bluuebunny/crossref_metadata_2025 huggingface dataset:
A minimal model of insulin secretion and kinetics to assess hepatic insulin extraction
Authors: Toffolo Gianna , Campioni Marco , Basu Rita , Rizza Robert A. , Cobelli Claudio
Published: September 2005

The liver is the principal site of insulin degradation, and assessing its ability to extract insulin is important to understand several pathological states. Noninvasive quantification of hepatic extraction (HE) in an individual requires comparing the profiles of insulin secretion (ISR) and posthepatic insulin delivery rate (IDR). To do this, we propose here the combined use of the classical C-peptide minimal model with a new minimal model of insulin delivery and kinetics. The models were identified on insulin-modified intravenous glucose tolerance test (IM-IVGTT) data of 20 healthy subjects. C-peptide kinetics were fixed to standard population values, whereas insulin kinetics were assessed in each individual, along with IDR parameters, thanks to the presence of insulin decay data observed after exogenous insulin administration. From the two models, profiles of ISR and IDR were predicted, and ISR and IDR indexes of β-cell responsivity to glucose in the basal state, as well as during first- and second-phase secretion, were estimated. HE profile, obtained by comparing ISR and IDR profiles, showed a rapid suppression immediately after the glucose administration. HE indexes, obtained by comparing ISR and IDR indexes, indicated that the liver is able to extract 70 ± 9% of insulin passing through it in the basal state and 54 ± 14% during IM-IVGTT. In conclusion, insulin secretion, kinetics, and hepatic extraction can be reliably assessed during an IM-IVGTT by using insulin and C-peptide minimal models.
Plasminogen activator inhibitor-1 modulates adipocyte differentiation
Authors: Liang Xiubin , Kanjanabuch Talerngsak , Mao Su-Li , Hao Chuan-Ming , Tang Yi-Wei , Declerck Paul J. , Hasty Alyssa H. , Wasserman David H. , Fogo Agnes B. , Ma Li-Jun
Published: September 2005

Increased plasminogen activator inhibitor-1 (PAI-1) is linked to obesity and insulin resistance. However, the functional role of PAI-1 in adipocytes is unknown. This study was designed to investigate effects and underlying mechanisms of PAI-1 on glucose uptake in adipocytes and on adipocyte differentiation. Using primary cultured adipocytes from PAI-1+/+and PAI-1−/−mice, we found that PAI-1 deficiency promoted adipocyte differentiation, enhanced basal and insulin-stimulated glucose uptake, and protected against tumor necrosis factor-α-induced adipocyte dedifferentiation and insulin resistance. These beneficial effects were associated with upregulated glucose transporter 4 at basal and insulin-stimulated states and upregulated peroxisome proliferator-activated receptor-γ (PPARγ) and adiponectin along with downregulated resistin mRNA in differentiated PAI-1−/−vs. PAI-1+/+adipocytes. Similarly, inhibition of PAI-1 with a neutralizing anti-PAI-1 antibody in differentiated 3T3-L1 adipocytes further promoted adipocyte differentiation and glucose uptake, which was associated with increased expression of transcription factors PPARγ, CCAAT enhancer-binding protein-α (C/EBPα), and the adipocyte-selective fatty acid-binding protein aP2, thus mimicking the phenotype in PAI-1−/−primary adipocytes. Conversely, overexpression of PAI-1 by adenovirus-mediated gene transfer in 3T3-L1 adipocytes inhibited differentiation and reduced PPARγ, C/EBPα, and aP2 expression. This was also associated with a decrease in urokinase-type plasminogen activator mRNA expression, decreased plasmin activity, and increased collagen I mRNA expression. Collectively, these results indicate that absence or inhibition of PAI-1 in adipocytes protects against insulin resistance by promoting glucose uptake and adipocyte differentiation via increased PPARγ expression. We postulate that these PAI-1 effects on adipocytes may, at least in part, be mediated via modulation of plasmin activity and extracellular matrix components.
Oxidant stress stimulates Ca2+-activated chloride channels in the apical activated membrane of cultured nonciliated human nasal epithelial cells
Authors: Jeulin Claudette , Guadagnini Rina , Marano Francelyne
Published: September 2005

Respiratory tissues can be damaged by the exposure of airway epithelial cells to reactive oxygen species that generate oxidative stress. We studied the effects of the hydroxyl radical ·OH, for which there is no natural intra- or extracellular scavenger, on a Ca2+-activated chloride channel (CACC) that participates in Cl− secretion in the apical membrane of airway epithelial cells. We identified and characterized CACC in cell-attached and in inside-out excised membrane patches from the apical membrane of cultured nonciliated human nasal epithelial cells. In these cells, the CACC was outwardly rectified, Ca2+/calmodulin-kinase II, and voltage dependent. The channel was activated in cell-attached and inside-out patches in a bath solution containing millimolar [Ca2+] and ran down quickly. The channel was reversibly or irreversibly activated by exposure of the internal surface of the membrane to ·OH, which depended on the concentration and the duration of exposure to H2O2. CACC activity evoked by oxidative stress was inhibited by 1,3-dimethyl-2-thiurea, an antioxidant that scavenges hydroxyl radicals, and by the reduced form of glutathione. The oxidized SH residues could be close to the Ca2+/calmodulin kinase site. The reversible or irreversible activation of CACC after a period of oxidative stress without change in [Ca2+] is a new observation. CACC play a direct role in mucus production by goblet cells and may thus contribute to the pathogenesis of asthma.
Intercalated cell H+/OH−transporter expression is reduced inSlc26a4null mice
Authors: Kim Young-Hee , Verlander Jill W. , Matthews Sharon W. , Kurtz Ira , Shin Wonkyong , Weiner I. David , Everett Lorraine A. , Green Eric D. , Nielsen Søren , Wall Susan M.
Published: September 2005

