bluuebunny/crossref_metadata_2025 huggingface dataset:
Crucial roles of GATA-2 and SP1 in adrenomedullin-affected expression of tissue factor pathway inhibitor in human umbilical vein endothelial cells exposed to lipopolysaccharide
Authors: Wang Wen , Zu Shu-Yu , Liu Wei , Zhu Zi-Qiang , Zhu Guang-Jin
Published: June 2007

Adrenomedullin (ADM) is a vasodilator peptide that has a variety of effects, including antithrombotic activities and resistant roles to lipopolysaccharide (LPS)-induced septic shock. During sepsis,LPS triggers the development of disseminated intravascular coagulation (DIC) via the tissue factor-dependent pathway of coagulation.It is unknown whether the antithrombotic activities of ADM contribute to its resistance to sepsis. In the present study, we investigated the effects of ADM on tissue factor pathway inhibitor (TFPI) (primary anticoagulant factor) expression in human umbilical vein endothelial cells (HUVECs) exposed to LPS,and the possible underlying mechanism for these effects.Exposure of HUVECs to LPS for 12 hours caused significant decrease of TFPI protein activities and mRNA expression.These effects were abolished by treatment withADM (10–10 to 10–6 M), cAMP analogue and calcium antagonist. Accordingly, cAMP antagonist inhibited the counteraction effect of ADM on LPS in TFPI expression. Electrophoresis mobility shift assay (EMSA) and Western blot analysis showed that the protein level of GATA-2 and SP1 transcriptional factors and their binding to the corresponding regulatory sequences decreased by LPS treatment. And these effects of LPS were antagonized by ADM. Promoter- reporter assays and mutational analysis also confirmed the roles of GATA-2 and SP1 motifs from –1247 to –381bp promoter sequence in TFPI inducible expression. Taken together, these results indicate that ADM antagonizes the effect of LPS on TFPI expression, which is mediated by affecting transcriptional factor GATA-2 and SP1 through cAMP and calcium signaling pathway.
A novel inhibitor of activated thrombin activatable fibrinolysis inhibitor (TAFIa) – Part II: Enhancement of both exogenous and endogenous fibrinolysis in animal models of thrombosis
Authors: da Cunha Valdeci , Vincelette Jon , Zhao Lei , Nagashima Mariko , Kawai Kohichi , Yuan Shendong , Emayan Kumar , Islam Imadul , Hosoya Junko , Sullivan Mark E. , Dole William P. , Morser John , Buckman Brad O. , Vergona Ronald , Wang Yi-Xin
Published: June 2007

We have discovered a novel small-molecule TAFIa inhibitor, BX 528, which is potent, highly selective against other carboxypeptidases and safe. The present study was to determine if BX 528 can enhance exogenous and endogenous thrombolysis in four different animal models. In the first three models, a thrombus was induced by FeCl2 (dogs) or laser (rats) injury of the femoral artery, or formed ex vivo and implanted in the jugular vein in rabbits. A low dose of exogenous t-PA was given to induce a lowlevel thrombolysis on an established thrombus. Co-treatment with BX 528 further enhanced the thrombolytic effects induced by the exogenous t-PA and, thus, r educed thrombosis in all three animal models. In a second rat model, fibrin deposition in the lungs was induced by batroxobin, which was spontaneously resolved in 30 minutes due to the activation of endogenous fibrinolysis. Pre-treatment with lipopolysaccharide (LPS) attenuated this spontaneous fibrinolysis. Co-treatment with 10 mg/kg BX 528 prevented the LPS-induced attenuation of endogenous fibrinolysis. Thus, these studies demonstrated that inhibition ofTAFIa by BX 528, our newly discovered small-molecule TAFIa inhibitor, enhanced both the exogenous (induced by a low dose of t-PA) and endogenous (LPS-induced resistance) thrombolysis without increasing the bleeding risk in four different animal models of thrombosis in different species (rat, dog and rabbit) employing different thrombogenic stimuli (FeCl2, laser, ex vivo and batroxobin) to induce thrombus formation in different tissues (artery, vein and lung microcirculation).
Antiphosphatidylethanolamine antibodies are associated with an increased odds ratio for thrombosis
Authors: Gayet Stéphane , Alessi Marie-Christine , Audrain Marie , de Maistre Emmanuel , Gris Jean-Christophe , de Groot Philip , Hachulla Eric , Harlé Jean-Robert , Sié Pierre , Boffa Marie-Claire , Sanmarco Marielle
Published: June 2007

A multicenter study was set up to evaluate the prevalence, clinical and biological significance of antiphosphatidylethanolamine antibodies (aPE) in thrombotic patients with or without the main known clinical and biological risk factors for thrombosis. APE and antibodies, defined as the laboratory criteria of antiphospholipid syndrome (APS) -lupus anticoagulant, anticardiolipin and anti-beta2-GPI antibodies were measured in 270 patients with thrombosis (234 venous and 37 arterial) and 236 matched controls. APE were found in 15% of thrombotic patients compared to 3% of controls (p<0.001) with no predominant isotype, no association with the main known clinical or biological risk factors for thrombosis neither with a type of thrombosis, arterial or venous. In a multivariate logistic regression analysis of antibodies, aPE showed the highest association with thrombosis (odds ratio [OR]: 4.2, p<0.001). Moreover, using a multivariate analysis in a case-control subgroup study on 158 patients, IgGaPE were found to be significantly associated with venous thrombosis (OR:6;p=0.005). Interestingly, 25 of the 40 aPE-positive patients (63%) were negative for the APS laboratory criteria. Most of them (21/25) had venous thrombosis, recurrent in ten of them. Four patients also suffered from early or late miscarriages. Our results underline the strength of the association between the presence of aPE and thrombosis and suggest their measurement in thrombotic patients, especially when lupus anticoagulant, anticardiolipin or anti-beta2-GPI antibodies are absent.
Differential impact of conventional and low-dose oral hormone therapy (HT), tibolone and raloxifene on functionality of the activated protein C system
Authors: Liestøl Sigurd , Mowinckel Marie-Christine , Hemker H. Coen , Sandset Per-Morten , Eilertsen Anette
Published: June 2007

