bluuebunny/crossref_metadata_2025 huggingface dataset:
Das Gehirn der Zelle: Datenverarbeitung durch Proteinnetzwerke
Authors: Marks Friedrich
Published: May 2004

Proteine sind durch ihre strukturelle Flexibilität befähigt, Rechenoperationen durchzuführen, also Eingangs‐ in Ausgangssignale umzuformen und Daten zu speichern. In der Zelle bilden sie logische Gatterschaltungen, die sich zu hochkomplexen datenverarbeitenden Netzwerken zusammenfügen. Diese enthalten biochemische Oszillatoren, arbeiten also nicht nur mit Amplituden‐ sondern auch mit Frequenzkodierung. Proteinnetzwerke sind flexibel und konstruieren sich je nach den Anforderungen auf chemische und mechanische Weise um. Das — seinerseits durch das Netzwerk kontrollierte — Genom liefert das Betriebssystem und die Bauanleitungen für die Proteine (Hardware). Im Verlauf von Entwicklungs‐ und Lernvorgängen entstehen durch dauernde Neukombination der Komponenten Netzwerkkonstruktionen, deren Komplexität sich nur bedingt aus der Größe des Genoms herleiten lässt.
Sehen statt riechen
Authors: Knoll Ulrike
Published: May 2004

Die Welt ist bunt — zumindest für den Menschen und seine nächsten Verwandten im Tierreich. Um ein breites Spektrum an Farben zu sehen, fangen im Auge drei Zapfenarten Licht unterschiedlicher Wellenlängen ein. Möglicherweise haben sich die Primaten das Farbensehen durch den Untergang vieler Riechgene erkauft.
Laus im Gefieder — schon im frühen Tertiär
Authors: Kremer Bruno P.
Published: May 2004

In den rund 44 Millionen Jahre alten Tonsedimenten von Eckfeld in der Südwesteifel hat eine Forschergruppe der Landessammlung für Naturkunde Rheinland‐Pfalz/Naturhistorisches Museum Mainz das weltweit erste und vollständige Fossil einer Laus entdeckt [1]. Die knapp sieben Millimeter lange, als Megamenopon rasnitsyni— beschriebene Art lässt zahlreiche systematisch relevante Details erkennen und liefert auch Hinweise auf ihr mutmaßliches Wirtsspektrum: Die „Eckfeld‐Laus”︁ saß einem Wasservogel im Gefieder und ist mit Resten ihrer letzten Mahlzeit überliefert.
David Baltimore
Authors: Breckwoldt Michael
Published: May 2004

Vor 35 Jahren entdeckte David Baltimore die reverse Transkriptase und widerlegte damit das „zentrale Dogma”︁ der noch jungen Disziplin Molekularbiologie. Völlig neue Möglichkeiten sollten sich der Wissenschaft eröffnen — vor allem in der Tumorvirologie. Schon wenige Jahre später gelang es erstmals, transgene Organismen zu erzeugen: Die Gentechnik, die unser Leben so grundlegend verändern sollte, war geboren.
Malunion of the ulnar styloid as a cause of ulnar wrist pain
Authors: Xarchas K.C. , Yfandithis P. , Kazakos K.
Published: May 2004

We present a case of ulnar wrist pain that had been wrongly attributed to non‐union of the ulnar styloid. Surgical exploration revealed an ulnar styloid malunion that had caused pain by impinging on the triquetrum and a triangular fibrocartilage complex (TFC) lesion. There was no fracture of the distal radius and no associated carpal instability or disruption of the distal radio‐ulnar joint. Treatment by resection of the ulnar styloid and re‐attachment of the TFC provided a satisfactory outcome. Clin. Anat. 17:418–422, 2004. © 2004 Wiley‐Liss, Inc.
Post‐mastectomy chylous fistula: Anatomical and clinical implications
Authors: Purkayastha Joydeep , Hazarika Sidhartha , Deo S.V.S. , Kar Madhabananda , Shukla N.K.
Published: May 2004

A chylous fistula after a modified radical mastectomy is a rare occurrence; however, major anatomical variations in the termination of the thoracic duct may occur, rendering it susceptible to injury. High output chylous fistulae are difficult to manage and have local, metabolic, and immunologic complications with a mortality rate varying from 12.5–50%. Herein such a case of postmastectomy chylous fistula and its management are discussed. A 56‐year‐old postmenopausal woman with invasive duct carcinoma of the left breast underwent modified radical mastectomy with complete axillary clearance (Level I, II, III nodes). The operative procedure was uneventful. On the commencement of a normal diet, however, the patient started exuding milky fluid from the axillary drain and analysis of the fluid revealed biochemical features compatible with chyle. After 2 weeks of failed conservative management, the axilla was re‐explored. A continuous flow of clear fluid was observed originating from a single major lymphatic trunk inferior to the axillary vein in the region of the former Level II nodes. The leak was controlled by the application of multiple mass ligatures using 2‐0 silk suture. A part of the pectoralis major muscle was rotated and sutured over the area of the leak as additional reinforcement. Suturing a muscle flap over the leak has been described previously and functions theoretically by causing fibrosis. The chylous fistula in the present case was managed successfully with mass ligatures and muscle flap reinforcement. Clin. Anat. 17:413–415, 2004. © 2004 Wiley‐Liss, Inc.
Anomalous branch of the left common carotid artery
Authors: Simic P. , Borovecki F. , Jelic M. , Jelic M. , Vinter I.
Published: May 2004

A previously unreported anomalous branch of the left common carotid artery (LCCA) was observed during dissection at the Zagreb Medical School. The anomalous branch arose from the anterior surface of the LCCA approximately 2 cm superior to the aortic arch, and subsequently bifurcated into a right and left branch. We describe its anatomic features. Clinical implications are also discussed. Clin. Anat. 17:409–412, 2004. © 2004 Wiley‐Liss, Inc.
Magnetic resonance microscopy versus light microscopy in human embryology teaching
Authors: Puerta‐Fonollá J. , Vázquez‐Osorio T. , Ruiz‐Cabello J. , Murillo‐González J. , Peña‐Melián A.
Published: May 2004

