bluuebunny/crossref_metadata_2025 huggingface dataset:
New bifurcation stenting technique: Shunt stenting
Authors: Prasan Ananth M. , Pitney Mark R. , Ramsay David , Jepson Nigel S. , Friedman Daniel , Taylor David , Giles Robert W.
Published: November 2004

The optimal treatment of bifurcation lesions remains controversial. We describe a new technique we term shunt stenting. This technique incorporates both the new technology of drug‐eluting stents and a novel procedure for optimizing the ostial side branch stent positioning. To date, early angiographic and clinical follow‐up have been encouraging. Catheter Cardiovasc Interv 2004;63:474–481. © 2004 Wiley‐Liss, Inc.
Relief of pseudostenosis using the transit exchange catheter
Authors: Fortuin F. David , Sweeney John P. , Lee Richard W.
Published: November 2004

Pseudostenosis is a generally benign complication of percutaneous coronary intervention that is caused by the mechanical deformation of a tortuous artery by the guidewire. We describe two cases of a tortuous right coronary artery in which pseudostenosis was relieved by placing a Transit exchange catheter (Cordis) distally and subsequently removing the guidewire. This technique safely confirmed the diagnosis of pseudostenosis without losing guidewire position or requiring additional wires and balloons. Catheter Cardiovasc Interv 2004;63:457–461. © 2004 Wiley‐Liss, Inc.
Role of temozolomide after radiotherapy for newly diagnosed diffuse brainstem glioma in children
Authors: Broniscer Alberto , Iacono Lisa , Chintagumpala Murali , Fouladi Maryam , Wallace Dana , Bowers Daniel C. , Stewart Clinton , Krasin Matthew J. , Gajjar Amar
Published: November 2004

BACKGROUND

The role of chemotherapy in the treatment of children with newly diagnosed diffuse brainstem glioma is uncertain. In the current study, the authors tested the efficacy of temozolomide treatment after radiotherapy (RT) in this setting.

METHODS

Patients ages 3–21 years were eligible for the current multiinstitutional study. An optional window therapy regimen consisting of 2 cycles of intravenous irinotecan (10 doses of 20 mg/m2 per day separated by 2 days of rest per cycle) was delivered over 6 weeks and was followed by conventionally fractionated RT. The 5‐day schedule of temozolomide (200 mg/m2 per day) was initiated 4 weeks after RT and was continued for a total of 6 cycles. The pharmacokinetics of temozolomide and its active metabolite, 5‐(3‐methyltriazen‐1‐yl)imidazole‐4‐carboxamide (MTIC), were analyzed during Cycles 1 and 3.

RESULTS

Thirty‐three patients (median age at diagnosis, 6.4 years) were enrolled. Of the 16 patients who received window therapy, 6 had irinotecan treatment discontinued due to clinical progression (n = 5) or toxicity (n = 1); the remaining 10 experienced disease stabilization after 2 cycles. All patients completed RT (median dose, 55.8 gray). Twenty‐nine patients received a combined total of 125 cycles of temozolomide. Grade 3/4 neutropenia and thrombocytopenia occurred in 33% and 29% of all temozolomide cycles, respectively. In approximately one‐third of the cycles, dose reduction was required due to myelosuppression. No correlation was demonstrated between temozolomide/MTIC exposure and myelosuppression at the conclusion of Cycle 1. All patients died of disease progression (median survival, 12 months). The estimated 1‐year survival rate was 48% (standard error, 8%).

CONCLUSIONS

The administration of temozolomide after RT did not alter the poor prognosis associated with newly diagnosed diffuse brainstem glioma in children. Cancer 2005. © 2004 American Cancer Society.
Solving the dilemma of the immunohistochemical and other methods used for scoring estrogen receptor and progesterone receptor in patients with invasive breast carcinoma
Authors: Fisher Edwin R. , Anderson Stewart , Dean Scott , Dabbs David , Fisher Bernard , Siderits Richard , Pritchard Jeffrey , Pereira Telma , Geyer Charles , Wolmark Norman
Published: November 2004

BACKGROUND

The authors attempted to resolve the dilemma posed by the lack of unanimity concerning the optimal immunohistochemical (IHC) method for determining and scoring estrogen receptor (ER) and progesterone receptor (PR).

