bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sympathetic function during whole body cooling is altered in hypertensive adults
Authors: Greaney Jody L. , Kenney W. Larry , Alexander Lacy M. 
Published: September 2017

During moderate cold exposure, cardiovascular-related morbidity and mortality increase disproportionately in hypertensive adults (HTN); however, the mechanisms underlying this association are not well defined. We hypothesized that whole body cold stress would evoke exaggerated increases in blood pressure (BP) and muscle sympathetic nerve activity (MSNA) in HTN compared with normotensive adults (NTN) and that sympathetic baroreflex function would be altered during cooling in HTN. MSNA (peroneal microneurography) and beat-to-beat BP (Finometer) were measured continuously in 10 NTN (6 men/4 women; age 53 ± 3 yr; resting BP 125 ± 3/79 ± 1 mmHg) and 13 HTN (7 men/6 women; age 58 ± 2 yr; resting BP 146 ± 5/88 ± 2 mmHg) during whole body cooling-induced reductions in mean skin temperature (Tsk; water-perfused suit) from 34.0 to 30.5°C. During cooling, the increase in mean arterial pressure was greater in HTN (NTN: Δ6 ± 2 vs. HTN: Δ11 ± 1 mmHg; P = 0.02) and accompanied by exaggerated increases in MSNA (NTN: Δ8 ± 3 vs. HTN: Δ20 ± 3 bursts/100 heart beats; P < 0.01). The slope of the relation between MSNA and diastolic BP did not change during cooling in NTN (Tsk 34.0°C: −4.4 ± 0.8 vs. Tsk 30.5°C: −5.0 ± 0.3 bursts·100 heart beats−1·mmHg−1; P = 0.47) but increased in HTN (Tsk 34.0°C: −3.6 ± 0.4 vs. Tsk 30.5°C: −5.4 ± 0.4 bursts·100 heart beats)−1·mmHg−1; P = 0.02). These findings demonstrate that the cooling-induced increases in BP and MSNA are exaggerated in HTN. Furthermore, during cooling, sympathetic baroreflex sensitivity increases in HTN, but not NTN, presumably to allow for baroreflex-mediated buffering of excessive cooling-induced increases in BP. Collectively, these findings suggest that sympathetic function is altered during whole body cooling in hypertension. NEW & NOTEWORTHY These novel findings demonstrate that whole body cooling-induced reductions in mean skin temperature elicited greater increases in blood pressure and muscle sympathetic nerve activity in hypertensive adults. In addition, during moderate cold exposure, sympathetic baroreflex sensitivity increased in hypertensive, but not normotensive, adults.
Hyperpolarization-activated cyclic-nucleotide-gated channels potentially modulate axonal excitability at different thresholds
Authors: Weerasinghe Dinushi , Menon Parvathi , Vucic Steve 
Published: September 2017

Hyperpolarization-activated cyclic-nucleotide-gated (HCN) channels mediate differences in sensory and motor axonal excitability at different thresholds in animal models. Importantly, HCN channels are responsible for voltage-gated inward rectifying ( Ih) currents activated during hyperpolarization. The Ih currents exert a crucial role in determining the resting membrane potential and have been implicated in a variety of neurological disorders, including neuropathic pain. In humans, differences in biophysical properties of motor and sensory axons at different thresholds remain to be elucidated and could provide crucial pathophysiological insights in peripheral neurological diseases. Consequently, the aim of this study was to characterize sensory and motor axonal function at different threshold. Median nerve motor and sensory axonal excitability studies were undertaken in 15 healthy subjects (45 studies in total). Tracking targets were set to 20, 40, and 60% of maximum for sensory and motor axons. Hyperpolarizing threshold electrotonus (TEh) at 90–100 ms was significantly increased in lower threshold sensory axons times ( F = 11.195, P < 0.001). In motor axons, the hyperpolarizing current/threshold ( I/ V) gradient was significantly increased in lower threshold axons ( F = 3.191, P < 0.05). The minimum I/ V gradient was increased in lower threshold motor and sensory axons. In conclusion, variation in the kinetics of HCN isoforms could account for the findings in motor and sensory axons. Importantly, assessing the function of HCN channels in sensory and motor axons of different thresholds may provide insights into the pathophysiological processes underlying peripheral neurological diseases in humans, particularly focusing on the role of HCN channels with the potential of identifying novel treatment targets. NEW & NOTEWORTHY Hyperpolarization-activated cyclic-nucleotide-gated (HCN) channels, which underlie inward rectifying currents ( Ih), appear to mediate differences in sensory and motor axonal properties. Inward rectifying currents are increased in lower threshold motor and sensory axons, although different HCN channel isoforms appear to underlie these changes. While faster activating HCN channels seem to underlie Ih changes in sensory axons, slower activating HCN isoforms appear to be mediating the differences in Ih conductances in motor axons of different thresholds. The differences in HCN gating properties could explain the predilection for dysfunction of sensory and motor axons in specific neurological diseases.
Anti-Jagged Immunotherapy Inhibits MDSCs and Overcomes Tumor-Induced Tolerance
Authors: Sierra Rosa A. , Trillo-Tinoco Jimena , Mohamed Eslam , Yu Lolie , Achyut Bhagelu R. , Arbab Ali , Bradford Jennifer W. , Osborne Barbara A. , Miele Lucio , Rodriguez Paulo C. 
Published: September 2017

