bluuebunny/crossref_metadata_2025 huggingface dataset:
Localized glucoprivation of hindbrain sites elicits corticosterone and glucagon secretion
Authors: Andrew Shayne F. , Dinh Thu T. , Ritter Sue
Published: January 2007

Glucose is required for brain energy metabolism. Decerebration, aqueduct occlusion, and cannula mapping studies have established that glucose-sensing cells capable of eliciting feeding and adrenal medullary responses to glucoprivation are localized in the hindbrain. Glucoprivation also evokes corticosterone and glucagon secretion, but the location of receptors mediating these responses is unknown. To determine whether glucoreceptive sites controlling these responses are present in the hindbrain, we administered the antiglycolytic agent, 5-d-thioglucose (5TG, 24 μg in 200 nl) into brain stem sites through implanted cannulas and examined plasma concentrations of corticosterone and glucagon. Both hindbrain and hypothalamic sites were tested. Blood was collected remotely from intra-atrial catheters at 0, 30, 60, 90, 120, 180, and 240 min after 5TG or control injection. Caudal hindbrain 5TG injections potently increased circulating corticosterone and glucagon concentrations. For corticosterone, the mean peak response (maximum concentration minus time 0 concentration) elicited at positive sites (23 of 40 sites) was 391 ng/ml (SE = 16). For glucagon, the mean peak response at positive sites (27 of 40 sites) was 46 pg/ml (SE = 6). Glucoprivically evoked glucagon secretion was abolished by the ganglionic blocker, hexamethonium, but not by adrenal denervation. Six of twenty-five hypothalamic sites were positive for corticosterone secretion, yielding plasma levels of 279 ± 23 ng/ml, but none of the hypothalamic injection sites elevated glucagon concentrations. Results demonstrate that receptor cells responsive to glucose deficit and capable of increasing corticosterone and glucagon concentrations exist within the hindbrain, thus further delineating central glucoregulatory neural circuitry.
Effects of hypercapnia and hypocapnia on ventilatory variability and the chaotic dynamics of ventilatory flow in humans
Authors: Fiamma Marie-Noëlle , Straus Christian , Thibault Sylvain , Wysocki Marc , Baconnier Pierre , Similowski Thomas
Published: January 2007

In humans, lung ventilation exhibits breath-to-breath variability and dynamics that are nonlinear, complex, sensitive to initial conditions, unpredictable in the long-term, and chaotic. Hypercapnia, as produced by the inhalation of a CO2-enriched gas mixture, stimulates ventilation. Hypocapnia, as produced by mechanical hyperventilation, depresses ventilation in animals and in humans during sleep, but it does not induce apnea in awake humans. This emphasizes the suprapontine influences on ventilatory control. How cortical and subcortical commands interfere thus depend on the prevailing CO2 levels. However, CO2 also influences the variability and complexity of ventilation. This study was designed to describe how this occurs and to test the hypothesis that CO2 chemoreceptors are important determinants of ventilatory dynamics. Spontaneous ventilatory flow was recorded in eight healthy subjects. Breath-by-breath variability was studied through the coefficient of variation of several ventilatory variables. Chaos was assessed with the noise titration method (noise limit) and characterized with numerical indexes [largest Lyapunov exponent (LLE), sensitivity to initial conditions; Kolmogorov-Sinai entropy (KSE), unpredictability; and correlation dimension (CD), irregularity]. In all subjects, under all conditions, a positive noise limit confirmed chaos. Hypercapnia reduced breathing variability, increased LLE ( P = 0.0338 vs. normocapnia; P = 0.0018 vs. hypocapnia), increased KSE, and slightly reduced CD. Hypocapnia increased variability, decreased LLE and KSE, and reduced CD. These results suggest that chemoreceptors exert a strong influence on ventilatory variability and complexity. However, complexity persists in the quasi-absence of automatic drive. Ventilatory variability and complexity could be determined by the interaction between the respiratory central pattern generator and suprapontine structures.
The extrinsic caspase pathway modulates endotoxin-induced diaphragm contractile dysfunction
Authors: Supinski Gerald S. , Ji Xinying , Wang Wenyi , Callahan Leigh A.
Published: January 2007

The mechanisms by which infections induce diaphragm dysfunction remain poorly understood. The purpose of this study was to determine which caspase pathways (i.e., the extrinsic, death receptor-linked caspase-8 pathway, and/or the intrinsic, mitochondrial-related caspase-9 pathway) are responsible for endotoxin-induced diaphragm contractile dysfunction. We determined 1) whether endotoxin administration (12 mg/kg IP) to mice induces caspase-8 or -9 activation in the diaphragm; 2) whether administration of a caspase-8 inhibitor ( N-acetyl-Ile-Glu-Thr-Asp-CHO, 3 mg/kg iv) or a caspase-9 inhibitor ( N-acetyl-Leu-Glu-His-Asp-CHO, 3 mg/kg iv) blocks endotoxin-induced diaphragmatic weakness and caspase-3 activation; 3) whether TNF receptor 1-deficient mice have reduced caspase activation and diaphragm dysfunction following endotoxin; and 4) whether cytokines (TNF-α or cytomix, a mixture of TNF-α, interleukin-1β, interferon-γ, and endotoxin) evoke caspase activation in C2C12 myotubes. Endotoxin markedly reduced diaphragm force generation ( P < 0.001) and induced increases in caspase-3 and caspase-8 activity ( P < 0.03), but failed to increase caspase-9. Inhibitors of caspase-8, but not of caspase-9, prevented endotoxin-induced reductions in diaphragm force and caspase-3 activation ( P < 0.01). Mice deficient in TNF receptor 1 also had reduced caspase-8 activation ( P < 0.001) and less contractile dysfunction ( P < 0.01) after endotoxin. Furthermore, incubation of C2C12 cells with either TNF-α or cytomix elicited significant caspase-8 activation. The caspase-8 pathway is strongly activated in the diaphragm following endotoxin and is responsible for caspase-3 activation and diaphragm weakness.
Insulin-like Growth Factor and Mammographic Density in Postmenopausal Norwegian Women
Authors: Bremnes Yngve , Ursin Giske , Bjurstam Nils , Rinaldi Sabina , Kaaks Rudolf , Gram Inger T.
Published: January 2007

