bluuebunny/crossref_metadata_2025 huggingface dataset:
Feasibility and Diagnostic Accuracy of Early Mood Screening to Diagnose Persisting Clinical Depression/Anxiety Disorder after Stroke
Authors: Lees Rosalind , Stott David J. , Quinn Terence J. , Broomfield Niall M.
Published: June 2014

Background: Depression/anxiety disorders are common after stroke and have a negative impact on outcomes. Guidelines recommend that all stroke survivors are screened for these problems. However, there is no consensus on timing or method of assessment. We investigated the feasibility and accuracy of a very early screening strategy and the diagnostic accuracy this has for depression/anxiety disorders at 1 month. Methods: Screening tools were Hospital Anxiety and Depression Scale (HADS) and Depression Intensity Scale Circles (DISCs); we also assessed cognition using the Montreal Cognitive Assessment (MoCA). Screening was offered to sequential stroke admissions. At 1 month we assessed for clinical depression/anxiety disorder using Mini-International Neuropsychiatric Interview (MINI) and retested screening tools. We described test accuracy of acute depression/anxiety screening for clinical diagnosis of depression/anxiety disorder at 1 month and described temporal change in screening test scores. We assessed feasibility by describing proportions that were able, agreed to and completed the screening tests. Results: Over 4 months, 102/146 admissions were suitable for screening following initial medical assessment, 69 (68%) agreed to screening, of whom 33 (48%) required researcher assistance to complete the screening test battery. Median time to assessment was 2 days (IQR: 1-4). Early HADS suggested n = 9 (13%) with depression; DISCs n = 25 (37%). Median acute MoCA was 21/30. At 1 month, n = 61 (88%) provided data. Repeat scores showed improvement over time; HADS (anxiety) mean difference: 2.5 (95% CI: 1.2-3.7), HADS (depression) mean difference: 1.6 (95% CI: 0.3-2.9). MINI defined n = 12 (20%) with depression and n = 6 (10%) with anxiety disorder. Comparing baseline screening to 1-month clinical diagnosis, HADS sensitivity was 0.25 (95% CI: 0.09-0.53) and specificity 0.94 (95% CI: 0.84-0.98); DISCs sensitivity was 0.92 (95% CI: 0.65-0.99) and specificity 0.78 (95% CI: 0.64-0.87). Conclusions: Even amongst ‘medically stable' stroke patients, depression/anxiety screening at the acute stage may not be feasible or accurate. Half of participants required assistance from the researcher to complete assessments. The poor predictive accuracy of HADS for depression/anxiety disorder at 1 month may be due in part to the high prevalence of cognitive impairment in our sample. Screening in the first few days after stroke does not appear useful for detecting clinically important and sustained depression/anxiety problems.
Incidence and Predictors of Ischemic Stroke Events during Hospitalization in Patients with Transient Ischemic Attack
Authors: Fujinami Jun , Uehara Toshiyuki , Kimura Kazumi , Okada Yasushi , Hasegawa Yasuhiro , Tanahashi Norio , Suzuki Akifumi , Takagi Shigeharu , Nakagawara Jyoji , Arii Kazumasa , Nagahiro Shinji , Ogasawara Kuniaki , Nagao Takehiko , Uchiyama Shinichiro , Matsumoto Masayasu , Iihara Koji , Minematsu Kazuo
Published: June 2014

Background: The purpose of this study was to elucidate the incidence and predictors of ischemic stroke or recurrent transient ischemic attack (TIA) during acute hospitalization in patients with TIA. Methods: We carried out a multicenter retrospective study to clarify the characteristics of in-patients with TIA. The subjects of this study were TIA patients admitted to 13 stroke hospitals within 7 days after onset between 2008 and 2009. TIA was defined as focal neurologic symptoms ascribable to a vascular etiology lasting less than 24 h. We investigated the incidence and predictors of ischemic events including ischemic stroke or recurrent TIA during hospitalization. Results: A total of 464 patients with TIA (292 men, 69 ± 13 years) were registered. Of those, 400 (86.2%) were admitted within 24 h of TIA onset. The mean length of hospital stay was 13 days. During hospitalization, 8 patients had ischemic strokes and 26 had recurrent TIAs. The leading subtype of 8 ischemic strokes was small vessel disease (n = 3) followed by cardioembolism (n = 2). Multiple logistic regression analysis showed that hypertension (OR: 3.41; 95% CI: 1.23-12.3), MRI-diffusion-weighted image positivity (OR: 2.49; 95% CI: 1.15-5.25), and hemiparesis (OR: 2.30; 95% CI: 1.02-5.88) were independently associated with ischemic events during hospitalization. Conclusions: In this study, 1.7% of patients with TIA had ischemic stroke during acute hospitalization, and the most common subtype was small vessel disease. Subsequent ischemic stroke and recurrent TIA were associated with hypertension, positive DWI findings, and hemiparesis.
Invariant Natural Killer T Cells: Boon or Bane in Immunity to Intracellular Bacterial Infections?
Authors: Shekhar Sudhanshu , Joyee Antony George , Yang Xi
Published: June 2014

