bluuebunny/crossref_metadata_2025 huggingface dataset:
How to contribute research results to internet standardization
Authors: Bagnulo Marcelo , Eardley Philip , Eggert Lars , Winter Rolf
Published: July 2011

The development of new technology is driven by scientific research. The Internet, with its roots in the ARPANET and NSFNet, is no exception. Many of the fundamental, long-term improvements to the architecture, security, end-to-end protocols and management of the Internet originate in the related academic research communities. Even shorter-term, more commercially driven extensions are oftentimes derived from academic research. When interoperability is required, the IETF standardizes such new technology. Timely and relevant standardization benefits from continuous input and review from the academic research community.

For an individual researcher, it can however by quite puzzling how to begin to most effectively participate in the IETF and - arguably to a much lesser degree - in the IRTF. The interactions in the IETF are much different than those in academic conferences, and effective participation follows different rules. The goal of this document is to highlight such differences and provide a rough guideline that will hopefully enable researchers new to the IETF to become successful contributors more quickly.
Involvement of JNK-AP-1 and ERK-NF-κB signaling in tension-stimulated expression of Type I collagen and MMP-1 in human periodontal ligament fibroblasts
Authors: Kook Sung-Ho , Jang Yong-Suk , Lee Jeong-Chae
Published: July 2011

Type I collagen (COL I) and matrix metalloproteinase-1 (MMP-1) are the predominant matrix proteins in the extracellular matrix of the human periodontal ligament (PDL). The expression of these proteins in PDL fibroblasts (PLF) is sensitive to physiological and mechanical stress and is critical for PDL remodeling accompanied by alveolar bone remodeling. This study examined how dose tensile force regulates the expression of COL I and MMP-1 and explored the possible roles of mitogen-activated protein kinases (MAPKs) and transcription factors, such as activator protein-1 (AP-1) and nuclear factor-κB (NF-κB). Tensile force stimulated the mRNA expression of COL I and MMP-1 in the cells and also activated MAPKs including extracellular signal-regulated kinase (ERK), c-Jun NH2-terminal kinase (JNK), and p38 MAPK. A pharmacological inhibitor of ERK or JNK prevented the expression of matrix genes and the nuclear translocation of c-Jun proteins in the force-applied PLF. The knockdown of c-Jun by transfecting the cells with its antisense oligonucleotides reduced the force-induced increase in matrix gene expression. In particular, the ERK inhibitor but not JNK or p38 MAPK inhibitor attenuated the force-mediated stimulation of NF-κB-DNA binding and MMP-1 expression. Overall, these results highlight the mechanotransduction pathways involved in matrix gene expression in PLF, where the tension-stimulated expression of COL I and MMP-1 is controlled by the ERK/JNK-AP-1 and ERK-NF-κB signaling pathways.
The effects of deformation, ischemia, and reperfusion on the development of muscle damage during prolonged loading
Authors: Loerakker S. , Manders E. , Strijkers G. J. , Nicolay K. , Baaijens F. P. T. , Bader D. L. , Oomens C. W. J.
Published: July 2011

Deep tissue injury (DTI) is a severe form of pressure ulcer where tissue damage starts in deep tissues underneath intact skin. In the present study, the contributions of deformation, ischemia, and reperfusion to skeletal muscle damage development were examined in a rat model during a 6-h period. Magnetic resonance imaging (MRI) was used to study perfusion (contrast-enhanced MRI) and tissue integrity (T2-weighted MRI). The levels of tissue deformation were estimated using finite element models. Complete ischemia caused a gradual homogeneous increase in T2 (∼20% during the 6-h period). The effect of reperfusion on T2 was highly variable, depending on the anatomical location. In experiments involving deformation, inevitably associated with partial ischemia, a variable T2 increase (17–66% during the 6-h period) was observed reflecting the significant variation in deformation (with two-dimensional strain energies of 0.60–1.51 J/mm) and ischemia (50.8–99.8% of the leg) between experiments. These results imply that deformation, ischemia, and reperfusion all contribute to the damage process during prolonged loading, although their importance varies with time. The critical deformation threshold and period of ischemia that cause muscle damage will certainly vary between individuals. These variations are related to intrinsic factors, such as pathological state, which partly explain the individual susceptibility to the development of DTI and highlight the need for regular assessments of individual subjects.
Acclimation to decompression: stress and cytokine gene expression in rat lungs
Authors: Chen Ye , Montcalm-Smith Elizabeth , Schlaerth Christine , Auker Charles , McCarron Richard M.
Published: July 2011

Previous studies demonstrated that animals exposed to repeated compression-decompression stress acclimated (i.e., developed reduced susceptibility) to rapid decompression. This study endeavored to characterize inflammatory and stress-related gene expression and signal transduction associated with acclimation to rapid decompression. Rats were divided into four groups: 1) control-sham: pressure naïve rats; 2) acclimation-sham: nine acclimation dives [70 feet seawater (fsw), 30 min]; 3) control-dive: test dive only (175 fsw, 60 min); and 4) acclimation-dive: nine acclimation dives and a test dive. After the test dive, rats were observed for decompression sickness (DCS). Expression of 13 inflammatory and stress-related genes and Akt (or PKB, a serine/threonine protein kinase) and MAPK phosphorylation of lung tissue were examined. The expression of immediate early gene/transcription factor early growth response gene 1 (Egr-1) was observed in both control and acclimation animals with DCS but not in animals without DCS. Increased Egr-1 in control-dive animals with DCS was significantly greater than in acclimation-dive animals with DCS. TNF-α, IL-1β, IL-6, and IL-10 were significantly elevated in control-DCS animals. Acclimation-DCS animals had increased TNF-α, but there was no change in IL-1β, IL-6, and IL-10. High levels of Akt phosphorylation were observed in lungs of acclimation-sham, acclimation-dive, and control-dive animals; phosphorylated ERK1/2 was only observed in animals with DCS. This study suggests that activation of ERK1/2 and upregulation of Egr-1 and its target cytokine genes by rapid decompression may play a role in the initiation and progression of DCS. It may be that the downregulated expression of these genes in animals with DCS is associated with previous exposure to repeated compression-decompression cycles. This study represents an initial step toward understanding the molecular mechanisms associated with acclimation to decompression.
An Energy-Aware Distributed Unequal Clustering Protocol for Wireless Sensor Networks
Authors: Yu Jiguo , Qi Yingying , Wang Gang , Guo Qiang , Gu Xin
Published: July 2011

