bluuebunny/crossref_metadata_2025 huggingface dataset:
Vasomotor sympathetic neural control is maintained during sustained upright posture in humans
Authors: Fu Qi , Shook Robin P. , Okazaki Kazunobu , Hastings Jeffrey L. , Shibata Shigeki , Conner Colin L. , Palmer M. Dean , Levine Benjamin D.
Published: September 2006

Vasomotor sympathetic activity plays an important role in arterial pressure maintenance via the baroreflex during acute orthostasis in humans. If orthostasis is prolonged, blood pressure may be supported additionally by humoral factors with a possible reduction in sympathetic baroreflex sensitivity. We tested the hypothesis that baroreflex control of muscle sympathetic nerve activity (MSNA) decreases during prolonged upright posture. MSNA and haemodynamics were measured supine and during 45 min 60 deg upright tilt in 13 healthy individuals. Sympathetic baroreflex sensitivity was quantified using the slope of the linear correlation between MSNA and diastolic pressure during spontaneous breathing. It was further assessed as the relationship between MSNA and stroke volume, with stroke volume derived from cardiac output (C2H2 rebreathing) and heart rate. Total peripheral resistance was calculated from mean arterial pressure and cardiac output. We found that MSNA increased from supine to upright (17 ± 8 (s.d.) versus 38 ± 12 bursts min−1; P < 0.01), and continued to increase to a smaller degree during sustained tilt (39 ± 11, 41 ± 12, 43 ± 13 and 46 ± 15 bursts min−1 after 10, 20, 30 and 45 min of tilt; between treatments P < 0.01). Sympathetic baroreflex sensitivity increased from supine to upright (−292 ± 180 versus−718 ± 362 units beat−1 mmHg−1; P < 0.01), but remained unchanged as tilting continued (−611 ± 342 and −521 ± 221 units beat−1 mmHg−1 after 20 and 45 min of tilt; P= 0.49). For each subject, changes in MSNA were associated with changes in stroke volume (r= 0.88 ± 0.13, P < 0.05), while total peripheral resistance was related to MSNA during 45 min upright tilt (r= 0.82 ± 0.15, P < 0.05). These results suggest that the vasoconstriction initiated by sympathetic adrenergic nerves is maintained by ongoing sympathetic activation during sustained (i.e. 45 min) orthostasis without obvious changes in vasomotor sympathetic neural control.
Novelty exploration elicits a reversal of acute stress‐induced modulation of hippocampal synaptic plasticity in the rat
Authors: Yang Chih‐Hao , Huang Chiung‐Chun , Hsu Kuei‐Sen
Published: September 2006

Acute behavioural stress has been recognized as a strong influence on the inducibility of hippocampal long‐term synaptic plasticity. We have reported previously that in adult male rats, acute behavioural stress impairs long‐term potentiation (LTP) but enhances long‐term depression (LTD) in the hippocampal CA1 region. In this study we report that the effects of stress on LTP and LTD were reversed when animals were introduced into a novel ‘stimulus‐rich’ environment immediately after the stress. Novelty exploration‐induced reversal of stress effects was prevented when the animals were given the NMDA receptor antagonist d‐(−)‐2‐amino‐5‐phosphonopentanoic acid, the cholinergic antagonist atropine and the protein phosphatase (PP) 2B inhibitors cyclosporin A and cypermethrin, but not the α1‐adrenergic antagonist prazosin, the β‐adrenergic antagonist propranolol or the PP1/2A inhibitor okadaic acid, respectively before being subjected to the novel environment. In addition, the ability of novelty exploration to reverse the stress effects was mimicked by a direct application of the cholinergic agonist carbachol. Exposure to the novel environment following stress was accompanied by the activation of both PP2B and striatal‐enriched tyrosine phosphatase (STEP). Taken together, these findings suggest that the activation of the cholinergic system and, in turn, the triggering of an NMDA receptor‐mediated activation of PP2B to increase STEP activity appear to mediate the novelty exploration‐induced reversal of stress‐related modulation of hippocampal long‐term synaptic plasticity.
Formal and effective autonomy in healthcare
Authors: Schwab A P
Published: September 2006

This essay lays the groundwork for a novel conception of autonomy that may be called “effective autonomy”—a conception designed to be genuinely action guiding in bioethics. As empirical psychology research on the heuristics and biases approach shows, decision making commonly fails to correspond to people’s desires because of the biases arising from bounded cognition. People who are classified as autonomous on contemporary philosophical accounts may fail to be effectively autonomous because their decisions are uncoupled from their autonomous desires. Accordingly, continuing attempts to value patient autonomy must go beyond existing philosophical conceptions of autonomy to consider the background conditions of human decision making.
Right of the living dead? Consent to experimental surgery in the event of cortical death
Authors: Sparrow R
Published: September 2006

Ravelingienet alhave suggested that early human xenotransplantation trials should be carried out on patients who are in a permanent vegetative state (PVS) and who have previously granted their consent to the use of their bodies in such research in the event of their cortical death. Unfortunately, their philosophical defence of this suggestion is unsatisfactory in its current formulation, as it equivocates on the key question of the status of patients who are in a PVS. The solution proposed by them rests on the idea that it should be up to people themselves to determine when they should be treated as dead. Yet the authors clearly believe (and state) that patients who are in a PVS are in fact dead. Finally, given the public good that their proposal is intended to achieve, the moral importance they place on the consent of a person to the use of his or her body in research is ultimately only defensible in so far as this consent represents the wishes of a living person. It is thus only a gentle caricature of their position to suggest that according to their account, consent to participation in xenotransplantation research is a “right of the living dead”. The equivocation by Ravelingienet alon the question of whether these people are living or dead means that they avoid confronting the implications of their argument. The solution proposed by Ravelingienet alto the problem of how we should proceed with xenotransplantation research is therefore not as neat as it first seems to be.
Mass public health programmes and the obligations of sponsoring and participating organisations
Authors: Dawson A , Paul Y
Published: September 2006

