bluuebunny/crossref_metadata_2025 huggingface dataset:
Expression of Cytokeratins 7 and 20 in Helicobacter pylori-associated Chronic Gastritis in Children
Authors: Cohen M. , Rúa E. Cueto , Balcarce N. , Drut R.
Published: March 2004

Helicobacter pylori gastric infection induces structural changes in the gastric epithelium. Among them, variations in the expression of cytokeratins have been reported in adult patients. In the present study, we describe the expression of CK7 and CK20 in gastric samples taken from the antrum in three groups of pediatric patients: (A) Helicobacter pylori-associated chronic gastritis (mean age: 11.4 years); (B) previous H. pylori chronic gastritis patients (mean age: 9.4 years); and (C) controls (mean age: 8.8 years). In all, the presence of sulfomucins was assessed with Alcian blue-periodic acid-Schiff pH 1.0. Immunoreactivity was graded as absent (0), weak (1 +), moderate (2+), or intense (3+), in accordance with the intensity of the staining, and its distribution as focal or diffuse. CK7 reactivity was 2 + either focal or diffuse in all group A biopsies. The reactivity was more evident in the cells at the neck of the glands, in the areas with more inflammatory infiltrates, decorating long vertical segments of epithelium. In groups B and C, CK7 reactivity was also focal and 1 + at the cells of the necks of the glands. However, group B presented longer vertical segments of positive cells as compared to group C, and shorter than those of group A. The deeper glandular structures were focally 1 + in both groups. CK20 expression was comparable in all three groups, depicting a 2+ diffuse reactivity at the surface epithelium and interposed pits with absence or focal reactivity at the neck and coiled gland areas. Ki-67 immunostaining paralleled that of the CK7. Staining for sulfated mucosubstances was positive in two of five cases of groups A and B, and in none of the cases of group C. We conclude that: (1) the long segments of CK7-positive glandular necks in H. pylori cases most probably indicate intense regenerative activity during active inflammation; (2) eradication of H. pylori does not warrant ad integrum restitution since long segments of Ki-67+, CK7+ cells at the germinative compartment of the glands (as well as cells with sulfomucins) were still recognizable in ex- H. pylori patients; (3) finally, differing from what happens in adults, children somehow manage to maintain fully differentiated CK20+ superficial epithelium while the H. pylori is in action.
Localized Nodular Hypertrophy Mimicking Rhabdomyoma in the Fetal Heart: Prenatal Sonographic and Pathology Findings
Authors: Tehrani Mahtab , Vettraino Ivana M. , Chang Chung-ho
Published: March 2004

Multiple intracardiac masses (ICM) are considered to be diagnostic of rhabdomyoma often associated with tuberous sclerosis. We describe a fetus with multiple ICM detected by fetal sonography at 18.7 wk gestation. The appearance and number were consistent with leading diagnosis of rhabdomyoma. Due to complications of pregnancy and extreme prematurity, the fetus did not survive. Autopsy showed the cardiac masses to be localized nodular hypertrophy (LNH) of the myocardium. No features of rhabdomyoma or tuberous sclerosis were present. In a review of the literature, similar lesions were reported in a child and two adults, perhaps as localized variants of hypertrophic cardiomyopathy. Our case does not, however, show the histopathologic features of hypertrophic cardiomyopathy. Isolated developmental abnormalities, such as in this case, can have a mass effect mimicking cardiac tumors. At the time of autopsy, the largest mass in the anterior wall of the right ventricle extended to and obstructed the right ventricular outflow tract.
Collapsing Glomerulopathy in a 16-Year-Old Girl with Pulmonary Tuberculosis: The Role of Systemic Inflammatory Mediators
Authors: Coventry Susan , Shoemaker Lawrence R.
Published: March 2004

Idiopathic collapsing glomerulopathy is an aggressive variant of focal segmental glomerulosclerosis (FSGS) seen primarily in adults. Its etiology is unknown. Nearly identical pathology is seen in association with nephrotic syndrome in human immunodeficiency virus type 1 (HIV-1)-infected patients, raising the possibility that viral infection plays a role in pathogenesis. This is supported by the recent discovery of parvovirus B19 DNA in some cases of idiopathic collapsing glomerulopathy. We report a case of collapsing glomerulopathy in a 16-year-old girl who presented with steroid-resistant nephrotic syndrome and pulmonary tuberculosis. In the absence of the usual associations (adult age group, African-American race, or history of intravenous drug abuse), infection is the sole known risk factor in this case. This lends support to the hypothesis that immune dysregulation due to infection per se, rather than infection by specific viral agents, may lead to collapsing glomerulopathy in susceptible individuals.
Dermoid Cysts of the Tongue: Report of Five Cases and Review of the Literature
Authors: Edwards Paul C. , Lustrin Liz , Valderrama Elsa
Published: March 2004

Dermoid cysts of the tongue are uncommon. To date, there have been nine reported cases in the English language literature. In this article, we describe five cases accessioned at our institution over a 12-year period, two of which have previously been reported. The prevalence of dermoid cysts at our institution over this period was quite low. Of 324,042 surgical cases, 0.24% (765 cases) were dermoid cysts. Of these, five were from the tongue, representing only 0.7% of the dermoid cysts accessioned and 0.0015% of the total surgical specimens. The literature is reviewed and the possible origin of these lesions is discussed.
Splenopancreatic Field Abnormality is Not Unique to Trisomy 13
Authors: Peres Luiz Cesar , De Sales Barbosa Gustavo Henrique T. , Careta Renata Scarpat , Nassif Cristiane Miziara , De Pina-Neto João Monteiro , Giuliani Liane R. , Martinhago Ciro Dresch , Gomy Israel
Published: March 2004

