bluuebunny/crossref_metadata_2025 huggingface dataset:
Avoiding evasion: medical ethics education and emotion theory
Authors: Leget C
Published: October 2004

Beginning with an exemplary case study, this paper diagnoses and analyses some important strategies of evasion and factors of hindrance that are met in the teaching of medical ethics to undergraduate medical students. Some of these inhibitions are inherent to ethical theories; others are connected with the nature of medicine or cultural trends. It is argued that in order to avoid an attitude of evasion in medical ethics teaching, a philosophical theory of emotions is needed that is able to clarify on a conceptual level the ethical importance of emotions. An approach is proposed with the help of the emotion theory Martha Nussbaum works out in her bookUpheavals of thought. The paper ends with some practical recommendations.
Euthanasia: above ground, below ground
Authors: Magnusson R S
Published: October 2004

The key to the euthanasia debate lies in how best to regulate what doctors do. Opponents of euthanasia frequently warn of the possible negative consequences of legalising physician assisted suicide and active euthanasia (PAS/AE) while ignoring the covert practice of PAS/AE by doctors and other health professionals. Against the background of survey studies suggesting that anything from 4% to 10% of doctors have intentionally assisted a patient to die, and interview evidence of the unregulated, idiosyncratic nature of underground PAS/AE, this paper assesses three alternatives to the current policy of prohibition. It argues that although legalisation may never succeed in making euthanasia perfectly safe, legalising PAS/AE may nevertheless be safer, and therefore a preferable policy alternative, to prohibition. At a minimum, debate about harm minimisation and the regulation of euthanasia needs to take account of PAS/AE wherever it is practised, both above and below ground.
Sex and the surgery: students’ attitudes and potential behaviour as they pass through a modern medical curriculum
Authors: Goldie J , Schwartz L , Morrison J
Published: October 2004

Objective:To examine students’ attitudes and potential behaviour to a possible intimate relationship with a patient as they pass through a modern medical curriculum.

Design:A cohort study of students entering Glasgow University’s new learner centred, integrated medical curriculum in October 1996.

Methods:Students’ pre year 1 and post year 1, post year 3, and post year 5 responses to the “attractive patient” vignette of the Ethics in Health Care Survey instrument were examined quantitatively and qualitatively. Analysis of students’ multi-choice answers enabled measurement of the movement towards professional consensus opinion. Analysis of written justifications helped determine whether their reasoning was consistent with professional consensus and enabled measurement of change in knowledge content and recognition of the values inherent in the vignette. Themes on students’ reasoning behind their decision to enter a relationship or not were also identified.

Results:No significant movement towards consensus was found at any point in the curriculum. There was little improvement in students’ performance in terms of knowledge content and their abilities to recognise the values inherent in the vignette. In deciding to enter a relationship with the patient the most frequently used reasoning was that it could be justified if the patient changed their doctor.

Conclusions:Teaching on the subject of sexual or improper relationships between doctors and patients, including relationships with former patients requires to be made explicit. Case based teaching would fit in with the ethos of the problem based, integrated medical curriculum.
Justified and unjustified use of growth hormone
Authors: van der Lely A J
Published: October 2004

Growth hormone (GH) replacement therapy for children and adults with proven GH deficiency due to a pituitary disorder has become an accepted therapy with proven efficacy. GH is increasingly suggested, however, as a potential treatment for frailty, osteoporosis, morbid obesity, cardiac failure, and various catabolic conditions. However, the available placebo controlled studies have not reported many significant beneficial effects, and it might even be dangerous to use excessive GH dosages in conditions in which the body has just decided to decrease GH actions. GH can indeed induce changes in body composition that are considered to be advantageous to GH deficient and non-GH deficient subjects. In contrast to GH replacement therapy in GH deficient subjects, however, excessive GH action due to GH misuse seems to be ineffective in improving muscle power. Moreover, there are no available study data to indicate that the use of GH for non-GH deficient subjects should be advocated, especially as animal data suggest that lower GH levels are positively correlated with longevity.
Gene therapy in clinical medicine
Authors: Selkirk S M
Published: October 2004

Although the field of gene therapy has experienced significant setbacks and limited success, it is one of the most promising and active research fields in medicine. Interest in this therapeutic modality is based on the potential for treatment and cure of some of the most malignant and devastating diseases affecting humans. Over the next decade, the relevance of gene therapy to medical practices will increase and it will become important for physicians to understand the basic principles and strategies that underlie the therapeutic intervention. This report reviews the history, basic strategies, tools, and several current clinical paradigms for application.
Fibrinolytic activity in Nigerian diabetics
Authors: Adediran I A , Ikem R T , Borisade M F
Published: October 2004

Fibrinolytic activity, using euglobulin lysis time (ELT), was assessed in 46 Nigerians with type 2 diabetes mellitus to study the effect of the disease on fibrinolytic component of haemostasis. There were 20 females and 26 males. Fifty age matched non-diabetics and apparently healthy Nigerians were similarly studied as controls; there were 24 females and 26 males. In the patients, the mean (SD) age of the females was 56.7 (12.0) years and mean (SD) ELT was 276.4 (62.2) min; the mean age of the males was 55.7 (8.5) years and mean ELT was 303.5 (51.5) min. The mean age for female controls was 54.3 (12.6) years and their mean ELT was 198.3 (37.5) min; the mean age of the male controls was 53.4 (11.0) years and mean ELT was 181.6 (39.4) min. There was reduced fibrinolytic activity in diabetic Nigerians as revealed by significantly prolonged ELT in diabetic patients compared with healthy controls. There was good correlation between the blood glucose level and ELT. The observed changes in fibrinolytic activity in this study were not affected by duration of illness. The prolonged ELT in the diabetic population is an additional risk factor for thromboembolic disorders. Fibrinolytic agents may therefore be useful in the management of diabetes mellitus.
Acute pancreatitis due to ramipril therapy
Authors: Kanbay M , Korkmaz M , Yılmaz U , Gur G , Boyacıoglu S
Published: October 2004

