bluuebunny/crossref_metadata_2025 huggingface dataset:
Adductor Tenotomy Combined with Palmar Capsulodesis for Spastic Thumb-in-Palm Deformity in Cerebral Palsy: Description of a Surgical Technique and Clinical Results
Authors: Luis-Alejandro García , Bárbara Gómez
Published: August 2017

Background: Spastic thumb deformity in cerebral palsy significantly impedes hand function. Flexion-adduction forces across the first ray is the result from imbalance between intrinsic and extrinsic muscles. Multiples surgeries have been devised for the treatment of this condition such as contracture release and by tendon transfers for balancing the muscles forces. We report the results of a less demanding surgical technique, intended to avoid hyperextension of the metacarpophalangeal joint previously described in other series.

Methods: Five patients with cerebral palsy who underwent a surgical correction for their thumb-in-palm deformity between January 2013 and August 2014 were included. All patients were assessed postoperatively with a minimum follow up of six months. Three criteria were chosen to evaluate functional ability: capacity to perform pinch, volitional muscle control and usefulness of the hand in daily life activities.

Results: Patients who had surgery for spastic thumb deformity were reviewed. The thumb was maintained out of the palm in all patients. Three patients were able to perform correct pinch, achieved volitional muscle control and a more functional hand. One patient had limitation to achieve one of the evaluated daily life activities and one patient lacked active thumb movement for pinch, motor control and achieved no daily life activities. No postoperative complications were recorded.

Conclusions: We present a less challenging technique that should be taken into account for the treatment of thumb-in-palm deformity. Appearance and functional improvement can be achieved with this surgical procedure avoiding disadvantages of secondary deformities.
Can Physical Examination Create a Stener Lesion?
Authors: Lankachandra Manesha , Eggers John P. , Bogener James W. , Hutchison Richard L.
Published: August 2017

Background: The purpose of this study is to determine whether a Stener lesion can be created while testing stability of the ulnar collateral ligament (UCL) of the thumb. Testing was performed in a manner that reproduced clinical examination.

Methods: Six fresh frozen hand and forearm specimens underwent sequential sectioning of the accessory UCL, the proper UCL, and the ulnar sagittal band. Measurements of radial deviation of the metacarpophalangeal (MCP) joint were taken with the thumb in neutral rotation, pronation and supination, both with 0 degrees and with 30 degrees of flexion of the MCP joint. Visual examination was performed to assess the presence of a Stener lesion.

Results: No Stener lesion was created in any position as long as the fascial origin of the ulnar sagittal band at the adductor pollicis longus remained intact. After creating a defect in the ulnar sagittal band, a Stener lesion was created in two specimens, but only when the thumb was flexed and supinated. Pronation provided more stability, and supination provided less stability, with one or both components cut, especially when testing at 30° of flexion. Compared to both components cut without flexion or rotation, there was a statistically significant difference in angulation with the 30 degrees of MCP joint flexion in both neutral rotation in supination.

Conclusions: Performing a physical examination to assess the amount of instability of an ulnar collateral ligament injury did not create a Stener lesion if the exam was performed in a controlled, gentle manner with the thumb held without rotation. If the thumb is held in neutral rotation during the exam, an iatrogenic Stener lesion should not be created.
Locking Screw Migration to the Palm Four Years Following Surgical Implantation of Distal Radius Locking Plate
Authors: Marwan Yousef , Makhdom Asim M. , Berry Gregory
Published: August 2017

Hardware-related complications are rare in patients with distal radius fractures who were surgically fixed with volar-locking plates. In this report, we present a case of locking screw loosening and migration to the palm four years following the treatment of type 23-C1 distal radius fracture with a volar locking-plate. This complication occurred without evidence of trauma, infection, non-union or plate breakage. Orthopaedic surgeons should be aware of such rare complication and add it to the list of potential postoperative complications when counseling their patients preoperatively.
A Stepwise Approach to Management of Open Radiocarpal Fracture-Dislocations: A Case Report
Authors: Woon Colin Yi-Loong , Baxamusa Taizoon
Published: August 2017

Radiocarpal dislocations are uncommon and occur after significant trauma. We describe a unique case of open radiocarpal fracture-dislocation presenting with progressive neurovascular compromise. Staged management was necessary. As a first stage, emergent provisional bedside reduction in the emergency room with manual pressure through the open wounds was performed. The second stage then involved formal open reduction and internal fixation as soon as operating room staff and resources became available.
Disruption of Flexor Tendon after Intrasheath Triamcinolone Acetonide Injection for Trigger Digits: Two Case Reports
Authors: Tanaka Toshikazu , Ogawa Takeshi , Yanai Takaji , Okano Eriko , Kohyama Sho , Ochiai Naoyuki
Published: August 2017

We experienced two cases of flexor tendons rupture after triamcinolone acetate (TA) injection for trigger finger. A 45-year-old man underwent injection of 40 mg of TA and 1 mL of 1% lidocaine solution into his little finger. While playing golf 3 months after the injection, he heard a popping sound, and was unable to flex it. A 57-year-old female nurse had undergone injection of 40 mg of TA and 1 mL of 1% lidocaine solution into her thumb twice at a 2-month interval. Two months after the second injection, she was unable to flex it. Both cases had high concentrated TA injection at trigger digits. The present and previous cases illustrate that when TA is injected into trigger digits, the dose should be low, the safety interval should be long, and refuse injection into the tendon proper.
Large scale document inversion using a multi-threaded computing system
Authors: Jung Sungbo , Chang Dar-Jen , Park Juw Won
Published: August 2017