Invariant natural killer T (iNKT) cells represent a specialized subset of innate lymphocytes that recognize lipid and glycolipid antigens presented to them by nonclassical MHC-I CD1d molecules and are able to rapidly secrete copious amounts of a variety of cytokines. iNKT cells possess the ability to modulate innate as well as adaptive immune responses against various pathogens. Intracellular bacteria are one of the most clinically significant human pathogens that effectively evade the immune system and cause a myriad of diseases of public health concern globally. Emerging evidence suggests that iNKT cells can confer immunity to intracellular bacteria but also inflict pathology in certain cases. We summarize the current knowledge on the contribution of iNKT cells in the host defense against intracellular bacterial infections, with a focus on the underlying mechanisms by which these cells induce protective or pathogenic reactions including the pathways of direct action (acting on infected cells) and indirect action (modulating dendritic, NK and T cells). The rational exploitation of iNKT cells for prophylactic and therapeutic purposes awaits a profound understanding of their functional biology.
Inhibitory Activity of Myrtus communis Oil on Some Clinically Isolated Oral Pathogens
Authors: Fani Mohammad Mehdi , Kohanteb Jamshid , Araghizadeh Abdolmehdi
Published: June 2014

Objectives: To determine the antimicrobial activities of Myrtus communis oil (MCO) on some oral pathogens. Material and Methods: Thirty strains of Streptococcus mutans, Aggregatibacteractinomycetemcomitans, Porphyromonas gingivalis and 20 strains of Streptococcus pyogenes and Candida albicans isolated from patients with dental caries, periodontal diseases, pharyngitis and oral lesions associated with artificial dentures were used for the antimicrobial activity of MCO. The oil was prepared by hydrodistillation procedures using a Clevenger apparatus. Agar disk diffusion and broth microdilution methods were performed on various concentrations of MCO (3.9-1,000 µg/ml) using all the pathogens isolated. Results: All isolates were sensitive to MCO at 125-1,000 µg/ml by agar disk diffusion producing inhibition zones of 8.1-41.25 mm in diameter. All of the S. pyogenes, S. mutans and C. albicans strains were sensitive to 62.5 µg/ml while 70% (21/30) of A. actinomycetemcomitans and 66.6% (20/30) of P. gingivalis were resistant to these concentrations. All S. pyogenes and S. mutans strains were sensitive to 31.25 µg/ml. All S. pyogenes strains were sensitive to 15.6 and 7.8 µg/ml of MCO. None of the clinical isolates in this study were sensitive to 3.9 µg/ml or to a lower concentration of oil. The minimum inhibitory concentrations of MCO for S. pyogenes, S. mutans, C. albicans, A.actinomycetemcomitans and P. gingivalis were 29.68 ± 4.8, 31.25 ± 0, 46.9 ± 16, 62.5 ± 0 and 62.5 ± 0 µg/ml, respectively. Conclusions: Data obtained in this study revealed a strong antimicrobial activity of MCO on the tested oral pathogens, and MCO could therefore be useful in the prevention of the related oral infections.
Validation and Comparison of CS-IHC4 Scores with a Nomogram to Predict Recurrence in Hormone Receptor-Positive Breast Cancers
Authors: Park Yeon Hee , Im Seock-Ah , Cho Eun Yoon , Ahn Joong Hyun , Woo Sook Young , Kim Seonwoo , Keam Bhumsuk , Lee Jeong Eon , Han Wonshik , Nam Seok Jin , Park In Ae , Noh Dong-Young , Yang Jung Hyun , Ahn Jin Seok , Im Young-Hyuck
Published: June 2014

The aim of this study was to both develop and validate a nomogram based on the Ki-67 index to predict recurrence. We constructed a nomogram using the Cox proportional hazards model with 953 N0 and N1 postoperative hormone receptor (HR)-positive breast cancer patients and validated it in an external cohort of 895 patients. A prognostic model that used classical variables, Adjuvant! Online, St. Gallen risk stratification, and the four immunohistochemistry (IHC) markers (IHC4 score) was created and assessed by the likelihood ratio χ2 (LR-χ2) test using the bootstrapping method. The nomogram showed an area under the receiver operating characteristic curve (AUC) of 0.75 (95% CI 0.72-0.77) in the training set. The validation set showed good discrimination with an AUC of 0.63 (95% CI 0.60-0.66). In the LR-χ2 test, the nomogram score was found to be more informative than the IHC4 with clinical score (CS) [LR-χ2 13.365 (1 d.f.); 95% CI 2.50-24.23 for CS-IHC4 + nomogram score vs. CS-IHC4] on distant recurrence-free survival. This study implies that the amount of prognostic information contained in the nomogram is superior to that in the CS-IHC4 score in HR-positive N0 and N1 breast cancer patients (NCT1273415).
Effects of Long-Term Developmental Patterns of Adiposity on Levels of C-Reactive Protein and Fibrinogen among North-American Men and Women: The Spokane Heart Study
Authors: Hoekstra Trynke , Barbosa-Leiker Celestina , Wright Bruce R. , Twisk Jos W.R.
Published: June 2014

This study examined the heterogeneity in BMI development by identifying distinct developmental trajectories. These trajectories were further investigated by relating them to markers of low-grade inflammation later in life. Data from approximately 400 healthy volunteers participating in the Spokane Heart Study were collected in 2-year intervals, and four waves of data were available for the current analyses. Body weight was measured by BMI and low-grade inflammation by high-sensitivity C-reactive protein (CRP) and fibrinogen. Up to date statistical techniques, i.e. latent class growth models, were used to analyse heterogeneity in body weight, and linear regressions were run to analyse possible associations between trajectories of body weight and CRP/fibrinogen levels. Six trajectories were identified (three stable, two increasing, and one decreasing) which differed significantly on CRP/fibrinogen levels, highlighting the importance of weight trajectories. The differences were only partly explained by variations in lifestyle habits.
Bond Strength of Calcium Silicate-Based Sealers to Dentine Dried with Different Techniques
Authors: Taşdemir Tamer , Er Kürşat , Çelik Davut , Tahan Erhan , Serper Ahmet , Ceyhanli Kadir Tolga , Yeşilyurt Cemal
Published: June 2014