Few data exist about the incidence of drug induced acute pancreatitis in the general population. Drugs are related to the aetiology of pancreatitis in about 1.4%–2% of cases. Although angiotensin converting enzymes are generally well tolerated, acute pancreatitis has been reported in a few subjects treated with captopril, enalapril, and lisinopril. A 85 year old man with a long standing history of hypertension, who was treated with ramipril 5 mg once daily, presented with acute pancreatitis. Other causes of the disease were ruled out. After cessation of ramipril his condition improved and amylase level decreased. This was his third episode of acute pancreatitis since ramipril was started in 2000. To the authors’ knowledge ramipril induced pancreatitis has not previously been reported.
THE COLLABORATIVE RESEARCH CENTER 588: "HUMANOID ROBOTS — LEARNING AND COOPERATING MULTIMODAL ROBOTS"
Authors: BECHER REGINE , STEINHAUS PETER , DILLMANN RÜDIGER
Published: October 2004

This paper gives an overview of the current and forthcoming research projects of the Collaborative Research Center 588 "Humanoid Robots — Learning and Cooperating Multimodal Robots." The activities can be divided into several areas: development of mechatronic components and construction of a demonstrator system, perception of user and environment, modeling and simulation of robots, environment and user, and finally cooperation and learning. The research activities in each of these areas are described in detail. Finally, we give an insight into the application scenario of our robot system, i.e. the training setup and the experimental setup "household."
DYNAMIC ROLL-AND-RISE MOTION BY AN ADULT-SIZE HUMANOID ROBOT
Authors: KUNIYOSHI YASUO , OHMURA YOSHIYUKI , TERADA KOJI , NAGAKUBO AKIHIKO
Published: October 2004

Whole-body dynamic actions under various contacts with the environment will be very important for future humanoid robots to support human tasks in unstructured environments. Such skills are very difficult to realize using the standard motion control methodology based on asymptotic convergence to the successive desired states. An alternative approach would be to exploit the passive dynamics of the body under constrained motion, and to navigate through multiple dynamics by imposing the least control in order to robustly reach the goal state. As a first example of such a strategy, we propose and investigate a "Roll-and-Rise" motion. This is a fully dynamic whole-body task including underactuated motion whose state trajectory is insoluble, and unpredictable perturbations due to complex contacts with the ground. First, we analyze the global structure of Roll-and-Rise motion. Then the critical points are analyzed using simplified models and simulations. The results suggest a non-uniform control strategy which focuses on sparse critical points in the global phase space, and allows deviations and trade-offs at other parts. Finally, experiments with a real adult-size humanoid robot are successfully carried out. The robot rose from a flat-lying posture to a crouching posture within 2 seconds.
von Willebrand factor-cleaving protease (ADAMTS13) activity in normal non-pregnant women, pregnant and post-delivery women
Authors: Farías Cristina , Amaral María , Kempfer Ana , Votta Roberto , Marchese Carlos , Salviú María , Woods Adriana , Meschengieser Susana , Lazzari María , Sánchez-Luceros Analía
Published: October 2004

ADAMTS13 dysfunction has been involved in the pathogenesis of Thrombotic Thrombocytopenic Purpura. This disorder occurs more frequently in women and, in 13% of them, is associated with pregnancy. However, there is little information on the protease behaviour in normal pregnancy. We studied von Willebrand factor and ADAMTS13 activity changes in normal non-pregnant, pregnant and post-delivery women. Fifty-five non-pregnant women, normal blood bank donors, who were not taking contraceptive pills were included as controls. A prospective cross-sectional study of 270 normal pregnant and post-delivery women was carried out. ADAMTS13 activity decreased progressively as from the period of 12–16 weeks up to the end of early puerperium (mean 52%, range 22–89, p < 0.0001), to increase slightly thereafter. Nulliparous presented mildly lower levels of ADAMTS13 activity than parous women (65% vs. 83%, p=0.0003), and primigravidae than multigravidae between 6–11 weeks up to 17–23 weeks of pregnancy (69% vs. 80%, p=0.005). Although in all women the protease levels were the same by blood groups, the O blood group non-pregnant women showed a higher mean of ADAMTS13 activity than those non-O (78% vs. 69%, p= 0.064). Our results suggest that the changing levels of protease activity during pregnancy and puerperium, induced by unidentified mechanisms, could render the peripartum time more vulnerable to developed thrombotic microangiopathies.
Aspirin and coronary artery disease
Authors: Fitzgerald Desmond , Maree Andrew
Published: October 2004