The obligations of organisations associated with policy formation and implementation of international mass public health programmes are explored. Lines of responsibility are considered to become unclear because of the large number of agencies associated with such programmes. A separation of the relevant obligations among the bodies responsible for the formulation (usually an international non-governmental organisation) and those responsible for the implementation of the policies (usually national bodies) is suggested. The continuing oral polio vaccine campaign against poliomyelitis in India is used to illustrate the general argument. Although the aim of the programme is legitimate and laudable, unnecessary harm is currently being caused to some children as a result of elements of the policy and this should be rectified immediately. Such mass programmes should take care to ensure that people are not unnecessarily sacrificed in the drive to attain the desirable ends of the policy.
Developing capacity to protect human research subjects in a post-conflict, resource-constrained setting: procedures and prospects
Authors: Kennedy S B , Harris A O , Oudemans E , Young L , Kollie J , Nelson E S , Nisbett R A , Morris C , Bartee N , George-Williams E , Jones J
Published: September 2006

The capacity-building strategy used by a US-based research organisation, the Pacific Institute for Research and Evaluation (PIRE), to strengthen the system for the protection of human research subjects and the infrastructure of its international collaborating partner, the University of Liberia, are discussed. To conduct the much-needed biomedical and social science-based research-related activities in the future, this partnership is expected by PIRE to gradually evolve over time to strengthen the capacity of the local investigators and administrators of the University of Liberia. Accordingly, a unique opportunity to share technology and resources with a post-conflict, resource-constrained country is created by this partnership. This capacity-building model to strengthen the protection of human subjects in research can also be replicated in similar resource-constrained international settings and, accordingly, our experiences and limitations are shared in this paper.
The need for a clinical ethics service and its goals in a community healthcare service centre: a survey
Authors: Racine E , Hayes K
Published: September 2006

Objectives:To (1) assess whether according to healthcare providers, the creation of an ethics service responds to a need; (2) assess the importance of an ethics service for healthcare providers; (3) determine what ethics services should be offered and the preferred formats of delivery; and (4) identify key issues to be initially dealt with by the ethics service.

Design:A survey of healthcare providers in Québec’s Centre Local de Services Communautaires (CLSC), healthcare institutions dedicated to community health and social services.

Findings:96 (95%) respondents agreed that an ethics service was needed, and on average the ethics service project was judged to be very important. Preferred formats for ethics consultation and education were identified, as well as key concerns such as the need of respect for the patient as a person, elder abuse and ethical issues in home care.

Conclusion:This survey is helping in the implementation of an ethics service and can guide others in similar healthcare institutions.
Killing people: what Kant could have said about suicide and euthanasia but did not
Authors: Brassington I
Published: September 2006

An agent who takes his own life acts in violation of the moral law, according to Kant; suicide, and, by extension, assisted suicide are therefore wrong. By a similar argument, and with a few important exceptions, killing is wrong; implicitly, then, voluntary euthanasia is also wrong. Kant’s conclusions are uncompelling and his argument in these matters is undermined on considering other areas of his thought. Kant, in forbidding suicide and euthanasia, is conflating respect for persons and respect for people, and assuming that, in killing a person (either oneself or another), we are thereby undermining personhood. But an argument along these lines is faulty according to Kant’s own standards. There is no reason why Kantians have to accept that self-killing and euthanasia are contrary to the moral law. Even if some Kantians adhere to this doctrine, others can reject it.
A taxonomic revision of Helichrysum sect. Stoechadina (Asteraceae, Gnaphalieae)
Authors: Galbany-Casals Mercè , Sáez Llorenç , Benedí Carles
Published: September 2006

A taxonomic revision of Helichrysum sect. Stoechadina, a section with a Mediterranean distribution, is presented. Taxonomic, nomenclatural, morphological, chromosomal, geographical, and ecological data are provided for each taxon. Eleven taxa are recognized, two lectotypifications are proposed, and a taxonomic key and a sectional description are included. The following new combinations are proposed: Helichrysum italicum subsp. siculum (Jord. & Fourr.) Galbany, L. Sáez & Benedí comb. nov. and Helichrysum italicum subsp. picardii (Boiss. & Reut.) Galbany, L. Sáez & Benedí comb. nov.
Understanding storage starch biosynthesis in plants: a means to quality improvement
Authors: Tetlow Ian J.
Published: September 2006

The many varied uses of starch in food and industrial applications often requires an understanding of its physicochemical properties and the detailed variations in granule structure that underpin these properties. The ability to manipulate storage starch structures depends on understanding the biosynthetic pathway, and in particular, how the many components of the pathway are coordinated and regulated. This article presents a current overview of starch structure and the known enzymes involved in the synthesis of the granule, with an emphasis on how current knowledge on the regulation of the pathway in cereals and other crops may be applied to the production of different functional starches.
M2and M3muscarinic receptors are involved in enteric nerve-mediated contraction of the mouse ileum: findings obtained with muscarinic-receptor knockout mouse
Authors: Takeuchi Tadayoshi , Tanaka Keisuke , Nakajima Hidemitsu , Matsui Minoru , Azuma Yasu-Taka
Published: September 2006

