischemic attack.

Clinical Trial Registration—

URL:
https://www.clinicaltrials.gov
. Unique identifier: NCT00979589.
Safety and Outcome of Endovascular Treatment in Prestroke-Dependent Patients
Authors: Goldhoorn Robert-Jan B. , Verhagen Merel , Dippel Diederik W.J. , van der Lugt Aad , Lingsma Hester F. , Roos Yvo B.W.E.M. , Majoie Charles B.L.M. , Vos Jan Albert , Boiten Jelis , van Zwam Wim H. , van Oostenbrugge Robert J. , van den Wijngaard Ido ,   on behalf of the MR CLEAN Registry Investigators
Published: September 2018

Background and Purpose—

Prestroke dependence is an exclusion criterion in most trials of endovascular treatment (EVT) for acute ischemic stroke. Little is known about outcomes after EVT in these patients. We compared outcome and safety of EVT between prestroke-dependent and prestroke-independent patients.

Methods—

We report patients with an anterior circulation occlusion who were included between March 2014 and June 2016 in the MR CLEAN registry (Multicenter Randomized Clinical Trial of Endovascular Treatment of Acute Ischemic Stroke)—a prospective, multicenter, observational study for stroke intervention centers in the Netherlands. Prestroke dependence was defined as modified Rankin Scale score of 3 to 5 before onset of current stroke. Primary outcome was favorable outcome at 90 days, defined as modified Rankin Scale of 0 to 2 or not worsening of the modified Rankin Scale score. Secondary outcomes included National Institutes of Health Stroke Scale score post-intervention, reperfusion grade, and safety outcomes. Logistic regression analyses (adjusted for age, baseline National Institutes of Health Stroke Scale score, collaterals, time to EVT, and intravenous thrombolysis before EVT) were used to assess the association between prestroke dependence and outcomes.

Results—

One thousand four hundred forty-one patients were included in the present study, of whom 157 (11%) were prestroke dependent. Favorable outcome was seen in 27% prestroke-dependent patients, compared with 42% prestroke-independent patients (
P
<0.05). After adjustment, prestroke dependence was not associated with less-favorable outcome (OR
adjusted
, 0.90; 95% CI, 0.58–1.39). The occurrence of symptomatic intracranial hemorrhage and ischemic stroke progression was similar in both groups.

Conclusions—

A substantial proportion of prestroke-dependent patients will reach prestroke modified Rankin Scale scores after EVT, and complication rates are comparable with prestroke-independent patients. Therefore, prestroke-dependent patients should not be routinely excluded from EVT.
Microstructural Damage in Normal-Appearing Brain Parenchyma and Neurocognitive Dysfunction in Adult Moyamoya Disease
Authors: Hara Shoko , Hori Masaaki , Murata Syo , Ueda Ryo , Tanaka Yoji , Inaji Motoki , Maehara Taketoshi , Aoki Shigeki , Nariai Tadashi
Published: September 2018

Background and Purpose

―Microstructural damage in the brain induced by chronic ischemia is suggested to play a pivotal role in the neurocognitive dysfunction of adults with Moyamoya disease (MMD). We investigated specific changes in the brain microstructure and their correlations with neurocognitive dysfunction in patients with MMD using a multishell diffusion magnetic resonance imaging technique called neurite orientation dispersion and density imaging.

Methods—

We evaluated 26 patients with MMD (16–63 years old, 20 females) and 20 age- and sex-matched normal volunteers using neurite orientation dispersion and density imaging and neuropsychological batteries. Neurite orientation dispersion and density imaging calculates 2 parameters: the intracellular volume fraction (Vic), which reflects the axon density in the white matter and dendrite density in the cortex, and the orientation dispersion index (OD), which reflects the network complexity. The microstructural damage and its correlation with neurocognitive performance were evaluated by performing a whole-brain analysis using SPM12 and correlation analysis with regional values.

Results—

Patients with MMD had significantly lower Vic in the white matter and a lower OD mainly in the cortex than those of the controls (
P
<0.001, family-wise error corrected). Of all neuropsychological scores, Processing Speed Index (PS) exhibited the strongest correlation with Vic in the white matter (
P
<0.001, family-wise error corrected). The Vic and OD values for regions with group differences, including both temporoparietal and frontal areas, correlated with neurocognitive performance (absolute r=0.37–0.64;
P
<0.01).