Objective: To assess the influence of various canal-drying techniques on the push-out bond strength between radicular dentine and both MTA Fillapex and iRoot SP sealers. Materials and Methods: Eighty extracted single-root teeth were instrumented with ProTaper Universal rotary instruments to a size F4. The teeth were randomly assigned to 1 of 4 groups as follows: group 1, excess fluid in the canals was removed using a Luer vacuum adapter; group 2, the canals were dried with a single paper point; group 3, the canals were dried with 3-5 paper points, and group 4, the canals were rinsed with 95% ethanol and then dried with 3-5 paper points. In each group, the specimens were subgrouped according to root canal sealer into either subgroup A (MTA Fillapex) or subgroup B (iRoot SP sealer). Horizontal sections (thickness 1 ± 0.1 mm) were obtained from each specimen and a push-out test was performed using a universal testing machine at a crosshead speed of 1 mm/min on root slices. Statistical analysis was done using the Kruskal-Wallis test and Dunn's test for pair-wise comparisons. p < 0.05 was considered statistically significant. Results: Canals dried with only 1 paper point and obturated with the iRoot SP sealer (subgroup 2B) showed significantly higher bond strengths to the root canal wall compared to all other subgroups (p < 0.05), except for subgroup 1B (p > 0.05). Conclusions: The canal-drying technique influenced the adhesive bond strength between calcium silicate-based root canal sealers and the root canal wall.
Relationship between Serum Soluble Vascular Adhesion Protein-1 Level and Gastric Cancer Prognosis
Authors: Kaplan Muhammet A. , Kucukoner Mehmet , Inal Ali , Urakci Zuhat , Evliyaoglu Osman , Firat Ugur , Kaya Muhsin , Isikdogan Abdurrahman
Published: June 2014

Background: Vascular adhesion protein-1 (VAP-1) is a glycoprotein that mediates tissue-selective lymphocyte adhesion in a sialic acid-dependent manner. The prognostic importance of VAP-1 was determined in various human cancers. The aim of this study was to determine the relationship between VAP-1 and prognosis of gastric cancer. Materials and Methods: Serum of operable and metastatic gastric cancer patients was collected before treatment (surgery, radiotherapy, and/or chemotherapy). VAP-1 levels were measured by enzyme-linked immunosorbent assay. Results: A total of 86 gastric cancer patients (32 female, 54 male) were included in the study. Curative surgical treatment was performed in 54 (62.8%) patients. The mean serum VAP-1 level was 324.4 pg/ml and significantly higher in operable gastric cancer patients compared to metastatic gastric cancer patients (383.1 ± 173.5 vs. 225.2 ± 113.9 pg/ml; p < 0.001). When a cut-off value for VAP-1 of 218.8 pg/ml was determined by receiver operating characteristic (ROC) curves for presence of metastasis, sensitivity and specificity were 81.5 and 65.6%, respectively. Patients with decreased VAP-1 levels had a significantly poorer prognosis compared to patients with increased serum VAP-1 levels (median survival 8.2 vs. 23.5 months; p < 0.001). Multivariate analysis showed that VAP-1 is an independent prognostic factor of gastric cancer (odds ratio 2.3, 95% confidence interval 1.1-4.9; p = 0.032). Conclusion: A low serum VAP-1 level may be an indicator of poor prognosis in gastric cancer. This study demonstrated that low serum VAP-1 levels are associated with poor prognosis in gastric cancer patients.
Influence of Xingnaojing Injection on the Expression of c-fos and c-jun Proteins in Brains of Rats in a Kindling Model of Epilepsy Chronically Induced by Pentetrazol
Authors: Cheng Ji-Wei , Bai Yu , Zhang Xiao-Jing , Zhang Li-Jun , Hou Yu-Qing
Published: June 2014

Objective: To investigate the molecular biological mechanism of the antiepileptic effect of Xingnaojing (XNJ) injection on a rat kindling model of epilepsy (KME). Methods: Fifty healthy 6-week-old male Sprague-Dawley rats were divided into the following five groups: blank control (BC) group, model (M) group, XNJ injection (XI) group, phenobarbital injection (PI) group and XNJ combined with phenobarbital (XP) group. There were 10 rats in each group. The intervention drugs were administered 30 min before the model-building drugs once a day for 5 weeks. The model-building drug pentetrazol was given to each group as an intraperitoneal injection 30 min after the use of the intervention drug once a day for 4 weeks for KME establishment (except for the BC group). The BC group was given physiological saline instead. All drugs were injected intraperitoneally. The behaviors of each group of rats were observed after the use of the model-building drugs for 1 h every day. The last kindling test was carried out at the end of week 5. Then, c-fos and c-jun protein expressions in the rat brains of each group were observed and analyzed by immunohistochemistry at the end of the experiment. Results: There was a large number of cells positive for the c-fos and c-jun proteins in the rat brains of the M group. Compared with the M group, the expression level of the c-fos and c-jun proteins was lower in the rat brains of the XI and PI groups (p < 0.01). There was no statistical difference between the XI and PI groups (p > 0.05). The number of positive cells in the rat brains of the XP group was even smaller than that of the XI or PI groups. Conclusion: The antiepileptic effect of the XNJ injection on the rat KME is probably related to its interruption function on the expression of the c-fos and c-jun proteins in rat brains.
The ‘Whistled' Fricative in Xitsonga: Its Articulation and Acoustics
Authors: Lee-Kim Sang-Im , Kawahara Shigeto , Lee Seunghun J.
Published: June 2014