A study was carried out on the application of magnetic resonance microscopy (MRM) in teaching prenatal human development. Human embryos measuring 8 mm, 15 mm, 18.5 mm, and 22 mm were fixed in a 4% paraformaldehyde solution and sections obtained with magnetic resonance imaging (MRI) were compared to those prepared for light microscopy (LM), using the same embryos. The MRM and LM slices were of a similar quality. In the MRM sections, embryonic organs and systems were clearly visible, particularly the peripheral and central nervous systems, and the cardiovascular and digestive systems. The digitalization and clarity of the MRM images make them an ideal teaching aid that is suitable for students during the first years of a health‐science degree, particularly medicine. As well as providing students with their first experience of MRM, these images allow students to access, at any time, all embryos used, to assess changes in the positions of different organs throughout their stages of development, and to acquire spatial vision, an absolute requirement in the study of human anatomy. We recommend that this technique be incorporated into the wealth of standard embryonic teaching methods already in use. Clin. Anat. 17:429–435, 2004. © 2004 Wiley‐Liss, Inc.
Numerische Simulationen für biomedizinische Anwendungen
Authors: Megahed M. , Mindt H.‐W. , Hansen‐Schmidt J.
Published: May 2004

No abstracts.
Vergärung von Flash‐Pyrolyseöl aus Holz zu Biogas
Authors: Willner T. , Scherer P. , Meier D. , Vanselow W.
Published: May 2004

No abstracts.
Propanoxidation an Katalysatoren mit Perowskitstruktur im Multimode‐Mikrowellenreaktor – Teil 2
Authors: Will H. , Scholz P. , Ondruschka B. , Burckhardt W.
Published: May 2004

No abstracts.
Intrinsic differences in brain and spinal cord mitochondria: Implication for therapeutic interventions
Authors: Sullivan Patrick G. , Rabchevsky Alexander G. , Keller Jeffery N. , Lovell Mark , Sodhi Ajeet , Hart Ronald P. , Scheff Stephen W.
Published: May 2004

It is well known that regions of the CNS differentially respond to insults. After brain injury, cyclosporine A reduces damage but is ineffective following spinal cord injury. We address this disparity by assessing several parameters of mitochondrial physiology in the normal neocortex and spinal cord. In situ measurements of O production, lipid peroxidation, and mitochondrial DNA oxidation revealed significantly higher levels in spinal cord vs. neocortical neurons. Real‐time PCR demonstrated differences in mitochondrial transcripts coupled with decreases in complex I enzyme activity and respiration in spinal cord mitochondria. The threshold for calcium‐induced mitochondrial permeability transition was substantially reduced in spinal cord vs. neocortex and modulated by lipid peroxidation. These intrinsic differences may provide a pivotal target for strategies to ameliorate neuronal damage following injury, and this imbalance in oxidative stress may contribute to the susceptibility of spinal cord motor neurons in neuropathologies such as amyotrophic lateral sclerosis. J. Comp. Neurol. 474:524–534, 2004. © 2004 Wiley‐Liss, Inc.
Lumbar commissural interneurons with reticulospinal inputs in the cat: Morphology and discharge patterns during fictive locomotion
Authors: Matsuyama Kiyoji , Nakajima Katsumi , Mori Futoshi , Aoki Mamoru , Mori Shigemi
Published: May 2004

The purpose of this study was 1) to characterize the morphology of lumbar commissural neurons (CNs) with reticulospinal inputs and 2) to quantitate their activity during locomotor rhythm generation. Intraaxonal recordings at the L4–7 level of the spinal cord were obtained in 67 neurons in the decerebrate, paralyzed cat. Fourteen of them were subsequently nearly fully visualized following their intraaxonal injection with the tracer neurobiotin. All 14 were CNs with axons projecting across the midline of the spinal cord. Their somata were located mainly in lamina VIII and additionally in laminae VII–VI. Most of the lamina VIII CNs were excited monosynaptically from reticulospinal pathways. They were judged to be interneuronal CNs if they had no, or a short, rostral projection. These CNs commonly gave off multiple axon collaterals in and around their somata's segmental level. They projected mainly to laminae VIII–VII and some additionally to lamina IX. Some laminae VIII and the laminae VII–VI CNs were excited polysynaptically from reticulospinal pathways or were not excited. They were judged to be long propriospinal or ascending tract CNs because they had only an ascending axon. Most lamina VIII CNs discharged rhythmically during fictive locomotion evoked by stimulation of the mesencephalic locomotor region, exhibiting one peak per locomotor cycle. The peak was in phase with neurographic activity of either a left or a right hindlimb extensor nerve. These results suggested that lamina VIII CNs are reciprocally connected bilaterally at each segmental level. Such an arrangement suggests their participation in the generation and coordination of reciprocal and bilateral locomotor activity. J. Comp. Neurol. 474:546–561, 2004. © 2004 Wiley‐Liss, Inc.
STAT3 phosphorylation in injured axons before sensory and motor neuron nuclei: Potential role for STAT3 as a retrograde signaling transcription factor
Authors: Lee Nancy , Neitzel Karen L. , Devlin Brenda K. , MacLennan A. John
Published: May 2004

