bluuebunny/crossref_metadata_2025 huggingface dataset:
Emerging role of hydrogen sulfide-microRNA crosstalk in cardiovascular diseases
Authors: Hackfort Bryan T. , Mishra Paras K.
Published: January 2016

Despite an obnoxious smell and toxicity at a high dose, hydrogen sulfide (H2S) is emerging as a cardioprotective gasotransmitter. H2S mitigates pathological cardiac remodeling by regulating several cellular processes including fibrosis, hypertrophy, apoptosis, and inflammation. These encouraging findings in rodents led to initiation of a clinical trial using a H2S donor in heart failure patients. However, the underlying molecular mechanisms by which H2S mitigates cardiac remodeling are not completely understood. Empirical evidence suggest that H2S may regulate signaling pathways either by directly influencing a gene in the cascade or interacting with nitric oxide (another cardioprotective gasotransmitter) or both. Recent studies revealed that H2S may ameliorate cardiac dysfunction by up- or downregulating specific microRNAs. MicroRNAs are noncoding, conserved, regulatory RNAs that modulate gene expression mostly by translational inhibition and are emerging as a therapeutic target for cardiovascular disease (CVD). Few microRNAs also regulate H2S biosynthesis. The inter-regulation of microRNAs and H2S opens a new avenue for exploring the H2S-microRNA crosstalk in CVD. This review embodies regulatory mechanisms that maintain the physiological level of H2S, exogenous H2S donors used for increasing the tissue levels of H2S, H2S-mediated regulation of CVD, H2S-microRNAs crosstalk in relation to the pathophysiology of heart disease, clinical trials on H2S, and future perspectives for H2S as a therapeutic agent for heart failure.
Responses of cardiac natriuretic peptides after paroxysmal supraventricular tachycardia: ANP surges faster than BNP and CNP
Authors: Kuo Jen-Yuan , Wang An-Mei , Chang Sheng-Hsiung , Hung Chung-Lieh , Chen Chun-Yen , Shih Bing-Fu , Yeh Hung-I
Published: January 2016

Atrial natriuretic peptide (ANP) secretion increases after 30 min of paroxysmal supraventricular tachycardia (PSVT). Whether this phenomenon also applies to brain or C-type natriuretic peptides (BNP or CNP) remains unknown. Blood samples of 18 patients (41 ± 11 yr old; 4 men) with symptomatic PSVT and normal left ventricular systolic function (ejection fraction 65 ± 6%) were collected from the coronary sinus (CS) and the femoral artery (FA) before and 30 min after the induction, and 30 min after the termination of PSVT. The results showed that the ANP levels rose steeply after the PSVT and then reduced at 30 min after the termination (baseline vs. post-PSVT vs. posttermination: CS: 34.0 ± 29.6 vs. 74.1 ± 42.3 vs. 46.1 ± 32.9; FA: 5.9 ± 3.24 vs. 28.2 ± 20.7 vs. 10.0 ± 4.6 pg/ml; all P < 0.05). In contrast, compared with ANP, the increases of BNP and CNP in CS after the PSVT were less sharp, but continued to rise after the termination of tachycardia (BNP, 10.2 ± 6.4 vs. 11.3 ± 7.1 vs. 11.8 ± 7.9; CNP, 4.5 ± 1.2 vs. 4.9 ± 1.4 vs. 5.0 ± 1.4 pg/ml; all P < 0.05). The rise of BNP and CNP in FA was similarly less sharp after the PSVT and remained stationary after the termination. PSVT exerted differential effects on cardiac natriuretic peptide levels. ANP increased greater after a 30-min induced PSVT, but dropped faster after termination of PSVT, compared with BNP and CNP.
Gene expression profile of angiogenic factors in pulmonary arteries in COPD: relationship with vascular remodeling
Authors: García-Lucio Jéssica , Argemi Gemma , Tura-Ceide Olga , Diez Marta , Paul Tanja , Bonjoch Cristina , Coll-Bonfill Nuria , Blanco Isabel , Barberà Joan A. , Musri Melina M. , Peinado Victor I.
Published: January 2016

Pulmonary vessel remodeling in chronic obstructive pulmonary disease (COPD) involves changes in smooth muscle cell proliferation, which are highly dependent on the coordinated interaction of angiogenic-related growth factors. The purpose of the study was to investigate, in isolated pulmonary arteries (PA) from patients with COPD, the gene expression of 46 genes known to be modulators of the angiogenic process and/or involved in smooth muscle cell proliferation and to relate it to vascular remodeling. PA segments were isolated from 29 patients and classified into tertiles, according to intimal thickness. After RNA extraction, the gene expression was assessed by RT-PCR using TaqMan low-density arrays. The univariate analysis only showed upregulation of angiopoietin-2 ( ANGPT-2) in remodeled PA ( P < 0.05). The immunohistochemical expression of ANGPT-2 correlated with intimal enlargement ( r = 0.42, P < 0.05). However, a combination of 10 factors in a multivariate discriminant analysis model explained up to 96% of the classification of the arteries. A network analysis of 46 genes showed major decentralization. In this network, the metalloproteinase-2 ( MMP-2) was shown to be the bridge between intimal enlargement and fibrogenic factors. In COPD patients, plasma levels of ANGPT-2 were higher in current smokers or those with pulmonary hypertension. We conclude that an imbalance in ANGPT-2, combined with related factors such as VEGF, β-catenin, and MMP-2, may partially explain the structural derangements of the arterial wall. MMP-2 may act as a bridge channeling actions from the main fibrogenic factors.
Triangle Interception Scenario: A Finite-Time Guidance Approach
Authors: Guo Yang , Hu Xiaoxiang , He Fenghua , Cheng Hongjie , Gao Qinhe
Published: January 2016

