bluuebunny/crossref_metadata_2025 huggingface dataset:
Abnormal spirometry after the Fontan procedure is common and associated with impaired aerobic capacity
Authors: Opotowsky Alexander R. , Landzberg Michael J. , Earing Michael G. , Wu Fred M. , Triedman John K. , Casey Alicia , Ericson Dawn A. , Systrom David , Paridon Stephen M. , Rhodes Jonathan
Published: May 2014

Impaired exercise capacity is common after the Fontan procedure and is attributed to cardiovascular limits. The Fontan circulation, however, is also distinctively vulnerable to unfavorable lung mechanics. This study aimed to define the prevalence and physiological relevance of pulmonary dysfunction in patients with Fontan physiology. We analyzed data from the Pediatric Heart Network Fontan Cross-Sectional Study to assess the prevalence and pattern of abnormal spirometry in Fontan patients (6–18 yr old) and investigated the relationship between low forced vital capacity (FVC) and maximum exercise variables, including peak O2consumption (V̇o2peak), among those who demonstrated adequate effort ( n = 260). Average ages at the time of exercise testing and Fontan completion were 13.2 ± 3.0 and 3.5 ± 2.2 yr old, respectively. Aerobic capacity was reduced (V̇o2peak: 67.3 ± 15.6% predicted). FVC averaged 79.0 ± 14.8% predicted, with 45.8% having a FVC less then the lower limit of normal. Only 7.8% demonstrated obstructive spirometry. Patients with low FVC had lower V̇o2peak(64.4 ± 15.9% vs. 69.7 ± 14.9% predicted, P < 0.01); low FVC independently predicted lower V̇o2peakafter adjusting for relevant covariates. Among those with V̇o2peak< 80% predicted ( n = 204/260), 22.5% demonstrated a pulmonary mechanical contribution to exercise limitation (breathing reserve < 20%). Those with both low FVC and ventilatory inefficiency (minute ventilation/CO2production > 40) had markedly reduced V̇o2peak(61.5 ± 15.3% vs. 72.0 ± 14.9% predicted, P < 0.01) and a higher prevalence of pulmonary mechanical limit compared with patients with normal FVC and efficient ventilation (36.1% vs. 4.8%). In conclusion, abnormal FVC is common in young patients after the Fontan procedure and is independently associated with reduced exercise capacity. A large subset has a pathologically low breathing reserve, consistent with a pulmonary mechanical contribution to exercise limitation.
Side-specific mechanical properties of valve endothelial cells
Authors: Miragoli Michele , Yacoub Magdi H. , El-Hamamsy Ismail , Sanchez-Alonso Jose L. , Moshkov Alexey , Mongkoldhumrongkul Napachanok , Padala Muralindar , Paramagurunathan Saravanan , Sarathchandra Padmini , Korchev Yuri E. , Gorelik Julia , Chester Adrian H.
Published: May 2014

Aortic valve endothelial cells (ECs) function in vastly different levels of shear stress. The biomechanical characteristics of cells on each side of valve have not been investigated. We assessed the morphology and mechanical properties of cultured or native valve ECs on intact porcine aortic valve cusps using a scanning ion conductance microscope (SICM). The autocrine influence of several endothelial-derived mediators on cell compliance and the expression of actin were also examined. Cells on the aortic side of the valve are characterized by a more elongated shape and were aligned along a single axis. Measurement of EC membrane compliance using the SICM showed that the cells on the aortic side of intact valves were significantly softer than those on the ventricular side. A similar pattern was seen in cultured cells. Addition of 10−6 M of the nitric oxide donor sodium nitroprusside caused a significant reduction in the compliance of ventricular ECs but had no effect on cells on the aortic side of the valve. Conversely, endothelin-1 (10−10-10−8 M) caused an increase in the compliance of aortic cells but had no effect on cells on the ventricular side of the valve. Aortic side EC compliance was also increased by 10−4 M of the nitric oxide synthase inhibitor NG-nitro-l-arginine methyl ester. Immunofluorescent staining of actin filaments revealed a great density of staining in ECs on the ventricular surface. The expression of actin and the relative membrane compliance of ECs on both side of the valve were not affected by ventricular and aortic patterns of flow. This study has shown side-specific differences in the biomechanics of aortic valve ECs. These differences can have important implications for valve function.
Dystrophin proteolysis: a potential target for MMP-2 and its prevention by ischemic preconditioning
Authors: Buchholz Bruno , Perez Virginia , Siachoque Nadezda , Miksztowicz Verónica , Berg Gabriela , Rodríguez Manuel , Donato Martín , Gelpi Ricardo J.
Published: May 2014

Dystrophin is responsible for the mechanical stabilization of the sarcolemma, and it has been shown that it is one of the most sensitive proteins to ischemic injury. However, the enzyme responsible for this proteolysis is still unknown. Isolated rabbit hearts were subjected to 30 min of global ischemia with and without reperfusion (180 min) to determine whether dystrophin is cleaved by matrix metalloproteinase (MMP)-2 during acute ischemia and whether ischemic preconditioning (PC) prevents dystrophin breakdown through MMP-2 inhibition. The activity of MMP-2 was evaluated by zymography and using doxycycline as an inhibitor. Also, to stimulate MMP-2 activity without ischemia, SIN-1 was administered in the absence and presence of doxycycline. Finally, we considered the PC effect on MMP-2 activity and dystrophin expression. The dystrophin level decreased during ischemia, reaching 21% of control values ( P < 0.05), but the spectrin level remained unchanged. MMP-2 activity increased 71% during ischemia compared with control values ( P < 0.05). Doxycycline administration before ischemia prevented dystrophin breakdown. In normoxic hearts, SIN-1 increased thiobarbituric acid-reactive substances by 33% ( P < 0.05) and MMP-2 activity by 36% ( P < 0.05) and significantly reduced the dystrophin level to 23% of control values ( P < 0.05). PC significantly prevented dystrophin breakdown by inhibiting MMP-2 activity, and the dystrophin level reached 89% of control values ( P < 0.05). In conclusion, MMP-2 could be responsible for the proteolysis of dystrophin. Thus, dystrophin emerges as a possible novel substrate for MMP-2 in the context of ischemic injury. Furthermore, our results demonstrate that ischemic PC prevents dystrophin breakdown most likely by inhibiting MMP-2 activity.
The role of dye affinity in optical measurements of Cai2+ transients in cardiac muscle
Authors: Kong Wei , Fast Vladimir G.
Published: May 2014

