bluuebunny/crossref_metadata_2025 huggingface dataset:
Increased and Decreased Cortical Reactivities in Novelty Seeking and Persistence
Authors: Ito Makoto , Fukuda Masato , Suto Tomohiro , Uehara Toru , Mikuni Masahiko
Published: June 2005

Background: Near-infrared spectroscopy (NIRS) has enabled completely noninvasive measurements of regional cerebral blood volume (rCBV) changes in cortices. In the present study, we investigated the relationships between rCBV changes assessed with NIRS and two dimensions of personality, novelty seeking and persistence. Methods: Thirty right-handed healthy volunteers participated in the study. Their personality traits were assessed using the Temperament and Character Inventory (TCI), and changes in oxy- and deoxy-hemoglobin concentrations were monitored during 40 s unilateral finger tapping tasks over the subjects’ bilateral temporal regions using a 24-channel NIRS machine. Results: The oxy-hemoglobin concentration increases were significantly correlated positively with novelty seeking scores and negatively with persistence scores in the TCI during the initial time segment of the left-finger tapping task. Conclusion: Increased and decreased brain activations demonstrated using multichannel NIRS were assumed to characterize the cortical reactivities underlying novelty seeking and persistence temperament, respectively.
Cardioprotective Effects of [5-(2-Methyl-5-Fluorophenyl)furan-2-ylcarbonyl]guanidine (KR-32568) in an Anesthetized Rat Model of Ischemia and Reperfusion Heart Injury
Authors: Roh Hui-Yul , Jung In-Sang , Park Jung-Woo , Yun Yeo-Pyo , Yi Kyu-Yang , Yoo Sung-Eun , Kwon Suk-Hyung , Chung Hun-Jong , Shin Hwa-Sup
Published: June 2005

The effects of a novel sodium/hydrogen exchanger-1 (NHE-1) inhibitor, KR-32568, were studied in an anesthetized rat model of 30 min ischemia/2.5 h reperfusion heart injury. KR-32568 dose-dependently inhibited NHE-1-mediated rabbit platelet swelling induced by intracellular acidification. In our anesthetized rat model, KR-32568 reduced infarct size from 67 (control) to 43 and 24% at 0.1 and 1.0 mg/kg (i.v. bolus, given 10 min before ischemia), respectively. KR-32568 at the same doses also significantly reduced the total number of ventricular premature beats during ischemia/reperfusion from 530 (control) to 266 and 115 beats, ventricular tachycardia (VT) incidence from 51 (control) to 21 and 8, VT duration from 238 s (control) to 63 and 33 s, ventricular fibrillation (VF) incidence from 17 (control) to 8 and 0, and VF duration from 85 s to 18 and 1 s. These results indicate that KR-32568 may exert potent cardioprotective effects in rats via inhibition of sodium/hydrogen exchanger-1.
Paramedic Identification of Stroke: Community Validation of the Melbourne Ambulance Stroke Screen
Authors: Bray Janet E. , Martin Jenepher , Cooper Greg , Barger Bill , Bernard Stephen , Bladin Christopher
Published: June 2005

Background: Paramedics require an effective prehospital tool to eliminate stroke mimics and to assist in the identification of suitable candidates for thrombolytic therapy. The Faster Access to Stroke Therapies study combined two validated stroke assessment tools (the Los Angeles Prehospital Stroke Screen, LAPSS, and the Cincinnati Prehospital Stroke Scale, CPSS) to form the Melbourne Ambulance Stroke Screen (MASS), and performed an in-field validation by Australian paramedics. Methods: Over a 12-month period, 18 paramedics participated in the Faster Access to Stroke Therapies study and prospectively collected data contained in the MASS on all stroke dispatches, and for other patients with a focal neurological deficit. Sensitivity and specificity analysis of the LAPSS, CPSS and MASS was calculated and equivalence analysis performed. Results: Paramedics completed 100 MASS assessments for 73 (73%) stroke/transient ischemic attack patients and 27 (27%) stroke mimics. The sensitivity of the MASS (90%, 95% CI: 81–96%) showed statistical equivalence to the sensitivity of the CPSS (95%, p = 0.45) and superiority to the LAPSS (78%, p = 0.008). The specificity of the MASS (74%, 95% CI: 53–88%) was equivalent to that of the LAPSS (85%, p = 0.25) and superior to the CPSS (54%, p = 0.007). All patients misidentified by the MASS (7 strokes, 7 mimics) were ineligible for thrombolytic therapy. Conclusion: The MASS is simple to use, with accurate prehospital identification of stroke. It distinguishes stroke mimics, with good recognition of suitable patients for thrombolytic therapy.
Lacunar Infarcts: Functional and Cognitive Outcomes at Five Years in Relation to MRI Findings
Authors: Appelros Peter , Samuelsson Margareta , Lindell Dan
Published: June 2005