The present study examines the articulation and acoustics of the typologically rare and understudied ‘whistled' fricative sound in Xitsonga, a Southern Bantu language. Using ultrasound imaging and video recording, we examine the lingual and labial articulation of the whistled fricative. For the acoustic analysis, we employ the multitaper spectral analysis, which ensures reliable spectral estimates. The results revealed an interplay between multiple articulators involved in the production of the sound: the retroflex lingual gesture and the narrowing of the lower lip toward the upper teeth. Acoustically, the spectra of the whistled fricative are more peaked and compact than the acoustically similar palatoalveolar fricative, and the differences manifest themselves most clearly in two acoustic parameters, dynamic amplitude (Ad) and M2 (variance). The acoustic differences are also manifested in F2 and F3 in the surrounding vowels. Additionally, the ‘whistled' fricative in Xitsonga is not quite whistled, contrary to the label given to the sound in previous studies. Building on the current articulatory and acoustic results, we discuss two different aerodynamic models for the whistled fricatives in Southern Bantu languages and conclude that the whistled fricative in Xitsonga is best characterized as a retroflex segment accompanied by weak whistling.
Calcium Signalling in Pericytes
Authors: Burdyga Theodor , Borysova Lyudmyla
Published: June 2014

Recent advances in pericyte research have contributed to our understanding of the physiology and pathophysiology of microvessels. The microvasculature consists of arteriolar and venular networks located upstream and downstream of the capillaries. Arterioles are surrounded by a monolayer of spindle-shaped myocytes, while terminal branches of precapillary arterioles, capillaries and all sections of postcapillary venules are encircled by a monolayer of morphologically diverse pericytes. There are physiological differences in the response of pericytes and myocytes to vasoactive molecules, suggesting that these two vascular cell types could have different functional roles in the regulation of local blood flow. The contractile activity of pericytes and myocytes is controlled by changes of cytosolic free Ca2+ concentration. In this short review, we summarize our results and those of other authors on the contractility of pericytes and their Ca2+ signalling. We describe results regarding sources of Ca2+ and mechanisms of Ca2+ release and Ca2+ entry in control of the spatiotemporal characteristics of the Ca2+ signals in pericytes.
Bladder Cancer versus Hemorrhagic Cystitis: A Case of Mistaken Identity in a 34-Year-Old Male Undergoing Therapy for Granulomatosis with Polyangiitis
Authors: Amatruda Jonathan , Dieckhaus Kevin , Hegde Poornima , Taylor 3rd John
Published: June 2014

A 34-year-old male was referred for management of bladder cancer noted on workup for gross hematuria and new-onset irritative voiding symptoms. The patient's history was significant for recently diagnosed granulomatosis with polyangiitis for which he was undergoing treatment with oral cyclophosphamide and corticosteroids. Cystoscopy revealed lesions suspicious for malignancy, but the patient was diagnosed with hemorrhagic cystitis secondary to BK virus infection upon cytology review, and immunostaining confirmed a polyomavirus infection of the urothelium. The patient's symptoms resolved after a modification of his immunosuppressive regimen, and antiviral therapy was ultimately unnecessary. Though symptomatic BK virus infection of the genitourinary tract is common in immunosuppressed transplant patients, its occurrence in a patient undergoing immunomodulation for an autoimmune disease has not been reported yet. This case illustrates the potential for active BK virus infections in atypical patient populations and underscores the importance of rigorous hematuria workup, particularly in patients with multiple risk factors.
Long-Term Safety of an Everolimus-Eluting Bioresorbable Vascular Scaffold and the Cobalt-Chromium XIENCE V Stent in a Porcine Coronary Artery Model
Authors: Otsuka Fumiyuki , Pacheco Erica , Perkins Laura E.L. , Lane Jennifer P. , Wang Qing , Kamberi Marika , Frie Michael , Wang Jin , Sakakura Kenichi , Yahagi Kazuyuki , Ladich Elena , Rapoza Richard J. , Kolodgie Frank D. , Virmani Renu
Published: June 2014

Background—

The Absorb everolimus-eluting bioresorbable vascular scaffold (Absorb) has shown promising clinical results; however, only limited preclinical data have been published. We sought to investigate detailed pathological responses to the Absorb versus XIENCE V (XV) in a porcine coronary model with duration of implant extending from 1 to 42 months.

Methods and Results—

A total of 335 devices (263 Absorb and 72 XV) were implanted in 2 or 3 main coronary arteries of 136 nonatherosclerotic swine and examined by light microscopy, scanning electron microscopy, pharmacokinetics, and gel permeation chromatography analyses at various time points. Vascular responses to Absorb and XV were largely comparable at all time points, with struts being sequestered within the neointima. Inflammation was mild to moderate (with absence of inflammation at 1 month) for both devices, although the scores were greater in Absorb at 6 to 36 months. Percent area stenosis was significantly greater in Absorb than XV at all time points except at 3 months. The extent of fibrin deposition was similar between Absorb and XV, which peaked at 1 month and decreased rapidly thereafter. Histomorphometry showed expansile remodeling of Absorb-implanted arteries starting after 12 months, and lumen area was significantly greater in Absorb than XV at 36 and 42 months. These changes correlated with dismantling of Absorb seen after 12 months. Gel permeation chromatography analysis confirmed that degradation of Absorb was complete by 36 months.

Conclusions—

Absorb demonstrates comparable long-term safety to XV in porcine coronary arteries with mild to moderate inflammation. Although Absorb was associated with greater percent stenosis relative to XV, expansile remodeling was observed after 12 months in Absorb with significantly greater lumen area at ≥36 months. Resorption is considered complete at 36 months.
Impact of Drug Policy on Regional Trends in Ezetimibe Use
Authors: Lu Lingyun , Krumholz Harlan M. , Tu Jack V. , Ross Joseph S. , Ko Dennis T. , Jackevicius Cynthia A.
Published: June 2014

Background—

Ezetimibe use has steadily increased in Canada during the past decade even in the absence of evidence demonstrating a beneficial effect on clinical outcomes. Among the 4 most populated provinces in Canada, there is a gradient in the restrictiveness of ezetimibe in public-funded formularies (most to least strict: British Columbia, Alberta, Quebec, and Ontario). The effect of formulary policy on the use of ezetimibe over time is unknown.