Abstract
Myeloid-derived suppressor cells (MDSC) are a major obstacle to promising forms of cancer immunotherapy, but tools to broadly limit their immunoregulatory effects remain lacking. In this study, we assessed the therapeutic effect of the humanized anti–Jagged1/2-blocking antibody CTX014 on MDSC-mediated T-cell suppression in tumor-bearing mice. CTX014 decreased tumor growth, affected the accumulation and tolerogenic activity of MDSCs in tumors, and inhibited the expression of immunosuppressive factors arginase I and iNOS. Consequently, anti-Jagged therapy overcame tumor-induced T-cell tolerance, increased the infiltration of reactive CD8+ T cells into tumors, and enhanced the efficacy of T-cell–based immunotherapy. Depletion of MDSC-like cells restored tumor growth in mice treated with anti-Jagged, whereas coinjection of MDSC-like cells from anti–Jagged-treated mice with cancer cells delayed tumor growth. Jagged1/2 was induced in MDSCs by tumor-derived factors via NFkB-p65 signaling, and conditional deletion of NFkB-p65 blocked MDSC function. Collectively, our results offer a preclinical proof of concept for the use of anti-Jagged1/2 to reprogram MDSC-mediated T-cell suppression in tumors, with implications to broadly improve the efficacy of cancer therapy. Cancer Res; 77(20); 5628–38. ©2017 AACR.
Optical Coherence Tomography Detects Necrotic Regions and Volumetrically Quantifies Multicellular Tumor Spheroids
Authors: Huang Yongyang , Wang Shunqiang , Guo Qiongyu , Kessel Sarah , Rubinoff Ian , Chan Leo Li-Ying , Li Peter , Liu Yaling , Qiu Jean , Zhou Chao 
Published: September 2017

Abstract
Three-dimensional (3D) tumor spheroid models have gained increased recognition as important tools in cancer research and anticancer drug development. However, currently available imaging approaches used in high-throughput screening drug discovery platforms, for example, bright-field, phase contrast, and fluorescence microscopies, are unable to resolve 3D structures deep inside (&gt;50 μm) tumor spheroids. In this study, we established a label-free, noninvasive optical coherence tomography (OCT) imaging platform to characterize 3D morphologic and physiologic information of multicellular tumor spheroids (MCTS) growing from approximately 250 to 600 μm in height over 21 days. In particular, tumor spheroids of two cell lines, glioblastoma (U-87MG) and colorectal carcinoma (HCT116), exhibited distinctive evolutions in their geometric shapes at late growth stages. Volumes of MCTS were accurately quantified using a voxel-based approach without presumptions of their geometries. In contrast, conventional diameter-based volume calculations assuming perfect spherical shape resulted in large quantification errors. Furthermore, we successfully detected necrotic regions within these tumor spheroids based on increased intrinsic optical attenuation, suggesting a promising alternative of label-free viability tests in tumor spheroids. Therefore, OCT can serve as a promising imaging modality to characterize morphologic and physiologic features of MCTS, showing great potential for high-throughput drug screening. Cancer Res; 77(21); 6011–20. ©2017 AACR.
A Randomized Controlled Trial of Green Tea Extract Supplementation and Mammographic Density in Postmenopausal Women at Increased Risk of Breast Cancer
Authors: Samavat Hamed , Ursin Giske , Emory Tim H. , Lee Eunjung , Wang Renwei , Torkelson Carolyn J. , Dostal Allison M. , Swenson Karen , Le Chap T. , Yang Chung S. , Yu Mimi C. , Yee Douglas , Wu Anna H. , Yuan Jian-Min , Kurzer Mindy S. 
Published: September 2017