Background: There are few long-term follow-up studies of patients with lacunar infarcts (LIs). The purpose of this 5-year follow-up study was to assess functional and cognitive outcome in relation to MRI findings. Methods: 81 patients with a first-ever LI were followed for 5 years with respect to mortality, stroke recurrence, functional and cognitive outcome. T2-weighted MRI was performed at baseline and at 5 years. The presence of basal ganglia lesions and white matter lesions was scored according to the European Task Force rating scale. Functional outcome was assessed with the Oxford Handicap Scale (OHP). Cognition was assessed with the Mini Mental State Examination (MMSE). Results: The 5-year mortality was 19%. Predictors for death were age (OR = 1.07, 95% CI 1.03–1.11), ischemic heart disease (OR = 2.1, 95% CI 1.1–4.1) and impairment score (OR = 1.16, 95% CI 1.02–1.32). 30% of the patients had a recurrent stroke. Predictors for recurrent stroke were diabetes mellitus (OR = 1.7, 95% CI 1.2–7.4) and amount of white matter lesions (OR = 1.7, 95% CI 1.2–2.7). 36% of the patients were functionally dependent (defined as OHP >2). Predictors for functional dependency were impairment score (OR = 1.71, 95% CI 1.12–2.59), MMSE (OR = 0.55, 95% CI 0.33–0.91) and stroke recurrence (OR = 84, 95% CI 9.4–745). 16% of the patients had cognitive impairment (defined as MMSE <24). Stroke recurrence and white matter score, but not basal ganglia score, were correlated to cognitive impairment. Conclusions: Many LI patients have a good functional outcome at 5 years. For older patients, for patients with an initial severe stroke, and with additional vascular risk factors, however, the prognosis is more severe, with an increased risk for mortality, stroke recurrence, and physical and cognitive decline.
Blood Pressure, Smoking and Oral Contraceptive Control after Cryptogenic Stroke in Young Adults in the PFO-ASA Study
Authors: Arquizan Caroline , Touzé Emmanuel , Moulin Thierry , Woimant France , Ducrocq Xavier , Mas Jean-Louis
Published: June 2005

Background: Management of vascular risk factors is not optimal in stroke patients. We assessed the control of hypertension, smoking and stopping of oral contraceptive in 581 consecutive young cryptogenic ischemic stroke patients followed in the PFO-ASA study and we identified factors associated with inadequate management. Methods: At each follow-up visit, blood pressure (BP), smoking and use of oral contraceptive were recorded. Data were analyzed at 6 months, 1 and 2 years. Hypertension was defined as systolic BP ≧140 or diastolic BP ≧90 mm Hg, recorded in at least two follow-up visits. Current smoking was defined as more than one cigarette per day reported during at least one follow-up visit. Results: During follow-up, 36% of patients were hypertensive and 30% were smokers. Among the 90 hypertensive patients at baseline, 60–68% remained with high BP and among the 278 patients who were current smokers at baseline, 54–58% still smoked during follow-up. Age (OR = 1.05, 95% CI 1.02–1.08), male sex (OR = 1.42, 95% CI 0.93–2.18), body mass index ≧27 (OR = 2, 95% CI 1.27–3.17) and known hypertension (OR = 3.08, 95% CI 1.80–5.28) were significantly associated with hypertension during follow-up. Tobacco consumption at baseline (OR = 35.2, 95% CI, 19.3–64.2), alcohol consumption at baseline (OR = 2.7, 95% CI 1.4–5.2) and Rankin ≤2 (OR = 2.6, 95% CI 1.4–4.9) were independently associated with persistent smoking. Among the 114 women who were using combined estrogen-progesterone pills at baseline, 96.5% stopped. Conclusions: Major risk factors for stroke are poorly controlled after stroke, even in the context of a prospective clinical study in young adults.
Distribution of Apolipoprotein E Alleles in a Scottish Healthy Newborn Population
Authors: Becher J.-C. , Bell J.E. , McIntosh N. , Keeling J.W.
Published: June 2005

The different alleles of the human apolipoprotein E polymorphism, ApoE Ε2, Ε3, Ε4, have important implications for systemic lipid metabolism, immunological function and for the brain in maintenance and in response to injury. Few studies have focussed on their role in early life. The ApoE alleles and genotypes were ascertained in the cord blood of 371 full-term and normal Scottish newborn infants using PCR methodology. The results were compared to previously published data for Scottish adults in late middle age. There was a marginally significant over-representation of Ε4 and under-representation of Ε3 alleles in healthy infants as compared with adults. Inspection of the individual genotypes confirms the over-representation of ApoE 4/4 and 2/4 with a reduction in ApoE 2/3 and 3/3 when compared with Scottish adults. Although these results may have occurred by chance, the ApoE Ε4 allele may confer an increased risk of premature death.
Hyperoxia with 100% Oxygen following Hypoxia-Ischemia Increases Brain Damage in Newborn Rats
Authors: Shimabuku Roberto , Ota Arturo , Pereyra Sonia , Véliz Betty , Paz Edith , Nakachi Graciela , More Mario , Oliveros Miguel
Published: June 2005

Objective: To describe the effect of reoxygenation with 100% O2 as compared to the effect of room air in newborn rat brains after asphyxia. Methods: Experimental asphyxia (carotid artery ligation followed by hypoxic exposure with 8% O2 for 2 h) was performed on 7-day-old rats. After hypoxia-ischemia the rats were reoxygenated with either 100% O2 (hyperoxia group) or 21% O2 (room air group) for 24 h and then returned to the dam. The rats were killed 1 week after the experiment to study the cerebral cortex and hippocampus. Results: Rats reoxygenated with 100% O2 post-asphyxia showed more frequency of cortical damage (10 of 24 rats) than those reoxy genated with room air (3 of 24 rats) (χ2 test, p = 0.02). Conclusion: We consider that hyperoxia with 100% oxygen after hypoxia-ischemia can cause more damage in the cerebral cortex than room air in newborn rats.
Assessment of the Stability of an Immunoadsorbent for the Extracorporeal Removal of Beta-2-Microglobulin from Blood
Authors: Daniels Cynthia M. , Woolverton Emily M. , Sprague Stuart M. , Ameer Guillermo A.
Published: June 2005

Background: Dialysis-related amyloidosis (DRA) is a devastating and costly condition that affects patients with end stage kidney disease. A key feature of DRA is the formation of amyloid fibrils, consisting primarily of β2-microglobulin. Except for kidney transplantation, conventional kidney replacement therapies, which are based on nonspecific mechanisms, do not adequately address β2-microglobulin removal. An antihuman β2-microglobulin single-chain variable region antibody fragment (scFv) was developed to confer specificity to β2-microglobulin removal during hemodialysis. Methods: The scFv was immobilized onto agarose and characterized for β2m binding capacity, thermal stability at 37°C, regeneration capacity, storage conditions, and sterility. Results: The β2-microglobulin binding capacity was 1.3 mg/ml scFv gel. The immunoadsorbent is thermally stable, can be regenerated, stored short-term in 20% ethanol, lyophilized for long-term storage, and withstand process conditions similar to that of a patient’s hemodialysis therapy. Conclusions: The results support further investigation of immobilized scFvs as a novel tool to remove β2-microglobulin from blood.
Calcitonin Gene-Related Peptide during Sweating in Young Healthy Women
Authors: Spetz Anna-Clara E. , Ellefsen Katrine , Theodorsson Elvar , Lassvik Claes T. , Hammar Mats L.
Published: June 2005