Slc26a4 ( Pds) encodes pendrin, a Cl−/HCO3−exchanger expressed in the apical region of type B and non-A, non-B cells, which mediates secretion of OH−equivalents. Thus genetic disruption of Slc26a4 leads to systemic alkalosis in some treatment models. However, humans and mice with genetic disruption of Slc26a4 have normal acid-base balance under basal conditions. Thus we asked: 1) Is net acid excretion altered in Slc26a4 (−/−) mice under basal conditions? 2) In the absence of pendrin-mediated OH−secretion, are increases in intracellular and systemic pH minimized through changes in intercalated cell subtype abundance or intercalated cell H+/OH−transporter expression? To answer these questions, net acid excretion and H+/OH−transporter expression were examined in Slc26a4 (−/−) and Slc26a4 (+/+) mice using balance studies, immunolocalization, and immunoblotting. Excretion of ammonium, titratable acid, and citrate were the same in Slc26a4 null and wild-type mice. However, urinary pH and Pco2were much lower in Slc26a4 null relative to wild-type mice due to reduced urinary buffering of secreted H+by HCO3−. Abundance of non-A, but not type A intercalated cells, was reduced within the cortical collecting ducts of Slc26a4 null mice. Moreover, kidneys from Slc26a4 null mice had reduced H+-ATPase, NBC3 and RhBG total protein expression, particularly within type B and non-A, non-B intercalated cells, although RhCG protein expression was unchanged. Reduced intercalated cell H+/OH−transporter expression is observed in Slc26a4 null mice, which likely attenuates the rise in intracellular and systemic pH expected with genetic disruption of Slc26a4.
cAMP increases surface expression of NKCC2 in rat thick ascending limbs: role of VAMP
Authors: Ortiz Pablo A.
Published: September 2005

NaCl absorption by the thick ascending limb of Henle’s loop (TAL) is mediated by the apical Na-K-2Cl cotransporter NKCC2. cAMP increases NaCl absorption in the TAL by stimulating NKCC2. In oocytes, cAMP increases NKCC2 activity by regulating its trafficking. However, the mechanism by which cAMP stimulates NKCC2 in TALs is not clear. We hypothesized that cAMP increases surface expression of NKCC2 and NaCl absorption in TALs and that vesicle-associated membrane protein (VAMP) is involved in this mechanism. We used surface biotinylation of rat medullary TALs (mTAL) to examine surface and total NKCC2 levels. When mTAL suspensions were treated with dibutyryl cAMP (db-cAMP) or forskolin plus IBMX for 20 min, surface NKCC2 expression increased by 126 ± 23 and 92 ± 17% above basal, respectively ( P < 0.03). No changes in total NKCC2 expression were observed, suggesting that cAMP increased translocation of NKCC2. We studied the role of VAMP in NKCC2 translocation and found that incubating mTALs with tetanus toxin (30 nM), which inhibits vesicle trafficking by inactivating VAMP-2 and -3, completely blocked the stimulatory effect of db-cAMP on surface NKCC2 expression (tetanus toxin = 100% vs. tetanus toxin + db-cAMP = 102 ± 21% of control; not significant). We studied VAMP-2 and -3 expression and localization in isolated perfused TALs by confocal microscopy and found that both of them were located in the subapical space of the TAL. Finally, in isolated perfused mTALs, db-cAMP increased net Cl absorption by 95.0 ± 34.8% ( P < 0.03), and pretreatment of TALs with tetanus toxin blocked the stimulation of Cl absorption (from 110.9 ± 15.9 to 109.7 ± 15.6 pmol·min−1·mm−1; not significant). We concluded that cAMP increases NKCC2 surface expression by a mechanism involving VAMP and that NKCC2 trafficking to the apical membrane is involved in the stimulation of TAL NaCl absorption by cAMP.
Hyperpolarization-Activated Cation Current (Ih) Is an Ethanol Target in Midbrain Dopamine Neurons of Mice
Authors: Okamoto Takashi , Harnett Mark T. , Morikawa Hitoshi
Published: September 2005

Ethanol stimulates the firing activity of midbrain dopamine (DA) neurons, leading to enhanced dopaminergic transmission in the mesolimbic system. This effect is thought to underlie the behavioral reinforcement of alcohol intake. Ethanol has been shown to directly enhance the intrinsic pacemaker activity of DA neurons, yet the cellular mechanism mediating this excitation remains poorly understood. The hyperpolarization-activated cation current, Ih, is known to contribute to the pacemaker firing of DA neurons. To determine the role of Ih in ethanol excitation of DA neurons, we performed patch-clamp recordings in acutely prepared mouse midbrain slices. Superfusion of ethanol increased the spontaneous firing frequency of DA neurons in a reversible fashion. Treatment with ZD7288, a blocker of Ih, irreversibly depressed basal firing frequency and significantly attenuated the stimulatory effect of ethanol on firing. Furthermore, ethanol reversibly augmented Ih amplitude and accelerated its activation kinetics. This effect of ethanol was accompanied by a shift in the voltage dependence of Ih activation to more depolarized potentials and an increase in the maximum Ih conductance. Cyclic AMP mediated the depolarizing shift in Ih activation but not the increase in the maximum conductance. Finally, repeated ethanol treatment in vivo induced downregulation of Ih density in DA neurons and an accompanying reduction in the magnitude of ethanol stimulation of firing. These results suggest an important role of Ih in the reinforcing actions of ethanol and in the neuroadaptations underlying escalation of alcohol consumption associated with alcoholism.
Comparative genomic sequence analysis coupled to chromatin immunoprecipitation: a screening procedure applied to search for regulatory elements at theRETlocus
Authors: Puppo Francesca , Musso Marco , Pirulli Doroti , Griseri Paola , Bachetti Tiziana , Crovella Sergio , Patrone Giovanna , Ceccherini Isabella , Ravazzolo Roberto
Published: September 2005