Considering an aircraft threatened by an interceptor, one of the effective penetration strategies is to release a Defender from the aircraft to confront the interceptor. In this case, the aircraft, the Defender, and the interceptor constitute the three-body guidance relationship, and the cooperation of the aircraft and its Defender to achieve the best tactical effects turns into a concerned problem. This paper studies the triangle interception guidance problem via the finite-time theory. The paper presents linear system Input-Output Finite-Time Stabilization (IO-FTS) method. The sufficient conditions of the linear system, being IO-FTS, under Finite-Time Boundedness (FTB) constraint are proposed, by which the state feedback controllers design method is obtained, via Linear Matrix Inequalities (LMIs). The triangle interception guidance problems are studied in three different cases, where the proposed methods are applied to the guidance design. The simulation results illustrate the effectiveness of the proposed methods.
Morphological and Rheological Characterization of Gold Nanoparticles Synthesized Using Pluronic P103 as Soft Template
Authors: Tepale Nancy , Fernández-Escamilla Victor V. A. , Álvarez Carlos , Flores-Aquino Eric , González-Coronel Valeria J. , Cruz Daniel , Sánchez-Cantú Manuel
Published: January 2016

The synthesis of gold nanoparticles (Au-NPs), using Pluronic®P103 as soft template to design tuned hybrid gold/P103 nanomaterials, is reported here. The effect of the concentration of P103 and the synthesis temperature on the growth, size, and morphology of Au-NPs were studied. The rheological properties of these hybrid nanomaterials at different measured temperatures were studied as well. By increasing the concentration of P103, the micelles progressively grew due to an increase in the number of surface cavities. These cavities came together causing large nucleation centers and developing larger Au-NPs. The synthesis temperature was varied to induce significant dehydration of the P103 micelles. Below the cloud point temperature micelles underwent distinct changes related to spherical-to-polymer-like micelles transitions. Two nanostructures were formed: (1) small Au-NPs arranged on the surface of micelles, which acted as soft templates, and (2) large and independent Au-NPs. Above the cloud point temperature, Au-NPs were related to the shape and size of the P103 micellar aggregates. Rheological measurements showed that viscosity was sensitive to the concentration of P103. Also, it was demonstrated that synthesis temperature had a considerable influence on viscosity of the produced nanomaterials.
Endothelial Plasticity: Shifting Phenotypes through Force Feedback
Authors: Krenning Guido , Barauna Valerio G. , Krieger José E. , Harmsen Martin C. , Moonen Jan-Renier A. J.
Published: January 2016

The endothelial lining of the vasculature is exposed to a large variety of biochemical and hemodynamic stimuli with different gradients throughout the vascular network. Adequate adaptation requires endothelial cells to be highly plastic, which is reflected by the remarkable heterogeneity of endothelial cells in tissues and organs. Hemodynamic forces such as fluid shear stress and cyclic strain are strong modulators of the endothelial phenotype and function. Although endothelial plasticity is essential during development and adult physiology, proatherogenic stimuli can induce adverse plasticity which contributes to disease. Endothelial‐to‐mesenchymal transition (EndMT), the hallmark of endothelial plasticity, was long thought to be restricted to embryonic development but has emerged as a pathologic process in a plethora of diseases. In this perspective we argue how shear stress and cyclic strain can modulate EndMT and discuss how this is reflected in atherosclerosis and pulmonary arterial hypertension.
Notch4 Signaling Induces a Mesenchymal–Epithelial–like Transition in Melanoma Cells to Suppress Malignant Behaviors
Authors: Bonyadi Rad Ehsan , Hammerlindl Heinz , Wels Christian , Popper Ulrich , Ravindran Menon Dinoop , Breiteneder Heimo , Kitzwoegerer Melitta , Hafner Christine , Herlyn Meenhard , Bergler Helmut , Schaider Helmut
Published: January 2016

The effects of Notch signaling are context-dependent and both oncogenic and tumor-suppressive functions have been described. Notch signaling in melanoma is considered oncogenic, but clinical trials testing Notch inhibition in this malignancy have not proved successful. Here, we report that expression of the constitutively active intracellular domain of Notch4 (N4ICD) in melanoma cells triggered a switch from a mesenchymal-like parental phenotype to an epithelial-like phenotype. The epithelial-like morphology was accompanied by strongly reduced invasive, migratory, and proliferative properties concomitant with the downregulation of epithelial–mesenchymal transition markers Snail2 (SNAI2), Twist1, vimentin (VIM), and MMP2 and the reexpression of E-cadherin (CDH1). The N4ICD-induced phenotypic switch also resulted in significantly reduced tumor growth in vivo. Immunohistochemical analysis of primary human melanomas and cutaneous metastases revealed a significant correlation between Notch4 and E-cadherin expression. Mechanistically, we demonstrate that N4ICD induced the expression of the transcription factors Hey1 and Hey2, which bound directly to the promoter regions of Snail2 and Twist1 and repressed gene transcription, as determined by EMSA and luciferase assays. Taken together, our findings indicate a role for Notch4 as a tumor suppressor in melanoma, uncovering a potential explanation for the poor clinical efficacy of Notch inhibitors observed in this setting. Cancer Res; 76(7); 1690–7. ©2016 AACR.
Aberrant Notch Signaling in the Bone Marrow Microenvironment of Acute Lymphoid Leukemia Suppresses Osteoblast-Mediated Support of Hematopoietic Niche Function
Authors: Wang Weihuan , Zimmerman Grant , Huang Xiaoran , Yu Shuiliang , Myers Jay , Wang Yiwei , Moreton Stephen , Nthale Joseph , Awadallah Amad , Beck Rose , Xin Wei , Wald David , Huang Alex Y. , Zhou Lan
Published: January 2016