METHODS

Sections for IHC were prepared from paraffin embedded tumor samples from 402 patients with lymph node positive breast carcinoma who had biochemical receptor values (obtained with the dextran‐coated charcoal [DCC] method) and who were enrolled in a prospective, randomized trial (National Surgical Adjuvant Breast and Bowel Project protocol B‐09). IHC receptors were scored independently by two observers according to percent, intensity, and any‐or‐none algorithms. Results from these evaluations and from two computer‐assisted evaluations, DCC, and common pathologic characteristics were analyzed for optimum splits for positive reactions in univariate and multivariate analyses using a tree‐structured model. Concordance, sensitivity, and specificity were determined between the DCC method and all other methods.

RESULTS

Interobserver agreement and concordance between the DCC method and the other methods and among the methods were high. Univariate analyses revealed that a positive ER score obtained with all methods was related significantly to overall survival (OS) at 5 years and at 10 years. Results related to PR scores and disease‐free survival and recurrence‐free survival were less consistent. In multivariate analysis, it also was found that all methods for scoring ER predicted a better prognosis for OS in patients with an unfavorable lymph node status at 5 years and 10 years. Patients in a favorable lymph node status group were discriminated further by nuclear grade.

CONCLUSIONS

All IHC methods for scoring ER appeared valid as prognostic indicators of OS in patients with positive lymph nodes. The any‐or‐none IHC method, by virtue of its simplicity, represents an appropriate choice for practical use. Cancer 2005. © 2004 American Cancer Society.
Trinuclear [NiFe] Clusters as Structural Models for [NiFe] Hydrogenase Active Sites
Authors: Sellmann Dieter , Lauderbach Frank , Heinemann Frank W.
Published: November 2004

[Fe(CH3COCH=CHPh)(CO)3] reacts with [Ni(‘S4’)]x (x = 1, 2) or [Ni(‘S4C3Me2’)] [‘S4’2− = 1,2‐bis(2‐mercaptophenylthio)ethane(2‐),‘S4C3Me2’2− = 1,3‐bis(2‐mercaptophenylthio)‐2,2‐dimethylpropane(2‐)] to afford trinuclear [NiFe] clusters [Ni(‘S4’){Fe(CO)3}2] (1) and [Ni(‘S4C3Me2’){Fe(CO)3}2] (2) and the dinuclear FeIIFe0 complex [Fe(CO)(‘S4C3Me2’)Fe(CO)3] (3). Clusters 1 and 2 have Ni−Fe bond lengths similar to those of active or reduced states of [NiFe] hydrogenases, a sulfur‐dominated coordination sphere of Ni and iron‐bound CO. Therefore, 1 and 2 may serve as structural model complexes for the [NiFe] hydrogenase active site. Combination of the ‘S4C3Me2’ ligand with FeCl2·4H2O yielded [Fe(‘S4C3Me2’)]2 (4), the dinuclearity of which suggests that the ‘S4C3Me2’ ligand is less flexible than its ethylene‐bridged derivative, which affords a tetrameric [Fe(‘S4’)]4 complex reported earlier. Compound 4 reacts with 2 equiv. of CO to give [Fe(CO)(‘S4C3Me2’)]2 (5), which like 4 is only sparingly soluble in all common organic solvents. Complex 5 easily loses CO even if stored in the solid state. [Fe(CH3COCH=CHPh)(CO)3] reacts with 5 to afford 3 as the only product. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005)
Towards the Design of Linear Homo‐Trinuclear Metal Complexes Based on a New Phenol‐Functionalised Diazamesocyclic Ligand: Structural Analysis and Magnetism
Authors: Du Miao , Zhao Xiao‐Jun , Guo Jian‐Hua , Bu Xian‐He , Ribas Joan
Published: November 2004

