bluuebunny/crossref_metadata_2025 huggingface dataset:
A novel murine model of esophageal nonerosive reflux disease: from inflammation to impairment in mucosal integrity
Authors: Silva Renan O. , Oliveira Francisco Fábio B. , Bingana Rudy D. , Arruda Mailton O. , Woodland Philip , Lee Chung , Souza Miguel A. N. , Soares Pedro M. G. , Santos Armênio A. , Sifrim Daniel , Souza Marcellus H. L. P.
Published: February 2017

Nonerosive reflux disease (NERD) is a highly prevalent phenotype of the gastroesophageal reflux disease. In this study, we developed a novel murine model of NERD in mice with microscopic inflammation and impairment in the epithelial esophageal barrier. Female Swiss mice were subjected to the following surgical procedure: the transitional region between the forestomach and the glandular portion of the stomach was ligated, and a nontoxic ring was placed around the duodenum near the pylorus. The control group underwent sham surgery. The animals were euthanized at 1, 3, 7, and 14 days after surgery. Survival and body weight were monitored daily. Esophageal wet weight, macroscopic lesion, histopathological alterations, myeloperoxidase (MPO) activity, cytokine levels, transepithelial electrical resistance (TEER), and mucosal permeability were evaluated. The survival rate was 78% at 14 days, with mild loss in body weight. Surgery did not induce erosive esophagitis but instead induced microscopic inflammation and increased esophageal wet weight, IL-6, keratinocyte-derived cytokine (KC) levels, and MPO activity with maximal peak between 3 and 7 days and resolution at 14 days postsurgery. Epithelial esophageal barrier was evaluated in operated mice at 7 and 14 days postsurgery; a decrease in TEER and increase in the esophageal epithelial permeability were observed compared with the sham-operated group. In addition, the inhibition of acid secretion with omeprazole significantly prevented the esophageal inflammation and impairment of barrier function at 7 days postsurgery. Thus we established a novel experimental model of NERD in mice, which can contribute to understanding the pathophysiological events associated with NERD.

NEW & NOTEWORTHY In this study, we standardized an experimental model of nonerosive reflux disease (NERD) in mice. This model involves an acute inflammatory response followed by impaired esophageal mucosal integrity, even in the absence of inflammation. Thus this model can serve for evaluation of pathophysiological aspects of NERD and open new perspectives for therapeutic strategies for patients with this disorder.
Insulin signaling via the PI3-kinase/Akt pathway regulates airway glucose uptake and barrier function in a CFTR-dependent manner
Authors: Molina Samuel A. , Moriarty Hannah K. , Infield Daniel T. , Imhoff Barry R. , Vance Rachel J. , Kim Agnes H. , Hansen Jason M. , Hunt William R. , Koval Michael , McCarty Nael A.
Published: February 2017

Cystic fibrosis-related diabetes is the most common comorbidity associated with cystic fibrosis (CF) and correlates with increased rates of lung function decline. Because glucose is a nutrient present in the airways of patients with bacterial airway infections and because insulin controls glucose metabolism, the effect of insulin on CF airway epithelia was investigated to determine the role of insulin receptors and glucose transport in regulating glucose availability in the airway. The response to insulin by human airway epithelial cells was characterized by quantitative PCR, immunoblot, immunofluorescence, and glucose uptake assays. Phosphatidylinositol 3-kinase/protein kinase B (Akt) signaling and cystic fibrosis transmembrane conductance regulator (CFTR) activity were analyzed by pharmacological and immunoblot assays. We found that normal human primary airway epithelial cells expressed glucose transporter 4 and that application of insulin stimulated cytochalasin B-inhibitable glucose uptake, consistent with a requirement for glucose transporter translocation. Application of insulin to normal primary human airway epithelial cells promoted airway barrier function as demonstrated by increased transepithelial electrical resistance and decreased paracellular flux of small molecules. This provides the first demonstration that airway cells express insulin-regulated glucose transporters that act in concert with tight junctions to form an airway glucose barrier. However, insulin failed to increase glucose uptake or decrease paracellular flux of small molecules in human airway epithelia expressing F508del-CFTR. Insulin stimulation of Akt1 and Akt2 signaling in CF airway cells was diminished compared with that observed in airway cells expressing wild-type CFTR. These results indicate that the airway glucose barrier is regulated by insulin and is dysfunctional in CF.
Higher mini-BAL total protein concentration in early ARDS predicts faster resolution of lung injury measured by more ventilator-free days
Authors: Hendrickson Carolyn M. , Abbott Jason , Zhuo Hanjing , Liu Kathleen D. , Calfee Carolyn S. , Matthay Michael A. ,   NHLBI ARDS Network
Published: February 2017

The protein concentration of alveolar edema fluid in acute respiratory distress syndrome (ARDS) is dynamic. It reflects alveolar flooding during acute injury, as well as fluid and protein clearance over time. We hypothesized that among ARDS patients treated with low tidal volume ventilation, higher concentrations of protein in mini-bronchoalveolar lavage (mBAL) samples would predict slower resolution of lung injury and worse clinical outcomes. Total protein and IgM concentrations in day 0 mBAL samples from 79 subjects enrolled in the aerosolized albuterol (ALTA) ARDS Network Albuterol Trial were measured by colorimetric assay and ELISA, respectively. Linear regression models were used to test the association of mBAL proteins with clinical outcomes and measures of length of illness, including ventilator-free days (VFDs). Median mBAL total protein concentration was 1,740 μg/ml [interquartile range (IQR): 890–3,170]. Each 500 μg/ml increase in day 0 mBAL total protein was associated with an additional 0.8 VFDs [95% confidence interval (CI): 0.05–1.6, P value = 0.038]. Median mBAL IgM concentration was 410 ng/ml (IQR: 340–500). Each 50 ng/ml increase in mBAL IgM was associated with an additional 1.1 VFDs (95% CI 0.2–2.1, P value = 0.022). These associations remained significant and were not attenuated in multivariate models adjusted for age, serum protein concentration, and vasopressor use in the 24 h before enrollment. Thus, higher mBAL total protein and IgM concentrations at day 0 are associated with more VFDs in patients with ARDS and may identify patients with preserved alveolar epithelial mechanisms for net alveolar fluid clearance.
Attenuation of endoplasmic reticulum stress by caffeine ameliorates hyperoxia-induced lung injury
Authors: Teng Ru-Jeng , Jing Xigang , Michalkiewicz Teresa , Afolayan Adeleye J. , Wu Tzong-Jin , Konduri Girija G.
Published: February 2017