More than half of T-cell acute lymphoblastic leukemia (T-ALL) patients harbor gain-of-function mutations in the intracellular domain of Notch1. Diffuse infiltration of the bone marrow commonly occurs in T-ALL and relapsed B-cell acute lymphoblastic leukemia patients, and is associated with worse prognosis. However, the mechanism of leukemia outgrowth in the marrow and the resulting biologic impact on hematopoiesis are poorly understood. Here, we investigated targetable cellular and molecular abnormalities in leukemia marrow stroma responsible for the suppression of normal hematopoiesis using a T-ALL mouse model and human T-ALL xenografts. We found that actively proliferating leukemia cells inhibited normal hematopoietic stem and progenitor cell (HSPC) proliferation and homing to the perivascular region. In addition, leukemia development was accompanied by the suppression of the endosteum-lining osteoblast population. We further demonstrated that aberrant Notch activation in the stroma plays an important role in negatively regulating the expression of CXLC12 on osteoblasts and their differentiation. Notch blockade reversed attenuated HSPC cycling, leukemia-associated abnormal blood lineage distribution, and thrombocytopenia as well as recovered osteoblast and HSPC abundance and improved the hematopoietic-supportive functions of osteoblasts. Finally, we confirmed that reduced osteoblast frequency and enhanced Notch signaling were also features of the marrow stroma of human ALL tissues. Collectively, our findings suggest that therapeutically targeting the leukemia-infiltrated hematopoietic niche may restore HSPC homeostasis and improve the outcome of ALL patients. Cancer Res; 76(6); 1641–52. ©2016 AACR.
Divergence of Antiangiogenic Activity and Hepatotoxicity of Different Stereoisomers of Itraconazole
Authors: Shim Joong Sup , Li Ruo-Jing , Bumpus Namandje N. , Head Sarah A. , Kumar Pasunooti Kalyan , Yang Eun Ju , Lv Junfang , Shi Wei , Liu Jun O.
Published: January 2016

Purpose: Itraconazole is a triazole antifungal drug that has recently been found to inhibit angiogenesis. Itraconazole is a relatively well-tolerated drug but shows hepatotoxicity in a small subset of patients. Itraconazole contains three chiral centers and the commercial itraconazole is composed of four cis-stereoisomers (named IT-A, IT-B, IT-C, and IT-D). We sought to determine whether the stereoisomers of itraconazole might differ in their antiangiogenic activity and hepatotoxicity.

Experimental Design: We assessed in vitro antiangiogenic activity of itraconazole and each stereoisomer using human umbilical vein endothelial cell (HUVEC) proliferation and tube formation assays. We also determined their hepatotoxicity using primary human hepatocytes in vitro and a mouse model in vivo. Mouse Matrigel plug and tumor xenograft models were used to evaluate in vivo antiangiogenic and antitumor activities of the stereoisomers.

Results: Of the four stereoisomers contained in commercial itraconazole, we found that IT-A (2S,4R,2′R) and IT-C (2S,4R,2′S) were more potent for inhibition of angiogenesis than IT-B (2R,4S,2′R) and IT-D (2R,4S,2′S). Interestingly, IT-A and IT-B were more hepatotoxic than IT-C and IT-D. In mouse models, IT-C showed more potent antiangiogenic/antitumor activity with lower hepatotoxicity compared with itraconazole and IT-A.

Conclusions: These results demonstrate the segregation of influence of stereochemistry at different positions of itraconazole on its antiangiogenic activity and hepatotoxicity, with the 2 and 4 positions affecting the former and the 2′ position affecting the latter. They also suggest that IT-C may be superior to the racemic mixture of itraconazole as an anticancer drug candidate due to its lower hepatotoxicity and improved antiangiogenic activity. Clin Cancer Res; 22(11); 2709–20. ©2016 AACR.
Phase I Study of Veliparib (ABT-888) Combined with Cisplatin and Vinorelbine in Advanced Triple-Negative Breast Cancer and/orBRCAMutation–Associated Breast Cancer
Authors: Rodler Eve T. , Kurland Brenda F. , Griffin Melissa , Gralow Julie R. , Porter Peggy , Yeh Rosa F. , Gadi Vijayakrishna K. , Guenthoer Jamie , Beumer Jan H. , Korde Larissa , Strychor Sandra , Kiesel Brian F. , Linden Hannah M. , Thompson John A. , Swisher Elizabeth , Chai Xiaoyu , Shepherd Stacie , Giranda Vincent , Specht Jennifer M.
Published: January 2016

Purpose: Cisplatin is synergistic with vinorelbine and the PARP inhibitor veliparib, and has antineoplastic activity in triple-negative breast cancer (TNBC) and BRCA mutation–associated breast cancer. This phase I study assessed veliparib with cisplatin and vinorelbine.

Experimental Design: A 3+3 dose-escalation design evaluated veliparib administered twice daily for 14 days with cisplatin (75 mg/m2 day 1) and vinorelbine (25 mg/m2 days 1, 8) every 21 days, for 6 to 10 cycles, followed by veliparib monotherapy. Pharmacokinetics, measurement of poly(ADP-ribose) in peripheral blood mononuclear cells, and preliminary efficacy were assessed. IHC and gene-expression profiling were evaluated as potential predictors of response.

Results: Forty-five patients enrolled in nine dose cohorts plus five in an expansion cohort at the highest dose level and recommended phase II dose, 300 mg twice daily. The MTD of veliparib was not reached. Neutropenia (36%), anemia (30%), and thrombocytopenia (12%) were the most common grade 3/4 adverse events. Best overall response for 48 patients was radiologic response with 9-week confirmation for 17 (35%; 2 complete, 15 partial), and stable disease for 21 (44%). Germline BRCA mutation presence versus absence was associated with 6-month progression-free survival [PFS; 10 of 14 (71%) vs. 8 of 27 (30%), mid-P = 0.01]. Median PFS for all 50 patients was 5.5 months (95% confidence interval, 4.1–6.7).