The formation of two novel phenoxo‐bridged linear trimetallic CuII and NiII complexes, [Cu3(μ‐L)2](CH3OH)2(ClO4)2 (1) and [Ni3(μ‐L)2(CH3OH)2](ClO4)2 (2), with a new diazamesocyclic ligand functionalised by additional phenol donor pendants (H2L = N,N′‐ bis(2‐hydroxybenzyl)‐1,4‐diazacycloheptane), has been achieved and both complexes have been characterised by IR spectroscopy, elemental analyses, conductivity measurements, thermal analyses and UV/Vis techniques. Single‐crystal X‐ray diffraction analyses revealed that both 1 and 2 have the similar phenoxo‐bridged linear trinuclear cores. For 1, two terminal and the central CuII ion are in square‐planar environments with the adjacent intramolecular Cu···Cu separation of 2.9376(9) Å. For 2, however, two terminal NiII ions are in square‐planar environments and the central NiII ion assumes an octahedral geometry by axial coordination of two methanol ligands, the adjacent intramolecular Ni···Ni distance being 3.007(3) Å. In both cases, the 1,4‐diazacycloheptane (DACH) ring adopts the normal boat configuration. The magnetic properties of complexes 1 and 2 have been investigated by variable‐temperature magnetic susceptibility measurements in the solid state. Complex 1 displays a very strong antiferromagnetic coupling interaction between the neighbouring μ‐phenoxo CuII centres with a J parameter of −314 cm−1 and the magneto‐structural correlation for such complexes is discussed in detail. For complex 2, the result indicates that both terminal NiII ions are diamagnetic and the central NiII shows typical paramagnetic behaviour. The presence of zero‐field splitting for NiII with a D parameter of 11 cm−1, being active at low temperature, is further corroborated by the magnetisation measurement at 2 K. Additionally, the interesting ESR spectra of 1 at different temperatures (from 298 K to 8 K) were investigated and interpreted. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005)
Syntheses and Characterizations of Multidimensional Metal‐Organic Frameworks Based on Rings and 1D Chains
Authors: Li Xiaoju , Cao Rong , Sun Yanqiong , Bi Wenhua , Li Xing , Wang Yanqin
Published: November 2004

Four novel multidimensional coordination polymers, {[Cd(3‐PYD)2(H2O)]·2H2O}n (1), [Pb(3‐PYD)2]n (2), {[Cu1.5(3‐PYD)3(H2O)]·1.5H2O}n (3) and [Zn(3‐PYD)2(H2O)2]n (4), have been hydrothermally synthesized from 3‐(3‐pyridyl)acrylic acid (3‐HPYD). In 1, 3‐PYD in a head‐to‐head arranged fashion bridges CdII, generating a two‐dimensional layer, which is further extended into a three‐dimensional supramolecular network by hydrogen‐bonding interactions. Compound 2 shows a two‐dimensional wave‐like layer that consists of {Pb(3‐PYD)}4 rings from head‐to‐tail arranged 3‐PYD. Compound 3 is a twofold interpenetrating three‐dimensional network consisting of {Cu(3‐PYD)}6 rings formed through the mixed head‐to‐head and head‐to‐tail arrangements of 3‐PYD. However, 4 is a three‐dimensional supramolecular framework constructed by one‐dimensional zinc‐3‐PYD chains through hydrogen‐bonding interactions. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005)
Pge1–Induced No Reduces Apoptosis by D–Galactosamine Through Attenuation of Nf–Kb and Nos–2 Expression in Rat Hepatocytes
Authors: Siendones Emilio , Fouad Dalia , Díaz–Guerra María José M. , de la Mata Manuel , Boscá Lisardo , Muntané Jordi
Published: November 2004