Coronary atherosclerosis (CAD), a chronic inflammatory disorder, arises when genetic susceptibility, intercurrent conditions such as diabetes and hypertension and environmental factors interact. Although CAD can remain stable for many years, thrombus formation at sites of plaque rupture may lead to unstable angina (UA) or myocardial infarction (MI). Already recognised as the central component of coronary thrombosis, platelets, through their interaction with monocytes and endothelial cells, may also be involved at the earliest stages of atheromatous plaque evolution. Aspirin, the prototype antiplatelet agent, covalently and irreversibly inhibits cyclooxygenase (COX) and thus inhibits platelet thromboxane (TX) A2 biosynthesis. Anti-oxidant properties and the ability to modulate transcription of immunologically important genes have also been attributed to aspirin. Non-selective COX inhibition, however, predisposes to bleeding, predominantly secondary to dosedependent gastro-intestinal toxicity. The emerging concept of “aspirin resistance” coincides with the development of alternative antiplatelet therapy and point-of-care platelet function assays. Though variable aspirin pharmacokinetics may explain many cases, heritable factors, inducible platelet COX expression and isoprostane formation may also contribute. In future, risk factor screening and point-of-care platelet function assay may identify vulnerable patients who would benefit from additional or alternate antiplatelet therapy.
Anti-CD40 antibodies in antiphospholipid syndrome and systemic lupus erythematosus
Authors: Balitsari Anthi , Routsias John , G.Vlachoyiannopoulos Panayiotis , Mavragani Clio , Bourazopoulou Efi
Published: October 2004

Anti-β2glycoprotein I (anti-β2GPI) antibodies constitute the main autoantibody specificity in the sera of patients with antiphospholipid syndrome (APS). There is evidence that antiβ2GPI antibodies induce the precoagulant activity of the endothelium by cross-linking the β2 glycoprotein I (β2GPI) on the cell surface. Since β2GPI lacks intracellular domains, homology with other molecules such as CD40 that could initiate signaling, was extensively searched. A 86% homology between the amino acid position 239-245 of the CD40 and 7-13 of the β2glycoprotein was found. The CD40 peptide corresponding to amino acids 239-245 of the CD40 molecule was synthesized and coupled to a multiple antigenic peptide carrier. Antibodies to CD40 peptide were found in 61.5% APS patients (n=39), in 72.7% of systemic lupus erythematosus (SLE) positive for anti β2GPI antibodies (n=11) and 31.6% of SLE negative for antiβ2GPI antibodies (n=19), but not in rheumatoid arthritis patients (n=28) or controls (n=36). Antibodies to CD40 peptide were associated with arterial thrombosis and/or brain microinfarcts. Affinity purified anti-CD40 peptide antibodies as well as affinity purified anti-β2GPI antibodies recognized both, the β2GPI and the CD40 peptide. The specificity of this recognition was confirmed with homologous and heterologous inhibition experiments. Confocal microscopy experiments demonstrated this cross-recognition of CD40 and β2GPI molecules, by the purified anti-CD40 peptide antibodies, at the protein level. Thus, antibodies reacting with the β2GPI can react and potentially activate different cells which express CD40 molecules at their surface.
Antiphospholipid antibodies and thrombosis: association with acquired activated protein C resistance in venous thrombosis and with hyperhomocysteinemia in arterial thrombosis
Authors: Kassis Jeannine , Neville Carolyn , Rauch Joyce , Busque Lambert , Chang Erika , Joseph Lawrence , Le Comte Martine , Subang Rebecca , Fortin Paul
Published: October 2004

Although antiphospholipid antibodies (aPL) are associated with thrombosis, it is not known who with aPL is at higher risk for thrombosis. It was the aim of this cross-sectional study to investigate how thrombophilic factors contribute to venous or arterial thrombosis in aPL-positive individuals. In outpatient test centres at two tertiary care hospitals, two hundred and eight (208) persons requiring aPL testing were matched by age, gender and centre to 208 persons requiring a complete blood count. Persons were classified as aPL-positive (having anticardiolipin, lupus anticoagulant and/or anti-β2-glycoprotein I antibodies) or aPL-negative. Several thrombophilic factors were studied using logistic regression modelling. Results showed that the aPL-positive group had three-fold more events (37%) than the aPL-negative group (12%). In unadjusted analyses, clinically important associations were observed between factor V Leiden and venous thrombosis, hyperhomocysteinemia and arterial thrombosis, and activated protein C resistance (APCR) and venous thrombosis (OR, 95% CI = 4.00, 1.35-11.91; 4.79, 2.03-11.33; and 2.03, 1.03-3.97, respectively). After adjusting for recruitment group, persons with both APCR and aPL had a three-fold greater risk (OR, 95% CI = 3.31, 1.30-8.41) for venous thrombosis than those with neither APCR nor aPL. Similarly, after adjusting for hypertension, family history of cardiovascular disease, gender and recruitment group, persons with both hyperhomocysteinemia and aPL had a five-fold increased risk (OR, 95% CI = 4.90, 1.37-17.37) for arterial thrombosis compared to those with neither risk factor. In conclusion, APCR phenotype and hyperhomocysteinemia are associated with a higher risk of venous and arterial thrombosis, respectively, in the presence of aPL.
Effect of activated platelets on expression of cytokines in peripheral blood mononuclear cells – potential role of prostaglandin E2
Authors: Wæhre Torgun , Damås Jan , Yndestad Arne , Taskén Kjetil , Pedersen Turid , Smith Camilla , Halvorsen Bente , Frøland Stig , Solum Nils , Aukrust Pål
Published: October 2004