Abstract
Epidemiologic and animal studies suggest a protective role of green tea against breast cancer. However, the underlying mechanism is not understood. We conducted a randomized, double-blinded, placebo-controlled phase II clinical trial to investigate whether supplementation with green tea extract (GTE) modifies mammographic density (MD), as a potential mechanism, involving 1,075 healthy postmenopausal women. Women assigned to the treatment arm consumed daily 4 decaffeinated GTE capsules containing 1,315 mg total catechins, including 843 mg epigallocatechin-3-gallate (EGCG) for 12 months. A computer-assisted method (Madena) was used to assess MD in digital mammograms at baseline and month 12 time points in 932 completers (462 in GTE and 470 in placebo). GTE supplementation for 12 months did not significantly change percent MD (PMD) or absolute MD in all women. In younger women (50–55 years), GTE supplementation significantly reduced PMD by 4.40% as compared with the placebo with a 1.02% PMD increase from pre- to postintervention (P = 0.05), but had no effect in older women (Pinteraction = 0.07). GTE supplementation did not induce MD change in other subgroups of women stratified by catechol-O-methyltransferase genotype or level of body mass index. In conclusion, 1-year supplementation with a high dose of EGCG did not have a significant effect on MD measures in all women, but reduced PMD in younger women, an age-dependent effect similar to those of tamoxifen. Further investigation of the potential chemopreventive effect of green tea intake on breast cancer risk in younger women is warranted. Cancer Prev Res; 10(12); 710–8. ©2017 AACR.
Relationship of Sleep Duration With All‐Cause Mortality and Cardiovascular Events: A Systematic Review and Dose‐Response Meta‐Analysis of Prospective Cohort Studies
Authors: Yin Jiawei , Jin Xiaoling , Shan Zhilei , Li Shuzhen , Huang Hao , Li Peiyun , Peng Xiaobo , Peng Zhao , Yu Kaifeng , Bao Wei , Yang Wei , Chen Xiaoyi , Liu Liegang 
Published: September 2017

Background
Effects of extreme sleep duration on risk of mortality and cardiovascular outcomes remain controversial. We aimed to quantify the dose‐response relationships of sleep duration with risk of all‐cause mortality, total cardiovascular disease, coronary heart disease, and stroke.

Methods and Results

PubMed and Embase were systematically searched for prospective cohort studies published before December 1, 2016, that examined the associations between sleep duration and at least 1 of the 4 outcomes in generally healthy populations. U‐shaped associations were indicated between sleep duration and risk of all outcomes, with the lowest risk observed for ≈7‐hour sleep duration per day, which was varied little by sex. For all‐cause mortality, when sleep duration was <7 hours per day, the pooled relative risk (RR) was 1.06 (95%
CI
, 1.04–1.07) per 1‐hour reduction; when sleep duration was >7 hours per day, the pooled
RR
was 1.13 (95%
CI
, 1.11–1.15) per 1‐hour increment. For total cardiovascular disease, the pooled
RR
was 1.06 (95%
CI
, 1.03–1.08) per 1‐hour reduction and 1.12 (95%
CI
, 1.08–1.16) per 1‐hour increment of sleep duration. For coronary heart disease, the pooled
RR
was 1.07 (95%
CI
, 1.03–1.12) per 1‐hour reduction and 1.05 (95%
CI
, 1.00–1.10) per 1‐hour increment of sleep duration. For stroke, the pooled
RR
was 1.05 (95%
CI
, 1.01–1.09) per 1‐hour reduction and 1.18 (95%
CI
, 1.14–1.21) per 1‐hour increment of sleep duration.

Conclusions
Our findings indicate that both short and long sleep duration is associated with an increased risk of all‐cause mortality and cardiovascular events.
The Impact of Heterozygous
KCNK3
Mutations Associated With Pulmonary Arterial Hypertension on Channel Function and Pharmacological Recovery
Authors: Bohnen Michael S. , Roman‐Campos Danilo , Terrenoire Cecile , Jnani Jack , Sampson Kevin J. , Chung Wendy K. , Kass Robert S. 
Published: September 2017

Background

Heterozygous loss of function mutations in the

KCNK
3

gene cause hereditary pulmonary arterial hypertension (
PAH
).

KCNK
3

encodes an acid‐sensitive potassium channel, which contributes to the resting potential of human pulmonary artery smooth muscle cells.
KCNK
3 is widely expressed in the body, and dimerizes with other
KCNK
3 subunits, or the closely related, acid‐sensitive
KCNK
9 channel.