Previous experiments in cultures of neonatal rat myocytes demonstrated that the shape of Cai2+ transients measured using high-affinity Ca2+-sensitive dyes may be misrepresented. The purpose of this study was to examine the role of dye affinity in Cai2+ measurements in intact adult cardiac tissue by comparing optical recordings obtained with high- and low-affinity dyes. Experiments were carried out in porcine left ventricular (LV) wedge preparations stained locally by intramural injection via microcapillaries (diameter = 150 μm) with a low-affinity Ca2+-sensitive dye Fluo-4FF or Fluo-2LA (nominal Kd, ∼7–10 μmol/l), high-affinity dye Rhod-2 ( Kd = 0.57 μmol/l), and Fluo-4 or Fluo-2MA ( Kd, ∼0.4 μmol/l); in addition, tissue was stained with transmembrane potential ( Vm)-sensitive dye RH-237. Optical recordings of Vm and Cai2+ were made using optical fibers (diameter = 325 μm) glued with the microcapillaries. The durations of Cai2+ transients measured at 50% level of recovery (CaD50) using high-affinity Fluo-4/Fluo-2MA dyes were up to ∼81% longer than those measured with low-affinity Fluo-4FF/Fluo-2LA at long pacing cycle lengths (CL). In Fluo-4/Fluo-2MA measurements at long CLs, Cai2+ transients often (∼50% of cases) exhibited slow upstroke rise and extended plateau. In Rhod-2 measurements, CaD50 was moderately longer (up to ∼35%) than in Fluo-4FF recordings, but Cai2+ transient shapes were similar. In all series of measurements, mean action potential duration values were not significantly different ( P > 0.05). The delays between Vm and Cai2+ upstrokes were comparable for low- and high-affinity dyes ( P > 0.05). In conclusion, measurements of Cai2+ transient in ventricular myocardium are strongly affected by the affinity of Ca2+ dyes. The high-affinity dyes may overestimate the duration and alter the shape of Cai2+ transients.
Henry Cavendish (1731–1810): hydrogen, carbon dioxide, water, and weighing the world
Authors: West John B.
Published: May 2014

Henry Cavendish (1731–1810) was an outstanding chemist and physicist. Although he was not a major figure in the history of respiratory physiology he made important discoveries concerning hydrogen, carbon dioxide, atmospheric air, and water. Hydrogen had been prepared earlier by Boyle but its properties had not been recognized; Cavendish described these in detail, including the density of the gas. Carbon dioxide had also previously been studied by Black, but Cavendish clarified its properties and measured its density. He was the first person to accurately analyze atmospheric air and reported an oxygen concentration very close to the currently accepted value. When he removed all the oxygen and nitrogen from an air sample, he found that there was a residual portion of about 0.8% that he could not characterize. Later this was shown to be argon. He produced large amounts of water by burning hydrogen in oxygen and recognized that these were its only constituents. Cavendish also worked on electricity and heat. However, his main contribution outside chemistry was an audacious experiment to measure the density of the earth, which he referred to as “weighing the world.” This involved determining the gravitational attraction between lead spheres in a specially constructed building. Although this was a simple experiment in principle, there were numerous complexities that he overcame with meticulous attention to experimental details. His result was very close to the modern accepted value. The Cavendish Experiment, as it is called, assures his place in the history of science.
Temsirolimus induces surfactant lipid accumulation and lung inflammation in mice
Authors: Washino Satoshi , Ando Hitoshi , Ushijima Kentarou , Hosohata Keiko , Kumazaki Masafumi , Mato Naoko , Sugiyama Yukihiko , Kobayashi Yutaka , Fujimura Akio , Morita Tatsuo
Published: May 2014

Interstitial lung disease (ILD) is a well-known adverse effect of mammalian target of rapamycin (mTOR) inhibitors. However, it remains unknown how lung toxicities are induced by mTOR inhibitors. Here, we constructed a mouse model of mTOR inhibitor-induced ILD using temsirolimus and examined the pathogenesis of the disease. Male ICR mice were treated with an intraperitoneal injection of different doses of temsirolimus (3 or 30 mg·kg−1·wk−1) or vehicle. Temsirolimus treatment increased capillary-alveolar permeability and induced neutrophil infiltration and fibrinous exudate into the alveolar space, indicating alveolar epithelial and/or endothelial injury. It also induced macrophage depletion and the accumulation of excessive surfactant phospholipids and cholesterols. Alveolar macrophage depletion is thought to cause surfactant lipid accumulation. To further examine whether temsirolimus has cytotoxic and/or cytostatic effects on alveolar macrophages and alveolar epithelial cells, we performed in vitro experiments. Temsirolimus inhibited cell proliferation and viability in both alveolar macrophage and alveolar epithelial cells. Temsirolimus treatment caused some signs of pulmonary inflammation, including upregulated expression of several proinflammatory cytokines in both bronchoalveolar lavage cells and lung homogenates, and an increase in lymphocytes in the bronchoalveolar lavage fluid. These findings indicate that temsirolimus has the potential to induce alveolar epithelial injury and to deplete alveolar macrophages followed by surfactant lipid accumulation, resulting in pulmonary inflammation. This is the first study to focus on the pathogenesis of mTOR inhibitor-induced ILD using an animal model.
Hypoxia-induced mitogenic factor (FIZZ1/RELMα) induces endothelial cell apoptosis and subsequent interleukin-4-dependent pulmonary hypertension
Authors: Yamaji-Kegan Kazuyo , Takimoto Eiki , Zhang Ailan , Weiner Noah C. , Meuchel Lucas W. , Berger Alan E. , Cheadle Chris , Johns Roger A.
Published: May 2014

