bluuebunny/crossref_metadata_2025 huggingface dataset:
Regular and Moderate Exercise Counteracts the Decline of Antioxidant Protection but Not Methylglyoxal‐Dependent Glycative Burden in the Ovary of Reproductively Aging Mice
Authors: Falone S. , Santini S. Jr , Cordone V. , Grannonico M. , Cacchio M. , Di Emidio G. , Tatone C. , Amicarelli F.
Published: December 2016

Population aging results in urgent needs of interventions aimed at ensuring healthy senescence. Exercise often results in healthy aging, yet many molecular mechanisms underlying such effects still need to be identified. We here investigated whether the age‐dependent accumulation of oxidative and methylglyoxal‐ (MG‐) related molecular damage could be delayed by moderate exercise in the mouse ovary, an organ that first exhibits impaired function with advancing age in mammals. CD1 female mice underwent two‐ or four‐month treadmill‐based running through the transition from adult to middle age, when ovaries show signs of senescence, and markers of protection against reactive oxygen species (ROS) and MG were measured. The long‐term exercise reduced the protein oxidative damage in the ovaries (P < 0.01), and this was linked to the preservation of the glutathione peroxidase protection against ROS (P < 0.001), as well as to the increased glutathione availability (P < 0.001). Conversely, even though the age‐related deactivation of the MG‐targeting systems was partially prevented by the long‐term running programme (P < 0.001), exercised mice were not protected from the age‐dependent glycative burden. In summary, lately initiated regular and moderate exercise limited some changes occurring in the ovaries of middle‐aged mice, and this might help to develop nonpharmacological cointerventions to reduce the vulnerability of mammalian ovaries towards redox dysfunctions.
In Vitro Evaluation of Colloidal Silver on Immune Function: Antilymphoproliferative Activity
Authors: Franco-Molina M. A. , Mendoza-Gamboa E. , Zarate-Triviño D. G. , Coronado-Cerda E. E. , Alcocer-González J. M. , Resendez-Pérez D. , Rodríguez-Salazar M. C. , Rivera-Morales L. G. , Tamez-Guerra R. , Rodríguez-Padilla C.
Published: December 2016

Colloidal silver (AgC) is currently used by humans and it can be internalized through inhalation, injection, ingestion, and dermal contact. However, there is limited information about immunological activity; more investigations using colloidal silver are needed. In the present study, the effects of AgC (17.5 ng/mL) on immunological parameters (proliferation and immunophenotyping) using human peripheral blood mononuclear cells (PBMC) and macrophages (phagocytosis) and cytotoxicity on leukemia and lymphoma cancer cell lines (1.75 to 17.5 ng/mL) were investigated. AgC was observed to significantly (p<0.05) decrease interleukin-2 (IL-2) production and proliferation induced by phytohemagglutinin or concanavalin A in PBMC without affecting its cell viability but with cytotoxic effect on cancer cells. IL-2, IL-4, IL-6, IL-10, INF-γ, and IL-17A cytokines production and CD3+, CD3−CD19+, CD3+CD4+, CD3+CD8+, and CD16+CD56+ PBMC phenotypes were not affected by AgC. The present study demonstrates that colloidal silver is harmless and nontoxic to the immune system cells and its ability to interfere with the immune response by decreasing cell proliferation when stimulated with mitogens demonstrated the antilymphoproliferative potential of AgC.
A Clinicoimmunohistopathologic Study of Anetoderma: Is Protruding Type More Advanced in Stage Than Indented Type?
Authors: Kim Jung Eun , Sohn Ki Min , Woo Young Jun , Jeong Kwan Ho , Kim Miri , Lee Jeong Deuk , Lee Jun Young , Park Hyun Jeong , Kim Gyong Moon , Park Chul Jong , Yu Dong Soo , Kang Hoon
Published: December 2016

Background. The clinical and histopathologic classification of anetoderma are not well characterized.Objective. We aimed to investigate the clinical and histopathologic characteristics of anetoderma and to correlate clinical phenotypes with immunohistopathologic findings.Methods. We retrospectively reviewed the medical records of 30 patients with anetoderma and performed immunohistochemistry for elastin, fibrillin-1, metalloproteinase- (MMP-) 2, MMP-7, MMP-9, and MMP-12, and tissue inhibitor of metalloproteinase- (TIMP-) 1 and TIMP-2.Results. Protruding type (n= 17) had a longer disease duration and more severe loss of elastin, without changes in fibrillin, than indented type (n= 13). MMP-2 and MMP-9 showed significantly higher expressions in the dermis compared with controls (p< 0.05). MMP-7 and MMP-12 showed little expressions in both anetoderma and control tissue. TIMP-1 was highly expressed in anetoderma lesions and controls. TIMP-2 expression was variable.Conclusions. Our findings suggest that protruding type anetoderma may represent a more advanced stage and that MMP-2 and MMP-9 could be responsible for elastic fiber degradation in anetoderma.
Accelerated Degradation Process Analysis Based on the Nonlinear Wiener Process with Covariates and Random Effects
Authors: Sun Li , Gu Xiaohui , Song Pu
Published: December 2016