Methods and Results

We engineered homomeric and heterodimeric mutant and nonmutant
KCNK
3 channels associated with
PAH
. Using whole‐cell patch‐clamp electrophysiology in human pulmonary artery smooth muscle and
COS
7 cell lines, we determined that homomeric and heterodimeric mutant channels in heterozygous
KCNK
3 conditions lead to mutation‐specific severity of channel dysfunction. Both wildtype and mutant
KCNK
3 channels were activated by
ONO
‐
RS
‐082 (10 μmol/L), causing cell hyperpolarization. We observed robust gene expression of

KCNK
3

in healthy and familial
PAH
patient lungs, but no quantifiable expression of

KCNK
9

, and demonstrated in functional studies that
KCNK
9 minimizes the impact of select
KCNK
3 mutations when the 2 channel subunits co‐assemble.

Conclusions

Heterozygous

KCNK
3

mutations in
PAH
lead to variable loss of channel function via distinct mechanisms. Homomeric and heterodimeric mutant
KCNK
3 channels represent novel therapeutic substrates in
PAH
. Pharmacological and
pH
‐dependent activation of wildtype and mutant
KCNK
3 channels in pulmonary artery smooth muscle cells leads to membrane hyperpolarization. Co‐assembly of
KCNK
3 with
KCNK
9 subunits may provide protection against
KCNK
3 loss of function in tissues where both

KCNK
9

and

KCNK
3

are expressed, contributing to the lung‐specific phenotype observed clinically in patients with
PAH
because of

KCNK
3

mutations.
γ-Glutamyl Transferase as a Risk Factor for All-Cause or Cardiovascular Disease Mortality Among 5912 Ischemic Stroke
Authors: Tu Wen-Jun , Liu Qiang , Cao Jian-Lei , Zhao Sheng-Jie , Zeng Xian-Wei , Deng Ai-Jun 
Published: September 2017

Background and Purpose—
The aim of the study was to evaluate the association of the measurement of serum γ-glutamyl transferase (GGT) concentrations at admission with 1-year all-cause or cardiovascular disease (CVD) mortality in patients with acute ischemic stroke.

Methods—
This prospective, multicenter cohort study was conducted in 4 stroke centers in China. Baseline GGT measurements were tested. The relationship of GGT to the risk of death from all-cause or CVD was examined among 1-year follow-up patients.

Results—

We recorded results from 5912 patients with stroke. In those patients, 51.0% were men, and the median age was 61 years. In both men and women, high GGT was significantly associated with total mortality from all-cause or CVD (
P
<0.001). The elevated GGT revealed adjusted hazard ratios (95% confidence interval) of 3.03 (1.99–4.54) and 3.24 (2.14–4.92) for mortality from all-cause and CVD, respectively. With an area under the curve of 0.69 (95% confidence interval, 0.66–0.73), GGT showed a significantly greater discriminatory ability to predict all-cause mortality as compared with others factors. GGT improved the National Institutes of Health Stroke Scale score (area under the curve of the combined model, 0.75 [95% confidence interval, 0.73–0.78];
P
<0.01).

Conclusions—
This study demonstrates that GGT is independently associated with all-cause and CVD mortality in patients with ischemic stroke.
Anesthesia-Related Outcomes for Endovascular Stroke Revascularization
Authors: Brinjikji Waleed , Pasternak Jeffrey , Murad Mohammad H. , Cloft Harry J. , Welch Tasha L. , Kallmes David F. , Rabinstein Alejandro A. 
Published: September 2017

Background and Purpose—
There is currently controversy on the ideal anesthesia strategy during mechanical thrombectomy for acute ischemic stroke. We performed a systematic review and meta-analysis of studies comparing clinical and angiographic outcomes of patients undergoing general anesthesia (GA group) and those receiving either local anesthesia or conscious sedation (non-GA group).

Methods—
A literature search on anesthesia and endovascular treatment of acute ischemic stroke was performed. Using random-effects meta-analysis, we evaluated the following outcomes: recanalization rate, good functional outcome at 90 days (modified Rankin Score≤2), symptomatic intracranial hemorrhage, death, vascular complications, respiratory complications, procedure time, and time to groin puncture.

Results—
Twenty-two studies (3 randomized controlled trials and 19 observational studies), including 4716 patients (1819 GA and 2897 non-GA) were included. In the nonadjusted analysis, patients in the GA group had higher odds of death (odds ratio [OR], 2.02; 95% confidence interval [CI], 1.66–2.45) and respiratory complications (OR, 1.70; 95% CI, 1.22–2.37) and lower odds of good functional outcome (OR, 0.58; 95% CI, 0.48–0.64) compared with the non-GA group. There was no difference in procedure time between the 2 primary comparison groups. When adjusting for baseline National Institutes of Health Stroke Scale, GA was still associated with lower odds of good functional outcome (OR, 0.59; 95% CI, 0.29–0.94). When considering studies performed in the stent-retriever/aspiration era, there was no significant difference in good neurological outcome rates (OR, 0.84; 95% CI, 0.67–1.06).