Prostaglandin E1 (PGE1) reduces cell death in experimental and clinical liver dysfunction. We have previously shown that PGE1 preadministration protects against NO–dependent cell death induced by d–galactosamine (D–GalN) through a rapid increase of nuclear factor κB (NF–κB) activity, inducible NO synthase (NOS–2) expression, and NO production. The present study investigates whether PGE1–induced NO was able to abolish NF–κB activation, NOS–2 expression, and apoptosis elicited by D–GalN. Rat hepatocytes were isolated following the classical method of collagenase perfusion of liver. PGE1 (1 μmol/L) was administered 2 hours before D–GalN (5 mmol/L) in primary culture rat hepatocytes. PGE1 reduced inhibitor κBα degradation, NF–κB activation, NOS–2 expression, and apoptosis induced by D–GalN. The administration of an inhibitor of NOS–2 abolished the inhibitory effect of PGE1 on NF–κB activation and NOS–2 expression in D–GalN-treated hepatocytes. Transfection studies using different plasmids corresponding to the NOS–2 promoter region showed that D–GalN and PGE1 regulate NOS–2 expression through NF–κB during the initial stage of hepatocyte treatment. PGE1 was able to reduce the promoter activity induced by D–GalN. In addition, a NO donor reduced NOS–2 promoter activity in transfected hepatocytes.

In conclusion

, administration of PGE1 to hepatocytes produces low levels of NO, which inhibits its own formation during D–GalN-induced cell death through the attenuation of NF–κB-dependent NOS–2 expression. Therefore, a dual role for NO in PGE1–treated D–GalN-induced toxicity in hepatocytes is characterized by a rapid NO release that attenuates the late and proapoptotic NOS–2 expression.

Supplementary material for this article can be found on the Hepatology website

(
http://interscience.wiley.com/jpages/0270–9139/suppmat/index.html
). (Hepatology 2004;40:1295-1303.)
Disruption of Hepatic Adipogenesis Is Associated With Impaired Liver Regeneration in Mice
Authors: Shteyer Eyal , Liao Yunjun , Muglia Louis J. , Hruz Paul W. , Rudnick David A.
Published: November 2004

The liver responds to injury with regulated tissue regeneration. During early regeneration, the liver accumulates fat. Neither the mechanisms responsible for nor the functional significance of this transient steatosis have been determined. In this study, we examined patterns of gene expression associated with hepatic fat accumulation in regenerating liver and tested the hypothesis that disruption of hepatic fat accumulation would be associated with impaired hepatic regeneration. First, microarray–based gene expression analysis revealed that several genes typically induced during adipocyte differentiation were specifically upregulated in the regenerating liver prior to peak hepatocellular fat accumulation. These observations suggest that hepatic fat accumulation is specifically regulated during liver regeneration. Next, 2 methods were employed to disrupt hepatocellular fat accumulation in the regenerating liver. Because exogenous leptin supplementation reverses hepatic steatosis in leptin–deficient mice, the effects of leptin supplementation on liver regeneration in wild–type mice were examined. The data showed that leptin supplementation resulted in suppression of hepatocellular fat accumulation and impairment of hepatocellular proliferation during liver regeneration. Second, because glucocorticoids regulate cellular fat accumulation during adipocyte differentiation, the effects of hepatocyte–specific disruption of the glucocorticoid receptor were similarly evaluated. The results showed that hepatic fat accumulation and hepatocellular proliferation were also suppressed in mice with liver specific disruption of glucocorticoid receptor.