The involvement of muscarinic receptors in neurogenic responses of the ileum was studied in wild-type and muscarinic-receptor (M-receptor) knockout (KO) mice. Electrical field stimulation to the wild-type mouse ileum induced a biphasic response, a phasic and sustained contraction that was abolished by tetrodotoxin. The sustained contraction was prolonged for an extended period after the termination of electrical field stimulation. The phasic contraction was completely inhibited by atropine. In contrast, the sustained contraction was enhanced by atropine. Ileal strips prepared from M2-receptor KO mice exhibited a phasic contraction similar to that seen in wild-type mice and a sustained contraction that was larger than that in wild-type mice. In M3-receptor KO mice, the phasic contraction was smaller than that observed in wild-type mice. Acetylcholine exogenously administrated induced concentration-dependent contractions in strips isolated from wild-type, M2- and M3-receptor KO mice. However, contractions in M3-receptor KO mice shifted to the right. The sustained contraction was inhibited by capsaicin and neurokinin NK2receptor antagonist, suggesting that it is mediated by substance P (SP). SP-induced contraction of M2-receptor KO mice did not differ from that of wild-type mice. SP immunoreactivity was located in enteric neurons, colocalized with M2receptor immunoreactivity. These results suggest that atropine-sensitive phasic contraction is mainly mediated via the M3receptor, and SP-mediated sustained contraction is negatively regulated by the M2receptor at a presynaptic level.
Persistent alterations to enteric neural signaling in the guinea pig colon following the resolution of colitis
Authors: Lomax Alan E. , O'Hara Jennifer R. , Hyland Niall P. , Mawe Gary M. , Sharkey Keith A.
Published: September 2006

Functional changes induced by inflammation persist following recovery from the inflammatory response, but the mechanisms underlying these changes are not well understood. Our aim was to investigate whether the excitability and synaptic properties of submucosal neurons remained altered 8 wk post-trinitrobenzene sulfonic acid (TNBS) treatment and to determine whether these changes were accompanied by alterations in secretory function in submucosal preparations voltage clamped in Ussing chambers. Mucosal serotonin (5-HT) release measurements and 5-HT reuptake transporter (SERT) immunohistochemistry were also performed. Eight weeks after TNBS treatment, colonic inflammation resolved, as assessed macroscopically and by myeloperoxidase assay. However, fast excitatory postsynaptic potential (fEPSP) amplitude was significantly increased in submucosal S neurons from previously inflamed colons relative to those in control tissue. In addition, fEPSPs from previously inflamed colons had a hexamethonium-insensitive component that was not evident in age-matched controls. AH neurons were hyperexcitable, had shorter action potential durations, and decreased afterhyperpolarization 8 wk following TNBS adminstration. Neuronally mediated colonic secretory function was significantly reduced after TNBS treatment, although epithelial cell signaling, as measured by responsiveness to both forskolin and bethanecol in the presence of tetrodotoxin, was comparable with control tissue. 5-HT levels and SERT immunoreactivity were comparable to controls 8 wk after the induction of inflammation, but there was an increase in glucagon-like peptide 2-immunoreactive L cells. In conclusion, sustained alterations in enteric neural signaling occur following the resolution of colitis, which are accompanied by functional changes in the absence of active inflammation.
A novel model of acute murine hindlimb ischemia
Authors: Crawford Robert S. , Hashmi Faraz F. , Jones John E. , Albadawi Hassan , McCormack Michael , Eberlin Kyle , Entabi Fateh , Atkins Marvin D. , Conrad Mark F. , Austen W. Gerald , Watkins Michael T.
Published: September 2006

The McGivney hemorrhoidal ligator (MHL), a band designed to cause tissue necrosis, is the preferred experimental tool to create hindlimb ischemia-reperfusion (I/R) injury in rodents. This report defines and compares the ex vivo band tension exerted by MHL and orthodontic rubber bands (ORBs) along with select in vivo characteristics of I/R. As to method, ex vivo band tension was measured over relevant diameters using a tensiometer. In vivo assessment of murine limb perfusion during ischemia with ORB and MHL was compared using laser Doppler imaging and measurement of wet weight-to-dry weight ratio. Neuromuscular scoring and histological extent of muscle fiber injury after I/R with MHL and ORB were also compared. A dose-response curve, between the duration of ORB-induced I/R with both mitochondrial activity (methyl-thiazol-tetrazolium) or tail perfusion [laser Doppler imaging (LDI)], was generated. As a results, ex vivo measurements showed that ORB exerted significantly less force than the MHL. Despite less tension in ORB, in vivo testing of the ORB confirmed complete ischemia by both LDI and wet weight-to-dry weight ratio. After I/R, caused by ORB, there was significantly less neuromuscular dysfunction. Histological assessment confirmed similar degrees of muscle fiber injury after I/R with either the MHL or ORB. Increasing durations of ischemia created by the ORB followed by reperfusion significantly decreased mitochondrial activity and tail perfusion after 24 h of ischemia. In conclusions, ORB produced similar levels of tissue ischemia in murine models of limb I/R with fewer levels of nonspecific injury. ORB may be the preferred model for selected studies of limb I/R.
Estrogen deficiency decreases ischemic tolerance in the aged rat heart: roles of PKCδ, PKCε, Akt, and GSK3β
Authors: Hunter J. C. , Kostyak J. C. , Novotny J. L. , Simpson A. M. , Korzick Donna H.
Published: September 2006