Insulin-like growth factor-I (IGF-I) is associated with breast cancer risk among premenopausal women but rarely among postmenopausal women. Recent data from two European studies suggested an increased risk of breast cancer with increasing levels of IGF-I among women >50 years old or among postmenopausal hormone therapy users ≥55 years old. Mammographic density is one of the strongest risk factors, and possibly an intermediate marker, for breast cancer. We examined the relationship between IGF and mammographic density among postmenopausal women overall and according to hormone therapy use. Altogether, 977 postmenopausal participants in the Norwegian governmental mammographic screening program had IGF concentrations measured by ELISA. Mammograms were classified according to percent and absolute mammographic densities using a previously validated computer-assisted method. After adjustment for age, number of children, age at menopause, body mass index, and hormone therapy use, both plasma IGF-I concentration (Ptrend = 0.02) and IGF-I/IGF binding protein 3 ratio (Ptrend = 0.02) were positively associated with percent mammographic density. The magnitudes of differences in percent mammographic density between women in the lowest and highest quartiles of IGF-I concentrations were 1.5% absolute difference and 21% relative difference. These associations were similar with absolute mammographic density as the outcome variable. When the analyses were stratified according to hormone therapy use, the associations between IGF-I and mammographic density were significant among noncurrent users (Ptrend = 0.03). In conclusion, we found a positive but weak association between plasma IGF-I concentrations and both percent and absolute mammographic densities among postmenopausal women. These associations were found among noncurrent hormone therapy users but not among current users. (Cancer Epidemiol Biomarkers Prev 2007;16(1):57–62)
XR5944: A potent inhibitor of estrogen receptors
Authors: Punchihewa Chandanamali , De Alba Adrian , Sidell Neil , Yang Danzhou
Published: January 2007

The anticancer drug XR5944 was originally developed as a topoisomerase inhibitor and was subsequently shown to be a transcription inhibitor. It has shown exceptional anticancer activity both in vitro and in vivo and was significantly more potent than traditional topoisomerase inhibitors. The solution structure of the XR5944/DNA complex recently obtained in our laboratory indicates that XR5944 bis-intercalates at the 5′-(TpG):(CpA) site of duplex DNA, which is found in the consensus DNA-binding site of estrogen receptor (ER). Thus, we tested the ability of XR5944 to inhibit ER activity both in vitro and in cultured cells. In electrophoretic mobility shift assays, it is seen that the DNA binding of recombinant ERα protein, as well as ER from nuclear extracts, is inhibited by XR5944 in a dose-dependent manner. In luciferase reporter assays, XR5944 inhibited the reporter gene expression from an estrogen response element–containing promoter but not from a basal promoter sequence that lacks any cis-acting elements. In contrast, the RNA polymerase inhibitor actinomycin D inhibits the transcription from both the above-mentioned promoters. The specificity of XR5944 activity is displayed by a separate reporter assay in which the transactivation of reporter gene expression by Sp1 proteins was not inhibited by XR5944. Collectively, these data suggest that XR5944 is capable of specifically inhibiting the binding of ER to its consensus DNA sequence and its subsequent activity. This represents a novel mechanism of ER inhibition, which may allow the development of agents capable of overcoming resistance to current antiestrogens. [Mol Cancer Ther 2007;6(1):213–9]
Osler and the Churg-Strauss Syndrome
Authors: Pearce J.M.S.
Published: January 2007

This paper records a patient of Osler’s, who showed many features compatible with the Churg-Strauss syndrome of allergic granulomatous angiitis to be described 50 years later.
Role of Free Fatty Acids in Regulating Gastric Emptying and Gallbladder Contraction
Authors: Degen Lukas , Matzinger Daniel , Drewe Juergen , Nisslé Sonja , Maecke Helmut , Lengsfeld Hans , Hadvary Paul , Beglinger Christoph
Published: January 2007

The limited effectiveness of orlistat, an inhibitor of gastrointestinal lipases, in inhibiting fat digestion is not completely understood. Therefore we studied the effect of orally and duodenally administered orlistat on gastric emptying, cholecystokinin (CCK) secretion, and gallbladder contraction. In healthy males, gastric emptying of solids and fat were quantified scintigraphically, gallbladder contraction by ultrasound and CCK release by radioimmunoassay. Three studies were performed: (1) oral and (2) duodenal orlistat with a fat-containing meal, and (3) duodenal orlistat with a fat-free meal. Gastric emptying rates of solids and fat (T50% accelerated by 16 and by 22%, p< 0.05, respectively) were significantly faster after duodenal perfusion of orlistat; gallbladder contraction and CCK release were reduced under these conditions (p < 0.005, respectively). With oral orlistat no significant effect was documented on these parameters. We conclude that fat hydrolysis is essential in the regulation of fat-induced gastric emptying and gallbladder contraction.
Opioids Induce Renal Abnormalities in Tumor-Bearing Mice
Authors: Arerangaiah Ramya , Chalasani Nagamala , Udager Aaron M. , Weber Marc L. , Manivel Juan C. , Griffin Robert J. , Song Chang W. , Gupta Kalpna
Published: January 2007