Pulmonary hypertension (PH) is characterized by elevated pulmonary artery pressure that leads to progressive right heart failure and ultimately death. Injury to endothelium and consequent wound repair cascades have been suggested to trigger pulmonary vascular remodeling, such as that observed during PH. The relationship between injury to endothelium and disease pathogenesis in this disorder remains poorly understood. We and others have shown that, in mice, hypoxia-induced mitogenic factor (HIMF, also known as FIZZ1 or RELMα) plays a critical role in the pathogenesis of lung inflammation and the development of PH. In this study, we dissected the mechanism by which HIMF and its human homolog resistin (hRETN) induce pulmonary endothelial cell (EC) apoptosis and subsequent lung inflammation-mediated PH, which exhibits many of the hallmarks of the human disease. Systemic administration of HIMF caused increases in EC apoptosis and interleukin (IL)-4-dependent vascular inflammatory marker expression in mouse lung during the early inflammation phase. In vitro, HIMF, hRETN, and IL-4 activated pulmonary microvascular ECs (PMVECs) by increasing angiopoietin-2 expression and induced PMVEC apoptosis. In addition, the conditioned medium from hRETN-treated ECs had elevated levels of endothelin-1 and caused significant increases in pulmonary vascular smooth muscle cell proliferation. Last, HIMF treatment caused development of PH that was characterized by pulmonary vascular remodeling and right heart failure in wild-type mice but not in IL-4 knockout mice. These data suggest that HIMF contributes to activation of vascular inflammation at least in part by inducing EC apoptosis in the lung. These events lead to subsequent PH.
An 11-nt sequence polymorphism at the 3′UTR of human SFTPA1 and SFTPA2 gene variants differentially affect gene expression levels and miRNA regulation in cell culture
Authors: Silveyra Patricia , DiAngelo Susan L. , Floros Joanna
Published: May 2014

Surfactant protein A (SP-A) plays a vital role in maintaining normal lung function and in host defense. Two genes encode SP-A in humans (SFTPA1, SFTPA2), and several gene variants have been identified for these. We have previously shown that sequence elements of SFTPA1 and SFTPA2 3′ untranslated regions (UTRs) differentially affect translation efficiency in vitro. Polymorphisms at the 3′UTRs of mRNA variants may account for differential binding of miRNAs, a class of small noncoding RNAs that regulate gene expression. In this work, we generated 3′UTR reporter constructs of the SFTPA1 and SFTPA2 variants most frequently found in the population, as well as mutants of a previously described 11-nt indel element (refSNP rs368700152). Reporter constructs were transfected in NCI-H441 cells in the presence or absence of miRNA mimics, and reporter gene expression was analyzed. We found that human miRNA mir-767 negatively affected expression of constructs containing SFTPA1 and SFTPA2 variants, whereas mir-4507 affected only constructs with 3′UTRs of SFTPA1 variants 6A, 6A3, and 6A4(not containing the 11-nt element). Three miRNAs (mir-183, mir-449b, and mir-612) inhibited expression of recombinants of SFTPA2 variants and the SFTPA1 variant 6A2, all containing the 11-nt element. Similar results were obtained for SP-A expression when these miRNAs were transfected in Chinese hamster ovary cells expressing SFTPA1 or SFTPA2 variants or in NCI-H441 cells (genotype 1A5/1A5-6A4/6A4). Moreover, transfection with a specific antagomir (antagomir-183) reversed the effects of mir-183 on SP-A mRNA levels. Our results indicate that sequence variability at the 3′UTR of SP-A variants differentially affects miRNA regulation of gene expression.
Class𝔄-KKM(X,Y,Z), GeneralKKMType Theorems, and Their Applications in Topological Vector Space
Authors: Tang Gusheng , Zhang Qingbang
Published: May 2014

The class𝔄-KKM(X,Y,Z)and generalizedKKMmapping are introduced, and some generalizedKKMtheorems are proved. As applications, Ky Fan’s matching theorem and Fan-Browder fixed-point theorem are extended, and some existence theorems of solutions for the generalized vector equilibrium problems are established under noncompact setting, which improve and generalize some known results.
Edible Polymers: Challenges and Opportunities
Authors: Shit Subhas C. , Shah Pathik M.
Published: May 2014

Edible polymers have established substantial deliberation in modern eons because of their benefits comprising use as edible materials over synthetic polymers. This could contribute to the reduction of environmental contamination. Edible polymers can practically diminish the complexity and thus improve the recyclability of materials, compared to the more traditional non-environmentally friendly materials and may be able to substitute such synthetic polymers. A synthetic hydrogel polymer unlocked a new possibility for development of films, coatings, extrudable pellets, and synthetic nanopolymers, particularly designed for medical, agricultural, and industrial fields. Edible polymers offer many advantages for delivering drugs and tissue engineering. Edible polymer technology helps food industries to make their products more attractive and safe to use. Novel edible materials have been derived from many natural sources that have conventionally been regarded as discarded materials. The objective of this review is to provide a comprehensive introduction to edible polymers by providing descriptions in terms of their origin, properties, and potential uses.
An Efficient Particle Swarm Optimizer with Application to Man‐Day Project Scheduling Problems
Authors: Chen Ruey-Maw , Sandnes Frode Eika
Published: May 2014