Current microprocessor architecture is moving towards multi-core/multi-threaded systems. This trend has led to a surge of interest in using multi-threaded computing devices, such as the Graphics Processing Unit (GPU), for general purpose computing. We can utilize the GPU in computation as a massive parallel co-processor because the GPU consists of multiple cores. The GPU is also an affordable, attractive, and user-programmable commodity. Nowadays a lot of information has been flooded into the digital domain around the world. Huge volume of data, such as digital libraries, social networking services, e-commerce product data, and reviews, etc., is produced or collected every moment with dramatic growth in size. Although the inverted index is a useful data structure that can be used for full text searches or document retrieval, a large number of documents will require a tremendous amount of time to create the index. The performance of document inversion can be improved by multi-thread or multi-core GPU. Our approach is to implement a linear-time, hash-based, single program multiple data (SPMD), document inversion algorithm on the NVIDIA GPU/CUDA programming platform utilizing the huge computational power of the GPU, to develop high performance solutions for document indexing. Our proposed parallel document inversion system shows 2--3 times faster performance than a sequential system on two different test datasets from PubMed abstract and e-commerce product reviews.
Effect of ovariectomy on intracellular Ca2+ regulation in guinea pig cardiomyocytes
Authors: Yang Hsiang-Yu , Firth Jahn M. , Francis Alice J. , Alvarez-Laviada Anita , MacLeod Kenneth T.
Published: August 2017

This study addressed the hypothesis that long-term deficiency of ovarian hormones after ovariectomy (OVx) alters cellular Ca2+-handling mechanisms in the heart, resulting in the formation of a proarrhythmic substrate. It also tested whether estrogen supplementation to OVx animals reverses any alterations to cardiac Ca2+ handling and rescues proarrhythmic behavior. OVx or sham operations were performed on female guinea pigs using appropriate anesthetic and analgesic regimes. Pellets containing 17β-estradiol (1 mg, 60-day release) were placed subcutaneously in selected OVx animals (OVx + E). Cardiac myocytes were enzymatically isolated, and electrophysiological measurements were conducted with a switch-clamp system. In fluo-4-loaded cells, Ca2+ transients were 20% larger, and fractional sarcoplasmic reticulum (SR) Ca2+ release was 7% greater in the OVx group compared with the sham group. Peak L-type Ca2+ current was 16% larger in OVx myocytes with channel inactivation shifting to more positive membrane potentials, creating a larger “window” current. SR Ca2+ stores were 22% greater in the OVx group, and these cells showed a higher frequency of Ca2+ sparks and waves and shorter wave-free intervals. OVx myocytes showed higher frequencies of early afterdepolarizations, and a greater percentage of these cells showed delayed afterdepolarizations after exposure to isoprenaline compared with sham myocytes. The altered Ca2+ regulation occurring in the OVx group was not observed in the OVx + E group. These findings suggest that long-term deprivation of ovarian hormones in guinea pigs lead to changes in myocyte Ca2+-handling mechanisms that are considered proarrhythmogenic. 17β-Estradiol replacement prevented these adverse effects.

NEW & NOTEWORTHY Ovariectomized guinea pig cardiomyocytes have higher frequencies of Ca2+ waves, and isoprenaline-challenged cells display more early afterdepolarizations, delayed afterdepolarizations, and extra beats compared with sham myocytes. These alterations to Ca2+ regulation were not observed in myocytes from ovariectomized guinea pigs supplemented with 17β-estradiol, suggesting that ovarian hormone deficiency modifies cardiac Ca2+ regulation, potentially creating proarrhythmic substrates.
Anomalous baroreflex functionality inherent in floxed and Cre-Lox mice: an overlooked physiological phenotype
Authors: Tsai Ching-Yi , Poon Yan-Yuen , Chen Chang-Han , Chan Samuel H. H.
Published: August 2017

The last two decades have seen the emergence of Cre-Lox recombination as one of the most powerful and versatile technologies for cell-specific genetic engineering of mammalian cells. Understandably, the primary concerns in the practice of Cre-Lox recombination are whether the predicted genome has been correctly modified and the targeted phenotypes expressed. Rarely are the physiological conditions of the animals routinely examined because the general assumption is that they are normal. Based on corroborative results from radiotelemetric recording, power spectral analysis, and magnetic resonance imaging/diffusion tensor imaging in brain-derived neurotrophic factor-floxed mice, the present study revealed that this assumption requires amendment. We found that despite comparable blood pressure and heart rate with C57BL/6 or Cre mice under the conscious state, floxed and Cre-Lox mice exhibited diminished baroreflex-mediated sympathetic vasomotor tone and cardiac vagal baroreflex. We further found that the capacity and plasticity of baroreflex of these two strains of mice under isoflurane anesthesia were retarded, as reflected by reduced connectivity between the nucleus tractus solitarii and rostral ventrolateral medulla or nucleus ambiguus. The identification of anomalous baroreflex functionality inherent in floxed and Cre-Lox mice points to the importance of incorporating physiological phenotypes into studies that engage gene manipulations such as Cre-Lox recombination.

