bluuebunny/crossref_metadata_2025 huggingface dataset:
Heightened muscle inflammation susceptibility may impair regenerative capacity in aging humans
Authors: Merritt Edward K. , Stec Michael J. , Thalacker-Mercer Anna , Windham Samuel T. , Cross James M. , Shelley David P. , Craig Tuggle S. , Kosek David J. , Kim Jeong-su , Bamman Marcas M.
Published: May 2013

The regenerative response of skeletal muscle to mechanically induced damage is impaired with age. Previous work in our laboratory suggests this may result from higher proinflammatory signaling in aging muscle at rest and/or a greater inflammatory response to damage. We, therefore, assessed skeletal muscle proinflammatory signaling at rest and 24 h after unaccustomed, loaded knee extension contractions that induced modest muscle damage (72% increase in serum creatine kinase) in a cohort of 87 adults across three age groups (AGE40, AGE61, and AGE76). Vastus lateralis muscle gene expression and protein cell signaling of the IL-6 and TNF-α pathways were determined by quantitative PCR and immunoblot analysis. For in vitro studies, cell signaling and fusion capacities were compared among primary myoblasts from young (AGE28) and old (AGE64) donors treated with TNF-α. Muscle expression was higher (1.5- to 2.1-fold) in AGE76 and AGE61 relative to AGE40 for several genes involved in IL-6, TNF-α, and TNF-like weak inducer of apoptosis signaling. Indexes of activation for the proinflammatory transcription factors signal transducer and activator of transcription-3 and NF-κB were highest in AGE76. Resistance loading reduced gene expression of IL-6 receptor, muscle RING finger 1, and atrogin-1, and increased TNF-like weak inducer of apoptosis receptor expression. Donor myoblasts from AGE64 showed impaired differentiation and fusion in standard media and greater NF-κB activation in response to TNF-α treatment (compared with AGE28). We show for the first time that human aging is associated with muscle inflammation susceptibility (i.e., higher basal state of proinflammatory signaling) that is present in both tissue and isolated myogenic cells and likely contributes to the impaired regenerative capacity of skeletal muscle in the older population.
Does an NSAID a day keep satellite cells at bay?
Authors: Mackey Abigail L.
Published: May 2013

Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely consumed by athletes worldwide, despite growing evidence for a negative influence on the adaptation of skeletal muscle to exercise, at least in young healthy individuals. This review focuses on the potential of NSAIDs to alter the activity of satellite cells, the muscle stem cell responsible for repair and maintenance of skeletal muscle. The signaling pathways that are potentially modified by NSAID exposure are also considered. Growth factors as well as inflammatory cells and connective tissue appear to be key factors in the response of muscle under conditions where cyclooxygenase and prostaglandin activity are blocked through NSAID ingestion or infusion. Discrepancies in the literature regarding the response of young and old individuals are addressed, where it appears that the elderly may benefit from NSAID ingestion, although this clearly requires further study. The long-term implications for the muscle of the apparent inhibitory effect of NSAIDs on satellite cells in younger individuals are not clear, and it is possible these may first become apparent with chronic use in athletes training at a high level or with advancing age. Reports of the potential for NSAIDs to alter prostaglandin and growth factor signaling provide a basis for further study of the mechanism of NSAID action on satellite cells.
The frequency response of cerebral autoregulation
Authors: Fraser Charles D. , Brady Ken M. , Rhee Christopher J. , Easley R. Blaine , Kibler Kathleen , Smielewski Peter , Czosnyka Marek , Kaczka David W. , Andropoulos Dean B. , Rusin Craig
Published: May 2013

The frequency-response of pressure autoregulation is not well delineated; therefore, the optimal frequency of arterial blood pressure (ABP) modulation for measuring autoregulation is unknown. We hypothesized that cerebrovascular autoregulation is band-limited and delineated by a cutoff frequency for which ABP variations induce cerebrovascular reactivity. Neonatal swine ( n = 8) were anesthetized using constant minute ventilation while positive end-expiratory pressure (PEEP) was modulated between 6 and 0.75 cycles/min (min−1). The animals were hemorrhaged until ABP was below the lower limit of autoregulation (LLA), and PEEP modulations were repeated. Vascular reactivity was quantified at each frequency according to the phase lag between ABP and intracranial pressure (ICP) above and below the LLA. Phase differences between ABP and ICP were small for frequencies of >2 min−1, with no ability to differentiate cerebrovascular reactivity between ABPs above or below the LLA. For frequencies of <2 min−1, ABP and intracranial pressure (ICP) showed phase shift when measured above LLA and no phase shift when measured below LLA [above vs. below LLA at 1 min−1: 156° (139–174°) vs. 30° (22–50°); P < 0.001 by two-way ANOVA for both frequency and state of autoregulation]. Data taken above LLA fit a Butterworth high-pass filter model with a cutoff frequency at 1.8 min−1 (95% confidence interval: 1.5–2.2). Cerebrovascular reactivity occurs for sustained ABP changes lasting 30 s or longer. The ability to distinguish intact and impaired autoregulation was maximized by a 60-s wave (1 min−1), which was 100% sensitive and 100% specific in this model.
Slow breathing as a means to improve orthostatic tolerance: a randomized sham-controlled trial
Authors: Lucas Samuel J. E. , Lewis Nia C. S. , Sikken Elisabeth L. G. , Thomas Kate N. , Ainslie Philip N.
Published: May 2013