Recent studies have shown that hormone therapy (HT) is associated with an acquired resistance to activated protein C (APC). The aims of the present study were to evaluate a possible dose-response relationship and differential effects of different HT regimens on functionality of the APC system. Two hundred two healthy women were randomly assigned to receive treatment for 12 weeks with tablets containing either low-dose HT containing 1 mg 17β-oestradiol + 0.5 mg norethisterone acetate (NETA) (n=50), conventional-dose HT containing 2 mg 17β-oestradiol and 1 mg NETA (n=50), 2.5 mg tibolone (n=51), or 60 mg raloxifene (n=51). Normalized APC system sensitivity ratios (nAPCsr) were determined in plasma collected at baseline and after 12 weeks using a thrombin generation-based APC resistance test probed with either recombinant APC (rAPC) or thrombomodulin (rTM). NAPCsr increased in both the conventional- and low-dose HT groups, consistent with reduced sensitivity to APC. The increase was slightly more pronounced in the conventional-dose group, but the difference between the two HT groups was not statistically significant. The sensitivity to APC was only marginally altered in those allocated to tibolone. Consequently, tibolone showed a different phenotype as compared with the low-dose HT group. A small increase in nAPCsr with both rAPC and rTM was seen in the raloxifene-group, but the increase was less than in the low-dose HT group. Our findings indicate that oestrogen-progestin therapy induces an APC resistant phenotype, which may be related to dose, whereas tibolone and raloxifene only marginally alter the sensitivity to APC.
Clinically suspected acute recurrent pulmonary embolism: A diagnostic challenge
Authors: Kwakkel-van Erp Hanneke , Söhne Maaike , Tick Lidwine , Kruip Marieke , Ullmann Eric , Kramer Mark , Büller Harry , Prins Martin , Leebeek Frank , Huisman Menno , Nijkeuter Mathilde
Published: June 2007

It is unknown whether strategies validated for diagnosing pulmonary embolism (PE) are valid in patients with a history of PE. It was the objective of this study to investigate whether a diagnostic algorithm consisting of sequential application of a clinical decision rule (CDR), a quantitative D-dimer test and computed tomography (CT) safely ruled out a clinical suspicion of acute recurrent PE. Data were obtained from a diagnostic outcome study of patients suspected of PE. Acute recurrent PE was ruled out by an unlikely probability of PE (CDR score ≤4 points) combined with a normal D-dimer test (≤500 ng/ml) or by a normal CT in all other patients. The primary outcome was the incidence of acute recurrent venous thromboembolism during three months of follow-up in patients with normal tests and not treated with anticoagulants. Of 3,306 patients suspected of acute PE, 259 patients (7.8%) had a history of PE of whom 234 were not treated with anticoagulants. The probability of PE was unlikely in 82 of 234 patients (35%), and 42 had a normal D-dimer test (18%), excluding recurrent PE. None of these patients had a thrombotic event during follow-up (0%, 95%CI: 0–6.9). A CT was indicated in all other patients (192) and ruled out recurrent PE in 127 patients (54%). Only one patient with a negative CT had a fatal recurrent PE during follow-up (0.8%; 95%CI: 0.02–4.3). In conclusion, this prospective study demonstrates the safety of ruling out a clinical suspicion of acute recurrent PE by a simple diagnostic algorithm in patients with a history of PE.
Activated coagulation factors in human malignant effusions and their contribution to cancer cell metastasis and therapy
Authors: Lühr Inke , Kunze Thomas , Mundhenke Christoph , Maass Nicolai , Erhart Tobias , Denker Momme , Beckmann Dennis , Tiemann Markus , Schulte Christoph , Dohrmann Peter , Cavaillé Françoise , Godeau François , Gespach Christian , Gieseler Frank
Published: June 2007

We have shown that the thrombin G-protein coupled receptors (GPCR) designated as protease-activated receptors (PAR-1) are expressed in primary cancer cells isolated from peritoneal and pleural malignant effusions. Here, our main goal was to evaluate several coagulation and thrombin activation effectors and markers in a series of 136 malignant effusions from cancer patients with gastrointestinal, lung and mammary carcinomas. All these patients present a highly activated coagulation system in blood and their malignant effusions, as indicated by high levels of prothrombin F1.2 fragments and D-dimers. Notably, we detected in the effusions all the coagulation factors of the tissue factor pathway inducing thrombin activation, namely factorsVII, V, X and II, as well as high VEGF levels and IGF-II in mature and precursor forms. Fibrin clot formation also correlated with higher levels of free ionized calcium (iCa), suggesting that iCa and its binding protein albumin are regulatory factors for fibrinogenesis in effusions. Consequently, thrombin,VEGF and IGFII appear to converge in the promotion of survival and invasivity of the metastatic cancer cells from blood to the malignant effusions. Thus, we add new insights on the interconnections between blood coagulation disorders in cancer patients and thrombin activation in malignant effusions, including their functional interaction with PAR in metastatic cancer cells. Based on these data we propose to counteract the metastatic cascades by targeted invalidation of key effectors of the coagulation system. Therefore, potential therapeutic approaches include the application of thrombin protease inhibitors, VEGF-blocking antibodies, and drugs targeting the VEGF and thrombin signaling pathways, such as tyrosine kinase or GPCR inhibitors.
Hyperresponsiveness of platelets in ischemic stroke
Authors: Tomandl Bernd , Sander Dirk , Stellos Konstantinos , Geisler Tobias , Langer Harald , Walton Kodwo , Handschu Rene , Garlichs Christoph , Daniel Werner , Fateh-Moghadam Suzanne , Htun Patrik , Gawaz Meinrad
Published: June 2007