Background/Aims: The etiology of renal dysfunction in cancer patients is likely to be multifactorial. A large proportion of these patients receive opioid analgesics, but whether opioids contribute to renal dysfunction remains uncertain. In a murine cancer model, we examined the effects of chronic opioid administration on renal function and pathology, and the molecular mechanisms involved. Methods: C3H/HeJ mice implanted with 2472 tumor cells were treated with either morphine or hydromorphone in clinically relevant doses, or PBS (controls). Renal function was assessed by blood and urine chemistry as well as by measuring mean arterial pressure (MAP) and kidney perfusion. Pathological changes in the kidneys were examined by routine histology. Molecular changes were examined by assessing eNOS, iNOS, HO-1 and COX-2 expression in whole-kidney lysates by Western immunoblotting, and cellular colocalization of these enzymes was determined using immunofluorescence microscopy. Results:Three weeks of opioid treatment resulted in increased kidney weight, elevated BUN and proteinuria, and decreased MAP. This was accompanied by histological abnormalities including glomerular enlargement, hypercellularity, peritubular congestion, vasodilatation and tubular casts. The vasoregulatory molecules iNOS, eNOS, HO-1 and COX-2 were upregulated in the kidneys. The NOS inhibitor L-NAME prevented the morphine-induced increase in perfusion and kidney weight. Conclusions: The chronic use of clinically relevant doses of opioidsleads to structural kidney abnormalities, upregulates NOS, COX-2 and HO-1, and results in renal dysfunction in a murine model of cancer.
Capillary Perfusion and Wall Shear Stress Are Restored in the Coronary Circulation of Hypertrophic Right Ventricle
Authors: Huo Yunlong , Linares Carlos O. , Kassab Ghassan S.
Published: January 2007

It has been shown that right ventricle (RV) hypertrophy involves significant compensatory vascular growth and remodeling. The objective of the present study was to determine the functional implications of the vascular growth and remodeling through a full flow analysis of arterial tree down to first capillary segments. A computer reconstruction of RV branches including the proximal right coronary artery to the posterior descending artery was established based on measured morphometric data in arrested, vasodilated porcine heart. The flows were computed throughout the reconstructed trees based on conservation of mass and momentum and appropriate pressure boundary conditions. It was found that the flow rate was significantly increased in large epicardial coronary arteries in hypertrophic as compared with control hearts but normalized in the intramyocardial coronary arteries and smaller vessels in RV hypertrophy primarily because of the significant increase in number of arterioles. Furthermore, the wall shear stress was restored to nearly homeostatic levels throughout most of the vasculature after 5 weeks of RV hypertrophy. The compensatory remodeling in RV hypertrophy functionally restores the perfusion at the arteriolar and capillary level and wall shear stress in most of larger vessels. This is the first full analysis of coronary arterial tree, with millions of vessels, in cardiac hypertrophy that reveals the compensatory adaptation of structure to function.
FTY720, a Synthetic Sphingosine 1 Phosphate Analogue, Inhibits Development of Atherosclerosis in Low-Density Lipoprotein Receptor–Deficient Mice
Authors: Nofer Jerzy-Roch , Bot Martine , Brodde Martin , Taylor Paul J. , Salm Paul , Brinkmann Volker , van Berkel Theo , Assmann Gerd , Biessen Erik A.L.
Published: January 2007

Background—

Numerous in vitro studies suggest that sphingosine 1-phosphate (S1P), a bioactive lysosphingolipid associated with high-density lipoproteins, accounts at least partly for the potent antiinflammatory properties of high-density lipoprotein and, thereby, contributes to the antiatherogenic potential attributed to high-density lipoproteins. The present study was undertaken to investigate whether modulation of S1P signaling would affect atherosclerosis in a murine model of disease.

Methods and Results—

Low-density lipoprotein receptor–deficient mice on a cholesterol-rich diet were given FTY720, a synthetic S1P analogue, at low (0.04 mg/kg per day) or high (0.4 mg/kg per day) doses for 16 weeks. FTY720 dose-dependently reduced atherosclerotic lesion formation, both in the aortic root and brachiocephalic artery, and almost completely blunted necrotic core formation. Plasma lipids remained unchanged during the course of FTY720 treatment. However, FTY720 lowered blood lymphocyte count (at a high dose) and significantly interfered with lymphocyte function, as evidenced by reduced splenocyte proliferation and interferon-γ levels in plasma. Plasma concentrations of proinflammatory cytokines such as tumor necrosis factor-α, interleukin (IL)-6, IL-12, and regulated on activation normal T cell expressed and secreted were reduced by FTY720 administration. Moreover, lipopolysaccharide-elicited generation of nitrite/nitrate and IL-6—two markers of classical (M1) macrophage activation—was inhibited, whereas IL-4–induced production of IL-1–receptor antagonist, a marker of alternative (M2) macrophage activation, was augmented in peritoneal macrophages from FTY720-treated low-density lipoprotein receptor–deficient mice.