RET gene expression is characterized by high tissue and stage specificity during the development of neural crest derivatives and in the pathogenesis of inherited cancer syndromes and Hirschsprung disease. Identifying all elements contributing to its transcriptional regulation might provide new clues to clarify both developmental and pathogenic mechanisms. We previously demonstrated that chromatin acetylation affects RET transcription; therefore, we have set up a strategy based on analysis of sequences conserved among species at the RET locus, combined with the characterization of their chromatin structure, to identify new potential regulatory elements. The histone acetylation level was evaluated by the chromatin immunoprecipitation method applied to cells displaying different degrees of endogenous RET expression. Real-time quantitative PCR of immunoprecipitated DNA-protein complexes and transfection experiments, with constructs expressing a reporter gene in which the putative regulatory regions are inserted, indicate a correlation between histone acetylation and endogenous RET expression and highlight conserved sequences with potential regulatory roles. This paper presents a reliable screening procedure to unearth elements able to affect gene regulation at the transcriptional level in a large genomic region.
Values in Psychiatric Diagnosis: Developments in Policy, Training and Research
Authors: Fulford K.W.M.
Published: September 2005

Diagnosis, although traditionally thought to be a value-free scientific process, incorporates values, for example in judgements of impaired functioning and clinical significance. Such judgements are particularly problematic in psychiatry because the values concerned are often diverse and hence potentially conflicting. Values-based practice is the theory and clinical skills-base for effective healthcare decision-making where, as in relation to psychiatric diagnosis, diverse and conflicting values are in play. The paper describes recent developments in values-based practice in the UK and with international partners, in policy (a national framework for values-based practice in mental health service provision), training (a training manual launched recently by the Minister responsible for mental health in the UK) and research (including an international research methods meeting on psychiatric diagnosis funded by the National Institute for Mental Health in England).
Positive Health: Conceptual Place, Dimensions and Implications
Authors: Mezzich Juan E.
Published: September 2005

Positive health combines with pathology or illness to yield a broader concept of health, etymologically anchored on the concept of wholeness and enshrined in WHO’s constitution. The most recognized aspects of positive health include functioning/resilience, resources/supports and quality of life. Systematic assessments of positive health are being incorporated into comprehensive diagnostic models that by attending to the totality of the person who consults may enhance effectiveness and ethics in diagnosis and care. Health, a precious human concern, constitutes a wide-ranging condition and experience. However, pathology, one of its important domains, has tended to monopolize attention when professionals discuss health and carry out health care. This short paper examines the concept of positive health, as opposed to ill-health, as well as some of its aspects or dimensions and its implications for comprehensive diagnosis and care.
Positioning and the Discursive Construction of Categories
Authors: Harré Rom
Published: September 2005

Psychological phenomena are semiotic, so the best model for understanding them must be ‘conversation’. Psychiatric conversations are dominated by complaints. In dealing with them the structure of the consequential conversation must be subjected to ‘positioning analysis’ to reveal the dynamics of rights and duties among the speakers.
Diagnosis and Reality: A Noun Is a Terrible Thing to Waste
Authors: Strauss John S.
Published: September 2005

The use of a diagnosis for identifying disease processes has been crucial in the field of medicine. But it is essential that the diagnostic noun represent real processes. In psychiatry, to meet the important criterion of reliability we have focused on objective phenomena. But since psychiatric disorders are human processes and a major aspect of being human is our subjectivity, we also need to pay far more attention to subjective phenomena, even those difficult to define reliably. The arts have much to teach us about the nature of those processes. It is essential that we learn from these and other sources to focus more effectively on subjectivity, and thereby understand the factors that underlie and define psychiatric disorders.
Social Context and Stakeholders’ Values in Building Diagnostic Systems
Authors: Sadler John Z.
Published: September 2005

Beginning with an acknowledgment of the scientific aspects of developing classifications for psychopathology, this essay describes how diagnostic classifications (DCs) also function as public policy. Using the methods of philosophical analysis and a brief review of pertinent literature, the paper describes the regulatory and prescriptive functions of official DCs like the DSM and ICD manuals, functions that de facto serve as public policies. This background then provides for a comparison of the values involved in good science alongside the values involved in good public policy. Important areas of overlap are described, and these point to areas, relevant to stakeholders’ interest, worth considering in developing future DCs.
A Dimensional Model of Psychopathology
Authors: Widiger Thomas A.
Published: September 2005

The question of whether mental disorders are discrete clinical conditions or arbitrary distinctions along dimensions of functioning is a longstanding issue, but the importance of this question is escalating with the growing recognition of the frustrations and limitations engendered by the categorical model. Researchers are now focusing their attention on developing alternative dimensional models of classification. Concerns have been raised with regard to these dimensional models. Addressed in this brief commentary are two of these concerns: clinical utility and credibility.
Psychiatric Conditions and the Social Sciences
Authors: Fabrega Horacio
Published: September 2005