Platelet activation and aggregation are critical in the pathogenesis of acute ischemic cerebrovascular diseases. The aim of our study was to characterize platelet function in patients with acute ischemic stroke or transient ischemic attack (TIA), and to evaluate the effect of platelet activation on clinical outcome. One hundred thirty-eight consecutive patients with TIA (n=74) or stroke (n=64) were enrolled in this study. Platelet aggregation in response to ADP, epinephrine, arachidonic acid, or collagen, and expression of platelet activation receptors (CD62P, CD63, LIBS-1 and PAC-1) in the acute phase and at three months follow-up were evaluated. Platelets derived from stroke patients were more hyperaggregable in response to agonists in the acute phase compared to TIA patients (p[ADP]=0.002, p[arachidonic acid]=0.047, p[epinephrine]=0.020). Platelet activation was enhanced in the acute phase irrespective of the severity of the disease (stroke or TIA) and returned to baseline levels three months later. Persistent elevated platelet activation at three months follow-up (PAC-1) was associated with increased incidence of recurrent stroke (median, [interquartile range] 3.4, [3.0–5.2] versus 2.9, [2.3–4.0], p=0.048). In conclusion, platelets are hyperactive in acute stroke compared with TIA. A more intensified dual antiplatelet therapy may be of benefit for stroke patients.
A novel P2Y12 adenosine diphosphate receptor antagonist that inhibits platelet aggregation and thrombus formation in rat and dog models
Authors: Vincelette Jon , Cunha Valdeci , Martin-McNulty Baby , Mallari Cornell , Fitch Richard , Alexander Serene , Islam Imadul , Buckman Brad , Yuan Shendong , Post Joseph , Subramanyam Babu , Vergona Ronald , Sullivan Mark , Dole William , Morser John , Bryant Judi , Wang Yi-Xin
Published: June 2007

Irreversible platelet inhibitors, such as aspirin and clopidogrel, have limited anti-thrombotic efficacy in the clinic due to their bleeding risk. We have developed an orally active reversible P2Y12 receptor antagonist, BX 667.The aim of this study was to determine if the reversible antagonist BX 667 had a greater therapeutic index than the irreversible P2Y12 receptor antagonist clopidogrel. Since BX 667 is rapidly converted to its active metabolite BX 048 in rats,we first injected BX 048 intravenously (iv) in a rat arterial venous (A-V) shunt model of thrombosis.BX 048 dose- and concentration-dependently attenuated thrombosis. When administered orally, BX 667 and clopidogrel had similar efficacy, but BX 667 caused less bleeding than clopidogrel. In a rat model of a platelet-rich thrombus induced by vessel injury with FeCl2, both BX 667 and clopidogrel exhibited higher levels of thrombus inhibition after oral administration compared to their potency in the A-V shunt model.Again, BX 667 caused less bleeding than clopidogrel. In a dog cyclic flow model, iv injection of either BX 667 or clopidogrel dose-dependently reduced thrombus formation with lower bleeding for BX 667 than clopidogrel. Inhibition of thrombosis was highly correlated with inhibition of ADP-induced platelet aggregation in these animal models. In dogs pre-treated with aspirin, BX 667 maintained its wider therapeutic index, measured by inhibition of platelet aggregation over bleeding, compared to the aspirin-clopidogrel combination.These data demonstrate that the reversible P2Y12 receptor antagonist, BX 667, has a wider therapeutic index than clopidogrel in experimental models of thrombosis.
Three reactive compartments in venous malformations
Authors: Bartnick Katja , Dörge Hilmar , Becker Jürgen , Schweigerer Lothar , Ebenebe Chinedu , Diehl Stefanie , Wilting Jörg
Published: June 2007

Vascular malformations affect 3% of neonates. Venous malformations (VMs) are the largest group representing more than 50% of cases. In hereditary forms of VMs gene mutations have been identified, but for the large group of spontaneous forms the primary cause and downstream dysregulated genes are unknown. We have performed a global comparison of gene expression in slow-flow VMs and normal saphenous veins using human whole genome micro-arrays.Genes of interest were validated with qRT-PCR. Gene expression in the tunica media was studied after laser micro-dissection of small pieces of tissue. Protein expression in endothelial cells (ECs) was studied with antibodies.We detected 511 genes more than four-fold down- and 112 genes more than four-fold up-regulated. Notably, chemokines, growth factors, transcription factors and regulators of extra-cellular matrix (ECM) turnover were regulated. We observed activation and “arterialization” of ECs of the VM proper, whereas ECs of vasa vasorum exhibited up-regulation of inflammation markers. In the tunica media, an altered ECM turnover and composition was found. Our studies demonstrate dysregulated gene expression in tunica interna, media and externa of VMs, and show that each of the three layers represents a reactive compartment.The dysregulated genes may serve as therapeutic targets.
Chemokines in cardiovascular risk prediction
Authors: Yndestad Arne , Smith Camilla , Ueland Thor , Gullesta Lars , Damås Jan , Aukrust Pål
Published: June 2007