Splenopancreatic fusion is an uncommon finding, usually only seen as part of the splenopancreatic field abnormality associated with trisomy 13. It may present itself either as ectopic splenic tissue in the cauda pancreatis, as ectopic pancreatic tissue in the spleen or accessory spleen, or as fusion of the cauda pancreatis and splenic hilum. In this study, we report four unrelated congenital anomaly cases presenting trisomy 21, osteocraniostenosis syndrome, isolated congenital heart defect, and oligohydramnios sequence due to prune belly syndrome, in which fusion was observed. This demonstrates that, although it may be more common in trisomy 13, this phenomenon should not be interpreted as pathognomonic to that syndrome.
Epstein-Barr Virus-Associated Smooth Muscle Tumor of the Basal Ganglia in an HIV+ Child: Case Report and Review of the Literature
Authors: Kumar Shimareet , Santi Mariarita , Vezina Gilbert , Rosser Tena , Chandra Roma S. , Keating Robert
Published: March 2004

We describe the clinicopathologic features of an Epstein-Barr virus (EBV)-associated smooth muscle tumor arising in the basal ganglia of a 10-year-old human immunodeficiency virus (HIV)-positive child. Only a few cases of intracranial smooth muscle tumors are reported in the literature and virtually all of these have been extra-axial, involving the dura or sinuses in HIV+ adults. Our case underscores the need to include an EBV-associated smooth muscle tumor in the differential diagnosis when evaluating intracranial mass lesions in immunodeficient children.
Maternal Vascular Underperfusion: Nosology and Reproducibility of Placental Reaction Patterns
Authors: Redline Raymond W. , Boyd Theonia , Campbell Valarie , Hyde Scott , Kaplan Cynthia , Khong T. Yee , Prashner Heather R. , Waters Brenda L. ,   For the Society for Pediatric Pathology, Perinatal Section, Maternal Vascular Underperfusion Nosology Committee
Published: March 2004

Placental examination can be a useful tool for specifying the etiology, prognosis, and recurrence risk of pregnancy disorders. The purpose of this study was to test the reliability of a predetermined set of placental reaction patterns seen with maternal vascular underperfusion in the hope that this might provide a useful diagnostic framework for practicing pathologists. Study cases (14 with clinical and pathologic evidence of maternal underperfusion plus 6 controls) were evaluated for the presence or absence of 11 lesions by eight perinatal pathologists. After analysis of initial results, diagnostic criteria were refined and a second, overlapping set of cases was reviewed. The collective sensitivity, specificity, and efficiency of individual assessments for the 11 lesions relative to the group consensus ranged from 74–93% (22/33 > 90%). Reproducibility was measured by unweighted kappa-values and interpreted as follows: < 0.2 poor, 0.2–0.6 fair/moderate, > 0.6 substantial. Kappa values for lesions affecting villi and the intervillous space were increased syncytial knots (any —0.42, severe —0.50), villous agglutination (0.42), increased intervillous fibrin (0.25), and distal villous hypoplasia (0.57). Individual estimates of percent involvement for syncytial knots, intervillous fibrin, and distal villous hypoplasia were correlated with placental and fetal weight for gestational age. Extent of increased intervillous fibrin showed the strongest correlation with both placental weight ( R = −0.64) and fetal weight ( R = −0.45). Kappa values for lesions affecting maternal vessels and the implantation site were acute atherosis (0.50), mural hypertrophy of membrane arterioles (0.43), muscularized basal plate arteries (0.48), increased placental site giant cells (0.54), and immature intermediate trophoblast (0.36). Correlation of maternal vessel and implantation site lesions with the clinical diagnosis of preeclampsia showed that excessive placental site giant cells and immature intermediate trophoblast were more sensitive and efficient predictors, whereas atherosis and muscularized basal plate arteries were more specific. Kappa value for a thin umbilical cord, a possible indicator of fetal volume depletion, was 0.61. Reproducibility for a global impression of maternal vascular underperfusion, taking into account all of the above lesions, was moderate (kappa 0.54) and improved after inclusion of additional pathologic and clinical data (kappa 0.68). Adoption of this clearly defined, clinically relevant, and pathologically reproducible terminology could enhance clinicopathologic correlation and provide a more objective framework for future clinical research.
HBL-3 Cell Line, Derived from Precursor B-cell Lymphoblastic Leukemia, Lacks Somatic Hypermutation of Immunoglobulin Heavy Chain Variable Region Genes
Authors: Hojo Hiroshi , Sasaki Yoshikazu , Nakamura Naoya , Sato Michiko , Abe Masafumi
Published: March 2004

Somatic mutation (SM) analysis provides a useful tool for understanding the stages at which neoplastic differentiate from normal B-cells. B-cell precursor neoplasms are considered to be somatically premutational. However, the variable frequency of SM of the variable region (VH) genes has been described in cases of precursor B-cell acute lymphoblastic leukemia (PB-ALL). To better characterize PB-ALL based on the differentiation stage, we investigated the SM of the VH genes expressed by tumor cells of the surface immunoglobulin (sIg)- HBL-3 cell line derived from childhood PB-ALL. In the HBL-3 cell line, the rearranged Ig heavy chain VH gene sequence showed no SM in the complementarity-determining regions of 1, 2, and 3, or in the framework regions of 1, 2, and 3 relative to the putative germline VH gene sequences. In addition, the VH segment of HBL-3 cells showed no intraclonal sequence heterogeneity, indicating ongoing SM. Our data demonstrated that HBL-3 cells express unmutated and developmentally regulated rearrangement of VH genes at the stage of B-cell precursor cells. HBL-3 cells, which are derived only from the sIg- PB-ALL, showed that SM cannot be recognized in VH genes of tumor cells before the expression of sIg.
Optimal Diagnostic Testing for Urinary Tract Infection in Young Children
Authors: Novak Robert , Powell Keith , Christopher Norman
Published: March 2004