NEW & NOTEWORTHY We established that anomalous baroreflex functionality is inherent in floxed and Cre-Lox mice. These two mouse strains exhibited diminished baroreflex-mediated sympathetic vasomotor tone and cardiac vagal baroreflex under the conscious state, retarded capacity and plasticity of baroreflex under isoflurane anesthesia, and reduced connectivity between key nuclei in the baroreflex neural circuits.
X-ray-based lung function measurement reveals persistent loss of lung tissue elasticity in mice recovered from allergic airway inflammation
Authors: Markus M. Andrea , Borowik Sergej , Reichardt Marius , Tromba Giuliana , Alves Frauke , Dullin Christian
Published: August 2017

Chronic asthma patients experience difficulties even years after the inciting allergen. Although studies in small animal asthma models have enormously advanced progress in uncovering the mechanisms of inception and development of the disease, little is known about the processes involved in the persistence of asthma symptoms in the absence of allergen exposure. Long-term asthma mouse models have so far been scarce or not been able to reproduce the findings in patients. Here we used a common ovalbumin-induced acute allergic airway inflammation mouse model to study lung function and remodeling after a 4-mo recovery period. We show by X-ray-based lung function measurements that the recovered mice continue to show impaired lung function by displaying significant air trapping compared with controls. High-resolution synchrotron phase-contrast computed tomography of structural alterations and diaphragm motion analysis suggest that these changes in pulmonary function are the result of a pronounced loss in lung elasticity. Histology of lung sections confirmed that this is most likely caused by a decrease in elastic fibers, indicating that remodeling can develop or persist independent of acute inflammation and is closely related to a loss in lung function. Our findings demonstrate that this X-ray-based imaging platform has the potential to comprehensively and noninvasively unravel long-term effects in preclinical mouse models of allergic airway inflammation and thus benefits our understanding of chronic asthma.
Repetitive intradermal bleomycin injections evoke T-helper cell 2 cytokine-driven pulmonary fibrosis
Authors: Singh Brijendra , Kasam Rajesh K. , Sontake Vishwaraj , Wynn Thomas A. , Madala Satish K.
Published: August 2017

IL-4 and IL-13 are major T-helper cell (Th) 2 cytokines implicated in the pathogenesis of several lung diseases, including pulmonary fibrosis. In this study, using a novel repetitive intradermal bleomycin model in which mice develop extensive lung fibrosis and a progressive decline in lung function compared with saline-treated control mice, we investigated profibrotic functions of Th2 cytokines. To determine the role of IL-13 signaling in the pathogenesis of bleomycin-induced pulmonary fibrosis, wild-type, IL-13, and IL-4Rα-deficient mice were treated with bleomycin, and lungs were assessed for changes in lung function and pulmonary fibrosis. Histological staining and lung function measurements demonstrated that collagen deposition and lung function decline were attenuated in mice deficient in either IL-13 or IL-4Rα-driven signaling compared with wild-type mice treated with bleomycin. Furthermore, our results demonstrated that IL-13 and IL-4Rα-driven signaling are involved in excessive migration of macrophages and fibroblasts. Notably, our findings demonstrated that IL-13-driven migration involves increased phospho-focal adhesion kinase signaling and F-actin polymerization. Importantly, in vivo findings demonstrated that IL-13 augments matrix metalloproteinase (MMP)-2 and MMP9 activity that has also been shown to increase migration and invasiveness of fibroblasts in the lungs during bleomycin-induced pulmonary fibrosis. Together, our findings demonstrate a pathogenic role for Th2-cytokine signaling that includes excessive migration and protease activity involved in severe fibrotic lung disease.
Alternative pre-mRNA splicing of Toll-like receptor signaling components in peripheral blood mononuclear cells from patients with ARDS
Authors: Blumhagen Rachel Z. , Hedin Brenna R. , Malcolm Kenneth C. , Burnham Ellen L. , Moss Marc , Abraham Edward , Huie Tristan J. , Nick Jerry A. , Fingerlin Tasha E. , Alper Scott
Published: August 2017

A key physiological feature of acute respiratory distress syndrome (ARDS) is inflammation. Toll-like receptor (TLR) signaling is required to combat the infection that underlies many ARDS cases but also contributes to pathological inflammation. Several TLR signaling pathway genes encoding positive effectors of inflammation also produce alternatively spliced mRNAs encoding negative regulators of inflammation. An imbalance between these isoforms could contribute to pathological inflammation and disease severity. To determine whether splicing in TLR pathways is altered in patients with ARDS, we monitored alternative splicing of MyD88 and IRAK1, two genes that function in multiple TLR pathways. The MyD88 and IRAK1 genes produce long proinflammatory mRNAs (MyD88L and IRAK1) and shorter anti-inflammatory mRNAs (MyD88S and IRAK1c). We quantified mRNA encoding inflammatory cytokines and MyD88 and IRAK1 isoforms in peripheral blood mononuclear cells (PBMCs) from 104 patients with ARDS and 30 healthy control subjects. We found that MyD88 pre-mRNA splicing is altered in patients with ARDS in a proinflammatory direction. We also observed altered MyD88 isoform levels in a second critically ill patient cohort, suggesting that these changes may not be unique to ARDS. Early in ARDS, PBMC IRAK1c levels were associated with patient survival. Despite the similarities in MyD88 and IRAK1 alternative splicing observed in previous in vitro studies, there were differences in how MyD88 and IRAK1 alternative splicing was altered in patients with ARDS. We conclude that pre-mRNA splicing of TLR signaling genes is altered in patients with ARDS, and further investigation of altered splicing may lead to novel prognostic and therapeutic approaches.
EZH2 Palmitoylation Mediated by ZDHHC5 in p53-Mutant Glioma Drives Malignant Development and Progression
Authors: Chen Xueran , Ma Huihui , Wang Zhen , Zhang Shangrong , Yang Haoran , Fang Zhiyou
Published: August 2017