Psychiatric disorders have a distinct shape, come in types and are inherent in Homo sapiens. To a social scientist, disorders exist by stipulation: contingent on a psychiatric frame of reference. Their materiality has meaning only in that framework. What is important is what that material might correspond to in a society’s systems of representation and associated institutions. If one assigns disorders some sort of ‘objective’ reality (a scientific ontology), then one needs to explain what that corresponds to in cultural terms. Moreover, if disorders exist and have an evolutionary history, one has to formulate how they might have been perceived and understood during phases of biological and cultural evolution. The article provides a way to conceptualize meanings psychiatric disorders have had in these two systems of representation and their change during evolution.
Maintenance of Hemostasis in Transoral Robotic Surgery
Authors: Hockstein Neil G. , Weinstein Gregory S. , O’Malley Jr. Bert W.
Published: September 2005

Background: The last decade has seen a tremendous growth in the field of robotic surgery with an increasing number of cardiac and urologic procedures performed each year. Several attributes of this technology may offer advantages to laryngeal and pharyngeal surgery in that it allows for exceptional visualization of the operative field, precise handling of soft tissues, and multiplanar transection of tissues. One potential limitation is the management of bleeding in transoral pharyngeal and laryngeal surgery, which is critical to prevent both intravascular volume loss and aspiration. Objectives: To demonstrate methods for management of bleeding in the surgical field during transoral robotic surgery (TORS). Methods: We developed a canine robotic surgery model for the evaluation of the ability to control bleeding in laryngeal and pharyngeal procedures using the daVinci® surgical robot (Intuitive Surgical, Inc., Sunnyvale, Calif., USA). Both large- and small-vessel hemostasis was obtained with both robotically controlled monopolar and bipolar cautery and with robotically controlled small hemoclips. Additionally, manually controlled large hemoclips were applied by an assistant surgeon viewing on a video monitor for management of large arterial vessels. Suction was performed with both flexible suction catheters controlled by the robotic arms and with manually controlled conventional suction catheters. Data were collected with still and video photography. Results: The lingual artery as well as small arteries and veins were easily controlled and there were no difficulties with maintenance of hemostasis. Conclusions: Effective hemostasis with control of both large and small vessels can be obtained using both surgical hemoclips and electrocautery during TORS in a canine model.
Evaluation of the Antioxidant Capacity and Preventive Effects of a Topical Emulsion and Its Vehicle Control on the Skin Response to UV Exposure
Authors: Zhai H. , Behnam S. , Villarama C.D. , Arens-Corell M. , Choi M.J. , Maibach H.I.
Published: September 2005

Supplying topical exogenous antioxidants to the skin may prevent or minimize free radical-induced damaging. This study determines antioxidative capacity of a topical skin care emulsion (an oil-in-water vitamin E-containing formulation) versus its vehicle on human skin that was exposed to ultraviolet radiation (UVR) by utilizing a photochemiluminescence device and biophysical methods. Ten healthy Caucasians (3 male and 7 female; mean age 47 ± 10 years) were enrolled. In a randomized and double-blind manner, a pH-balanced vitamin E emulsion or its vehicle control was applied onto predesignated forearm prior to UVR exposure. Thirty minutes after application, these test sites were exposed to a UV light to induce the minimal erythema dose. One untreated site served as a blank control. Visual scoring and instrumental measurements were recorded at baseline and at 24 h and 48 h thereafter. At day 3, after completing instrumental measurements, each test site was stripped three times in a consecutive manner with a proprietary adhesive tape disc. These tapes were quantified for antioxidant capacity using a photochemiluminescence device.Vitamin E emulsion and vehicle control significantly (p < 0.05) suppressed visual scores when compared with blank control at day 2 and day 3 after UV exposure. However, vitamin E emulsion showed significantly (p < 0.05) lower visual scores when compared with vehicle control at day 2 and day 3 after UV exposure.Also,vitamin E emulsion and its vehicle control significantly (p < 0.05) diminished skin color measurement (a*) values when compared with blank control at day 2 and day 3 after UV exposure. At day 2 after UV exposure, only vitamin E emulsion significantly (p < 0.05) reduced skin blood flow volume when compared with blank control. Vitamin E emulsion and its vehicle control showed significant (p < 0.05) reduction of blood flow volume when compared with blank control at day 3 after UV exposure. Vitamin E emulsion and its vehicle control proved effective in preventing induction of erythema and reducing inflammatory damage caused by UV exposure. The effect of vitamin E emulsion exceeded that of an ‘active control’.
The Hallym Stroke Registry: A Web-Based Stroke Data Bank with an Analysis of 1,654 Consecutive Patients with Acute Stroke
Authors: Lee Byung-Chul , Hwang Sung-Hee , Jung San , Yu Kyung-Ho , Lee Ju-Hun , Cho Su-Jin , Lee Sang-Mu , Song Hong-Ki
Published: September 2005

Objectives:In Korea, stroke ranks as one of the leading causes of death along with cancer and ischemic heart disease. The purpose of this study was to better understand clinical characteristics, risk factors and subtypes of acute stroke among Korean people. Method: 1,654 acute stroke patients within 7 days of onset were consecutively enrolled in the Hallym Stroke Registry (HSR). The study was a prospective hospital-based registry aided with a web-based, computerized data bank system. The project began in January 1996 and the data obtained until September 2002 were analyzed. The analysis was basically carried out regarding demographic features, risk factors, time elapsed before coming to the hospitals after the symptom onset, duration of hospitalization, and 30-day mortality rate. Results: 1,567 patients had ischemic stroke and 87 patients had hemorrhagic stroke. The mean age of the patients was 63.6 ± 11.8 years, and 815 patients (56.8%) were men. The estimated time interval between stroke onset and hospital visit was 1.3 days on average and the mean duration of hospital stay was 12.1 days. Only a small fraction (12%) of patients reached the hospital within 3 h after the symptom onset. As for the risk factors, hypertension topped for both ischemic and hemorrhagic strokes followed by smoking and prior history of stroke, diabetes, hyperlipidemia and cardioembolism. With respect to subtype classification of ischemic stroke, large-artery atherosclerosis was most frequent (42.0%), followed by small-vessel occlusion (31.0%), cardioembolism (8.7%), other determined etiology (1.9%), and undetermined etiology (16.4%). The 30-day mortality rate was 7.2%. Conclusion: In the HSR, demographic features were essentially comparable with other major registries. However, the data analysis varies from registry to registry. This may in part be due to a different study design, racial-ethnic differences and patient selection methods.
Expression of Heregulin in Human Coronary Atherosclerotic Lesions
Authors: Panutsopulos Dimitrios , Arvanitis Dimitrios L. , Tsatsanis Christos , Papalambros Efstathios , Sigala Fragiska , Spandidos Demetrios A.
Published: September 2005