Rodent pups exposed to hyperoxia develop lung changes similar to bronchopulmonary dysplasia (BPD) in extremely premature infants. Oxidative stress from hyperoxia can injure developing lungs through endoplasmic reticulum (ER) stress. Early caffeine treatment decreases the rate of BPD, but the mechanisms remain unclear. We hypothesized that caffeine attenuates hyperoxia-induced lung injury through its chemical chaperone property. Sprague-Dawley rat pups were raised either in 90 (hyperoxia) or 21% (normoxia) oxygen from postnatal day 1 (P1) to postnatal day 10 (P10) and then recovered in 21% oxygen until P21. Caffeine (20 mg/kg) or normal saline (control) was administered intraperitoneally daily starting from P2. Lungs were inflation-fixed for histology or snap-frozen for immunoblots. Blood caffeine levels were measured in treated pups at euthanasia and were found to be 18.4 ± 4.9 μg/ml. Hyperoxia impaired alveolar formation and increased ER stress markers and downstream effectors; caffeine treatment attenuated these changes at P10. Caffeine also attenuated the hyperoxia-induced activation of cyclooxygenase-2 and markers of apoptosis. In conclusion, hyperoxia-induced alveolar growth impairment is mediated, in part, by ER stress. Early caffeine treatment protects developing lungs from hyperoxia-induced injury by attenuating ER stress.
Myocardial ischemic tolerance in rats subjected to endurance exercise training during adaptation to chronic hypoxia
Authors: Alánová Petra , Chytilová Anna , Neckář Jan , Hrdlička Jaroslav , Míčová Petra , Holzerová Kristýna , Hlaváčková Markéta , Macháčková Kristýna , Papoušek František , Vašinová Jana , Benák Daniel , Nováková Olga , Kolář František
Published: February 2017

Chronic hypoxia and exercise are natural stimuli that confer sustainable cardioprotection against ischemia-reperfusion (I/R) injury, but it is unknown whether they can act in synergy to enhance ischemic resistance. Inflammatory response mediated by tumor necrosis factor-α (TNF-α) plays a role in the infarct size limitation by continuous normobaric hypoxia (CNH), whereas exercise is associated with anti-inflammatory effects. This study was conducted to determine if exercise training performed under conditions of CNH (12% O2) affects myocardial ischemic resistance with respect to inflammatory and redox status. Adult male Wistar rats were assigned to one of the following groups: normoxic sedentary, normoxic trained, hypoxic sedentary, and hypoxic trained. ELISA and Western blot analysis, respectively, were used to quantify myocardial cytokines and the expression of TNF-α receptors, nuclear factor-κB (NF-κB), and selected components of related signaling pathways. Infarct size and arrhythmias were assessed in open-chest rats subjected to I/R. CNH increased TNF-α and interleukin-6 levels and the expression of TNF-α type 2 receptor, NF-κB, inducible nitric oxide synthase (iNOS), cytosolic phospholipase A2α, cyclooxygenase-2, manganese superoxide dismutase (MnSOD), and catalase. None of these effects occurred in the normoxic trained group, whereas exercise in hypoxia abolished or significantly attenuated CNH-induced responses, except for NF-κB, iNOS, and MnSOD. Both CNH and exercise reduced infarct size, but their combination provided the same degree of protection as CNH alone. In conclusion, exercise training does not amplify the cardioprotection conferred by CNH. High ischemic tolerance of the CNH hearts persists after exercise, possibly by maintaining the increased antioxidant capacity despite attenuating TNF-α-dependent protective signaling.

NEW & NOTEWORTHY Chronic hypoxia and regular exercise are natural stimuli that confer sustainable myocardial protection against acute ischemia-reperfusion injury. Signaling mediated by TNF-α via its type 2 receptor plays a role in the cardioprotective mechanism of chronic hypoxia. In the present study, we found that exercise training of rats during adaptation to hypoxia does not amplify the infarct size-limiting effect. Ischemia-resistant phenotype is maintained in the combined hypoxia-exercise setting despite exercise-induced attenuation of TNF-α-dependent protective signaling.
Skeletal muscle bioenergetics during all-out exercise: mechanistic insight into the oxygen uptake slow component and neuromuscular fatigue
Authors: Broxterman Ryan M. , Layec Gwenael , Hureau Thomas J. , Amann Markus , Richardson Russell S.
Published: February 2017