Gliomas with mutant p53 occurring in 30% of glioma patients exhibit therapeutic resistance and poor outcomes. In this study, we identify a novel mechanism through which mutant p53 drives cancer cell survival and malignant growth. We documented overexpression of the zinc finger protein ZDHHC5 in glioma compared with normal brain tissue and that this event tightly correlated with p53 mutations. Mechanistic investigations revealed that mutant p53 transcriptionally upregulated ZDHHC5 along with the nuclear transcription factor NF-Y. These events contributed to the development of glioma by promoting the self-renewal capacity and tumorigenicity of glioma stem-like cells, by altering the palmitoylation and phosphorylation status of the tumor suppressor EZH2. Taken together, our work highlighted ZDHHC5 as a candidate therapeutic target for management of p53-mutated gliomas. Cancer Res; 77(18); 4998–5010. ©2017 AACR.
Bypassing Drug Resistance Mechanisms of Prostate Cancer with Small Molecules that Target Androgen Receptor–Chromatin Interactions
Authors: Dalal Kush , Che Meixia , Que Nanette S. , Sharma Aishwariya , Yang Rendong , Lallous Nada , Borgmann Hendrik , Ozistanbullu Deniz , Tse Ronnie , Ban Fuqiang , Li Huifang , Tam Kevin J. , Roshan-Moniri Mani , LeBlanc Eric , Gleave Martin E. , Gewirth Daniel T. , Dehm Scott M. , Cherkasov Artem , Rennie Paul S.
Published: August 2017

Human androgen receptor (AR) is a hormone-activated transcription factor that is an important drug target in the treatment of prostate cancer. Current small-molecule AR antagonists, such as enzalutamide, compete with androgens that bind to the steroid-binding pocket of the AR ligand–binding domain (LBD). In castration-resistant prostate cancer (CRPC), drug resistance can manifest through AR-LBD mutations that convert AR antagonists into agonists, or by expression of AR variants lacking the LBD. Such treatment resistance underscores the importance of novel ways of targeting the AR. Previously, we reported the development of a series of small molecules that were rationally designed to selectively target the AR DNA-binding domain (DBD) and, hence, to directly interfere with AR–DNA interactions. In the current work, we have confirmed that the lead AR DBD inhibitor indeed directly interacts with the AR-DBD and tested that substance across multiple clinically relevant CRPC cell lines. We have also performed a series of experiments that revealed that genome-wide chromatin binding of AR was dramatically impacted by the lead compound (although with lesser effect on AR variants). Collectively, these observations confirm the novel mechanism of antiandrogen action of the developed AR-DBD inhibitors, establishing proof of principle for targeting DBDs of nuclear receptors in endocrine cancers. Mol Cancer Ther; 16(10); 2281–91. ©2017 AACR.
Development of Aggressive Pancreatic Ductal Adenocarcinomas Depends on Granulocyte Colony Stimulating Factor Secretion in Carcinoma Cells
Authors: Pickup Michael W. , Owens Philip , Gorska Agnieszka E. , Chytil Anna , Ye Fei , Shi Chanjuan , Weaver Valerie M. , Kalluri Raghu , Moses Harold L. , Novitskiy Sergey V.
Published: August 2017

The survival rate for pancreatic ductal adenocarcinoma (PDAC) remains low. More therapeutic options to treat this disease are needed, for the current standard of care is ineffective. Using an animal model of aggressive PDAC (Kras/p48TGFβRIIKO), we discovered an effect of TGFβ signaling in regulation of G-CSF secretion in pancreatic epithelium. Elevated concentrations of G-CSF in PDAC promoted differentiation of Ly6G+ cells from progenitors, stimulated IL10 secretion from myeloid cells, and decreased T-cell proliferation via upregulation of Arg, iNOS, VEGF, IL6, and IL1b from CD11b+ cells. Deletion of csf3 in PDAC cells or use of a G-CSF–blocking antibody decreased tumor growth. Anti–G-CSF treatment in combination with the DNA synthesis inhibitor gemcitabine reduced tumor size, increased the number of infiltrating T cells, and decreased the number of Ly6G+ cells more effectively than gemcitabine alone. Human analysis of human datasets from The Cancer Genome Atlas and tissue microarrays correlated with observations from our mouse model experiments, especially in patients with grade 1, stage II disease. We propose that in aggressive PDAC, elevated G-CSF contributes to tumor progression through promoting increases in infiltration of neutrophil-like cells with high immunosuppressive activity. Such a mechanism provides an avenue for a neoadjuvant therapeutic approach for this devastating disease. Cancer Immunol Res; 5(9); 718–29. ©2017 AACR.
Role for High-Affinity IgE Receptor in Prognosis of Lung Adenocarcinoma Patients
Authors: Ly Dalam , Zhu Chang-Qi , Cabanero Michael , Tsao Ming-Sound , Zhang Li
Published: August 2017

Cancer development and biology is influenced by the host immune system. Emerging data indicate that the context of immune cell infiltrates may contribute to cancer prognosis. However, the types of infiltrating immune cells that are critical for cancer development remain controversial. In attempts to gain insights into the immune networks that regulate and/or predict tumor progression, gene expression analysis was conducted on microarray datasets of resected tumor samples from 128 early-stage non–small cell lung cancer (NSCLC) adenocarcinoma patients. By limiting analysis to immune-related genes, we identified a 9-gene signature using MAximizing R Square Algorithm that selected for the greatest separation between favorable and adverse prognostic patient subgroups. The prognostic value of this 9-gene signature was validated in 10 additional independently published microarray datasets of lung adenocarcinoma [n = 1,097; overall survival hazard ratio (HR), 2.05; 95% confidence interval, 1.64–2.56; P < 0.0001] and was found to be an independent prognostic indicator relative to tumor stage (overall survival HR, 2.09, 95% confidence interval, 1.65–2.66; P < 0.0001). Network analysis revealed that genes associated with Fcϵ complex (FCER1, MS4A2) formed the largest and most significant pathway of the signature. Using immunohistochemistry, we validated that MS4A2, the β subunit of the IgE receptor expressed on mast cells, is a favorable prognostic indicator and show that MS4A2 gene expression is an independent prognostic marker for early-stage lung cancer patient survival. Cancer Immunol Res; 5(9); 821–9. ©2017 AACR.
Effect of High-Intensity Interval Training on Plasma Omentin-1 Concentration in Overweight/Obese and Normal-Weight Youth
Authors: Ouerghi Nejmeddine , Ben Fradj Mohamed Kacem , Bezrati Ikram , Feki Moncef , Kaabachi Naziha , Bouassida Anissa
Published: August 2017