It is assumed that the drift parameter is dependent on the acceleration variables and the diffusion coefficient remains the same across the whole accelerated degradation test (ADT) in most of the literature based on Wiener process. However, the diffusion coefficient variation would also become obvious in some applications with the stress increasing. Aiming at the phenomenon, the paper concludes that both the drift parameter and the diffusion parameter depend on stress variables based on the invariance principle of failure mechanism and Nelson assumption. Accordingly, constant stress accelerated degradation process (CSADP) and step stress accelerated degradation process (SSADP) with random effects are modeled. The unknown parameters in the established model are estimated based on the property of degradation and degradation increment, separately for CASDT and SSADT, by the maximum likelihood estimation approach with measurement error. In addition, the simulation steps of accelerated degradation data are provided and simulated step stress accelerated degradation data is designed to validate the proposed model compared to other models. Finally, a case study of CSADT is conducted to demonstrate the benefits of our model in the practical engineering.
Postoperative Pain, an Unmet Problem in Day or Overnight Italian Surgery Patients: A Prospective Study
Authors: Campagna Sara , Antonielli D’Oulx Maria Delfina , Paradiso Rosetta , Perretta Laura , Re Viglietti Silvia , Berchialla Paola , Dimonte Valerio
Published: December 2016

Background. Because of economic reasons, day surgery rates have steadily increased in many countries and the trend is to perform around 70% of all surgical procedures as day surgery. Literature shows that postoperative pain treatment remains unfulfilled in several fields such as orthopedic and general surgery patients. In Italy, the day surgery program is not yet under governmental authority and is managed regionally by local practices. Aim. To investigate the trends in pain intensity and its relation to type of surgeries and pain therapy protocols, in postoperative patients, discharged from three different Ambulatory Surgeries located in North West Italy (Piedmont region). Method. The present study enrolled 276 patients who undergone different surgical procedures in ambulatory regimen. Patients recorded postoperative pain score twice a day, compliance with prescribed drugs, and pain related reasons for contacting the hospital. Monitoring lasted for 7 days. Results. At discharge, 72% of patients were under weak opioids, 12% interrupted the treatment due to side effects, 17% of patients required extra drugs, and 15% contacted the hospital reporting pain problems. About 50% of patients experienced moderate pain during the first day after surgery. Results from our study show that most of the patients experienced avoidable pain after discharge.
Peroxisome Proliferator-Activated Receptor Modulation during Metabolic Diseases and Cancers: Master and Minions
Authors: Vitale Salvatore Giovanni , Laganà Antonio Simone , Nigro Angela , La Rosa Valentina Lucia , Rossetti Paola , Rapisarda Agnese Maria Chiara , La Vignera Sandro , Condorelli Rosita Angela , Corrado Francesco , Buscema Massimo , D’Anna Rosario
Published: December 2016

The prevalence of obesity and metabolic diseases (such as type 2 diabetes mellitus, dyslipidaemia, and cardiovascular diseases) has increased in the last decade, in both industrialized and developing countries. This also coincided with our observation of a similar increase in the prevalence of cancers. The aetiology of these diseases is very complex and involves genetic, nutritional, and environmental factors. Much evidence indicates the central role undertaken by peroxisome proliferator-activated receptors (PPARs) in the development of these disorders. Due to the fact that their ligands could become crucial in future target-therapies, PPARs have therefore become the focal point of much research. Based on this evidence, this narrative review was written with the purpose of outlining the effects of PPARs, their actions, and their prospective uses in metabolic diseases and cancers.
Driver Behavior Modeling: Developments and Future Directions
Authors: AbuAli Najah , Abou-zeid Hatem
Published: December 2016

The advances in wireless communication schemes, mobile cloud and fog computing, and context-aware services boost a growing interest in the design, development, and deployment of driver behavior models for emerging applications. Despite the progressive advancements in various aspects of driver behavior modeling (DBM), only limited work can be found that reviews the growing body of literature, which only targets a subset of DBM processes. Thus a more general review of the diverse aspects of DBM, with an emphasis on the most recent developments, is needed. In this paper, we provide an overview of advances of in-vehicle and smartphone sensing capabilities and communication and recent applications and services of DBM and emphasize research challenges and key future directions.
Alginate: Current Use and Future Perspectives in Pharmaceutical and Biomedical Applications
Authors: Szekalska Marta , Puciłowska Agata , Szymańska Emilia , Ciosek Patrycja , Winnicka Katarzyna
Published: December 2016

Over the last decades, alginates, natural multifunctional polymers, have increasingly drawn attention as attractive compounds in the biomedical and pharmaceutical fields due to their unique physicochemical properties and versatile biological activities. The focus of the paper is to describe biological and pharmacological activity of alginates and to discuss the present use and future possibilities of alginates as a tool in drug formulation. The recent technological advancements with using alginates, issues related to alginates suitability as matrix for three-dimensional tissue cultures, adjuvants of antibiotics, and antiviral agents in cell transplantation in diabetes or neurodegenerative diseases treatment, and an update on the antimicrobial and antiviral therapy of the alginate based drugs are also highlighted.
Acanthopanaxversus3-Methyladenine Ameliorates Sodium Taurocholate-Induced Severe Acute Pancreatitis by Inhibiting the Autophagic Pathway in Rats
Authors: Wang Xiaohong , Zhou Guoxiong , Liu Chun , Wei Ronglong , Zhu Shunxing , Xu Yuefen , Wu Mengjie , Miao Qing
Published: December 2016