Although all-out exercise protocols are commonly used, the physiological mechanisms underlying all-out exercise performance are still unclear, and an in-depth assessment of skeletal muscle bioenergetics is lacking. Therefore, phosphorus magnetic resonance spectroscopy (31P-MRS) was utilized to assess skeletal muscle bioenergetics during a 5-min all-out intermittent isometric knee-extensor protocol in eight healthy men. Metabolic perturbation, adenosine triphosphate (ATP) synthesis rates, ATP cost of contraction, and mitochondrial capacity were determined from intramuscular concentrations of phosphocreatine (PCr), inorganic phosphate (Pi), diprotonated phosphate ([Formula: see text]), and pH. Peripheral fatigue was determined by exercise-induced alterations in potentiated quadriceps twitch force (Qtw) evoked by supramaximal electrical femoral nerve stimulation. The oxidative ATP synthesis rate (ATPOX) attained and then maintained peak values throughout the protocol, despite an ~63% decrease in quadriceps maximal force production. ThusATPOXnormalized to force production (ATPOXgain) significantly increased throughout the exercise (1st min: 0.02 ± 0.01, 5th min: 0.04 ± 0.01 mM·min−1·N−1), as did the ATP cost of contraction (1st min: 0.048 ± 0.019, 5th min: 0.052 ± 0.015 mM·min−1·N−1). Additionally, the pre- to postexercise change in Qtw(−52 ± 26%) was significantly correlated with the exercise-induced change in intramuscular pH ( r = 0.75) and [Formula: see text] concentration ( r = 0.77). In conclusion, the all-out exercise protocol utilized in the present study elicited a “slow component-like” increase in intramuscular ATPOXgain as well as a progressive increase in the phosphate cost of contraction. Furthermore, the development of peripheral fatigue was closely related to the perturbation of specific fatigue-inducing intramuscular factors (i.e., pH and [Formula: see text] concentration).

NEW & NOTEWORTHY The physiological mechanisms and skeletal muscle bioenergetics underlying all-out exercise performance are unclear. This study revealed an increase in oxidative ATP synthesis rate gain and the ATP cost of contraction during all-out exercise. Furthermore, peripheral fatigue was related to the perturbation in pH and deprotonated phosphate ion. These findings support the concept that the oxygen uptake slow component arises from within active skeletal muscle and that skeletal muscle force generating capacity is linked to the intramuscular metabolic milieu.
A Synthetic Strategy for Conjugation of Paromomycin to Cell-Penetrating Tat(48-60) for Delivery and Visualization into Leishmania Parasites
Authors: Defaus Sira , Gallo Maria , Abengózar María A. , Rivas Luis , Andreu David
Published: February 2017

A successful approach to deliver paromomycin, a poorly absorbed aminoglycoside antibiotic, to parasite cells is reported, based on selective protection of amino and hydroxyl groups followed by conjugation to a fluorolabeled, PEG-functionalized cell-penetrating Tat(48-60) peptide. The resulting construct is efficiently internalized into Leishmania cells, evidencing the fitness of cell-penetrating peptides as vectors for efficiently transporting low-bioavailability drugs into cells.
Narrow Artificial Intelligence with Machine Learning for Real-Time Estimation of a Mobile Agent’s Location Using Hidden Markov Models
Authors: Beaulac Cédric , Larribe Fabrice
Published: February 2017

We propose to use a supervised machine learning technique to track the location of a mobile agent in real time. Hidden Markov Models are used to build artificial intelligence that estimates the unknown position of a mobile target moving in a defined environment. This narrow artificial intelligence performs two distinct tasks. First, it provides real-time estimation of the mobile agent’s position using the forward algorithm. Second, it uses the Baum–Welch algorithm as a statistical learning tool to gain knowledge of the mobile target. Finally, an experimental environment is proposed, namely, a video game that we use to test our artificial intelligence. We present statistical and graphical results to illustrate the efficiency of our method.
Path Tracking Control of Automatic Parking Cloud Model considering the Influence of Time Delay
Authors: Hua Yiding , Jiang Haobin , Cai Yingfeng , Zhang Xupei , Ma Shidian , Wu Di
Published: February 2017

This paper establishes the kinematic model of the automatic parking system and analyzes the kinematic constraints of the vehicle. Furthermore, it solves the problem where the traditional automatic parking system model fails to take into account the time delay. Firstly, based on simulating calculation, the influence of time delay on the dynamic trajectory of a vehicle in the automatic parking system is analyzed under the transverse distance Dlateral between different target spaces. Secondly, on the basis of cloud model, this paper utilizes the tracking control of an intelligent path closer to human intelligent behavior to further study the Cloud Generator‐based parking path tracking control method and construct a vehicle path tracking control model. Moreover, tracking and steering control effects of the model are verified through simulation analysis. Finally, the effectiveness and timeliness of automatic parking controller in the aspect of path tracking are tested through a real vehicle experiment.
Pancreatic Cancer: Progress and Challenges in a Rapidly Moving Field
Authors: Collisson Eric A. , Olive Kenneth P.
Published: February 2017

“Pancreatic Cancer: Advances in Science and Clinical Care,” a Special Conference of the American Association for Cancer Research, was held in Orlando, FL, on May 12 to 15, bringing together more than 450 basic, translational, clinical, and epidemiologic pancreatic cancer researchers as well as pancreatic cancer patients, survivors, and advocates. Pancreatic cancer remains one of the great challenges in medicine, but the accelerating pace of research and early hints of clinical successes to come were palpable throughout the meeting. Prominent meeting themes included immunology and the tumor microenvironment, heterogeneity of both the epithelial and stromal compartments, personalized medicine efforts to integrate molecular information into clinical practice, new approaches to early detection, and clinical trials using a host of novel targeted therapies. Adding to the vibrant atmosphere of the meeting, a coalition of pancreatic cancer research and support foundations participated, with several innovative initiatives announced by individual organizations. We present here a summary of meeting highlights, a series of “success factors” that will benchmark the progress of the field over the next 2 years, and three challenges to the pancreatic cancer research community as it moves toward to the goal of extending patient survival. Cancer Res; 77(5); 1060–2. ©2017 AACR.
Prediagnosis Leukocyte Telomere Length and Risk of Ovarian Cancer
Authors: Yang Meng , Prescott Jennifer , Poole Elizabeth M. , Rice Megan S. , Kubzansky Laura D. , Idahl Annika , Lundin Eva , De Vivo Immaculata , Tworoger Shelley S.
Published: February 2017

Background: The associations between telomere length and cancer risk are equivocal, and none have examined the association between prediagnosis leukocyte telomere length (LTL) and the risk of developing ovarian cancer.