Due to the imbalance of energy consumption of nodes in wireless sensor networks (WSNs), some local nodes die prematurely, which causes the network partitions and then shortens the lifetime of the network. The phenomenon is called “hot spot” or “energy hole” problem. For this problem, an energy-aware distributed unequal clustering protocol (EADUC) in multihop heterogeneous WSNs is proposed. Compared with the previous protocols, the cluster heads obtained by EADUC can achieve balanced energy, good distribution, and seamless coverage for all the nodes. Moreover, the complexity of time and control message is low. Simulation experiments show that EADUC can prolong the lifetime of the network significantly.
Optical Coherence Tomography of Retinal and Choroidal Tumors
Authors: Say Emil Anthony T. , Shah Sanket U. , Ferenczy Sandor , Shields Carol L.
Published: July 2011

Optical coherence tomography (OCT) has revolutionized the field of ophthalmology since its introduction 20 years ago. Originally intended primarily for retina specialists to image the macula, it has found its role in other subspecialties that include glaucoma, cornea, and ocular oncology. In ocular oncology, OCT provides axial resolution to approximately 7 microns with cross-sectional images of the retina, delivering valuable information on the effects of intraocular tumors on the retinal architecture. Some effects include retinal edema, subretinal fluid, retinal atrophy, photoreceptor loss, outer retinal thinning, and retinal pigment epithelial detachment. With more advanced technology, OCT now provides imaging deeper into the choroid using a technique called enhanced depth imaging. This allows characterization of the thickness and reflective quality of small (<3 mm thick) choroidal lesions including choroidal nevus and melanoma. Future improvements in image resolution and depth will allow better understanding of the mechanisms of visual loss, tumor growth, and tumor management.
Using to Determine Inhaled Contaminant Volumes and Blower Effectiveness in Several Types of Respirators
Authors: Johnson Arthur T. , Koh Frank C. , Scott William H. , Rehak Timothy E.
Published: July 2011

This experiment was conducted to determine how much contaminant could be expected to be inhaled when overbreathing several different types of respirators. These included several tight-fitting and loose-fitting powered air-purifying respirators (PAPRs) and one air-purifying respirator (APR). CO2was used as a tracer gas in the ambient air, and several loose-and tight-fitting respirators were tested on the head form of a breathing machine. CO2concentration in the exhaled breath was monitored as well as CO2concentration in the ambient air. This concentration ratio was able to give a measurement of protection factor, not for the respirator necessarily, but for the wearer. Flow rates in the filter/blower inlet and breathing machine outlet were also monitored, so blower effectiveness (defined as the blower contribution to inhaled air) could also be determined. Wearer protection factors were found to range from 1.1 for the Racal AirMate loose-fitting PAPR to infinity for the 3M Hood, 3M Breath-Easy PAPR, and SE 400 breath-responsive PAPR. Inhaled contaminant volumes depended on tidal volume but ranged from 2.02 L to 0 L for the same respirators, respectively. Blower effectiveness was about 1.0 for tight-fitting APRs, 0.18 for the Racal, and greater than 1.0 for two of the loose-fitting PAPRs. With blower effectiveness greater than 1.0, some blower flow during the exhalation phase contributes to the subsequent inhalation. Results from this experiment point to different ways to measure respirator efficacy.
Multiple Method Contraception Use among African American Adolescents in Four US Cities
Authors: Brown Jennifer L. , Hennessy Michael , Sales Jessica M. , DiClemente Ralph J. , Salazar Laura F. , Vanable Peter A. , Carey Michael P. , Romer Daniel , Valois Robert F. , Brown Larry K. , Stanton Bonita
Published: July 2011

We report on African American adolescents' (N=850;Mage = 15.4) contraceptive practices and type of contraception utilized during their last sexual encounter. Respondents completed measures of demographics, contraceptive use, sexual partner type, and ability to select “safe” sexual partners. 40% endorsed use of dual or multiple contraceptive methods; a total of 35 different contraceptive combinations were reported. Perceived ability to select “safe” partners was associated with not using contraception (OR = 1.25), using less effective contraceptive methods (OR = 1.23), or hormonal birth control (OR = 1.50). Female gender predicted hormonal birth control use (OR = 2.33), use of less effective contraceptive methods (e.g., withdrawal; OR = 2.47), and using no contraception (OR = 2.37). Respondents' age and partner type did not predict contraception use. Adolescents used contraceptive methods with limited ability to prevent both unintended pregnancies and STD/HIV. Adolescents who believed their partners posed low risk were more likely to use contraceptive practices other than condoms or no contraception. Reproductive health practitioners are encouraged to help youth negotiate contraceptive use with partners, regardless of the partner's perceived riskiness.
Optical Coherence Tomography Findings in Idiopathic Macular Holes
Authors: Huang Lynn L. , Levinson David H. , Levine Jonathan P. , Mian Umar , Tsui Irena
Published: July 2011