Calcitonin gene-related peptide (CGRP) concentrations are increased in postmenopausal women and castrated men with symptomatic flushing. We wanted to determine if a CGRP increase exists in the plasma of healthy fertile-age women during sweating. Plasma concentrations of CGRP were measured by radioimmunoassay at maximal sweating during a sauna session and during bicycle exercise both at maximal and 70% of maximal work capacity in 8 healthy women of fertile age. Plasma concentrations of CGRP were unaffected (>90% statistical power) during both experimental sessions. We suggest that sweating itself does not explain the rise in CGRP concentrations observed in flushing postmenopausal women.
Variation in Stomatopod (Gonodactylus smithii) Color Signal Design Associated with Organismal Condition and Depth
Authors: Cheroske Alexander G. , Cronin Thomas W.
Published: June 2005

In interactions, many tropical stomatopod species display conspicuous colored body spots that can communicate information about the sender’s state (e.g., sex, aggressiveness, etc.). Species inhabiting a variety of depths experience large differences in illumination spectrum and intensity due to filtering of light by water and its constituents. Stomatopod spectral sensitivity is known to vary phenotypically with changes in light environment (associated with depth) that potentially affects the detection of color signals. Animals collected at different depths also have different body coloration. This study examines how spectral differences in colored body spots vary with organismal condition and models the effects of changing body coloration, light environment, and spectral sensitivity on the detection of color signals in a gonodactyloid species, Gonodactylus smithii. Of the seven conspicuous color spots that were measured in G. smithii, three had spectral differences that correlated with sex, aggression, and female reproductive state. A model of color detection in G. smithii indicates that longer-wavelength spectral content was affected most by varying body coloration and light conditions. Most color signals were perceived similarly both by shallow- and by deep-adapted photoreceptor sets over a range of depths (1–13 m). Eye spot (‘meral spot’) color detection also was invariant over the same depth range in shallow- and deep-adapted, long-wavelength receptors, but deep-adapted receptors continued to maintain a consistent detection of these spots down to 18 meters. These results suggest that meral spot coloration may have evolved as a constant signal when viewed by conspecifics from various depths.
Cyto- and Chemoarchitecture of the Cortex of the Tammar Wallaby (Macropuseugenii): Areal Organization
Authors: Ashwell K.W.S. , Zhang L.-L. , Marotte L.R.
Published: June 2005

We have examined the cyto- and chemoarchitecture of the isocortex of a diprotodontid marsupial, the tammar wallaby (Macropus eugenii), using Nissl staining in combination with enzyme histochemical (acetylcholinesterase – AChE, NADPH-diaphorase – NADPHd, cytochrome oxidase) and immunohistochemical (non-phosphorylated neurofilament – SMI-32) markers. The primary sensory cortex showed distinctive patterns of reactivity in cytochrome oxidase, acetylcholinesterase and NADPH diaphorase. For example, in AChE material, S1 showed a heterogeneous appearance, with regions exhibiting a double layer of AChE activity (layers II and IV) adjacent to poorly reactive regions. In NADPHd preparations, activity in S1 was strongest in layers I to IV although, as in AChE material, there were consistent patches of reduced NADPHd activity which corresponded to poorly reactive regions in the AChE sections. Each of the primary sensory areas of the isocortex showed a different pattern of distribution of SMI-32+ neurons. In V1, SMI-32+ neurons were distributed in two layers (III and V) throughout the tangential extent of that region. In S1, SMI-32+ neurons were concentrated in layer V, but large and discrete patches within S1 had additional SMI-32+ neurons in layer III. In primary auditory cortex there was a dense band of SMI-32+ neurons in layer V, with only occasional labeled pyramidal neurons in layer III. In the secondary sensory areas (V2 and S2) SMI-32+ neurons were either distributed in layers III and V (V2) or solely within layer V (S2). The tangential and laminar distribution of Type I reactive NADPH diaphorase neurons in the tammar wallaby cortex was more like that seen in eutheria than in polyprotodontid metatheria.
Determinants of Circulating Adiponectin in Women with Polycystic Ovary Syndrome
Authors: Vrbíková Jana , Dvořáková Kateřina , Hill Martin , Včelák Josef , Stanická Soňa , Vaňková Markéta , Šrámková Daniela , Vondra Karel , Bendlová Běla , Stárka Luboslav
Published: June 2005

Background and Aim: Adiponectin is regarded as a possible link between adiposity and insulin resistance. Ghrelin and leptin are considered as signals of energy status. We evaluated the relationships between these peptides, androgens and insulin sensitivity in women affected by polycystic ovary syndrome. Methods: Thirty-six women with PCOS were examined with euglycemic hyperinsulinemic clamp (to determine M/I, index of insulin sensitivity). Leptin, ghrelin, adiponectin, androgens, and SHBG were determined. Statistics was done using correlation analysis and backward stepwise multiple regression. Results: The positive correlation of adiponectin with testosterone remains significant even after adjustment for BMI (p = 0.01), M/I (p = 0.009) and for both M/I and BMI (p = 0.02). In multiple regression with testosterone, M/I, leptin and ghrelin as independent variables, the model including testosterone (p = 0.03) and ghrelin (p = 0.002) explained 49% of the variability (p < 0.0012) of adiponectin. Conclusions: Both adiponectin and ghrelin can be involved in the pathophysiology of PCOS but their relation must be delineated further.
No effect of folic acid supplementation in the course of 1 year on haemostasis markers and C-reactive protein in older adults
Authors: Klerk Mariska , Durga Jane , Schouten Evert G. , Kluft Cornelis , Kok Frans J. , Verhoef Petra
Published: June 2005