Platelets may act as inflammatory cells. To study the effects of soluble and cell-bound platelet factors on the expression of several cytokines and related mediators in leukocytes, peripheral blood mononuclear cells (PBMC) were incubated with platelet-free supernatants from SFLLRN-activated platelet-rich plasma (PRP) or SFLLRN-activated PRP in itself. Our main findings were: (i) the gene expression of several chemokines and some cytokines were markedly increased by both activated PRP and supernatants, as also confirmed at the protein level for IL-6, IL-8 and MIP-1α; (ii) the selective protein kinase A type I (PKAI) antagonist Rp-8-Br-cAMP reduced this platelet-induced expression of IL-6, IL-8 and MIP-1α in PBMC, suggesting a role of cAMP/PKAI mediated mechanisms in this interaction; (iii) PGE2 dose-dependently increased the release of IL-6, IL-8 and MIP-1α from PBMC mimicking the effect of activated platelets. Furthermore, activated platelets released comparable amounts of PGE2, suggesting that platelet-derived PGE2 could interact with PBMC in co-cultures; (iv) IL-10 inhibited the platelet-inducing effect on IL-6, IL-8 and MIP-1α in PBMC, and notably, the addition PGE2 totally abolished this IL-10 effect suggesting that the suppressive effect of IL-10 on the plateletinduced activation of PBMC might at least partly involve PGE2related mechanisms. The present study supports a view of platelets as inflammatory cells, and suggests a potential role of platelet-derived PGE2 in platelet-induced inflammatory responses.
Glanzmann thrombasthenia Frankfurt I is associated with a point mutation Thr176Ile in the N-terminal region of αIIb subunit integrin
Authors: Santoso Sentot , Follert-Hagendorff Katja , Bassus Steffen , Just Melitta , Jablonka Bernd , Kirchmaier Carl , Westrup Dagmar
Published: October 2004

In this study, we report on the characterization of a patient with Glanzmann thrombasthenia (GT). Immunochemical analysis on platelets from the patient showed that the expression of αIIbβ3 was only 25% of that in normal healthy controls, suggesting a case of GT. Functional analysis revealed a total lack of fibrinogen binding capacity. Molecular genetic analysis of the full-length cDNA sequences of αIIb and β3 subunits showed a novel point mutation C621T in αIIb cDNA, leading to a missense substitution of threonine for isoleucine at position 176. Coexpression of normal β3 and mutant αIIbI176 isoform in mammalian cells showed a marked reduction in the expression of αIIbβ3 heterodimer when compared to the wild-type and a decreased intracellular level of αIIb. The T176 I mutation is located in the N-terminal region in the W3:1-2 connecting strand of the β-propeller. These data suggest that the N-terminal αIIb domain plays an important structural role in the formation of heterodimer and that it is also involved in fibrinogen binding.
The K+-channel opener NS1619 increases endothelial NO-synthesis involving p42/p44 MAP-kinase
Authors: Carl Trümper Jan Rasmus , Abdallah Yaser , Lüdders Dörte , Schaefer Christian , Most Astrid , Backenköhler Ulrich , Neumann Thomas , Walther Sabine , Piper Hans , Tillmanns Harald , Erdogan Ali , Kuhlmann Christoph Rüdiger
Published: October 2004

Ca2+-activated K+ channels with large conductance (BKCa) have been shown to play an important role in the regulation of vascular tone. We examined the role of the p42/p44 MAP-kinase (p42/p44MAPK) on nitric oxide (NO) production in human endothelial cells induced by the BKCa-opener NS1619. Using DiBAC-fluorescence imaging a concentration-dependent (2.5-12.5 µM) hyperpolarization induced by NS1619 was observed. A significant increase of intracellular Ca2+-concentration by NS1619 was seen using Fura-2-fluorescence-imaging, which was blocked by 2-APB, or reduction of extracellular Ca2+ (n=30; p<0.05). A cGMP-radioimmunoassay was used to examine NO synthesis. NS1619 significantly increased cGMP levels which was inhibited by LNMMA, iberiotoxin, BAPTA, 2-APB, reduction of extracellular Ca2+, PD 98059, or U0126 (cGMP (pmol/mg protein): NS1619 3.25 ± 0.85; NS1619 + L-NMMA 0.86 ± 0.02; NS1619 + iberiotoxin 0.99 ± 0.09; NS1619 + BAPTA 0.93 ± 0.29; NS1619 + 2-APB 0.99 ± 0.31; NS1619 + Ca2+-reduction 1.17 ± 0.06; NS1619 + PD98059 1.06 ± 0.49; NS1619 + U0126 1.10 ± 0.24; n=10; p<0.05). The phosphorylation of eNOS and p42/p44MAPK was examined by immunocytochemistry. Phosphorylation of p42/p44MAPK was significantly increased after 10 minutes of NS1619 stimulation, whereas eNOS phosphorylation was not changed over a period of 1 to 30 minutes. NS1619-induced hyperpolarization was not affected by treatment with PD 98059 or U0126. Additionally, NS1619 inhibited endothelial proliferation involving a NO-dependent mechanism. Our data demonstrate that NS1619 causes a transmembrane Ca2+-influx leading to an increased NO production involving p42/p44MAPK. This rise of NO formation is responsible for the NS1619 induced reduction of endothelial cell growth.
Combined effects of a factor Xa inhibitor YM466 and a GPIIb/IIIa antagonist YM128 on thrombosis and neointima formation in mice
Authors: Iwatsuki Yoshiyuki , Hayashi Kazumi , Moritani Yumiko , Nii Tomoko , Miyata Keiji , Kawasaki Tomihisa
Published: October 2004