Purpose. To describe the characteristics of idiopathic macular holes (MH) on optical coherence tomography (OCT) and correlate OCT with clinical assessment.Design. Cross-sectional chart review and OCT assessment.Participants. Sixty-seven eyes with a clinically diagnosed idiopathic MH with available OCT data.Methods. A retrospective chart review and OCT assessment.Results. Based on OCT grading, 40 eyes had a full-thickness macular hole (FTMH) and 21 eyes had a lamellar macular hole (LMH). Clinical exam and OCT assessment agreed in 53 (87%) eyes when assessing the extent of MH. Six eyes (14.6%) in the FTMH group, and 3 eyes in the LMH group (14.3%) had persistent vitreomacular traction. Thirty-seven eyes (92.5%) in the FTMH group and 11 eyes (52.4%) in the LMH group had associated intraretinal cysts. Two eyes (5.0%) in the FTMH group and zero eyes in the LMH group had subretinal fluid. Intraretinal cysts were found to be more frequently associated with FTMH than with LMH (P<0.001).Conclusion. This paper described OCT findings in a group of patients with clinically diagnosed MH. A high level of correlation between clinical assessment and OCT findings of LMH and FTMH was observed, and intraretinal cysts were often present in FTMH.
Coprescription of Chinese Herbal Medicine and Western Medications among Prostate Cancer Patients: A Population-Based Study in Taiwan
Authors: Lin Yi-Hsien , Chen Kuang-Kuo , Chiu Jen-Hwey
Published: July 2011

Use of herbal medicine is popular among cancer patients. This study aimed to explore the coprescription of CHM and WM among prostate cancer patients in Taiwan. This cross-sectional retrospective study used a population-based database containing one million beneficiaries of National Health Insurance. Claims and prescriptions were analyzed. In 2007, 218 (22.4%) prostate cancer patients were CHM users. Among CHM users, 200 (91.7%) patients with 5618 (79.5%) CHM prescriptions were on coprescription of CHM and WM. A total of 484 types of CHM and 930 types of WM were used. The most commonly used CHMs on coprescription were Shu Jing Huo Xue Tang, Ma Zi Ren Wan, and Xue Fu Zhu Yu Tang. The most commonly used WMs on coprescription were magnesium oxide, amlodipine, and aspirin. The average number of prescriptions per user per year was 261.2 versus 151.7 in all (P<0.001), 123.6 versus 76.9 in WM (P=0.033), and 34.8 versus 5.1 in CHM (P<0.001) for patients with and without coprescription, respectively. In conclusion, use of CHM among prostate cancer patients was popular in Taiwan. Most CHMs were used with WM concurrently. The potential drug-herb interactions should be investigated, especially for patients with more prescriptions.
Human Neural Stem Cell Transplantation Ameliorates Radiation-Induced Cognitive Dysfunction
Authors: Acharya Munjal M. , Christie Lori-Ann , Lan Mary L. , Giedzinski Erich , Fike John R. , Rosi Susanna , Limoli Charles L.
Published: July 2011

Cranial radiotherapy induces progressive and debilitating declines in cognition that may, in part, be caused by the depletion of neural stem cells. The potential of using stem cell replacement as a strategy to combat radiation-induced cognitive decline was addressed by irradiating athymic nude rats followed 2 days later by intrahippocampal transplantation with human neural stem cells (hNSC). Measures of cognitive performance, hNSC survival, and phenotypic fate were assessed at 1 and 4 months after irradiation. Irradiated animals engrafted with hNSCs showed significantly less decline in cognitive function than irradiated, sham-engrafted animals and acted indistinguishably from unirradiated controls. Unbiased stereology revealed that 23% and 12% of the engrafted cells survived 1 and 4 months after transplantation, respectively. Engrafted cells migrated extensively, differentiated along glial and neuronal lineages, and expressed the activity-regulated cytoskeleton-associated protein (Arc), suggesting their capability to functionally integrate into the hippocampus. These data show that hNSCs afford a promising strategy for functionally restoring cognition in irradiated animals. Cancer Res; 71(14); 4834–45. ©2011 AACR.
Severer Phenotype in Unverricht-Lundborg Disease (EPM1) Patients Compound Heterozygous for the Dodecamer Repeat Expansion and the c.202C>T Mutation in the CSTB Gene
Authors: Koskenkorva Päivi , Hyppönen Jelena , Äikiä Marja , Mervaala Esa , Kiviranta Tuula , Eriksson Kai , Lehesjoki Anna-Elina , Vanninen Ritva , Kälviäinen Reetta
Published: July 2011

Background/Aims: Unverricht-Lundborg disease (EPM1) is caused by mutations in the cystatin B (CSTB) gene. Most patients are homozygous for the expanded dodecamer repeat mutation alleles, but 9 other EPM1-associated mutations have also been identified. We describe the clinical, cognitive and imaging characteristics of 5 Finnish EPM1 patients who are compound heterozygous for the dodecamer repeat expansion and the c.202C>T mutations. Methods: Five compound heterozygous patients and 21 patients homozygous for the expansion mutation, participating in an ongoing nationwide clinical and molecular genetics study, were evaluated using the Unified Myoclonus Rating Scale test and comprehensive neuropsychological testing. All patients underwent MR imaging. The MR data were also compared with those of 24 healthy control subjects. Results: Age at onset of symptoms was significantly lower in the compound heterozygotes than in the homozygous EPM1 patients. They also had severer myoclonus and drug-resistant tonic-clonic seizures. Moreover, they had lower cognitive performance. In MRI a voxel-based morphometry analysis of primary and premotor cortex, supplementary motor cortex and thalami revealed gray matter volume loss when compared with the healthy controls, similar to patients homozygous for the expansion mutation. Conclusion: Patients compound heterozygous for the dodecamer repeat expansion and the c.202C>T mutations seem to have a severer form of EPM1 than patients homozygous for the expansion mutation. These findings have implications for counseling of EPM1 patients with different genetic defects.
Distribution of Bacteria in the Epidermal Layers and Hair Follicles of the Human Skin
Authors: Lange-Asschenfeldt B. , Marenbach D. , Lang C. , Patzelt A. , Ulrich M. , Maltusch A. , Terhorst D. , Stockfleth E. , Sterry W. , Lademann J.
Published: July 2011