Endogenous oscillations in blood pressure (BP) and cerebral blood flow have been associated with improved orthostatic tolerance. Although slow breathing induces such responses, it has not been tested as a therapeutic strategy to improve orthostatic tolerance. With the use of a randomized, crossover sham-controlled design, we tested the hypothesis that breathing at six breaths/min (vs. spontaneous breathing) would improve orthostatic tolerance via inducing oscillations in mean arterial BP (MAP) and cerebral blood flow. Sixteen healthy participants (aged 25 ± 4 yr; mean ± SD) had continuous beat-to-beat measurements of middle cerebral artery blood velocity (MCAv), BP (finometer), heart rate (ECG), and end-tidal carbon dioxide partial pressure during an incremental orthostatic stress test to presyncope by combining head-up tilt with incremental lower-body negative pressure. Tolerance time to presyncope was improved (+15%) with slow breathing compared with spontaneous breathing (29.2 ± 5.4 vs. 33.7 ± 6.0 min; P < 0.01). The improved tolerance was reflected in elevations in low-frequency (LF; 0.07-0.2 Hz) oscillations of MAP and mean MCAv, improved metrics of dynamic cerebrovascular control (increased LF phase and reduced LF gain), and a reduced rate of decline for MCAv (−0.60 ± 0.27 vs. −0.99 ± 0.51 cm·s−1·min−1; P < 0.01) and MAP (−0.50 ± 0.37 vs. −1.03 ± 0.80 mmHg/min; P = 0.01 vs. spontaneous breathing) across time from baseline to presyncope. Our findings show that orthostatic tolerance can be improved within healthy individuals with a simple, nonpharmacological breathing strategy. The mechanisms underlying this improvement are likely mediated via the generation of negative intrathoracic pressure during slow and deep breathing and the related beneficial impact on cerebrovascular and autonomic function.
Five days of head-down-tilt bed rest induces noninflammatory shedding of L-selectin
Authors: Feuerecker M. , Feuerecker B. , Matzel S. , Long M. , Strewe C. , Kaufmann I. , Hoerl M. , Schelling G. , Rehm M. , Choukèr A.
Published: May 2013

Head-down-tilt bed rest (HDTBR) is a popular model, simulating alterations of gravitation during space missions. The aim of this study was to obtain a better insight into the complexly orchestrated regulations of HDTBR-induced immunological responses, hypothesizing that artificial gravity can mitigate these HDTBR-related physiological effects. This crossover-designed 5 days of HDTBR study included three protocols with no, or daily 30 min of centrifugation or 6 × 5 min of centrifugation. Twelve healthy, male participants donated blood pre-HDTBR, post-HDTBR, and twice during HDTBR. Cellular immune changes were assessed either by enumerative and immune cell phenotyping assays or by functional testing of responses to either recall antigens or receptor-dependent activation by chemotactic agents N-formyl-methionyl-leucyl-phenylalanine (fMLP) and with TNF-α. The expression of the adhesion molecule L-selectin (CD62L) on the surface of granulocytes and its shedding into plasma samples were measured. In parallel, other humoral factor, such as interleukin-6 and interleukin-8, parameters of endothelial damage (glycocalyx) were determined. Hematocrit and hemoglobin were significantly increased during HDTBR. Although immune functional tests did not indicate a change in the immune performance, the expression of CD62L on resting granulocytes was significantly shed by 50% during HDTBR. Although the latter is normally associated to an activation of inflammatory innate immune responses and during interaction of granulocytes with the endothelium, CD62L shedding was, however, not related either to a systemic inflammatory alteration or to shedding of the endothelial glycocalyx during bed rest. This suggests a noninflammatory or “mechanical” shedding related to fluid shifts during head-down intervention and not to an acute inflammatory process.
Economy and rate of carbohydrate oxidation during running with rearfoot and forefoot strike patterns
Authors: Gruber Allison H. , Umberger Brian R. , Braun Barry , Hamill Joseph
Published: May 2013

It continues to be argued that a forefoot (FF) strike pattern during running is more economical than a rearfoot (RF) pattern; however, previous studies using one habitual footstrike group have found no difference in running economy between footstrike patterns. We aimed to conduct a more extensive study by including both habitual RF and FF runners. The purposes of this study were to determine whether there were differences in running economy between these groups and whether running economy would change when they ran with the alternative footstrike pattern. Nineteen habitual RF and 18 habitual FF runners performed the RF and FF patterns on a treadmill at 3.0, 3.5, and 4.0 m/s. Steady-state rates of oxygen consumption (V̇o2, ml·kg−1·min−1) and carbohydrate contribution to total energy expenditure (%CHO) were determined by indirect calorimetry for each footstrike pattern and speed condition. A mixed-model ANOVA was used to assess the differences in each variable between groups and footstrike patterns (α = 0.05). No differences in V̇o2 or %CHO were detected between groups when running with their habitual footstrike pattern. The RF pattern resulted in lower V̇o2 and %CHO compared with the FF pattern at the slow and medium speeds in the RF group ( P < 0.05) but not in the FF group ( P > 0.05). At the fast speed, a significant footstrike pattern main effect indicated that V̇o2 was greater with the FF pattern than with the RF pattern ( P < 0.05), but %CHO was not different ( P > 0.05). The results suggest that the FF pattern is not more economical than the RF pattern.
G-CSF Receptor Positive Neuroblastoma Subpopulations Are Enriched in Chemotherapy-Resistant or Relapsed Tumors and Are Highly Tumorigenic
Authors: Hsu Danielle M. , Agarwal Saurabh , Benham Ashley , Coarfa Cristian , Trahan Denae N. , Chen Zaowen , Stowers Paris N. , Courtney Amy N. , Lakoma Anna , Barbieri Eveline , Metelitsa Leonid S. , Gunaratne Preethi , Kim Eugene S. , Shohet Jason M.
Published: May 2013