The multimode resource‐constrained project scheduling problem (MRCPSP) has been confirmed to be an NP‐hard problem. Particle swarm optimization (PSO) has been efficiently applied to the search for near optimal solutions to various NP‐hard problems. MRCPSP involves solving two subproblems: mode assignment and activity priority determination. Hence, two PSOs are applied to each subproblem. A constriction PSO is proposed for the activity priority determination while a discrete PSO is employed for mode assignment. A least total resource usage (LTRU) heuristic and minimum slack (MSLK) heuristic ensure better initial solutions. To ensure a diverse initial collection of solutions and thereby enhancing the PSO efficiency, a best heuristic rate (HR) is suggested. Moreover, a new communication topology with random links is also introduced to prevent slow and premature convergence. To verify the performance of the approach, the MRCPSP benchmarks in PSPLIB were evaluated and the results compared to other state‐of‐the‐art algorithms. The results demonstrate that the proposed algorithm outperforms other algorithms for the MRCPSP problems. Finally, a real‐world man‐day project scheduling problem (MDPSP)—a MRCPSP problem—was evaluated and the results demonstrate that MDPSP can be solved successfully.
Recursive Elucidation of Polynomial Congruences Using Root-Finding Numerical Techniques
Authors: Mahmood M. Khalid , Ahmad Farooq
Published: May 2014

In this paper we put forward a family of algorithms for lifting solutions of a polynomial congruencemod pto polynomial congruencemod pk. For this purpose, root-finding iterative methods are employed for solving polynomial congruences of the formaxn≡b(mod pk),k≥1,wherea,b,andn>0are integers which are not divisible by an odd primep. It is shown that the algorithms suggested in this paper drastically reduce the complexity for such computations to a logarithmic scale. The efficacy of the proposed technique for solving negative exponent equations of the formax-n≡b(mod pk)has also been addressed.
Acoustic Radiation Force Impulse Elastography for Efficacy Evaluation after Hepatocellular Carcinoma Radiofrequency Ablation: A Comparative Study with Contrast-Enhanced Ultrasound
Authors: Xu Xiaohong , Luo Liangping , Chen Jiexin , Wang Jiexin , Zhou Honglian , Li Mingyi , Jin Zhanqiang , Chen Nianping , Miao Huilai , Lin Manzhou , Dai Wei , Ahuja Anil T. , Wang Yi-Xiang J.
Published: May 2014

Aim. To explore acoustic radiation force impulse (ARFI) elastography in assessing residual tumors of hepatocellular carcinoma (HCC) after radiofrequency ablation (RFA).Materials and Methods. There were 83 HCC lesions among 72 patients. All patients were examined with ARFI, contrast enhanced ultrasound (CEUS), and CT or MRI. Tumor brightness on virtual touch tissue imaging (VTI) and shear wave velocity (SWV) were assessed before and approximately one month after RFA.Results. There were 14 residual tumors after RFA. VTI showed that all the tumors were darker after RFA. VTI was not able to distinguish the ablated lesions and the residual tumors. 13 residual tumor lesions were detected by CEUS. All completely ablated nodules had SWV demonstration of x.xx., while with those residual nodules, 6 tumors had x.xx measurement and 8 tumors had measurable SWV. nine lesions with residual tumors occurred in cirrhosis subjects and 5 lesions with residual tumors occurred in fibrosis subjects; there was no residual tumor in the normal liver subjects.Conclusion. VTI technique cannot demonstrate residual tumor post RFA. While SWV measurement of less than x.xx is likely associated with residual tumors, measurement of less than x.xx cannot exclude residual tumors. Liver cirrhosis is associated with decreased chance of a complete ablation.
Molecular Pathways: CDK4 Inhibitors for Cancer Therapy
Authors: Dickson Mark A.
Published: May 2014

Unrestrained growth is the hallmark of cancer, and disrupted cell-cycle regulation is, therefore, common. CDK4 is the key regulator of the G1–S transition. In complex with cyclin D, CDK4 phosphorylates retinoblastoma protein (Rb) and drives cell-cycle progression, a process inhibited by p16. The p16–CDK4–cyclin D–Rb is aberrant in the majority of cancers and is, thus, a logical target for anticancer therapy. Previous attempts to block CDK4 with nonselective cyclin-dependent kinase (CDK) inhibitors led to toxicity and little efficacy. However, the recent development of selective CDK4 inhibitors launched the first successful efforts to target the pathway for cancer therapy. Three oral selective CDK4 inhibitors have entered clinical trials: palbociclib (PD0332991), LEE011, and LY2835219. CDK4 inhibitors have in vitro activity against a broad range of cancers and in patients have shown antitumor activity in breast cancer, lymphoma, sarcoma, and other tumors. Major efforts are under way to develop biomarkers of response, understand potential mechanisms of resistance, and develop rational combinations of CDK4 inhibitors with chemotherapy and other targeted drugs. Clin Cancer Res; 20(13); 3379–83. ©2014 AACR.
Chemoprevention of Urothelial Cell Carcinoma Growth and Invasion by the Dual COX–LOX Inhibitor Licofelone in UPII-SV40T Transgenic Mice
Authors: Madka Venkateshwar , Mohammed Altaf , Li Qian , Zhang Yuting , Patlolla Jagan M.R. , Biddick Laura , Lightfoot Stan , Wu Xue-Ru , Steele Vernon , Kopelovich Levy , Rao Chinthalapally V.
Published: May 2014