Objectives. To observe the therapeutic effects of Acanthopanax and 3-methyladenine against severe acute pancreatitis (SAP).Methods. Sodium taurocholate-induced SAP rats were equally randomized into a SAP group, an Acanthopanax group, and a 3-methyladenine group. Serum amylase levels were determined by ELISA; protein and mRNA expression levels of nucleus nuclear factor kappa B (NF-κB) p65, light chain 3II (LC3-II), and Beclin-1 and mRNA expression levels of Class III phosphatidylinositol 3-kinase (PI3K-III) in pancreas tissue were detected by Western blot and quantitative real-time PCR, respectively; mortality and pathological change of the pancreas were observed at 3, 12, and 24 h after operation.Results. There was no significant difference in mortality between SAP group and both treatment groups (P>0.05). Serum amylase levels, protein, and mRNA expression levels of nucleus NF-κB p65, LC3-II, and Beclin-1 protein, mRNA expression levels of PI3K-III, and pathological score of the pancreas in both treatment groups were significantly lower than those in SAP group at 12 and 24 h after operation (P<0.05or 0.01). The number of autophagosomes and autophagolysosomes of pancreatic acinar cells in both treatment groups was smaller than that in SAP group at 12 and 24 h.Conclusions. Acanthopanax and 3-methyladenine had similar therapeutic effects against SAP in rats. The mechanism may be through inhibiting abnormal autophagy activation of pancreatic acinar cells.
Species Composition and Visiting Frequencies of Flower Visitors ofChromolaena odoratain a Dry Zone Forest Patch of Sri Lanka
Authors: Rathnayake D. G. R. M. M. Kaushalya , Wijetunga W. M. G. Asanga S. T. B.
Published: December 2016

Plant-animal interaction has been a major theme in ecology as it has helped ecologists to rule out different patterns they observed in the surrounding environments.Chromolaena odoratais another plant species that is studied extensively as it has become a major troublesome weed in many parts of the tropics. But, handful of studies are available on pollination of this invasive plant species in dry forests and its function as a pollinator sink in these environments. The current study was carried out in a dry zone secondary forest patch in North-Central Sri Lanka to assess the diversity, abundance, and pollination strength of flower visitors associated with theC. odorata. The results suggest that the diversity of Hymenoptera and Lepidoptera is higher than the other insect orders that visitedC. odorata, but all species exerted equal pollination strength on the plant. The attraction of large numbers of insects is concluded to as one of the factors that contribute to the reproductive success ofC. odoratain dry zone forests.
Clinical and Immunologic Profiles in Incomplete Lupus Erythematosus and Improvement with Hydroxychloroquine Treatment
Authors: Olsen Nancy J. , McAloose Carl , Carter Jamie , Han Bobby Kwanghoon , Raman Indu , Li Quan-Zhen , Liao Duanping
Published: December 2016

Objective. The study goals were to evaluate performance of SLE classification criteria, to define patients with incomplete lupus erythematosus (ILE), and to probe for features in these patients that might be useful as indicators of disease status and hydroxychloroquine response. Methods. Patients with ILE (N=70) and SLE (N=32) defined by the 1997 American College of Rheumatology criteria were reclassified using the 2012 Systemic Lupus International Collaborating Clinics criteria. Disease activity, patient reported outcomes, and levels of Type I interferon- (IFN-) inducible genes, autoantibodies, and cytokines were measured. Subgroups treated with hydroxychloroquine (HCQ) were compared to patients not on this drug. Results. The classification sets were correlated (R2=0.87). ILE patients were older (P=0.0043) with lower disease activity scores (P<0.001) and greater dissatisfaction with health status (P=0.034) than SLE patients. ILE was associated with lower levels of macrophage-derived cytokines and levels of expressed Type I IFN-inducible genes. Treatment of ILE with HCQ was associated with better self-reported health status scores and lower expression levels of Type I IFN-inducible genes than ILE patients not on HCQ. Conclusion. The 2012 SLICC SLE classification criteria will be useful to define ILE in trials. Patients with ILE have better health status and immune profiles when treated with HCQ.
Implementation of an Automated Primary Care Acute Kidney Injury Warning System: A Quantitative and Qualitative Review of 2 Years of Experience
Authors: Alavijeh Omid Sadeghi , Bansal Jas , Hadfield Katie , Laing Christopher , Dawnay Anne
Published: December 2016

Background: Acute kidney injury (AKI) is often detected late, leading to worse clinical outcomes. In 2012, we pioneered an AKI-alerting system for primary care clinicians (PCCs). We retrospectively analysed the alerts and evaluated PCC satisfaction to assess the feasibility of the system. Methods: The study used a 2-pronged approach. AKI alerts, generated by an algorithm designed by University College London Hospital biochemistry department between June 2012 and June 2014, were analysed to reveal the demographics and outcomes of each patient generating an alert. Second, a survey was sent to all PCCs assessing awareness and satisfaction with the service. Simple statistical methods were applied (mean, median, SD and interquartile range). Results: One hundred forty-two alerts were generated, of which 101 were genuine. Generally, the patient demographics, AKI stratification and aetiology were in keeping with the inpatient AKI population. Forty-eight percent of cases were referred to the hospital with a median length of stay of 9.9 days. Three-month mortality was 12%. Among PCCs, there was good awareness of the system with most finding it valuable. The key complaints around the system were to do with lack of knowledge of its existence. Conclusions: Our evaluation has demonstrated that the implementation of AKI alerts in the community is technically feasible, does not result in excessive demand on hospital services, appears to influence PCC behaviour and was perceived overwhelmingly as a useful service by these clinicians. This experience should inform further developments including behavioural interventions (such as clinician alerts) to improve community AKI care.
Increase of Mast Cell-Nerve Association and Neuropeptide Receptor Expression on Mast Cells in Perennial Allergic Rhinitis
Authors: Le Duc Dung , Schmit David , Heck Sebastian , Omlor Albert Joachim , Sester Martina , Herr Christian , Schick Bernhard , Daubeuf François , Fähndrich Sebastian , Bals Robert , Frossard Nelly , Al Kadah Basel , Dinh Quoc Thai
Published: December 2016