In consideration of the important role of inflammation in plaque progression and stability, recent work has focused on whether plasma markers of inflammation can non-invasively diagnose and predict coronary artery disease (CAD) and other forms of atherosclerotic disorders. Although several studies support an important pathogenic role of chemokines in atherogenesis and plaque destabilization, potentially representing attractive therapeutic targets in atherosclerotic disorders,this does not necessarily mean that chemokines are suitable parameters for risk prediction. In fact, the ability to reflect up-stream inflammatory activity, stable levels in individuals and high stability of the actual protein (e.g. long half-life and negligible circadian variation), are additional important criteria for an ideal biomarker in cardiovascular disease. Although plasma/serum levels of certain chemokines (e.g. interleukin 8 and monocyte chemoattractant protein- 1) have been shown to be predictive for future cardiac events in some studies, independent of traditional cardiovascular risk factors and C-reactive protein,and although certain gene polymorphisms of chemokines/chemokine receptors (e.g. fractalkine receptor) have been shown to be predictive of future atherosclerotic disease, further prospective studies, including a larger number patients,are needed to make any firm conclusion. While the demonstrations of an association between chemokines and CAD are a necessary first step, such studies do not establish the full clinical utility of a biomarker, which is a more demanding process that requires validation in multiple cohorts, and clear demonstration of incremental prognostic value over traditional risk models. If successful, such new biomarker will be a useful indicator for better risk assessment,diagnosis,and prognosis, as well as monitoring pharmacological treatments for atherosclerosis.
International Registry on Factor XIII Deficiency: A basis formed mostly on European data
Authors: Seitz Rainer , Kohler Hans , Schroeder Verena , Muszbek Laszlo , Ariens Robert , Seifried Erhard , Oldenburg Johannes , Ivaskevicius Vytautas ,   and The Study Group
Published: June 2007

FXIII deficiency is known as one of the rarest blood coagulation disorders. In this study, the phenotypic and in part genotypic data of 104 FXIII-deficient patients recorded from 1993 – 2005 are presented. The most common bleeding symptoms were subcutaneous bleeding (57%) followed by delayed umbilical cord bleeding (56%), muscle hematoma (49%), hemorrhage after surgery (40%), hemarthrosis (36%), and intracerebral bleeding (34%). Prophylactic treatment was initiated in about 70% of all patients. FXIII-B subunit-deficient patients had a milder phenotype than patients with FXIII-A subunit deficiency. The most frequent mutation affecting the F13A gene was a splice site mutation in intron 5 (IVS5–1G>A). This mutation was found in eight (17%) of 46 analyzed families. The haplotype analysis of patients carrying the IVS5–1A allele was consistent with a founder effect. The international registry (http://www.f13-database.de) will provide clinicians and scientists working on FXIII deficiency with a helpful tool to improve patient care and direct future studies towards better understanding and treatment of the disease.
Chemokines as mediators of angiogenesis
Authors: Mehrad Borna , Keane Michael , Strieter Robert
Published: June 2007

Chemokines were originally described as cytokines that mediate leukocyte recruitment to sites of inflammation. Members of a subgroup of chemokines, the CXC family, also play a critical role in both physiologic and pathologic angiogenesis, including in the context of chronic inflammation, fibrosis, and malignancy.A unique feature of this family of cytokines is that, on the basis of their structure and receptor binding, individual ligands display either angiogenic or angiostatic biological activity in the regulation of angiogenesis. In this review, we summarize the key literature in this growing field.
Chemokines at large: In-vivo mechanisms of their transport, presentation and clearance
Authors: Colditz Ian , Schneider Martin , Pruenster Monika , Rot Antal
Published: June 2007

Compelling evidence implicates chemokines in the induction of leukocyte emigration from blood into tissues.This arguably most fundamental effect of chemokines is accomplished by triggering cognate classical G-protein-coupled chemokine receptors on the leukocyte surface. In vitro, these same receptors mediate leukocyte migration; however, the mechanisms of chemokine-induced migration differ between in-vivo and in-vitro settings. Leukocyte egress from blood is greatly influenced by haemodynamic conditions and requires full cooperation of endothelial cells.The behaviour of chemokines in their“native habitat” in vivo is controlled by their interaction with several accessory molecules which influence immobilisation, transport, clearance and degradation of chemokines and thereby determine the sites and duration of their action. Here we discuss peculiarities of the invivo actions of chemokines,the mechanisms of chemokine interaction with receptors and auxiliary molecules including interceptors, glycosaminoglycans and enzymes and illustrate how these interactions influence the outcome of chemokine activities in vivo.
Circulating P-selectin and the risk of recurrent venous thromboembolism
Authors: Hron Gregor , Eichinger Sabine , Wagner Oswald , Kyrle Paul
Published: June 2007

The clinical relevance of high P-selectin levels in venous thrombosis is unknown. We prospectively followed 544 patients with first unprovoked venous thromboembolism (VTE) after cessation of anticoagulation and evaluated P-selectin as a risk factor of recurrent VTE. VTE recurred in 63 (12%) patients. Patients with recurrence had significantly higher P-selectin levels than those without (45.8 mg/dl ± 16.4 vs. 40.1 mg/dl ± 13.3; p = 0.006). After four years, the probability of recurrence was 20.6% (95% confidence interval [CI] 12.6–28.5) among patients with P-selectin values above the 75th percentile of the patient population and was 10.8% (95% CI 7.2–14.3) among patients with lower values (p = 0.046). Compared to patients with low P-selectin, adjusted risk of recurrence was 1.7-fold (95% CI 1.0–2.9, p = 0.045) increased among patients with P-selectin levels exceeding the 75th percentile. We conclude that high circulating P-selectin is a risk factor of recurrent VTE.
The effect of measurement method on static weight distribution to all legs in dogs using the Quadruped Biofeedback System
Authors: Ramos V. , Shires P. K. , Werre S. R. , Phelps H. A.
Published: June 2007