STAT3 is a latent transcription factor that is activated by plasma membrane growth factor receptor complexes. Conditional gene disruption data indicate that it contributes to the survival of cranial motor neurons after peripheral nerve lesion. In agreement, levels of activated STAT3 (Tyr705‐phosphorylated STAT3) have been shown to increase in the nuclei of adult cranial motor neurons during their regeneration after the same injury. The data presented here demonstrate that STAT3 is similarly but not identically affected in sciatic motor neurons after sciatic nerve injury. In addition, we find that sensory neuron nuclei also display an analogous increase in activated STAT3, thereby supporting a role for STAT3 in the survival and regeneration of these cells. Most interesting, the present data indicate that peripheral nerve lesion leads to a very rapid activation of STAT3 in axons at the lesion site. This response increases during the first 24 hours after injury and extends back to the motor and sensory neurons such that phospho‐STAT3–immunoreactive axons are first detected in the dorsal root ganglia and ventral spinal cord at the same postlesion time intervals at which the activated STAT3 is first detected in the neuronal nuclei. Together these data raise the possibility that axonal STAT3, activated at the injury site, acts as a retrograde signaling transcription factor, which promotes the survival and regeneration of both sensory and motor neurons. J. Comp. Neurol. 474:535–545, 2004. © 2004 Wiley‐Liss, Inc.
Subcellular and subsynaptic localization of group I metabotropic glutamate receptors in the monkey subthalamic nucleus
Authors: Kuwajima Masaaki , Hall Randy A. , Aiba Atsu , Smith Yoland
Published: May 2004

Both subtypes of group I metabotropic glutamate receptor, mGluR1 and mGluR5, are expressed postsynaptically in neurons of the subthalamic nucleus (STN), and their activation induces different physiological responses. To test whether these effects could be explained by a differential localization of the two group I mGluRs, we analyzed the subcellular and subsynaptic distribution of mGluR1a and mGluR5 in the monkey STN. Double‐immunofluorescence and light microscopic analyses revealed that both group I mGluR subtypes were strongly coexpressed in the neuropil and neuronal perikarya. Astrocytic perikarya exhibited intense mGluR1a, but no detectable mGluR5, immunoreactivity. At the electron microscopic level, immunoperoxidase labeling for both mGluR1a and mGluR5 was localized mainly in dendrites. A significant proportion of the total pool of mGluR1a‐immunoreactive elements was accounted for by glial cell processes, whereas glial cell labeling was much less frequently encountered in sections immunostained for mGluR5. Preembedding immunogold labeling in STN dendrites revealed that 60–70% of the gold labeling for both mGluR subtypes was intracellular, whereas 30–40% was apposed to the plasma membrane. Of the plasma membrane‐apposed particles, more than 90% were extrasynaptic; fewer than 10% were associated with symmetric or asymmetric synapses. Most of the synapse‐associated labeling was found at the edges of both asymmetric and symmetric postsynaptic specializations. Some extrasynaptic gold particles were aggregated on parts of the plasma membrane tightly apposed by glial processes. These findings demonstrate that mGluR1a and mGluR5 exhibit a similar pattern of subsynaptic localization in monkey STN neurons, with both receptor subtypes exhibiting substantial extrasynaptic and perisynaptic localization. J. Comp. Neurol. 474:589–602, 2004. © 2004 Wiley‐Liss, Inc.
Supramolecular Hydrogen‐Bond Structures and Magnetic Interactions in Basal‐Apical, Dinuclear, Azide‐Bridged Copper(II) Complexes
Authors: Ray Mau Sinha , Ghosh Ashutosh , Chaudhuri Siddhartha , Drew Michael G. B. , Ribas Joan
Published: May 2004

The synthesis, characterisation, X‐ray single crystal structures and magnetic properties of three new basal‐apical μ2‐1,1‐azide‐bridged complexes [CuL1N3]2 (1), [CuL2N3]2 (2) and [CuL3N3]2 (3) with very similar tridentate Schiff‐base blocking ligands {HL1 = N‐[2‐(ethylamino)ethyl]salicylaldimine; HL2 = 7‐(ethylamino)‐4‐methyl‐5‐azahept‐3‐en‐2‐one; HL3 = 7‐amino‐4‐methyl‐5‐azaoct‐3‐en‐2‐one} have been reported [complex 1: monoclinic, P21/c, a = 8.390(2), b = 7.512(2), c = 19.822(6) Å, β = 91.45(5)°; complex 2: monoclinic, P21/c, a = 8.070(9), b = 9.787(12), c = 15.743(17) Å, β = 98.467(10)°; complex 3: monoclinic, P21/n, a = 5.884(7), b = 16.147(18), c = 11.901(12) Å, β = 90.050(10)°]. The structures consist of neutral dinuclear entities resulting from the pairing of two mononuclear units through end‐on azide bridges connecting an equatorial position of one copper centre to an axial position of the other. The copper ions adopt a (4+1) square‐based geometry in all the complexes. In complex 2, there is no inter‐dimer hydrogen‐bonding. However, complexes 1 and 3 form two different supramolecular structures in which the dinuclear entities are linked by H‐bonds giving one‐dimensional systems. Variable temperature (300−2 K) magnetic‐susceptibility measurements and magnetisation measurements at 2 K reveal that all three complexes have antiferromagnetic coupling. Magneto‐structural correlations have been made taking into consideration both the azido bridging ligands and the existence of intermolecular hydrogen bonds. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004)
A Neural Network Model in the Calibration of Glucose Sensor Based on the Immobilization of Glucose Oxidase into Polypyrrole Matrix
Authors: Seker S. , Becerik I.
Published: May 2004

The immobilization of enzymes on an electrode surface is of great importance in bioelectrochemistry. The entrapment of enzymes into a polymer matrix is simple and a speedy technique for the production of biosensors. This procedure of enzyme immobilization by electropolymerization has a great significance in fabrication of micro sensors in the preparation of multiplayer devices. In current study, glucose oxidase enzyme that is specific for the glucose determination was entrapped into polypyrrole matrix containing p‐benzoquinone in PIPES buffer and glucose sensitivity of the biosensor was investigated. Then, artificial neural network analysis was done for the nonlinear calibration plot. This implementation can be used for the sensor failure detection, as well. The estimation power of the neural network used in the direct and inverse calibration modelling was examined by statistical methods. It presented the good performance for the estimation power.
Nitric oxide protects rat hepatocytes against reperfusion injury mediated by the mitochondrial permeability transition
Authors: Kim Jae-Sung , Ohshima Shigetoshi , Pediaditakis Peter , Lemasters John J.
Published: May 2004