Conclusions: Veliparib at 300 mg twice daily combined with cisplatin and vinorelbine is well tolerated with encouraging response rates. A phase II randomized trial is planned to assess veliparib's contribution to cisplatin chemotherapy in metastatic TNBC and BRCA mutation–associated breast cancer. Clin Cancer Res; 22(12); 2855–64. ©2016 AACR.
A DNA-binding Molecule Targeting the Adaptive Hypoxic Response in Multiple Myeloma Has Potent Antitumor Activity
Authors: Mysore Veena S. , Szablowski Jerzy , Dervan Peter B. , Frost Patrick J.
Published: January 2016

Multiple myeloma is incurable and invariably becomes resistant to chemotherapy. Although the mechanisms remain unclear, hypoxic conditions in the bone marrow have been implicated in contributing to multiple myeloma progression, angiogenesis, and resistance to chemotherapy. These effects occur via adaptive cellular responses mediated by hypoxia-inducible transcription factors (HIF), and targeting HIFs can have anticancer effects in both solid and hematologic malignancies. Here, it was found that in most myeloma cell lines tested, HIF1α, but not HIF2α expression was oxygen dependent, and this could be explained by the differential expression of the regulatory prolyl hydroxylase isoforms. The anti–multiple myeloma effects of a sequence-specific DNA-binding pyrrole-imidazole (Py-Im) polyamide (HIF-PA), which disrupts the HIF heterodimer from binding to its cognate DNA sequences, were also investigated. HIF-PA is cell permeable, localizes to the nuclei, and binds specific regions of DNA with an affinity comparable with that of HIFs. Most of the multiple myeloma cells were resistant to hypoxia-mediated apoptosis, and HIF-PA treatment could overcome this resistance in vitro. Using xenograft models, it was determined that HIF-PA significantly decreased tumor volume and increased hypoxic and apoptotic regions within solid tumor nodules and the growth of myeloma cells engrafted in the bone marrow. This provides a rationale for targeting the adaptive cellular hypoxic response of the O2-dependent activation of HIFα using polyamides.

Implications: Py-Im polyamides target and disrupt the adaptive hypoxic responses in multiple myeloma cells that may have clinical significance as a therapeutic strategy to treat myeloma engrafted in the bone marrow microenvironment. Mol Cancer Res; 14(3); 253–66. ©2016 AACR.
Inhibition of Akt Enhances the Chemopreventive Effects of Topical Rapamycin in Mouse Skin
Authors: Dickinson Sally E. , Janda Jaroslav , Criswell Jane , Blohm-Mangone Karen , Olson Erik R. , Liu Zhonglin , Barber Christy , Petricoin Emanuel F. , Calvert Valerie S. , Einspahr Janine , Dickinson Jesse E. , Stratton Steven P. , Curiel-Lewandrowski Clara , Saboda Kathylynn , Hu Chengcheng , Bode Ann M. , Dong Zigang , Alberts David S. , Timothy Bowden G.
Published: January 2016

The PI3Kinase/Akt/mTOR pathway has important roles in cancer development for multiple tumor types, including UV-induced nonmelanoma skin cancer. Immunosuppressed populations are at increased risk of aggressive cutaneous squamous cell carcinoma (SCC). Individuals who are treated with rapamycin (sirolimus, a classical mTOR inhibitor) have significantly decreased rates of developing new cutaneous SCCs compared with those that receive traditional immunosuppression. However, systemic rapamycin use can lead to significant adverse events. Here, we explored the use of topical rapamycin as a chemopreventive agent in the context of solar-simulated light (SSL)-induced skin carcinogenesis. In SKH-1 mice, topical rapamycin treatment decreased tumor yields when applied after completion of 15 weeks of SSL exposure compared with controls. However, applying rapamycin during SSL exposure for 15 weeks, and continuing for 10 weeks after UV treatment, increased tumor yields. We also examined whether a combinatorial approach might result in more significant tumor suppression by rapamycin. We validated that rapamycin causes increased Akt (S473) phosphorylation in the epidermis after SSL, and show for the first time that this dysregulation can be inhibited in vivo by a selective PDK1/Akt inhibitor, PHT-427. Combining rapamycin with PHT-427 on tumor prone skin additively caused a significant reduction of tumor multiplicity compared with vehicle controls. Our findings indicate that patients taking rapamycin should avoid sun exposure, and that combining topical mTOR inhibitors and Akt inhibitors may be a viable chemoprevention option for individuals at high risk for cutaneous SCC. Cancer Prev Res; 9(3); 215–24. ©2016 AACR.
Lentivirus-TAZ Administration Alleviates Osteoporotic Phenotypes in the Femoral Neck of Ovariectomized Rats
Authors: Yin Zhanhai , Zhang Yan , Wang Zheyang , Ding Lin , Damaolar Ainiwaerjiang , Li Zhiqiang , Qiu Yusheng , Yin Zhanhai
Published: January 2016