Urinary tract infection (UTI) is a major concern in young febrile children. Current recommendations favor use of urine obtained by bladder catheterization or aspiration, but opinion varies as to the best ancillary tests to predict a positive culture and guide initial management. The utility of dipstick leukocyte esterase, blood, and nitrite; unspun urine leukocyte count; gram stain of cytocentrifuged urine; and standard spun sediment examination was evaluated in 142 febrile, < 5-year-old children seen in the Emergency Department, 25 of whom had culture-proven UTI. Using sensitivity and negative predictive values as criteria for performance, unspun urine leukocyte count and gram stain of cytocentrifuged urine used in parallel was the best approach but still failed to detect some UTI. Analysis of the nature of the specimens evaluated provided explanation of differences from previous observations. Adoption of this modified approach to prediction of urinary tract infection appears to improve prediction but has operational implications and creates potential problems for the laboratory.
Placental Findings after Laser Ablation of Communicating Vessels in Twin-to-Twin Transfusion Syndrome
Authors: De Paepe Monique E. , Friedman Rebecca M. , Poch Michael , Hansen Katrine , Carr Stephen R. , Luks Francois I.
Published: March 2004

As laser ablation of placental vascular communications gains acceptance as treatment option for severe twin-to-twin transfusion syndrome (TTTS), pathologists are increasingly confronted with the interpretation of laser-treated placentas. We present our preliminary institutional experience with the gross and microscopic analysis of these specimens. Patients underwent selective ablation for severe TTTS (Quintero stages II to V) between 16 and 25 wk gestation and the placentas were examined between < 24 h and 19 wk postoperatively. The placental vasculature was injected with gelatin-dye mixtures. The type and number of vascular anastomoses were recorded, followed by routine histopathological analysis of the placenta. Foci of laser impact were identified in all placentas examined within 1 month after laser coagulation. Located along the recipient side of the dividing membrane, the laser-treated vessels appeared hemorrhagic and showed a characteristic abrupt interruption of dye filling after vascular injection. In placentas examined more than 1 month after intervention, the most frequent gross finding was the absence or relative paucity of intertwin anastomoses, associated with subchorionic fibrin deposition. Microscopically, laser-treated vessels showed varying degrees of necrosis, associated with focal hemorrhage, avascular villi, and fibrin deposition in the underlying parenchyma. In some cases of intrauterine fetal demise or placental disruption, no definite laser scars were identified. As expected, the number of residual anastomoses (all types) was significantly smaller in laser-treated placentas than in control monochorionic placentas (2.4 ± 2.2 [ n = 10] vs. 6.2 ± 3.2 [ n = 70], P < 0.01). Velamentous cord insertion was noted in 50% of cases; markedly uneven placental sharing in 60%. Detailed analysis of laser-treated placentas and clinicopathological correlation may lead to a better understanding of the pathophysiology of TTTS and continued refinement of therapeutic approaches for this often lethal condition.
Ergebnisse musiktherapeutischer Entspannung im sozialtherapeutischen Strafvollzug
Authors: Zeuch Andreas , Hillecke Thomas
Published: March 2004

Zusammenfassung. In diesem Artikel werden die qualitativ-quantitativen Ergebnisse einer Orientierungsstudie (2000-2002) zur Wirkung und Wirkungsweise musiktherapeutischer Entspannung im (sozialtherapeutischen) Strafvollzug vorgestellt. Die Untersuchungsgruppe umfasste n = 11 Teilnehmer, die jeweils über einen Zeitraum von einem halben Jahr mit Interviews zu drei Messzeitpunkten befragt wurden. Darüber hinaus kam in jeder Behandlungsstunde ein Prä-Post-Fragebogen zur Anwendung, der statistisch mit einem t-Test für abhängige Daten analysiert wurde. Als Ergebnis ergab sich ein Modell zur besonderen Wirkungsweise und Bedeutung von Musik als Entspannungsmedium im Strafvollzug sowie ein erster Signifikanznachweis der Wirkung der musiktherapeutischen Entspannung.
“Musiktherapeutische Lehrtherapie“
Authors: Hörmann Karl
Published: March 2004

Zusammenfassung. Wie alle künstlerischen Therapien bedarf auch die Musiktherapie im Hinblick auf ein Berufs- und Ausbildungsgesetz eines gewissen Maßes an Vereinheitlichung wenigstens der Hochschulstudiengänge. Im Gegensatz zu diesen Bestrebungen soll aber nun in einigen Musiktherapieausbildungen ein Studienteil Lehrtherapie obligatorisch und seine Durchführung an außerinstitutionelle Privatpersonen mit gravierenden Folgen für die Studierenden delegiert werden. Die Auslagerung wird damit begründet, dass es sich um Lehranalyse handelt, wie sie ausschließlich von privaten psychoanalytischen Instituten für Therapieberufe mit dem Ziel und mit den für Musiktherapeuten nicht erreichbaren Vorteilen der Approbation angeboten wird. Die lange Geschichte der Lehranalyse zeigt, dass sie an sich schon fragwürdig ist und weder von Medizin- noch von Psychologiestudierenden gefordert werden darf. Die Neukonzeption des Medizinstudiums nach bewährtem amerikanischem Vorbild beweist, dass sich die für Therapeuten wünschenswerte Selbsterfahrung integrieren lässt. Fachmusiker sind mitunter die besseren Therapeuten. Dementsprechend hat ein Gericht nach Hinzuziehung eines medizinischen, psychologischen und musikwissenschaftlichen Sachverständigen des Berufsverbands für Musik-, Tanz- und Kunsttherapie (BKMT) am 8.12.2003 entschieden, dass die durch einen Fachmusiker durchgeführte musiktherapeutische Behandlung erstattet werden muss. Benötigt wird eine Lehrtherapie, die Therapie lehrt und die Lehre nicht an selbsternannte oder von ebenso wenig zuständigen Interessenverbänden bestimmte Personen delegiert, die mangels grundständigen Musikstudiums auf Themen ausweichen, zu denen primitive Attribute von Musik instrumentalisiert werden, ohne jedoch die der Musik eigenen, umfassenderen Möglichkeiten zu nutzen. Es stellt sich somit die Frage, ob unter Lehrtherapie analog zu Psychotherapie als Therapie der Psyche die Therapie der Lehre zu verstehen ist. Hierzu werden Perspektiven aufgezeigt.
Kritik standardisierter empirischer Bilderfassung aus kunsttherapeutisch-phänomenologischer Sicht
Authors: Elbing Ulrich , Stuhler-Bauer Angela
Published: March 2004