Methods: We prospectively measured LTL collected from 442 ovarian cancer cases and 727 controls in the Nurses' Health Studies and the Northern Sweden Health and Disease Study. Cases were matched to one or two controls on age, menopausal status, and date of blood collection. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using conditional logistic regression.

Results: LTL was measured a median of 9.5 years before ovarian cancer diagnosis among cases. We observed a decreased risk of ovarian cancer with longer LTL. In multivariable models, women in the top quartile of LTL had an OR for ovarian cancer of 0.67 (95% CI, 0.46–0.97) compared with those in the bottom quartile. Inverse associations were stronger for nonserous cases (ORquartile 4 vs. quartile 1 of LTL = 0.55, 95% CI, 0.33–0.94) and rapidly fatal cases (i.e., cases who died within 3 years of diagnosis; ORquartile 4 vs. quartile 1 of LTL = 0.55, 95% CI, 0.32–0.95).

Conclusions: Our prospective findings suggest that longer circulating LTL may be associated with a lower ovarian cancer risk, especially for nonserous and rapidly fatal cases. The evaluation of LTL in relation to ovarian cancer risk by tumor subtypes is warranted in larger prospective studies.

Impact: Prediagnosis LTL may reflect an early event in the ovarian cancer development and could serve as a biomarker to predict future risk. Cancer Epidemiol Biomarkers Prev; 26(3); 339–45. ©2017 AACR.
Adolescents and Young Adults with Acute Lymphoblastic Leukemia and Acute Myeloid Leukemia: Impact of Care at Specialized Cancer Centers on Survival Outcome
Authors: Wolfson Julie , Sun Can-Lan , Wyatt Laura , Stock Wendy , Bhatia Smita
Published: February 2017

Background: Adolescents and young adults (AYA; 15–39 years) with acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) experience inferior survival when compared with children. Impact of care at NCI-designated Comprehensive Cancer Centers (CCC) or Children's Oncology Group sites (COG) on survival disparities remains unstudied.

Methods: Using the Los Angeles cancer registry, we identified 1,870 ALL or AML patients between 1 and 39 years at diagnosis. Cox regression analyses assessed risk of mortality; younger age + CCC/COG served as the referent group. Logistic regression was used to determine odds of care at CCC/COG, adjusting for variables above.

Results: ALL outcome: AYAs at non-CCC/COG experienced inferior survival (15–21 years: HR = 1.9, P = 0.005; 22–29 years: HR = 2.6, P < 0.001; 30–39 years: HR = 3.0, P < 0.001). Outcome at CCC/COG was comparable between children and young AYAs (15–21 years: HR = 1.3, P = 0.3; 22–29 years: HR = 1.2, P = 0.2) but was inferior for 30- to 39-year-olds (HR = 3.4, P < 0.001). AML outcome: AYAs at non-CCC/COG experienced inferior outcome (15–21 years: HR = 1.8, P = 0.02; 22–39 years: HR = 1.4, P = 0.06). Outcome at CCC/COG was comparable between children and 15- to 21-year-olds (HR = 1.3, P = 0.4) but was inferior for 22- to 39-year-olds (HR = 1.7, P = 0.05). Access: 15- to 21-year-olds were less likely to use CCC/COG than children (P < 0.001). In 22- to 39-year-olds, public/uninsured (ALL: P = 0.004; AML<0.001), African American/Hispanics (ALL: P = 0.03), and 30- to 39-year-olds (ALL: P = 0.03) were less likely to use CCC/COG.

Conclusions: Poor survival in AYAs with ALL and AML is mitigated by care at CCC/COG. Barriers to CCC/COG care include public/uninsured, and African American/Hispanic race/ethnicity.

Impact: Care at CCC/COG explains, in part, inferior outcomes in AYAs with ALL and AML. Key sociodemographic factors serve as barriers to care at specialized centers. Cancer Epidemiol Biomarkers Prev; 26(3); 312–20. ©2017 AACR.
Atorvastatin Decreases HBx-Induced Phospho-Akt in Hepatocytes via P2X Receptors
Authors: Ghalali Aram , Martin-Renedo Javier , Högberg Johan , Stenius Ulla
Published: February 2017

Hepatocellular carcinoma (HCC) is rated as the fifth most common malignancy and third in cancer-related deaths worldwide. Statins, HMG-CoA reductase inhibitors, are potent cholesterol-lowering drugs, and recent epidemiologic evidence suggests that statins prevent aggressive HCC development. Previous experiments revealed that statins downregulate phosphorylated Akt (pAkt). Here, it is demonstrated that atorvastatin decreases nuclear pAkt levels in pancreatic and lung cancer cell lines within minutes, and this rapid effect is mediated by the purinergic P2X receptors. Akt is upregulated by hepatitis viruses and has oncogenic activity in HCC; therefore, we tested the possibility that the P2X–Akt pathway is important for the anticipated anticancer effects of statins in hepatocytes. Atorvastatin decreased hepatitis B virus X protein- and insulin-induced pAkt and pGsk3β (Ser9) levels. Furthermore, Akt-induced lipogenesis was counteracted by atorvastatin, and these statin-induced effects were dependent on P2X receptors. Statin also decreased proliferation and invasiveness of hepatocytes. These data provide mechanistic evidence for a P2X receptor–dependent signaling pathway by which statins decrease pAkt, its downstream phosphorylation target pGsk3β, and lipogenesis in hepatocytes.