Conclusions—

The present results demonstrate that an S1P analogue inhibits atherosclerosis by modulating lymphocyte and macrophage function, and these results are consistent with the notion that S1P contributes to the antiatherogenic potential of high-density lipoprotein.
PF-4/CXCL4 and CXCL4L1 exhibit distinct subcellular localization and a differentially regulated mechanism of secretion
Authors: Lasagni Laura , Grepin Renaud , Mazzinghi Benedetta , Lazzeri Elena , Meini Claudia , Sagrinati Costanza , Liotta Francesco , Frosali Francesca , Ronconi Elisa , Alain-Courtois Nathalie , Ballerini Lara , Netti Giuseppe Stefano , Maggi Enrico , Annunziato Francesco , Serio Mario , Romagnani Sergio , Bikfalvi Andreas , Romagnani Paola
Published: January 2007

PF-4/CXCL4 is a member of the CXC chemokine family, which is mainly produced by platelets and known for its pleiotropic biological functions. Recently, the proteic product of a nonallelic variant gene of CXCL4 was isolated from human platelets and named as CXCL4L1. CXCL4L1 shows only 4.3% amino acid divergence in the mature protein, but exhibits a 38% amino acid divergence in the signal peptide region. We hypothesized that this may imply a difference in the cell type in which CXCL4L1 is expressed or a difference in its mode of secretion. In different types of transfected cells, CXCL4 and CXCL4L1 exhibited a distinct subcellular localization and a differential regulation of secretion, CXCL4 being stored in secretory granules and released in response to protein kinase C activation, whereas CXCL4L1 was continuously synthesized and secreted through a constitutive pathway. A protein kinase C-regulated CXCL4 secretion was observed also in lymphocytes, a cell type expressing mainly CXCL4 mRNA, whereas smooth muscle cells, which preferentially expressed CXCL4L1, exhibited a constitutive pathway of secretion. These results demonstrate that CXCL4 and CXCL4L1 exhibit a distinct subcellular localization and are secreted in a differentially regulated manner, suggesting distinct roles in inflammatory or homeostatic processes.
Use of tobacco and alcohol by Swiss primary care physicians: a cross-sectional survey
Authors: Sebo Paul , Bouvier Gallacchi Martine , Goehring Catherine , Künzi Beat , Bovier Patrick A
Published: January 2007

Background

Health behaviours among doctors has been suggested to be an important marker of how harmful lifestyle behaviours are perceived. In several countries, decrease in smoking among physicians was spectacular, indicating that the hazard was well known. Historical data have shown that because of their higher socio-economical status physicians take up smoking earlier. When the dangers of smoking become better known, physicians began to give up smoking at a higher rate than the general population. For alcohol consumption, the situation is quite different: prevalence is still very high among physicians and the dangers are not so well perceived. To study the situation in Switzerland, data of a national survey were analysed to determine the prevalence of smoking and alcohol drinking among primary care physicians.

Methods

2'756 randomly selected practitioners were surveyed to assess subjective mental and physical health and their determinants, including smoking and drinking behaviours. Physicians were categorised as never smokers, current smokers and former smokers, as well as non drinkers, drinkers (AUDIT-C < 4 for women and < 5 for men) and at risk drinkers (higher scores).

Results

1'784 physicians (65%) responded (men 84%, mean age 51 years). Twelve percent were current smokers and 22% former smokers. Sixty six percent were drinkers and 30% at risk drinkers. Only 4% were never smokers and non drinkers. Forty eight percent of current smokers were also at risk drinkers and 16% of at risk drinkers were also current smokers. Smoking and at risk drinking were more frequent among men, middle aged physicians and physicians living alone. When compared to a random sample of the Swiss population, primary care physicians were two to three times less likely to be active smokers (12% vs. 30%), but were more likely to be drinkers (96% vs. 78%), and twice more likely to be at risk drinkers (30% vs. 15%).

Conclusion

The prevalence of current smokers among Swiss primary care physicians was much lower than in the general population in Switzerland, reflecting that the hazards of smoking are well known to doctors. However, the opposite was found for alcohol use, underlining the importance of making efforts in this area to increase awareness among physicians of the dangers of alcohol consumption.
HEE-GER: a systematic review of German economic evaluations of health care published 1990–2004
Authors: Schwappach David LB , Boluarte Till A
Published: January 2007

Background

Studies published in non-English languages are systematically missing in systematic reviews of growth and quality of economic evaluations of health care. The aims of this study were: to characterize German evaluations, published in English or German-language, in terms of various key parameters; to investigate methods to derive quality-of-life weights in cost-utility studies; and to examine changes in study characteristics over the years.

Methods

We conducted a country-specific systematic review of the German and English-language literature of German economic evaluations (assessment of or application to the German health care system) published 1990–2004. Generic and specialized health economic databases were searched. Two independent reviewers verified fulfillment of inclusion criteria and extracted study characteristics.

Results

The fulltexts of 730 articles were reviewed of which 283 fulfilled all entry criteria. 32% of included studies were published in German-language. 51% of studies evaluated pharmaceuticals and 63% were cost-effectiveness analyses. Economic appraisals concentrate on few disease categories and important health areas are strongly underrepresented. Declaration of sponsorship was associated with article language (49% English articles vs. 29% German articles, p < 0.001). The methodology used to obtain quality-of-life weights in published cost-utility studies was very diverse, poorly reported and most studies did not use German patients' or community health state valuations.