An application to measure static quadruped load distribution would be highly beneficial in the assessment of rehabilitation and lameness in many small animal patients. The scope of this study was to analyze the effects of confinement, location and local environment on the measurement of static quadruped load distribution as measured by the Quadruped Biofeedback System in normal dogs in order to better prescribe the use of this system. A prospective study of 20 healthy adult dogs was performed to evaluate effects on measurement on quadruped load distribution. Data collection in the form of mean load per extremity was recorded four times in five positions for a total of 20 measurements for each limb. A replicated cross-over design in which a mixed effect, repeated measures analysis of variance was used to test for main effects of treatment and end as well as their interaction. The effects of right vs. left within each end and for each end was analyzed for each treatment and significance of p<0.01 was established. Measurements were taken from 20 healthy adult dogs with no obvious lameness at the time of data collection. Analysis by end suggests that measurements were affected in similar manners in comparable locations. Each method demonstrated consistency in measurement without any significant influence by day or session, suggesting that one standardized method be established for measurement. With standardization, the Quadruped Biofeedback System has potential use as a reliable instrument for the measurement of quadruped load distribution in dogs.
Measurement differences between three versus five photocells during collection of ground reaction forces in dogs
Authors: Punke J. P. , Speas A. L. , Reynolds L. R. , Andrews C. M. , Budsberg S. C.
Published: June 2007

The differences between velocities and accelerations obtained from three and five photocells were examined when obtaining ground reaction force (GRF) data in dogs. Ground reaction force data was collected 259 times from 16 different dogs in two experimental phases. The first phase compared velocities and accelerations reported by the two systems based on trials accepted by the three photocell system. The second phase accepted trials based on data from five photocells. Three photocell data were calculated mathematically in the second phase in order to compare the values of both systems. The velocity and acceleration values obtained from each system were significantly different (at the hundredth of a meter per second). Differences in measured values did not result in acceptance of data by the three photocell system that would not have been acceptable with the five photocell system (false positives), but did result in rejection of acceptable data by the three photocell system (11% false negative rate). Given the small differences between the two systems, GRF data collected should not be significantly different, though the three photocell system is less efficient in gathering data due to the number of trials rejected as false negatives.
Evaluation of clinical, radiographical and cytological findings compared to arthroscopic findings in shoulder joint lameness in the dog
Authors: Sjöström L. , Åkerblom S.
Published: June 2007

Forty-two dogs with lameness emanating from the shoulder joint were studied by clinical examination, radiographic examination, joint fluid analysis, and arthroscopic examination, following a set protocol. Dogs with mild clinical signs, absent or mild radiographic signs of osteoarthrosis, and without or with very mild changes in the synovial fluid, may still have moderate to severe degenerative pathological changes in the shoulder joint.
Comparison of trot kinetics between dogs with stifle or hip arthrosis
Authors: Huneault L. , Moreau M. , Dupuis J. , Madore E.
Published: June 2007

The purposes of this study were: 1) to describe and compare the trotting gait of normal and lame dogs secondary to stifle (GONOA) or hip (COXOA) osteoarthritis (OA) using multiple ground reaction forces (GRF) parameters, and 2) to pinpoint any characteristic in gait profile (‘signatures’) which could help to discriminate a lameness secondary to GONOA or COXOA. Fifty-one large breed dogs with OA (19 GONOA, 32 COXOA) and 22 normal dogs were included in the study. The vertical and cranio-caudal (braking-propelling) GRF were collected. The total stance time, and for each orthogonal vector, the peak force, impulse, time to peak, and the rate of limb loading were recorded. Vertical and craniocaudal forces were found to be significantly decreased in both OA groups compared to normal dogs. Vertical, cranial and caudal limb loading were also most often lower for both OA groups. In addition, the vertical and cranial forces were significantly lower in dogs with GONOA compared to COXOA and normal dogs. This study has demonstrated that, at a trotting gait, OA dogs secondary to GONOA and COXOA load their affected limb, brake and propel earlier during the stance phase, but generally with less magnitude than normal dogs. Dogs affected by GONOA also present more severe gait alterations than dogs with COXOA. The vertical and braking specific GRF alterations described may be kinetic ‘signatures’ linked more to lame dogs secondary to GONOA versus COXOA. Finally, this study has also provided useful baseline GRF data for further clinical and research investigations.
3D kinematics of the equine metacarpophalangeal joint at walk and trot
Authors: Sha D. , Stick J. , Elvin N. , Clayton H. M.
Published: June 2007

The metacarpophalangeal (MCP) joint and its supporting soft tissues are common sites of injury in athletic horses. Equine gait analysis has focused on 2D analysis in the sagittal plane and little information is available which describes 3D motions of the MCP joint and their possible role in the development of injuries. The aim was to characterize the 3D rotations of the equine MCP joint during walking and trotting. Three-dimensional trajectories of marker triads fixed rigidly to the third metacarpus and proximal phalanx of the right forelimb of healthy horses were recorded at walk (n=4) and trot (n=6) at 120 Hz using eight infra-red cameras. Kinematics of the MCP joint were calculated in terms of helical angles between the two segments using singular-value decomposition and spatial attitude methods. The ranges of motion were: flexion/extension: 62 ± 7° at walk, 77 ± 5° at trot; adduction/abduction: 13 ± 7° at walk, 18 ± 7° at trot; and axial rotation: 6 ± 3° at walk, 9 ± 5° at trot. Flexion/extension had a consistent pattern and amplitude in all horses and appeared to be coupled with adduction/abduction, such that stance phase extension was accompanied by abduction and swing phase flexion was accompanied by adduction. Axial rotation was small in amount and the direction varied between horses but was consistent within an individual for the two gaits.
Randomized Trial of Acupuncture to Lower Blood Pressure
Authors: Flachskampf Frank A. , Gallasch Joachim , Gefeller Olaf , Gan Junxue , Mao Juntong , Pfahlberg Annette B. , Wortmann Alois , Klinghammer Lutz , Pflederer Wolfgang , Daniel Werner G.
Published: June 2007

Background—

Arterial hypertension is a prime cause of morbidity and mortality in the general population. Pharmacological treatment has limitations resulting from drug side effects, costs, and patient compliance. Thus, we investigated whether traditional Chinese medicine acupuncture is able to lower blood pressure.