Thrombosis and neointima formation limit the efficacy of coronary angioplasty. Factor Xa inhibitors and GPIIb/IIIa antagonists have shown to be effective on acute thrombosis and late neointima formation, however, their combined effects remain to be elucidated. Vascular injury was induced by FeCl3 in the carotid artery in mice. For thrombosis studies, the test drug was orally administered 1 hour before vascular injury. For neointima studies, the test drug was orally administered 1 hour before and twice daily for 1 week after vascular injury, and then histological analysis was performed 3 weeks after vascular injury. YM466 inhibited thrombotic occlusion at 30 mg/kg with prolongation of prothrombin time (PT), and tail transection bleeding time (BT) was affected at 100 mg/kg. YM466 also inhibited neointima formation at 10 mg/kg. YM128 inhibited thrombotic occlusion and neointima formation at 10 and 30 mg/kg, respectively, with inhibition of platelet aggregation and prolongation of BT. In contrast, the combination of 10 mg/kg YM466 and 3 mg/kg YM128 inhibited thrombotic occlusion and neointima formation without affecting PT, platelet aggregation and BT. Concomitant inhibition of factor Xa and GPIIb/IIIa may provide a safer and more effective therapeutic regimen for treatment of coronary angioplasty.
Cyclooxygenase COX-2a, a novel COX-2 mRNA variant, in platelets from patients after coronary artery bypass grafting
Authors: Censarek Petra , Freidel Kerstin , Udelhoven Michael , Ku Sun-Jung , Hohlfeld Thomas , Meyer-Kirchrath Jutta , Schrör Karsten , Weber Artur-Aron
Published: October 2004

There are two principal cyclooxygenase isoforms referred to as COX-1 and COX-2. Recently, COX-3 has been identified. We have demonstrated the expression of COX-2 in platelets from patients after coronary artery bypass grafting (CABG). Careful biochemical analysis revealed that, when compared to recombinant COX-2, platelet COX-2 had a slightly higher electrophoretic mobility. Two COX-2 sequences (∼1.8 kb, ∼1.7 kb) were cloned from platelet mRNA. The ∼1.7 kb sequence, designated COX-2a, differed from the human COX-2 sequence only in a deletion from position +458 to +567. Similar to the human COX-3, there is a frame shift in the COX-2a sequence resulting in a TAA stop codon at position +490. Thus, the expression of a COX-2a protein corresponding to the 67 kDa COX-2 protein is not clear. However, the marked shifting from COX-2 to COX-2a in platelets from some patients after CABG is a striking finding.
Percutaneous endoluminal arterial cryoenergy improves vascular remodelling after angioplasty
Authors: Geoffroy Pascale , Dorval Jean-François , Sirois Martin , Tanguay Jean-François
Published: October 2004

This study aimed to investigate the effect of percutaneous endoluminal arterial cryoenergy immediately after balloon angioplasty on vascular remodeling. Restenosis, the main complication after coronary artery angioplasty, is a complex phenomenon in which vascular remodeling plays a prominent role. Observations of reduced scarring in freeze-induced wounds suggest potential value for cryoenergy in the prevention of restenosis. Juvenile swine underwent a first oversized balloon injury in both carotid arteries (CA) (3 injury sites/artery) and a second injury at day 14. At that time, one CA was randomly assigned to endoluminal cryoenergy of the sequential segments (proximal, medial, distal) at −15ºC, −30ºC, and −50ºC for 120 sec, and the other CA was used as control. Animals were sacrificed 28 days after the second procedure. Compared with intact reference segments, angioplasty reduced both the luminal (LA) and the external elastic lamina (EEL) areas from 6.66±0.59 to 3.13±0.54 mm2 (p<0.05) and from 8.81±0.81 to 6.48±0.52 mm2 (p<0.05), respectively. Cryoenergy, at the temperature with maximal benefits (-50°C), caused a temperature-related protection, as the LA was maintained (6.79±0.89 versus 7.18± 0.78 mm2 for reference) and the EEL area increased from 9.12±0.78 to 12.98±1.07 mm2, p<0.05. Moreover, cryoenergy increased the density of collagen III (p<0.05) which correlated with the maintenance of the LA (r=0.8045, p<0.009). Cryoenergy prevents late luminal loss after double-injury angioplasty by improving vascular remodeling, and is an interesting new therapeutic approach for the prevention of restenosis after angioplasty. The increased synthesis of collagen III appears to be involved in this phenomenon and could be a potential method of stabilizing the vulnerable plaque.
Prostaglandin E2 activates channel-mediated calcium entry in human erythrocytes: an indication for a blood clot formation supporting process
Authors: Tabellion Wiebke , Lipp Peter , Bernhardt Ingolf , Kaestner Lars
Published: October 2004

Prostaglandin E2 (PGE2) is released from platelets when they are activated. Using fluorescence imaging and the patch-clamp technique, we provide evidence that PGE2 at physiological concentrations (10−10 M) activates calcium rises mediated by calcium influx through a non-selective cation-channel in human red blood cells. The extent of calcium increase varied between cells with a total of 45% of the cells responding. It is well known that calcium increases elicited the calcium-activated potassium channel (Gardos channel) in the red cell membrane. Previously, it was shown that the Gardos channel activation results in potassium efflux and shrinkage of the cells. Therefore, we conclude that the PGE2 responses of red blood cells described here reveal a direct and active participation of erythrocytes in blood clot formation.
Risk of Coronary Artery Disease Associated With Polymorphism of the Cytochrome P450 Epoxygenase CYP2J2
Authors: Spiecker Martin , Darius Harald , Hankeln Thomas , Soufi Muhidien , Sattler Alexander M. , Schaefer Jürgen R. , Node Koichi , Börgel Jan , Mügge Andreas , Lindpaintner Klaus , Huesing Anika , Maisch Bernhard , Zeldin Darryl C. , Liao James K.
Published: October 2004

Background—

Cytochrome P450 (CYP) 2J2 is expressed in the vascular endothelium and metabolizes arachidonic acid to biologically active epoxyeicosatrienoic acids (EETs). The EETs are potent endogenous vasodilators and inhibitors of vascular inflammation. However, it is not known whether genetic polymorphisms of CYP2J2 are associated with increased cardiovascular risks.