Neuroblastoma is a neural crest-derived embryonal malignancy, which accounts for 13% of all pediatric cancer mortality, primarily due to tumor recurrence. Therapy-resistant cancer stem cells are implicated in tumor relapse, but definitive phenotypic evidence of the existence of these cells has been lacking. In this study, we define a highly tumorigenic subpopulation in neuroblastoma with stem cell characteristics, based on the expression of CSF3R, which encodes the receptor for granulocyte colony-stimulating factor (G-CSF). G-CSF receptor positive (aka G-CSFr+ or CD114+) cells isolated from a primary tumor and the NGP cell line by flow cytometry were highly tumorigenic and capable of both self-renewal and differentiation to progeny cells. CD114+ cells closely resembled embryonic and induced pluripotent stem cells with respect to their profiles of cell cycle, miRNA, and gene expression. In addition, they reflect a primitive undifferentiated neuroectodermal/neural crest phenotype revealing a developmental hierarchy within neuroblastoma tumors. We detected this dedifferentiated neural crest subpopulation in all established neuroblastoma cell lines, xenograft tumors, and primary tumor specimens analyzed. Ligand activation of CD114 by the addition of exogenous G-CSF to CD114+ cells confirmed intact STAT3 upregulation, characteristic of G-CSF receptor signaling. Together, our data describe a novel distinct subpopulation within neuroblastoma with enhanced tumorigenicity and a stem cell–like phenotype, further elucidating the complex heterogeneity of solid tumors such as neuroblastoma. We propose that this subpopulation may represent an additional target for novel therapeutic approaches to this aggressive pediatric malignancy. Cancer Res; 73(13); 4134–46. ©2013 AACR.
Connective Tissue Growth Factor Activates Pluripotency Genes and Mesenchymal–Epithelial Transition in Head and Neck Cancer Cells
Authors: Chang Cheng-Chi , Hsu Wen-Hao , Wang Chen-Chien , Chou Chun-Hung , Kuo Mark Yen-Ping , Lin Been-Ren , Chen Szu-Ta , Tai Shyh-Kuan , Kuo Min-Liang , Yang Muh-Hwa
Published: May 2013

The epithelial–mesenchymal transition (EMT) is a key mechanism in both embryonic development and cancer metastasis. The EMT introduces stem-like properties to cancer cells. However, during somatic cell reprogramming, mesenchymal–epithelial transition (MET), the reverse process of EMT, is a crucial step toward pluripotency. Connective tissue growth factor (CTGF) is a multifunctional secreted protein that acts as either an oncoprotein or a tumor suppressor among different cancers. Here, we show that in head and neck squamous cell carcinoma (HNSCC), CTGF promotes the MET and reduces invasiveness. Moreover, we found that CTGF enhances the stem-like properties of HNSCC cells and increases the expression of multiple pluripotency genes. Mechanistic studies showed that CTGF induces c-Jun expression through αvβ3 integrin and that c-Jun directly activates the transcription of the pluripotency genes NANOG, SOX2, and POU5F1. Knockdown of CTGF in TW2.6 cells was shown to reduce tumor formation and attenuate E-cadherin expression in xenotransplanted tumors. In HNSCC patient samples, CTGF expression was positively correlated with the levels of CDH1, NANOG, SOX2, and POU5F1. Coexpression of CTGF and the pluripotency genes was found to be associated with a worse prognosis. These findings are valuable in elucidating the interplay between epithelial plasticity and stem-like properties during cancer progression and provide useful information for developing a novel classification system and therapeutic strategies for HNSCC. Cancer Res; 73(13); 4147–57. ©2013 AACR.
ETS Transcription Factor ESE1/ELF3 Orchestrates a Positive Feedback Loop That Constitutively Activates NF-κB and Drives Prostate Cancer Progression
Authors: Longoni Nicole , Sarti Manuela , Albino Domenico , Civenni Gianluca , Malek Anastasia , Ortelli Erica , Pinton Sandra , Mello-Grand Maurizia , Ostano Paola , D'Ambrosio Gioacchino , Sessa Fausto , Garcia-Escudero Ramon , Thalmann George N. , Chiorino Giovanna , Catapano Carlo V. , Carbone Giuseppina M.
Published: May 2013

Chromosomal translocations leading to deregulated expression of ETS transcription factors are frequent in prostate tumors. Here, we report a novel mechanism leading to oncogenic activation of the ETS factor ESE1/ELF3 in prostate tumors. ESE1/ELF3 was overexpressed in human primary and metastatic tumors. It mediated transforming phenotypes in vitro and in vivo and induced an inflammatory transcriptome with changes in relevant oncogenic pathways. ESE1/ELF3 was induced by interleukin (IL)-1β through NF-κB and was a crucial mediator of the phenotypic and transcriptional changes induced by IL-1β in prostate cancer cells. This linkage was mediated by interaction of ESE1/ELF3 with the NF-κB subunits p65 and p50, acting by enhancing their nuclear translocation and transcriptional activity and by inducing p50 transcription. Supporting these findings, gene expression profiling revealed an enrichment of NF-κB effector functions in prostate cancer cells or tumors expressing high levels of ESE1/ELF3. We observed concordant upregulation of ESE1/ELF3 and NF-κB in human prostate tumors that was associated with adverse prognosis. Collectively, our results define an important new mechanistic link between inflammatory signaling and the progression of prostate cancer. Cancer Res; 73(14); 4533–47. ©2013 AACR.
Mechanism of Differentiation-Enhanced Photodynamic Therapy for Cancer: Upregulation of Coproporphyrinogen Oxidase by C/EBP Transcription Factors
Authors: Anand Sanjay , Hasan Tayyaba , Maytin Edward V.
Published: May 2013