Elevated homocysteine levels are associated with an increased cardiovascular disease (CVD) risk, but the underlying mechanism is still unclear. High homocysteine might affect the endothelium, and consequently lead to impaired haemostasis. In a randomized placebo controlled trial among 276 older adults with plasma total homocysteine concentrations above 13 mM at screening, we investigated the effect of homocysteine lowering by folic acid supplementation (0.8 mg/day) for 1 year on markers of endothelial function (vonWillebrand factor), coagulation (tissue factor, factor VIIa, fragments 1+2), and fibrinolysis (fibrin degradation products, tissue-type plasminogen activator), and inflammation (C-reactive protein). Despite a 24% reduction in plasma homocysteine concentration and four-fold increase in serum folate concentration in the folic acid group compared to the placebo group, there was no clear change in any of the haemostasis markers, nor CRP. Although homocysteine is associated with vascular disease risk in the general population, marked lowering of slightly elevated homocysteine concentrations by one-year folic acid supplementation does not influence haemostasis markers.
Polymorphisms of haemostasis genes as risk factors for preterm delivery
Authors: Härtel Christoph , von Otte Sören , Koch Julia , Ahrens Peter , Kattner Evelyn , Segerer Hugo , Möller Jens , Diedrich Klaus , Göpel Wolfgang
Published: June 2005

Clinical trials evaluating the potential benefit of anticoagulant treatment in pregnant women with inherited thrombophilia are based on the observation that a genetic predisposition to thrombosis is associated with frequent abortions and preterm birth. It was the aim of our study to delineate the impact of genetic polymorphisms with prothrombotic and antithrombotic effects on the occurrence of preterm birth in a large cohort of very-low-birth-weight (VLBW)-infants and their mothers. We examined the factor V Leiden and the prothrombin G20210A mutation, the factor VII 121del/ins and the factor XIII Val34Leu polymorphism in preterm very-low-birth-weight (VLBW, n=593) and term-born-infants (n=278) and their mothers (n=785).The primary outcome was preterm vs. term birth. From all polymorphisms tested, the maternal factor VII-121del/ins polymorphism (26.2 vs. 17.6 %; p=0.009) and the infant’s factor VII-121del/ins polymorphism (29.0 vs. 20.0 %; p=0.009) were more frequent in singletonVLBW and their mothers compared to term infants and their mothers. Furthermore, the frequency of the factor XIII-Val34Leu polymorphism was significantly lower in singleton VLBW than in term infant controls (5.1 vs. 9.6%, p=0.025). In a multivariate regression analysis, previous preterm delivery (OR=3.8, 95% CI: 1.7–8.4), the maternal carrier status of the factor-VII-121del/ins polymorphism (OR=1.7, 95% CI: 1.12–2.5, p=0.007) and the lower frequency of infant’s factor-XIII-Val34Leu polymorphism (OR=0.53; 95% CI: 0.29–0.96; p=0.038) were found to be independently associated with preterm delivery. InVLBW mothers with pathological CTG as cause of preterm delivery, the frequency of factor V Leiden mutation was significantly increased compared to VLBW mothers without pathological CTG (14.1 vs. 6.1%, p=0.01).The investigated haemostasis gene polymorphisms have a much lower impact on subsequent preterm delivery than known risk factors such as previous preterm birth. The reported association of the factor-VII-121del/ins polymorphism on preterm delivery and its clinical relevance needs to be further elucidated.
Increased prevalence of factor V Leiden in patients with retinal vein occlusion and under 60 years of age
Authors: Arsène Sophie , Delahousse Bénédicte , Regina Sandra , Lez Marie-Laure Le , Pisella Pierre-Jean , Gruel Yves
Published: June 2005

Retinal vein occlusion (RVO) is a multifactorial disease involving vessel damage, stasis, viscosity and thrombosis. Conflicting findings on hereditary thrombophilic risk factors have been reported and their impact on RVO features remains to be defined. The aim of the present study was to evaluate the prevalence of hereditary thrombophilic risk factors (HTRF) and characteristics of RVO in patients with or without HTRF. The design of the study was a prospective, observational case series. Two hundred and thirty-four patients with RVO were included consecutively. A French healthy population of the same region was studied as control group. The HTRF studied were protein C (PC), protein S (PS) and antithrombin (AT) deficiencies, factor V Leiden (FVL) and factor II 20210A polymorphisms. Chi-Square was used for comparison with the healthy subjects and between RVO patient with and without HTRF according to localisation (branch vs. central), type of RVO (ischemic or non-ischemic), recurrence, age at first event and classical vascular risk factors. Twenty-two patients had HTRF (12 FV Leiden heterozygotes, 9 FII 20210A heterozygotes and 1 PS deficiency). No AT or PC deficiency was detected. Frequencies of PS deficiency, FVL and FII 20210A allele were similar to the reference population as well as to published data in the general caucasian population. Eighty-six patients experienced their first episode before the age of 60 years. Systemic hypertension, glaucoma and angina were significantly less frequent in patients with RVO before 60 years. Fourteen of the 22 patients with one HTRF (64%) experienced their first episode of RVO before the age of 60 years compared to 72 of 212 without HTRF (34%) (p = 0.006). Heterozygote status for FV Leiden was significantly more frequent in patients who had experienced their first episode of RVO before 60 years (p = 0.027). In conclusion, this study suggests a role of FV Leiden in the occurrence of RVO in patients younger than 60 years who exhibit fewer acquired vascular risk factors than in older patients.
Impaired inactivation by antithrombin and hirudin and preserved fibrinogen-clotting activity of thrombin in complex with antithrombin antibody from a patient with antiphospholipid syndrome
Authors: Léránt István , Skopál Judit , Kelemen Anna , Nagy Zoltán , Machovich Raymund , Kolev Krasimir
Published: June 2005