Background: Endothelial cells, monocytes/macrophages, and vascular smooth muscle cells contribute to the establishment and progression of atherosclerotic lesions by expressing growth and inflammatory factors. The aim of the present study was to determine whether heregulin (HRG) is associated with human coronary artery disease. Methods: Twenty-six fresh human coronary artery segments were collected at autopsy. Expression of cysteine-rich 61 (CYR61) and VEGF in response to HRG was studied in the human endothelial cell line EA.hy926, and expression of CYR61 and HRG was evaluated in activated macrophages isolated from peripheral blood of healthy donors. Results: We found that HRG was overexpressed at the protein and mRNA level in all lesions analyzed and gradually increased as the stages of the lesions progressed. Expression of HRG was observed in the intima primarily in macrophages. The same specimens were analyzed for the expression of CYR61, an angiogenetic factor regulated by HRG in breast cancer epithelial cells. CYR61 was expressed in both normal and atheromatic specimens, but its expression was significantly enhanced in macrophages of the intima. Activation of primary human macrophages results in increased expression of both HRG and CYR61. In addition, studies in endothelial cells where no endogenous HRG is present showed that HRG induces expression of CYR61 and secretion of VEGF. Conclusions: HRG may, therefore, play an important role in the development of coronary artery disease and the expansion of the atherosclerotic plaque and may locally regulate the expression of the angiogenetic factor CYR61.
Balance between Plasma Levels of Tumor Necrosis Factor-α and Interleukin-10 in Rheumatic Mitral Stenosis
Authors: Chen Mien-Cheng , Chang Hsueh-Wen , Wu Chiung-Jen , Yang Cheng-Hsu , Yu Teng-Hung , Chen Chien-Jen , Hung Wei-Chin
Published: September 2005

The study population consisted of 16 patients with rheumatic mitral stenosis undergoing percutaneous transluminal mitral valvuloplasty (group 1). The plasma levels of tumor necrosis factor-α (TNF-α) and interleukin-10 (IL-10) in the femoral vein and the right and left atria before valvuloplasty were determined by ELISA. Additionally, we measured plasma concentrations of TNF-α and IL-10 in the venous blood obtained from 19 control patients, including 12 healthy volunteers in sinus rhythm (group 2) and 7 patients in permanent lone atrial fibrillation (group 3). The venous plasma levels of TNF-α were significantly elevated in group 1 patients compared with group 2 patients (p < 0.002). Correlation analysis demonstrated that there was a significantly direct relationship between the plasma TNF-α and IL-10 concentrations in the left atrial, right atrial and peripheral venous blood (p < 0.008, r = 0.640; p < 0.04, r = 0.538; p< 0.03, r = 0.571, respectively). In conclusion, the plasma concentrations of TNF-α of patients with rheumatic mitral stenosis were significantly higher than those of healthy volunteers. In addition, there was a significantly direct relationship between the soluble TNF-α and IL-10 concentrations in the atrial and peripheral venous blood, indicating a balance between circulating TNF-α and IL-10 levels in patients with rheumatic mitral stenosis.
Thalamic Stimulation for Disabling Tremor in a Patient with Spinocerebellar Degeneration
Authors: Shimojima Yasuhiro , Hashimoto Takao , Kaneko Kazuma , Yazaki Masahide , Yoshida Kunihiro , Goto Tetsuya , Yamada Ryuzo , Hongo Kazuhiro , Ikeda Shu-ichi
Published: September 2005

Thalamic stimulation alleviated coarse action tremor in a patient with spinocerebellar degeneration (SCD) and led to substantial improvement in daily functioning, though disability from ataxia remained. Intraoperative microrecording revealed a significant correlation between neuronal activity of the ventral intermediate nucleus (Vim) and tremor electromyograms. The tremor-correlated activities of Vim neurons and abolition of the tremor by Vim stimulation suggest that Vim may be related to the generation of action tremor in SCD. Thalamic stimulation can be a useful treatment option for SCD patients with disabling tremor.
Intraoperative Cortical Mapping Has Low Sensitivity for the Detection of Motor Function in Proximity to a Tumor in the Primary Motor Area
Authors: Shinoura N. , Yamada R. , Kodama T. , Suzuki Y. , Takahashi M. , Yagi K.
Published: September 2005