Conclusion

Many of the German-language evaluations included in our study are likely to be missing in international reviews and may be systematically different from English-language reviews from Germany. Lack of transparency and adherence to recommended reporting practices constitute a serious problem in German economic evaluations.
Identification and Characterization of Multiple Corticotropin-Releasing Factor Type 2 Receptor Isoforms in the Rat Esophagus
Authors: Wu S. Vincent , Yuan Pu-qing , Wang Lixin , Peng Yen L. , Chen Chih-Yen , Taché Yvette
Published: January 2007

The rat esophagus shares some cellular features with skin squamous epithelium and striated muscle that express high levels of corticotropin-releasing factor type 2 (CRF2) receptors or their cognate ligand urocortin (Ucn) 1, 2, and 3. We investigated the expression and cell signaling of CRF2 receptors and ligands in the rat esophagus and lower esophageal sphincter (LES) by RT-PCR and quantitative PCR in normal and corticosterone-treated whole esophageal tissue, laser capture microdissected layers, and isolated esophageal cells. The expression of CRF2 receptor protein and intracellular cAMP and ERK1/2 responses to CRF agonists and CRF2 antagonist were determined in cultured esophageal cells and HEK-293 cells transfected with CRF2b receptors. CRF2 was abundantly expressed in the mucosa and longitudinal muscle layers of the esophagus and LES, whereas CRF1 expression was scarce. CRF2b wild-type transcript was predominantly expressed in the esophagus, and in addition, several new CRF2 splice variants including six CRF2a isoforms were identified. Expression of Ucn 1, Ucn 2, and to a smaller extent Ucn 3, but not CRF mRNA, was detected in the esophagus and LES. Ucn 1 and Ucn 2 stimulated dose-dependent cAMP production and ERK1/2 phosphorylation in the esophageal cells, whereas CRF and CRF1 agonist, cortagine, had less potent effects. In addition, Ucn 2-stimulated cAMP and ERK responses were blocked by the CRF2 antagonist, astressin2-B. These data established the presence of a prominent CRF2 signaling system in the esophagus and LES-encompassing multiple CRF2 receptor variants and Ucn, suggesting a functional role in secretomotor activity and epithelial and muscle cell proliferation.
Neuroendocrine Plasticity in the Anterior Pituitary: Gonadotropin-Releasing Hormone-Mediated Movement in Vitro and in Vivo
Authors: Navratil Amy M. , Knoll J. Gabriel , Whitesell Jennifer D. , Tobet Stuart A. , Clay Colin M.
Published: January 2007

The secretion of LH is cued by the hypothalamic neuropeptide, GnRH. After delivery to the anterior pituitary gland via the hypothalamic-pituitary portal vasculature, GnRH binds to specific high-affinity receptors on the surface of gonadotrope cells and stimulates synthesis and secretion of the gonadotropins, FSH, and LH. In the current study, GnRH caused acute and dramatic changes in cellular morphology in the gonadotrope-derived αT3-1 cell line, which appeared to be mediated by engagement of the actin cytoskeleton; disruption of actin with jasplakinolide abrogated cell movement and GnRH-induced activation of ERK. In live murine pituitary slices infected with an adenovirus-containing Rous sarcoma virus-green fluorescent protein, selected cells responded to GnRH by altering their cellular movements characterized by both formation and extension of cell processes and, surprisingly, spatial repositioning. Consistent with the latter observation, GnRH stimulation increased the migration of dissociated pituitary cells in transwell chambers. Our data using live pituitary slices are a striking example of neuropeptide-evoked movements of cells outside the central nervous system and in a mature peripheral endocrine organ. These findings call for a fundamental change in the current dogma of simple passive diffusion of LH from gonadotropes to capillaries in the pituitary gland.
Utilization of AC Impedance Measurements for Electrochemical Glucose Sensing Using Glucose Oxidase to Improve Detection Selectivity
Authors: Kohma Takuya , Hasegawa Hidefumi , Oyamatsu Daisuke , Kuwabata Susumu
Published: January 2007

The electrochemical detection of glucose using glucose oxidase (GOx) has been conducted by means of AC impedance measurements. In the absence of glucose, the Nyquist plots were straight line due to a reversible redox reaction involving the electron mediator. On the other hand, the Nyquist plots became a circular arc in the presence of glucose, and its radius decreased with an increase in the glucose concentration. The shape of the Nyquist plots were explained with assistance of numerical calculations. Since the reaction impedance due to direct oxidation of interfering species was significantly higher than that of glucose oxidation catalyzed by glucose oxidase, unfavorable influence from interfering species could be eliminated without needing a complicated sensor device. When ferrocenecarboxylic acid was used as an electron mediator, the calibration curve obtained from the Nyquist plots was not affected by the presence of ascorbic acid. Based on those findings, a sensing system, which has no interference from both ascorbic acid and uric acid, was fabricated by using [Os(bpy)3]Cl2, which has a highly positive redox potential (0.65 V), as an electron mediator. A method to prepare calibration curves from AC impedance measurements with a fixed frequency was established so that this technique can be put to practical use.
Gas-Phase Lithium Cation Basicities of Acetophenones: A Linear Relationship between Lithium Cation and Proton Basicities
Authors: Maeda Hideaki , Irie Maki , Than Soe , Kikukawa Kiyoshi , Mishima Masaaki
Published: January 2007