Objectives: Omentin-1 is a recently discovered adipokine, mainly produced by visceral adipose tissue, which is thought to improve insulin sensitivity. The study aimed to assess the association of plasma omentin-1 with cardiometabolic traits and physical performance and to test its response to high-intensity interval training (HIIT) in obese and normal-weight subjects. Methods: Nine overweight/obese (OG) and 9 normal-weight (NWG) young men performed an 8-week HIIT program. Body composition, physical performance, homeostasis model assessment index for insulin resistance (HOMA-IR) as well as plasma omentin-1and lipid levels were assessed before and after the HIIT program. Results: Baseline plasma omentin-1 was lower in OG than NWG men (359 ± 138 vs. 470 ± 114 ng/ml; p = 0.052). Plasma omentin-1 was related to body fat (r = -0.57; p = 0.03) and LDL-cholesterol (r = -0.49; p = 0.04). There was a trend towards significant association of omentin-1 with BMI (r = -0.47; p = 0.06) and VO2max (r = 0.41; p = 0.09). However, no association was observed with HOMA-IR. Following the HIIT program, omentin-1 concentrations have significantly (p < 0.01) increased in OG (359 ± 138 to 455 ± 126 ng/ml) and NWG men (470 ± 114 to 572 ± 115 ng/ml). In parallel, the cardiometabolic profile has improved with a significant decrease of HOMA-IR in OG. Conclusions: HIIT resulted in a plasma omentin-1 increase and an improvement with regard to cardiometabolic traits in the OG men, which may contribute to modulate insulin sensitivity.
Effect of Restriction of Foods with High Fructose Corn Syrup Content on Metabolic Indices and Fatty Liver in Obese Children
Authors: Ibarra-Reynoso Lorena del Rocio , López-Lemus Hilda Lissette , Garay-Sevilla Ma Eugenia , Malacara Juan Manuel
Published: August 2017

Objective: We examined the effect of restriction of foods with high fructose content in obese school children. Methods: In a clinical study, we selected 54 obese children 6 to 11 years old with high fructose consumption (>70 g/day) in order indicate dietary fructose restriction (<20 g/day) for 6 weeks. Anthropometry, liver ultrasound as well as glucose, insulin, lipids, leptin, IGFBP1, and RBP4 serum levels were collected. Results: The group of children had 80% adherence and reported decreased fructose consumption (110 ± 38.6 to 11.4 ± 12.0 g/day) and also a significant decrease in caloric (2,384 ± 568 to 1,757 ± 387 kcal/day) and carbohydrate consumption (302 ± 80.4 to 203 ± 56.0 g/day). The severity of steatosis improved significantly after fructose restriction (p < 0.000001). However, no changes in BMI, systolic blood pressure, or diastolic blood pressure were found. Only triglyceride levels decreased (1.44 ± 0.43 to 1.31 ± 0.38 mmol/l), High-densitiy lipoprotein cholesterol showed a marginal increase (1.45 ± 0.19 to 1.56 ± 0.44 mmol/l). Insulin resistance and RBP4 did not change. Conclusions: In school children, the restriction of high fructose foods with a decrease of caloric and carbohydrate intake at 6 weeks did not induce weight loss; however, triglyceride levels and hepatic steatosis decreased. Differences with other studies in regard to weight loss may be explained by adaptive changes on metabolic expenditure.
Antenatal Treatment with Intravenous Immunoglobulin to Prevent Gestational Alloimmune Liver Disease: Comparative Effectiveness of 14-Week versus 18-Week Initiation
Authors: Whitington Peter F. , Kelly Susan , Taylor Sarah A. , Nóbrega Sara , Schreiber Richard A. , Sokal Etienne M. , Hibbard Judith U.
Published: August 2017

Background: Antenatal therapy with high-dose intravenous immunoglobulin (IVIG) may prevent gestational alloimmune liver disease (GALD). Objective: The objective of this study was to determine the effectiveness of this approach in a large cohort of women at risk for poor pregnancy outcome due to GALD. Methods: Women with a history of affected offspring were provided antenatal IVIG treatment and data were acquired prospectively from 1997 to 2015. The outcomes of treated pregnancies were compared to those of untreated pregnancies, and the effectiveness of starting at 14 weeks was compared to that of starting at 18 weeks. Results: A total of 188 treated pregnancies in 151 women were analyzed. Only 30% (n = 105) of untreated gestations resulted in healthy offspring as compared to 94% (n = 177) of treated pregnancies (p < 0.0001). Treated gestations of both the 14-week (n = 108) and the 18-week (n = 80) start cohort showed a decreased rate of fetal loss relative to untreated gestations (p < 0.0001). Equivalent outcomes were recorded in the 18-week versus the 14-week start cohort (p > 0.05). Few adverse events or complications of antenatal therapy were recorded. Conclusion: Antenatal therapy with high-dose IVIG initiated at either 18 or 14 gestational weeks effectively prevents poor outcome of pregnancies at risk for GALD.
First Selective 12-LOX Inhibitor, ML355, Impairs Thrombus Formation and Vessel Occlusion In Vivo With Minimal Effects on Hemostasis
Authors: Adili Reheman , Tourdot Benjamin E. , Mast Katherine , Yeung Jennifer , Freedman John C. , Green Abigail , Luci Diane K. , Jadhav Ajit , Simeonov Anton , Maloney David J. , Holman Theodore R. , Holinstat Michael
Published: August 2017

Objective—

Adequate platelet reactivity is required for maintaining hemostasis. However, excessive platelet reactivity can also lead to the formation of occlusive thrombi. Platelet 12(S)-lipoxygenase (12-LOX), an oxygenase highly expressed in the platelet, has been demonstrated to regulate platelet function and thrombosis ex vivo, supporting a key role for 12-LOX in the regulation of in vivo thrombosis. However, the ability to pharmacologically target 12-LOX in vivo has not been established to date. Here, we studied the effect of the first highly selective 12-LOX inhibitor, ML355, on in vivo thrombosis and hemostasis.