Six patients with brain tumors within or near the primary motor cortex underwent preoperative functional magnetic resonance imaging (fMRI) and intraoperative cortical mapping, and the accuracy of those techniques for localization of the primary motor cortex and motor function beside the tumor were determined by comparison against neuroanatomical correlates from pre-, intra- and postoperative neurological observations. The location of the primary motor cortex was detected by intraoperative cortical mapping in 5 of 6 cases and by fMRI in all 6 cases. Brain mapping provided equivocal information on the cortical representation of motor territories, and with the technique used in close proximity to the tumor, the motor territories were not detected in all but 1 case. In contrast, the areas controlling motor function in close proximity to the tumor were detected by fMRI in 4 of 6 cases.These data indicate that intraoperative cortical mapping has a low sensitivity for the detection of motor function in the area beside the tumor. Therefore, this technique may not be sufficient to prevent compromise of motor areas during tumor resection.
Tissue-Engineered Vessel Strengthens Quickly under Physiological Deformation: Application of a New Perfusion Bioreactor with Machine Vision
Authors: Xu Jie , Ge Haiyan , Zhou Xiaolin , Yang Daping , Guo Tiefang , He Jian , Li Qing , Hao Zhenhong
Published: September 2005

In order to develop a patent tissue-engineered blood vessel that grossly resembles native tissue, required culture times in most studies exceed 8 weeks. For the sake of shortening the maturation period of the constructs, we have used deformation as the basic index for mechanical environment control. A new bioreactor with a machine vision identifier was developed to accurately control the deformation of the construct during the perfusion process. Two groups of seeded constructs (n = 4 per group) were investigated in this study, with one group stimulated by a cyclic deformation of 10% and the other by a pulsatile pressure that gradually increased to 120 mm Hg (the control group). After 21 days of culture, the mechanical properties of the constructs were examined. The average burst strength and suture retention strength in the two groups were significantly different (t test, p < 0.05). For the experimental group, the average burst strength and suture retention strength were higher than those of the control group, by 31.6 and 23.4%, respectively. Specifically, the average burst strength of the constructs reached 1,402 mm Hg (close to that of the native vessel, i.e. 1,680 mm Hg) within a relatively short period of 21 days. In conclusion, deformation is an observable, controllable and very valuable index for mechanical environment control in vascular tissue engineering. It makes the control of mechanical stimuli more essential and experiments more comparable.
Identification of Sex Hormone-Binding Globulin in the Human Hypothalamus
Authors: Herbert Zsófia , Göthe Susanne , Caldwell Jack D. , Bernstein Hans-Gert , Melle Christian , von Eggeling Ferdinand , Lewis John , Jirikowski Gustav F.
Published: September 2005

Gonadal steroids are known to influence hypothalamic functions through both genomic and non-genomic pathways. Sex hormone-binding globulin (SHBG) may act by a non-genomic mechanism independent of classical steroid receptors. Here we describe the immunocytochemical mapping of SHBG-containing neurons and nerve fibers in the human hypothalamus and infundibulum. Mass spectrometry and Western blot analysis were also used to characterize the biochemical characteristics of SHBG in the hypothalamus and cerebrospinal fluid (CSF) of humans. SHBG-immunoreactive neurons were observed in the supraoptic nucleus, the suprachiasmatic nucleus, the bed nucleus of the stria terminalis, paraventricular nucleus, arcuate nucleus, the perifornical region and the medial preoptic area in human brains. There were SHBG-immunoreactive axons in the median eminence and the infundibulum. A partial colocalization with oxytocin could be observed in the posterior pituitary lobe in consecutive semithin sections. We also found strong immunoreactivity for SHBG in epithelial cells of the choroid plexus and in a portion of the ependymal cells lining the third ventricle. Mass spectrometry showed that affinity-purified SHBG from the hypothalamus and choroid plexus is structurally similar to the SHBG identified in the CSF. The multiple localizations of SHBG suggest neurohypophyseal and neuroendocrine functions. The biochemical data suggest that CSF SHBG is of brain rather than blood origin.
VR1-Mediated Depressor Effects During High-Salt Intake
Authors: Wang Youping , Kaminski Norbert E. , Wang Donna H.
Published: September 2005

This study was designed to test the hypothesis that increased sensitivity of blood pressure to anandamide (AEA), an endocannabinoid compound, occurs during high-salt intake, which can be blocked by a selective vanilloid receptor 1(VR1) antagonist, capsazepine (CAPZ). Intravenous administration of a metabolically stable analog, methanandamide (MethA), dose-dependently decreased mean arterial pressure (MAP) in conscious rats fed a high-sodium diet (HS) for 3 weeks but it had a minimal effect in normal sodium (NS)-treated rats. The MethA-induced decrease in MAP was significantly attenuated but not abolished by CAPZ, or a selective cannabinoid receptor 1 (CB1) antagonist, SR141716A, administered separately in HS-treated rats. The MethA-induced depressor effect was prevented by the combined administration of CAPZ and SR141716A in HS-treated rats. Likewise, administration of capsaicin, a selective VR1 receptor agonist, dose-dependently decreased MAP in both HS- and NS-treated rats. The depressor effect of capsaicin was more profound in HS-treated rats, which was prevented by CAPZ. Western blot showed that expression of VR1 but not CB1 in mesenteric arteries was increased in HS-treated compared with NS-treated rats. Therefore, these data show that: (1) HS upregulates mesenteric VR1 expression; (2) HS increases sensitivity of blood pressure to AEA; and (3) HS-induced enhancement of the depressor effect of AEA can be prevented only when both VR1 and CB1 receptors are blocked. These results indicate that AEA contributes to the prevention of salt induced increases in blood pressure via, at least in part, activating the VR1 receptor.
Decrease in Urinary Albumin Excretion Associated With the Normalization of Nocturnal Blood Pressure in Hypertensive Subjects
Authors: Hermida Ramón C. , Calvo Carlos , Ayala Diana E. , López José E.
Published: September 2005