Epidemiologic and clinical data suggest that use of anti-inflammatory agents is associated with reduced risk for bladder cancer. We determined the chemopreventive efficacy of licofelone, a dual COX–lipoxygenase (LOX) inhibitor, in a transgenic UPII-SV40T mouse model of urothelial transitional cell carcinoma (TCC). After genotyping, six-week-old UPII-SV40T mice (n = 30/group) were fed control (AIN-76A) or experimental diets containing 150 or 300 ppm licofelone for 34 weeks. At 40 weeks of age, all mice were euthanized, and urinary bladders were collected to determine urothelial tumor weights and to evaluate histopathology. Results showed that bladders of the transgenic mice fed control diet weighed 3 to 5-fold more than did those of the wild-type mice due to urothelial tumor growth. However, treatment of transgenic mice with licofelone led to a significant, dose-dependent inhibition of the urothelial tumor growth (by 68.6%–80.2%, P < 0.0001 in males; by 36.9%–55.3%, P < 0.0001 in females) compared with the control group. The licofelone diet led to the development of significantly fewer invasive tumors in these transgenic mice. Urothelial tumor progression to invasive TCC was inhibited in both male (up to 50%; P < 0.01) and female mice (41%–44%; P < 0.003). Urothelial tumors of the licofelone-fed mice showed an increase in apoptosis (p53, p21, Bax, and caspase3) with a decrease in proliferation, inflammation, and angiogenesis markers (proliferating cell nuclear antigen, COX-2, 5-LOX, prostaglandin E synthase 1, FLAP, and VEGF). These results suggest that licofelone can serve as potential chemopreventive for bladder TCC. Cancer Prev Res; 7(7); 708–16. ©2014 AACR.
Rare Mutations in RINT1 Predispose Carriers to Breast and Lynch Syndrome–Spectrum Cancers
Authors: Park Daniel J. , Tao Kayoko , Le Calvez-Kelm Florence , Nguyen-Dumont Tu , Robinot Nivonirina , Hammet Fleur , Odefrey Fabrice , Tsimiklis Helen , Teo Zhi L. , Thingholm Louise B. , Young Erin L. , Voegele Catherine , Lonie Andrew , Pope Bernard J. , Roane Terrell C. , Bell Russell , Hu Hao , Shankaracharya  , Huff Chad D. , Ellis Jonathan , Li Jun , Makunin Igor V. , John Esther M. , Andrulis Irene L. , Terry Mary B. , Daly Mary , Buys Saundra S. , Snyder Carrie , Lynch Henry T. , Devilee Peter , Giles Graham G. , Hopper John L. , Feng Bing-Jian , Lesueur Fabienne , Tavtigian Sean V. , Southey Melissa C. , Goldgar David E.
Published: May 2014

Approximately half of the familial aggregation of breast cancer remains unexplained. A multiple-case breast cancer family exome-sequencing study identified three likely pathogenic mutations in RINT1 (NM_021930.4) not present in public sequencing databases: RINT1 c.343C>T (p.Q115X), c.1132_1134del (p.M378del), and c.1207G>T (p.D403Y). On the basis of this finding, a population-based case–control mutation-screening study was conducted that identified 29 carriers of rare (minor allele frequency < 0.5%), likely pathogenic variants: 23 in 1,313 early-onset breast cancer cases and six in 1,123 frequency-matched controls [OR, 3.24; 95% confidence interval (CI), 1.29–8.17; P = 0.013]. RINT1 mutation screening of probands from 798 multiple-case breast cancer families identified four additional carriers of rare genetic variants. Analysis of the incidence of first primary cancers in families of women carrying RINT1 mutations estimated that carriers were at increased risk of Lynch syndrome–spectrum cancers [standardized incidence ratio (SIR), 3.35; 95% CI, 1.7–6.0; P = 0.005], particularly for relatives diagnosed with cancer under the age of 60 years (SIR, 10.9; 95% CI, 4.7–21; P = 0.0003).

Significance: The work described in this study adds RINT1 to the growing list of genes in which rare sequence variants are associated with intermediate levels of breast cancer risk. Given that RINT1 is also associated with a spectrum of cancers with mismatch repair defects, these findings have clinical applications and raise interesting biological questions. Cancer Discov; 4(7); 804–15. ©2014 AACR.

See related commentary by Ngeow and Eng, p. 762

This article is highlighted in the In This Issue feature, p. 745
Ventricular Arrhythmias Arising From the Left Ventricular Outflow Tract Below the Aortic Sinus Cusps
Authors: Ouyang Feifan , Mathew Shibu , Wu Shulin , Kamioka Masashi , Metzner Andreas , Xue Yumei , Ju Weizhu , Yang Bing , Zhan Xianzhang , Rillig Andreas , Lin Tina , Rausch Peter , Deiß Sebastian , Lemes Christine , Tönnis Tobias , Wissner Erik , Tilz Roland Richard , Kuck Karl-Heinz , Chen Minglong
Published: May 2014

Background—

Ventricular arrhythmias (VAs) originating from the anterosuperior left ventricular outflow tract (LVOT) represent a challenging location for catheter ablation. This study investigates mapping and ablation of VA from anterosuperior LVOT via a transseptal approach.