Approach and Results—

ML355 dose-dependently inhibited human platelet aggregation and 12-LOX oxylipin production, as confirmed by mass spectrometry. Interestingly, the antiplatelet effects of ML355 were reversed after exposure to high concentrations of thrombin in vitro. Ex vivo flow chamber assays confirmed that human platelet adhesion and thrombus formation at arterial shear over collagen were attenuated in whole blood treated with ML355 comparable to aspirin. Oral administration of ML355 in mice showed reasonable plasma drug levels by pharmacokinetic assessment. ML355 treatment impaired thrombus growth and vessel occlusion in FeCl
3
-induced mesenteric and laser-induced cremaster arteriole thrombosis models in mice. Importantly, hemostatic plug formation and bleeding after treatment with ML355 was minimal in mice in response to laser ablation on the saphenous vein or in a cremaster microvasculature laser–induced rupture model.

Conclusions—

Our data strongly support 12-LOX as a key determinant of platelet reactivity in vivo, and inhibition of platelet 12-LOX with ML355 may represent a new class of antiplatelet therapy.
Association of Concentric Left Ventricular Hypertrophy With Subsequent Change in Left Ventricular End-Diastolic Volume
Authors: Garg Sonia , de Lemos James A. , Matulevicius Susan A. , Ayers Colby , Pandey Ambarish , Neeland Ian J. , Berry Jarett D. , McColl Roderick , Maroules Christopher , Peshock Ronald M. , Drazner Mark H.
Published: August 2017

Background

In the conventional paradigm of the progression of left ventricular hypertrophy, a thick-walled left ventricle (LV) ultimately transitions to a dilated cardiomyopathy. There are scant data in humans demonstrating whether this transition occurs commonly without an interval myocardial infarction.

Methods and Results

Participants (n=1282) from the Dallas Heart Study underwent serial cardiac magnetic resonance ≈7 years apart. Those with interval cardiovascular events and a dilated LV (increased LV end-diastolic volume [EDV] indexed to body surface area) at baseline were excluded. Multivariable linear regression models tested the association of concentric hypertrophy (increased LV mass and LV mass/volume
0.67
) with change in LVEDV. The study cohort had a median age of 44 years, 57% women, 43% black, and 11% (n=142) baseline concentric hypertrophy. The change in LVEDV in those with versus without concentric hypertrophy was 1 mL (−9 to 12) versus −2 mL (−11 to 7), respectively,
P
<0.01. In multivariable linear regression models, concentric hypertrophy was associated with larger follow-up LVEDV (
P
≤0.01). The progression to a dilated LV was uncommon (2%, n=25).

Conclusions

In the absence of interval myocardial infarction, concentric hypertrophy was associated with a small, but significantly greater, increase in LVEDV after 7-year follow-up. However, the degree of LV enlargement was minimal, and few participants developed a dilated LV. These data suggest that if concentric hypertrophy does progress to a dilated cardiomyopathy, such a transition would occur over a much longer timeframe (eg, decades) and may be less common than previously thought.

Clinical Trial Registration

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00344903.
Variation in the Echocardiographic Surveillance of Primary Mitral Regurgitation
Authors: Tanguturi Varsha K. , Hidrue Michael K. , Picard Michael H. , Atlas Steven J. , Weilburg Jeffrey B. , Ferris Timothy G. , Armstrong Katrina , Wasfy Jason H.
Published: August 2017

Background—

Clinical outcomes after surgical treatment of mitral regurgitation are worse if intervention occurs after deterioration of left ventricular size and function. Transthoracic echocardiographic (TTE) surveillance of patients with mitral regurgitation is indicated to avoid adverse ventricular remodeling. Overly frequent TTEs can impair patient access and reduce value in care delivery. This balance between timely surveillance and overutilization of TTE in valvular disease provides a model to study variation in the delivery of healthcare services. We investigated patient and provider factors contributing to variation in TTE utilization and hypothesized that variation was attributable to provider practice even after adjustment for patient characteristics.

Methods and Results—

We obtained records of all TTEs from 2001 to 2016 completed at a large echocardiography laboratory. The outcome variable was time interval between TTEs. We constructed a mixed-effects linear regression model with the individual physician as the random effect in the model and used intraclass correlation coefficient to assess the proportion of outcome variation because of provider practice. Our study cohort was 55 773 TTEs corresponding to 37 843 intervals ordered by 635 providers. The mean interval between TTEs was 12.4 months, 17.0 months, 18.3 months, and 17.4 months for severe, moderate, mild, and trace mitral regurgitation, respectively, with 20% of providers deemed overutilizers of TTEs and 25% underutilizers.