The efficacy of photodynamic therapy (PDT) for epithelial cancers is increased when PDT is combined with calcitriol (Vit D), a form of differentiation therapy (DT). Here, we describe an underlying mechanism for this effect. Differentiation-promoting agents are known to upregulate CCAAT/enhancer–binding proteins (C/EBP), powerful regulators of cellular differentiation. In subcutaneous A431 tumors in mice, pretreatment with Vit D induced the expression of C/EBPβ isoforms, and of coproporphyrinogen oxidase (CPO), a heme pathway enzyme responsible for the conversion of 5-aminolevulinic acid (ALA) into protoporphyrin IX (PpIX), the principal light-absorbing molecule during PDT. To further investigate this apparent link between C/EBPs and CPO, two cell lines (MEL and LNCaP) were exposed to differentiating agents, and levels of PpIX, C/EBPs, and CPO were measured. Differentiating agents, or transfection of C/EBP expression vectors, increased C/EBP and CPO levels in parallel. Focusing on approximately 1,300 bp of upstream CPO gene promoter, we tested the ability of recombinant C/EBPα, C/EBPβ, C/EBPδ, and C/EBPζ to bind to CPO gene sequences [electrophoretic mobility shift assay (EMSA) assays] and to affect transcriptional activity (luciferase assays). Multiple C/EBP consensus binding sites were identified (15 for mouse, 18 for human). Individual probes representing each site bound to C/EBPs with characteristic affinities (strong, moderate, or weak), but when sites were inactivated in the context of the native promoter, transcriptional activity was reduced nearly equally for strong or weak sites. Cooperative interactions between regularly spaced C/EBP sites seem critical for CPO transcriptional regulation by differentiation therapy. These results provide a mechanistic rationale for DT/PDT combination therapy for cancer. Mol Cancer Ther; 12(8); 1638–50. ©2013 AACR.
Effect of Zileuton and Celecoxib on Urinary LTE4 and PGE-M Levels in Smokers
Authors: Mohebati Arash , Milne Ginger L. , Zhou Xi Kathy , Duffield-Lillico Anna J. , Boyle Jay O. , Knutson Allison , Bosworth Brian P. , Kingsley Philip J. , Marnett Lawrence J. , Brown Powel H. , Akpa Esther G. , Szabo Eva , Dannenberg Andrew J.
Published: May 2013

COX-2 and 5-lipoxygenase (5-LO) use arachidonic acid for the synthesis of eicosanoids that have been implicated in carcinogenesis and cardiovascular disease. The ability of celecoxib, a selective COX-2 inhibitor, to redirect arachidonic acid into the 5-LO pathway can potentially reduce its efficacy as a chemopreventive agent and increase the risk of cardiovascular complications. Levels of urinary prostaglandin E metabolite (PGE-M) and leukotriene E4 (LTE4), biomarkers of the COX and 5-LO pathways, are elevated in smokers. Here, we investigated the effects of zileuton, a 5-LO inhibitor, versus zileuton and celecoxib for 6 ± 1 days on urinary PGE-M and LTE4 levels in smokers. Treatment with zileuton led to an 18% decrease in PGE-M levels (P = 0.03); the combination of zileuton and celecoxib led to a 62% reduction in PGE-M levels (P < 0.001). Levels of LTE4 decreased by 61% in subjects treated with zileuton alone (P < 0.001) and were unaffected by the addition of celecoxib. Although zileuton use was associated with a small overall decrease in PGE-M levels, increased PGE-M levels were found in a subset (19 of 52) of subjects. Notably, the addition of celecoxib to the 5-LO inhibitor protected against the increase in urinary PGE-M levels (P = 0.03). In conclusion, zileuton was an effective inhibitor of 5-LO activity resulting in marked suppression of urinary LTE4 levels and possible redirection of arachidonic acid into the COX-2 pathway in a subset of subjects. Combining celecoxib and zileuton was associated with inhibition of both the COX-2 and 5-LO pathways manifested as reduced levels of urinary PGE-M and LTE4. Cancer Prev Res; 6(7); 646–55. ©2013 AACR.
Interleukin-6–Signal Transducer and Activator of Transcription-3 Signaling Mediates Aortic Dissections Induced by Angiotensin II via the T-Helper Lymphocyte 17–Interleukin 17 Axis in C57BL/6 Mice
Authors: Ju Xiaoxi , Ijaz Talha , Sun Hong , Ray Sutapa , Lejeune Wanda , Lee Chang , Recinos Adrian , Guo Dong-Chuan , Milewicz Dianna M. , Tilton Ronald G. , Brasier Allan R.
Published: May 2013

Objective—

Dysregulated angiotensin II (Ang II) signaling induces local vascular interleukin-6 (IL-6) secretion, producing leukocyte infiltration and life-threatening aortic dissections. Precise mechanisms by which IL-6 signaling induces leukocyte recruitment remain unknown. T-helper 17 lymphocytes (Th17) have been implicated in vascular pathology, but their role in the development of aortic dissections is poorly understood. Here, we tested the relationship of IL-6–signal transducer and activator of transcription-3 signaling with Th17-induced inflammation in the formation of Ang II–induced dissections in C57BL/6 mice.

Approach and Results—

Ang II infusion induced aortic dissections and CD4
+
-interleukin 17A (IL-17A)–expressing Th17 cell accumulation in C57BL/6 mice. A blunted local Th17 activation, macrophage recruitment, and reduced incidence of aortic dissections were seen in IL-6
−/−
mice. To determine the pathological roles of Th17 lymphocytes, we treated Ang II–infused mice with IL-17A–neutralizing antibody or infused Ang II in genetically deficient IL-17A mice and found decreased aortic chemokine monocytic chemotactic protein-1 production and macrophage recruitment, leading to a reduction in aortic dissections. This effect was independent of blood pressure in IL-17A–neutralizing antibody experiment. Application of a cell-permeable signal transducer and activator of transcription-3 inhibitor to downregulate the IL-6 pathway decreased aortic dilation and Th17 cell recruitment. We also observed increased aortic Th17 infiltration and IL-17 mRNA expression in patients with thoracic aortic dissections. Finally, we found that Ang II–mediated aortic dissections occurred independent of blood pressure changes.