Methods and Results—

This study included 27 patients with symptomatic VA, of which 13 patients had previous failed ablations. LVOT endocardial 3-dimensional mapping via retrograde transaortic and antegrade transseptal approaches was performed. Previous ECG markers for procedure failure were analyzed. In all patients, earliest activation with low-amplitude potentials was identified at the anterosuperior LVOT 5.1±2.8 mm below the aortic cusp and preceded the QRS onset by 39.5±7.7 ms only via an antegrade transseptal approach using a reversed S curve. In all patients, pace mapping failed to demonstrate perfect QRS morphology match. The anatomic location was below the left coronary cusp in 16, below the left coronary cusp/right coronary cusp junction in 8, and below the right coronary cusp in 3 patients. Radiofrequency energy resulted in rapid disappearance of VAs in all patients. ECG analysis showed aVL/aVR Q-wave amplitude ratio >1.4 in 7, lead III/II R-wave amplitude ratio >1.1 in 10, and peak deflection index >0.6 in 11 patients. There were no complications or clinical VA recurrence during a mean follow-up of 8.4±2.5 months.

Conclusions—

The anterosuperior LVOT can be reached via a transseptal approach with a reversed S curve of the ablation catheter. The rapid effect from radiofrequency energy indicates that the VA is most likely located under the endocardium. Also, previous ECG markers for procedure failure need further investigation.
A Mutation Causing Brugada Syndrome Identifies a Mechanism for Altered Autonomic and Oxidant Regulation of Cardiac Sodium Currents
Authors: Aiba Takeshi , Farinelli Federica , Kostecki Geran , Hesketh Geoffrey G. , Edwards David , Biswas Subrata , Tung Leslie , Tomaselli Gordon F.
Published: May 2014

Background—

The mechanisms of the electrocardiographic changes and arrhythmias in Brugada syndrome (BrS) remain controversial. Mutations in the sodium channel gene,
SCN5A
, and regulatory proteins that reduce or eliminate sodium current (
I
Na
) have been linked to BrS. We studied the properties of a BrS-associated
SCN5A
mutation in a protein kinase A (PKA) consensus phosphorylation site, R526H.

Methods and Results—

In vitro PKA phosphorylation was detected in the I-II linker peptide of wild-type (WT) channels but not R526H or S528A (phosphorylation site) mutants. Cell surface expression of R526H and S528A channels was reduced compared with WT. Whole-cell
I
Na
through all channel variants revealed no significant differences in the steady-state activation, inactivation, and recovery from inactivation. Peak current densities of the mutants were significantly reduced compared with WT. Infection of 2D cultures of neonatal rat ventricular myocytes with WT and mutant channels increased conduction velocity compared with noninfected cells. PKA stimulation significantly increased peak
I
Na
and conduction velocity of WT but not mutant channels. Oxidant stress inhibits cardiac
I
Na
; WT and mutant
I
Na
decreases with the intracellular application of reduced nicotinamide adenine dinucleotide (NADH), an effect that is reversed by PKA stimulation in WT but not in R526H or S528A channels.

Conclusions—

We identified a family with BrS and an
SCN5A
mutation in a PKA consensus phosphorylation site. The BrS mutation R526H is associated with a reduction in the basal level of
I
Na
and a failure of PKA stimulation to augment the current that may contribute to the predisposition to arrhythmias in patients with BrS, independent of the precipitants.
Gestational Age at Birth and Outcomes After Neonatal Cardiac Surgery
Authors: Costello John M. , Pasquali Sara K. , Jacobs Jeffrey P. , He Xia , Hill Kevin D. , Cooper David S. , Backer Carl L. , Jacobs Marshall L.
Published: May 2014

Background—

Gestational age at birth is a potentially important modifiable risk factor in neonates with congenital heart disease. We evaluated the relationship between gestational age and outcomes in a multicenter cohort of neonates undergoing cardiac surgery, focusing on those born at early term (ie, 37–38 weeks’ gestation).

Methods and Results—

Neonates in the Society of Thoracic Surgeons Congenital Heart Surgery Database who underwent cardiac surgery between 2010 and 2011 were included. Multivariable logistic regression was used to evaluate the association of gestational age at birth with in-hospital mortality, postoperative length of stay, and complications, adjusting for other important patient characteristics. Of 4784 included neonates (92 hospitals), 48% were born before 39 weeks’ gestation, including 31% at 37 to 38 weeks. Compared with a 39.5-week gestational age reference level, birth at 37 weeks’ gestational age was associated with higher in-hospital mortality, with an adjusted odds ratio (95% confidence interval) of 1.34 (1.05–1.71;
P
=0.02). Complication rates were higher and postoperative length of stay was significantly prolonged for those born at 37 and 38 weeks’ gestation (adjusted
P
<0.01 for all). Late-preterm births (34–36 weeks’ gestation) also had greater mortality and postoperative length of stay (adjusted
P
≤0.003 for all).

Conclusions—

Birth during the early term period of 37 to 38 weeks’ gestation is associated with worse outcomes after neonatal cardiac surgery. These data challenge the commonly held perception that delivery at any time during term gestation is equally safe and appropriate and question the related practice of elective delivery of fetuses with complex congenital heart disease at early term.
Impact of Farnesylation Inhibitors on Survival in Hutchinson-Gilford Progeria Syndrome
Authors: Gordon Leslie B. , Massaro Joe , D’Agostino Ralph B. , Campbell Susan E. , Brazier Joan , Brown W. Ted , Kleinman Monica E. , Kieran Mark W.
Published: May 2014

Background—

Hutchinson-Gilford progeria syndrome is an ultrarare segmental premature aging disease resulting in early death from heart attack or stroke. There is no approved treatment, but starting in 2007, several recent single-arm clinical trials administered inhibitors of protein farnesylation aimed at reducing toxicity of the disease-producing protein progerin. No study assessed whether treatments influence patient survival. The key elements necessary for this analysis are a robust natural history of survival and comparison with a sufficiently large patient population that has been treated for a sufficient time period with disease-targeting medications.