Previous studies over recent years have revealed the presence of a resident bacterial population in the human skin throughout the entire body. However, the localization and composition of the bacteria within the epidermis and the skin appendages have not been fully investigated. Using differential tape stripping, cyanoacrylate skin surface biopsies and mapping of hair follicles, bacteria on the forearms of study participants were isolated, mapped, cultured and identified with respect to their origin within the epidermis and the hair follicles. Our studies showed that 85% of the bacteria were found within the first 6 corneocyte layers and roughly 25% of the cutaneous bacterial population were localized within the hair follicles. The microbial flora of the skin between individuals is subject to considerable fluctuations. Micrococcaceae represent the biggest fraction of hair-follicle-associated bacteria. The techniques developed for this study allowed us to selectively investigate the bacterial population within the hair follicles. Our results point out the role of skin appendages as potential microbial reservoirs and the need to develop new antiseptic formulations that sufficiently penetrate into the hair follicles.
Where Are the New Cough Treatments: A Debriefing of Recent Clinical Proof-of-Concept Trials with the NOP Agonist SCH 486757
Authors: McLeod Robbie L. , Tulshian Deen B. , Sadeh Jonathan
Published: July 2011

Cough continues to be one of the top reasons why patients seek medical attention from health care providers. The prescription antitussive market is dominated by opioids, such as codeine that produces inconsistent efficacy and is often accompanied by significant side effect liabilities. Consequently, cough represents an unmet medical need and an underserved market. Yet, against the backdrop of increasing cough research, the development of novel treatments has been exceptionally challenging with dextromethorphan being the last US drug approved for cough almost a half century ago. We support the position that an unambiguous and actionable ‘road map’ that clearly delineates the pathway forward for new cough suppressants from basic research to and beyond clinical proof-of-concept studies will be an important aspect for future success of this pharmacological class of drug. Pivotal to the establishment of such a road map will be the review of lessons learned from antitussive agents that have been recently progressed to proof-of-concept trials. In the present commentary, we briefly discuss observations and challenges pertaining to SCH 486757, a selective orally active NOP agonist that has recently advanced to human antitussive testing.
Quality of Life among Elderly Patients with Dementia in Institutions
Authors: Barca Maria L. , Engedal Knut , Laks Jerson , Selbæk Geir
Published: July 2011

Aim: To study quality of life among the elderly with dementia in institutions. Methods: Patients above 60 years with dementia, 82 in nursing home and 74 in departments of geriatric psychiatry, were included. They were assessed with the Quality of Life in Late-Stage Dementia (QUALID); the Self-Maintenance scale, Mini Mental State Examination (MMSE) and Clinical Dementia Rating scale. Patient’s age, gender, previous medical and psychiatric history were recorded. Dementia was diagnosed according to ICD-10 criteria for research. Based on information in an interview with the patient and a carer and information in the patient’s record, a geriatric psychiatrist made a diagnosis of major depression according to DSM-IV, if present. Results: The patients’ mean (± SD) age was 82.9 ± 7.7 years, 103 (66%) were women. A factor analysis of the QUALID scale resulted in two factors: ‘discomfort’ and ‘comfort’. Three linear regression analyses were performed. Variables associated with lower quality of life (total QUALID score) were: a diagnosis of major depression (p < 0.001), lower score on MMSE (p = 0.032), impaired function in activities of daily living (p = 0.007) and female gender (p = 0.046). Variables associated with the ‘discomfort’ subscale score were: major depression (p < 0.001), lower score on MMSE (p = 0.006) and living in a department of geriatric psychiatry (p = 0.041). The ‘comfort’ subscale score was associated with impaired function in activities of daily living (p < 0.001). Explained variance for the three models was 34, 33 and 23%, respectively. Conclusion: Quality of life is diminished among elderly patients in institutions and the most marked correlates were a diagnosis of major depression, worse performance in activities of daily living and worse cognitive function.
Irradiation with Water-Filtered Infrared A plus Visible Light Improves Cutaneous Scleroderma Lesions in a Series of Cases
Authors: von Felbert V. , Kernland-Lang K. , Hoffmann G. , Wienert V. , Simon D. , Hunziker T.
Published: July 2011

Background: Cutaneous scleroderma is a chronic inflammatory disease of the dermal and subcutaneous connective tissue leading to sclerosis. Sclerosis of the skin can lead to dysmorphism, contractures and restrictions of movement. Objective: The purpose of the study was to evaluate sclerosis in cutaneous scleroderma patients and to determine the efficacy of water-filtered infrared A plus visible light treatment, wIRA(+VIS), in 10 patients. Methods: Hardness of the normal and diseased skin was measured by durometry in 10 controls and 8 patients. Moreover, circumscribed scleroderma (CS) was treated with wIRA(+VIS) irradiations in 10 patients who had not responded to conventional therapies. Results: wIRA(+VIS) therapy led to a marked improvement, persistent even during long-term follow-up, in 7 out of 10 patients with CS. Of the other patients, 1 showed decreased sclerosis and disease activity and developed a worsening after cessation of therapy. In 2 further patients, where previous UVA1 treatment had failed to reduce disease activity, wIRA(+VIS) produced a slight decrease in sclerosis, but disease activity was still present. Conclusion: wIRA(+VIS) appears to be effective in the treatment of CS. Durometry proved to be helpful in assessing the degree of sclerosis and in documenting the response to therapy in these patients.
Amicrobial Pustulosis-Like Rash in a Patient with Crohn’s Disease under Anti-TNF-Alpha Blocker
Authors: Lee Haur Yueh , Pelivani Nedzmidin , Beltraminelli Helmut , Hegyi Ivan , Yawalkar Nikhil , Borradori Luca
Published: July 2011