Methods and Results—

We randomized 160 outpatients (age, 58±8 years; 78 men) with uncomplicated arterial hypertension in a single-blind fashion to a 6-week course of active acupuncture or sham acupuncture (22 sessions of 30 minutes’ duration). Seventy-eight percent were receiving antihypertensive medication, which remained unchanged. Primary outcome parameters were mean 24-hour ambulatory blood pressure levels after the treatment course and 3 and 6 months later. One hundred forty patients finished the treatment course (72 with active treatment, 68 with sham treatment). There was a significant (
P
<0.001) difference in posttreatment blood pressures adjusted for baseline values between the active and sham acupuncture groups at the end of treatment. For the primary outcome, the difference between treatment groups amounted to 6.4 mm Hg (95% CI, 3.5 to 9.2) and 3.7 mm Hg (95% CI, 1.6 to 5.8) for 24-hour systolic and diastolic blood pressures, respectively. In the active acupuncture group, mean 24-hour ambulatory systolic and diastolic blood pressures decreased significantly after treatment by 5.4 mm Hg (95% CI, 3.2 to 7.6) and 3.0 mm Hg (95% CI, 1.5 to 4.6), respectively. At 3 and 6 months, mean systolic and diastolic blood pressures returned to pretreatment levels in the active treatment group.

Conclusions—

Acupuncture according to traditional Chinese medicine, but not sham acupuncture, after 6 weeks of treatment significantly lowered mean 24-hour ambulatory blood pressures; the effect disappeared after cessation of acupuncture treatment.
Tobacco Smoke Exposure Is Associated With Attenuated Endothelial Function in 11-Year-Old Healthy Children
Authors: Kallio Katariina , Jokinen Eero , Raitakari Olli T. , Hämäläinen Mauri , Siltala Marja , Volanen Iina , Kaitosaari Tuuli , Viikari Jorma , Rönnemaa Tapani , Simell Olli
Published: June 2007

Background—

Passive smoking is associated with early arterial damage in adults, but its effect on endothelial function in children is unknown.

Methods and Results—

Serum cotinine concentration was measured annually in children between 8 and 11 years of age who had participated since infancy in a randomized, prospective atherosclerosis prevention trial (Special Turku Coronary Risk Factor Intervention Project for children [STRIP]). At age 11, endothelium-dependent flow-mediated vasodilatory responses of the brachial artery were examined with high-resolution ultrasound in 402 children. These children were divided into 3 groups according to serum cotinine concentrations: the noncotinine group (nondetectable cotinine, n=229), the low cotinine group (cotinine between 0.2 and 1.6 ng/mL, n=134), and the top decile cotinine group (cotinine ≥1.7 ng/mL, n=39). Longitudinal cotinine data in children aged 8 to 11 years and ultrasound studies were available in 327 children. At age 11, the increase in cotinine concentration was associated with attenuated peak flow-mediated dilation response (mean±SD: the noncotinine group 9.10±3.88%, the low-cotinine group 8.57±3.78%, and the top-decile cotinine group 7.73±3.85%;
P
=0.03 for trend). Similarly, total dilation response (the area under the dilation response versus time curve between 40 and 180 seconds after hyperemia) was affected by the cotinine level (
P
=0.02 for trend). These trends were not explained by traditional atherosclerosis risk factors. Arterial measures and passive smoking showed even stronger associations when longitudinal cotinine data were used (peak flow-mediated dilation,
P
=0.01 for trend; total dilation response,
P
=0.008 for trend).

Conclusions—

Exposure to environmental tobacco smoke confirmed by serum cotinine concentrations impairs endothelial function in a dose-dependent manner in 11-year-old children.
Superior Cardiovascular Effect of Aerobic Interval Training Versus Moderate Continuous Training in Heart Failure Patients
Authors: Wisløff Ulrik , Støylen Asbjørn , Loennechen Jan P. , Bruvold Morten , Rognmo Øivind , Haram Per Magnus , Tjønna Arnt Erik , Helgerud Jan , Slørdahl Stig A. , Lee Sang Jun , Videm Vibeke , Bye Anja , Smith Godfrey L. , Najjar Sonia M. , Ellingsen Øyvind , Skjærpe Terje
Published: June 2007

Background—

Exercise training reduces the symptoms of chronic heart failure. Which exercise intensity yields maximal beneficial adaptations is controversial. Furthermore, the incidence of chronic heart failure increases with advanced age; it has been reported that 88% and 49% of patients with a first diagnosis of chronic heart failure are >65 and >80 years old, respectively. Despite this, most previous studies have excluded patients with an age >70 years. Our objective was to compare training programs with moderate versus high exercise intensity with regard to variables associated with cardiovascular function and prognosis in patients with postinfarction heart failure.