Methods and Results—

All 9 exons of the
CYP2J2
gene and its proximal promoter were sequenced in 132 patients to identify potential variants. Functional consequence of a single nucleotide polymorphism (SNP) in the promoter of CYP2J2 was further evaluated by use of transcription factor-binding and reporter assays. A total of 17 polymorphisms were identified. One of the most relevant polymorphisms in terms of frequency and functional importance is located at −50 (G-50T) in the proximal promoter of CYP2J2. Screening of 289 patients with coronary artery disease and 255 control subjects revealed 77 individuals with the G-50T SNP (17.3% of coronary artery disease patients, 10.6% of control subjects;
P
=0.026). The association of the G-50T polymorphism remained significant after adjustment for age, gender, and conventional cardiovascular risk factors (OR, 2.23; 95% CI, 1.04 to 4.79). The G-50T mutation resulted in the loss of binding of the Sp1 transcription factor to the CYP2J2 promoter and resulted in a 48.1±2.4% decrease in CYP2J2 promoter activity (
P
<0.01). Plasma concentrations of stable EET metabolites were significantly lower in individuals with the G-50T SNP.

Conclusions—

A functionally relevant polymorphism of the
CYP2J2
gene is independently associated with an increased risk of coronary artery disease.
Mother Rotors and the Mechanisms of D600-Induced Type 2 Ventricular Fibrillation
Authors: Wu Tsu-Juey , Lin Shien-Fong , Baher Ali , Qu Zhilin , Garfinkel Alan , Weiss James N. , Ting Chih-Tai , Chen Peng-Sheng
Published: October 2004

Background—

Two types of ventricular fibrillation (VF) have been demonstrated in isolated rabbit hearts during D600 infusion. Type 1 VF is characterized by the presence of multiple, wandering wavelets, whereas type 2 VF shows local spatiotemporal periodicity. We hypothesized that a single mother rotor underlies type 2 VF.

Methods and Results—

One (protocol I) or 2 (protocol II) cameras were used to map the epicardial ventricular activations in Langendorff-perfused rabbit hearts. Multiple episodes of type 2 VF were induced in 22 hearts by high-concentration (≥2.5 mg/L) D600 (protocol I). During type 2 VF, a single spiral wave (n=19) and/or an epicardial breakthrough pattern (n=11) was present in 14 hearts. These spiral waves either slowly drifted or intermittently anchored on the papillary muscle (PM) of the left ventricle. Dominant-frequency (DF) analyses showed that the highest local DF was near the PM (12.5±1.1 Hz). There was an excellent correlation between the highest local DF of these spiral waves and breakthroughs (11.8±1.7 Hz) and the DF of simultaneously obtained global pseudo-ECG (11.2±1.8 Hz,
r
=0.97,
P
<0.0001) during type 2 VF. We also successfully reproduced the major features of type 2 VF by using the Luo-Rudy action-potential model in a simulated, 3-dimensional tissue slab, under conditions of reduced excitability and flat action-potential duration restitution.

Conclusions—

Either a stationary or a slowly drifting mother rotor can result in type 2 VF. Colocalization of the stationary mother rotors with the PM suggests the importance of underlying anatomic structures in mother rotor formation.
Epicardial Stenosis Severity Does Not Affect Minimal Microcirculatory Resistance
Authors: Aarnoudse Wilbert , Fearon William F. , Manoharan Ganesh , Geven Maartje , van de Vosse Frans , Rutten Marcel , De Bruyne Bernard , Pijls Nico H.J.
Published: October 2004

Background—

Whether minimal microvascular resistance of the myocardium is affected by the presence of an epicardial stenosis is controversial. Recently, an index of microcirculatory resistance (IMR) was developed that is based on combined measurements of distal coronary pressure and thermodilution-derived mean transit time. In normal coronary arteries, IMR correlates well with true microvascular resistance. However, to be applicable in the case of an epicardial stenosis, IMR should account for collateral flow. We investigated the feasibility of determining IMR in humans and tested the hypothesis that microvascular resistance is independent of epicardial stenosis.

Methods and Results—

Thirty patients scheduled for percutaneous coronary intervention were studied. The stenosis was stented with a pressure guidewire, and coronary wedge pressure (P
w
) was measured during balloon occlusion. After successful stenting, a short compliant balloon with a diameter 1.0 mm smaller than the stent was placed in the stented segment and inflated with increasing pressures, creating a 10%, 50%, and 75% area stenosis. At each of the 3 degrees of stenosis, fractional flow reserve (FFR) and IMR were measured at steady-state maximum hyperemia induced by intravenous adenosine. A total of 90 measurements were performed in 30 patients. When uncorrected for P
w
, an apparent increase in microvascular resistance was observed with increasing stenosis severity (IMR=24, 27, and 37 U for the 3 different degrees of stenosis;
P
<0.001). In contrast, when P
w
is appropriately accounted for, microvascular resistance did not change with stenosis severity (IMR=22, 23, and 23 U, respectively;
P
=0.28).

Conclusions—

Minimal microvascular resistance does not change with epicardial stenosis severity, and IMR is a specific index of microvascular resistance when collateral flow is properly taken into account.
Heparin and Air Filters Reduce Embolic Events Caused by Intra-Arterial Cerebral Angiography
Authors: Bendszus Martin , Koltzenburg Martin , Bartsch Andreas J. , Goldbrunner Roland , Günthner-Lengsfeld Thomas , Weilbach Franz X. , Roosen Klaus , Toyka Klaus V. , Solymosi László
Published: October 2004

Background—

Intra-arterial cerebral angiography is associated with a low risk for neurological complications, but clinically silent ischemic events after angiography have been seen in a substantial number of patients.