Background: Osteoporosis is characterized by impairment of bone mass, strength, and microarchitecture, leading to the susceptibility to fragility fractures, especially in femoral neck region. Transcriptional coactivator with PDZ-binding motif (TAZ) facilitates osteogenesis while suppressing adipogenesis via regulation of transcriptional activities of runt-related transcription factor 2 and peroxisome proliferator-activated receptor γ. Here, we validated the role of TAZ in vivo using an ovariectomized (OVX) rat model of osteoporosis. Methods: Serum alkaline phosphatase, triglyceride, cholesterol and urinary hydroxyproline were measured on an automatic analyzer using diagnostic reagent kits. Serum OCN and C-terminal cross-linked telopeptides of type I collagen were measured using ELISA. Bone mineral density was measured using dual-energy X-ray scanner. Mechanical parameters were detected by three-point bending assays. Bone volume per tissue volume (BV/TV), trabecular thickness (Tb. Th), trabecular number (Tb. No), and trabecular separation (Tb. Sp) were measured by MicroCT. The mRNA and protein levels were quantified by Realtime PCR and Western Blotting respectively. Results: After injections of lentivirus overexpressing TAZ into the femoral neck region, bone mineral density, ultimate force, stiffness, BV/TV, Tb. Th, and Tb. No were significantly increased, whereas Tb. Sp was dramatically decreased. In the TAZ-overexpression region in the femoral neck of OVX rats, the mRNA levels of Runx2 and osteocalcin were obviously elevated, whereas that of PPARγ and adipocyte protein 2 were downregulated. Conclusion: Lentivirus-mediated TAZ gene therapy alleviated the osteoporotic phenotypes in the femoral neck of OVX rats, providing an alternative strategy for the treatment of postmenopausal osteoporosis and prevention of osteoporotic fracture.
Hepatocellular Carcinoma Cells Induce Regulatory T Cells and Lead to Poor Prognosis via Production of Transforming Growth Factor-β1
Authors: Wang Yi , Liu Taotao , Tang Wenqing , Deng Bin , Chen Yanjie , Zhu Jimin , Shen Xizhong
Published: January 2016

Background/Aims: Regulatory T cells (Tregs) are associated with a poor prognosis in hepatocellular carcinoma (HCC). The purpose of the study was to explore the mechanisms of Tregs accumulation in HCC. Methods: We analyzed the frequency of Tregs in HCC by flow cytometry and immunohistochemistry. We also established a transforming growth factor (TGF)-β1-knockdown cell line by lentivirus-mediated RNA interference. Mouse CD4+CD25- T cells were cultured in supernatants from various cell lines. Results: HCC patients had a high frequency of Tregs, and high numbers of Tregs correlated with a poor prognosis. Liver cancer cells induced Treg production by secreting TGF-β1. In vivo experiments indicated that knockdown of TGF-β1 reduced the numbers of Tregs and metastatic nodules in mice. Conclusions: These results indicate that cancer-secreted TGF-β1 may increase Tregs, and TGF-β1 knockdown might impair immunosuppression in the tumor microenvironment by decrease Tregs.
Celiac Disease and Drug-Based Therapies: Inquiry into Patients Demands
Authors: Branchi Federica , Tomba Carolina , Ferretti Francesca , Norsa Lorenzo , Roncoroni Leda , Bardella Maria Teresa , Conte Dario , Elli Luca
Published: January 2016

Background/Aim: Medical research is looking for alternative drug-based options to the gluten-free diet (GFD) for celiac disease. We aimed at evaluating the need for alternative therapies perceived by celiac patients. Methods: During the 2013 meeting of the Lombardy section of the Italian Celiac Patients Association, adult subjects were invited to fill in a questionnaire investigating their clinical profile in relation to compliance to the diet, quality of life (QOL) as well as their opinion on alternative therapies. Results: Three hundred and seventy two patients (76 m, mean age 41.7 ± 13.9 years) completed the questionnaire. Patients reported a significant improvement in health status (HS) and QOL after the diet was started (p < 0.001). The GFD was accepted by 88% patients, but the need for alternative therapies was reported by 65%. Subjects expressing the need for a drug-based therapy showed a lower increase in QOL (p = 0.003) and HS (p = 0.005) on GFD. The preferred option for an alternative therapy was the use of enzymes (145 subjects), followed by a vaccine (111 subjects). Conclusion: The GFD is favorably accepted by most celiac patients. Nevertheless, a proportion of patients pronounce themselves in favor of the development of alternative drugs.
Attentional Bias in Patients with Decompensated Tinnitus: Prima Facie Evidence from Event-Related Potentials
Authors: Li Zhicheng , Gu Ruolei , Zeng Xiangli , Zhong Weifang , Qi Min , Cen Jintian
Published: January 2016

Tinnitus refers to the auditory perception of sound in the absence of external sound or electric stimuli. The influence of tinnitus on cognitive processing is at the cutting edge of ongoing tinnitus research. In this study, we adopted an objective indicator of attentional processing, i.e. the mismatch negativity (MMN), to assess the attentional bias in patients with decompensated tinnitus. Three kinds of pure tones, D1 (8,000 Hz), S (8,500 Hz) and D2 (9,000 Hz), were used to induce event-related potentials (ERPs) in the normal ear. Employing the oddball paradigm, the task was divided into two blocks in which D1 and D2 were set as deviation stimuli, respectively. Only D2 induced a significant MMN in the tinnitus group, while neither D1 nor D2 was able to induce MMN in the control group. In addition, the ERPs in the left hemisphere, which were recorded within the time window of 90-150 ms (ERP90-150 ms), were significantly higher than those in the right hemisphere in the tinnitus group, while no significant difference was observed in the control group. Lastly, the amplitude of ERP90-150 ms in the tinnitus group was significantly higher than that in the control group. These findings suggest that patients with decompensated tinnitus showed automatic processing of acoustic stimuli, thereby indicating that these patients allocated more cognitive resources to acoustic stimulus processing. We suggest that the difficulty in disengaging or facilitated attention of patients might underlie this phenomenon. The limitations of the current study are discussed.
Contribution of the Endocrine Perspective in the Evaluation of Endocrine Disrupting Chemical Effects: The Case Study of Pubertal Timing
Authors: Bourguignon Jean-Pierre , Juul Anders , Franssen Delphine , Fudvoye Julie , Pinson Anneline , Parent Anne-Simone
Published: January 2016