The mechanisms underlying the age-dependent reversal of female cardioprotection are poorly understood and complicated by findings that estrogen replacement is ineffective at reducing cardiovascular mortality in postmenopausal women. Although several protective signals have been identified in young animals, including PKC and Akt, how these signals are affected by age, estrogen deficiency, and ischemia-reperfusion (I/R) remains unknown. To determine the independent and combined effects of age and estrogen deficiency on I/R injury and downstream PKC-Akt signaling, adult and aged female F344 rats ( n = 12/age) with ovaries intact or ovariectomy (Ovx) were subjected to I/R using Langendorff perfusion (31-min global-ischemia). Changes in cytosolic (s), nuclear (n), mitochondrial (m) PKC (δ, ε) levels, and changes in total Akt and mGSK-3β phosphorylation after I/R were assessed by Western blot analysis. Senescence increased infarct size 50% in ovary-intact females ( P < 0.05), whereas no differences in LV functional recovery or estradiol levels were observed. Ovx reduced functional recovery to a greater extent in aged compared with adult rats ( P < 0.05). In aged (vs. adult), levels of m- and nPKC(-δ, -ε) were markedly decreased, whereas mGSK3β levels were increased ( P < 0.05). Ovx led to greater levels of sPKC(-δ, -ε) independent of age ( P < 0.05). I/R reduced p-Akt(Ser473) levels by 57% and increased mGSK-3β accumulation 1.77-fold ( P < 0.05) in aged, ovary-intact females. These data suggest, for the first time, that estrogen alone cannot protect the aged female myocardium from I/R damage and that age- and estrogen-dependent alterations in PKC, Akt, and GSK-3β signaling may contribute to loss of ischemic tolerance.
Thermoregulation: some concepts have changed. Functional architecture of the thermoregulatory system
Authors: Romanovsky Andrej A.
Published: September 2006

While summarizing the current understanding of how body temperature (Tb) is regulated, this review discusses the recent progress in the following areas: central and peripheral thermosensitivity and temperature-activated transient receptor potential (TRP) channels; afferent neuronal pathways from peripheral thermosensors; and efferent thermoeffector pathways. It is proposed that activation of temperature-sensitive TRP channels is a mechanism of peripheral thermosensitivity. Special attention is paid to the functional architecture of the thermoregulatory system. The notion that deep Tb is regulated by a unified system with a single controller is rejected. It is proposed that Tb is regulated by independent thermoeffector loops, each having its own afferent and efferent branches. The activity of each thermoeffector is triggered by a unique combination of shell and core Tbs. Temperature-dependent phase transitions in thermosensory neurons cause sequential activation of all neurons of the corresponding thermoeffector loop and eventually a thermoeffector response. No computation of an integrated Tb or its comparison with an obvious or hidden set point of a unified system is necessary. Coordination between thermoeffectors is achieved through their common controlled variable, Tb. The described model incorporates Kobayashi’s views, but Kobayashi’s proposal to eliminate the term sensor is rejected. A case against the term set point is also made. Because this term is historically associated with a unified control system, it is more misleading than informative. The term balance point is proposed to designate the regulated level of Tb and to attract attention to the multiple feedback, feedforward, and open-loop components that contribute to thermal balance.
Heterogeneity of responses to orthostatic stress in homozygous twins
Authors: O'Leary D. D. , Hughson R. L. , Shoemaker J. K. , Greaves D. K. , Watenpaugh D. E. , Macias B. R. , Hargens A. R.
Published: September 2006

Early analysis into the role of genetics on cardiovascular regulation has been accomplished by comparing blood pressure and heart rate in homozygous twins during unstressed, resting physiological conditions. However, many variables, including cognitive and environmental factors, contribute to the regulation of cardiovascular hemodynamics. Therefore, the purpose of this study was to determine the hemodynamic response of identical twins to an orthostatic stress, ranging from supine rest to presyncope. Heart rate, arterial blood pressure, middle cerebral artery blood velocity, an index of cerebrovascular resistance, cardiac output, total peripheral resistance, and end-tidal carbon dioxide were measured in 16 healthy monozygotic twin pairs. Five minutes of supine resting baseline data were collected, followed by 5 min of 60° head-up tilt. After 5 min of head-up tilt, lower body negative pressure was applied in increments of 10 mmHg every 3 min until the onset of presyncope, at which time the subject was returned to the supine position for a 5-min recovery period. The data indicate that cardiovascular regulation under orthostatic stress demonstrates a significant degree of variance between identical twins, despite similar orthostatic tolerance. As the level of stress increases, so does the difference in the cardiovascular response within a twin pair. The elevated variance with increasing stress may be due to an increase in the role of environmental factors, as the influential role of genetics nears a functional limit. Therefore, although orthostatic tolerance times were very similar between identical twins, the mechanism involved in sustaining cardiovascular function during increasing stress was different.
Fiber type-specific muscle glycogen sparing due to carbohydrate intake before and during exercise
Authors: De Bock K. , Derave W. , Ramaekers M. , Richter E. A. , Hespel P.
Published: September 2006