Methods and Results—

We conducted a population-level cohort study using Intercontinental Marketing Services Health Canada’s data from June 2003 to December 2012 to examine ezetimibe use in these 4 provinces to better understand the association between use and formulary restrictiveness. We found regional variations in the patterns of ezetimibe use. From June 2003 to December 2012, British Columbia (most restrictive) had the lowest monthly increasing rate from $261 to $21 926 ($190/100 000 population/mo), whereas Ontario (least restrictive) had the most rapid monthly increase from $223 to $74 030 ($ 647/100 000 population/mo), and Quebec from $130 to $59 690 ($522/100 000 population/mo) and Alberta from $356 to $ 37 604 ($327/100 000 population/mo) were intermediate (
P
<0.001).

Conclusions—

Ezetimibe use remains common, increasing during the past decade. Use steadily increased in provinces with the most lenient formularies. In contrast, use was lower, plateauing since 2008 in British Columbia and Alberta, which have more restrictive formularies. The gradient in ezetimibe use was related to variability in restrictiveness of the provincial formularies, illustrating the potential of a policy response gradient that may be used to more effectively manage medication use.
PDZ Domain–Binding Motif Regulates Cardiomyocyte Compartment-Specific Na
V
1.5 Channel Expression and Function
Authors: Shy Diana , Gillet Ludovic , Ogrodnik Jakob , Albesa Maxime , Verkerk Arie O. , Wolswinkel Rianne , Rougier Jean-Sébastien , Barc Julien , Essers Maria C. , Syam Ninda , Marsman Roos F. , van Mil Anneke M. , Rotman Samuel , Redon Richard , Bezzina Connie R. , Remme Carol Ann , Abriel Hugues
Published: June 2014

Background—

Sodium channel Na
V
1.5 underlies cardiac excitability and conduction. The last 3 residues of Na
V
1.5 (Ser-Ile-Val) constitute a PDZ domain–binding motif that interacts with PDZ proteins such as syntrophins and SAP97 at different locations within the cardiomyocyte, thus defining distinct pools of Na
V
1.5 multiprotein complexes. Here, we explored the in vivo and clinical impact of this motif through characterization of mutant mice and genetic screening of patients.

Methods and Results—

To investigate in vivo the regulatory role of this motif, we generated knock-in mice lacking the SIV domain (ΔSIV). ΔSIV mice displayed reduced Na
V
1.5 expression and sodium current (
I
Na
), specifically at the lateral myocyte membrane, whereas Na
V
1.5 expression and
I
Na
at the intercalated disks were unaffected. Optical mapping of ΔSIV hearts revealed that ventricular conduction velocity was preferentially decreased in the transversal direction to myocardial fiber orientation, leading to increased anisotropy of ventricular conduction. Internalization of wild-type and ΔSIV channels was unchanged in HEK293 cells. However, the proteasome inhibitor MG132 rescued ΔSIV
I
Na
, suggesting that the SIV motif is important for regulation of Na
V
1.5 degradation. A missense mutation within the SIV motif (p.V2016M) was identified in a patient with Brugada syndrome. The mutation decreased Na
V
1.5 cell surface expression and
I
Na
when expressed in HEK293 cells.

Conclusions—

Our results demonstrate the in vivo significance of the PDZ domain–binding motif in the correct expression of Na
V
1.5 at the lateral cardiomyocyte membrane and underline the functional role of lateral Na
V
1.5 in ventricular conduction. Furthermore, we reveal a clinical relevance of the SIV motif in cardiac disease.
Protein Changes Contributing to Right Ventricular Cardiomyocyte Diastolic Dysfunction in Pulmonary Arterial Hypertension
Authors: Rain Silvia , Bos Denielli da Silva Goncalves , Handoko M. Louis , Westerhof Nico , Stienen Ger , Ottenheijm Coen , Goebel Max , Dorfmüller Peter , Guignabert Christophe , Humbert Marc , Bogaard Harm‐Jan , Remedios Cris dos , Saripalli Chandra , Hidalgo Carlos G. , Granzier Henk L. , Vonk‐Noordegraaf Anton , van der Velden Jolanda , de Man Frances S.
Published: June 2014

Background

Right ventricular (
RV
) diastolic function is impaired in patients with pulmonary arterial hypertension (
PAH
). Our previous study showed that elevated cardiomyocyte stiffness and myofilament Ca
2+
sensitivity underlie diastolic dysfunction in
PAH
. This study investigates protein modifications contributing to cellular diastolic dysfunction in
PAH
.

Methods and Results

RV samples from PAH patients undergoing heart‐lung transplantation were compared to non‐failing donors (Don).
Titin stiffness
contribution to RV diastolic dysfunction was determined by Western‐blot analyses using antibodies to protein‐kinase‐A (PKA), Cα (PKCα) and Ca
2+
/calmoduling‐dependent‐kinase (CamKIIδ) titin and phospholamban (PLN) phosphorylation sites: N2B (Ser469), PEVK (Ser170 and Ser26), and PLN (Thr17), respectively. PKA and PKCα sites were significantly less phosphorylated in PAH compared with donors (
P
<0.0001). To test the functional relevance of PKA‐, PKCα‐, and CamK
IIδ
‐mediated titin phosphorylation, we measured the stiffness of single RV cardiomyocytes before and after kinase incubation. PKA significantly decreased PAH RV cardiomyocyte diastolic stiffness, PKCα further increased stiffness while CamK
IIδ
had no major effect. CamKIIδ activation was determined indirectly by measuring PLN Thr17phosphorylation level. No significant changes were found between the groups. Myofilament Ca
2+
sensitivity is mediated by sarcomeric
troponin I
(
cTnI
) phosphorylation. We observed increased unphosphorylated
cTnI
in PAH compared with donors (
P
<0.05) and reduced PKA‐mediated
cTnI
phosphorylation (Ser22/23) (
P
<0.001). Finally, alterations in
Ca

2+

‐handling proteins
contribute to RV diastolic dysfunction due to insufficient diastolic Ca
2+
clearance. PAH SERCA2a levels and PLN phosphorylation were significantly reduced compared with donors (
P
<0.05).