Objectives: Mast cells (MCs) and nerves play an important role in allergic rhinitis (AR), but little is known about their crosstalk in AR. The aim of this study was to investigate MC-nerve interaction in the human nasal mucosa during AR. Methods: The association between MCs and nerves, the expression of neuropeptide receptors (neurokinin 1 receptor [NK1R], neurokinin 2 receptor [NK2R], calcitonin gene-related peptide receptor [CGRPR], and MrgX2) on MCs, and protease-activated receptor 2 (PAR2) and tyrosine receptor kinase A (TrkA) on nerve fibres in the human nasal mucosa were investigated with immunofluorescence and real-time PCR. Results: The association between MCs and nerves was found to be significantly increased, although the numbers of MCs and nerve fibres were unchanged during AR. MCs expressing tryptase-chymase (MCtc) were frequently associated with nerve fibres and these contacts increased significantly in AR. Neuropeptide receptors NK1R, NK2R, and CGRPR were firstly found to be largely localised on MCs. The number of MCs expressing NK1R and NK2R, but not CGRPR, was significantly increased in AR. Interestingly, MCtc mostly expressed these neuropeptide receptors. The newly discovered tachykinin receptor MrgX2 was not expressed on nasal MCs, but was expressed on gland cells and increased in AR. Additionally, tachykinergic nerve fibres were found to express PAR2 or TrkA as receptors for MCs. Conclusions: This study revealed for the first time an increase of MC-nerve association and neuropeptide receptor expression on MCs during AR as well as nerve fibres containing receptors for MCs. These results suggest that targeting or controlling airway sensory nerve function as a modulator of MCs may prevent allergic airway inflammation such as AR.
Apolipoprotein L1 Genetic Variants Are Associated with Chronic Kidney Disease but Not with Cardiovascular Disease in a Population Referred for Cardiac Catheterization
Authors: Wang Hanghang , Pun Patrick H. , Kwee Lydia , Craig Damian , Haynes Carol , Chryst-Ladd Megan , Svetkey Laura P. , Patel Uptal D. , Hauser Elizabeth R. , Pollak Martin R. , Kraus William E. , Shah Svati H.
Published: December 2016

Background: While the association between APOL1 genetic variants and chronic kidney disease (CKD) has been established, their association with cardiovascular disease (CVD) is unclear. This study sought to understand CKD and cardiovascular risk conferred by APOL1 variants in a secondary cardiovascular prevention population. Methods: Two risk variants in APOL1 were genotyped in African-Americans (n = 1,641) enrolled in the CATHGEN biorepository, comprised of patients referred for cardiac catheterization at Duke University Hospital, Durham, NC, USA (2001-2010). Individuals were categorized as noncarriers (n = 722), heterozygote (n = 771), or homozygote carriers (n = 231) of APOL1 risk alleles. Multivariable logistic regression and Cox proportional hazards models adjusted for CVD risk factors were used to assess the association between APOL1 risk variants and prevalent and incident CKD, prevalent coronary artery disease (CAD), incident CVD events, and mortality. Results: The previously identified association between APOL1 variants and prevalent CKD was confirmed (OR: 1.85, 95% CI: 1.33-2.57, p = 0.0002). No statistically significant associations were detected between APOL1 variants and incident CKD or prevalent CAD, incident CVD events or mortality. Age, type 2 diabetes, and ejection fraction at baseline were significant clinical factors that predicted the risk of incident CKD in a subgroup analysis of APOL1 homozygous individuals. Conclusion:APOL1 genetic variants are not associated with CAD or incident CVD events in a cohort of individuals with a high burden of cardiometabolic risk factors. In individuals with homozygous APOL1 status, factors that predicted subsequent CKD included age, presence of type 2 diabetes, and ejection fraction at baseline.
The Chromosomes of Birds during Meiosis
Authors: Pigozzi María I.
Published: December 2016

The cytological analysis of meiotic chromosomes is an exceptional tool to approach complex processes such as synapsis and recombination during the division. Chromosome studies of meiosis have been especially valuable in birds, where naturally occurring mutants or experimental knock-out animals are not available to fully investigate the basic mechanisms of major meiotic events. This review highlights the main contributions of synaptonemal complex and lampbrush chromosome research to the current knowledge of avian meiosis, with special emphasis on the organization of chromosomes during prophase I, the impact of chromosome rearrangements during meiosis, and distinctive features of the ZW pair.
Uveal Melanoma with Histopathologic Intratumoral Heterogeneity Associated with Gene Expression Profile Discordance
Authors: Miller Audra K. , Benage Matthew J. , Wilson David J. , Skalet Alison H.
Published: December 2016

Purpose: To report a case of intratumoral gene expression profile discordance in a malignant uveal melanoma, associated with intratumoral heterogeneity based upon histopathologic features. Methods: The clinical history, fundus findings, imaging and histopathologic features, and DecisionDx-UM gene expression profile results (Castle Biosciences, Inc., Phoenix, AZ, USA) of the tumor were reviewed. Results: A trans-retinal fine-needle aspiration biopsy was performed for a thin, pigmented choroidal tumor in a 33-year-old man. Cells obtained from this biopsy were tested using the DecisionDx-UM gene expression profile test and the tumor was classified as class 1A. Cytology confirmed melanoma. The patient subsequently elected to undergo enucleation. On microscopic examination of the globe, the tumor was composed primarily of spindle B cells, but had a focal area composed of epithelioid cells. This portion of the tumor was subsequently tested and demonstrated a class 1B gene expression profile. Conclusion: Intratumoral discordance in gene expression profile results has been described in uveal melanomas. Here we demonstrate that this discordance may be associated in some cases with intratumoral heterogeneity based upon histopathologic features.
A Rare de novo Interstitial Duplication at 4p15.2 in a Boy with Severe Congenital Heart Defects, Limb Anomalies, Hypogonadism, and Global Developmental Delay
Authors: Liang Liyang , Xie Yingjun , Shen Yiping , Yin Qibin , Yuan Haiming
Published: December 2016