The effect of carbohydrate intake before and during exercise on muscle glycogen content was investigated. According to a randomized crossover study design, eight young healthy volunteers ( n = 8) participated in two experimental sessions with an interval of 3 wk. In each session subjects performed 2 h of constant-load bicycle exercise (∼75% maximal oxygen uptake). On one occasion (CHO), they received carbohydrates before (∼150 g) and during (1 g·kg body weight−1·h−1) exercise. On the other occasion they exercised after an overnight fast (F). Fiber type-specific relative glycogen content was determined by periodic acid Schiff staining combined with immunofluorescence in needle biopsies from the vastus lateralis muscle before and immediately after exercise. Preexercise glycogen content was higher in type IIa fibers [9.1 ± 1 × 10−2optical density (OD)/μm2] than in type I fibers (8.0 ± 1 × 10−2OD/μm2; P < 0.0001). Type IIa fiber glycogen content decreased during F from 9.6 ± 1 × 10−2OD/μm2to 4.5 ± 1 × 10−2OD/μm2( P = 0.001), but it did not significantly change during CHO ( P = 0.29). Conversely, in type I fibers during CHO and F the exercise bout decreased glycogen content to the same degree. We conclude that the combination of carbohydrate intake both before and during moderate- to high-intensity endurance exercise results in glycogen sparing in type IIa muscle fibers.
Immunoregulatory T Cells in the Peripheral Blood of Patients with Hodgkin’s Lymphoma
Authors: Baráth Sándor , Aleksza Magdolna , Keresztes Katalin , Tóth Judit , Sipka Sándor , Szegedi Gyula , Illés Árpád
Published: September 2006

We aimed at investigating the distribution of various types of immunoregulatory T cells in the peripheral blood of patients with Hodgkin’s lymphoma (HL) (n = 94) being in the state of long-lasting complete remission using flow cytometry. Healthy patients (n = 41) as ‘negative’ and patients in complete remission with breast cancer (n = 47) as ‘positive’ controls were investigated in the study. We found significant elevations in the number of CD4+CD25high naturally occurring regulatory T cells, CD4+/intracellular IL-10+ (Tr1) and CD8+/intracellular IL-10+ T cells in HL compared to the healthy controls. In carcinoma patients, however, the number of Tr1 and CD8+/IL-10+ T cells was higher than that in the other two groups. The increase in the number of CD4+CD25high T cells seems to be characteristic of HL compared to the two other types of regulatory T cells. This change exists for a long time and it seems to be a characteristic of HL and independent of the types of therapy and the duration of time since therapy.
Histologic Assessment of Right Atrial Appendage Myocardium in Patients with Atrial Fibrillation after Coronary Artery Bypass Graft Surgery
Authors: Nakai Toshiko , Chandy Joby , Nakai Kazuhiko , Bellows Wayne H. , Flachsbart Keith , Lee Randall J. , Leung Jacqueline M.
Published: September 2006

Atrial fibrillation (AF) is a common complication after coronary artery bypass graft (CABG) surgery. Despite the prevalence of AF occurring after cardiac surgery, its pathophysiology is incompletely understood. Our previous study demonstrated that age and left atrial enlargement were independent predictors of postoperative AF. Accordingly, the purpose of this study was to determine whether cellular changes such as fibrosis and/or hypertrophy occurred in the atrium in patients who subsequently developed postoperative AF. Right atrial appendage tissue was obtained during atriotomy in patients undergoing elective CABG surgery. Quantitative assessment of atrial fibrosis was performed with Sirius red stain, and atrial cell diameter was measured with the HE stain. Linear regression, t test, χ2 test or Fisher exact test were used for statistical analysis. Sixty-one patients (mean age 71 ± 8 years) were studied. Increasing age was significantly associated with fibrosis (beta 0.3, 95% CI: 0.06–0.55, p = 0.017). The amount of right atrial fibrosis tended to correlate with the incidence of postoperative AF (p = 0.08). Cell diameter was not significantly different between patients with versus without postoperative AF (p = 0.85). These results suggest that the age-related atrial fibrosis rather than cellular hypertrophy may be important in the pathogenesis of AF after CABG surgery and should be further investigated.
Morphologic, Phenotypic and Functional Characteristics of Endothelial Cells Derived from Human Hepatic Cavernous Hemangioma
Authors: Zhang Wen-jian , Ye Li-ya , Wu Lian-qiu , Xin Yu-ling , Gu Feng , Niu Ji-xiao , Yang Zhi-hua , Zhu Guang-jin , Grau Georges E. , Lou Jin-ning
Published: September 2006

Backgrounds/Aims: The pathogenesis of cavernous hemangiomas is largely unknown, and it is speculated that abnormal vasculogenesis and angiogenesis may be involved. In this study, the characteristics of cavernous hemangioma endothelial cells (CHECs) derived from the human liver were analyzed in terms of morphology, phenotype and function and compared with human liver sinusoidal endothelial cells (LSECs). Methods and Results: By transmission electron microscopy, abnormally expanded endoplasmic reticulum (ER) and similarly arranged cytoplasmic vacuoles were only found in CHECs. Phenotypic analysis showed that the expression of αvβ3 was significantly increased in CHECs. mRNA expression of vascular endothelial growth factor A, and angiopoietins 1 and 2 was significantly increased in CHECs compared to LSECs. The functional analysis indicated that CHECs released more vascular endothelial growth factor A, produced significantly more pro-matrix metalloproteinase 2 (pro-MMP2) and activated MMP2, and exhibited higher procoagulant and fibrinolytic activities compared with LSECs. Confocal microscopy revealed that MMP2 was concentrated in some cytoplasmic granules of CHECs and was consistent with the distribution of expanded ER. CHECs exhibited more activated angiogenesis capacity and formed abnormal capillary-like structures in vitro. Conclusion: These results suggested that endothelial cells (ECs) derived from human cavernous hemangiomas differ from normal ECs in morphology, phenotype and function.
Modulation of the Immune System by Human Rhinoviruses
Authors: Kirchberger Stefanie , Majdic Otto , Stöckl Johannes
Published: September 2006