Methods and Results—

Twenty-seven patients with stable postinfarction heart failure who were undergoing optimal medical treatment, including β-blockers and angiotensin-converting enzyme inhibitors (aged 75.5±11.1 years; left ventricular [LV] ejection fraction 29%; V̇
o
2peak
13 mL · kg
−1
· min
−1
) were randomized to either moderate continuous training (70% of highest measured heart rate, ie, peak heart rate) or aerobic interval training (95% of peak heart rate) 3 times per week for 12 weeks or to a control group that received standard advice regarding physical activity. V̇
o
2peak
increased more with aerobic interval training than moderate continuous training (46% versus 14%,
P
<0.001) and was associated with reverse LV remodeling. LV end-diastolic and end-systolic volumes declined with aerobic interval training only, by 18% and 25%, respectively; LV ejection fraction increased 35%, and pro-brain natriuretic peptide decreased 40%. Improvement in brachial artery flow-mediated dilation (endothelial function) was greater with aerobic interval training, and mitochondrial function in lateral vastus muscle increased with aerobic interval training only. The MacNew global score for quality of life in cardiovascular disease increased in both exercise groups. No changes occurred in the control group.

Conclusions—

Exercise intensity was an important factor for reversing LV remodeling and improving aerobic capacity, endothelial function, and quality of life in patients with postinfarction heart failure. These findings may have important implications for exercise training in rehabilitation programs and future studies.
Effect of Nocturnal Nasal Continuous Positive Airway Pressure on Blood Pressure in Obstructive Sleep Apnea
Authors: Bazzano Lydia A. , Khan Zia , Reynolds Kristi , He Jiang
Published: June 2007

Obstructive sleep apnea (OSA) is a very common risk factor for hypertension, and continuous positive airway pressure (CPAP) has been widely used to treat OSA. We conducted a meta-analysis of randomized, controlled trials to evaluate the effects of CPAP on blood pressure, reported as either a primary or secondary end point, among patients with OSA. Studies were retrieved by searching Medline (January 1980 to July 2006), the Cochrane Database of Systematic Reviews, conference abstracts, and bibliographies of review and original articles. From 255 relevant reports, 16 randomized clinical trials were selected that compared CPAP to control among participants with OSA, had a minimum treatment duration of 2 weeks, and reported blood pressure changes during the intervention or control period. Data on sample size, participant characteristics, study design, intervention methods, duration, and treatment results were independently abstracted by 2 investigators using a standardized protocol. Data from 16 trials representing 818 participants were examined using a random-effects model. Mean net change in systolic blood pressure for those treated with CPAP compared with control was −2.46 mm Hg (95% CI: −4.31 to −0.62); mean net change in diastolic blood pressure was −1.83 mm Hg (95% CI: −3.05 to −0.61); and mean net change in mean arterial pressure was −2.22 mm Hg (95% CI: −4.38 to −0.05). Net reductions in blood pressure were not statistically different between daytime and nighttime. These results indicate that CPAP decreases blood pressure among those with OSA and may help prevent hypertension.
From High School Jocks to College Grads
Authors: Troutman Kelly P. , Dufur Mikaela J.
Published: June 2007

Various studies show that interscholastic sport participants, and specifically female athletes, enjoy numerous educational benefits at the high school level. Because of the influx in the number of females engaging in high school sport that has occurred during the past 30 years, few studies have been able to adequately assess whether females' involvement in interscholastic sport has any long-term consequences. In this study, the authors examine whether females who participated in high school athletics are more likely to graduate from college than are their counterparts. The authors use data from the National Education Longitudinal Study and employ multilevel models with random effects. They find that females who engage in interscholastic high school sport have higher odds of completing college than do their counterparts.
Conversion of platelets from a proaggregatory to a proinflammatory adhesive phenotype: role of PAF in spatially regulating neutrophil adhesion and spreading
Authors: Kulkarni Suhasini , Woollard Kevin J. , Thomas Stephen , Oxley David , Jackson Shaun P.
Published: June 2007

The ability of platelets to provide a highly reactive surface for the recruitment of other platelets and leukocytes to sites of vascular injury is critical for hemostasis, atherothrombosis, and a variety of inflammatory diseases. The mechanisms coordinating platelet-platelet and platelet-leukocyte interactions have been well defined and, in general, it is assumed that increased platelet activation correlates with enhanced reactivity toward other platelets and neutrophils. In the current study, we demonstrate a differential role for platelets in supporting platelet and neutrophil adhesive interactions under flow. We demonstrate that the conversion of spread platelets to microvesiculated procoagulant (annexin A5–positive [annexin A5+ve]) forms reduces platelet-platelet adhesion and leads to a paradoxical increase in neutrophil-platelet interaction. This enhancement in neutrophil adhesion and spreading is partially mediated by the proinflammatory lipid, platelet-activating factor (PAF). PAF production, unlike other neutrophil chemokines (IL-8, GRO-α, NAP-2, IL-1β) is specifically and markedly up-regulated in annexin A5+ve cells. Physiologically, this spatially controlled production of PAF plays an important role in localizing neutrophils on the surface of thrombi. These studies define for the first time a specific proinflammatory function for annexin A5+ve platelets. Moreover, they demonstrate an important role for platelet-derived PAF in spatially regulating neutrophil adhesion under flow.
A novel role for HMGB1 in TLR9-mediated inflammatory responses to CpG-DNA
Authors: Ivanov Stanimir , Dragoi Ana-Maria , Wang Xin , Dallacosta Corrado , Louten Jennifer , Musco Giovanna , Sitia Giovanni , Yap George S. , Wan Yinsheng , Biron Christine A. , Bianchi Marco E. , Wang Haichao , Chu Wen-Ming
Published: June 2007