Proximal 4p deletion syndrome is a relatively rare genetic condition characterized by dysmorphic facial features, limb anomalies, minor congenital heart defects, hypogonadism, cafe-au-lait spots, developmental delay, tall and thin habitus, and intellectual disability. At present, over 20 cases of this syndrome have been published. However, duplication of the same region in proximal 4p has never been reported. Here, we describe a 2-year-5-month-old boy with severe congenital heart defects, limb anomalies, hypogonadism, distinctive facial features, pre- and postnatal developmental delay, and mild cognitive impairments. A de novo 4.5-Mb interstitial duplication at 4p15.2p15.1 was detected by chromosomal microarray analysis. Next-generation sequencing was employed and confirmed the duplication, but revealed no additional pathogenic variants. Several candidate genes in this interval responsible for the complex clinical phenotype were identified, such as RBPJ, STIM2, CCKAR, and LGI2. The results suggest a novel contiguous gene duplication syndrome.
Clinical Efficacy of Afatinib Treatment for a Patient with Leptomeningeal Carcinomatosis
Authors: Kawaguchi Yo , Hanaoka Jun , Hayashi Hideki , Mizusaki Naoki , Iihara Hirotoshi , Itoh Yoshinori , Sugiyama Tadashi
Published: December 2016

Leptomeningeal metastases occur in 1% of patients with non-small-cell lung cancer. There have been several reports on the treatment of leptomeningeal metastases with afatinib. Our patient was a 41-year-old woman who had never smoked and was diagnosed with stage IV adenocarcinoma of the lung with an epidermal growth factor receptor (EGFR) mutation. She was treated with afatinib for the recurrence of leptomeningeal metastases. After the treatment with afatinib was initiated, the neurological symptoms dramatically regressed, and she achieved progression-free survival for 7 months. The concentration of afatinib in the cerebrospinal fluid (CSF) ranged from 0.05 to 0.14 ng/mL, and the penetration rate of afatinib from the plasma to the CSF ranged from 0.28 to 0.40%. This concentration might be sufficient to achieve a clinical effect for leptomeningeal carcinomatosis. Therefore, afatinib administered at the usual doses may be an effective treatment for leptomeningeal carcinomatosis of EGFR-mutated or EGFR-tyrosine kinase inhibitor-sensitive lung adenocarcinoma.
Releasing the Brakes on the Fibrinolytic System in Pulmonary Emboli
Authors: Singh Satish , Houng Aiilyan , Reed Guy L.
Published: December 2016

Background:

In patients with hemodynamically significant pulmonary embolism, physiological fibrinolysis fails to dissolve thrombi acutely and r-tPA (recombinant tissue-type plasminogen activator) therapy may be required, despite its bleeding risk. To examine potential mechanisms, we analyzed the expression of key fibrinolytic molecules in experimental pulmonary emboli, assessed the contribution of α2-antiplasmin to fibrinolytic failure, and compared the effects of plasminogen activation and α2-antiplasmin inactivation on experimental thrombus dissolution and bleeding.

Methods:

Pulmonary embolism was induced by jugular vein infusion of
125
I-fibrin or fluorescein isothiocyanate-fibrin labeled emboli in anesthetized mice. Thrombus site expression of key fibrinolytic molecules was determined by immunofluorescence staining. The effects of r-tPA and α2-antiplasmin inactivation on fibrinolysis and bleeding were examined in a humanized model of pulmonary embolism.

Results:

The plasminogen activation and plasmin inhibition system assembled at the site of acute pulmonary emboli in vivo. Thrombus dissolution was markedly accelerated in mice with normal α2-antiplasmin levels treated with an α2-antiplasmin–inactivating antibody (
P
<0.0001). Dissolution of pulmonary emboli by α2-antiplasmin inactivation alone was comparable to 3 mg/kg r-tPA. Low-dose r-tPA alone did not dissolve emboli, but was synergistic with α2-antiplasmin inactivation, causing more embolus dissolution than clinical-dose r-tPA alone (
P
<0.001) or α2-antiplasmin inactivation alone (
P
<0.001). Despite greater thrombus dissolution, α2-antiplasmin inactivation alone, or in combination with low-dose r-tPA, did not lead to fibrinogen degradation, did not cause bleeding (versus controls), and caused less bleeding than clinical-dose r-tPA (
P
<0.001).

Conclusions:

Although the fibrinolytic system assembles at the site of pulmonary emboli, thrombus dissolution is halted by α2-antiplasmin. Inactivation of α2-antiplasmin was comparable to pharmacological r-tPA for dissolving thrombi. However, α2-antiplasmin inactivation showed a unique pattern of thrombus specificity, because unlike r-tPA, it did not degrade fibrinogen or enhance experimental bleeding. This suggests that modifying the activity of a key regulator of the fibrinolytic system, like α2-antiplasmin, may have unique therapeutic value in pulmonary embolism.
Smooth Muscle Endothelin B Receptors Regulate Blood Pressure but Not Vascular Function or Neointimal Remodeling
Authors: Miller Eileen , Czopek Alicja , Duthie Karolina M. , Kirkby Nicholas S. , van de Putte Elisabeth E. Fransen , Christen Sibylle , Kimmitt Robert A. , Moorhouse Rebecca , Castellan Raphael F.P. , Kotelevtsev Yuri V. , Kuc Rhoda E. , Davenport Anthony P. , Dhaun Neeraj , Webb David J. , Hadoke Patrick W.F.
Published: December 2016