Zusammenfassung. Dieser Artikel unterzieht die “Nürtinger Beurteilungsskala“ und die “Diagnostic Assessment of Psychiatric Art - deutsche Version“ (DAPA-D; Elbing & Hacking, 2001 ) einer substantiellen Kritik aus einer phänomenologisch kunsttherapeutischen Sicht. Grundlage der Kritik ist die qualitative Bildanalyse der gleichen Bilder mit dem von Stuhler-Bauer und Elbing (2003) vorgestellten kunsttherapeutischen Instrument, die Elbing und Hacking (2001) mit den genannten quantitativen Instrumenten untersucht haben. Auf die Erläuterung der Methode der Kritikgewinnung folgt zunächst eine vergleichende Beschreibung der drei Instrumente und darauf die Kritik an den quantitativen Instrumenten. Die Kritik behandelt die vorgegebene konkrete Vorgehensweise bei der Bilderfassung, die verwendeten Kriterien und den methodischen Ansatz, der beidem zugrunde liegt. Die Diskussion thematisiert die zentralen Kriterien von Wissenschaftlichkeit, die über der Kritik deutlich werden, das Spannungsfeld zwischen Wissenschaftskriterien und Wissenschaftspraxis und mögliche Folgerungen für die Weiterentwicklung kunsttherapeutischer Instrumente der Bilderfassung.
Instrumentelle Bewegungsaktivitäten von Herzinfarktpatienten
Authors: Höner Oliver , Sudeck Gorden , Willimczik Klaus
Published: March 2004

Zusammenfassung. Die Initiierung regelmäßiger Sportaktivitäten von Herzinfarktpatienten nach ihrer Anschlussheilbehandlung (AHB) bildet eine wesentliche Voraussetzung zur Sicherung eines langfristigen Rehabilitationserfolges. Im Sinne einer theoretischen Rekonstruktion solcher instrumenteller Bewegungsaktivitäten wird ein integratives Modell vorgestellt. Darin werden mit der Rubikontheorie der Handlungsphasen ( Heckhausen, 1989 ; Gollwitzer, 1996 ) eine handlungspsychologische Perspektive und mit sozial-kognitiven Determinanten aus Modellen zum Gesundheitsverhalten (z.B. Fuchs, 1997 ) eine gesundheitsspezifische Perspektive miteinander verknüpft. Zur empirischen Anwendung des Modells werden in einer Feldstudie 135 Herzinfarktpatienten während ihrer stationären AHB schriftlich und drei Monate poststationär telefonisch hinsichtlich der Initiierung regelmäßiger Sportaktivitäten im Alltag befragt. Ein zentrales Ergebnis der Studie deutet auf die besondere Rolle volitionaler Merkmale (z.B. Realisierungsintentionen, Selbstwirksamkeitserwartungen) bei der Initiierung regelmäßiger Sportaktivitäten hin. Abschließend werden neben untersuchungsmethodischen Aspekten die Ergebnisse im Hinblick auf die theoretische Weiterentwicklung des integrativen Modells sowie die Gestaltung von Interventionen zur Förderung regelmäßiger Sportaktivitäten diskutiert.
Persönlichkeit, chronischer Stress und körperliche Gesundheit
Authors: Becker Peter , Schulz Peter , Schlotz Wolff
Published: March 2004

Zusammenfassung. Die prospektive Studie dient der Überprüfung eines systemischen Anforderungs-Ressourcen-Modells der körperlichen Gesundheit. Untersucht wurden 276 nach Zufall ausgewählte Erwachsene im Alter von 17 bis 70 Jahren. Sie beantworteten das Trierer Integrierte Persönlichkeitsinventar (TIPI) und zwei Jahre später das Trierer Inventar zum chronischen Stress (TICS), den Fragebogen zur habituellen körperlichen Gesundheit (FHKG) sowie einen Fragebogen zum aktuellen Gesundheitszustand (FGZ). Die theoretischen Annahmen wurden als Strukturgleichungsmodell formuliert und mit dem Programm LISREL 8.5 überprüft. Modellkonform zeigte sich, dass sich beträchtliche Varianzanteile in zwei Facetten der körperlichen Gesundheit (“habituelle körperliche Gesundheit“ und “akute Beschwerden und Erkrankungen“) mit Hilfe von personalen Ressourcen (bzw. Ressourcendefiziten) und chronischem Stress (vor allem “Mangel an Bedürfnisbefriedigung“) aufklären lassen. Die Ergebnisse werden unter anderem bezüglich ihrer Relevanz für die Gesundheitsförderung und Prävention diskutiert.
Potent inhibitors of anthrax lethal factor from green tea
Authors: Dell'Aica Isabella , Donà Massimo , Tonello Fiorella , Piris Alejandro , Mock Michèle , Montecucco Cesare , Garbisa Spiridione
Published: March 2004

The anthrax lethal factor (LF) has a major role in the development of anthrax. LF is delivered by the protective antigen (PA) inside the cell, where it exerts its metalloprotease activity on the N‐terminus of MAPK‐kinases. PA+LF are cytotoxic to macrophages in culture and kill the Fischer 344 rat when injected intravenously. We describe here the properties of some polyphenols contained in green tea as powerful inhibitors of LF metalloproteolytic activity, and how the main catechin of green tea, (−)epigallocatechin‐3‐gallate, prevents the LF‐induced death of macrophages and Fischer 344 rats.
Signature of the oligomeric behaviour of nuclear receptors at the sequence and structural level
Authors: Brelivet Yann , Kammerer Sabrina , Rochel Natacha , Poch Olivier , Moras Dino
Published: March 2004