Conclusions

Increased titin stiffness, reduced
cTnI
phosphorylation, and altered levels of phosphorylation of Ca
2+
handling proteins contribute to RV diastolic dysfunction in PAH.
Functional Analysis of the TRIB
1
Associated Locus Linked to Plasma Triglycerides and Coronary Artery Disease
Authors: Douvris Adrianna , Soubeyrand Sébastien , Naing Thet , Martinuk Amy , Nikpay Majid , Williams Andrew , Buick Julie , Yauk Carole , McPherson Ruth
Published: June 2014

Background

The
TRIB
1
locus has been linked to hepatic triglyceride metabolism in mice and to plasma triglycerides and coronary artery disease in humans. The lipid‐associated single nucleotide polymorphisms (
SNP
s), identified by genome‐wide association studies, are located ≈30 kb downstream from
TRIB
1,
suggesting complex regulatory effects on genes or pathways relevant to hepatic triglyceride metabolism. The goal of this study was to investigate the functional relationship between common
SNP
s at the
TRIB
1
locus and plasma lipid traits.

Methods and Results

Characterization of the risk locus reveals that it encompasses a gene,
TRIB1
‐associated locus (
TRIBAL
), composed of a well‐conserved promoter region and an alternatively spliced transcript. Bioinformatic analysis and resequencing identified a single SNP, rs2001844, within the promoter region that associates with increased plasma triglycerides and reduced high‐density lipoprotein cholesterol and coronary artery disease risk. Further, correction for triglycerides as a covariate indicated that the genome‐wide association studies association is largely dependent on triglycerides. In addition, we show that rs2001844 is an expression trait locus (
eQTL
) for
TRIB1
expression in blood and alters
TRIBAL
promoter activity in a reporter assay model. The
TRIBAL
transcript has features typical of long noncoding RNAs, including poor sequence conservation. Modulation of
TRIBAL
expression had limited impact on either
TRIB1
or lipid regulatory genes
mRNA
levels in human hepatocyte models. In contrast,
TRIB1
knockdown markedly increased
TRIBAL
expression in HepG2 cells and primary human hepatocytes.

Conclusions

These studies demonstrate an interplay between a novel locus,
TRIBAL,
and
TRIB1
.
TRIBAL
is located in the genome‐wide association studies identified risk locus, responds to altered expression of
TRIB1,
harbors a risk SNP that is an
eQTL
for
TRIB1
expression, and associates with plasma triglyceride concentrations.
Acute White Matter Injury After Experimental Subarachnoid Hemorrhage
Authors: Egashira Yusuke , Hua Ya , Keep Richard F. , Xi Guohua
Published: June 2014

Background and Purpose—

White matter injury occurs after subarachnoid hemorrhage (SAH) and has not been well studied. In this study, we investigated acute white matter injury in a mouse SAH model and the role of lipocalin 2 (LCN2) in that injury.

Methods—

SAH was induced by endovascular perforation in wild-type (WT) or LCN2 knockout (LCN2
−/−
) mice. Sham WT mice underwent the same procedure without perforation. MRI was performed 24 hours after SAH and the volumes of the T2-hyperintensity in white matter were measured. Immunohistochemistry was performed to determine white matter injury.

Results—

Mortality rates and SAH severity were not significantly different between WT and LCN2
−/−
animals. T2-hyperintensity in the white matter was observed in all WT animals at 24 hours after SAH (6.1±2.7 versus 0.06±0.07 mm
3
in sham;
P
<0.001), and the volume of T2-hyperintensity tended to correlate with SAH severity (
r
=0.30;
P
=0.055). In WT animals with SAH, numerous LCN2-positive cells were observed in white matter. In contrast, LCN2
−/−
animals scarcely developed white matter T2-hyperintensity after SAH (0.5±0.5 mm
3
;
P
<0.001, versus WT). Markers of axonal damage and myelin degradation were increased in white matter after SAH in WT compared with those in LCN2
−/−
animals (
P
<0.05).

Conclusions—

SAH results in an acute white matter injury at 24 hours in mice, and LCN2 plays an important role in SAH-induced white matter injury.
Age-related Differences in the Neural Bases of Phonological and Semantic Processes
Authors: Diaz Michele T. , Johnson Micah A. , Burke Deborah M. , Madden David J.
Published: June 2014