Implications: The Akt pathway is deregulated and may act as a driver in HCC development; the P2X–Akt signaling pathway may have a role in anticancer effects of statins. Mol Cancer Res; 15(6); 714–22. ©2017 AACR.
Revisiting Seed and Soil: Examining the Primary Tumor and Cancer Cell Foraging in Metastasis
Authors: de Groot Amber E. , Roy Sounak , Brown Joel S. , Pienta Kenneth J. , Amend Sarah R.
Published: February 2017

Metastasis is the consequence of a cancer cell that disperses from the primary tumor, travels throughout the body, and invades and colonizes a distant site. On the basis of Paget's 1889 hypothesis, the majority of modern metastasis research focuses on the properties of the metastatic "seed and soil," but the implications of the primary tumor "soil" have been largely neglected. The rare lethal metastatic "seed" arises as a result of the selective pressures in the primary tumor. Optimal foraging theory describes how cancer cells adopt a mobile foraging strategy to balance predation risk and resource reward. Further selection in the dispersal corridors leading out of the primary tumor enhances the adaptive profile of the potentially metastatic cell. This review focuses on the selective pressures of the primary tumor "soil" that generate lethal metastatic "seeds" which is essential to understanding this critical component of prostate cancer metastasis.

Implication: Elucidating the selective pressures of the primary tumor “soil” that generate lethal metastatic “seeds” is essential to understand how and why metastasis occurs in prostate cancer. Mol Cancer Res; 15(4); 361–70. ©2017 AACR.
Efficacy of Glucosamine Sulphate in Skin Ageing: Results from an ex vivo Anti-Ageing Model and a Clinical Trial
Authors: Gueniche Audrey , Castiel-Higounenc Isabelle
Published: February 2017

Background: Glucosamine sulphate (GS) is essential in the biosynthesis of glycolipids, glycoproteins, glycosaminoglycans (GAGs), hyaluronate, and proteoglycans. Connective tissues primarily contain collagen and proteoglycans and play an important role in skin ageing. Objective: The objectives were to assess ex vivo the impact of GS on skin ageing parameters and in vivo the effect of GS on the skin physiology of mature healthy volunteers after oral intake. Methods: The impact of GS on skin ageing was assessed ex vivo via different immunohistochemical assays and histology and via a clinical study using biopsies. Modulation of selected skin physiology markers was assessed by real-time quantitative PCR on skin punch biopsies obtained from 8 healthy >50-year-old women having ingested GS 250 mg once daily for 8 weeks. Results: Ex vivo, GS significantly (all p ≤ 0.02) increased the expression of CD44 and collagen type IV, the epidermis GAG level, and collagen type I synthesis. After 8 weeks of oral GS administration, a significantly increased expression was observed at the mRNA level for vimentin, fibromodulin, biglycan, xylosyl transferase, hyaluronan synthase, collagen types I and III, bone morphogenic protein-1, and decorin (all p ≤ 0.05). Conclusion: Both experiments showed that GS has a positive effect on epidermal and dermal markers associated with age.
A Developmental Study of the Cerebellar Nucleus in the Catshark, a Basal Gnathostome
Authors: Pose-Méndez Sol , Rodríguez-Moldes Isabel , Candal Eva , Mazan Sylvie , Anadón Ramón
Published: February 2017

The output of the cerebellar cortex is mainly released via cerebellar nuclei which vary in number and complexity among gnathostomes, extant vertebrates with a cerebellum. Cartilaginous fishes, a basal gnathostome lineage, show a conspicuous, well-organized cerebellar nucleus, unlike ray-finned fishes. To gain insight into the evolution and development of the cerebellar nucleus, we analyzed in the shark Scyliorhinus canicula (a chondrichthyan model species) the developmental expression of several genes coding for transcription factors (ScLhx5,ScLhx9,ScTbr1, and ScEn2) and the distribution of the protein calbindin, since all appear to be involved in cerebellar nuclei patterning in other gnathostomes. Three regions (subventricular, medial or central, and lateral or superficial) became recognizable in the cerebellar nucleus of this shark during development. Present genoarchitectonic and neurochemical data in embryos provide insight into the origin of the cerebellar nucleus in chondrichthyans and support a tripartite mediolateral organization of the cerebellar nucleus, as previously described in adult sharks. Furthermore, the expression pattern of ScLhx5,ScLhx9, and ScTbr1 in this shark, together with that of markers of proliferation, migration, and early differentiation of neurons, is compatible with the hypothesis that, as in mammals, different subsets of cerebellar nucleus neurons are originated from progenitors of 2 different sources: the ventricular zone of the cerebellar plate and the rhombic lip. We also present suggestive evidence that Lhx9 expression is involved in cerebellar nuclei patterning early on in gnathostome evolution, rather than representing an evolutionary innovation of the dentate nucleus in mammals, as previously hypothesized.
Impact of Renal Disease on Patients with Hepatitis C: A Retrospective Analysis of Disease Burden, Clinical Outcomes, and Health Care Utilization and Cost
Authors: Solid Craig A. , Peter Senaka A. , Natwick Tanya , Guo Haifeng , Collins Allan J. , Arduino Jean Marie
Published: February 2017