Previous results have indicated that valsartan administration at bedtime as opposed to on wakening improves the diurnal/nocturnal ratio of blood pressure without loss in efficacy and therapeutic coverage. We hypothesized that increasing this ratio could reduce microalbuminuria. We conducted a prospective, randomized, open-label, blinded endpoint trial on 200 previously untreated nonproteinuric patients with grade 1 to 2 essential hypertension, assigned to receive valsartan (160 mg/d) as a monotherapy either on awakening or at bedtime. Blood pressure was measured by ambulatory monitoring for 48 consecutive hours before and after 3 months of treatment. Physical activity was simultaneously monitored every minute by wrist actigraphy to accurately calculate the diurnal and nocturnal means of blood pressure on a per-subject basis. The significant blood pressure reduction after 3 months of therapy was similar for both treatment times. The diurnal/nocturnal blood pressure ratio was unchanged after valsartan on awakening, but significantly increased from 7.5 to 12.2 (
P
<0.001) when valsartan was administered at bedtime. Urinary albumin excretion was significantly reduced by 41% after bedtime treatment. This reduction was independent of the 24-hour blood pressure decrease but highly correlated with the decrease in nocturnal blood pressure and mainly with the increase in diurnal/nocturnal ratio (
P
<0.001). Bedtime valsartan administration improves the diurnal/nocturnal blood pressure ratio to a more dipper profile. This normalization of the circadian blood pressure pattern is associated with a significant decrease in urinary albumin excretion and plasma fibrinogen, and could thus reduce the increased cardiovascular risk in nondipper hypertensive patients.
Hypertension Produced by Reductions in Uterine Perfusion in the Pregnant Rat
Authors: LaMarca B. Babbette D. , Bennett William A. , Alexander Barbara T. , Cockrell Kathy , Granger Joey P.
Published: September 2005

Inflammatory cytokines such as tumor necrosis factor (TNF)-α are elevated in preeclamptic women and are thought to be an important link between placental ischemia and endothelial dysfunction. The purpose of this study was to determine the role of TNF in mediating hypertension in response to chronic reductions in uterine perfusion (RUPPs) in pregnant rats. Arterial pressure was significantly higher in RUPP rats (138±1 mm Hg) than in pregnant rats (107±1 mm Hg). Serum TNF-α levels in the RUPP rats were 17±4 pg/mL compared with 8±1 pg/mL in normal pregnant rats. To determine the long-term effects of a 2- to 3-fold elevation in plasma TNF-α on renal and systemic hemodynamics in pregnant rats, we infused TNF-α for 5 days at a rate of 50 ng/d during days 14 to 19 of gestation in pregnant rats. Serum levels were 7±2 pg/mL in the control pregnant rats and 14±2 pg/mL in the TNF-α–treated pregnant rats. Mean arterial pressure was higher in the TNF-α–treated pregnant rats (123±3 mm Hg) compared with pregnant controls (96±3 mm Hg) at day 19 of gestation. TNF-α increased renal vascular resistance in pregnant rats by 182%. Renal plasma flow was 5.4±1.2 mL/min in the TNF-α–treated group and 9.2±1.6 mL/min in the control group. Glomerular filtration rate was 1.7±0.4 mL/min in the TNF-α–treated group and 2.6±0.4 mL/min in the control group. In summary, these data suggest that TNF-α may play an important role in mediating the increased arterial pressure in response to chronic RUPPs in pregnant rats.
Association of the T8590C Polymorphism of
CYP4A11
With Hypertension in the MONICA Augsburg Echocardiographic Substudy
Authors: Mayer Bjoern , Lieb Wolfgang , Götz Anika , König Inke R. , Aherrahrou Zouhair , Thiemig Annett , Holmer Stephan , Hengstenberg Christian , Doering Angela , Loewel Hannelore , Hense Hans-Werner , Schunkert Heribert , Erdmann Jeanette
Published: September 2005

Genetic variants of the arachidonic acid monooxygenase
CYP4A11
result in decreased synthesis of 20-hydroxyeicostatetraenoic acid and experimental hypertension. Moreover, in humans, the T8590C polymorphism of
CYP4A11
displayed association with arterial hypertension. The aim of the present study was to further investigate this association in a large population-based sample. Therefore, the participants of the echocardiographic substudy of the third MONICA (MONitoring trends and determinants In CArdiovascular disease) survey (n=1397) were studied by standardized anthropometric, echocardiographic, and biochemical measurements as well as genotyping for
CYP4A11
T8590C allele status. Individuals with the CC genotype have higher systolic (CC 141.4±3.17 mm Hg versus CT 134.2±0.97 mm Hg and TT 134.3±0.53 mm Hg;
P
=0.03) and diastolic blood pressure levels (CC 85.4±2.06 mm Hg versus CT 80.3±0.63 mm Hg and TT 80.7±0.34 mm Hg;
P
=0.02). Accordingly, the odds ratio (adjusted for age, body mass index, and gender) of the CC genotype versus the CT and TT genotypes for hypertension was 3.31 (95% confidence interval [CI]), 1.38 to 7.96;
P
=0.016) in the entire study population, with similar trends in men (4.30 [95% CI, 1.08 to 17.15]) and women (2.93 [95% CI, 0.88 to 9.84]). Consistent with the renal effects of the gene, no blood pressure–independent association between the T8590C polymorphism and echocardiographic parameters of left ventricular function and geometry was found. In conclusion, our data strengthen the association between the T8590C polymorphism of
CYP4A11
and hypertension and suggest a recessive mode of inheritance. In contrast, we found no blood pressure–independent modulatory effect of
CYP4A11
T8590C on cardiac size, structure, and function.
Nongenomic Effects of Aldosterone in the Human Heart
Authors: Chai Wenxia , Garrelds Ingrid M. , de Vries René , Batenburg Wendy W. , van Kats Jorge P. , Jan Danser A.H.
Published: September 2005