We investigated the effects of nitric oxide (NO) on hepatocellular killing after simulated ischemia/reperfusion and characterized signaling factors triggering cytoprotection by NO. Cultured rat hepatocytes were incubated in anoxic Krebs-Ringer-HEPES buffer at pH 6.2 for 4 hours and reoxygenated at pH 7.4 for 2 hours. During reoxygenation, some hepatocytes were exposed to combinations of NO donors (S-nitroso-N-acetylpenicillamine [SNAP] and others), a cGMP analogue (8-bromoguanosine-3,5-cGMP [8-Br-cGMP]), and a cGMP-dependent protein kinase inhibitor (KT5823). Cell viability was determined by way of propidium iodide fluorometry. Inner membrane permeabilization and mitochondrial depolarization were monitored by confocal microscopy. SNAP, but not oxidized SNAP, increased cGMP during reperfusion and decreased cell killing. Other NO donors and 8-Br-cGMP also prevented cell killing. Both guanylyl cyclase and cGMP-dependent kinase inhibition blocked the cytoprotection of NO. However, 5-hydroxydecanoate and diazoxide— mitochondrial KATP channel modulators—did not affect NO-dependent cytoprotection or reperfusion injury. During reoxygenation, confocal microscopy showed mitochondrial repolarization, followed by depolarization, inner membrane permeabilization, and cell death. In the presence of either SNAP or 8-Br-cGMP, mitochondrial repolarization was sustained after reperfusion preventing inner membrane permeabilization and cell death. In isolated rat liver mitochondria, a cGMP analogue in the presence of a cytosolic extract and adenosine triphosphate blocked the Ca2+-induced mitochondrial permeability transition (MPT), an effect that was reversed by KT5823. In conclusion, NO prevents MPT-dependent necrotic killing of ischemic hepatocytes after reperfusion through a guanylyl cyclase and cGMP-dependent kinase signaling pathway, events that may represent the target of NO cytoprotection in preconditioning. (Hepatology 2004;39:1533-1543.)
Interleukin-1β represses MRP 2 gene expression through inactivation of interferon regulatory factor 3 in HepG2 cells
Authors: Hisaeda Keiji , Inokuchi Akihiko , Nakamura Takanori , Iwamoto Yukihide , Kohno Kimitoshi , Kuwano Michihiko , Uchiumi Takeshi
Published: May 2004

The human multidrug resistance protein 2 (MRP2/ABCC2), expressed on the bile canalicular membrane, mediates the multispecific efflux of several organic anions, including conjugates of glucuronate, sulfate, and glutathione. Expression of MRP2 can be altered in response to environmental stimuli such as cholestasis and jaundice. We previously reported that MRP2 mRNA expression levels are decreased in the nontumorous part of hepatitis C virus-infected human liver tissues, and that inflammatory cytokines inhibit MRP2 expression in human hepatic (HepG2) cells. We investigated the molecular mechanisms by which inflammatory cytokines modulate MRP2 gene expression in hepatic cells. Treatment of human hepatic cells with interleukin-1β (IL-1β) or tumor necrosis factor α resulted in a decrease in the protein and mRNA levels of MRP2. IL-1β inhibited the transcriptional activity of MRP2 promoter constructs by 40%, and this inhibition of MRP2 promoter activity was mediated through the interferon stimulatory response element (ISRE). Electrophoretic mobility shift assays with IL-1β-treated nuclear extracts showed a decrease in the formation of DNA protein complexes, specifically those including interferon regulatory factor 3 (IRF3). Expression of recombinant human IRF3 increased MRP2 promoter activity. Treatment with a specific extracellular signal-regulated kinase inhibitor relieved IL-1β-induced MRP2 mRNA downregulation and abrogated the binding of IRF3 to the ISRE element. In conclusion, IL-1β induces downregulation of the MRP2 gene by inactivating IRF3 binding to ISRE on the MRP2 promoter in human hepatic cells; this inactivation is accomplished via interference with the extracellular signal-regulated kinase pathway. (Hepatology 2004;39:1574-1582.)
Susceptibility of murine periportal hepatocytes to hypoxia-reoxygenation: Role for NO and Kupffer cell-derived oxidants
Authors: Taniai Hisashi , Hines Ian N. , Bharwani Sulaiman , Maloney Ronald E. , Nimura Yuji , Gao Bifeng , Flores Sonia C. , McCord Joe M. , Grisham Matthew B. , Aw Tak Yee
Published: May 2004

Ischemia/reperfusion (I/R) is an important problem in liver resection and transplantation that is associated with hepatocellular dysfunction and injury. This study was designed to investigate whether a difference in hepatocyte susceptibility occurs in the periportal (PP) and/or perivenous (PV) zones in response to hypoxia/reoxygenation (H/R), and to delineate the mechanisms underlying this susceptibility. H/R was induced in an in situ perfused mouse liver model with deoxygenated Krebs-Henseleit buffer followed by oxygenated buffer. Selective destruction of PP or PV sites was achieved by digitonin perfusion into the portal or inferior vena cava, and was confirmed by histological evaluations and zone-specific enzymes. Hepatocellular injury was assessed by alanine aminotransferase (ALT) release. In whole liver, H/R significantly increased perfusate ALT. H/R of PP-enriched zones caused ALT release that was similar to that of whole liver (80 + 10 vs. 70 + 12 U/mg protein), consistent with significant PP hepatocyte injury. Minimal ALT release occurred in PV zones (10 + 5 U/mg protein). Administration of N-acetyl L-cysteine or a chimeric superoxide dismutase (SOD)—SOD2/3, a genetically engineered SOD—abrogated ALT release in H/R-perfused PP zones, implicating a role for superoxide (OSymbol). This elevated ALT release was attenuated by gadolinium chloride pretreatment, indicating that Kupffer cells are the OSymbol source. Enzymatic inhibition of cellular nitric oxide synthase (NOS) or genetic depletion of endothelial nitric oxide synthase (eNOS) aggravated hypoxia injury while exogenous NO and inducible nitric oxide synthase (iNOS) deficiency abolished reoxygenation injury. In conclusion, PP hepatocytes are more vulnerable to H/R; this injury is mediated directly or indirectly by Kupffer cell derived OSymbol and is limited by eNOS-derived NO. (Hepatology 2004;39:1544-1552.)
Halting the interaction between vascular endothelial growth factor and its receptors attenuates liver carcinogenesis in mice
Authors: Yoshiji Hitoshi , Kuriyama Shigeki , Yoshii Junichi , Ikenaka Yasuhide , Noguchi Ryuichi , Hicklin Daniel J. , Wu Yan , Yanase Koji , Namisaki Tadashi , Kitade Mitsuteru , Yamazaki Masaharu , Tsujinoue Hirohisa , Masaki Tsutomu , Fukui Hiroshi
Published: May 2004