The role of smooth muscle endothelin
B
(ET
B
) receptors in regulating vascular function, blood pressure (BP), and neointimal remodeling has not been established. Selective knockout mice were generated to address the hypothesis that loss of smooth muscle ET
B
receptors would reduce BP, alter vascular contractility, and inhibit neointimal remodeling. ET
B
receptors were selectively deleted from smooth muscle by crossing floxed ET
B
mice with those expressing cre-recombinase controlled by the transgelin promoter. Functional consequences of ET
B
deletion were assessed using myography. BP was measured by telemetry, and neointimal lesion formation induced by femoral artery injury. Lesion size and composition (day 28) were analyzed using optical projection tomography, histology, and immunohistochemistry. Selective deletion of ET
B
was confirmed by genotyping, autoradiography, polymerase chain reaction, and immunohistochemistry. ET
B
-mediated contraction was reduced in trachea, but abolished from mesenteric veins, of knockout mice. Induction of ET
B
-mediated contraction in mesenteric arteries was also abolished in these mice. Femoral artery function was unaltered, and baseline BP modestly elevated in smooth muscle ET
B
knockout compared with controls (+4.2±0.2 mm Hg;
P
<0.0001), but salt-induced and ET
B
blockade–mediated hypertension were unaltered. Circulating endothelin-1 was not altered in knockout mice. ET
B
-mediated contraction was not induced in femoral arteries by incubation in culture medium or lesion formation, and lesion size was not altered in smooth muscle ET
B
knockout mice. In the absence of other pathology, ET
B
receptors in vascular smooth muscle make a small but significant contribution to ET
B
-dependent regulation of BP. These ET
B
receptors have no effect on vascular contraction or neointimal remodeling.
Evidence for Reverse Causality in the Association Between Blood Pressure and Cardiovascular Risk in Patients With Chronic Kidney Disease
Authors: Herrington William , Staplin Natalie , Judge Parminder K. , Mafham Marion , Emberson Jonathan , Haynes Richard , Wheeler David C. , Walker Robert , Tomson Charlie , Agodoa Larry , Wiecek Andrzej , Lewington Sarah , Reith Christina A. , Landray Martin J. , Baigent Colin
Published: December 2016

Among those with moderate-to-advanced chronic kidney disease, the relationship between blood pressure (BP) and cardiovascular disease seems U shaped but is loglinear in apparently healthy adults. The SHARP (Study of Heart and Renal Protection) randomized 9270 patients with chronic kidney disease to ezetimibe/simvastatin versus matching placebo and measured BP at each follow-up visit. Cox regression was used to assess the association between BP and risk of cardiovascular disease among (1) those with a self-reported history of cardiovascular disease and (2) those with no such history and, based on plasma troponin-I concentration, a low probability of subclinical cardiac disease. A total of 8666 participants had a valid baseline BP and troponin-I measurement, and 2188 had at least 1 cardiovascular event during follow-up. After adjustment for relevant confounders, the association between systolic BP and cardiovascular events was U shaped, but among participants without evidence of previous cardiovascular disease, there was a positive loglinear association throughout the range of values studied. Among those with the lowest probability of subclinical cardiac disease, each 10 mm Hg higher systolic BP corresponded to a 27% increased risk of cardiovascular disease (hazard ratio, 1.27; 95% confidence interval, 1.11–1.44). In contrast, the relationship between diastolic BP and cardiovascular risk remained U shaped irrespective of cardiovascular disease history or risk of subclinical disease. In conclusion, the lack of a clear association between systolic BP and cardiovascular risk in this population seems attributable to confounding, suggesting that more intensive systolic BP reduction may be beneficial in such patients.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00125593.
Valproate Reduces Delayed Brain Injury in a Rat Model of Subarachnoid Hemorrhage
Authors: Hamming Arend M. , van der Toorn Annette , Rudrapatna Umesh S. , Ma Lisha , van Os Hine J.A. , Ferrari Michel D. , van den Maagdenberg Arn M.J.M. , van Zwet Erik , Poinsatte Katherine , Stowe Ann M. , Dijkhuizen Rick M. , Wermer Marieke J.H.
Published: December 2016

Background and Purpose—

Spreading depolarizations (SDs) may contribute to delayed cerebral ischemia after subarachnoid hemorrhage (SAH). We tested whether SD-inhibitor valproate reduces brain injury in an SAH rat model with and without experimental SD induction.

Methods—

Rats were randomized in a 2×2 design and pretreated with valproate (200 mg/kg) or vehicle for 4 weeks. SAH was induced by endovascular puncture of the right internal carotid bifurcation. One day post-SAH, brain tissue damage was measured with T
2
-weighted magnetic resonance imaging, followed by cortical application of 1 mol/L KCl (to induce SDs) or NaCl (no SDs). Magnetic resonance imaging was repeated on day 3 followed by histology to confirm neuronal death. Neurological function was measured with an inclined slope test.

Results—

In the groups with KCl application, lesion growth between days 1 and 3 was 57±73 mm3 in the valproate-treated versus 237±232 mm3 in the vehicle-treated group. In the groups without SD induction, lesion growth in the valproate- and vehicle-treated groups was 8±20 mm3 versus 27±52 mm3. On fitting a 2-way analysis of variance model, we found a significant interaction effect between treatment and KCl/NaCl application of 161 mm3 (
P
=0.04). Number and duration of SDs, mortality, and neurological function were not statistically significantly different between groups. Lesion growth on magnetic resonance imaging correlated to histological infarct volume (Spearman’s rho =0.83;
P
=0.0004), with areas of lesion growth exhibiting reduced neuronal death compared with primary lesions.