Conclusions—

We conclude that there is substantial variation in follow-up intervals for TTE assessment of mitral regurgitation, despite risk-adjustment for patient variables, likely because of provider factors.
De Novo
FGF12
(Fibroblast Growth Factor 12) Functional Variation Is Potentially Associated With Idiopathic Ventricular Tachycardia
Authors: Li Qianqian , Zhao Yuanyuan , Wu Gang , Chen Shanshan , Zhou Yingchao , Li Sisi , Zhou Mengchen , Fan Qian , Pu Jielin , Hong Kui , Cheng Xiang , Kenneth Wang Qing , Tu Xin
Published: August 2017

Background

Idiopathic ventricular tachycardia (
VT
) is a type of cardiac arrhythmia occurring in structurally normal hearts. The heritability of idiopathic VT remains to be clarified, and numerous genetic factors responsible for development of idiopathic VT are as yet unclear. Variations in

FGF
12

(fibroblast growth factor 12), which is expressed in the human ventricle and modulates the cardiac Na
+
channel Na
V
1.5, may play an important role in the genetic pathogenesis of
VT
.

Methods and Results

We tested the hypothesis that genetic variations in

FGF
12

are associated with
VT
in 2 independent Chinese cohorts and resequenced all the exons and exon–intron boundaries and the 5′ and 3′ untranslated regions of

FGF
12

in 320 unrelated participants with idiopathic
VT
. For population‐based case–control association studies, we chose 3 single‐nucleotide polymorphisms—rs1460922, rs4687326, and rs2686464—which included all the exons of

FGF
12

. The results showed that the single‐nucleotide polymorphism rs1460922 in

FGF
12

was significantly associated with
VT
after adjusting for covariates of sex and age in 2 independent Chinese populations: adjusted
P
=0.015 (odds ratio: 1.54 [95% CI, 1.09–2.19]) in the discovery sample, adjusted
P
=0.018 (odds ratio: 1.64 [95% CI, 1.09–2.48]) in the replication sample, and adjusted
P
=2.52E‐04 (odds ratio: 1.59 [95% CI, 1.24–2.03]) in the combined sample. After resequencing all amino acid coding regions and untranslated regions of

FGF
12

, 5 rare variations were identified. The result of western blotting revealed that a de novo functional variation, p.P211Q (1.84% of 163 patients with right ventricular outflow tract VT), could downregulate

FGF
12

expression significantly.

Conclusions

In this study, we observed that rs1460922 of

FGF
12

was significantly associated with
VT
and identified that a de novo variation of

FGF
12

may be an important genetic risk factor for the pathogenesis of
VT
.
Association of High‐Density Lipoprotein‐Cholesterol Versus Apolipoprotein A‐I With Risk of Coronary Heart Disease: The European Prospective Investigation Into Cancer‐Norfolk Prospective Population Study, the Atherosclerosis Risk in Communities Study, and the Women's Health Study
Authors: van Capelleveen Julian C. , Bochem Andrea E. , Boekholdt S. Matthijs , Mora Samia , Hoogeveen Ron C. , Ballantyne Christie M. , Ridker Paul M , Sun Wensheng , Barter Philip J. , Tall Alan R. , Zwinderman Aeilko H. , Kastelein John J. P. , Wareham Nick J. , Khaw Kay‐Tee , Hovingh G. Kees
Published: August 2017

Background

The contribution of apolipoprotein A‐I (apoA‐I) to coronary heart disease (
CHD
) risk stratification over and above high‐density lipoprotein cholesterol (
HDL
‐C) is unclear. We studied the associations between plasma levels of
HDL
‐C and apoA‐I, either alone or combined, with risk of
CHD
events and cardiovascular risk factors among apparently healthy men and women.

Methods and Results

HDL
‐C and apoA‐I levels were measured among 17 661 participants of the
EPIC
(European Prospective Investigation into Cancer)‐Norfolk prospective population study. Hazard ratios for
CHD
events and distributions of risk factors were calculated by quartiles of
HDL
‐C and apoA‐I. Results were validated using data from the
ARIC
(Atherosclerosis Risk in Communities) and
WHS
(Women's Health Study) cohorts, comprising 15 494 and 27 552 individuals, respectively. In
EPIC
‐Norfolk, both
HDL
‐C and apoA‐I quartiles were strongly and inversely associated with
CHD
risk. Within
HDL
‐C quartiles, higher apoA‐I levels were not associated with lower
CHD
risk; in fact,
CHD
risk was higher within some
HDL
‐C quartiles. ApoA‐I levels were associated with higher levels of
CHD
risk factors: higher body mass index, HbA1c, non‐
HDL
‐C, triglycerides, apolipoprotein B, systolic blood pressure, and C‐reactive protein, within fixed
HDL
‐C quartiles. In contrast,
HDL
‐C levels were consistently inversely associated with overall
CHD
risk and
CHD
risk factors within apoA‐I quartiles (
P
<0.001). These findings were validated in the
ARIC
and
WHS
cohorts.

Conclusions

Our findings demonstrate that apoA‐I levels do not offer predictive information over and above
HDL
‐C. In fact, within some
HDL
‐C quartiles, higher apoA‐I levels were associated with higher risk of
CHD
events, possibly because of the unexpected higher prevalence of cardiovascular risk factors in association with higher apoA‐I levels.