Background/Aims: Few studies explore the magnitude of the disease burden and health care utilization imposed by renal disease among patients with hepatitis C virus (HCV). We aimed to describe the characteristics, outcomes, and health care utilization and costs of patients with HCV with and without renal impairment. Methods: This retrospective analysis used 2 administrative claims databases: the US commercially insured population in Truven Health MarketScan® data (aged 20-64 years), and the US Medicare fee-for-service population in the Medicare 20% sample (aged ≥65 years). Baseline characteristics and comorbid conditions were identified from claims during 2011; patients were followed for up to 1 year (beginning January 1, 2012) to identify health outcomes of interest and health care utilization and costs. Results: In the MarketScan and Medicare databases, 35,965 and 10,608 patients with HCV were identified, 8.5 and 26.5% with evidence of renal disease (chronic kidney disease [CKD] or end-stage renal disease [ESRD]). Most comorbid conditions and unadjusted outcome rates increased across groups from patients with no evidence of renal disease to non-ESRD CKD to ESRD. Health care utilization followed a similar pattern, as did the costs. Conclusions: Our findings suggest that HCV patients with concurrent renal disease have significantly more comorbidity, a higher likelihood of negative health outcomes, and higher health care utilization and costs.
Restraint Stress during Pregnancy Rapidly Raises Kynurenic Acid Levels in Mouse Placenta and Fetal Brain
Authors: Notarangelo Francesca M. , Schwarcz Robert
Published: February 2017

Stressful events during pregnancy adversely affect brain development and may increase the risk of psychiatric disorders later in life. Early changes in the kynurenine (KYN) pathway (KP) of tryptophan (TRP) degradation, which contains several neuroactive metabolites, including kynurenic acid (KYNA), 3-hydroxykynurenine (3-HK), and quinolinic acid (QUIN), may constitute a molecular link between prenatal stress and delayed pathological consequences. To begin testing this hypothesis experimentally, we examined the effects of a 2-h restraint stress on KP metabolism in pregnant FVB/N mice on gestational day 17. TRP, KYN, KYNA, 3-HK, and QUIN levels were measured in maternal and fetal plasma and brain, as well as in the placenta, immediately after stress termination and 2 h later. In the same animals, we determined the activity of TRP 2,3-dioxygenase (TDO) in the maternal liver and in the placenta. Compared to unstressed controls, mostly transient changes in KP metabolism were observed in all of the tissues examined. Specifically, stress caused significant elevations of KYNA levels in the maternal plasma, placenta, and fetal brain, and also resulted in increased levels of TRP and KYN in the placenta, fetal plasma, and fetal brain. In contrast, 3-HK and QUIN levels remained unchanged from control values in all tissues at any time point. In the maternal liver, TDO activity was increased 2 h after stress cessation. Taken together, these findings indicate that an acute stress during the late gestational period preferentially affects the KYNA branch of KP metabolism in the fetal brain. Possible long-term consequences for postnatal brain development and pathology remain to be examined.
The Clinical Manifestation and Genetic Evaluation in Patients with 45,X/46,XY Mosaicism
Authors: Wu Qinghua , Wang Cong , Shi Huirong , Kong Xiangdong , Ren Shumin , Jiang Miao
Published: February 2017

45,X/46,XY mosaicism is a rare chromosomal abnormality and probably underdiagnosed. Although clinical and genetic analyses have been performed in some disorders of sexual development, there have been few studies focusing on the phenotype and genetic details of 45,X/46,XY mosaicism, especially in the Chinese population. The aim of this study was to describe the experience of our service in relation to 16 cases with 45,X/46,XY mosaicism. The age at the first evaluation of the patients ranged from 43 days to 30 years. Eight patients were reared as female and 8 as male. The main reasons for examination were primary amenorrhea, sterility, or ambiguous genitalia. Short stature was more common in female than in male patients. Two patients accepted gonadectomy due to tumor risk and none presented gonadal malignancy. The SRY gene was amplified positively in all of the patients. AZF gene microdeletions were present in 6 of 8 male patients, and all adult male patients had no sperm. No correlation has been found between clinical manifestations and the proportion of mosaic cells in peripheral blood. Our observations may permit a better management of people with 45,X/46,XY mosaicism.
Thiamine Deprivation Produces a Liver ATP Deficit and Metabolic and Genomic Effects in Mice: Findings Are Parallel to Those of Biotin Deficiency and Have Implications for Energy Disorders
Authors: Hernandez-Vazquez Alain de J. , Garcia-Sanchez Josue Andres , Moreno-Arriola Elizabeth , Salvador-Adriano Ana , Ortega-Cuellar Daniel , Velazquez-Arellano Antonio
Published: February 2017

Thiamine is one of several essential cofactors for ATP generation. Its deficiency, like in beriberi and in the Wernicke-Korsakoff syndrome, has been studied for many decades. However, its mechanism of action is still not completely understood at the cellular and molecular levels. Since it acts as a coenzyme for dehydrogenases of pyruvate, branched-chain keto acids, and ketoglutarate, its nutritional privation is partly a phenocopy of inborn errors of metabolism, among them maple syrup urine disease. In the present paper, we report metabolic and genomic findings in mice deprived of thiamine. They are similar to the ones we have previously found in biotin deficiency, another ATP generation cofactor. Here we show that thiamine deficiency substantially reduced the energy state in the liver and activated the energy sensor AMP-activated kinase. With this vitamin deficiency, several metabolic parameters changed: blood glucose was diminished and serum lactate was increased, but insulin, triglycerides, and cholesterol, as well as liver glycogen, were reduced. These results indicate a severe change in the energy status of the whole organism. Our findings were associated with modified hepatic levels of the mRNAs of several carbon metabolism genes: a reduction of transcripts for liver glucokinase and fatty acid synthase and augmentation of those for carnitine palmitoyl transferase 1 and phosphoenolpyruvate carboxykinase as markers for glycolysis, fatty acid synthesis, beta-oxidation, and gluconeogenesis, respectively. Glucose tolerance was initially increased, suggesting augmented insulin sensitivity, as we had found in biotin deficiency; however, in the case of thiamine, it was diminished from the 3rd week on, when the deficient animals became undernourished, and paralleled the changes in AKT and mTOR, 2 main proteins in the insulin signaling pathway. Since many of the metabolic and gene expression effects on mice deprived of thiamine are similar to those in biotin deficiency, it may be that they result from a more general impairment of oxidative phosphorylation due to a shortage of ATP generation cofactors. These findings may be relevant to energy-related disorders, among them several inborn errors of metabolism, as well as common energy disorders like obesity, diabetes, and neurodegenerative illnesses.
Choroidal Nevus-Associated Neovascular Membrane Demonstrated by OCT Angiography
Authors: Hanhart Joel , Brosh Kobi , Weill Yishay , Rozenman Yaakov
Published: February 2017