The free energy changes (ΔG) for the reaction B2Li+ = Li+ + 2B were obtained in the gas phase for m- and p-substituted acetophenones based on the measurement of ligand-exchange equilibria of the type LiA2+ + 2B = LiB2+ + 2A using a FT-ICR spectrometer. A plot of ΔG (relative lithium cation basicity, ΔLCB[B2Li+]) values against the ΔGB (proton basicity) showed a limited linear correlation for meta substituents and para electron-withdrawing groups with a slope of 1.06. Negative deviations observed for strong π-donor susbstituents suggested that the resonance effect of these substituents is reduced in the Li+ complex compared to that in the protonated ion. Based on the correlation analysis using the Yukawa–Tsuno equation, , the substituent effect on ΔLCB[B2Li+] of acetophenone was characterized by a ρ value of −12.5 and an r+ value of 0.49. A ρ value of −8.3 was determined for ΔLCB[BLi+] based on the reaction LiB+ = Li+ + B from a ρ value for ΔLCB[B2Li+] by using a factor of 1.5 that was obtained from a linear relationship between calculated ΔLCB[B2Li+] and ΔLCB[BLi+]. In comparison with the corresponding results for other Lewis cation basicities, it was shown that the ρ value decreases in the order of H+ (−11.6) > Me3Si+ (−11.0) > Me3Ge+ (−9.7) > Li+ (−8.3). The decrease in the ρ value indicates that the positive charges at the Lewis cation moiety of the adduct ion increases in this order. The small ρ value for the Li+ basicity is consistent with largely ionic (ion–dipole interaction) nature of the bonding interaction between Li+ and the carbonyl oxygen atom. The r+ value that indicates the degree of charge-delocalization into the aromatic π-system also decreases in the same order. In spite of a small charge transfer from Li+ to acetophenone ligand, the moderate r+ value of 0.49 observed for the Li+ complex is interpreted to be due to the redistribution of the induced positive charge in the acetophenone moiety by binding with Li+.
Treatment of acromegaly with the GH receptor antagonist pegvisomant in clinical practice: Safety and efficacy evaluation from the German Pegvisomant Observational Study
Authors: Schreiber I , Buchfelder M , Droste M , Forssmann K , Mann K , Saller B , Strasburger C J
Published: January 2007

Objective: The GH receptor antagonist pegvisomant is a highly effective new treatment option in acromegaly. The German Pegvisomant Observational Study (GPOS) was started to monitor long-term safety and efficacy of pegvisomant as prescribed in clinical practice.

Design: GPOS is an observational, multi-center, surveillance study, which comprises non-interventional data collection.

Methods: Of the 229 patients included in the study, 90.4% had previous pituitary surgery, 43.2% were treated by radiation therapy, and 94.3% had previous medical therapy for acromegaly that had been discontinued mainly due to persistent IGF-I elevation or side effects. The intention-to-treat population included 177 patients with at least one post-baseline efficacy measurement.

Results: IGF-I levels decreased from 1.75±0.91-fold the upper limit of normal at baseline to 1.05± 0.62 at the 6-month visit, 0.96±0.60 at the 12-month visit, and to 0.89±0.41-fold after 24 months (P<0.0001). Mean duration of pegvisomant therapy was 51.8±35.8 weeks (median=51.9 weeks). IGF-I was normalized in 64.4% at 6 months with a median dose of 15.0 mg/day, in 70.9% at 12 months, and in 76.3% at 24 months. Fasting glucose levels improved from 114.4±45.9 to 101.5± 42.8 mg/dl after 6 months (P<0.01) and to 100.6±33.2 mg/ml after 12 months (P<0.01). General physical condition measured by specific signs and symptoms score improved significantly. Adverse events occurring in >1% were injection site reactions in 7.4%, elevated liver enzymes (>3 times of normal) in 5.2% (3.1% spontaneously normalized during continued treatment), reported increase of pituitary tumor volume in 5.2% (which was verified in 3.1%), and headache in 1.7%.

Conclusions: Pegvisomant is generally well tolerated with a safety profile similar to that reported in clinical trials and can effectively reduce IGF-I in patients with acromegaly refractory to conventional therapy.
A new functional parameter measured at the time of ablation that can be used to predict differentiated thyroid cancer recurrence during follow-up
Authors: Verkooijen Robbert B T , Rietbergen Daphne , Smit Jan W , Romijn Johannes A , Stokkel Marcel P M
Published: January 2007

Background: This study addresses the questions whether patients with a high risk for recurrent thyroid cancer can be identified at initial stage, i.e. at the time of ablation.

Methods: We evaluated tumor recurrence in consecutive patients treated for differentiated thyroid cancer (DTC). Prognostic factors were statistically analyzed. We defined prognostic parameters based on thyroglobulin (Tg) levels, 24-h I-131 uptake rates and TSH values: (a) Tg/TSH, (b) Tg/24-h I-131 uptake value, and (c) Tg/(TSH×24-h I-131 uptake).

Results: We included 190 patients (50 male, 140 female; mean age 47 years) with DTC for analysis, 146 without distant metastases and 44 with M1 tumor stage at initial presentation. The mean period of follow-up was 10.4 years (s.d. ± 3.7 years). In 18 out of the 146 DTC patients with M0 disease (12.4%), tumor recurrence was found during follow-up. Although tumor stage, age, and standard biochemical values significantly differ between patients with and without recurrent disease or between patients with M0 and M1 tumor stage, the newly defined parameter Tg/(TSH×24-h I-131 uptake) was the best independent significant prognostic parameter in the assessment whether patients will develop a tumor recurrence during follow-up or not.