Conclusions—

Our results indicate that the IL-6–signal transducer and activator of transcription-3 signaling pathway converges on Th17 recruitment and IL-17A signaling upstream of macrophage recruitment, mediating aortic dissections.
Evidence of a Polygenic Origin of Extreme High-Density Lipoprotein Cholesterol Levels
Authors: Motazacker Mohammad Mahdi , Peter Jorge , Treskes Marco , Shoulders Carol C. , Kuivenhoven Jan Albert , Hovingh G. Kees
Published: May 2013

Objective—

There are several known monogenic causes of high and low high-density lipoprotein cholesterol (HDL-C) levels, but traditional sequencing studies have had limited success in identifying mutations in the majority of individuals with extreme HDL-C levels. The aim of this study was to assess the power of a targeted high-throughput sequencing strategy to elucidate the genetic basis of extreme HDL-C phenotypes.

Approach and Results—

We sequenced 195 genes with either established or implicated roles in lipid and lipoprotein metabolism plus 78 lipid-unrelated genes in patients with HDL-C <1st (n=40) or >99th (n=40) percentile values, and the results were compared with those of 498 individuals representative of the Dutch general population and 95 subjects with normal HDL-C (between 40th and 60th percentile values). The extreme HDL cohort carried more rare nonsynonymous variants in the lipid geneset than both the general population (odds ratio, 1.39;
P
=0.019) and normal HDL-C (odds ratio, 1.43;
P
=0.040) cohorts. The prevalence of such variants in the lipid-related and lipid-unrelated genesets was similar in the control groups, indicative of equal mutation rates. In the extreme HDL cohort, however, there was enrichment of rare nonsynonymous variants in the lipid versus the control geneset (odds ratio, 2.23;
P
<0.0001), and 70% of the lipid-related variants altered conserved nucleotides. The lipid geneset comprised 4 nonsense, 10 splice-site, and 8 coding indel variants, whereas the control geneset contained only 1 such variant. In the lipid geneset, 87% and 28% of the patients carried ≥2 and ≥5 rare variants.

Conclusions—

This study suggests that most extreme HDL-C phenotypes have a polygenic origin.
Regional Density of Cardiologists and Rates of Mortality for Acute Myocardial Infarction and Heart Failure
Authors: Kulkarni Vivek T. , Ross Joseph S. , Wang Yongfei , Nallamothu Brahmajee K. , Spertus John A. , Normand Sharon-Lise T. , Masoudi Frederick A. , Krumholz Harlan M.
Published: May 2013

Background—

Cardiologists are distributed unevenly across regions of the United States. It is unknown whether patients in regions with fewer cardiologists have worse outcomes after hospitalization for acute myocardial infarction (AMI) or heart failure (HF).

Methods and Results—

Using Medicare administrative claims data from 2010, we examined the relationship between regional density of cardiologists and risk of death after hospitalization for AMI and HF using hospitalizations for pneumonia as a comparison. We defined density as the number of cardiologists divided by population aged≥65 years within hospital referral regions, categorized into quintiles. Among 171 126 admissions for AMI, 352 853 admissions for HF, and 343 053 admissions for pneumonia, we tested associations between density of cardiologists and 30-day and 1-year mortality for each condition. We used 2-level hierarchical logistic regression models that adjusted for characteristics of patients and hospital referral regions. Patients hospitalized for AMI (odds ratios [OR], 1.13; 95% confidence interval [CI], 1.06–1.21) and HF (OR, 1.19; 95% CI, 1.12–1.27) in the lowest quintile of density had modestly higher 30-day mortality risk compared with patients in the highest quintile, unlike patients hospitalized for pneumonia (OR, 1.02; 95% CI, 0.96–1.09). Patients hospitalized for AMI (OR, 1.06; 95% CI, 1.00–1.12) and HF (OR, 1.09; 95% CI, 1.04–1.13) in the lowest quintile had slightly higher 1-year mortality risk, unlike patients hospitalized for pneumonia (OR, 1.00; 95% CI, 0.95–1.05).

Conclusions—

Patients hospitalized for AMI and HF in regions with a low density of cardiologists experienced modestly higher 30-day and 1-year mortality risk, unlike patients with pneumonia.
Prognostic Value of the Index of Microcirculatory Resistance Measured After Primary Percutaneous Coronary Intervention
Authors: Fearon William F. , Low Adrian F. , Yong Andy S. , McGeoch Ross , Berry Colin , Shah Maulik G. , Ho Michael Y. , Kim Hyun-Sook , Loh Joshua P. , Oldroyd Keith G.
Published: May 2013

Background—

Most methods for assessing microvascular function are not readily available in the cardiac catheterization laboratory. The aim of this study is to determine whether the Index of Microcirculatory Resistance (IMR), measured at the time of primary percutaneous coronary intervention, is predictive of death and rehospitalization for heart failure.

Methods and Results—

IMR was measured immediately after primary percutaneous coronary intervention in 253 patients from 3 institutions with the use of a pressure–temperature sensor wire. The primary end point was the rate of death or rehospitalization for heart failure. The prognostic value of IMR was compared with coronary flow reserve, TIMI myocardial perfusion grade, and clinical variables. The mean IMR was 40.3±32.5. Patients with an IMR >40 had a higher rate of the primary end point at 1 year than patients with an IMR ≤40 (17.1% versus 6.6%;
P
=0.027). During a median follow-up period of 2.8 years, 13.8% experienced the primary end point and 4.3% died. An IMR >40 was associated with an increased risk of death or rehospitalization for heart failure (hazard ratio [HR], 2.1;
P
=0.034) and of death alone (HR, 3.95;
P
=0.028). On multivariable analysis, independent predictors of death or rehospitalization for heart failure included IMR >40 (HR, 2.2;
P
=0.026), fractional flow reserve ≤0.8 (HR, 3.24;
P
=0.008), and diabetes mellitus (HR, 4.4;
P
<0.001). An IMR >40 was the only independent predictor of death alone (HR, 4.3;
P
=0.02).