Debate makes science progress. In the field of endocrine disruption, endocrinology has brought up findings that substantiate a specific perspective on the definition of endocrine disrupting chemicals (EDCs), the role of the endocrine system and the endpoints of hormone and EDC actions among other issues. This paper aims at discussing the relevance of the endocrine perspective with regard to EDC effects on pubertal timing. Puberty involves particular sensitivity to environmental conditions. Reports about the advancing onset of puberty in several countries have led to the hypothesis that the increasing burden of EDCs could be an explanation. In fact, pubertal timing currently shows complex changes since advancement of some manifestations of puberty (e.g. breast development) and no change or delay of others (e.g. menarche, pubic hair development) can be observed. In a human setting with exposure to low doses of tenths or hundreds of chemicals since prenatal life, causation is most difficult to demonstrate and justifies a translational approach using animal models. Studies in rodents indicate an exquisite sensitivity of neuroendocrine endpoints to EDCs. Altogether, the data from both human and animal studies support the importance of concepts derived from endocrinology in the evaluation of EDC effects on puberty.
Biomechanical Properties and Microstructural Analysis of the Human Nonaneurysmal Aorta as a Function of Age, Gender and Location: An Autopsy Study
Authors: Ninomiya Otavio Henrique , Tavares Monteiro José Augusto , Higuchi Maria de Lourdes , Puech-Leão Pedro , de Luccia Nelson , Raghavan Madhavan Lakshmi , da Silva Erasmo Simão
Published: January 2016

Introduction: The biomechanical failure properties and histological composition of the human nonaneurysmal aorta were studied. Methods: Twenty-six human aortas were harvested from fresh cadavers at autopsy. A total of 153 circumferentially oriented strips were obtained from the aortas for biomechanical and histological studies. Results: The failure load (6.18 ± 2.03 vs. 4.85 ± 2.04 N; p = 0.001), failure tension (19.88 ± 9.05 vs. 14.53 ± 7 N/cm; p = 0.001), failure strain (0.66 ± 0.31 vs. 0.49 ± 0.25; p = 0.003) and amount of elastic fibers (19.39 ± 15.57 vs. 14.06 ± 9.5%; p = 0.011) were all significantly higher for the thoracic than the abdominal aorta. There was a significant negative correlation between age and failure load (R = -0.35; p < 0.0001), failure stress (R = -0.63; p < 0.0001), failure tension (R = -0.52; p < 0.0001) and failure strain (R = -0.8; p < 0.0001). Male aortas had a higher failure load and failure tension than female aortas. Conclusion: The thoracic aorta has a higher strength and elasticity than the abdominal aorta. The elderly have weaker and stiffer aortas than the young. Male aortas are stronger than female aortas.
Primary FSGS in Nephrotic Adults: Clinical Profile, Response to Immunosuppression and Outcome
Authors: Bagchi Soumita , Agarwal Sanjay , Kalaivani Mani , Bhowmik Dipankar , Singh Geetika , Mahajan Sandeep , Dinda Amit
Published: January 2016

Aim: Primary focal segmental glomerulosclerosis (FSGS) is a common cause of nephrotic proteinuria in adults. Most studies on FSGS have combined pediatric and adult patients. This study aims at assessing the response to immunosuppression and its impact on renal survival in adults with primary FSGS. Methods: Patients with nephrotic proteinuria with primary FSGS seen from January 2010 to December 2014 were included. Clinical, laboratory and treatment details were recorded. Deterioration in renal function was defined as ≥50% decline in estimated glomerular filtration rate (eGFR) or progression to end-stage renal disease. Results: There were 116 patients with median follow-up of 23.6 (6-65.1) months. Baseline proteinuria was 5.1 ± 2.6 g/day and eGFR was 96.9 ± 35.1 ml/min/1.73 m2. One hundred one (94.4%) patients had received angiotensin converting enzyme inhibitor/angiotensin receptor blocker (ACEi/ARB). One hundred fourteen patients received steroids. Forty two of 114 patients (36.8%)were steroid resistant. Thirty eight received calcineurin inhibitors (CNI). Seventeen (44.7%) were CNI resistant of which 2 achieved remission with alternate immunosuppression. Eleven (9.5%) patients had worsening renal function - 9 had no remission, 2 had PR with none in CR (30 vs. 5.6% vs. 0, respectively, log-rank, p < 0.001). ACEi/ARBs use and remission of proteinuria were independently associated with better renal survival. Conclusion: Achieving remission, whether complete or partial, is the critical factor in predicting renal survival in nephrotic adults with primary FSGS. Steroid-resistant patients have reasonable renal survival, if proteinuria is reduced with timely use of alternate immunosuppression. CNI resistance is a major hurdle in management with limited treatment options.
Cytomegalovirus Colitis, Cytomegalovirus Hepatitis and Systemic Cytomegalovirus Infection: Common Features and Differences
Authors: Nakase Hiroshi , Herfarth Hans
Published: January 2016

Cytomegalovirus (CMV) is a ubiquitous human herpes virus, which, after often asymptomatic primary infection, establishes a lifelong latent infection that can periodically be reactivated in both immunocompetent and immunosuppressed carriers. Whereas the diagnostic approach in case of a suspicion of CMV reactivation is well defined, the indication for antiviral therapy can often only be made in the context of an extent of organ involvement, the immune status, and comorbidities of the patient. This article reviews the epidemiology, diagnosis, and therapy of CMV reactivation with a focus on inflammatory bowel diseases and potentially different diagnostic and therapeutic approaches in Asia and the Western world.
Enhanced Recovery after Surgery Protocol in Abdominal Hysterectomies for Malignant versus Benign Disease
Authors: Wijk Lena , Franzén Karin , Ljungqvist Olle , Nilsson Kerstin
Published: January 2016