Conclusion: High Tg/(TSH×24-h I-131 uptake) ratios justify an adjustment of the I-131 activity for ablation therapy. To assess the optimal cut-off value for a dose adjustment, however, further studies are required in more patients, but the initial results are encouraging with respect to improving outcome in DTC patients.
Bone Morphogenetic Protein-Mediated Modulation of Lineage Diversification During Neural Differentiation of Embryonic Stem Cells
Authors: Gossrau Gudrun , Thiele Janine , Konang Rachel , Schmandt Tanja , Brüstle Oliver
Published: January 2007

Embryonic stem cells (ES cells) can give rise to a broad spectrum of neural cell types. The biomedical application of ES cells will require detailed knowledge on the role of individual factors modulating fate specification during in vitro differentiation. Bone morphogenetic proteins (BMPs) are known to exert a multitude of diverse differentiation effects during embryonic development. Here, we show that exposure to BMP2 at distinct stages of neural ES cell differentiation can be used to promote specific cell lineages. During early ES cell differentiation, BMP2-mediated inhibition of neuroectodermal differentiation is associated with an increase in mesoderm and smooth muscle differentiation. In fibroblast growth factor 2-expanded ES cell-derived neural precursors, BMP2 supports the generation of neural crest phenotypes, and, within the neuronal lineage, promotes distinct subtypes of peripheral neurons, including cholinergic and autonomic phenotypes. BMP2 also exerts a density-dependent promotion of astrocyte differentiation at the expense of oligodendrocyte formation. Experiments involving inhibition of the serine threonine kinase FRAP support the notion that these effects are mediated via the JAK/STAT pathway. The preservation of diverse developmental BMP2 effects in differentiating ES cell cultures provides interesting prospects for the enrichment of distinct neural phenotypes in vitro.

Disclosure of potential conflicts of interest is found at the end of this article.
Analysis of the Origin and Population Dynamics of Cardiac Progenitor Cells in a Donor Heart Model
Authors: Li Tao-Sheng , Suzuki Ryo , Ueda Kazuhiro , Murata Tomoaki , Hamano Kimikazu
Published: January 2007

Cardiac progenitor (stem) cells have recently been detected in and isolated from the myocardium of neonatal and adult mice, rats, and humans; however, the precise origin and characterization of these cells remain unclear. Using a heterotopic mouse heart transplantation model, we investigated the origin and population dynamics of cardiac progenitor cells. Donor hearts from wild-type C57/BL6 female mice were transplanted into green fluorescent protein (GFP)-transgenic C57/BL6 male mice. The donor hearts were collected 0, 2, 4, 8, and 12 weeks after transplantation. We used quantitative flow cytometry to analyze the number and origin of stem cells in the donor hearts and immunostaining to evaluate the time-related changes in their characteristics. Extracardiac GFP-positive stem cells immigrated into the donor hearts soon after transplantation. Immunostaining revealed that these GFP-positive stem cells in the donor hearts gradually lost expression of the hematopoietic markers of CD45 and CD34 and shifted to express the cardiac-specific transcription factors GATA-4 and NKx2.5. A few of the GFP-positive cells in the donor hearts finally acquired the mature cardiac phenotype in the absence of cell fusion with donor cardiomyocytes. Our discovery provides the first evidence that extracardiac stem cells may be of bone marrow origin, from which they can transform into cardiac progenitor cells in response to myocardial environment cues.

Disclosure of potential conflicts of interest is found at the end of this article.
Shaw's Abstract Clarity
Authors: Whittemore Reed
Published: January 2007

Those of you who have taken any courses here in English literature—and I believe a number of you have—have surely at one time or another used, and therefore abused, that difficult word, Realism. For we all abuse it, whether we naively rub it, as Aladdin rubbed his lamp, hoping thereby to produce the jinni of Ernest Hemingway, or like grand metaphysicians toy with it by conjuring up the likes of Plato, Berkeley and Dr. Johnson. It seems to be a word made to be abused, and sometimes I think we would be better off if we did not regard it as a word at all but as a lower form of utterance, a noise perhaps, like a pig's grunt or a dog's bark, that we just have to give off with on certain literary occasions.
Notes on the Plays of Michel de Ghelderode
Authors: Hauger George
Published: January 2007

Perhaps the most immediately striking quality of the plays of Michel de Ghelderode is their size—not their physical length, but their dramatic dimension. Like Strindberg, this author has written very short plays and extremely long ones. The lengths may vary, but the theme is constant, and this theme is Man, essential Man, who is revealed as both fascinating and terrifying in all his potentialities. Ghelderode represents’ men in a fashion that derives from the painters he loves so much, especially Bosch and Breughel, and from the expressionist theatre. Fundamentally, he is a romantic, and at best he creates works of powerful feeling and remarkable organic form. At worst he becomes possessed, and his work is then the prey of mounting hysteria. The authenticity of feeling in all that he writes is unquestionable. It is when this feeling so grips him that he loses aesthetic perspective that his work deteriorates.
Off-Broadway Review: Adamov in New york…and Out Again
Authors: Bermel Albert
Published: January 2007

TDR has never believed the reviewing of New York productions to be one of its functions. It does not now. But in the case of Arthur Adamov's PING-PONG an exception must be made. Adamov is an important and imaginative dramatist. Together with Duerrenmatt, Beckett, Ionesco, and Ghelderode, he is opening up new territories for the theatre zuhich other playwrights (and audiences) must also explore if our theatre is ever to go beyond the narrow and mechanical limits of naturalism. We regret that the New York critics rejected this play and believe they have done our theatre a disservice. What follows is our dissenting opinion. The Grove Press, which has done more than any other publisher to make good translations of the work of the new dramatists of Europe available to American readers, has recently published PING-PONG in both cloth and paper bound editions.
Farce (TDR Document)
Authors: Meyerhold Vsevolod
Published: January 2007

“Mystery in the Russian Theatre” is the title given by Benois to one of his “Letters on Art.” One might think that in this article he is discussing a production of one of Aleksei Remizov's plays written in the style of a medieval mystery play. Or, perhaps, Scriabin has already realized one of his dreams, and Benois is hastening to announce to the public the greatest event on the Russian stage—the appearance of a new theatrical form reviewing the mystic rites of ancient Greek culture.