Amicrobial pustulosis of the folds (APF) is a recently described entity characterized by relapsing pustular lesions predominantly involving the cutaneous flexures and scalp. This disease typically occurs in association with systemic lupus erythematosus and a variety of other autoimmune diseases. We here describe an APF-like pustular eruption predominantly affecting the scalp, face and trunk, occurring during long-term infliximab treatment for Crohn’s disease. Immunohistochemical staining of skin biopsy specimens for myxovirus resistance protein A, a marker for type 1 interferon-inducible proteins, showed increased staining in the epidermis and dermal mononuclear inflammatory infiltrate. Our observation further extends the spectrum of cutaneous adverse reactions potentially related to anti-tumor necrosis factor-α, the clinical context in which APF can occur as well as its clinical presentations.
White Matter Disease Independently Predicts Progression from Mild Cognitive Impairment to Alzheimer’s Disease in a Clinic Cohort
Authors: Prasad Kalpana , Wiryasaputra Lynn , Ng Amanda , Kandiah Nagaendran
Published: July 2011

Background: The contribution of vascular pathology to the rate of progression from mild cognitive impairment (MCI) to Alzheimer’s disease (AD) remains unclear. Objective: To ascertain the relative roles of cerebral white matter disease and medial temporal atrophy (MTA) in predicting progression from MCI to AD. Methods: MCI patients with baseline MRI and ≧18 months of longitudinal follow-up were evaluated. DSM-IV-TR criteria were used to diagnose conversion to dementia. MTA and white matter hyperintensity (WMH) were quantified using the Scheltens scale and modified Fazekas scale. Results: Of a total of 171 MCI patients, 79 patients with baseline MRI and longitudinal follow-up were studied. Twenty-three MCI patients who progressed to dementia (MCI-P) were identified corresponding to a 19.4% annual risk of conversion. In MCI-P patients, the mean Mini-Mental State Examination and Montreal Cognitive Assessment decline was 1.3 and 2.9 points, respectively. MTA, periventricular WMH and deep subcortical WMH were significantly greater in the MCI-P cohort. WMH was found to predict MCI-P with an odds ratio of 7.69 (p = 0.03). Conclusion: MTA and deep subcortical WMH independently predict conversion from MCI to AD. Optimization of vascular risk factors among patients with MCI can potentially reduce the conversion from MCI to AD.
Bone Gla Protein Increases HIF-1α–Dependent Glucose Metabolism and Induces Cartilage and Vascular Calcification
Authors: Idelevich Anna , Rais Yoach , Monsonego-Ornan Efrat
Published: July 2011

Objective—

Bone Gla Protein (BGP, osteocalcin) is commonly present in the calcified vasculature and was recently shown as energy metabolism-regulating hormone. This study investigates the role of BGP in cartilage and vasculature mineralization.

Methods and Results—

We established an in vitro BGP-overexpression model in chondrocytes (ATDC5) and vascular smooth muscle cells (MOVAS). BGP overexpression upregulated markers of chondrogenic differentiation and intensified staining for minerals. BGP overexpression enhanced glucose uptake and increased expression of glucose transporters and glycolysis enzymes while decreasing gluconeogenesis enzymes. Treatment with purified BGP activated insulin signaling pathway and upregulated genes of glucose transport and utilization. Both BGP overexpression and treatment with purified BGP resulted in stabilization of hypoxia-inducible factor 1α (HIF-1α) in chondrocytes and vascular smooth muscle cells, shown essential in mediating the direct metabolic effect of BGP. The in vivo model of 1,25(OH)
2
D
3
-induced vascular calcification in rats revealed a correlation between calcification, elevated BGP levels, and increased HIF-1α expression in aortas and bone growth plates. The in vivo introduction of BGP siRNA, coadministered with 1,25(OH)
2
D
3
, prevented 1,25(OH)
2
D
3
-induced HIF-1α stabilization, and diminished osteochondrogenic differentiation and mineralization of aortas.

Conclusion—

This study demonstrates novel mechanism by which BGP locally shifts cells toward glycolytic breakdown of glucose, in a HIF-1α–dependent manner, and stimulates calcification of cartilage and vasculature.
Enhanced Angiogenesis by Transplantation of Mesenchymal Stem Cell Sheet Created by a Novel Magnetic Tissue Engineering Method
Authors: Ishii Masakazu , Shibata Rei , Numaguchi Yasushi , Kito Tetsutaro , Suzuki Hirohiko , Shimizu Kazunori , Ito Akira , Honda Hiroyuki , Murohara Toyoaki
Published: July 2011

Objective—

Therapeutic angiogenesis with cell transplantation represents a novel strategy for severe ischemic diseases. However, some patients have poor response to such conventional injection-based angiogenic cell therapy. Here, we investigated a therapeutic potential of mesenchymal stem cell (MSC) sheet created by a novel magnetite tissue engineering technology for reparative angiogenesis.