Conclusions—

An elevated IMR at the time of primary percutaneous coronary intervention predicts poor long-term outcomes.
New Generation of Flow Diverter (Surpass) for Unruptured Intracranial Aneurysms
Authors: De Vries Joost , Boogaarts Jeroen , Van Norden Anouk , Wakhloo Ajay K.
Published: May 2013

Background and Purpose—

In patients harboring intracranial aneurysms, the major goal in treatment is to prevent bleeding. A new generation of an endoluminal device (Surpass Flow Diverter [Surpass]) was developed to reconstruct parent artery and occlude the aneurysm. We present our clinical and angiographic single-center experience.

Methods—

Patients with a wide range of complex unruptured aneurysms were treated with the Surpass placed in the parent artery and bridging the aneurysm. Clinical and angiographic follow-up were performed at 6 months. Data were prospectively collected.

Results—

Thirty seven patients (mean age, 56 years; range, 32–79), harboring 49 unruptured aneurysms were treated at our center. All except 1 patient were treated with a single device. Successful delivery of the device was achieved in all patients. All 35 nonbifurcation aneurysm necks were covered completely, whereas 14 bifurcation aneurysms were only partially covered. There was no major periprocedural morbidity or mortality. During follow-up, 4 patients (10.4%) experienced transient neurological deficit. One patient (3%) developed a minor stroke at 4-month follow-up with persistent neurological deficit. Twelve patients had neurological symptoms related to their aneurysm and 7 showed improvement of these symptoms during follow-up. At 6-month follow-up, 29 of 31 aneurysms studied that had complete neck coverage showed a complete occlusion (94%) including 1 case with a 95% to 100% occlusion, whereas 5 of the 10 bifurcation aneurysms were occluded.

Conclusions—

Our study shows high safety and efficacy profile of a new generation endoluminal device in treatment of complex intracranial aneurysms. Long-term studies of treated bifurcation aneurysms are needed.
Baseline Cognitive Function, Recurrent Stroke, and Risk of Dementia in Patients With Stroke
Authors: Rist Pamela M. , Chalmers John , Arima Hisatomi , Anderson Craig , MacMahon Stephen , Woodward Mark , Kurth Tobias , Tzourio Christophe
Published: May 2013

Background and Purpose—

To determine the interrelationships between baseline Mini-Mental State Examination (MMSE) score and risk of overall dementia, post-recurrent stroke dementia, and dementia without recurrent stroke among patients with a history of stroke.

Methods—

Prospective cohort study among participants enrolled in the Perindopril Protection Against Recurrent Stroke Study (PROGRESS) for whom baseline MMSE score was available. Baseline MMSE score was divided into 4 categories: 30, 29–27, 26–24, and <24. Participants were followed for incident dementia and recurrent stroke. Logistic regression models were used to examine the association between MMSE score and dementia.

Results—

Of the 6080 participants included in this analysis, 2493 had an MMSE score of 30, 1768 had a score of 29–28, 1369 had a score of 26–24, and 450 had a score of <24. Average follow-up time was 3.8 years. There were 407 cases of dementia, 106 of which were preceded by a recurrent stroke. The risk of overall dementia increased with decreasing MMSE score. However, the impact of MMSE score on the risk of dementia without recurrent stroke was much stronger than the impact of MMSE score on the risk of post-recurrent stroke dementia. For those with MMSE score <24, the risk of dementia without recurrent stroke was 47.89 (95% confidence interval, 28.57–80.26), whereas the risk of post-recurrent stroke dementia was only 7.17 (95% confidence interval, 3.70–13.89). Higher MMSE scores were even less strongly associated with the risk of post-recurrent stroke dementia.

Conclusions—

Patients with stroke with low MMSE scores are at high risk of dementia over time, even in the absence of a recurrent stroke, and should therefore be followed closely for further cognitive decline.
Accuracy and Clinical Usefulness of Intracerebral Hemorrhage Grading Scores
Authors: Parry-Jones Adrian R. , Abid Kamran A. , Di Napoli Mario , Smith Craig J. , Vail Andy , Patel Hiren C. , King Andrew T. , Tyrrell Pippa J.
Published: May 2013

Background and Purpose—

Various grading scores to predict survival after intracerebral hemorrhage (ICH) have been described. We aimed to test the accuracy and clinical usefulness of 3 well-known scores (original ICH score, modified ICH score, and ICH grading scale) in a large unselected cohort of typical ICH patients.

Methods—

A total of 1364 ICH cases were referred to our center from January 1, 2008, to October 17, 2010. Clinical details were prospectively recorded, and the first computed tomography brain scan was retrospectively reviewed to determine ICH volume and location and to identify intraventricular hemorrhage. The original ICH, ICH grading scale, and modified ICH score were calculated. Receiver operating characteristic and decision curves for 30-day mortality were generated.

Results—

A total of 1175 patients were included in the final analysis. All 3 scores and the Glasgow Coma Scale (GCS) divided cases into groups with highly significant differences in mortality. The area under the receiver operating characteristic curve was very similar for original ICH (0.861), ICH grading scale (0.874), and GCS (0.872), but was less for modified ICH score (0.824). Age was much less predictive (0.565). Combining GCS with age, log ICH volume, and intraventricular hemorrhage to derive a multifactorial risk of death at 30 days significantly increased the area under the receiver operating characteristic curve (0.897). All scores and GCS demonstrated a similar net benefit for threshold probabilities of 10% to 95%. Above 95%, the net benefit of GCS became inferior to the prognostic scores.