We present a case of choroidal nevus, complicated by a choroidal neovascular membrane (CNV) that was detected by OCT angiography. Choroidal nevi are relatively common intraocular tumors. The presence of subretinal and intraretinal fluids can indicate that a CNV has occurred as a complication, warranting prompt management. However, subretinal and intraretinal fluids are also documented in nevi without CNV. OCT angiography may be of great help in determining whether those fluids are associated or not with a CNV, therefore guiding therapy.
A Comparative Study of Intravenous Injection Form and Oral Jelly Form of Alendronate Sodium Hydrate for Bone Mineral Disorder after Gastrectomy
Authors: Kunisaki Chikara , Tanaka Yusaku , Kosaka Takashi , Miyamoto Hiroshi , Sato Sho , Suematsu Hideaki , Yukawa Norio , Sato Kei , Izumisawa Yusuke , Akiyama Hirotoshi , Taguri Masataka , Yamanaka Takeharu , Endo Itaru
Published: February 2017

Background/Aims: Osteoporosis is found to have high prevalence after gastrectomy and therefore, it is important to prevent this condition by means of effective medication, such as alendronate sodium hydrate. Methods: A total number of 48 gastric cancer patients diagnosed with osteoporosis after R0 gastrectomy was registered in this study between December 2013 and August 2014. Twenty-three patients received intravenous (i.v.) alendronate sodium hydrate and 25 patients received the drug in an oral jelly form. Serological and urinary examinations related to bone metabolism and bone mineral density (BMD) were performed periodically and the results obtained from the 2 groups were compared. Results: BMD increased, serum levels of bone-specific alkaline phosphatase and tartrate-resistant acid phosphatase-5b, and the urine level of urine N-terminal telopeptide decreased with time in both groups. However, the serum Ca level did not change. Two-way analysis of variance revealed no significant differences in these factors between the 2 groups. Conclusion: It is essential to prevent both forms of osteoporosis by using alendronate sodium hydrate after gastrectomy for gastric cancer. A prospective, randomized, controlled trial in many patients following long duration should be conducted to clarify the benefits of i.v. alendronate sodium hydrate.
Renin–Angiotensin System Inhibition, Worsening Renal Function, and Outcome in Heart Failure Patients With Reduced and Preserved Ejection Fraction
Authors: Beldhuis Iris E. , Streng Koen W. , Ter Maaten Jozine M. , Voors Adriaan A. , van der Meer Peter , Rossignol Patrick , McMurray John J.V. , Damman Kevin
Published: February 2017

Background—

Renin–angiotensin aldosterone system (RAAS) inhibitors significantly improve outcome in heart failure (HF) patients with reduced ejection fraction (HFREF), irrespective of the occurrence of worsening renal function (WRF). However, in HF patients with preserved ejection fraction (HFPEF), RAAS inhibitors have not been shown to improve outcome but are still frequently prescribed.

Methods and Results—

Random effect meta-analysis was performed to investigate the relationship between RAAS inhibitor therapy, WRF in both HF phenotypes, and mortality. Studies were selected based on literature search in MEDLNE and included randomized, placebo controlled trials of RAAS inhibitors in chronic HF. The primary outcome consisted of the interaction analysis for the association between RAAS inhibition–induced WRF, HF phenotype and outcome. A total of 8 studies (6 HFREF and 2 HFPEF, including 28 961 patients) were included in our analysis. WRF was more frequent in the RAAS inhibitor group, compared with the placebo group, in both HFREF and HFPEF. In HFREF, WRF induced by RAAS inhibitor therapy was associated with a less increased relative risk of mortality (relative risk, 1.19 (1.08–1.31);
P
<0.001), compared with WRF induced by placebo (relative risk, 1.48 (1.35–1.62);
P
<0.001;
P
for interaction 0.005). In contrast, WRF induced by RAAS inhibitor therapy was strongly associated with worse outcomes in HFPEF (relative risk, 1.78 (1.43–2.21);
P
<0.001), whereas placebo-induced WRF was not (relative risk, 1.25 (0.88–1.77);
P
=0.21;
P
for interaction 0.002).

Conclusions—

RAAS inhibitors induce renal dysfunction in both HFREF and HFPEF. However, in contrast to patients with HFREF where mortality increase with WRF is small, HFPEF patients with RAAS inhibitor–induced WRF have an increased mortality risk, without experiencing improved outcome with RAAS inhibition.
Demethylation of H3K27 Is Essential for the Induction of Direct Cardiac Reprogramming by miR Combo
Authors: Dal-Pra Sophie , Hodgkinson Conrad P. , Mirotsou Maria , Kirste Imke , Dzau Victor J.
Published: February 2017

Rationale:

Direct reprogramming of cardiac fibroblasts to cardiomyocytes has recently emerged as a novel and promising approach to regenerate the injured myocardium. We have previously demonstrated the feasibility of this approach in vitro and in vivo using a combination of 4 microRNAs (miR-1, miR-133, miR-208, and miR-499) that we named miR combo. However, the mechanism of miR combo mediated direct cardiac reprogramming is currently unknown.