Changes in language functions during normal aging are greater for phonological compared with semantic processes. To investigate the behavioral and neural basis for these age-related differences, we used fMRI to examine younger and older adults who made semantic and phonological decisions about pictures. The behavioral performance of older adults was less accurate and less efficient than younger adults' in the phonological task but did not differ in the semantic task. In the fMRI analyses, the semantic task activated left-hemisphere language regions, and the phonological task activated bilateral cingulate and ventral precuneus. Age-related effects were widespread throughout the brain and most often expressed as greater activation for older adults. Activation was greater for younger compared with older adults in ventral brain regions involved in visual and object processing. Although there was not a significant Age × Condition interaction in the whole-brain fMRI results, correlations examining the relationship between behavior and fMRI activation were stronger for younger compared with older adults. Our results suggest that the relationship between behavior and neural activation declines with age, and this may underlie some of the observed declines in performance.
Differentiating Semantic Categories during the Acquisition of Novel Words: Correspondence Analysis Applied to Event-related Potentials
Authors: Fargier Raphaël , Ploux Sabine , Cheylus Anne , Reboul Anne , Paulignan Yves , Nazir Tatjana A.
Published: June 2014

Growing evidence suggests that semantic knowledge is represented in distributed neural networks that include modality-specific structures. Here, we examined the processes underlying the acquisition of words from different semantic categories to determine whether the emergence of visual- and action-based categories could be tracked back to their acquisition. For this, we applied correspondence analysis (CA) to ERPs recorded at various moments during acquisition. CA is a multivariate statistical technique typically used to reveal distance relationships between words of a corpus. Applied to ERPs, it allows isolating factors that best explain variations in the data across time and electrodes. Participants were asked to learn new action and visual words by associating novel pseudowords with the execution of hand movements or the observation of visual images. Words were probed before and after training on two consecutive days. To capture processes that unfold during lexical access, CA was applied on the 100–400 msec post-word onset interval. CA isolated two factors that organized the data as a function of test sessions and word categories. Conventional ERP analyses further revealed a category-specific increase in the negativity of the ERPs to action and visual words at the frontal and occipital electrodes, respectively. The distinct neural processes underlying action and visual words can thus be tracked back to the acquisition of word-referent relationships and may have its origin in association learning. Given current evidence for the flexibility of language-induced sensory-motor activity, we argue that these associative links may serve functions beyond word understanding, that is, the elaboration of situation models.
Unseen Fearful Faces Influence Face Encoding: Evidence from ERPs in Hemianopic Patients
Authors: Cecere Roberto , Bertini Caterina , Maier Martin E. , Làdavas Elisabetta
Published: June 2014

Visual threat-related signals are not only processed via a cortical geniculo-striatal pathway to the amygdala but also via a subcortical colliculo-pulvinar-amygdala pathway, which presumably mediates implicit processing of fearful stimuli. Indeed, hemianopic patients with unilateral damage to the geniculo-striatal pathway have been shown to respond faster to seen happy faces in their intact visual field when unseen fearful faces were concurrently presented in their blind field [Bertini, C., Cecere, R., & Làdavas, E. I am blind, but I “see” fear. Cortex, 49, 985–993, 2013]. This behavioral facilitation in the presence of unseen fear might reflect enhanced processing of consciously perceived faces because of early activation of the subcortical pathway for implicit fear perception, which possibly leads to a modulation of cortical activity. To test this hypothesis, we examined ERPs elicited by fearful and happy faces presented to the intact visual field of right and left hemianopic patients, whereas fearful, happy, or neutral faces were concurrently presented in their blind field. Results showed that the amplitude of the N170 elicited by seen happy faces was selectively increased when an unseen fearful face was concurrently presented in the blind field of right hemianopic patients. These results suggest that when the geniculo-striate visual pathway is lesioned, the rapid and implicit processing of threat signals can enhance facial encoding. Notably, the N170 modulation was only observed in left-lesioned patients, favoring the hypothesis that implicit subcortical processing of fearful signals can influence face encoding only when the right hemisphere is intact.
Retinotopy versus Face Selectivity in Macaque Visual Cortex
Authors: Rajimehr Reza , Bilenko Natalia Y. , Vanduffel Wim , Tootell Roger B. H.
Published: June 2014

Retinotopic organization is a ubiquitous property of lower-tier visual cortical areas in human and nonhuman primates. In macaque visual cortex, the retinotopic maps extend to higher-order areas in the ventral visual pathway, including area TEO in the inferior temporal (IT) cortex. Distinct regions within IT cortex are also selective to specific object categories such as faces. Here we tested the topographic relationship between retinotopic maps and face-selective patches in macaque visual cortex using high-resolution fMRI and retinotopic face stimuli. Distinct subregions within face-selective patches showed either (1) a coarse retinotopic map of eccentricity and polar angle, (2) a retinotopic bias to a specific location of visual field, or (3) nonretinotopic selectivity. In general, regions along the lateral convexity of IT cortex showed more overlap between retinotopic maps and face selectivity, compared with regions within the STS. Thus, face patches in macaques can be subdivided into smaller patches with distinguishable retinotopic properties.
Auditory Evoked Responses in Musicians during Passive Vowel Listening Are Modulated by Functional Connectivity between Bilateral Auditory-related Brain Regions
Authors: Kühnis Jürg , Elmer Stefan , Jäncke Lutz
Published: June 2014

Currently, there is striking evidence showing that professional musical training can substantially alter the response properties of auditory-related cortical fields. Such plastic changes have previously been shown not only to abet the processing of musical sounds, but likewise spectral and temporal aspects of speech. Therefore, here we used the EEG technique and measured a sample of musicians and nonmusicians while the participants were passively exposed to artificial vowels in the context of an oddball paradigm. Thereby, we evaluated whether increased intracerebral functional connectivity between bilateral auditory-related brain regions may promote sensory specialization in musicians, as reflected by altered cortical N1 and P2 responses. This assumption builds on the reasoning that sensory specialization is dependent, at least in part, on the amount of synchronization between the two auditory-related cortices. Results clearly revealed that auditory-evoked N1 responses were shaped by musical expertise. In addition, in line with our reasoning musicians showed an overall increased intracerebral functional connectivity (as indexed by lagged phase synchronization) in theta, alpha, and beta bands. Finally, within-group correlative analyses indicated a relationship between intracerebral beta band connectivity and cortical N1 responses, however only within the musicians' group. Taken together, we provide first electrophysiological evidence for a relationship between musical expertise, auditory-evoked brain responses, and intracerebral functional connectivity among auditory-related brain regions.
Done That: Short-term Repetition Related Modulations of Motor Cortex Activity as a Stable Signature for Overnight Motor Memory Consolidation
Authors: Gabitov Ella , Manor David , Karni Avi
Published: June 2014