Background: The enhanced recovery after surgery (ERAS) protocol combines unimodal evidence-based interventions aiming to enhance recovery after surgery and reduce length of stay (LOS). We introduced an ERAS protocol in gynecological surgery and compared outcomes after hysterectomies performed for malignant vs. benign indications. Methods: This prospective cohort study was conducted at the Department of Obstetrics and Gynecology, Örebro University Hospital, Sweden, among 121 consecutive patients undergoing abdominal hysterectomy and salpingo-oophorectomy for malignant (n = 40) or benign (n = 81) indications between 2012 and 2014. Clinical data were prospectively collected and extracted from the patient records and from a specific database. The primary outcomes were LOS and proportion of patients achieving target LOS (2 days). Results: Patients operated for malignant vs. benign disease did not differ significantly in terms of LOS (2 (1-5) vs. 2 (1-11) days; p = 0.505), proportion discharged at target LOS (62 vs. 69%; p = 0.465; OR 0.74, 95% CI 0.3-1.6), complications (2 vs. 7% in primary stay, 8 vs. 11% within 30 days after discharge), reoperations (0 vs. 2%), or readmissions (2 vs. 1%). Conclusion: The ERAS protocol may be equally applicable to patients undergoing hysterectomy either for a malignant or for a benign disease.
Urine Calcium and Bone Mineral Density in Calcium Stone-Forming Patients Treated with Alendronate and Hydrochlorothiazide
Authors: Arrabal-Martín Miguel , González-Torres Samuel , Cano-García María del Carmen , De Haro-Muñoz Tomás , Abad-Menor Félix , Arrabal-Polo Miguel Ángel , Cózar-Olmo José Manuel
Published: January 2016

Introduction: The objective was to evaluate the effect of hydrochlorothiazide and alendronate on urine calcium and bone mineral density in calcium stone-forming patients. Material and Methods: A prospective, non-randomized, non-observational comparative study was performed; this study included 111 patients with recurrent calcium stones, divided into 3 groups according to the treatment received. Group 1: 36 patients were treated with alendronate, 70 mg/week; Group 2: 34 patients were treated with alendronate, 70 mg/week + hydrochlorothiazide, 50 mg/day; Group 3: 41 patients were treated with hydrochlorothiazide, 50 mg/day. All patients received recommendations on diet and fluid intake. Other variables of bone mineral density were studied and analyzed, including bone remodeling markers and urinary calcium before and after 2 years of treatment. The statistical analysis was performed using the SPSS 17.0 program, with a statistical significance of p < 0.05. Results: After 2 years of treatment, a significant difference was observed in the β-crosslaps and a bone mineral density improvement in Group 1, along with a decrease in urinary calcium. In Group 3, a statistically significant difference was found in urinary calcium and fasting calcium/creatinine ratio, as well as an improvement in bone mineral density after 2 years of medical treatment. In Group 2 patients treated with the combination, there was an improvement in bone mineral density and a decrease in the β-crosslaps marker similar to patients in Group 1, and a decrease in urinary calcium similar to those in Group 3. Conclusion: Combined alendronate + hydrochlorothiazide treatment offers the best results along with the improvement in bone mineral density and decrease in urine calcium in patients with recurrent calcium stones.
Cyclosporine-Associated Leukoencephalopathy in a Case of Sympathetic Ophthalmitis
Authors: Tagami Mizuki , Azumi Atsushi
Published: January 2016

Purpose: Cyclosporine (CsA) is currently widely used as a primary immunosuppressive agent in ocular disease, particularly in severe uveitis. Posterior reversible encephalopathy syndrome (PRES) is a significant complication of CsA therapy. However, there are no reports of the occurrence of PRES in response to the treatment of uveitis in the ophthalmological area. Case Presentation: We report a case with CsA-associated PRES. A 70-year-old woman with sympathetic ophthalmitis was treated with 50 mg/day of CsA for 1 week. However, the trough level in her blood was too low; thus, we increased the dose to 100 mg/day of CsA with prednisolone. She had headaches, hypertension (systolic blood pressure 180-200 mm Hg), loss of consciousness for several hours, and reduced limb movement, and her MRI showed a high signal intensity in both posterior lobes, consistent with PRES. Examination of the cerebrospinal fluid indicated that it was within normal limits. Her CsA trough level in the blood was within normal ranges on the day of the attack. Her symptoms gradually improved over the next several days; however, she presented with cortical blindness, which lasted for several weeks. Finally, she returned to her baseline values from before the attack. Her MRI findings showed that PRES had essentially disappeared. Conclusion: PRES is not directly associated with the dosage of CsA administered; however, in general, it is well known that PRES can affect strongly immunosuppressed cases undergoing organ and bone marrow transplantation. Nevertheless, our CsA dose was only 100 mg (1.8 mg/kg). In this study, we report on the occurrence of PRES after the administration of CsA to treat sympathetic ophthalmia. To our knowledge, PRES can also occur after the administration of a small dose of CsA; thus, ophthalmologists using CsA should carefully observe the systemic conditions of CsA-treated patients.
Serum Magnesium and the Risk of Death From Coronary Heart Disease and Sudden Cardiac Death
Authors: Kieboom Brenda C. T. , Niemeijer Maartje N. , Leening Maarten J. G. , van den Berg Marten E. , Franco Oscar H. , Deckers Jaap W. , Hofman Albert , Zietse Robert , Stricker Bruno H. , Hoorn Ewout J.
Published: January 2016

Background

Low serum magnesium has been implicated in cardiovascular mortality, but results are conflicting and the pathway is unclear. We studied the association of serum magnesium with coronary heart disease (
CHD
) mortality and sudden cardiac death (
SCD
) within the prospective population‐based Rotterdam Study, with adjudicated end points and long‐term follow‐up.