Immunoglobulin G (IgG) isolated from the blood plasma of a patient with secondary antiphospholipid syndrome (APS) expresses fibrinogen-clotting and amidolytic activity (the thrombin activity in 20 μmole IgG is equivalent to approximately 5 nmole pure thrombin), and activates factor XIII. Hirudin (1 μM) decreases the intrinsic thrombin activity of the APS IgG by only 25%, whereas it inhibits completely pure thrombin with equivalent activity. Under conditions, when antithrombin inactivates 60% of the thrombin activity in the presence of normal IgG, the APS IgG protects almost completely the added thrombin against inactivation by antithrombin. Heparin, however, partially relieves this protective effect and at the same time it facilitates the inhibition of the intrinsic thrombin activity by antithrombin. The APS IgG reduces the thrombin activity in protein C activation assay by 50% compared to the activity in the presence of normal IgG. All described properties are related to the Fab fragment of the antibody. The IgG preserving the fibrin-generating activity of thrombin with concomitant protection against inhibitors unravels a new aspect of the thrombotic mechanism in APS. This condition is probably rare: only one out of 23 examined patients with primary or secondary APS expresses IgG with the described properties.
Mechanism for the homocysteine-enhanced antifibrinolytic potential of lipoprotein(a) in human plasma
Authors: Nardulli Marina , Durlach Vincent , Pepe Gabriella , Anglés-Cano Eduardo
Published: June 2005

Lipoprotein(a) and total plasma homocysteine levels are now established as independent atherothrombogenic risk factors. A distinctive pathophysiological feature of lipoprotein(a) is its antifibrinolytic activity, an effect dependent on plasma concentration and high affinity for fibrin of its small size apo(a) component. A stimulating effect of homocysteine on purified lipoprotein(a) has been proposed. However, little is known about their specific interactions in human plasma. We demonstrate by immunochemical, ligand-binding and plasminogen activation studies, that homocysteine modifies the structure and function of lipoprotein(a) in human plasma; it reduces the apo(a)/apoB disulfide bond causing the appearance of free apo(a) with high affinity for fibrin that inhibits plasminogen binding and plasmin formation (r= −0.995, p=0.002). These effects were evident particularly in plasma samples containing lipoprotein(a) with low affinity for fibrin and more than 22 kringles apo(a) isoforms. In contrast, for plasmas containing high fibrin affinity lipoprotein(a) (less than 22 kringles apo[a] isoforms) no significant change neither in fibrin binding nor in plasmin formation was observed. Furthermore, isolated apo(a) recombinants (10 to 34 kringles) that have been shown to display size-independent high affinity for fibrin were not affected by homocysteine, thus confirming lipoprotein(a) as its main target. These results suggest that the pro-atherogenic role already conferred to lipoprotein(a) by small apo(a) isoforms may be extended to large apo(a) isoforms if released in plasma by homocysteine, as this mechanism reveals their high fibrin affinity. Lipoprotein(a) and homocysteine may therefore constitute, if acting in concert, a new risk factor for athero-thrombotic vascular disease.
Glycosaminoglycan: a candidate to stimulate the repair of chronic wounds
Authors: Peplow Philip V.
Published: June 2005

A persistent inflammation with large numbers of neutrophils is found in chronic wounds. Secretory products released from the neutrophils, which include proteinases and a heparin-binding protein, are detrimental to wound healing as they cause degradation of the extracellular matrix and growth factors, and promote further recruitment of neutrophils to the wound area. The neutrophil-derived elastase, cathepsin G, proteinase-3 and heparin-binding protein are cationic, and it is hypothesized that their effects can be inhibited by electrostatic binding with certain anionic polymers such as glycosaminoglycans or functionalized dextrans. A sustained delivery of such compounds alone or in combination from a biodegradable carrier may provide a stimulus for these wounds to pass to the next stage of repair.
Residual venous obstruction in patients with a single episode of deep vein thrombosis and in patients with recurrent deep vein thrombosis
Authors: Galli Matteo , Squizzato Alessandro , Dentali Francesco , Manfredi Elisa , Steidl Luigi , Venco Achille , Ageno Walter
Published: June 2005

Residual venous obstruction (RVO) in patients with previous deep vein thrombosis (DVT) of the lower limbs has been suggested as an independent risk factor for recurrent venous thromboembolism (VTE).RVO could be a marker of a persistent prothrombotic state. We have compared the rate of RVO in patients with DVT and a personal history of at least one previous episode of VTE to the rate of RVO among patients with a first episode of DVT. All patients underwent compression ultrasonography (CUS) of the lower limbs 1 year after index DVT. RVO was arbitrarily defined as a thrombus occupying, at maximal compressibility, more than 20% of the vein area in the absence of compression. 50 consecutive patients with recurrent DVT and 50 age and sex-matched patients with a single episode of DVT were enrolled. The index event was idiopathic in 62% of patients with recurrent DVT and in 60% of patients with a single episode. In 74% of patients with recurrent DVT the index event occurred in either the contralateral leg or in a different segment of the ipsilateral leg. RVO was detected in 50% of patients with a single episode of DVT and in 88% of patients with recurrent DVT (p<0.00001). The prevalence of RVO is significantly higher in patients with recurrent DVT than in patients with a single episode. This finding supports the importance of RVO as a potential marker of a persistent prothrombotic state.
Additive effects of anticoagulants: recombinant human activated protein C and heparin or melagatran, in tissue factor-activated umbilical-cord plasma
Authors: Gallistl Siegfried , Muntean Wolfgang , Leschnik Bettina , Fritsch Peter , Cvirn Gerhard , Koestenberger Martin
Published: June 2005