Methods and Results—

In a prospective study, diffusion-weighted magnetic resonance imaging (DW-MRI) before and after intra-arterial cerebral angiography and transcranial Doppler sonography during angiography were used to evaluate the frequency of cerebral embolism. One hundred fifty diagnostic cerebral angiographies were randomized into 50 procedures, each using conventional angiographic technique, or systemic heparin treatment throughout the procedure, or air filters between the catheter and both the contrast medium syringe and the catheter flushing. There was no neurological complication during or after angiography. Overall, DW-MRI revealed 26 new ischemic lesions in 17 patients (11%). In the control group, 11 patients showed a total of 18 lesions. In the heparin group, 3 patients showed a total of 4 lesions. In the air filter group, 3 patients exhibited a total of 4 lesions. The reduced incidence of ischemic events in the heparin and air filter groups compared with the control group was significantly different (
P
=0.002). Transcranial Doppler sonography demonstrated a large number of microembolic signals that was significantly lower in the air filter group compared with the heparin and control groups (
P
<0.01), which did not differ from each other.

Conclusions—

Air filters and heparin both reduce the incidence of silent ischemic events detected by DW-MRI after intra-arterial cerebral angiography and can potentially lower clinically overt ischemic complications. This may apply to any intra-arterial angiographic procedure.
Giant Fetal Magnetocardiogram P Waves in Congenital Atrioventricular Block
Authors: Li Zhimin , Strasburger Janette F. , Cuneo Bettina F. , Gotteiner Nina L. , Wakai Ronald T.
Published: October 2004

Background—

Cardiogram signal amplitude is a key index of hypertrophy but has not been investigated extensively in utero. In this study, magnetocardiography was used to assess P and QRS amplitude in normal subjects and subjects with fetal arrhythmia.

Methods and Results—

The study cohort consisted of 68 normal fetuses and 25 with various arrhythmias: 9 reentrant supraventricular tachycardia (SVT), 2 ventricular tachycardia (VT), 2 sinus tachycardia, 2 blocked atrial bigeminy, 2 congenital second-degree atrioventricular (AV) block, and 8 congenital complete AV block. Subjects with congenital AV block, all presenting with bradycardia, showed large QRS amplitude, exceedingly large P-wave amplitude, and long P-wave duration. The 2 subjects with VT, both with poor ventricular function, also exhibited large P waves. SVT was associated with only moderate signal amplitude elevation.

Conclusions—

The data imply that AV block in utero is accompanied by hypertrophy, which is more pronounced for the atria than the ventricles. We hypothesize that the hypertrophy results from a compensatory response associated with regulation of cardiac output and is likely to be observable in other arrhythmias and disease states. Magnetocardiography may be more sensitive than fetal echocardiography for detection of atrial hypertrophy in utero.
K
ATP
Channel Activation Induces Ischemic Preconditioning of the Endothelium in Humans In Vivo
Authors: Broadhead M.W. , Kharbanda R.K. , Peters M.J. , MacAllister R.J.
Published: October 2004

Background—

Endothelial dysfunction contributes to ischemia-reperfusion injury (IRI) and is reduced by ischemic preconditioning (IPC). IPC may involve activation of ATP-sensitive potassium channels (K
ATP
). We determined whether modulation of K
ATP
channels occurs in endothelial IPC in humans.

Methods and Results—

IRI of the forearm was induced by inflating a blood pressure cuff to 200 mm Hg for 20 minutes in healthy volunteers. K
ATP
activation was modulated by intra-arterial glibenclamide (blocker) and diazoxide (opener). Endothelial function (response to intra-arterial acetylcholine) was assessed with forearm plethysmography before and after (1) 15-minute reperfusion, (2) IRI preceded by IPC (3 five-minute periods of ischemia), (3) IRI preceded by IPC with glibenclamide, (4) IPC followed by glibenclamide before IRI, (5) IRI preceded by diazoxide, and (6) IRI preceded by coinfusion of glibenclamide with diazoxide. IRI caused endothelial dysfunction (
P
=0.002), which IPC prevented (
P
=0.40). Glibenclamide abolished IPC when given contemporaneously with (
P
=0.003) or during IRI (
P
=0.0005). Diazoxide prevented endothelial dysfunction after IRI (
P
=0.68) but not when coinfused with glibenclamide.

Conclusion—

Glibenclamide abolishes and diazoxide mimics endothelial IPC in humans. The time course of the effect of glibenclamide suggests involvement of K
ATP
channels as effectors of endothelial IPC in vivo. These data may have implications for understanding the therapeutic role of agents that modulate K
ATP
channel function.
Differential Effects of Theophylline on Sympathetic Excitation, Hemodynamics, and Breathing in Congestive Heart Failure
Authors: Andreas Stefan , Reiter Hartwig , Lüthje Lars , Delekat André , Grunewald Rolf W. , Hasenfuss Gerd , Somers Virend K.
Published: October 2004

Background—

Patients with heart failure have high levels of central sympathetic outflow and also have a high prevalence of sleep-related breathing disorders, predominantly central sleep apnea. The options for treating central sleep apnea in heart failure are limited and include theophylline. Whether theophylline alters sympathetic activity in heart failure patients is not known.

Methods and Results—

Using a single-blinded, randomized, placebo-controlled study design, we investigated the sympathetic, hemodynamic, neurohumoral, and ventilatory effects of theophylline in patients with congestive heart failure compared with healthy control subjects closely matched for age, sex, and body mass index. Theophylline increased muscle sympathetic nerve activity and lowered transcutaneous CO
2
in the control subjects but only lowered transcutaneous CO
2
in the heart failure patients. Theophylline nearly doubled plasma renin concentration in both the healthy subjects (
P
<0.01) and the heart failure patients (
P
<0.02).