Human rhinoviruses (HRV) are the major cause of the common cold, one of the most frequent infectious diseases in humans. Though HRV infections of the upper respiratory tract are usually rather harmless, there is increasing evidence that HRV sets the stage for more dangerous pathogens, elicits asthmatic exacerbations, severe diseases in the lower respiratory tract and even autoimmunity. The pathogenic mechanisms of HRV infections leading to such complications are still poorly understood. It is a common strategy of pathogens to manipulate our immune system in order to evade an efficient immune response. A major characteristic of HRV is a high degree of species specificity. Thus, analyzing the potential immune evasion mechanisms used by HRV will be helpful for a better understanding of the pathogenesis of the common cold and may contribute to a better understanding of the human immune system as well. In this review we want to illuminate what is known about potential immune escape mechanisms used by HRV and discuss how such disturbances might lead to a suppressed and dysregulated immune competence in man.
Standardization of an Ash (Fraxinus excelsior) Pollen Allergen Extract
Authors: Hrabina Maud , Purohit Ashok , Oster Jean-Philippe , Papanikolaou Ioanna , Jain Karine , Pascal Poncet , Sicard Hubert , Gouyon Brigitte , Moingeon Philippe , Pauli Gabrielle , André Claude
Published: September 2006

Background: Ash tree (Fraxinus excelsior) is the main representative of the Oleaceae family in temperate zones. Diagnosis of ash pollen allergy is made difficult due to (1) an overlapping pollinization period with Betulaceae, (2) non-inclusion in current diagnostic assays, and (3) some cross- reactivity with minor allergens from Betulaceae. The aim of this study was to calibrate an ash pollen in-house reference preparation (IHRP) in allergic patients in order to produce standardized products for diagnosis and immunotherapy purposes. Methods: Ash pollen IHRP was extracted, ultrafiltered and freeze dried. Allergens in the extract were detected after 2-dimensional PAGE using specific sera and a monoclonal antibody. The Fra e 1 content of IHRP was evaluated by quantitative immunoprint. Forty-eight subjects from the North-East of France exhibiting clinical symptoms, a positive skin test and specific IgE levels ≧class 2 to ash pollen were recruited. IgE immunoprints were performed to select patients sensitized to the ash Fra e 1 allergen as opposed to cross-reacting allergens. Serial 10-fold dilutions of the IHRP were tested by skin prick tests in order to determine the concentration inducing a geometrical mean wheal diameter of 7 mm, said to correspond to an index of reactivity (IR) of 100 per millilitre. Results: IgE-reactive molecules in IHRP comprise Fra e 1, Fra e 2, a 9-kDa molecule (presumably Fra e 3), as well as a doublet at 15 kDa and high molecular weight allergens. The 100 IR concentration of IHRP inducing a geometrical mean wheal diameter of 7 mm in 22 patients sensitized to Fra e 1 corresponds to the 1/126 (w/v) extraction ratio (i.e. 259 µg/ml of protein by Bradford) and contains 17 µg/ml of Fra e 1. The variability in total activity of 5 batches of standardized extracts was found to be significantly reduced when compared with 7 non-standardized extracts. Conclusion: An ash pollen IHRP was defined and molecularly characterized. Its successful standardization at 100 IR/ml in patients specifically sensitized to Fra e 1 allowed a skin reactivity-based calibration in properly diagnosed patients. Such a standardized ash pollen extract is a reliable tool to support immunotherapy of ash pollen allergy.
High Vascular Endothelial Growth Factor Levels in NZW Mice Do Not Correlate with Collagen Deposition in Allergic Asthma
Authors: Vasquez-Pinto Luciana M.C. , Landgraf Richardt G. , Bozza Patrícia T. , Jancar Sonia
Published: September 2006

Background: Eosinophils contribute to the early features of allergic lung inflammation through the generation and release of a plethora of mediators. Eosinophil peroxidase (EPO) is one of the eosinophil granule proteins involved in the early response, but its participation in airway remodeling is not established. The present study addressed this question comparing an EPO-deficient mouse strain (NZW) with BALB/c and C57Bl/c strains. Methods: Mice were immunized with ovalbumin/alum, challenged twice with ovalbumin aerosol, and lung responses were measured at day 22 or 28. Collagen, mucus and eosinophils were determined in lung sections stained with picrosirius, periodic acid-Schiff or hematoxylin-eosin; transforming growth factor-β and vascular endothelial growth factor were determined by ELISA, lipid bodies by enumeration in osmium-stained eosinophils, and airway reactivity to methacholine in isolated lung preparations. Results: NZW mice showed significantly less collagen around bronchi and blood vessels, less mucus and less eosinophils around bronchi. Eosinophil lipid body formation and airway hyperreactivity were comparable among strains. Levels of transforming growth factor-β were also comparable; however, the NZW mice showed much higher levels of vascular endothelial growth factor, even under basal conditions. Conclusions: In allergic lung inflammation, the combination of EPO deficiency and overexpression of VEGF found in NZW mice is associated with less collagen deposition, less mucus and reduced tissue eosinophilia. Eosinophil activation and airway hyperreactivity in NZW mice were similar to the other strains.
Efficacy of S-1 for Patients with Peritoneal Metastasis of Gastric Cancer
Authors: Ishizone Satoshi , Maruta Fukuto , Saito Hiroyasu , Koide Naohiko , Sugiyama Atsushi , Nakayama Jun , Miyagawa Shinichi
Published: September 2006