Nuclear receptors (NRs) are ligand‐dependent transcription factors that control a large number of physiological events through the regulation of gene transcription. NRs function either as homodimers or as heterodimers with retinoid X receptor/ultraspiracle protein (RXR/USP). A structure‐based sequence analysis aimed at discovering the molecular mechanism that controls the dimeric association of the ligand‐binding domain reveals two sets of differentially conserved residues, which partition the entire NR superfamily into two classes related to their oligomeric behaviour. Site‐directed mutagenesis confirms the functional importance of these residues for the dimerization process and/or transcriptional activity. All homodimers belong to class I, in which the related residues contribute a communication pathway of two salt bridges linking helix 1 on the cofactor‐binding site to the dimer interface. A salt bridge involving a differentially conserved arginine residue in loop H8–H9 defines the signature motif of heterodimers. RXR/USP and all Caenorhabditis elegans NRs belong to class I, supporting the hypothesis of an earlier emergence of this class.
The Snf1 kinase controls glucose repression in yeast by modulating interactions between the Mig1 repressor and the Cyc8‐Tup1 co‐repressor
Authors: Papamichos‐Chronakis Manolis , Gligoris Thomas , Tzamarias Dimitris
Published: March 2004

Among lower eukaryotes, glucose repression is a conserved, widely spread mechanism regulating carbon catabolism. The yeast Snf1 kinase, the Mig1 DNA‐binding repressor and the Mig1‐interacting co‐repressor complex Cyc8(Ssn6)–Tup1 are central components of this pathway. Previous experiments suggested that cytoplasmic translocation of Mig1, upon its phosphorylation by Snf1 in the nucleus, is the key regulatory step for releasing glucose repression. In this report we re‐evaluate this model. We establish the coordinated repressive action of Mig1 and Cyc8–Tup1 on GAL1 transcription, but we find that Cyc8–Tup1 is not tethered by Mig1 to the promoter DNA. We demonstrate that both negative regulators occupy GAL1 continuously under either repression or activation conditions, although the majority of the Mig1 is redistributed to the cytoplasm upon activation. We show that Snf1‐dependent phosphorylation of Mig1 abolishes interaction with Cyc8–Tup1, and we propose that regulation of this interaction, not the Mig1 cytoplasmic localization, is the molecular switch that controls transcriptional repression/de‐repression.
Cell‐type‐specific processing of the amyloid precursor protein by Presenilin during Drosophila development
Authors: Loewer Alexander , Soba Peter , Beyreuther Konrad , Paro Renato , Merdes Gunter
Published: March 2004

The cleavage of proteins within their transmembrane domain by Presenilin (PS) has an important role in different signalling pathways and in Alzheimer's disease. Nevertheless, not much is known about the regulation of PS activity. It has been suggested that substrate recognition by the PS complex depends only on the size of the extracellular domain independent of the amino‐acid sequence and that PS activity is constitutive in all cells that express the minimal components of the complex. We report here the development of an in vivo reporter system that allowed us to analyse the processing of human amyloid precursor protein (APP) and the Notch receptor tissue specifically during Drosophila development in the living organism. Using this system, we demonstrate differences between APP and Notch processing and show that PS‐mediated cleavage of APP can be regulated in different cell types independent of the size of the extracellular domain.
Kupffer cell activation by lipopolysaccharide in rats: Role for lipopolysaccharide binding protein and toll-like receptor 4
Authors: Su Grace L. , Klein Richard D. , Aminlari Alireza , Zhang Hong Y. , Steinstraesser Lars , Alarcon William H. , Remick Daniel G. , Wang Stewart C.
Published: March 2004

Lipopolysaccharide (LPS) binding protein (LBP) is a key serum factor that mediates LPS activation of mononuclear cells. In the presence of LBP, 1/1,000 the concentration of LPS is sufficient to activate peripheral blood monocytes. Previous studies with Kupffer cells have shown a variable effect of serum on LPS activation of these cells and led to the conclusion that, unlike extrahepatic mononuclear cells, Kupffer cells do not respond to LPS in an LBP-dependent fashion. Because there are multiple components in serum other than LBP that might affect LPS activation, these reports with serum are difficult to interpret. To investigate the specific role of LBP in LPS activation of Kupffer cells, we produced a functional recombinant rat LBP using a baculovirus expression system, which we used to selectively examine the role of LBP’s on Kupffer-cell function. Isolated Kupffer cells exposed to increasing concentrations of LPS (0, 1, 10 ng/mL) showed a dose-dependent increase in TNF-α production, which was augmented and accelerated by the presence of LBP. The effects of LBP on Kupffer cell activation by LPS are dependent on a functional Toll-like receptor 4 (Tlr 4) because Kupffer cells from C3H/HeJ mice failed to respond to LPS in the presence of LBP. LBP plays an important role in mediating Kupffer cell activation by LPS, and these effects are dependent on the presence of functioning Tlr 4.
The cost-effectiveness of hepatitis A vaccination in patients with chronic hepatitis C
Authors: Myers Robert P. , Gregor James C. , Marotta Paul J.
Published: March 2004