Conclusions—

Our study shows that in heart failure patients, there are differential effects of theophylline: in contrast to healthy subjects, theophylline does not increase sympathetic activity in heart failure, whereas increases in plasma renin and ventilation are still evident. These novel findings may have important implications for understanding the potential harmful and beneficial effects of theophylline and related substances in heart failure patients.
Chondrogenic and Adipogenic Potential of Microvascular Pericytes
Authors: Farrington-Rock C. , Crofts N.J. , Doherty M.J. , Ashton B.A. , Griffin-Jones C. , Canfield A.E.
Published: October 2004

Background—

Previous studies have shown that pericytes can differentiate into osteoblasts and form bone. This study investigated whether pericytes can also differentiate into chondrocytes and adipocytes.

Methods and Results—

Reverse transcription–polymerase chain reaction demonstrated that pericytes express mRNA for the chondrocyte markers Sox9, aggrecan, and type II collagen. Furthermore, when cultured at high density in the presence of a defined chondrogenic medium, pericytes formed well-defined pellets comprising cells embedded in an extracellular matrix rich in sulfated proteoglycans and type II collagen. In contrast, when endothelial cells were cultured under the same conditions, the pellets disintegrated after 48 hours. In the presence of adipogenic medium, pericytes but not endothelial cells expressed mRNA for peroxisome proliferator–activated receptor-γ2 (an adipocyte-specific transcription factor) and incorporated lipid droplets that stained with oil red O. To confirm that pericytes can differentiate along the chondrocytic and adipocytic lineages in vivo, these cells were inoculated into diffusion chambers and implanted into athymic mice for 56 days. Accordingly, mineralized cartilage, fibrocartilage, and a nonmineralized cartilaginous matrix with lacunae containing chondrocytes were observed within these chambers. Small clusters of cells that morphologically resembled adipocytes were also identified.

Conclusions—

These data demonstrate that pericytes are multipotent cells that may contribute to growth, wound healing, repair, and/or the development and progression of various pathological states.
Hypertrophy, Fibrosis, and Sudden Cardiac Death in Response to Pathological Stimuli in Mice With Mutations in Cardiac Troponin T
Authors: Maass Alexander H. , Ikeda Kaori , Oberdorf-Maass Silke , Maier Sebastian K.G. , Leinwand Leslie A.
Published: October 2004

Background—

Transgenic mouse models expressing a missense mutation (R92Q) or a splice donor site mutation (trunc) in the cardiac troponin T (cTnT) model familial hypertrophic cardiomyopathy (FHC) in humans. Although males from these strains share the unusual property of having significantly smaller ventricles and cardiac myocytes, they differ with regard to systolic function, fibrosis, and gene expression. Little is known about how these phenotypes affect the responses to additional pathological stimuli.

Methods and Results—

We tested the ability of hearts of both sexes of wild-type and mutant mice to respond to defined pathological, pharmacological, hypertrophic stimuli in vivo. Hearts of mutant cTnT models of both sexes were able to undergo hypertrophy in response to at least one stimulus, but the extent differed between the 2 mutants and was sex specific. Interestingly, the trunc-mutant mouse heart was resistant to the development of fibrosis in response to pharmacological stimuli. Stimulation with 2 adrenergic agonists led to sudden cardiac death of all male but not female mutant animals, which suggests altered adrenergic responsiveness in these 2 models of FHC.

Conclusions—

Hypertrophic signaling is differentially affected by distinct mutations in cTnT and is sex modified. Hearts can respond with either an augmented hypertrophic and fibrotic response or a diminished hypertrophy and resistance to fibrosis. Sudden cardiac death is related to adrenergic stress and is independent of the development of fibrosis but occurred only in male mice. These results suggest that patients with certain TnT mutations may respond to certain pathological situations with a worsened phenotype.
Endothelium-Restricted Overexpression of Human Endothelin-1 Causes Vascular Remodeling and Endothelial Dysfunction
Authors: Amiri Farhad , Virdis Agostino , Neves Mario Fritsch , Iglarz Marc , Seidah Nabil G. , Touyz Rhian M. , Reudelhuber Timothy L. , Schiffrin Ernesto L.
Published: October 2004

Background—

Endothelin (ET)-1 is a potent vasoconstrictor that contributes to vascular remodeling in hypertension and other cardiovascular diseases. Endogenous ET-1 is produced predominantly by vascular endothelial cells. To directly test the role of endothelium-derived ET-1 in cardiovascular pathophysiology, we specifically targeted expression of the human preproET-1 gene to the endothelium by using the Tie-2 promoter in C57BL/6 mice.

Methods and Results—

Ten-week-old male C57BL/6 transgenic (TG) and nontransgenic (wild type; WT) littermates were studied. TG mice exhibited 3-fold higher vascular tissue ET-1 mRNA and 7-fold higher ET-1 plasma levels than did WT mice but no significant elevation in blood pressure. Despite the absence of significant blood pressure elevation, TG mice exhibited marked hypertrophic remodeling and oxidant excess-dependent endothelial dysfunction of resistance vessels, altered ET-1 and ET-3 vascular responses, and significant increases in ET
B
expression compared with WT littermates. Moreover, TG mice generated significantly higher oxidative stress, possibly through increased activity and expression of vascular NAD(P)H oxidase than did their WT counterparts.

Conclusions—

In this new murine model of endothelium-restricted human preproET-1 overexpression, ET-1 caused structural remodeling and endothelial dysfunction of resistance vessels, consistent with a direct nonhemodynamic effect of ET-1 on the vasculature, at least in part through the activation of vascular NAD(P)H oxidase.