Severe sepsis in children or adults may cause a life-threatening coagulopathy, with widespread consumption of activated protein C (APC); recombinant human APC (rhAPC) is a promising candidate anticoagulant treatment. We investigated the effects of rhAPC and other anticoagulants on coagulation triggered by adding small quantities of lipidated tissue factor to human umbilical-cord plasma in vitro. rhAPC, unfractionated heparin (UH),and melagatran (a direct thrombin inhibitor) were studied individually, and in combinations of rhAPC with either UH or melagatran. rhAPC alone dose-dependently prolonged the activated partial-thromboplastin time (aPTT) but not the prothrombin time (PT), and dose-dependently suppressed two indices of thrombin generation, namely prothrombin fragment F 1.2 (F 1.2) generation and thrombin–antithrombin (TAT) complex formation. UH alone dose-dependently prolonged the aPTT but not the PT, while melagatran alone dose-dependently prolonged both the aPTT and the PT. Adding either UH or melagatran dose-dependently augmented the capacity of rhAPC to suppress F 1.2 generation (with addition of UH showing a greater effect) and TAT formation (with addition of melagatran showing a greater effect). Both the capacity of UH to prolong the aPTT and the capacity of melagatran to prolong the aPTT and the PT were augmented by adding rhAPC. In our in-vitro study, adding either UH or melagatran augmented the capacity of rhAPC to suppress thrombin generation in human umbilical-cord plasma, with the anticoagulant effect of melagatran being more predictable than that of UH. Hence, combining rhAPC with melagatran might be a valuable therapeutic option in patients with severe sepsis.
Early antithrombotic and anti-inflammatory effects of simvastatin versus fenofibrate in patients with hypercholesterolemia
Authors: Undas Anetta , Celinska-Löwenhoff Magdalena , Domagala Teresa B. , Iwaniec Teresa , Dropinski Jerzy , Löwenhoff Tomasz , Szczeklik Andrew
Published: June 2005

The aim of the study was to determine whether a short-term treatment with simvastatin or fenofibrate may result in beneficial anti-inflammatory and antithrombotic effects in patients with high risk of coronary artery disease. In a randomized, double-blind study, we compared markers of inflammation, thrombin formation and platelet activation in patients with LDL cholesterol >130 mg/dl assigned to receive simvastatin (40 mg/d; n=20) or micronised fenofibrate (160 mg/d; n=22) for 28 days. Simvastatin, but not fenofibrate, lowered C-reactive protein (CRP) by 32% on day 3 (p<0.001), while both drugs reduced CRP significantly on day 28. Interleukin-6, soluble CD40 ligand, and monocyte chemoattractant protein-1 levels decreased significantly (by 20 to 50%) in both treatment groups on days 3 and 28. Soluble cell adhesion molecules remained unchanged in both groups. Simvastatin and fenofibrate significantly lowered plasma concentrations of thrombin-antithrombin complexes on days and 28, but not platelet β-thromboglobulin (βTG) levels. Soluble P-selectin was lowered only in the simvastatin group. The total amount of thrombin generated at the site of microvascular injury also declined (by about 30%) as early as after 3 days of fenofibrate or simvastatin therapy, whereas βTG release was reduced only in the simvastatin group on days 3 and 28.All the effects were independent of the changes in lipid profiles. Our results suggest that statins and fibrates can exert antithrombotic and anti-inflammatory effects as early as after 3 days of therapy. However, in contrast to statins, fibrates have no influence on platelet function within one month of therapy.
The functional significance of the autolysis loop in protein C and activated protein C
Authors: Yang Likui , Manithody Chandrashekhara , Rezaie Alireza R.
Published: June 2005

The autolysis loop of activated protein C (APC) is five residues longer than the autolysis loop of other vitamin K-dependent coagulation proteases. To investigate the role of this loop in the zymogenic and anticoagulant properties of the molecule, a protein C mutant was constructed in which the autolysis loop of the protein was replaced with the corresponding loop of factor X. The protein C mutant was activated by thrombin with ~5-fold higher rate in the presence of Ca2+. Both kinetics and direct binding studies revealed that the Ca2+ affinity of the mutant has been impaired ∼3-fold. The result of a factorVa degradation assay revealed that the anticoagulant function of the mutant has been improved 4–5-fold in the absence but not in the presence of protein S. The improvement was due to a better recognition of both the P1-Arg506 and P1-Arg306 cleavage sites by the mutant protease. However, the plasma half-life of the mutant was markedly shortened due to faster inactivation by plasma serpins. These results suggest that the autolysis loop of protein C is critical for the Ca2+-dependence of activation by thrombin. Moreover, a longer autolysis loop in APC is not optimal for interaction with factor Va in the absence of protein S, but it contributes to the lack of serpin reactivity and longer half-life of the protease in plasma.
PPARγ-Activating Angiotensin Type-1 Receptor Blockers Induce Adiponectin
Authors: Clasen Ronald , Schupp Michael , Foryst-Ludwig Anna , Sprang Christiane , Clemenz Markus , Krikov Maxim , Thöne-Reineke Christa , Unger Thomas , Kintscher Ulrich
Published: June 2005