Infection with hepatitis A virus (HAV) occasionally leads to acute liver failure and has a higher fatality rate in patients with chronic hepatitis C virus (HCV). Vaccination of patients with HCV against HAV is effective and well tolerated. This study examines the cost-effectiveness of HAV vaccination in North American patients with chronic HCV. A decision analysis model was constructed to compare 3 HAV vaccination strategies in adult patients with chronic HCV over a period of 5 years: (1) vaccinate no patients (treat none); (2) vaccinate only susceptible (anti-HAV negative) patients (selective); or (3) vaccinate all patients without prior testing of immune status (universal). Probabilities and direct costs were estimated from hospital data and the literature. The cost per patient for the 3 vaccination strategies were: treat none, $2.00; selective, $56.00; and universal, $82.00. For every 1,000,000 patients with HCV vaccinated over a 5-year period, the selective strategy prevented 128 symptomatic cases of HAV, 3 liver transplantations, and 3 deaths owing directly to HAV compared with the treat none strategy. In addition, the selective strategy costs an additional $427,000 per patient with HAV prevented, and $23 million per HAV-related death averted, compared with the treat none strategy. The results were most sensitive to the incidence of HAV infection; vaccination increased costs if the annual rate of infection was less than 0.56% (baseline, 0.01%). Vaccination of North American patients with chronic HCV against HAV infection is not a cost-effective therapy.
Effect of cisapride on intestinal bacterial overgrowth and bacterial translocation in cirrhosis
Authors: Pardo Albert , Bartolí Ramon , Lorenzo-Zúñiga Vicente , Planas Ramon , Viñado Belén , Riba Joan , Cabré Eduard , Santos Justiniano , Luque Teresa , Ausina Vicenç , Gassull Miguel A.
Published: March 2004

Deranged intestinal motility, which occurs in cirrhosis, may facilitate the development of intestinal bacterial overgrowth (IBO), which can lead to bacterial translocation (BT). To assess the effect of cisapride on IBO and BT in cirrhosis, cirrhotic rats received cisapride or a placebo for 7 days, and measurements of jejunal bacterial content and BT studies were performed. In addition, jejunal fluid from 46 cirrhotic patients was obtained for quantitative bacterial culture. Those patients in whom gram-negative IBO was detected were randomized to receive or not to receive cisapride (20 mg twice per day) for 1 week. Cisapride significantly reduced IBO in cirrhotic rats. In addition, no BT was documented in treated animals, whereas it occurred in 40% in nontreated cirrhotic rats. Total IBO was documented in 23 of 46 cirrhotic patients, which was caused by gram-negative organisms in 10 cases. Orocecal transit time (OCT) significantly decreased after cisapride therapy, and was associated with the abolishment of bacterial overgrowth caused by gram-negative organisms in 4 out of 5 treated patients, whereas it persisted in nontreated cases. Cisapride administration to cirrhotic rats resulted in a reduction of the IBO, which is associated with a marked decrease in BT. On the other hand, cisapride facilitates the abolition of IBO caused by gram-negative organisms in cirrhotic patients.
Primary liver resection and salvage transplantation or primary liver transplantation in patients with single, small hepatocellular carcinoma and preserved liver function: An outcome-oriented decision analysis
Authors: Majno Pietro E. , Sarasin François P. , Mentha Gilles , Hadengue Antoine
Published: March 2004

Two treatments are accepted for patients with solitary hepatocellular carcinoma ≤5 cm in size and with preserved hepatic function: (1) liver resection, which can be performed without delay but has a high recurrence rate, and (2) liver transplantation, which has a better long-term survival, but is not easily available because grafts are scarce. A third possibility is to offer liver resection first and liver transplantation for tumor recurrence or deteriorating liver function (“salvage” transplantation). We investigated the implications of such a strategy with a Markov-based decision analytic model. In a scenario assuming intermediate values for 4 main variables (12-month waiting list; tumor progression outside transplantation criteria: 4% per month; recurrence after resection: 20% per year; recurrences eligible for transplantation: 60%), the life expectancy was 8.8 years for primary transplantation versus 7.8 years for primary resection and salvage transplantation, with a calculated use of grafts at 5 years of 52% for primary transplantation versus 23% for salvage transplantation. This study estimates of the survival and graft-saving of a strategy of primary resection and salvage transplantation according to variables that are to some extent predictable. This strategy may be a rational way to cope with lengthening waiting lists, especially for patients with tumors close to the limit for transplantation criteria, if the results of liver resection are good, if patients with the lowest risks of recurrence can be selected, and if a strict follow-up can detect recurrences when the patients are still transplantable.
Fas-mediated cholangiopathy in the murine model of graft versus host disease
Authors: Ueno Yoshiyuki , Ishii Motoyasu , Yahagi Kaichiro , Mano Yutaka , Kisara Norihiro , Nakamura Norio , Shimosegawa Tooru , Toyota Takayoshi , Nagata Shigekazu
Published: March 2004

Bile-duct injury observed in hepatic graft versus host disease (GVHD) is regarded as an immune-mediated injury, although its precise mechanism is unclear. However, recent studies have suggested the involvement of Fas-mediated cell death in this immune-mediated cholangiopathy. In this study, we first showed the constitutive expression of Fas receptor by cholangiocytes in situfrom normal BALB/c mice, which was upregulated in GVHD mice. Also, we confirmed the Fas protein expression in the isolated cholangiocytes from normal BALB/c mice by immunocytochemistry and immunoblotting. Furthermore, the addition of agonistic Fas antibody-(Jo2)-induced cholangiocyte apoptosis confirmed by DNA-ladder formation and annexin V staining. Cholangiocytes from Fas-deficient mice (MRL lpr/lpr) did not show Jo2-induced apoptosis. Interferon-γ augmented Fas expression and Fas-mediated cell death, respectively. Following these observations, experimental GVHD was induced by transfer of splenocytes from B10.D2 mice to irradiated (800 rad) BALB/c mice. Liver-infiltrating lymphocytes from the recipient showed dose-dependent cytotoxicity against 51Cr-labeled cholangiocytes isolated from BALB/c mice. Moreover, the addition of blocking Fas-Fc fusion protein reduced this cytotoxicity to 44.7%. Finally, administration of this Fas-Fc protein to the BALB/c mice, which had been adoptively transferred with splenocytes of B10.D2 mice, prevented the development of hepatic GVHD in vivo. These results showed the involvement of Fas-mediated cell death in cholangiopathy observed in GVHD, and a soluble Fas-Fc protein may have a therapeutic potential for hepatic GVHD.
A model to predict poor survival in patients undergoing transjugular intrahepatic portosystemic shunts
Authors: Malinchoc Michael , Kamath Patrick S. , Gordon Fredric D. , Peine Craig J. , Rank Jeffrey , ter Borg Pieter C.J.
Published: March 2004