Methods and Results—

We generated Kaplan–Meier survival analyses for the largest untreated Hutchinson-Gilford progeria syndrome cohort to date. Mean survival was 14.6 years. Comparing survival for treated versus age- and sex-matched untreated cohorts, hazard ratio was 0.13 (95% confidence interval, 0.04–0.37;
P
<0.001) with median follow-up of 5.3 years from time of treatment initiation. There were 21 of 43 deaths in untreated versus 5 of 43 deaths among treated subjects. Treatment increased mean survival by 1.6 years.

Conclusions—

This study provides a robust untreated disease survival profile that can be used for comparisons now and in the future to assess changes in survival with treatments for Hutchinson-Gilford progeria syndrome. The current comparisons estimating increased survival with protein farnesylation inhibitors provide the first evidence of treatments influencing survival for this fatal disease.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique Indentifiers: NCT00425607, NCT00879034, and NCT00916747.
The Drunkard's Directions: Mapping Urban Space in the Antebellum Temperance Drama
Authors: D'Alessandro Michael
Published: May 2014

William H. Smith's The Drunkard (premiering in 1844) broke attendance records at Moses Kimball's Boston Museum and P. T. Barnum's American Museum in New York. Portraying the ills of intemperance, the melodrama also foregrounded thrilling scenes of local urbanity to inspire middle-class tourists to navigate convoluted and potentially dangerous city streets.
New data on Salix anatolica (Salicaceae) endemic to Turkey
Authors: TERZİOĞLU SALİH , SERDAR BEDRİ , KARAKÖSE MUSTAFA , COŞKUNÇELEBİ KAMİL , GÜLTEPE MUTLU
Published: May 2014

The endemic Anatolian willow, Salix anatolica (Salicaceae), was described based on solely female individuals in 2008. It was re-collected and the description was emended based on both male and female flower properties in the present study. Additionally, the pollen morphology, wood anatomical features and conservation status of S. anatolica are presented for the first time.
Health-Related Quality of Life in Coronary Heart Disease in Korea
Authors: Lee Hyung Tak , Shin Jinho , Lim Young-Hyo , Kim Kyung Soo , Kim Soon Gil , Kim Jeong Hyun , Lim Heon Kil
Published: May 2014

Using data from 2007 to 2011 of the Korea National Health and Nutrition Examination Survey, we evaluated the influence of coronary heart disease (CHD) on health-related quality of life (HRQoL) as measured by the EQ-5D in comparison with the general population and the predictors of HRQoL in CHD. Compared with the general population, HRQoL was impaired in the EQ-5D dimensions of mobility, usual activities, pain/discomfort, and anxiety/depression. The impairment of HRQoL was much greater in the older age group and in females. In subjects with CHD, the predictors for a low EQ-5D index were old age, female sex, low education, stroke, and noncardiovascular comorbidities, and the predictors for a low EQ Visual Analogue Scale were low income and noncardiovascular comorbidities. For the improvement in HRQoL, preventing stroke and noncardiovascular comorbidities is important, especially among female and older Asian patients with CHD.
Understanding the episodic everyday of disrupted lives: Scoping the occupational therapy literature
Authors: Milbourn Benjamin T. , McNamara Beverley A. , Buchanan Angus J.
Published: May 2014

Background.

The concept “everyday” appears unchallenged and problematic when applied to people who experience disrupted lives through illness or disability.

Purpose.

This study draws upon social and philosophical theory to review the relevance of the concept “everyday” when applied to contemporary occupational therapy and the lives of individuals who experience biographical disruption.

Method.

A literature review guided by a scoping framework was undertaken followed by a critical analysis drawing on Bauman to determine the frequency and meaning of the concept “everyday” used in the occupational therapy and occupational science literature.

Findings.

Definitions of the “everyday” are used infrequently despite recurrent use of the concept. A large proportion of literature reviewed in this manuscript does not acknowledge or discuss the philosophical and sociological influences that contribute to an understanding of the “everyday,” leaving the reader to make her or his own interpretations.

Implications.

Reconceptualizing lived “everyday” experience within the contextual “here and now” provides a postmodern “episodic” lens for occupational therapists working with individuals who experience biographical disruption.
Language and identities in US communities of Italian origin
Authors: De Fina Anna
Published: May 2014

In this article I discuss relationships between language use and identity among Italian Americans. I argue that the study of identities needs to abandon essentialist stances that are particularly common in research on Italian Americans, and approach identity construction as a process that takes place within concrete social practices enacted by specific communities. I provide a brief overview of the linguistic development of Italian Americans in the USA in order to provide a frame of reference to the discussion of the links between language use and identities. I then focus in particular on the following phenomena: symbolic uses of individual Italian words or expressions within talk in English, engagement with the heritage language in Italian-American families and storytelling, to illustrate how Italianness is constructed through those practices in different communities. I use these examples also to problematize the idea that knowledge of the heritage language is central to ethnic identification.
The Italian new wave: Identity work and socialization practices in a community of new Italian immigrants in America
Authors: Fellin Luciana
Published: May 2014