The adipose-specific protein adiponectin has been recently discovered to improve insulin sensitivity. Angiotensin type-1 receptor (AT1R) blockers (ARBs) reduce the incidence of type 2 diabetes mellitus by mostly unknown molecular mechanisms. To identify new antidiabetic mechanisms of ARBs, we studied the regulation of adiponectin by angiotensin II (Ang II) and different ARBs in murine 3T3-L1 adipocytes and obese Zucker rats. Adiponectin protein expression was markedly stimulated by Ang II (5 nmol/L), which was inhibited by blockade of the AT2R, and further enhanced by the ARB irbesartan. Irbesartan-mediated adiponectin upregulation started beyond the concentrations needed for AT1R blockade and was also present in the absence of Ang II, implicating an AT1R-independent mechanism of action. Recently, certain ARBs (irbesartan, telmisartan) were identified as ligands of the peroxisome proliferator-activated receptor (PPAR)γ. Telmisartan also stimulated adiponectin protein expression, whereas the non-PPARγ-activating ARB eprosartan had no effect. Blockade of PPARγ activation by the PPARγ antagonist GW9662 markedly inhibited irbesartan-induced adiponectin expression. Cognate mRNA levels of adiponectin were not affected by ARBs. Kinetic studies using the protein synthesis inhibitor cycloheximide showed that irbesartan prevented the cellular depletion of adiponectin protein. Finally, administration of irbesartan to obese Zucker rats improved insulin sensitivity and attenuated adiponectin serum depletion. The present study demonstrates that AT2R activation and certain ARBs induce adiponectin in adipocytes, which was associated with an improvement of parameters of insulin sensitivity in vivo. ARB-induced adiponectin stimulation is likely to be mediated via PPARγ activation involving a post-transcriptional mechanism.
Activation of 5-Hydroxytryptamine 1A Receptors Suppresses the Cardiovascular Response Evoked From the Dorsomedial Hypothalamic Nucleus
Authors: Horiuchi Jouji , Wakabayashi Sonoe , Dampney Roger A.L.
Published: June 2005

The dorsomedial hypothalamic nucleus is a key component of the central pathways subserving the cardiovascular response to psychological stress, which is believed to be an important risk factor for hypertension. Previous studies indicate that 5-hydroxytryptamine 1A receptors can modulate the cardiovascular responses associated with stress. In this study, we determined in anesthetized rats the effects of systemic or intracisternal administration of 8-hydroxy-2-(di-n-propylamino)tetralin, a selective agonist of 5-hydroxytryptamine 1A receptors, and then subsequent administration of the selective antagonist WAY-100635 on the cardiovascular response evoked by activation of the dorsomedial hypothalamic nucleus (by microinjection of bicuculline). The increase in mean arterial pressure, heart rate, and renal sympathetic nerve activity (RSNA) evoked by bicuculline injection into the dorsomedial hypothalamic nucleus was greatly reduced (by 80% to 90%) by administration of 8-hydroxy-2-(di-n-propylamino)tetralin and then completely restored by subsequent administration of WAY-100635, whether administered systemically or intracisternally. In contrast, systemic administration of 8-hydroxy-2-(di-n-propylamino)tetralin had no significant effect on the baseline level or reflex changes in RSNA evoked by chemoreceptor or baroreceptor stimulation and resulted in only a modest reduction (12 mm Hg) in baseline mean arterial pressure. The results indicate that activation of 5-hydroxytryptamine 1A receptors in the brain stem causes a potent and selective suppression of the hypertensive and sympathoexcitatory response evoked by stimulation of the dorsomedial hypothalamic nucleus but has little effect on the tonic level or baroreceptor or chemoreceptor reflex control of RSNA.
Lys418Asn Polymorphism of the α2-Adrenoceptor Gene Relates to Serum Uric Acid Levels But Not to Insulin Sensitivity
Authors: Masuo Kazuko , Katsuya Tomohiro , Fu Yuxiao , Rakugi Hiromi , Ogihara Toshio , Tuck Michael L.
Published: June 2005

Hyperuricemia is associated with cardiovascular risk. The present study examines the association between serum uric acid (UA) elevation and the α2-, β2-, and β3-adrenoceptor polymorphisms. In 219 nonobese, normotensive, normouricemic (serum UA <6.5 mg/dL at entry) men, serum UA, plasma norepinephrine (NE), the homeostasis model assessment of insulin resistance (HOMA-IR), body mass index, total body fat mass, the α2A(Lys418Asn)-, β2(Arg16Gly, Gln27Glu)-, and β3(Trp64Arg)-adrenoceptor polymorphisms were measured annually over 5 years. Hyperuricemia was defined as a serum UA level of ≥mean+1 SD of 5.0 mg/dL in the participants. At entry, there were 36 subjects who had hyperuricemia and 183 who had normal UA levels. A significant UA elevation for 5 years was defined as an increase in ≥10% in UA levels. There were 82 subjects who had significant UA elevations. The subjects who had hyperuricemia at entry in addition to the subjects who had significant UA elevations over the 5-year period carried a significantly higher frequency of the Asn418 allele of Lys418Asn. Additionally, subjects carrying the Asn418 allele had higher UA and plasma NE and greater elevations in UA over the study period, but HOMA-IR was similar. Insulin resistance at entry and during the study was associated with Arg16Gly polymorphisms but not with Lys418Asn polymorphisms. In conclusion, the Asn418 allele of Lys418Asn is associated with either established hyperuricemia or the progressive elevation of UA over time. This polymorphism was not associated with insulin resistance in nonobese, normotensive individuals. Although hyperuricemia is of known relevance to insulin resistance, it appears to have different genetic determinants from insulin resistance in terms of adrenoceptor polymorphisms.
Three-Dimensional Electroanatomic Voltage Mapping Increases Accuracy of Diagnosing Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia
Authors: Corrado Domenico , Basso Cristina , Leoni Loira , Tokajuk Barbara , Bauce Barbara , Frigo Gianfranco , Tarantini Giuseppe , Napodano Massimo , Turrini Pietro , Ramondo Angelo , Daliento Luciano , Nava Andrea , Buja Gianfranco , Iliceto Sabino , Thiene Gaetano
Published: June 2005

Background—

Three-dimensional electroanatomic voltage mapping offers the potential to identify low-voltage areas that correspond to regions of right ventricular (RV) myocardial loss and fibrofatty replacement in patients with arrhythmogenic RV cardiomyopathy/dysplasia (ARVC/D).