Conclusions—
Acute ischemic stroke patients undergoing intra-arterial therapy may have worse outcomes when treated with GA as compared with conscious sedation/local anesthesia. However, major limitations of current evidence (ie, retrospective studies and selection bias) indicate a need for adequately powered, multicenter randomized controlled trials to answer this question.
Fibrin Clot Permeability as a Predictor of Stroke and Bleeding in Anticoagulated Patients With Atrial Fibrillation
Authors: Drabik Leszek , Wołkow Paweł , Undas Anetta 
Published: September 2017

Background and Purpose—
Formation of denser fiber networks has been reported in atrial fibrillation and ischemic stroke. In this longitudinal cohort study, we evaluated whether fibrin clot density may predict thromboembolic and bleeding risk in patients with atrial fibrillation on vitamin K antagonists.

Methods—

In 236 patients with atrial fibrillation receiving vitamin K antagonists treatment, we measured ex vivo plasma clot permeability (K
s
), a measure of the pore size in fibrin networks.

Results—

During a median follow-up of 4.3 (interquartile range, 3.7–4.8) years, annual rates of ischemic stroke or transient ischemic attack and major bleeds were 2.96% and 3.45%, respectively. In multivariate Cox regression analysis, patients with lower K
s
(<6.8 cm
2
×10
−9
, median) had increased risk of ischemic stroke or transient ischemic attack (hazard ratio [HR], 6.55; 95% confidence interval [CI], 2.17–19.82) and major bleeds (HR, 10.65; 95% CI, 3.52–32.22). Patients with elevated K
s
(≥6.8 cm
2
×10
−9
) had an increased rate of minor bleeding compared with the remainder (11.63% per year versus 3.55% per year;
P
<0.0001). The independent predictors of stroke or transient ischemic attack were low K
s
(<6.8 cm
2
×10
−
9
; HR, 7.24; 95% CI, 2.53–20.76), age (HR, 1.05; 95% CI, 1.01–1.10), and treatment with angiotensin-converting enzyme inhibitors (HR, 2.27; 95% CI, 1.08–4.77). Major bleeds were predicted by low K
s
(<6.8 cm
2
×10
−9
; HR, 8.48; 95% CI, 2.99–24.1) and HAS-BLED score ≥3 (HR, 2.22; 95% CI, 1.12–4.38).

Conclusions—
This study is the first to show that unfavorable fibrin properties reflected by formation of denser fibrin networks determine, in part, the efficacy and safety of anticoagulation with vitamin K antagonists in patients with atrial fibrillation.
Response of Tropical Cyclone Activity and Structure to Global Warming in a High-Resolution Global Nonhydrostatic Model
Authors: Yamada Yohei , Satoh Masaki , Sugi Masato , Kodama Chihiro , Noda Akira T. , Nakano Masuo , Nasuno Tomoe 
Published: September 2017

Future changes in tropical cyclone (TC) activity and structure are investigated using the outputs of a 14-km mesh climate simulation. A set of 30-yr simulations was performed under present-day and warmer climate conditions using a nonhydrostatic icosahedral atmospheric model with explicitly calculated convection. The model projected that the global frequency of TCs is reduced by 22.7%, the ratio of intense TCs is increased by 6.6%, and the precipitation rate within 100 km of the TC center increased by 11.8% under warmer climate conditions. These tendencies are consistent with previous studies using a hydrostatic global model with cumulus parameterization. The responses of vertical and horizontal structures to global warming are investigated for TCs with the same intensity categories. For TCs whose minimum sea level pressure (SLP) reaches less than 980 hPa, the model predicted that tangential wind increases in the outside region of the eyewall. Increases in the tangential wind are related to the elevation of the tropopause caused by global warming. The tropopause rise induces an upward extension of the eyewall, resulting in an increase in latent heating in the upper layers of the inclined eyewall. Thus, SLP is reduced underneath the warmed eyewall regions through hydrostatic adjustment. The altered distribution of SLP enhances tangential winds in the outward region of the eyewall cloud. Hence, this study shows that the horizontal scale of TCs defined by a radius of 12 m s−1 surface wind is projected to increase compared with the same intensity categories for SLP less than 980 hPa.