The majority of works on language in Italian immigrant communities in the USA concern immigrants of the 19th and 20th century migratory waves and their descendants. There is, however, a lack of studies focusing on the most recent influx of Italians who have migrated to the USA in the last 30 years. They have arrived in smaller numbers, yet in a constant stream and are adding to the ranks of the new generations of Italian Americans. The context of emigration of the two groups is notably different, as is their sociolinguistic background and their linguistic practices in the new context of arrival. The ‘new wave’ of Italians is intersecting with American society at large and with the Italian American community that preceded them, with which there is a complex relationship. This article focuses on this new wave of Italians, centering, in particular, on the symbolic practices enacted by a group of families who have recently immigrated to the USA, dealing with the language socialization of their American-born children. Drawing from interviews and ethnographic observation, it highlights new immigrants’ approach to language maintenance and transmission, and their symbolic practices relied on for identity performance. Identity is viewed through a constructivist lens, as negotiated and performed in interaction (Bucholtz and Hall, 2005, 2008), and language maintenance strategies are analyzed through the perspective of language socialization (Ochs, 1993, 1998; Scheiffelin, 1990). This study expands the discussion on Italian immigrant identity in the USA to include its most recent arrivals and simultaneously broadens the scope of Italian diasporic studies.
Rice husk flour biocomposites based on recycled high-density polyethylene/polyethylene terephthalate blend: effect of high filler loading on physical, mechanical and thermal properties
Authors: Chen Ruey Shan , Ab Ghani Mohd Hafizuddin , Ahmad Sahrim , Salleh Mohd Nazry , Tarawneh Mou’ad A
Published: May 2014

Biocomposites of recycled high-density polyethylene (rHDPE)/recycled polyethylene terephthalate (rPET) matrices with a high loading of rice husk flour (RHF) were fabricated through a two-step extrusion. The use of ethylene-glycidyl methacrylate (E-GMA) copolymer improved the compatibility of the immiscible rHDPE/rPET blend. Maleic anhydride polyethylene (MAPE) was used as a coupling agent to increase the adhesion of the fibre–matrix interface. In this study, the effect of natural fibre loadings on rHDPE/rPET blends was examined. The water absorption process in the RHF-filled composites followed the kinetics and mechanisms of Fickian diffusion. Compared with samples without RHF, the rHDPE/rPET/RHF system had 58–172% higher tensile modulus and 80–305% flexural modulus. The thermal stability of the composites slightly increased with the addition of the RHF filler. The storage modulus of biocomposites was greatly enhanced by RHF. From these results, we can conclude that RHF can work well with rHDPE/rPET for manufacturing high loading biocomposite products.
Core-thickness effect on the impact response of sandwich composites with poly(vinyl chloride) and poly(ethylene terephthalate) foam cores
Authors: Ozdemir Okan , Karakuzu Ramazan , Al-Shamary Aidel Kadum Jassim
Published: May 2014

The objective of this study was to investigate the effects of core material and its thickness on impact behavior of sandwich composite plates subjected to low-velocity impact, experimentally. Poly(vinyl chloride) (PVC) and poly(ethylene terephthalate) (PET) foams were selected as the core material, having approximate density of 65 kg/m3 and 60 kg/m3, respectively, and thicknesses of 5, 10, and 15 mm. The stacking sequence of the sandwich composites is [Formula: see text] Impact tests were carried out by using Ceast 9350 Fractovis Plus impact testing machine under room temperature. Various impact energies were selected ranging from 10 J to 70 J to analyze the impact energy level. The dimensions of the specimens are 100 mm × 100 mm. After the impact tests, contact-force deflection curves and also maximum contact force, maximum contact time, and maximum deflection versus impact energy curves were obtained for mentioned impact energies for sandwich composites with PVC and PET foams and [Formula: see text]-laminated composites. As a result, it is seen that the core material and its thickness have notable effects on the impact behavior of sandwich composite plates. Sandwich composites also have higher absorbed energy, penetration, and perforation thresholds.
Beliefs of Vocational Rehabilitation Counselors About Competitive Employment for People With Severe Mental Illness in Belgium
Authors: Knaeps Jeroen , Neyens Inge , Donceel Peter , van Weeghel Jaap , Van Audenhove Chantal
Published: May 2014

Vocational rehabilitation (VR) counselors do not always focus on competitive employment for people with severe mental illness (SMI). Based on the Theory of Planned Behavior (TPB), this study examines how three types of VR counselors (i.e., gatekeepers, case managers, and specialists) vary in their underlying beliefs about competitive employment. VR counselors ( N = 286) from Belgium completed an online TPB survey measuring behavioral, normative, control, and self-efficacy beliefs. Differences in beliefs were analyzed by one-way ANOVAs and post hoc comparisons using Bonferroni correction. Results indicate that counselors differ in their beliefs regarding competitive employment for people with SMI. Specialized counselors are stronger convinced that competitive employment results in latent benefits (e.g., increased integration and self-confidence). In contrast, gatekeepers consider income as the most recurrent and positive effect. The more specialized VR counselors are, the more often they perceive significant others valuing competitive employment and the more often they may comply with these norms. Finally, specialized counselors experience fewer barriers, more control, and more self-efficacy in dealing with problems compared with less specialized counselors. The differences in beliefs determining the focus on competitive employment may result in a lack of an integrated approach. Training, outcome feedback, and intersectoral communication can enhance consistency between different VR services.
Human Trafficking in Malaysia
Authors: Wan Ismail Wan Nur Ibtisam , Raja Ariffin Raja Noriza , Cheong Kee Cheok
Published: May 2014

Recent studies have suggested that migrants are highly vulnerable to being trafficked. Malaysia, with its large number of migrants is vulnerable and is struggling to implement its Anti-Trafficking in Persons and Anti-Smuggling of Migrants Act 2007. There is also little information on implementation experience so far. Through in-depth interviews with government bureaucrats and other stakeholders, this study seeks to gain some insight into Malaysia’s policy implementation experience. It finds inadequate coordination, limited resources, poor information flow, enforcement approach, hierarchical control structure, and need for change as the major factors constraining effective policy implementation.