Methods and Results—

Thirty-one consecutive patients (22 men and 9 women; mean age, 30.8±7 years) who fulfilled the criteria of the Task Force of the European Society of Cardiology and International Society and Federation of Cardiology (ESC/ISFC) for ARVC/D diagnosis after noninvasive clinical evaluation underwent further invasive study including RV electroanatomic voltage mapping and endomyocardial biopsy (EMB) to validate the diagnosis. Multiple RV endocardial, bipolar electrograms (175±23) were sampled during sinus rhythm. Twenty patients (group A; 65%) had an abnormal RV electroanatomic voltage mapping showing ≥1 area (mean 2.25±0.7) with low-voltage values (bipolar electrogram amplitude <0.5 mV), surrounded by a border zone (0.5 to 1.5 mV) that transitioned into normal myocardium (>1.5 mV). Low-voltage electrograms appeared fractionated with significantly prolonged duration and delayed activation. In 11 patients (group B; 35%), electroanatomic voltage mapping was normal, with preserved electrogram voltage (4.4±0.7 mV) and duration (37.2±0.9 ms) throughout the RV. Low-voltage areas in patients from group A corresponded to echocardiographic/angiographic RV wall motion abnormalities and were significantly associated with myocyte loss and fibrofatty replacement at EMB (
P
<0.0001) and familial ARVC/D (
P
<0.0001). Patients from group B had sporadic disease and histopathological evidence of inflammatory cardiomyopathy (
P
<0.0001). During the time interval from onset of symptoms to the invasive study, 11 patients (55%) with electroanatomic low-voltage regions received an implantable cardioverter/defibrillator because of life-threatening ventricular arrhythmias, whereas all but 1 patient with a normal voltage map remained stable on antiarrhythmic drug therapy (
P
=0.02).

Conclusions—

Three-dimensional electroanatomic voltage mapping enhanced accuracy for diagnosing ARVC/D (1) by demonstrating low-voltage areas that were associated with fibrofatty myocardial replacement and (2) by identifying a subset of patients who fulfilled ESC/ISFC Task Force diagnostic criteria but showed a preserved electrogram voltage, an inflammatory cardiomyopathy mimicking ARVC/D, and a better arrhythmic outcome.
Does Autonomic Function Link Social Position to Coronary Risk?
Authors: Hemingway Harry , Shipley Martin , Brunner Eric , Britton Annie , Malik Marek , Marmot Michael
Published: June 2005

Background—

Laboratory and clinical studies suggest that the autonomic nervous system responds to chronic behavioral and psychosocial stressors with adverse metabolic consequences and that this may explain the relation between low social position and high coronary risk. We sought to test this hypothesis in a healthy occupational cohort.

Methods and Results—

This study comprised 2197 male civil servants 45 to 68 years of age in the Whitehall II study who were undergoing standardized assessments of social position (employment grade) and the psychosocial, behavioral, and metabolic risk factors for coronary disease previously found to be associated with low social position. Five-minute recordings of heart rate variability (HRV) were used to assess cardiac parasympathetic function (SD of N-N intervals and high-frequency power [0.15 to 0.40 Hz]) and the influence of sympathetic and parasympathetic function (low-frequency power [0.04 to 0.15 Hz]). Low employment grade was associated with low HRV (age-adjusted trend for each modality,
P
≤0.02). Adverse behavioral factors (smoking, exercise, alcohol, and diet) and psychosocial factors (job control) showed age-adjusted associations with low HRV (
P
<0.03). The age-adjusted mean low-frequency power was 319 ms
2
among those participants in the bottom tertile of job control compared with 379 ms
2
in the other participants (
P
=0.004). HRV showed strong (
P
<0.001) linear associations with components of the metabolic syndrome (waist circumference, systolic blood pressure, HDL cholesterol, triglycerides, and fasting and 2-hour postload glucose). The social gradient in prevalence of metabolic syndrome was explained statistically by adjustment for low-frequency power, behavioral factors, and job control.

Conclusions—

Chronically impaired autonomic function may link social position to different components of coronary risk in the general population.
Conditional Mineralocorticoid Receptor Expression in the Heart Leads to Life-Threatening Arrhythmias
Authors: Ouvrard-Pascaud Antoine , Sainte-Marie Yannis , Bénitah Jean-Pierre , Perrier Romain , Soukaseum Christelle , Cat Aurelie Nguyen Dinh , Royer Anne , Le Quang Khai , Charpentier Flavien , Demolombe Sophie , Mechta-Grigoriou Fatima , Beggah Ahmed T. , Maison-Blanche Pierre , Oblin Marie-Edith , Delcayre Claude , Fishman Glenn I. , Farman Nicolette , Escoubet Brigitte , Jaisser Frederic
Published: June 2005

Background—

Life-threatening cardiac arrhythmia is a major source of mortality worldwide. Besides rare inherited monogenic diseases such as long-QT or Brugada syndromes, which reflect abnormalities in ion fluxes across cardiac ion channels as a final common pathway, arrhythmias are most frequently acquired and associated with heart disease. The mineralocorticoid hormone aldosterone is an important contributor to morbidity and mortality in heart failure, but its mechanisms of action are incompletely understood.

Methods and Results—

To specifically assess the role of the mineralocorticoid receptor (MR) in the heart, in the absence of changes in aldosteronemia, we generated a transgenic mouse model with conditional cardiac-specific overexpression of the human MR. Mice exhibit a high rate of death prevented by spironolactone, an MR antagonist used in human therapy. Cardiac MR overexpression led to ion channel remodeling, resulting in prolonged ventricular repolarization at both the cellular and integrated levels and in severe ventricular arrhythmias.

Conclusions—

Our results indicate that cardiac MR triggers cardiac arrhythmias, suggesting novel opportunities for prevention of arrhythmia-related sudden death.