It has been shown that angiogenesis plays an important role not only in tumor growth, but also in early carcinogenesis. The expression of a potent angiogenic factor, vascular endothelial growth factor (VEGF), increased during the early stage of carcinogenesis. In this study, the effects of the neutralizing monoclonal antibodies R1 mAb and R2 mAb of the VEGF receptors Flt-1 (VEGFR-1) and KDR/Flk-1 (VEGFR-2), respectively, on murine hepatocarcinogenesis induced by diethylnitrosamine (DEN) were examined. The effects of R1 mAb and R2 mAb on spontaneous lung metastasis from hepatocellular carcinoma (HCC) were also investigated. VEGF expression and neovascularization in the tumor increased stepwise during hepatocarcinogenesis. Treatment with both R1 mAb and R2 mAb markedly inhibited the development of HCC and adenoma in the liver. The inhibitory effect of R2 mAb was more potent than that of R1 mAb, and the combination treatment with both mAbs almost completely attenuated hepatocarcinogenesis. Both R1 mAb and R2 mAb treatment significantly suppressed the development of angiogenesis in HCC. The suppressive effects against angiogenesis R1 mAb and R2 mAb were similar in magnitude to their inhibitory effects against hepatocarcinogenesis. Furthermore, spontaneous lung metastasis from HCC was also significantly suppressed by R1 mAb and R2 mAb treatment. In conclusion, these results suggest that VEGF and receptor interaction plays an important role in hepatocarcinogenesis and in spontaneous lung metastasis from HCC. (Hepatology 2004;39:1517-1524.)
Prediction of liver fibrosis in patients with features of the metabolic syndrome regardless of alcohol consumption
Authors: Lainé Fabrice , Bendavid Claude , Moirand Romain , Tessier Sabrina , Perrin Michèle , Guillygomarc'h Anne , Guyader Dominique , Calon Emmanuelle , Renault Alain , Brissot Pierre , Turlin Bruno , Deugnier Yves
Published: May 2004

The aim of this study was to determine noninvasive predictive factors of significant liver fibrosis in patients with increased serum aminotransferases associated with features of metabolic syndrome (abdominal obesity, systemic hypertension, fasting hyperglycemia, and dyslipidemia). One hundred seventy-three patients were prospectively examined, regardless of alcohol consumption. Biometric, metabolic, and hepatic biochemical variables were tested for association with fibrosis assessed on liver biopsy according to the Metavir score system. Significant fibrosis, defined as Metavir scores F2, F3, or F4, was observed in 42 of 173 patients (24%). A logistic regression model and receiver operating characteristic curve were used to construct a simple index predictive of significant fibrosis. None of the patients with serum hyaluronate levels of 35 μg/L or less had significant fibrosis. In patients with serum hyaluronate levels >35 μg/L, no case of fibrosis stage F3 or F4 was found when serum carbohydrate-deficient transferrin/transferrin ratio was less than 0.9. In conclusion, in patients with increased serum aminotransferases associated with features of metabolic syndrome, a simple algorithm, including serum hyaluronate and serum carbohydrate-deficient transferrin/transferrin ratio, allows the exclusion of clinically relevant hepatic fibrosis, regardless of current or past alcohol consumption. (Hepatology 2004;39:1639-1646.)
Patient and graft survival after liver transplantation for hereditary hemochromatosis: Implications for pathogenesis
Authors: Crawford Darrell H.G. , Fletcher Linda M. , Hubscher Stefan G. , Stuart Katherine A. , Gane Edward , Angus Peter W. , Jeffrey Gary P. , McCaughan Geoffrey W. , Kerlin Paul , Powell Lawrie W. , Elias Elwyn E.
Published: May 2004

The clinical outcome of patients who have undergone liver transplantation for hereditary hemochromatosis (HH) or who have received iron-loaded donor grafts is unclear. We reviewed 3,600 adult primary orthotopic liver transplants and assessed the outcomes in 22 patients with HH. We also evaluated graft function and iron mobilization in 12 recipients of iron-loaded donor grafts. All 22 subjects who received liver transplants for HH were male; 13 had other risk factors for liver disease. HH patients had comparatively poor outcomes following transplantation: survival at 1, 3, and 5 years posttransplantation were 72%, 62%, and 55%, respectively. Recurrent hepatocellular cancer was the most common cause of death. There was no convincing evidence of reaccumulation of iron in the grafted liver in HH; however, 1 subject demonstrated increased serum ferritin concentration and grade 2 hepatic siderosis. Liver iron stores were slow to mobilize in 7 of the 12 recipients of iron-loaded grafts. These recipients had appropriate early graft function, but 2 patients with heavy iron loading and increased hepatic iron developed hepatic fibrosis. In conclusion, (1) HH is an uncommon indication for liver transplantation, and the majority of patients requiring transplantation had other risk factors for chronic liver disease; (2) reaccumulation of liver iron in HH patients is very unusual, but increased iron stores may be slow to mobilize in normal recipients of iron-loaded grafts, potentially compromising late graft function; (3) post-liver transplant survival is reduced in HH, and affected patients require careful clinical evaluation of perioperative and postoperative risk factors. Our data suggest that iron excess in HH does not wholly depend on intestinal iron absorption but is also influenced by liver factors that moderate iron metabolism. (Hepatology 2004;39:1655-1662.)
Improvement of rat liver graft quality by pifithrin-α-mediated inhibition of hepatocyte necrapoptosis
Authors: El-Gibaly Amr M. , Scheuer Claudia , Menger Michael D. , Vollmar Brigitte
Published: May 2004