Methods and Results—

Human MSCs incubated with magnetic nanoparticle-containing liposomes were cultured, and a magnet was placed on the reverse side. Magnetized MSCs formed multilayered cell sheets according to magnetic force. Nude mice were subjected to unilateral hind limb ischemia and separated into 3 groups. For the control group, saline was injected into ischemic tissue. In the MSC-injected group, mice received magnetized MSCs by conventional needle injections without sheet formula as a control cell group. In the MSC-sheet group, MSC sheet was layered onto the ischemic tissues before skin closure. Blood flow recovery and the extent of angiogenesis were assessed by a laser Doppler blood flowmetry and histological capillary density, respectively. The MSC-sheet group had a greater angiogenesis in ischemic tissues compared to the control and MSC-injected groups. The angiogenic and tissue-preserving effects of MSC sheets were attributable to an increased expression of vascular endothelial growth factor and reduced apoptosis in ischemic tissues. In cultured MSCs, magnetic labeling itself inhibited apoptosis via a catalase-like antioxidative mechanism.

Conclusion—

MSC sheet created by the novel magnetic nanoparticle-based tissue engineering technology would represent a new modality for therapeutic angiogenesis and tissue regeneration.
Nitroglycerin-Induced Endothelial Dysfunction and Tolerance Involve Adverse Phosphorylation and
S
-Glutathionylation of Endothelial Nitric Oxide Synthase
Authors: Knorr Maike , Hausding Michael , Kröller-Schuhmacher Swenja , Steven Sebastian , Oelze Matthias , Heeren Tjebo , Scholz Alexander , Gori Tommaso , Wenzel Philip , Schulz Eberhard , Daiber Andreas , Münzel Thomas
Published: July 2011

Objective—

Continuous administration of nitroglycerin (GTN) causes tolerance and endothelial dysfunction by inducing reactive oxygen species (ROS) production from various enzymatic sources, such as mitochondria, NADPH oxidase, and an uncoupled endothelial nitric oxide synthase (eNOS). In the present study, we tested the effects of type 1 angiotensin (AT
1
)-receptor blockade with telmisartan on GTN-induced endothelial dysfunction in particular on eNOS phosphorylation and
S
-glutathionylation sites and the eNOS cofactor synthesizing enzyme GTP–cyclohydrolase I.

Methods and Results—

Wistar rats were treated with telmisartan (2.7 or 8 mg/kg per day PO for 10 days) and with GTN (50 mg/kg per day SC for 3 days). Aortic eNOS phosphorylation and
S
-glutathionylation were assessed using antibodies against phospho-Thr495 and Ser1177 or protein-bound glutathione, which regulate eNOS activity and eNOS-dependent superoxide production (uncoupling). Expression of mitochondrial aldehyde dehydrogenase was determined by Western blotting. Formation of aortic and cardiac ROS was assessed by fluorescence, chemiluminescence, and 3-nitrotyrosine/malondialdehyde-positive protein content. Telmisartan prevented endothelial dysfunction and partially improved nitrate tolerance. Vascular, cardiac, mitochondrial, and white blood cell ROS formation were significantly increased by GTN treatment and inhibited by telmisartan. GTN-induced decrease in Ser1177, increase in Thr495 phosphorylation or
S
-glutathionylation of eNOS, and decrease in mitochondrial aldehyde dehydrogenase expression were normalized by telmisartan.

Conclusion—

These data identify modification of eNOS phosphorylation as an important component of GTN-induced endothelial dysfunction. Via its pleiotropic “antioxidant” properties, telmisartan prevents, at least in part, GTN-induced oxidative stress, nitrate tolerance, and endothelial dysfunction.
Focal Adhesion Kinase Regulates Smooth Muscle Cell Recruitment to the Developing Vasculature
Authors: Cheng Zhaokang , Sundberg-Smith Liisa J. , Mangiante Lee E. , Sayers Rebecca L. , Hakim Zeenat S. , Musunuri Srilaxmi , Maguire Colin T. , Majesky Mark W. , Zhou Zhigang , Mack Christopher P. , Taylor Joan M.
Published: July 2011

Objective—

The investment of newly formed endothelial cell tubes with differentiated smooth muscle cells (SMC) is critical for appropriate vessel formation, but the underlying mechanisms remain unknown. We previously showed that depletion of focal adhesion kinase (FAK) in the
nkx2.5
expression domain led to aberrant outflow tract (OFT) morphogenesis and strove herein to determine the cell types and mechanisms involved.

Methods and Results—

We crossed
fak
loxp
targeted mice with available Cre drivers to deplete FAK in OFT SMC (FAK
wnt
and FAK
nk
) or coronary SMC (FAK
cSMC
). In each case, depletion of FAK led to defective vasculogenesis that was incompatible with postnatal life. Immunohistochemical analysis of the mutant vascular structures revealed that FAK was not required for progenitor cell proliferation, survival, or differentiation into SMC but was necessary for subsequent SMC recruitment to developing vasculature. Using a novel FAK-null SMC culture model, we found that depletion of FAK did not influence SMC growth or survival, but blocked directional SMC motility and invasion toward the potent endothelial-derived chemokine, platelet-derived growth factor PDGFBB. FAK depletion resulted in unstable lamellipodial protrusions due to defective spatial-temporal activation of the small GTPase, Rac-1, and lack of Rac1-dependent recruitment of cortactin (an actin stabilizing protein) to the leading edge. Moreover, FAK null SMC exhibited a significant reduction in stimulated extracellular matrix degradation.