Background: This study was designed to examine the efficacy and compliance of S-1 for the patients with peritoneal metastasis of gastric cancer. Methods: Sixteen consecutive patients with peritoneal metastasis of gastric cancer were treated with S-1. Their survival was compared with that of the historical control group (25 patients). Thymidylate synthase, dihydropyrimidine dehydrogenase, thymidine phosphorylase and orotate phosphoribosyl transferase mRNA expression in the tumor were evaluated. Results: The median survival time of S-1-treated patients was 550 days, which was significantly longer than that of the historical control group (215 days). We elucidated some factors to prolong the survival of the patients treated with S-1 for peritoneal metastasis: peritoneal metastasis without other distant metastases, the combination of S-1 treatment and gastrectomy, and low expression of thymidine phosphorylase mRNA in primary tumors. Conclusions: S-1 showed a surprisingly long-term survival with minimum toxicity in patients with peritoneal metastasis of gastric cancer.
Smooth Muscle Cells in Atherosclerosis Originate From the Local Vessel Wall and Not Circulating Progenitor Cells in ApoE Knockout Mice
Authors: Bentzon Jacob F. , Weile Charlotte , Sondergaard Claus S. , Hindkjaer Johnny , Kassem Moustapha , Falk Erling
Published: September 2006

Objective—

Recent studies of bone marrow (BM)-transplanted apoE knockout (apoE
−/−
) mice have concluded that a substantial fraction of smooth muscle cells (SMCs) in atherosclerosis arise from circulating progenitor cells of hematopoietic origin. This pathway, however, remains controversial. In the present study, we reexamined the origin of plaque SMCs in apoE
−/−
mice by a series of BM transplantations and in a novel model of atherosclerosis induced in surgically transferred arterial segments.

Methods and Results—

We analyzed plaques in lethally irradiated apoE
−/−
mice reconstituted with sex-mismatched BM cells from eGFP
+
apoE
−/−
mice, which ubiquitously express enhanced green fluorescent protein (eGFP), but did not find a single SMC of donor BM origin among ≈10 000 SMC profiles analyzed. We then transplanted arterial segments between eGFP
+
apoE
−/−
and apoE
−/−
mice (isotransplantation except for the eGFP transgene) and induced atherosclerosis focally within the graft by a recently invented collar technique. No eGFP
+
SMCs were found in plaques that developed in apoE
−/−
artery segments grafted into eGFP
+
apoE
−/−
mice. Concordantly, 96% of SMCs were eGFP
+
in plaques induced in eGFP
+
apoE
−/−
artery segments grafted into apoE
−/−
mice.

Conclusions—

These experiments show that SMCs in atherosclerotic plaques are exclusively derived from the local vessel wall in apoE
−/−
mice.
Cholesterol 7α-Hydroxylase Deficiency in Mice on an APOE*3-Leiden Background Increases Hepatic ABCA1 mRNA Expression and HDL-Cholesterol
Authors: Post Sabine M. , Groenendijk Martine , van der Hoogt Caroline C. , Fievet Catherine , Luc Gérald , Hoekstra Menno , Princen Hans M.G. , Staels Bart , Rensen Patrick C.N.
Published: September 2006

Objective—

High-density lipoprotein (HDL) plays a key role in protection against development of atherosclerosis by reducing inflammation, protecting against LDL oxidation, and promoting reverse cholesterol transport from peripheral tissues to the liver for secretion into bile. Cholesterol 7α-hydroxylase (
Cyp7a1
) catalyzes the rate-limiting step in the intrahepatic conversion of cholesterol to bile acids that may have a role in HDL metabolism. We investigated the effect of Cyp7a1 deficiency on HDL metabolism in APOE*3-Leiden transgenic mice.

Methods and Results—

Reduced bile acid biosynthesis in
Cyp7a1−/−
.APOE*3-Leiden mice versus APOE*3-Leiden mice did not affect total plasma cholesterol levels, but the distribution of cholesterol over various lipoproteins was different. Cholesterol was decreased in apoB-containing lipoproteins (ie, VLDL and IDL/LDL), whereas cholesterol was increased in HDL. The activity of PLTP and LCAT, which play a role in HDL catabolism, were not changed, and neither was HDL clearance. However, the hepatic cholesterol content was 2-fold increased, which was accompanied by a 2-fold elevated expression of hepatic ABCA1 and increased rate of cholesterol efflux from the liver to HDL.

Conclusions—

Strongly reduced bile acid synthesis in
Cyp7a1−/−
.APOE*3-Leiden mice leads to increased plasma HDL-cholesterol levels, as related to an increased hepatic expression of ABCA1.
Transient Receptor Potential Vanilloid 4–Mediated Disruption of the Alveolar Septal Barrier
Authors: Alvarez Diego F. , King Judy A. , Weber David , Addison Emile , Liedtke Wolfgang , Townsley Mary I.
Published: September 2006

Disruption of the alveolar septal barrier leads to acute lung injury, patchy alveolar flooding, and hypoxemia. Although calcium entry into endothelial cells is critical for loss of barrier integrity, the cation channels involved in this process have not been identified. We hypothesized that activation of the vanilloid transient receptor potential channel TRPV4 disrupts the alveolar septal barrier. Expression of TRPV4 was confirmed via immunohistochemistry in the alveolar septal wall in human, rat, and mouse lung. In isolated rat lung, the TRPV4 activators 4α-phorbol-12,13-didecanoate and 5,6- or 14,15-epoxyeicosatrienoic acid, as well as thapsigargin, a known activator of calcium entry via store-operated channels, all increased lung endothelial permeability as assessed by measurement of the filtration coefficient, in a dose- and calcium-entry dependent manner. The TRPV antagonist ruthenium red blocked the permeability response to the TRPV4 agonists, but not to thapsigargin. Light and electron microscopy of rat and mouse lung revealed that TRPV4 agonists preferentially produced blebs or breaks in the endothelial and epithelial layers of the alveolar septal wall, whereas thapsigargin disrupted interendothelial junctions in extraalveolar vessels. The permeability response to 4α-phorbol-12,13-didecanoate was absent in TRPV4
−/−
mice, whereas the response to thapsigargin remained unchanged. Collectively, these findings implicate TRPV4 in disruption of the alveolar septal barrier and suggest its participation in the pathogenesis of acute lung injury.
Homocysteine and Carotid Intima-Media Thickness in a German Population
Authors: Linnebank Michael , Moskau Susanna , Farmand Susan , Fliessbach Klaus , Kölsch Heike , Bös Monika , Grothe Christoph , Becker Dietmar , Harbrecht Ursula , Pohl Christoph , Wüllner Ullrich , Klockgether Thomas
Published: September 2006