CpG-DNA or its synthetic analog CpG-ODN activates innate immunity through Toll-like receptor 9 (TLR9). However, the mechanism of TLR9 activation by CpG-DNA remains elusive. Here we have identified HMGB1 as a CpG-ODN–binding protein. HMGB1 interacts and preassociates with TLR9 in the endoplasmic reticulum-Golgi intermediate compartment (ERGIC), and hastens TLR9's redistribution to early endosomes in response to CpG-ODN. CpG-ODN stimulates macrophages and dendritic cells to secrete HMGB1; in turn, extracellular HMGB1 accelerates the delivery of CpG-ODNs to its receptor, leading to a TLR9-dependent augmentation of IL-6, IL-12, and TNFα secretion. Loss of HMGB1 leads to a defect in the IL-6, IL-12, TNFα, and iNOS response to CpG-ODN. However, lack of intracellular TLR9-associated HMGB1 can be compensated by extracellular HMGB1. Thus, the DNA-binding protein HMGB1 shuttles in and out of immune cells and regulates inflammatory responses to CpG-DNA.
EPO modulation of cell-cycle regulatory genes, and cell division, in primary bone marrow erythroblasts
Authors: Fang Jing , Menon Madhu , Kapelle William , Bogacheva Olga , Bogachev Oleg , Houde Estelle , Browne Sarah , Sathyanarayana Pradeep , Wojchowski Don M.
Published: June 2007

Erythropoietin (EPO's) actions on erythroblasts are ascribed largely to survival effects. Certain studies, however, point to EPO-regulated proliferation. To investigate this problem in a primary system, KitposCD71high erythroblasts were prepared from murine bone marrow, and were first used in the array-based discovery of EPO-modulated cell-cycle regulators. Five cell-cycle progression factors were rapidly up-modulated: nuclear protein 1 (Nupr1), G1 to S phase transition 1 (Gspt1), early growth response 1 (Egr1), Ngfi-A binding protein 2 (Nab2), and cyclin D2. In contrast, inhibitory cyclin G2, p27/Cdkn1b, and B-cell leukemia/lymphoma 6 (Bcl6) were sharply down-modulated. For CYCLIN G2, ectopic expression also proved to selectively attenuate EPO-dependent UT7epo cell-cycle progression at S-phase. As analyzed in primary erythroblasts expressing minimal EPO receptor alleles, EPO repression of cyclin G2 and Bcl6, and induction of cyclin D2, were determined to depend on PY343 (and Stat5) signals. Furthermore, erythroblasts expressing a on PY-null EPOR-HM allele were abnormally distributed in G0/G1. During differentiation divisions, EPOR-HM Ter119pos erythroblasts conversely accumulated in S-phase and faltered in an apparent EPO-directed transition to G0/G1. EPO/EPOR signals therefore control the expression of select cell-cycle regulatory genes that are proposed to modulate stage-specific decisions for erythroblast cell-cycle progression.
The oxidase activity of vascular adhesion protein-1 (VAP-1) induces endothelial E- and P-selectins and leukocyte binding
Authors: Jalkanen Sirpa , Karikoski Marika , Mercier Nathalie , Koskinen Kaisa , Henttinen Tiina , Elima Kati , Salmivirta Katriina , Salmi Marko
Published: June 2007

Leukocyte migration from the blood into tissues is pivotal in immune homeostasis and in inflammation. During the multistep extravasation cascade, endothelial selectins (P- and E-selectin) and vascular adhesion protein-1 (VAP-1), a cell-surface–expressed oxidase, are important in tethering and rolling. Here, we studied the signaling functions of the catalytic activity of VAP-1. Using human endothelial cells transfected with wild-type VAP-1 and an enzymatically inactive VAP-1 point mutant, we show that transcription and translation of E- and P-selectins are induced through the enzymatic activity of VAP-1. Moreover, use of VAP-1–deficient animals and VAP-1–deficient animals carrying the human VAP-1 as a transgene show a VAP-enzyme activity–dependent induction of P-selectin in vivo. Up-regulation of P-selectin was found both in high endothelial venules in lymphoid tissues and in flat-walled vessels in noninflamed tissues. VAP-1 activity in vivo led to increased P-selectin–dependent binding of lymphocytes to endothelial cells. These data show that the oxidase reaction catalyzed by VAP-1 alters the expression of other molecules involved in the leukocyte extravasation cascade. Our findings indicate cross-talk between adhesion molecules involved in the tethering and rolling of leukocytes and show that VAP-1–dependent signaling can prime the vessels for an enhanced inflammatory response.
Interventions for increasing chlamydia screening in primary care: a review
Authors: Ginige Samitha , Fairley Christopher K , Hocking Jane S , Bowden Francis J , Chen Marcus Y
Published: June 2007

Background

Despite guidelines recommending opportunistic chlamydia screening of younger women, screening rates in some countries remain low. Our aim was to review the evidence for specific interventions aimed at increasing chlamydia screening rates in primary care.

Methods

A Medline search was conducted for controlled trials that assessed the effectiveness of interventions aimed at improving chlamydia screening rates in primary health care settings. The Medline search was done for studies in English published prior to December 2005 using the following key words: chlamydia, screening, intervention, primary care and GPs. In addition, the references cited in the articles were reviewed. Studies in English published prior to December 2005 were reviewed.

Results

Four controlled studies met the inclusion criteria – 3 were randomized studies and one was not. Strategies to increase screening rates included the use of educational packages targeting primary care physicians and the correction of barriers to screening within clinic systems. In 3 studies, the intervention was associated with an increase in screening rates of between 100% and 276% (p < 0.04). In the fourth study, the intervention was associated with a significant attenuation in declining screening rates over time (4% versus 34% decline, p = 0.04).

Conclusion

There are only a limited number of randomized or controlled studies that demonstrate improved chlamydia screening of younger women in primary care.