Conclusions—

Chronic ischemia in MMD may decrease the axon density in the white matter and dendrite density in the cortex (Vic) and simplify network complexity (OD), leading to neurocognitive dysfunction. Processing Speed Index may be the most sensitive index used to evaluate the ischemic burden, and the posterior part of the brain may play an important role in neurocognitive function.

Clinical Trial Registration—

URL:
http://www.umin.ac.jp/ctr/
. Unique identifier: UMIN000023082.
Incidence of Atrial Fibrillation in Patients With Recent Ischemic Stroke Versus Matched Controls
Authors: Witsch Jens , Merkler Alexander E. , Chen Monica Lin , Navi Babak B. , Sheth Kevin N. , Freedman Ben , Schwamm Lee H. , Kamel Hooman
Published: September 2018

Background and Purpose—

It is unclear whether atrial fibrillation/flutter (AF) newly diagnosed after ischemic stroke represents a preexisting risk factor that led to stroke, an arrhythmia triggered by poststroke autonomic dysfunction, or an incidental finding.

Methods—

We compared AF incidence after hospitalizations for ischemic stroke, hemorrhagic stroke, and nonstroke conditions using inpatient and outpatient claims between 2008 and 2015 from a nationally representative 5% sample of Medicare beneficiaries. We used validated
International Classification of Diseases, Ninth Revision, Clinical Modification
(
ICD-9-CM
) codes to identify AF-free patients hospitalized with ischemic or hemorrhagic stroke and matched them in a 1:1 ratio by age, sex, race, calendar year, vascular risk factors, and Charlson comorbidities. We then matched the combined stroke cohort in a 1:1 ratio to patients hospitalized for nonstroke diagnoses. We used survival statistics and Cox regression to compare postdischarge AF incidence among groups.

Results—

We matched 2580 patients with ischemic stroke, 2580 with hemorrhagic stroke, and 5160 patients with other conditions. The annual postdischarge AF incidence was 3.4% (95% CI, 3.1%–3.7%) after ischemic stroke, 2.2% (95% CI, 1.9%–2.4%) after hemorrhagic stroke, and 2.9% (95% CI, 2.6%–3.1%) after nonstroke hospitalization. Ischemic stroke was associated with a somewhat higher risk of AF than hemorrhagic stroke (hazard ratio, 1.5; 95% CI, 1.3–1.8) or nonstroke conditions (hazard ratio, 1.2; 95% CI, 1.1–1.3). The latter association attenuated in sensitivity analyses limiting the outcome to AF diagnoses made by cardiologists (hazard ratio, 1.1; 95% CI, 0.8–1.5) or limiting the outcome to a minimum of 2 AF claims on separate dates (hazard ratio, 1.2; 95% CI, 1.0–1.5;
P
=0.09).

Conclusions—

New diagnoses of AF were more common after hospitalization for ischemic stroke than after hospitalization for hemorrhagic stroke or nonstroke conditions, but all hospitalized patients had a substantial incidence of new AF diagnoses after discharge and differences were attenuated when using more stringent definitions.
When Law Calls, Does Science Answer? A Survey of Distinguished Scientists & Engineers
Authors: Diamond Shari Seidman , Lempert Richard O.
Published: September 2018

Sound legal decision-making frequently requires the assistance of scientists and engineers. The survey we conducted with the cooperation of the American Academy examines the views of the legal system held by some of the nation's most distinguished scientists and engineers, what motivates them to participate or to refuse to assist in lawsuits when asked, and their assessment of their experiences when they do participate. The survey reveals that a majority of the responding scientists and engineers will agree to participate when asked, and when they turn down requests, the most common reasons are lack of time and absence of relevant expertise. Dissatisfaction with legal procedures is also a deterrent, but our respondents indicated that some procedural changes would make their participation more likely. In addition, participation appears to be associated with a greater belief in the ability of the legal system to deal well with scientific matters.
Law & Neuroscience: The Case of Solitary Confinement
Authors: Lobel Jules , Akil Huda
Published: September 2018