Early graft dysfunction due to ischemia reperfusion injury remains a major clinical challenge in liver transplantation. Because apoptosis may contribute to graft dysfunction, we studied whether transient inhibition of p53 is capable of improving graft quality by reducing apoptotic cell death. Rat livers were harvested and stored for 24 hours or 48 hours in a 4°C solution containing either pifithrin-α (PFT-α), a specific p53-inhibitor, or the vehicle dimethyl-sulfoxide. Storage was followed by 2-hour reperfusion with 37°C Krebs-Henseleit buffer in an isolated liver perfusion system. Besides caspase-3 activation, apoptosis was quantified using fluorescence microscopy and hematoxylin-eosin histology. Trypan blue allowed for assessment of cell membrane damage, indicating both secondary apoptosis and primary necrosis. Bile flow, oxygen consumption, K+-excretion and enzyme release served as indicators of overall graft quality. Upon 2-hour reperfusion, livers developed procaspase activation as well as a mixture of apoptotic and necrotic cell death, representing necrapoptosis. In livers that had been stored for 48 hours, necrapoptotic injury was more pronounced compared with that after 24-hour storage. PFT-α effectively attenuated caspase activation as well as hepatocellular apoptosis and necrosis. Attenuation of both modes of cell death by PFT-α was associated with improved liver function, metabolism, and integrity. Experiments with the caspase inhibitor z-VAD-fmk confirmed that apoptosis is one mode of cell death in cold ischemia reperfusion. In conclusion, inhibition of p53-dependent apoptosis by PFT-α reduces hepatic preservation-reperfusion injury and improves primary organ function and metabolism. Fortification of the preservation solution with PFT-α may represent a promising and easily applicable approach to mitigate reperfusion injury in liver transplants. (Hepatology 2004;39:1553-1562.)
Tauroursodeoxycholic acid protects rat hepatocytes from bile acid-induced apoptosis via activation of survival pathways†
Authors: Schoemaker Marieke H. , de la Rosa Laura Conde , Buist-Homan Manon , Vrenken Titia E. , Havinga Rick , Poelstra Klaas , Haisma Hidde J. , Jansen Peter L. M. , Moshage Han
Published: May 2004

Ursodeoxycholic acid (UDCA) is used in the treatment of cholestatic liver diseases, but its mechanism of action is not yet well defined. The aim of this study was to explore the protective mechanisms of the taurine-conjugate of UDCA (tauroursodeoxycholic acid [TUDCA]) against glycochenodeoxycholic acid (GCDCA)-induced apoptosis in primary cultures of rat hepatocytes. Hepatocytes were exposed to GCDCA, TUDCA, the glyco-conjugate of UDCA (GUDCA), and TCDCA. The phosphatidylinositol-3 kinase pathway (PI3K) and nuclear factor-κB were inhibited using LY 294002 and adenoviral overexpression of dominant-negative IκB, respectively. The role of p38 and extracellular signal-regulated protein kinase mitogen-activated protein kinase (MAPK) pathways were investigated using the inhibitors SB 203580 and U0 126 and Western blot analysis. Transcription was blocked by actinomycin-D. Apoptosis was determined by measuring caspase-3, -9, and -8 activity using fluorimetric enzyme detection, Western blot analysis, immunocytochemistry, and nuclear morphological analysis. Our results demonstrated that uptake of GCDCA is needed for apoptosis induction. TUDCA, but not TCDCA and GUDCA, rapidly inhibited, but did not delay, apoptosis at all time points tested. However, the protective effect of TUDCA was independent of its inhibition of caspase-8. Up to 6 hours of preincubation with TUDCA before addition of GCDCA clearly decreased GCDCA-induced apoptosis. At up to 1.5 hours after exposure with GCDCA, the addition of TUDCA was still protective. This protection was dependent on activation of p38, ERK MAPK, and PI3K pathways, but independent of competition on the cell membrane, NF-κB activation, and transcription. In conclusion, TUDCA contributes to the protection against GCDCA-induced mitochondria-controlled apoptosis by activating survival pathways. Supplemental material for this article can be found on the Hepatology website (http://interscience.wiley.com/jpages/0270-9139/supplmat/index.html). (Hepatology 2004;39:1563-1573.)
DDB treatment of patients with chronic hepatitis
Authors: Huber Roman , Hockenjos Birgit , Blum Hubert E.
Published: May 2004

We report 13 patients (10 with chronic hepatitis C, 1 with chronic hepatitis B, 2 with nonalcoholic steatohepatitis) with persistently elevated alanine aminotransferase (ALT) levels who were treated with dimethyl-4,4′-dimethoxy-5,6,5′,6-dimethylenedioxybiphenyl-2,2′ dicarboxylate (DDB). ALT rapidly normalized in 12/13 patients and remained normal during treatment. Unlike ALT levels, aspartate aminotransferase, gamma-glutamyl transferase and glutamate dehydrogenase levels were not affected. Furthermore, there was no beneficial effect on the histological grade and stage of liver disease. In vitro experiments with hepatocytes resulted in a significant decrease of hepatocellular ALT levels in the DDB treated cells, suggesting, that DDB affects the synthesis and/or degradation of ALT in liver cells. In conclusion, the normalization of ALT during DDB treatment does not indicate therapeutic efficacy. In view of the wide use of DDB in patients with chronic liver diseases who participate in clinical studies DDB use should be excluded. (Hepatology 2004;39:1732-1733.)
Overdependence on the host—an Achilles' heel of HCV?
Authors: Glenn Jeffrey S. , Jaeschke Hartmut , Mullen Kevin , Moradpour Darius
Published: May 2004