Objective:

Here, we investigated the possibility that miR combo initiated direct cardiac reprogramming through an epigenetic mechanism.

Methods and Results:

Using a quantitative polymerase chain reaction array, we found that histone methyltransferases and demethylases that regulate the trimethylation of H3K27 (H3K27me3), an epigenetic modification that marks transcriptional repression, were changed in miR combo–treated fibroblasts. Accordingly, global H3K27me3 levels were downregulated by miR combo treatment. In particular, the promoter region of cardiac transcription factors showed decreased H3K27me3 as revealed by chromatin immunoprecipitation coupled with quantitative polymerase chain reaction. Inhibition of H3K27 methyltransferases or of the PRC2 (Polycomb Repressive Complex 2) by pharmaceutical inhibition or siRNA reduced the levels of H3K27me3 and induced cardiogenic markers at the RNA and protein level, similarly to miR combo treatment. In contrast, knockdown of the H3K27 demethylases Kdm6A and Kdm6B restored the levels of H3K27me3 and blocked the induction of cardiac gene expression in miR combo–treated fibroblasts.

Conclusions:

In summary, we demonstrated that removal of the repressive mark H3K27me3 is essential for the induction of cardiac reprogramming by miR combo. Our data not only highlight the importance of regulating the epigenetic landscape during cell fate conversion but also provide a framework to improve this technique.
Depression Treatment and 1-Year Mortality After Acute Myocardial Infarction
Authors: Smolderen Kim G. , Buchanan Donna M. , Gosch Kensey , Whooley Mary , Chan Paul S. , Vaccarino Viola , Parashar Susmita , Shah Amit J. , Ho P. Michael , Spertus John A.
Published: February 2017

Background:

Depression among patients with acute myocardial infarction (AMI) is prevalent and associated with an adverse quality of life and prognosis. Despite recommendations from some national organizations to screen for depression, it is unclear whether treatment of depression in patients with AMI is associated with better outcomes. We aimed to determine whether the prognosis of patients with treated versus untreated depression differs.

Methods:

The TRIUMPH study (Translational Research Investigating Underlying Disparities in Acute Myocardial Infarction Patients’ Health Status) is an observational multicenter cohort study that enrolled 4062 patients aged ≥18 years with AMI between April 11, 2005, and December 31, 2008, from 24 US hospitals. Research coordinators administered the Patient Health Questionnaire-9 (PHQ-9) during the index AMI admission. Depression was defined by a PHQ-9 score of ≥10. Depression was categorized as treated if there was documentation of a discharge diagnosis, medication prescribed for depression, or referral for counseling, and as untreated if none of these 3 criteria was documented in the medical records despite a PHQ score ≥10. One-year mortality was compared between patients with AMI having: (1) no depression (PHQ-9<10; reference); (2) treated depression; and (3) untreated depression adjusting for demographics, AMI severity, and clinical factors.

Results:

Overall, 759 (18.7%) patients met PHQ-9 criteria for depression and 231 (30.4%) were treated. In comparison with 3303 patients without depression, the 231 patients with treated depression had 1-year mortality rates that were not different (6.1% versus 6.7%; adjusted hazard ratio, 1.12; 95% confidence interval, 0.63–1.99). In contrast, the 528 patients with untreated depression had higher 1-year mortality in comparison with patients without depression (10.8% versus 6.1%; adjusted hazard ratio, 1.91; 95% confidence interval, 1.39–2.62).

Conclusions:

Although depression in patients with AMI is associated with increased long-term mortality, this association may be confined to patients with untreated depression.
Uncovering environmental, land-use and fire effects on the distribution of a low-dispersal species, the Hermann’s tortoise Testudo hermanni
Authors: Badiane Arnaud , Matos Cátia , Santos Xavier
Published: February 2017

Habitat destruction has resulted in the fragmented distribution of numerous terrestrial species, which poses a challenge for conservationists. Furthermore, species management can be further compounded by life history constraints such as low dispersal, hindering the ability of species to recolonize areas they formerly occupied. For these species, a thorough understanding of the local threats and factors that limit their distribution is crucial for effective management. We used occupancy models to examine which factors at landscape and habitat scales (i.e. land uses, fire history, and vegetation structure) explain the presence of terrestrial tortoises within the range of the westernmost isolated population of the endangeredTestudo hermanni hermanniin the Albera Range (NE of the Iberian Peninsula). We randomly surveyed 25 sites (75% of the area known with presence of tortoises) of natural woodlands with 5 to 8 replicates per site in spring 2012-2014. From a sampling effort of 148 hours, we only detected 52 tortoises in 12 of 25 transects. These low numbers are evidence of low population densities. Sites with presence of tortoises were spatially aggregated although the species was absent from apparently adequate sites on the edges of its distribution range. Current and historic land-use primarily explained the presence of tortoises. Besides, wildfires and reduction of habitat complexity also participate to explain the distribution of Hermann’s tortoises. We also discuss some aspects of the conservation ofTestudo hermanniin relation to our results.
It’s not the Cases, It’s the System
Authors: Koskenniemi Martti
Published: February 2017

M. Sornarajah’s recent analysis of investment arbitration as an offshoot of ‘neoliberalism’ is basically correct. But it attaches too much importance to the bias of the arbitrators and the procedural problems in arbitral practice. The controversy over the Trans-Pacific Partnership (TPP), the Transatlantic Trade and Investment Partnership (TTIP) and investment arbitration generally is not about the niceties of arbitral procedure, the discretion of arbitrators or the pros and cons of the European Union proposed ‘investment court’. The significance of investment arbitration has to do with the many ways in which already the very presence of a ‘dis-embedded’ and one-sided system of claims automatically skews public policies in favour of foreign investors. The juristic debate is but the surface of struggle over the role of public power and democratic governance of domestic and global economy.