Conclusions—

In our rat SAH model, valproate treatment significantly reduced brain lesion growth after KCl application. Future studies are needed to confirm that this protective effect is based on SD inhibition.
ABCA1/ApoE/HDL Pathway Mediates GW3965-Induced Neurorestoration After Stroke
Authors: Cui Xu , Chopp Michael , Zhang Zhenggang , Li Rongwen , Zacharek Alex , Landschoot-Ward Julie , Venkat Poornima , Chen Jieli
Published: December 2016

Background and Purpose—

ATP-binding cassette transporter A1 (ABCA1) is a major reverse cholesterol transporter and plays critical role in the formation of brain high-density lipoprotein (HDL) cholesterol. Apolipoprotein E (ApoE) is the most abundant apolipoprotein and transports cholesterol into cells in brain. ABCA1 and ApoE are upregulated by liver-X receptors. Activation of liver-X receptors has neurorestorative benefit for stroke. The current study investigates whether ABCA1/ApoE/HDL pathway mediates GW3965, a synthetic dual liver-X receptor agonist, induced neurorestoration after stroke.

Methods—

Middle-aged male specific brain ABCA1–deficient (ABCA1
−B/−B
) and floxed-control (ABCA1
fl/fl
) mice were subjected to distal middle-cerebral artery occlusion (dMCAo) and gavaged with saline or GW3965 (10 mg/kg) or intracerebral infusion of artificial cerebrospinal fluid or human plasma HDL3 in ABCA1
−B/−B
stroke mice, starting 24 hours after dMCAo and daily until euthanization 14 days after dMCAo.

Results—

No differences in the blood level of total cholesterol and triglyceride and lesion volume were found among the groups. Compared with ABCA1
fl/fl
ischemic mice, ABCA1
−B/−B
ischemic mice exhibited impairment functional outcome and decreased ABCA1/ApoE expression and decreased gray/white matter densities in the ischemic boundary zone 14 days after dMCAo. GW3965 treatment of ABCA1
fl/fl
ischemic mice led to increased brain ABCA1/ApoE expression, concomitantly to increased blood HDL, gray/white matter densities and oligodendrocyte progenitor cell numbers in the ischemic boundary zone, as well as improved functional outcome 14 days after dMCAo. GW3965 treatment had negligible beneficial effects in ABCA1
−B/−B
ischemic mice. However, intracerebral infusion of human plasma HDL3 significantly attenuated ABCA1
−B/−B
-induced deficits. In vitro, GW3965 treatment (5 μM) increased ABCA1/synaptophysin level and neurite/axonal outgrowth in primary cortical neurons derived from ABCA1
fl/fl
embryos, but not in neurons derived from ABCA1
−B/−B
embryos. HDL treatment (80 μg/mL) attenuated the reduction of neurite/axonal outgrowth in neurons derived from ABCA1
−B/−B
embryos.

Conclusions—

ABCA1/ApoE/HDL pathway, at least partially, contributes to GW3965-induced neurorestoration after stroke.
Local and Global Gestalt Laws: A Neurally Based Spectral Approach
Authors: Favali Marta , Citti Giovanna , Sarti Alessandro
Published: December 2016

This letter presents a mathematical model of figure-ground articulation that takes into account both local and global gestalt laws and is compatible with the functional architecture of the primary visual cortex (V1). The local gestalt law of good continuation is described by means of suitable connectivity kernels that are derived from Lie group theory and quantitatively compared with long-range connectivity in V1. Global gestalt constraints are then introduced in terms of spectral analysis of a connectivity matrix derived from these kernels. This analysis performs grouping of local features and individuates perceptual units with the highest salience. Numerical simulations are performed, and results are obtained by applying the technique to a number of stimuli.
Ask1 regulates murine platelet granule secretion, thromboxane A2 generation, and thrombus formation
Authors: Naik Meghna U. , Patel Pravin , Derstine Randall , Turaga Ramya , Chen Xi , Golla Kalyan , Neeves Keith B. , Ichijo Hidenori , Naik Ulhas P.
Published: December 2016

Key Points

ASK1 regulates TxA2 generation through p38 MAPK-dependent phosphorylation of cPLA2. Because of impaired platelet function, Ask1−/− mice are protected from arterial thrombosis and pulmonary thromboembolism.
Incomplete inhibition by eculizumab: mechanistic evidence for residual C5 activity during strong complement activation
Authors: Harder Markus J. , Kuhn Nadine , Schrezenmeier Hubert , Höchsmann Britta , von Zabern Inge , Weinstock Christof , Simmet Thomas , Ricklin Daniel , Lambris John D. , Skerra Arne , Anliker Markus , Schmidt Christoph Q.
Published: December 2016

Key Points

Strong complement activation overrides the terminal pathway inhibition by the anti-C5 antibody eculizumab. The more powerful complement is activated, the less effective is terminal pathway inhibition by diverse anti-C5 agents.
Mastocytosis: 2016 updated WHO classification and novel emerging treatment concepts
Authors: Valent Peter , Akin Cem , Metcalfe Dean D.
Published: December 2016