Hepatitis C virus (HCV) RNA replication depends on viral protein association with intracellular membranes, but the influence of membrane composition on viral replication is unclear. We report that HCV RNA replication and assembly of the viral replication complex require geranylgeranylation of one or more host proteins. In cultured hepatoma cells, HCV RNA replication was disrupted by treatment with lovastatin, an inhibitor of 3-hydroxy-3-methyglutaryl CoA reductase, or with an inhibitor of protein geranylgeranyl transferase I, each of which induced the dissolution of the HCV replication complex. Viral replication was not affected by treatment of cells with an inhibitor of farnesyl transferase. When added to lovastatin-treated cells, geranylgeraniol, but not farnesol, restored replication complex assembly and viral replication. Inasmuch as the HCV genome does not encode a canonical geranylgeranylated protein, the data suggest the involvement of a geranylgeranylated host protein in HCV replication. Inhibition of its geranylgeranylation affords a therapeutic strategy for treatment of HCV infection.
Two reentrant pathways in the hippocampal‐entorhinal system
Authors: Kloosterman Fabian , van Haeften Theo , Lopes da Silva Fernando H.
Published: May 2004

The entorhinal cortex has long been recognized as an important interface between the hippocampal formation and the neocortex. The notion of bidirectional connections between the entorhinal cortex and the hippocampal formation have led to the suggestion that hippocampal output originating in CA1 and subiculum may reenter hippocampal subfields via the entorhinal cortex. To investigate this, we used simultaneous multi‐site field potential recordings and current source density analysis in the entorhinal cortex and hippocampal formation of the rat in vivo. Under ketamine/xylazine anesthesia, we found that repetitive stimulation of subiculum or Schaffer collaterals facilitated entorhinal responses, such that a population spike appeared in layer III. In addition, a current sink in stratum lacunosum‐moleculare of area CA1 was found, that followed responses in the entorhinal cortex, indicating reentrance into this area. Responses indicating reentrance in the dentate gyrus were not found under ketamine/xylazine anesthesia, but were readily evoked under urethane anesthesia. Reentrance into CA1 was also encountered under urethane anesthesia. These results suggest that parallel, but possibly functionally distinct, connections are present between the output of the hippocampal formation and cells in layers III and II of the entorhinal cortex that project to area CA1 and the dentate gyrus, respectively. © 2004 Wiley‐Liss, Inc.
Group work in a Dutch home care organization: does it improve the quality of working life?
Authors: Schouteten Roel
Published: May 2004

Home care in the Netherlands is facing a trend towards increasing workloads, giving it the image of an unattractive sector to work in. To deal with increasing workloads and their effects, many solutions have been developed, including the concept of team or group work. This paper will address the possibilities, conditions and effects involved in the implementation of group work in home care as a means of improving the quality of working life (QWL) in this sector. To this end I have studied QWL in three jobs in two organizations for home care, one of which implemented group work. This comparison concludes that jobs in the team‐based organization are more complete and challenging, bringing more job decision latitude, but also higher work pressure. Copyright © 2004 John Wiley & Sons, Ltd.
Health service quality and users' perceptions in West Nile, Uganda
Authors: Witter Sophie , Osiga Gamba
Published: May 2004

Save the Children (UK) has been working in health in the West Nile region of Uganda since 1980. Between 2000 and 2002, a number of operational research studies have been conducted which shed light on patient perceptions of the quality of services, of barriers to access and utilization patterns. These are brought together in this paper. They show that despite considerable progress in rebuilding infrastructure, training staff and investing in health systems in these districts, there is still a long way to go to provide services of an acceptable quality to users. Copyright © 2004 John Wiley & Sons, Ltd.
Comparative efficacy of newer hypnotic drugs for the short‐term management of insomnia: a systematic review and meta‐analysis
Authors: Dündar Yenal , Dodd Susanna , Strobl Judith , Boland Angela , Dickson Rumona , Walley Tom
Published: May 2004

Objectives

To compare the clinical effectiveness of zaleplon, zolpidem or zopiclone (Z‐drugs) with either benzodiazepines licensed and approved for use in the UK for the short‐term management of insomnia (diazepam, loprazolam, lorazepam, lormetazepam, nitrazepam, temazepam) or with each other.

Methods

MEDLINE, EMBASE, PsycINFO, Science Citation Index/Web of Science were searched from 1966 to March 2003 and The Cochrane Library, reference lists of included studies and a number of psychopharmacology journals. Randomized controlled trials comparing either benzodiazepines with the Z‐drugs or any two of the Z‐drugs in patients with insomnia were included. Outcome measures included: sleep onset latency, total sleep duration, number of awakenings, quality of sleep, adverse events, tolerance, rebound insomnia and daytime alertness.

Results and conclusions

Twenty four eligible studies were identified with a total study population of 3909 (17 studies comparing a Z‐drug with a benzodiazepine and 7 comparing a Z‐drug). Insufficient or inappropriately reported data meant that meta‐analysis was possible only for a small number of outcomes. There are few clear, consistent differences between the drugs. Some evidence suggests that zaleplon gives shorter sleep latency but shorter duration of sleep than zolpidem, reflecting the pharmacological profiles of the drugs. Copyright © 2004 John Wiley & Sons, Ltd.
Serum disposition of sertraline, N‐desmethylsertraline and paroxetine: a pharmacokinetic evaluation of repeated drug concentration measurements during 6 months of treatment for major depression
Authors: Reis Margareta , Åberg‐Wistedt Anna , Ågren Hans , Höglund Peter , Åkerblad Ann‐Charlotte , Bengtsson Finn
Published: May 2004

Sertraline and paroxetine are frequently prescribed SSRIs for long‐term treatment of major depression. Nevertheless, continuous follow‐ups of drug concentrations prevailing in patients during the whole treatment period are not available. Hence, in a large phase IV clinical trial, a total of 353 patients with major depression were enrolled for a 6‐month comparison of sertraline (50–150 mg daily) and paroxetine (20–60 mg daily). The present study reports the pharmacokinetic results of up to eight serum samples per patient.