Clinical Trial Registration

URL
:
https://www.clinicaltrials.gov
. Unique identifier:
NCT
00000479.
Modality-specific Changes in Motor Cortex Excitability After Visuo-proprioceptive Realignment
Authors: Munoz-Rubke Felipe , Mirdamadi Jasmine L. , Lynch Anna K. , Block Hannah J.
Published: August 2017

Spatial realignment of visual and proprioceptive estimates of hand position is necessary both to keep the estimates in register over time and to compensate for sensory perturbations. Such realignment affects perceived hand position, which the brain must use to plan hand movements. We would therefore expect visuo-proprioceptive realignment to affect the motor system at some level, but the physiological basis of this interaction is unknown. Here, we asked whether activity in primary motor cortex (M1), a well-known substrate of motor control, shows evidence of change after visuo-proprioceptive realignment. In two sessions each, 32 healthy adults experienced spatially misaligned or veridical visual and proprioceptive information about their static left index finger. Participants indicated perceived finger position with no performance feedback or knowledge of results. Using TMS over the M1 representation of the misaligned finger, we found no average difference between sessions. However, regression analysis indicated that, in the misaligned session only, proprioceptive realignment was linked with a decrease in M1 activity and visual realignment was linked with an increase in M1 activity. Proprioceptive and visual realignment were inversely related to each other. These results suggest that visuo-proprioceptive realignment does indeed have a physiological impact on the motor system. The lack of a between-session mean difference in M1 activity suggests that the basis of the effect is not the multisensory realignment computation itself, independent of modality. Rather, the changes in M1 are consistent with a modality-specific neural mechanism, such as modulation of somatosensory cortex or dorsal stream visual areas that impact M1.
Neural Representation of Working Memory Content Is Modulated by Visual Attentional Demand
Authors: Kiyonaga Anastasia , Dowd Emma Wu , Egner Tobias
Published: August 2017

Recent theories assert that visual working memory (WM) relies on the same attentional resources and sensory substrates as visual attention to external stimuli. Behavioral studies have observed competitive tradeoffs between internal (i.e., WM) and external (i.e., visual) attentional demands, and neuroimaging studies have revealed representations of WM content as distributed patterns of activity within the same cortical regions engaged by perception of that content. Although a key function of WM is to protect memoranda from competing input, it remains unknown how neural representations of WM content are impacted by incoming sensory stimuli and concurrent attentional demands. Here, we investigated how neural evidence for WM information is affected when attention is occupied by visual search—at varying levels of difficulty—during the delay interval of a WM match-to-sample task. Behavioral and fMRI analyses suggested that WM maintenance was impacted by the difficulty of a concurrent visual task. Critically, multivariate classification analyses of category-specific ventral visual areas revealed a reduction in decodable WM-related information when attention was diverted to a visual search task, especially when the search was more difficult. This study suggests that the amount of available attention during WM maintenance influences the detection of sensory WM representations.
Causal Evidence from Humans for the Role of Mediodorsal Nucleus of the Thalamus in Working Memory
Authors: Peräkylä Jari , Sun Lihua , Lehtimäki Kai , Peltola Jukka , Öhman Juha , Möttönen Timo , Ogawa Keith H. , Hartikainen Kaisa M.
Published: August 2017

The mediodorsal nucleus of the thalamus (MD), with its extensive connections to the lateral pFC, has been implicated in human working memory and executive functions. However, this understanding is based solely on indirect evidence from human lesion and imaging studies and animal studies. Direct, causal evidence from humans is missing. To obtain direct evidence for MD's role in humans, we studied patients treated with deep brain stimulation (DBS) for refractory epilepsy. This treatment is thought to prevent the generalization of a seizure by disrupting the functioning of the patient's anterior nuclei of the thalamus (ANT) with high-frequency electric stimulation. This structure is located superior and anterior to MD, and when the DBS lead is implanted in ANT, tip contacts of the lead typically penetrate through ANT into the adjoining MD. To study the role of MD in human executive functions and working memory, we periodically disrupted and recovered MD's function with high-frequency electric stimulation using DBS contacts reaching MD while participants performed a cognitive task engaging several aspects of executive functions. We hypothesized that the efficacy of executive functions, specifically working memory, is impaired when the functioning of MD is perturbed by high-frequency stimulation. Eight participants treated with ANT-DBS for refractory epilepsy performed a computer-based test of executive functions while DBS was repeatedly switched ON and OFF at MD and at the control location (ANT). In comparison to stimulation of the control location, when MD was stimulated, participants committed 2.26 times more errors in general (total errors; OR = 2.26, 95% CI [1.69, 3.01]) and 2.86 times more working memory-related errors specifically (incorrect button presses; OR = 2.88, CI [1.95, 4.24]). Similarly, participants committed 1.81 more errors in general (OR = 1.81, CI [1.45, 2.24]) and 2.08 times more working memory-related errors (OR = 2.08, CI [1.57, 2.75]) in comparison to no stimulation condition. “Total errors” is a composite score consisting of basic error types and was mostly driven by working memory-related errors. The facts that MD and a control location, ANT, are only few millimeters away from each other and that their stimulation produces very different results highlight the location-specific effect of DBS rather than regionally unspecific general effect. In conclusion, disrupting and recovering MD's function with high-frequency electric stimulation modulated participants' online working memory performance providing causal, in vivo evidence from humans for the role of MD in human working memory.
Nonconvex Policy Search Using Variational Inequalities
Authors: Zhan Yusen , Ammar Haitham Bou , Taylor Matthew E.
Published: August 2017

Policy search is a class of reinforcement learning algorithms for finding optimal policies in control problems with limited feedback. These methods have been shown to be successful in high-dimensional problems such as robotics control. Though successful, current methods can lead to unsafe policy parameters that potentially could damage hardware units. Motivated by such constraints, we propose projection-based methods for safe policies.

These methods, however, can handle only convex policy constraints. In this letter, we propose the first safe policy search reinforcement learner capable of operating under nonconvex policy constraints. This is achieved by observing, for the first time, a connection between nonconvex variational inequalities and policy search problems. We provide two algorithms, Mann and two-step iteration, to solve the above problems and prove convergence in the nonconvex stochastic setting. Finally, we demonstrate the performance of the algorithms on six benchmark dynamical systems and show that our new method is capable of outperforming previous methods under a variety of settings.