An almost universally accepted tacit expectation is that learning and memory consolidation processes must be reflected in the average brain activity in brain areas relevant to task performance. Motor cortex (M1) plasticity has been implicated in motor skill acquisition and its consolidation. Nevertheless, no consistent pattern of changes in the average signal, related to motor learning or motor memory consolidation following a single session of training, has emerged from imaging studies. Here we show that the pattern and magnitude of short-term brain activity modulations in response to task repetition, in M1, may provide a robust signature for effective motor memory consolidation processes. We studied participants during the paced performance of a finger-to-thumb opposition sequence (FOS), intensively trained a day earlier, and a similarly constructed untrained FOS. In addition to within-session “on-line” gains, most participants expressed delayed, consolidation-phase gains in the performance of the trained FOS. The execution of the trained FOS induced repetition enhancements in the contralateral M1 and bilaterally in the medial-temporal lobes, offsetting novelty-related repetition suppression effects. Moreover, the M1 modulations were positively correlated with the magnitude of each participant's overnight delayed gains but not with absolute performance levels. Our results suggest that short-term enhancements of brain signals upon task repetition reflect the effectiveness of overnight motor memory consolidation. We propose that procedural memory consolidation processes may affect the excitation–inhibition balance within cortical representations of the trained movements; this new balance is better reflected in repetition effects than in the average level of evoked neural activity.
Thermoregulation during the summer season in the Goode’s horned lizard Phrynosoma goodei (Iguania: Phrynosomatidae) in Sonoran Desert
Authors: Lara-Resendiz Rafael Alejandro , Jezkova Tereza , Rosen Philip C. , Méndez-de La Cruz Fausto Roberto
Published: June 2014

Reptiles in desert environments depend on habitat thermal quality to regulate their body temperature and perform biological activities. Understanding thermoregulation with respect to habitat thermal quality is critical for accurate predictions of species responses to climate change. We evaluated thermoregulation in Goode’s horned lizard, Phrynosoma goodei, and measured habitat thermal quality at the Reserva de la Biosfera El Pinacate y Gran Desierto de Altar, Sonora, Mexico, during the hottest season of the year. We found that field-active body temperature averaged 38.1 ± 0.38°C, preferred body temperature in laboratory averaged 34.9 ± 0.18°C and preferred body temperature range was 32.5-37.3°C. Operative temperature (i.e. environmental temperature available to the lizards) averaged 43.0 ± 0.07°C, with maximum temperature being near 70°C, and 62.9% of operative temperatures were above preferred body temperature range of P. goodei. Microhabitat thermal quality occupied by the lizards was high in the morning (7:00-10:30) and afternoon (5:50-dusk). We found that despite strong thermal constraints P. goodei was highly accurate and efficient in regulating its body temperature and that it presented a bimodal thermoregulatory pattern, being active in the mornings and in the evenings in order to avoid high mid-day environmental temperatures. Despite its thermoregulatory ability, P. goodei may be vulnerable to climate warming.
First comprehensive insights into nuclear and mitochondrial DNA based population structure of Near East mountain brook newts (Salamandridae: genus Neurergus) suggest the resurrection of Neurergus derjugini
Authors: Hendrix Ralf , Fleck Jürgen , Schneider Willi , Schneider Christoph , Geller Daniel , Avci Aziz , Olgun Kurtulus , Steinfartz Sebastian
Published: June 2014

Due to their extraordinary coloration, mountain brook newts of the genus Neurergus found in the Near East have fascinated herpetologists since their initial description more than 150 years ago. Although the monophyly of Neurergus newts within the Salamandridae has been unambiguously shown for mitochondrial genes, and recent comprehensive molecular phylogenies placed Neurergus as a sister taxon of banded newts (genus Ommatotriton), we know almost nothing about the structure and relatedness of populations at the intraspecific level. In this study, we therefore analysed sequence variation of a mitochondrial DNA segment (covering a partial region of the control region and the 12S ribosomal RNA) from more than 100 individuals and of two nuclear genes (KIAA and SACS) for a representative subset of individuals originating from nine distinct populations, representing N. strauchii, N. crocatus and N. microspilotus. We also studied individuals of N. derjugini, a taxon that has long been synonymized as N. crocatus, and of which individuals have not been accessible to the scientific community since its original description in 1916. Our results suggest high genetic diversity of populations within species for the mitochondrial DNA marker, while the resolution of applied nuclear genes did not go beyond the level of species. For N. strauchii and N. crocatus, two species that inhabit the largest geographic ranges within the genus, we found a high proportion of diversity both within and between populations for the mitochondrial control region. Individuals of N. microspilotus and N. derjugini only displayed considerable genetic differentiation for one nuclear gene (SACS), while only very little or none genetic differentiation could be found for the mitochondrial control region and the KIAA gene, respectively. As both taxa are also morphologically not well differentiated, we suggest on the basis of the current dataset to taxonomically synonymize N. microspilotus due to priority reasons as N. derjugini. It can be therefore concluded that the most accurate taxonomy of the genus Neurergus should consider N. crocatus, N. strauchii, N. kaiseri and N. derjugini as valid taxonomic units at the species level.