Transjugular intrahepatic portosystemic shunts (TIPS) may worsen liver function and decrease survival in some patients. The Child-Pugh classification has several drawbacks when used to determine survival in such patients. The survival of 231 patients at 4 medical centers within the United States who underwent elective TIPS was studied to develop statistical models to (1) predict patient survival and (2) identify those patients whose liver-related mortality post-TIPS would be 3 months or less. Among these elective TIPS patients, 173 had the procedure for prevention of variceal rebleeding and 58 for treatment of refractory ascites. Death related to liver disease occurred in 110 patients, 70 within 3 months. Cox proportional-hazards regression identified serum concentrations of bilirubin and creatinine, international normalized ratio for prothrombin time (INR), and the cause of the underlying liver disease as predictors of survival in patients undergoing elective TIPS, either for prevention of variceal rebleeding or for treatment of refractory ascites. These variables can be used to calculate a risk score (R) for patients undergoing elective TIPS. Patients with R > 1.8 had a median survival of 3 months or less. This model was superior to both the Child-Pugh classification, as well as the Child-Pugh score, in predicting survival. Using logistic regression and the same variables, we also developed a nomogram that indicates which patients survive less than 3 months. Finally, the model was validated among an independent set of 71 patients from the Netherlands. This Mayo TIPS model may predict early death following elective TIPS for either prevention of variceal rebleeding or for treatment of refractory ascites.
Mild hypothermia delays the onset of coma and prevents brain edema and extracellular brain glutamate accumulation in rats with acute liver failure
Authors: Rose Christopher , Michalak Adrianna , Pannunzio Marc , Chatauret Nicolas , Rambaldi Andrea , Butterworth Roger F.
Published: March 2004

Mild hypothermia is effective in the prevention of brain edema associated with cerebral ischemia and traumatic brain injury. Brain edema is also a serious complication of acute liver failure (ALF). To assess the effectiveness of hypothermia in ALF, groups of rats were subjected to hepatic devascularization (portacaval anastomosis, followed 48 hours later by hepatic artery ligation), and body temperatures were maintained at either 35°C (hypothermic) or 37°C (normothermic). Mild hypothermia resulted in a significant delay in the onset of severe encephalopathy and in reduction of brain water content compared with normothermic ALF rats (control [n = 8] 80.22%; ALF-37°C [n = 8] 81.74%; ALF-35°C [n = 8] 80.48% [P < .01 compared with ALF-37°C]). This protective effect was accompanied by a significant reduction of cerebrospinal fluid (CSF) (but not plasma) ammonia concentrations (CSF ammonia: control: 0.05 mg/dL; ALF-37°C: 1.01 mg/dL; ALF-35°C: 0.07 mg/dL, P < .01 compared with ALF-37°C). In vivo cerebral microdialysis studies revealed that mild hypothermia resulted in a significant reduction of extracellular glutamate concentrations in the brains of rats with ALF (control: 1.06 μmol/L; ALF-37°C: 2.74 μmol/L; ALF-35°C: 1.49 μmol/L [P < .01 compared with ALF-37°C]). These findings suggest that: 1) mild hypothermia is an effective approach to the prevention of the central nervous system consequences of experimental ALF; and that 2) the beneficial effect of hypothermia is mediated via mechanisms involving reduced blood-brain transfer of ammonia and/or reduction of extracellular brain glutamate concentrations. Mild hypothermia may be an effective approach to delay the onset of brain edema in patients with ALF awaiting liver transplantation.
Genetic polymorphism of alcohol dehydrogenase in europeans: The ADH2*2 allele decreases the risk for alcoholism and is associated with ADH3*1
Authors: Borràs Emma , Coutelle Christiane , Rosell Albert , Fernández-Muixi Fina , Broch Montserrat , Crosas Bernat , Hjelmqvist Lars , Lorenzo Alfons , Gutiérrez Cristina , Santos Mauro , Szczepanek Malgorzata , Heilig Markus , Quattrocchi Pierrette , Farrés Jaume , Vidal Francesc , Richart Cristóbal , Mach Tomasz , Bogdal Józef , Jörnvall Hans , Seitz Helmut K. , Couzigou Patrice , Parés Xavier
Published: March 2004

Polymorphism at the ADH2 and ADH3 loci of alcohol dehydrogenase (ADH) has been shown to have an effect on the predisposition to alcoholism in Asian individuals. However, the results are not conclusive for white individuals. We have analyzed the ADH genotype of 876 white individuals from Spain (n = 251), France (n = 160), Germany (n = 184), Sweden (n = 88), and Poland (n = 193). Peripheral blood samples from healthy controls and groups of patients with viral cirrhosis and alcohol-induced cirrhosis, as well as alcoholics with no liver disease, were collected on filter paper. Genotyping of the ADH2 and ADH3 loci was performed using polymerase chain reaction-restriction fragment length polymorphism methods on white cell DNA. In healthy controls, ADH2*2 frequencies ranged from 0% (France) to 5.4% (Spain), whereas ADH3*1 frequencies ranged from 47.6% (Germany) to 62.5% (Sweden). Statistically significant differences were not found, however, between controls from different countries, nor between patients with alcoholism and/or liver disease. When all individuals were grouped in nonalcoholics (n = 451) and alcoholics (n = 425), ADH2*2 frequency was higher in nonalcoholics (3.8%) than in alcoholics (1.3%) (P = .0016), whereas the ADH3 alleles did not show differences. Linkage disequilibrium was found between ADH2 and ADH3, resulting in an association of the alleles ADH2*2 and ADH3*1, both coding for the most active enzymatic forms. In conclusion, the ADH2*2 allele decreases the risk for alcoholism, whereas the ADH2*2 and ADH3*1 alleles are found to be associated in the European population.
Probability of hepatocellular carcinoma of small hepatocellular nodules undetectable by computed tomography during arterial portography
Authors: Tanaka Yoshio , Sasaki Yutaka , Katayama Kazuhiro , Hiramatsu Naoki , Ito Akihiko , Murata Hiroaki , Enomoto Norihiro , Oshita Masahide , Mochizuki Kiyoshi , Tsujii Masahiko , Tsuji Shingo , Kasahara Akinori , Tomoda Kaname , Nakamura Hironobu , Hayashi Norio , Hori Masatsugu
Published: March 2004