Background and Purpose—

Common carotid artery intima-media thickness (CCA IMT) is a predictor of stroke. This study aimed to analyze whether homocysteine (Hcys) metabolism influences CCA IMT.

Methods—

We analyzed the association of personal, clinical, and biochemical data (multivariate analysis) and of 9 polymorphisms involved in Hcys metabolism (ANOVA) with CCA IMT in 714 individuals of 187 families.

Results—

CCA IMT was significantly predicted by age, sex, creatinine levels, lipoprotein(a) levels, pack-years of smoking, the presence of hypertension, and the presence of diabetes mellitus but not by Hcys levels. Homozygosity for the
T
allele of the polymorphism methylenetetrahydrofolate reductase c.677C>T was significantly associated with higher Hcys levels but not with a higher CCA IMT.

Conclusions—

These data do not support the thesis that elevated Hcys levels are causally involved in cerebrovascular disease.
Transcranial Doppler Monitoring of Transcervical Carotid Stenting With Flow Reversal Protection
Authors: Ribo Marc , Molina Carlos A. , Alvarez Beatriz , Rubiera Marta , Alvarez-Sabin Jose , Matas Manel
Published: September 2006

Background and Purpose—Transfemoral carotid stenting, despite becoming very frequent, has some limitations such as difficult groin access in few patients, lack of distal protection during filter placement, or embolization despite protection. Transcervical stenting (TCS) is a novel technique during which a common carotid to jugular vein shunt is placed creating a protective reversal flow in the internal carotid artery after proximal common carotid artery (CCA) clamping. We aim to study, with transcranial Doppler (TCD), cerebral flow changes and microemboli detection during transcervical stenting.

Methods—From September 2005 to March 2006, of 65 consecutive patients eligible for carotid revascularization, 23 were considered high risk (sapphire criteria) and underwent TCS. Neurologic examination was performed before and after the procedure by a neurologist and a preprocedure vascular reactivity TCD examination was done in all patients.

Results—After CCA clamping, flow inversion was observed in the anterior cerebral artery, supplying blood to the middle cerebral artery (MCA) and internal carotid artery (reversal). TCD did not detect any air/solid emboli during stent deployment and angioplasty confirming the reversal flow protection hypothesis. Mean reversal flow time was 15.4 minutes; in all cases, substantial MCA flow was present during CCA clamping (initial mean velocity 30 cm/s), and a slow gradual increase was observed traducing collateral flow recruitment (mean velocity after 5 minutes 36 cm/s,P<0.001). Flow increase was observed in all patients except in those with preprocedural exhausted ipsilateral vascular reactivity (16% versus 2%,P=0.036). The only in-procedure complication was one transient ischemic attack. After CCA unclamping, normal antegrade flow was restored in anterior cerebral artery and mean final MCA velocity increased 16% according to preprocedure flow.

Conclusions—TCS with protective internal carotid artery flow reversal can eliminate showers of micoremboli during stent deployment making it a promising carotid revascularization technique in high-risk patients with carotid stenosis.
The Impact of Poststroke Depression on Healthcare Use by Veterans With Acute Stroke
Authors: Jia Huanguang , Damush Teresa M. , Qin Haijing , Ried L. Douglas , Wang Xinping , Young Linda J. , Williams Linda S.
Published: September 2006

Background and Purpose—

Poststroke depression (PSD) is common among stroke survivors, and it is associated with worse functional outcomes and increased poststroke mortality. Limited information is available about its impact on healthcare use. This study assessed the impact of PSD on healthcare use by veterans with acute stroke.

Methods—

In this retrospective, observational national study, 5825 veterans with acute stroke were identified from Veterans Affairs’ (VA) inpatient databases. To determine the patients’ comprehensive PSD and use status, VA and Medicare fee-for-service inpatient and outpatient as well as VA pharmacy data were used. PSD was established if a patient had an inpatient or outpatient depression diagnosis or if a patient received one of the antidepressants within the VA 12 months postindex stroke. Healthcare use referred to the number of hospital stays, outpatient visits, and cumulative length of inpatient stays under both VA and Medicare fee-for-service programs. Poisson regression was fitted to estimate the impact of PSD on use controlling for sociodemographic, clinical, and disease severity factors.

Results—

Forty-one percent of the sample had PSD. After adjusting for patient demographic and clinical factors, we found that the patients with stroke with PSD had significantly (
P
<0.0001) more hospitalizations, outpatient visits, and longer length of stays 12 months poststroke compared with these patients with stroke without PSD.

Conclusions—

Patients with PSD had greater 12-month poststroke healthcare use even when controlling for other demographic and clinical variables. Early detection and appropriate management of PSD for veterans with acute stroke may help reduce their poststroke healthcare use.