Aldosterone exerts rapid “nongenomic” effects in various nonrenal tissues. Here, we investigated whether such effects occur in the human heart. Trabeculae and coronary arteries obtained from 57 heart valve donors (25 males; 32 females; 17 to 66 years of age) were mounted in organ baths. Aldosterone decreased contractility in atrial and ventricular trabeculae by maximally 34±3% and 15±4%, respectively, within 5 to 15 minutes after its application. The protein kinase C (PKC) inhibitor chelerythrine chloride, but not the mineralocorticoid receptor antagonists spironolactone and eplerenone, blocked this effect. Aldosterone also relaxed trabeculae that were prestimulated with angiotensin II (Ang II), and its negative inotropic effects were mimicked by hydrocortisone (at 10-fold lower potency) but not 17β-estradiol. Aldosterone concentrations required to reduce inotropy were present in failing but not in normal human hearts. Previous exposure of coronary arteries to 1 μmol/L aldosterone or 17β-estradiol (but not hydrocortisone) doubled the maximum contractile response (E
max
) to Ang II. ΔE
max
correlated with extracellular signal-regulated kinase (ERK) 1/2 phosphorylation (
P
<0.01). Spironolactone and eplerenone did not block the potentiating effect of aldosterone. Studies in porcine renal arteries showed that potentiation also occurred at pmol/L aldosterone levels but not at 17β-estradiol levels <1 μmol/L. Aldosterone did not potentiate the α
1
-adrenoceptor agonist phenylephrine. In conclusion, aldosterone induces a negative inotropic response in human trabeculae (thereby antagonizing the positive inotropic actions of Ang II) and potentiates the vasoconstrictor effect of Ang II in coronary arteries. These effects are specific and involve PKC and ERK 1/2, respectively. Furthermore, they occur in a nongenomic manner, and require pathological aldosterone concentrations.
Mechanisms of Ventricular Fibrillation in Canine Models of Congestive Heart Failure and Ischemia Assessed by In Vivo Noncontact Mapping
Authors: Everett Thomas H. , Wilson Emily E. , Foreman Scott , Olgin Jeffrey E.
Published: September 2005

Background—

Much of the research performed studying the mechanism of ventricular fibrillation (VF) has been in normal ventricles rather than under a pathological condition predisposing to VF. We hypothesized that different ventricular substrates would alter the mechanism and characteristics of VF.

Methods and Results—

Three groups of dogs were studied: (1) control (n=8), (2) pacing-induced congestive heart failure (n=7), and (3) acute ischemia produced by 30 minutes of mid left anterior descending artery ligation (n=5). A noncontact mapping catheter (Ensite 3000, ESI) was placed via transseptal into the left ventricle (LV), along with an electrophysiology catheter. A multielectrode basket catheter (EP Technologies) was placed in the right ventricle, along with an electrophysiology catheter. Several episodes of VF were recorded in each animal. In addition to constructing isopotential and isochronal maps of the VF episodes, signals underwent frequency domain analysis as a fast Fourier transform was performed over a 2-second window every 1 second. From the fast Fourier transform, the dominant frequency was determined, and the organization was calculated. In control dogs, meandering, reentrant spiral wave activity was the main feature of the VF. The congestive heart failure group showed evidence of a stable rotor (n=3), evidence of a focal source (n=3), or no evidence of a driver in the LV (n=1). The ischemic group showed evidence of an initial focal mechanism that transitioned into reentry. In the control and ischemic groups, the LV always had higher dominant frequencies than the right ventricle.

Conclusions—

Different ventricular substrates produced by the different animal models altered the characteristics of VF. Thus, different mechanisms of VF may be present in the LV, depending on the animal model.
Deletion of Angiotensin II Type 2 Receptor Exaggerated Atherosclerosis in Apolipoprotein E–Null Mice
Authors: Iwai Masaru , Chen Rui , Li Zhen , Shiuchi Tetsuya , Suzuki Jun , Ide Ayumi , Tsuda Masahiro , Okumura Midori , Min Li-Juan , Mogi Masaki , Horiuchi Masatsugu
Published: September 2005

Background—

The role of angiotensin II (Ang II) type 2 (AT
2
) receptor in atherosclerosis was explored with the use of AT
2
receptor/apolipoprotein E (ApoE)–double-knockout (AT
2
/ApoE-DKO) mice, with a focus on oxidative stress.

Methods and Results—

After treatment with a high-cholesterol diet (1.25% cholesterol) for 10 weeks, ApoE-knockout (KO) mice developed atherosclerotic lesions in the aorta. In AT
2
/ApoE-DKO mice receiving a high-cholesterol diet, the atherosclerotic changes were further exaggerated, without significant changes in plasma cholesterol level and blood pressure. In the atherosclerotic lesion, an increase in superoxide production, NADPH oxidase activity, and expression of p47
phox
was observed. These changes were also greater in AT
2
/ApoE-DKO mice. An Ang II type 1 (AT
1
) receptor blocker, valsartan, inhibited atherosclerotic lesion formation, superoxide production, NADPH oxidase activity, and p47
phox
expression; these inhibitory effects were significantly weaker in AT
2
/ApoE-KO mice. We further examined the signaling mechanism of the AT
2
receptor–mediated antioxidative effect in cultured fetal vascular smooth muscle cells. NADPH oxidase activity and phosphorylation and translocation of p47
phox
induced by Ang II were inhibited by valsartan but enhanced by an AT
2
receptor blocker, PD123319.

Conclusions—

These results suggest that AT
2
receptor stimulation attenuates atherosclerosis through inhibition of oxidative stress and that the antiatherosclerotic effect of valsartan could be at least partly due to AT
2
receptor stimulation by unbound Ang II.