A profound variability was found in the interindividual steady state and trough serum levels of sertraline, desmethylsertraline and paroxetine: the coefficient of variation (CV) was 59% for sertraline, 51% for desmethylsertraline, 27% for the ratio desmethylsertraline/sertraline (50 mg/day), and 71% for paroxetine (20 mg/day). The intraindividual CV for the ratio desmethylsertraline/sertraline was only 19%, indicating intraindividual metabolizing stability over time. Both sertraline and paroxetine displayed sex differences in the dose‐concentration correlation.

It was possible to predict sertraline, but not paroxetine, steady state levels.

The terminal elimination t½ for both drugs after 6 months of treatments was similar to data previously reported from short‐term withdrawal studies.

No correlation between serum drug concentrations and clinical effect was detected for either sertraline or paroxetine.

For the future, continuous efforts are warranted to perform PK investigations in the natural clinical setting in which the drugs are usually prescribed. Copyright © 2004 John Wiley & Sons, Ltd.
Coping and responses to stress in Navajo adolescents: Psychometric properties of the Responses to Stress Questionnaire
Authors: Wadsworth Martha E. , Rieckmann Traci , Benson Molly A. , Compas Bruce E.
Published: May 2004

This study tested the factor structure of coping and stress responses in Navajo adolescents and examined the reliability and validity of the Responses to Stress Questionnaire (RSQ; Connor‐Smith, Compas, Wadsworth, Thomsen, & Saltzman, 2000) with this population. Confirmatory factor analyses revealed that a correlated five‐factor model of stress responses using the five factors of the RSQ fit the data well for this group of adolescents. The factor structure of the RSQ did not differ by gender. Internal consistency of the RSQ scales and factors was acceptable, and convergent and discriminant validity were moderate to high. Primary and secondary control engagement coping responses were associated with fewer depressive symptoms in the sample, whereas disengagement coping and involuntary engagement responses were associated with more depressive symptoms. The promising implications for stress and coping research with American Indian adolescents are emphasized. © 2004 Wiley Periodicals, Inc. J Comm Psychol 32: 391–411, 2004.
Role of caspases in the regulation of apoptotic pancreatic islet beta‐cells death
Authors: Hui Hongxiang , Dotta Francesco , Mario Umberto Di , Perfetti Riccardo
Published: May 2004

The homeostatic control of beta‐cell mass in normal and pathological conditions is based on the balance of proliferation, differentiation, and death of the insulin‐secreting cells. A considerable body of evidence, accumulated during the last decade, has emphasized the significance of the disregulation of the mechnanisms regulating the apoptosis of beta‐cells in the sequence of events that lead to the development of diabetes. The identification of agents capable of interfering with this process needs to be based on a better understanding of the beta‐cell specific pathways that are activated during apoptosis. The aim of this article is fivefold: (1) a review of the evidence for beta‐cell apoptosis in Type I diabetes, Type II diabetes, and islet transplantation, (2) to review the common stimuli and their mechanisms in pancreatic beta‐cell apoptosis, (3) to review the role of caspases and their activation pathway in beta‐cell apoptosis, (4) to review the caspase cascade and morphological cellular changes in apoptotic beta‐cells, and (5) to highlight the putative strategies for preventing pancreatic beta‐cells from apoptosis. © 2004 Wiley‐Liss, Inc.
Subgraphs in vertex neighborhoods of Kr‐free graphs
Authors: Bang‐Jensen Jorgen , Brandt Stephan
Published: May 2004

In a Kr‐free graph, the neighborhood of every vertex induces a Kr − 1‐free subgraph. The Kr‐free graphs with the converse property that every induced Kr − 1‐free subgraph is contained in the neighborhood of a vertex are characterized, based on the characterization in the case r − 3 due to Pach [8]. © 2004 Wiley Periodicals, Inc. J Graph Theory 47: 29–38, 2004
Effects of unilateral vestibular ganglionectomy on glutaminase activity in the vestibular nerve root and vestibular nuclear complex of the rat
Authors: Godfrey Donald A. , Xu Jiansong , Godfrey Matthew A. , Li Hongyan , Rubin Allan M.
Published: May 2004

The metabolism of glutamate, the most likely neurotransmitter of vestibular ganglion cells, includes synthesis from glutamine by the enzyme glutaminase. We used microdissection combined with a fluorometric assay to measure glutaminase activity in the vestibular nerve root and nuclei of rats with unilateral vestibular ganglionectomy. Glutaminase activity in the lesioned‐side vestibular nerve root decreased by 62% at 4 days after ganglionectomy and remained at similar values through 30 days. No change occurred in the contralateral vestibular nerve root. Glutaminase activity changes in the vestibular nuclei were lesser in magnitude and more complex, including contralateral increases as well as ipsilateral decreases. At 4 days after ganglionectomy, glutaminase activity was 10–20% lower in individual lesioned‐side nuclei compared with their contralateral counterparts. By 14 and 30 days after ganglionectomy, there were no statistically significant differences between the nuclei on the two sides. This transient asymmetry of glutaminase activities in the vestibular nuclei contrasts with the sustained asymmetry in the vestibular nerve root and suggests that intrinsic, commissural, or descending pathways are involved in the recovery of chemical symmetry. This recovery resembles our previous finding for glutamate concentrations in the vestibular nuclei and may partially underlie central vestibular compensation after peripheral lesions. © 2004 Wiley‐Liss, Inc.