This essay discusses the interface between neuroscience and the law. It underscores the potential for neuroscience to break down the division that currently exists in law between physiological and psychological harm and between physical and mental injury. To show how scientific knowledge can illuminate a complex legal issue, we analyze the recent use of neuroscience in evaluating the harm caused by prolonged solitary confinement.
Alternatives to Traditional Adversary Methods of Presenting Scientific Expertise in the Legal System
Authors: Gertner Nancy , Sanders Joseph
Published: September 2018

The twin goals of any litigation are to arrive at a correct outcome and provide the parties with a sense that they were treated justly, even if they do not prevail. Adversarial proceedings are often perceived to be superior to inquisitorial proceedings with respect to the second goal but inferior with respect to the first. This is especially the case when proceedings involve expert testimony. In this essay, we discuss several relatively minor changes to typical adversarial processes that offer the potential of improving trial accuracy without disrupting the overall structure of adversarial proceedings. These changes include 1) alterations to the organization of the trial, including concurrent expert testimony; 2) alterations to the role of the jury, including taking notes, asking questions, and receiving written expert reports; and 3) formal expert witness codes of conduct designed to better arm experts to resist the adversarial pressures that lead to biased testimony.
Medial Temporal Lobe Amnesia Is Associated with a Deficit in Recovering Temporal Context
Authors: Palombo Daniela J. , Di Lascio Joseph M. , Howard Marc W. , Verfaellie Mieke
Published: September 2018

Medial-temporal lobe (MTL) lesions are associated with severe impairments in episodic memory. In the framework of the temporal context model, the hypothesized mechanism for episodic memory is the reinstatement of a prior experienced context (i.e., “jump back in time”), which relies upon the MTL [Howard, M. W., Fotedar, M. S., Datey, A. V., & Hasselmo, M. E. The temporal context model in spatial navigation and relational learning: Toward a common explanation of medial temporal lobe function across domains. Psychological Review, 112, 75–116, 2005]. This hypothesis has proven difficult to test in amnesia because of the floor-level performance by patients in recall tasks. To circumvent this issue, in this study, we used a “looped-list” format, in which a set of verbal stimuli was presented multiple times in a consistent order. This allowed for comparison of statistical properties such as probability of first recall and lag-conditional response probability (lag-CRP) between amnesic patients and healthy controls. Results revealed that the lag-CRP, but not the probability of first recall, is altered in amnesia, suggesting a selective disruption of temporal contiguity. To further characterize the results, we fit a scale-invariant version of the temporal context model [Howard, M. W., Shankar, K. H., Aue, W. R., & Criss, A. H. A distributed representation of internal time. Psychological Review, 122, 24–53, 2015] to the probability of first recall and lag-CRP curves. The modeling results suggested that the deficit in temporal contiguity in amnesia is best described as a failure to recover temporal context. These results provide the first direct evidence for an impairment in a jump-back-in-time mechanism in patients with MTL amnesia.
Political Office and the Rule of Law in Plato’s Statesman
Authors: Sørensen Anders Dahl
Published: September 2018

The article discusses the relation between political office (archē) and the rule of law in Plato’s dialogue Statesman. Taking its starting-point from an observation about the Statesman’s peculiar approach to constitutional analysis, the article argues that what Plato is concerned to show is how the reconceptualisation of the role of law in government proposed in that dialogue has important implications for what we take the role of the institution of office-holding to be. While Greek political tradition held the main aim of archē to be the formal circumscription and control of official power within a constitutional order, Plato insists that it should primarily be understood as ensuring that the exercise of political power approximates, by means of law, the ideal rule by a political expert. The article ends by pointing out how this reading complements another recent discussion of office-holding in the Statesman.
Resemblance, Resonance and Reconstitution: Some Remarks on Śaṃkara and Creative Skepsis
Authors: Ovens Martin
Published: September 2018

This essay explores the possibility of dialogue between creative skepsis and Śaṃkara’s Advaita Vedānta based on a phenomenology of the structure and dynamics of both traditions. Externally, the essay shows how critical reflection on Śaṃkara/West comparative philosophy may culminate in standpoints of creative skepsis. Internally, the essay indicates how both traditions “resonate” as living “via negativas” that involve disciplines of enquiry within the practical context of a way of life.