Over the past few years, substantial advances have been made in understanding the pathogenesis, evolution, and complexity of mast cell neoplasms. New diagnostic and prognostic parameters and novel therapeutic targets with demonstrable clinical impact have been identified. Several of these new markers, molecular targets, and therapeutic approaches have been validated and translated into clinical practice. At the same time, the classification of mastocytosis and related diagnostic criteria have been refined and updated by the consensus group and the World Health Organization (WHO). As a result, more specific therapies tailored toward prognostic subgroups of patients have been developed. Emerging treatment concepts use drugs directed against KIT and other relevant targets in neoplastic mast cells and will hopefully receive recognition by health authorities in the near future. This article provides an overview of recent developments in the field, with emphasis on the updated WHO classification, refined criteria, additional prognostic parameters, and novel therapeutic approaches. Based on these emerging concepts, the prognosis, quality of life, and survival of patients with advanced mastocytosis are expected to improve in the coming years.
Emerging treatments for classical myeloproliferative neoplasms
Authors: Vannucchi Alessandro M. , Harrison Claire N.
Published: December 2016

There has been a major revolution in the management of patients with myeloproliferative neoplasms (MPN), and in particular those with myelofibrosis and extensive splenomegaly and symptomatic burden, after the introduction of the JAK1 and JAK2 inhibitor ruxolitinib. The drug also has been approved as second-line therapy for polycythemia vera (PV). However, the therapeutic armamentarium for MPN is still largely inadequate for coping with patients’ major unmet needs, which include normalization of life span (myelofibrosis and some patients with PV), reduction of cardiovascular complications (mainly PV and essential thrombocythemia), prevention of hematological progression, and improved quality of life (all MPN). In fact, none of the available drugs has shown clear evidence of disease-modifying activity, even if some patients treated with interferon and ruxolitinib showed reduction of mutated allele burden, and ruxolitinib might extend survival of patients with higher-risk myelofibrosis. Raised awareness of the molecular abnormalities and cellular pathways involved in the pathogenesis of MPN is facilitating the development of clinical trials with novel target drugs, either alone or in combination with ruxolitinib. Although for most of these molecules a convincing preclinical rationale was provided, the results of early phase 1 and 2 clinical trials have been quite disappointing to date, and toxicities sometimes have been limiting. In this review, we critically illustrate the current landscape of novel therapies that are under evaluation for patients with MPN on the basis of current guidelines, patient risk stratification criteria, and previous experience, looking ahead to the chance of a cure for these disorders.
Evaluation of the effectiveness of an online transition planning program for adolescents on the autism spectrum: trial protocol
Authors: Hatfield Megan , Falkmer Marita , Falkmer Torbjorn , Ciccarelli Marina
Published: December 2016

Background

The transition from high school to post-secondary education and work is difficult for adolescents on the autism spectrum. Transition planning can be an effective way of supporting adolescents on the autism spectrum to prepare for leaving school and to succeed in obtaining employment; however, there is a need for an autism-specific transition planning program with proven effectiveness. This paper describes a trial protocol for evaluating the Better OutcOmes & Successful Transitions for Autism (BOOST-A™); an online interactive program that empowers adolescents on the autism spectrum to plan their transition from school to further study, training, or employment.

Methods

The trial will involve adolescents on the autism spectrum in high school and their parents, who will be alternately assigned to a control group (regular practice) or an intervention group (using the BOOST-A™). The BOOST-A™ was developed using the PRECEDE-PROCEED model, and is based on the self-determination model, and the strengths- and technology-based approaches. It involves participants completing a series of online modules. The primary outcome will be self-determination, because high self-determination has been linked to successful transition to employment among adolescents on the autism spectrum. Secondary outcomes will include domain-specific self-determination, career planning and exploration, quality of life, and environmental support. Data will be obtained from questionnaires completed by the adolescent on the autism spectrum and their parent/s. Data collection will take place at baseline (Time point 1) and 12 months later (Time point 2).

Discussion and conclusions

This trial will provide evidence of the effectiveness of the BOOST-A™ to assist adolescents on the autism spectrum to successfully transition from school.

Trial registration #ACTRN12615000119594
The detailed 3D multi-loop aggregate/rosette chromatin architecture and functional dynamic organization of the human and mouse genomes
Authors: Knoch Tobias A. , Wachsmuth Malte , Kepper Nick , Lesnussa Michael , Abuseiris Anis , Ali Imam A. M. , Kolovos Petros , Zuin Jessica , Kockx Christel E. M. , Brouwer Rutger W. W. , van de Werken Harmen J. G. , van IJcken Wilfred F. J. , Wendt Kerstin S. , Grosveld Frank G.
Published: December 2016

Background

The dynamic three-dimensional chromatin architecture of genomes and its co-evolutionary connection to its function—the storage, expression, and replication of genetic information—is still one of the central issues in biology. Here, we describe the much debated 3D architecture of the human and mouse genomes from the nucleosomal to the megabase pair level by a novel approach combining selective high-throughput high-resolution chromosomal interaction capture (T2C), polymer simulations, and scaling analysis of the 3D architecture and the DNA sequence.

Results

The genome is compacted into a chromatin quasi-fibre with ~5 ± 1 nucleosomes/11 nm, folded into stable ~30–100 kbp loops forming stable loop aggregates/rosettes connected by similar sized linkers. Minor but significant variations in the architecture are seen between cell types and functional states. The architecture and the DNA sequence show very similar fine-structured multi-scaling behaviour confirming their co-evolution and the above.

Conclusions

This architecture, its dynamics, and accessibility, balance stability and flexibility ensuring genome integrity and variation enabling gene expression/regulation by self-organization of (in)active units already in proximity. Our results agree with the heuristics of the field and allow “architectural sequencing” at a genome mechanics level to understand the inseparable systems genomic properties.