Conclusions—

Although existing grading scores are highly predictive of 30-day mortality, GCS alone was as predictive in our cohort, but age was not.
Nonrelevant Cerebral Atherosclerosis is a Strong Prognostic Factor in Acute Cerebral Infarction
Authors: Kim Jinkwon , Song Tae-Jin , Song Dongbeom , Lee Hye Sun , Nam Chung Mo , Nam Hyo Suk , Kim Young Dae , Heo Ji Hoe
Published: May 2013

Background and Purpose—

We investigated whether the presence of nonrelevant cerebral atherosclerosis (NRCA) had prognostic value in patients with acute stroke.

Methods—

We compared prognosis in 780 consecutive patients with first-ever acute cerebral infarction who underwent cerebral angiography and diffusion-weighted MRI.

Results—

NRCA was present in 267 patients (34.2%). Multivariate analysis demonstrated that the presence of NRCA was independently associated with less improvement in National Institute of Health Stroke Scale score during the first 7 days (
P
=0.004), and a poor functional outcome (modified Rankin Scale score >2) after 3 months (odds ratio, 2.51; 95% confidence interval, 1.55–4.07). An increase in burden count of NRCA was also associated with poor outcomes.

Conclusions—

The presence and burden count of NRCA were associated with poor neurological outcomes in patients with acute cerebral infarction.
Endovascular Treatment of Intracranial Aneurysms in Elderly Patients
Authors: Sturiale Carmelo L. , Brinjikji Waleed , Murad Mohammad H. , Lanzino Giuseppe
Published: May 2013

Background and Purpose—

Use of endovascular coiling for treatment of ruptured and unruptured intracranial aneurysms (IAs) in the elderly is increasing. We performed a meta-analysis of the literature examining clinical and angiographic outcomes for treatment of IAs in the elderly.

Methods—

We performed a comprehensive review of the literature from 1995 to 2012, reporting series of patients ≥65 years of age with ruptured or unruptured IAs treated with endovascular approach. Event rates were pooled across studies using random effects meta-analysis.

Results—

A total of 21 studies reporting on 1511 patients were included. Long-term aneurysm occlusion rates were 79% (95% confidence interval [CI], 70%–85%). Perioperative stroke occurred in 4% (95% CI, 3%–6%), with similar rates between patients with ruptured (5%; 95% CI, 3%–7%) and unruptured aneurysms (4%; 95% CI, 1%–14%;
P
=0.68). Intraprocedural rupture occurred in 1% (95% CI, 0%–3%) and 4% (95% CI, 2–6%;
P
=0.04) of patients with unruptured and ruptured aneurysms, respectively. Perioperative mortality rate for patients with ruptured aneurysms was 23% (95% CI, 17%–30%) and 1% (95% CI, 0%–6%) for patients with unruptured aneurysms (
P
<0.01). Rates of good clinical outcome at 1 year were 93% (95% CI, 88%–96%) and 66% (95% CI, 59%–72%) in patients with unruptured and ruptured aneurysms, respectively.

Conclusions—

This study suggests that endovascular treatment of IAs in the elderly is associated with high long-term occlusion rates. Given the morbidity and mortality associated with endovascular treatment of IAs in the elderly, careful patient selection, especially in the case of patients with unruptured aneurysm, is recommended.
Neuroprotection of Ischemic Postconditioning by Downregulating the Postsynaptic Signaling Mediated by Kainate Receptors
Authors: Liu Jing , Xu Qin , Wang Hui , Wang Ran , Hou Xiao-Yu
Published: May 2013

Background and Purpose—

Ischemic postconditioning, a brief episode of ischemia after a prolonged ischemic insult, has been found to reduce the delayed neuronal loss after stroke. However, the mechanisms underlying such endogenous neuroprotective strategy remain obscure. In this study, we try to explore the excitatory postsynaptic signal events associated with neuroprotective effect of ischemic postconditioning.

Methods—

Global cerebral ischemia was induced for 15 minutes by the 4-vessel occlusion method in male Sprague–Dawley rats. Ischemic postconditioning was conducted 10 minutes later by a single reocclusion for 3 minutes.

Results—

A severe global cerebral ischemia after 5 days of reperfusion destroyed almost all hippocampal CA1 pyramidal neurons. A brief ischemic postconditioning robustly reduced the neuronal loss after ischemia. Preadministration of phosphoinositide 3-kinase inhibitor LY294002 blocked the neuroprotection of postconditioning, whereas mitogen-activated protein kinase kinase 1 inhibitor PD98059 had no effect. Ischemic postconditioning significantly increased the Akt phosphorylation (Ser473). In addition, postconditioning not only perturbed the binding of postsynaptic density protein-95 with glutamatergic kainate receptor subunit 2 and mixed lineage kinase 3 but also suppressed the downstream activation of mixed lineage kinase 3, mitogen-activated protein kinase kinase 7, and c-Jun N-terminal kinase 3. LY294002, but not PD98059, abolished the postconditioning-induced decreases in the assembly of glutamatergic kainate receptor subunit 2–postsynaptic density protein-95–mixed lineage kinase 3 complex and in the mixed lineage kinase 3–c-Jun N-terminal kinase 3 signaling. Akt inhibitor IV, a specific Akt inhibitor, showed the same effects as LY294002.