Methods and Results

Nine‐thousand eight‐hundred and twenty participants (mean age 65.1 years, 56.8% female) were included with a median follow‐up of 8.7 years. We used multivariable Cox proportional hazard models and found that a 0.1 mmol/L increase in serum magnesium level was associated with a lower risk for
CHD
mortality (hazard ratio: 0.82, 95%
CI
0.70–0.96). Furthermore, we divided serum magnesium in quartiles, with the second and third quartile combined as reference group (0.81–0.88 mmol/L). Low serum magnesium (≤0.80 mmol/L) was associated with an increased risk of
CHD
mortality (N=431, hazard ratio: 1.36, 95%
CI
1.09–1.69) and
SCD
(N=217, hazard ratio: 1.54, 95%
CI
1.12–2.11). Low serum magnesium was associated with accelerated subclinical atherosclerosis (expressed as increased carotid intima‐media thickness: +0.013 mm, 95%
CI
0.005–0.020) and increased
QT
‐interval, mainly through an effect on heart rate (
RR
‐interval: −7.1 ms, 95%
CI
−13.5 to −0.8). Additional adjustments for carotid intima‐media thickness and heart rate did not change the associations with
CHD
mortality and
SCD
.

Conclusions

Low serum magnesium is associated with an increased risk of
CHD
mortality and
SCD
. Although low magnesium was associated with both carotid intima‐media thickness and heart rate, this did not explain the relationship between serum magnesium and
CHD
mortality or
SCD
. Future studies should focus on why magnesium associates with
CHD
mortality and
SCD
and whether intervention reduces these risks.
Downward and Parallel Perspectives in an Experimental Study of Out-of-Body Experiences
Authors: Hiromitsu Kentaro , Midorikawa Akira
Published: January 2016

Out-of-body experiences (OBEs) have been reported in patients with neurological or psychiatric disorders. According to these reports, the patients looked down on their body from overhead. Based on this phenomenon, we adopted a downward perspective in an experimentally induced OBE paradigm and compared responses to an OBE questionnaire (sensations of OBE) with self-location mapping (feelings of body drift). The results revealed a correlation between the sensation of an OBE and self-location under the downward-perspective condition but not under the parallel-perspective condition; however, no significant difference was observed between the two conditions. Thus, the effect of perspective on OBE illusion that has been reported in clinical research of OBE did not affect the results obtained in previous studies inducing OBE.
Human-Driven Atmospheric Deposition of N and P Controls on the East Mediterranean Marine Ecosystem
Authors: Christodoulaki S. , Petihakis G. , Mihalopoulos N. , Tsiaras K. , Triantafyllou G. , Kanakidou M.
Published: January 2016

The historical and future impacts of atmospheric deposition of inorganic nitrogen (N) and phosphorus (P) on the marine ecosystem in the east Mediterranean Sea are investigated by using a 1D coupled physical– biogeochemical model, set up for the Cretan Sea as a representative area of the basin. For the present-day simulation (2010), the model is forced by observations of atmospheric deposition fluxes at Crete, while for the hindcast (1860) and forecast (2030) simulations, the changes in atmospheric deposition calculated by global chemistry–transport models are applied to the present-day observed fluxes. The impact of the atmospheric deposition on the fluxes of carbon in the food chain is calculated together with the contribution of human activities to these impacts. The results show that total phytoplanktonic biomass increased by 16% over the past 1.5 centuries. Small fractional changes in carbon fluxes and planktonic biomasses are predicted for the near future. Simulations show that atmospheric deposition of N and P may be the main mechanism responsible for the anomalous N:P ratio observed in the Mediterranean Sea.
Langmuir Turbulence Parameterization in Tropical Cyclone Conditions
Authors: Reichl Brandon G. , Wang Dong , Hara Tetsu , Ginis Isaac , Kukulka Tobias
Published: January 2016

The Stokes drift of surface waves significantly modifies the upper-ocean turbulence because of the Craik–Leibovich vortex force (Langmuir turbulence). Under tropical cyclones the contribution of the surface waves varies significantly depending on complex wind and wave conditions. Therefore, turbulence closure models used in ocean models need to explicitly include the sea state–dependent impacts of the Langmuir turbulence. In this study, the K-profile parameterization (KPP) first-moment turbulence closure model is modified to include the explicit Langmuir turbulence effect, and its performance is tested against equivalent large-eddy simulation (LES) experiments under tropical cyclone conditions. First, the KPP model is retuned to reproduce LES results without Langmuir turbulence to eliminate implicit Langmuir turbulence effects included in the standard KPP model. Next, the Lagrangian currents are used in place of the Eulerian currents in the KPP equations that calculate the bulk Richardson number and the vertical turbulent momentum flux. Finally, an enhancement to the turbulent mixing is introduced as a function of the nondimensional turbulent Langmuir number. The retuned KPP, with the Lagrangian currents replacing the Eulerian currents and the turbulent mixing enhanced, significantly improves prediction of upper-ocean temperature and currents compared to the standard (unmodified) KPP model under tropical cyclones and shows improvements over the standard KPP at constant moderate winds (10 m s−1).
Applying Automated Underway Ship Observations to Numerical Model Evaluation
Authors: Smith Shawn R. , Briggs Kristen , Lopez Nicolas , Kourafalou Vassiliki
Published: January 2016

Numerical models are used widely in the oceanic and atmospheric sciences to estimate and forecast conditions in the marine environment. Herein the application of in situ observations collected by automated instrumentation on ships at sampling rates ≤5 min is demonstrated as a means to evaluate numerical model analyses. Specific case studies use near-surface ocean observations collected by a merchant vessel, an ocean racing yacht, and select research vessels to evaluate various ocean analyses from the Hybrid Coordinate Ocean Model (HYCOM). Although some specific differences are identified between the observations and numerical model analyses, the purpose of these comparisons is to demonstrate the value of high-sampling-rate in situ observations collected on ships for numerical model evaluation.