It seems that neither Remizov nor Scriabin has written a mystery; according to Benois the Moscow Art Theatre has produced a mystery with its performance of The Brothers Karamasov. But just what characteristics of the medieval mystery plays could be found in the performance of The Brothers Karamasov? Perhaps here the purified ancient Greek mysteries were combined with the visual edification of the medieval mystery play?
The Plays of Tennessee Williams
Authors: Popkin Henry
Published: January 2007

In the plays of Tennessee Williams, as in the works of other able and prolific American dramatists, a pattern emerges that continues to appear, with minor variations, over and over again. Williams is remarkably loyal to his favorite archetypal pattern, and, for that reason, it seems to provide an indispensable key to the nature and meaning of his plays. The typical event is the meeting of a healthy, handsome man and a nervous older woman who is losing her looks. I call this couple Adonis and the Gargoyle—Adonis after the classical ideal of male beauty and the Gargoyle after the grotesque by-products of medieval architecture. The contrast between them is alone enough to enforce one major point: it is better to be a carefree man dian to be a worried, married woman. A second diought occurs: freedom is better than dependence, but, first, any examination of these plays must begin with close scrutiny of their protagonists.
Friedrich Duerrenmatt and the Tragic Sense of Comedy
Authors: Klarmann Adolf D.
Published: January 2007

From its origins in the comos and mimos to the complicated gyrations of the Paris avant garde, the term comedy has come to mean different things to different people. Taking a glance at its development in modern literature, we discover that the very basis of comedy is tragic; indeed, the modern playwright no longer cares to separate his worlds into tragedy and comedy but prefers to use the term tragicomedy or, like Brecht, omit any designation altogether. However, we need not be too surprised if we remember the tragic background of The Birds or Lysistrata, The Merchant of Venice or The Tempest, The Misanthrope or Georges Dandin. The reason for calling a play a comedy or a tragedy frequently is historical or personal. Were Wozzeck to be written today it certainly would have been called something like a tragicomedy. After all, Eliot's The Cocktail Party is a comedy, Beckett's Waiting for Godot is a tragicomedy and Ionesco's The Chairs a tragic farce.
On the Late Plays of Eugene O‘Neill
Authors: Driver Tom F.
Published: January 2007

Death has not lessened Eugene O’Neill’s dominance over the serious American theatre. He towers over other American dramatists with a gigantism almost equal to that with which his characters tower over ordinary mortals. He died in 1953 at the age of 65, having had only one Broadway production in nineteen years, and none thoroughly successful in twenty years. Yet anyone who would evaluate the American theatre since the second World War is obliged to reckon with Eugene O’Neill, and that hardly at all because of the 1946 production of The Iceman Cometh but rather because of the amazing concentration of his works which began to be produced in 1956. In May of that year, the off-Broadway group at The Circle-in-the-Square gave The Iceman Cometh its first successful performance in New York.
The Gods are Just: A Reading of King Lear
Authors: Ribner Irving
Published: January 2007

By the time that Shakespeare set out, probably sometime in 1605, to retell the ancient story of King Lear and his daughters, he had already approached the problem of man's relation to the forces of evil from various directions, and in doing so he had developed certain distinctive modes of tragedy. In King Lear Shakespeare’s primary emphasis is upon the process of human regeneration. That he chose for the hero of such a play an old man at the very end of physical life was thematicaUy appropriate, for the emphasis is upon a spiritual rebirth for which man never can grow too old. Shakespeare dramatically juxtaposes the physical age of his hero against the new manhood he attains through suffering, and thus he asserts dramatically that Lear's four score years of pride and self-deception were merely the prelude to life, and not life at all.
On the Psychology of Comedy
Authors: Jekels Ludwig
Published: January 2007

We are indebted to psycho-analysis for much valuable insight into the psychology of tragedy. Not only has psycho-analysis made us recognize that the “tragic guilt” of the hero, postulated by aesthetics, actually stems from the repressed Oedipus-wishes of the dramatist but it has also drawn our attention to the interrelation of dramatist and audience; that is, to the fact of a common guilt as the decisive psychological factor which, on the one hand, enables the dramatist to create his work and, on the other, produces the Aristotelian catharsis, or “purging of the passions.” Freud, in particular, established the psychological traces of the primal crime in classical tragedy and following in his tracks, Winterstein has recently subjected the origins of tragedy to intensive study and radically clarified them.

By contrast, how little has psycho-analysis bothered about comedy! So far it has hardly attracted any interest worth mentioning: at most it was granted a modest domicile in that basement of research, the footnote, there to be dealt with in a cursory manner.
… Strictly Controversial
Authors: Gelb Phillip
Published: January 2007

When my favorite drama critic, Brooks Atkinson, and my favorite playwright, Arthur Miller, make the same mistakes about politics and playwriting, I can conclude only that Atkinson and Miller, like most people, are very nice guys who don't always appreciate the appeal of evil. In an interview I had with Mr. Miller for the radio series “Ideas and the Theatre,” he stated that he would like to see more right-wingers and even fascists writing for the theatre, to keep the drama a true forum. Approaching the same error from another angle, Mr. Atkinson devotes more than a thousand words in his column of June 22nd (1958) answering the question “why don't you do something about the spate of depressing plays?” without ever seeing any political implications in the topic.