Conclusions—

Ischemic postconditioning protects neurons against stroke by attenuating the postsynaptic glutamatergic kainate receptor subunit 2–postsynaptic density protein-95–mixed lineage kinase 3–c-Jun N-terminal kinase 3 signal cascade via phosphoinositide 3-kinase–Akt pathway. (Stroke. 2013;44:2031-2035.)
What Is a Paraphrase?
Authors: Bhagat Rahul , Hovy Eduard
Published: May 2013

Paraphrases are sentences or phrases that convey the same meaning using different wording. Although the logical definition of paraphrases requires strict semantic equivalence, linguistics accepts a broader, approximate, equivalence—thereby allowing far more examples of “quasi-paraphrase.” But approximate equivalence is hard to define. Thus, the phenomenon of paraphrases, as understood in linguistics, is difficult to characterize. In this article, we list a set of 25 operations that generate quasi-paraphrases. We then empirically validate the scope and accuracy of this list by manually analyzing random samples of two publicly available paraphrase corpora. We provide the distribution of naturally occurring quasi-paraphrases in English text.
The Missionary Impulse in the Atlantic World, 1500-1800: Or How Protestants Learned to be Missionaries
Authors: Gardina Pestana Carla
Published: May 2013

Advocates of European expansion often justified their acquisition of territories in terms of the imperative to spread Christianity to non-believers. While Iberian Catholics converted large numbers of native Americans and later Africans imported as slaves within their New World colonies, Protestant colonizers were relatively slow to embrace the missionary imperative. This essay seeks to explain why that was the case, and to do so by considering doctrinal, institutional and political impediments. It shows how Protestants did finally put missions not only to their fellow Europeans but also to Native Americans and to slaves at the center of their imperial project.
Grice on Irony and Metaphor: Discredited by the Experimental Evidence?
Authors: Reimer Marga
Published: May 2013

Recent experimental studies appear to discredit Gricean accounts of irony and metaphor. I argue that appearances are decidedly misleading here and that Gricean accounts of these figures of speech are actually confirmed by the studies in question. However, my primary aim is not so much to defend Gricean accounts of irony and metaphor as it is to motivate two related points: one substantive and one methodological. The substantive point concerns something Grice suggests in his brief remarks on irony: that the interpretation of an ironical (vs. metaphorical) utterance requires two distinct applications of second-order theory of mind (ToM). I argue that such a view has considerable explanatory power. It can explain an intuitive contrast between irony and metaphor, some interesting data on the ToM abilities of patients with schizophrenia, and some intuitive similarities between irony on the one hand and hyperbole and meiosis on the other. The methodological point concerns the relationship between the empirical psychologist’s (or experimental philosopher’s) experimental studies and the armchair philosopher’s thought-experiments. I suggest that the credibility of an experimentally supported claim is enhanced when it captures the reflective judgments captured in the armchair philosopher’s thought-experiments.
Transmitting Haoqiu zhuan in Eighteenth-Century Chosŏn Korea
Authors: Son Suyoung
Published: May 2013

Abstract

This paper focuses on the process of transmission of Haoqiu zhuan in eighteenth-century Chosŏn Korea. The spread of the Haoqiu zhuan did not involve a straightforward transmission of the Chinese text to a Korean readership, but rather a multiple process of mediation—the translation from vernacular Chinese to vernacular Korean, and the transmutation from the printed text to transcribed copies. The text was thus shaped as material for domestic consumption by and for elite women, by bringing about certain adaptations attuned to what was seen as their pressing needs. The transformation of the format and meaning of the text diluted the traces of the work’s national origin and made the distinction between the foreign and the indigenous insignificant. The process of transmission of Haoqiu zhuan not only highlights the fluid nature intrinsic to text transmission but also challenges the adequacy of the impact-response approach based on a nationalist reflex.
Causal attribution of mental illness in south-eastern Nigeria
Authors: Ikwuka Ugo , Galbraith Niall , Nyatanga Lovemore
Published: May 2013

Background:

Understanding of mental illness in sub-Saharan Africa has remained under-researched in spite of the high and increasing neuropsychiatric burden of disease in the region.

Aims:

This study investigated the causal beliefs that the Igbo people of south-eastern Nigeria hold about schizophrenia, with a view to establishing the extent to which the population makes psychosocial, biological and supernatural attributions.

Method:

Multi-stage sampling was used to select participants ( N = 200) to which questionnaires were administered.

Results:

Mean comparison of the three causal models revealed a significant endorsement of supernatural causation. Logistic regressions revealed significant contributions of old age and female gender to supernatural attribution; old age, high education and Catholic religious denomination to psychosocial attributions; and high education to biological attributions.

Conclusions:

It is hoped that the findings would enlighten, augment literature and enhance mental health care service delivery.
The availability and quality across Europe of outpatient care for difficult-to-engage patients with severe mental illness: A survey among experts
Authors: Mulder Cornelis L , Ruud Torleif , Bahler Michiel , Kroon Hans , Priebe Stefan
Published: May 2013

Background:

As many patients with severe mental illness (SMI) who have complex needs are difficult to engage, outreach mental health services are needed to engage them into treatment. The extent to which these services exist in large European cities is unknown.

Methods:

Experts in 29 European countries were sent a structured questionnaire containing two case vignettes of difficult-to-engage patients (a first-episode psychosis patient and a homeless chronic schizophrenia patient). The type and quality of outpatient care was assessed and related to several national indices.

Results:

The questionnaire was returned by experts from 22 countries (76%) representing 92% of the EU population. Six countries (21%) had a systematic method for detecting difficult-to-engage patients. The most important route whereby such patients entered the mental health system was through informal care; the most important reasons for entering it were the level of psychiatric symptoms, nuisance and violence. Assertive outreach was available in nine countries (41%), with coverage ranging from a few teams (sometimes for a specific target group) to most of the country. The case vignettes showed that outpatient care for these difficult-to-engage patients varied widely. In seven (30%) of the 22 countries, a hospital would take no action if such patients who had been admitted voluntarily discharged themselves prematurely. On a scale of 0–10, the experts’ mean scores regarding the quality of outpatient care for patients with SMI in general were 5.2 (SD = 1.9) and 3.2 (SD = 2.2) in difficult-to-engage ones. Explorative analyses showed that the quality of outpatient care for difficult-to-engage patients was associated with gross national income and the number of psychiatrists per capita.

Conclusions:

Outpatient mental health services for difficult-to-engage SMI patients varied widely among European countries; experts judged their overall quality to be poor. It is now important to achieve consensus on a minimum European standard for the quality of care for such patients.