Conclusion—

FAK drives PDGFBB-stimulated SMC chemotaxis/invasion and is essential for SMC to appropriately populate the aorticopulmonary septum and the coronary vascular plexus.
LXRα Regulates Macrophage Arginase 1 Through PU.1 and Interferon Regulatory Factor 8
Authors: Pourcet Benoit , Feig Jonathan E. , Vengrenyuk Yuliya , Hobbs Adrian J. , Kepka-Lenhart Diane , Garabedian Michael J. , Morris Sidney M. , Fisher Edward A. , Pineda-Torra Inés
Published: July 2011

Rationale:

Activation of liver X receptors (LXRs) inhibits the progression of atherosclerosis and promotes regression of existing lesions. In addition, LXRα levels are high in regressive plaques. Macrophage arginase 1 (Arg1) expression is inversely correlated with atherosclerosis progression and is markedly decreased in foam cells within the lesion.

Objective:

To investigate LXRα regulation of Arg1 expression in cultured macrophages and atherosclerotic regressive lesions.

Methods and Results:

We found that Arg1 expression is enhanced in CD68+ cells from regressive versus progressive lesions in a murine aortic arch transplant model. In cultured macrophages, ligand-activated LXRα markedly enhances basal and interleukin-4–induced Arg1 mRNA and protein expression as well as promoter activity. This LXRα-enhanced Arg1 expression correlates with a reduction in nitric oxide levels. Moreover, Arg1 expression within regressive atherosclerotic plaques is LXRα-dependent, as enhanced expression of Arg1 in regressive lesions is impaired in LXRα-deficient CD68+ cells. LXRα does not bind to the Arg1 promoter but instead promotes the interaction between PU.1 and interferon regulatory factor (IRF)8 transcription factors and induces their binding of a novel composite element. Accordingly, knockdown of either IRF8 or PU.1 strongly impairs LXRα regulation of Arg1 expression in macrophage cells. Finally, we demonstrate that LXRα binds the IRF8 locus and its activation increases IRF8 mRNA and protein levels in these cells.

Conclusions:

This work implicates Arg1 in atherosclerosis regression and identifies LXRα as a novel regulator of Arg1 and IRF8 in macrophages. Furthermore, it provides a unique molecular mechanism by which LXRα regulates macrophage target gene expression through PU.1 and IRF8.
Identification of
cis
- and
trans
-Acting Genetic Variants Explaining Up to Half the Variation in Circulating Vascular Endothelial Growth Factor Levels
Authors: Debette Stephanie , Visvikis-Siest Sophie , Chen Ming-Huen , Ndiaye Ndeye-Coumba , Song Ci , Destefano Anita , Safa Radwan , Azimi Nezhad Mohsen , Sawyer Douglas , Marteau Jean-Brice , Xanthakis Vanessa , Siest Gerard , Sullivan Lisa , Pfister Michele , Smith Holly , Choi Seung-Hoan , Lamont John , Lind Lars , Yang Qiong , Fitzgerald Peter , Ingelsson Erik , Vasan Ramachandran S. , Seshadri Sudha
Published: July 2011

Rationale:

Vascular endothelial growth factor (VEGF) affects angiogenesis, atherosclerosis, and cancer. Although the heritability of circulating VEGF levels is high, little is known about its genetic underpinnings.

Objective:

Our aim was to identify genetic variants associated with circulating VEGF levels, using an unbiased genome-wide approach, and to explore their functional significance with gene expression and pathway analysis.

Methods and Results:

We undertook a genome-wide association study of serum VEGF levels in 3527 participants of the Framingham Heart Study, with preplanned replication in 1727 participants from 2 independent samples, the STANISLAS Family Study and the Prospective Investigation of the Vasculature in Uppsala Seniors study. One hundred forty single nucleotide polymorphism (SNPs) reached genome-wide significance (
P
<5×10
−8
). We found evidence of replication for the most significant associations in both replication datasets. In a conditional genome-wide association study, 4 SNPs mapping to 3 chromosomal regions were independently associated with circulating VEGF levels: rs6921438 and rs4416670 (6p21.1,
P
=6.11×10
−506
and
P
=1.47×10
−12
), rs6993770 (8q23.1,
P
=2.50×10
−16
), and rs10738760 (9p24.2,
P
=1.96×10
−34
). A genetic score including these 4 SNPs explained 48% of the heritability of serum VEGF levels. Six of the SNPs that reached genome-wide significance in the genome-wide association study were significantly associated with VEGF messenger RNA levels in peripheral blood mononuclear cells. Ingenuity pathway analyses showed found plausible biological links between VEGF and 2 novel genes in these loci (
ZFPM2
and
VLDLR
).

Conclusions:

Genetic variants explaining up to half the heritability of serum VEGF levels were identified. These new insights provide important clues to the pathways regulating circulating VEGF levels.
Stem Cell Research in Stroke
Authors: Lindvall Olle , Kokaia Zaal
Published: July 2011

Stem cell-based approaches hold much promise as potential novel treatments to restore function after stroke. Studies in animal models have shown that stem cell transplantation can improve function by replacing neurons or by trophic actions, modulation of inflammation, promotion of angiogenesis, remyelination and axonal plasticity, and neuroprotection. Endogenous neural stem cells are also potential therapeutic targets because they produce new neurons after stroke. Clinical trials are ongoing but there is currently no proven stem cell-based therapy for stroke. Preclinical studies and clinical research will be needed to optimize the therapeutic benefit and minimize the risks of stem cells in stroke.
Effects of Posture on Right-to-Left Shunt Detection by Contrast Transcranial Doppler
Authors: Agustin Sherwin Joy U. , Yumul Maricar P. , Kalaw Angelito Jonas L. , Teo Boon Choon , Eng Johnny , Phua Ziqun , Singh Rajinder , Gan Robert N. , Venketasubramanian Narayanaswamy
Published: July 2011

Background and Purpose—

There is controversy about the optimal patient position for the detection of right-to-left shunt (RLS). The study was performed to investigate which patient position best detects RLS during contrast-enhanced transcranial Doppler.