Recent advances in imaging modalities enable the identification of small hepatocellular nodules. Among the imaging techniques currently used for detecting hepatocellular carcinomas (HCC), computed tomography (CT) during arterial portography (CTAP) is one of the most sensitive techniques available for detecting hemodynamic change. Even so, well-differentiated HCCs that display only limited hemodynamic change, a feature shared with nonmalignant hepatocellular nodules, are not always detectable by CTAP. To improve our ability to distinguish well-differentiated HCCs from nonmalignant hepatocellular nodules, we have attempted to clarify how the characteristics of the nodules are shown by each imaging technique. We studied the imaging and pathological characteristics of 31 nodules (in 22 patients) detected by ultrasonography (US), but not by CTAP. Histological diagnoses were as follows: HCC, 17 of 31 nodules (55%); high-grade dysplastic nodules, 1 of 31 (3%); and nonmalignant nodules, 13 of 31 (42%). Neither digital substraction angiography (DSA) nor CT arteriography (CTA) were able to detect any of the nodules. Detection rates for plain CT were: 5 of 17 (29%) HCC, 1 of 1 (100%) high-grade dysplastic nodules, and 1 of 13 (8%) nonmalignant nodules. Detection rates for T1/T2-weighted magnetic resonance imaging (MRI) were: 4 of 17 (24%) HCC, 1 of 1 (100%) high-grade dysplastic nodules, and 3 of 13 (23%) nonmalignant nodules. Dynamic CT and dynamic MRI provided no additional information. In conclusion, there is some probability that hepatocellular nodules detected by US, but not by CTAP, are HCC. Presently, it is difficult to distinguish between benign nodules and malignant ones with these imaging techniques, and our findings indicate that biopsy may be advisable for nodules detected under these conditions.
The role of activin and transforming growth factor-β in the regulation of organ mass in the rat liver
Authors: Kogure Kimitaka , Zhang You-Qing , Maeshima Akito , Suzuki Keiji , Kuwano Hiroyuki , Kojima Itaru
Published: March 2004

The present study was conducted to assess the role of activin(s) in the regulatory mechanism to maintain constant liver mass. To this end, we infused follistatin, an activin antagonist, into the portal vein of the rat. Follistatin induced DNA synthesis, as assessed by bromodeoxy uridine labeling, in intact livers. Small peaks of bromodeoxy uridine labeling were observed after 3 and 18 hours of infusion, and a large peak was observed after 48 hours. In follistatin-treated rats, the DNA content of the liver was significantly elevated after 72 hours and returned to the basal value within 120 hours. Likewise, liver weight increased significantly after 60 and 72 hours, but returned to the control value within 120 hours. Apoptosis of hepatocytes, assessed by the Tdt-mediated, dUTP-biotin nick end labeling method was observed after 72 hours or later. Messenger RNA (mRNA) expression of hepatocyte growth factor, transforming growth factor-α, tumor necrosis factor-α, and interleukin-6 did not increase after the addition of follistatin. The mRNA expression and immunoreativity of transforming growth factor-β increased after the administration of follistatin. These results suggest that the blockade of activin action leads to the initiation of DNA synthesis in the intact liver. Activins may tonically inhibit hepatocyte growth in the intact liver. Transforming growth factor-β may also act to maintain constant liver mass when activin action is blocked.
Modulation of transforming growth factor β response and signaling during transdifferentiation of rat hepatic stellate cells to myofibroblasts
Authors: Dooley Steven , Delvoux Bert , Lahme Birgit , Mangasser-Stephan Kerstin , Gressner Axel M.
Published: March 2004

Activation of hepatic stellate cells (HSCs) is the key step in liver fibrogenesis. Increased transforming growth factor β (TGF-β) expression and extracellular matrix production in patients with hepatic fibrosis and experimental models of liver fibrogenesis support implication of TGF-β in the pathogenesis of this disease. However, a causative role for TGF-β during transdifferentiation of HSCs has not been delineated in molecular detail. Using a rat cell culture model of HSC transdifferentiation, we analyzed TGF-β signal transduction and identified changes between stellate cells and their transdifferentiated phenotype. Fully transdifferentiated myofibroblasts, opposed to HSCs, were not inhibited in proliferation activity on treatment with TGF-β1. Furthermore, stimulation of α2 (I) collagen and Smad7 messenger RNA (mRNA) expression by TGF-β1 was achieved in stellate cells but not in myofibroblasts. Northern and Western blot analyses indicated significant expression of TGF-β receptors I and II in both cell types. In contrast, [125I]-TGF-β1 receptor affinity labeling displayed strongly reduced types I, II, and III receptor presentation at the cell surface of myofibroblasts. Moreover, myofibroblasts did not display DNA-binding SMAD proteins in electrophoretic mobility shift assays with a CAGA box. These data indicate that stellate cells are responsive to TGF-β1 treatment and transduce a signal that may play an important role in liver fibrogenesis. Myofibroblasts display decreased availability of surface receptors for TGF-β, which could be based on autocrine stimulation. However, lack of activated SMAD complexes with DNA-binding activity and absence of α2 (I) collagen transcription inhibition by latency-associated peptide (LAP)/anti-TGF-β antibody raise the possibility of TGF-β signaling independent receptor down-regulation in myofibroblasts.