Methods—

We prospectively evaluated consecutive patients with ischemic stroke or TIA referred to our Noninvasive Cerebrovascular Laboratory for suspected paradoxical embolism. The standard protocol for RLS detection recommended by the International Consensus Criteria was followed. Each patient was examined at rest and after Valsalva maneuver in 4 positions: supine, right lateral decubitus, right lateral leaning, and upright sitting, in random order. RLS was graded 0 (no microbubbles [mB] detected), 1 (1–10 mB), 2 (>10 mB but no curtain), and 3 (curtain, shower of mB). Blood pressure, heart rate, and neurological symptoms were monitored. Data were analyzed using SPSS version 17.

Results—

RLS was detected in at least 1 position in 89 of 240 patients (37.1%; 95% CI, 33.1%–43.3%). The detection of at least 1 mB with normal breathing was lowest in supine position and highest in right lateral decubitus. With Valsalva maneuver, this was highest in upright sitting (20.4% versus 8.3%;
P
<0.0002). If mB were undetected on upright sitting position, then they may still be detected in other positions. Changes in the position of the body and the injection of agitated saline were well-tolerated.

Conclusions—

RLS is best detected in the upright sitting position with Valsalva maneuver. If negative, then other positions may be used. Validation of our findings by other centers may be helpful.
Stroke Public Awareness Campaigns Have Increased Ambulance Dispatches for Stroke in Melbourne, Australia
Authors: Bray Janet E. , Mosley Ian , Bailey Michael , Barger Bill , Bladin Chris
Published: July 2011

Background and Purpose—

Launch of the National Stroke Foundation stroke awareness campaigns has occurred annually during Stroke Week (September) since 2004. From 2006, the campaign used FAST (Face, Arm, Speech, Time) with calling an ambulance added in 2007. The aim of this study was to explore the impact of these campaigns on ambulance dispatches for stroke (Medical Priority Dispatch Card 28) in Melbourne, Australia.

Methods—

A cross-sectional study examining the monthly proportions of ambulance dispatches for stroke between August 1999 and 2010 was conducted. The proportions of dispatches for stroke were used due to increases in the population and in ambulance dispatches over the study period. These proportions were statistically compared for the month before Stroke Week (August) and the month after Stroke Week (October) for each year and seasonal variation was examined.

Results—

Between 1999 and 2009, the annual proportion of dispatches for stroke increased from 2.1% (n=4327) to 2.95% (n=9918). When stroke dispatches in August were compared with those in October, a significant increase in October was only detected since the call an ambulance message was added to FAST: 2007 (2.62% to 3.00%,
P
=0.006), 2008 (2.62% to 3.05%,
P
=0.003), and 2009 (2.70% to 3.09%,
P
=0.007). From 2005, the peak season for stroke dispatches shifted from winter to spring.

Conclusions—

Ambulance dispatches for stroke significantly increased after the National Stroke Foundation campaigns began, particularly in years receiving greater funding and featuring the FAST symptoms and the message to call an ambulance. Monitoring ambulance use appears to be an effective measure of campaign penetration.
Cerebral Microbleeds and Depression in Lacunar Stroke
Authors: Tang W.K. , Chen Y.K. , Lu J.Y. , Chu Winnie C.W. , Mok V.C.T. , Ungvari Gabor S. , Wong K.S.
Published: July 2011

Background and Purpose—

Cerebral microbleeds (CMB) are common in stroke survivors and the community-dwelling elderly. The clinical significance of CMB in the development of depression after a stroke is unknown. This study examined the association between poststroke depression (PSD) and CMB.

Methods—

A cohort of 235 patients with acute lacunar stroke admitted to the stroke unit of a university-affiliated regional hospital in Hong Kong was recruited. Three months after the onset of the index stroke, a research assistant administered the locally validated 15-item Geriatric Depression Scale. PSD was defined as a Genetic Depression Scale score of ≥7. The presence and location of CMB were evaluated with MRI.

Results—

In comparison with the non-PSD group, PSD patients were more likely to have lobar CMB (33.3% versus 19.9%;
P
=0.022). Lobar CMB remained an independent predictor of PSD in the multivariate analysis, with an odds ratio of 2.08 (
P
=0.032).

Conclusions—

The results suggest that lobar CMB may play a role in the development of PSD. The importance of CMB in the pathogenesis of depression in stroke survivors and the general elderly population warrants further investigation.
Liver Cirrhosis and Risk of Intracerebral Hemorrhage
Authors: Lai Chien-Hsu , Cheng Pei-Yu , Chen Yen-Yu
Published: July 2011

Background and Purpose—

The purpose of this study was to investigate the risk of future intracerebral hemorrhage development in patients with liver cirrhosis.

Methods—

Data were collected from the National Health Insurance Research Database of Taiwan. The study cohort included 948 patients with liver cirrhosis diagnosed in 1999 and 9480 age- and sex-matched patients of the same year. All patients were tracked from their index visits for 9 years.

Results—

Intracerebral hemorrhage developed in 1.3% of patients with liver cirrhosis and 1.0% of patients in the comparison cohort during the follow-up period. Log-rank test analysis showed no significant difference between the 2 cohorts (
P
=0.39). A stratified Cox proportional regression model showed an adjusted hazard ratio of 1.62 (95% CI, 0.85 to 3.10) for patients with liver cirrhosis to develop intracerebral hemorrhage compared with patients without liver cirrhosis.

Conclusions—

Patients with liver cirrhosis had a similar intracerebral hemorrhage incidence rate but a trend of increased risk for intracerebral hemorrhage compared with the comparison cohort during the 9-year follow-up period.