In conclusion

, suppression of hepatocellular fat accumulation is associated with impaired hepatocellular proliferation following partial hepatectomy, indicating that hepatocellular fat accumulation is specifically regulated during and may be essential for normal liver regeneration. (Hepatology 2004;40:1322-1332.)
Initial Response To Percutaneous Ablation Predicts Survival in Patients With Hepatocellular Carcinoma
Authors: Sala Margarita , Llovet Josep M. , Vilana Ramon , Bianchi Lluís , Solé Manel , Ayuso Carmen , Brú Concepció , Bruix Jordi
Published: November 2004

Outcome predictors in patients with hepatocellular carcinoma (HCC) who are treated with percutaneous ablation are ill defined, and it is unknown if successful therapy is associated with improved survival. In our study, 282 cirrhotic patients with early nonsurgical HCC were treated with percutaneous ablation during a 15–year period. Single tumors were seen in 244 patients, and 2 to 3 nodules were seen in 38 patients. Initial complete response was achieved in 192 patients and was independently related to the size of the main tumor (

P

= .015) and tumor stage (

P

= .0001) (≤2 cm, 96%; 2.1–3 cm, 78%; >3 cm, 56%; 2–3 nodules, 46%). At the end of follow–up, 80 patients presented sustained complete response. The 1–, 3–, and 5–year survival rates were 87%, 51%, and 27%, respectively. The independent predictors of survival were Child–Turcotte–Pugh class (

P

= .0001) and initial complete response (

P

= .006). Child–Turcotte–Pugh class A patients with initial complete response achieved 42% survival at 5 years; this figure increased to 63% in patients with tumors 2 cm or smaller.

In conclusion

, our results demonstrate that initial complete response to percutaneous ablation is associated with an improved survival in both Child–Turcotte–Pugh class A and B patients with nonsurgical HCC. Accordingly, initial complete tumor necrosis should be considered a relevant therapeutic target irrespective of tumor size and liver function. (Hepatology 2004;40:1352-1360.)
Chronic Hepatitis C Virus Infection: Does It Really Impact Health–Related Quality of Life? A Study in Rural Egypt
Authors: Schwarzinger Michaël , Dewedar Sahar , Rekacewicz Claire , Abd Elaziz Khaled Mahmoud , Fontanet Arnaud , Carrat Fabrice , Mohamed Mostafa Kamal
Published: November 2004

Previous Western studies showed a consistent and marked reduction in health–related quality of life (HRQOL) in patients chronically infected with hepatitis C virus (HCV). However, these studies were conducted on patients whose knowledge of their serological status may have affected their HRQOL. This HRQOL survey conducted in the Egyptian rural population provides a unique opportunity to clarify this issue among a population whose serological status is unknown. HRQOL was assessed by an Arabic translation of the Short–Form 12, and a visual analog scale of the relative severity of one's health status. HCV chronic infection was defined by positive tests for anti–HCV antibody and HCV–RNA. HRQOL was compared according to HCV chronic infection status in linear mixed models adjusted for potential confounding factors, such as age, sex, education, and health care-related risk factors, and adjusted for interviewer as a random effect. One hundred forty–six Egyptians chronically infected with HCV had similar Short–Form 12 and visual analog scale scores, compared with 1,140 uninfected controls from the same rural community. In individuals chronically infected with HCV, serum aminotransferase levels did not correlate with HRQOL.

In conclusion

, this study did not find a significant reduction of HRQOL in patients chronically infected with HCV compared with uninfected, contemporaneous controls. This may be explained in part by a lower morbidity amongst patients chronically infected with HCV in rural Egypt and a higher morbidity amongst uninfected controls as compared with those of Western studies, as well as a lack of awareness of hepatitis C serological status. (Hepatology 2004;40:1434-1441.)
Glutathione S –Transferase and Liver Function in Intrahepatic Cholestasis of Pregnancy and Pruritus Gravidarum
Authors: Dann Anthony T. , Kenyon Anna P. , Seed Paul T. , Poston Lucilla , Shennan Andrew H. , Tribe Rachel M.
Published: November 2004

Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy–specific liver disease associated with poor maternal and fetal outcome. The diagnosis is based on pruritus with abnormal liver function in the absence of other pathological conditions. However, pruritus in pregnancy is common, and it may be the only presenting feature in ICP. No reliable test currently exists that can discriminate between those women destined to develop ICP and those with the benign condition of pruritus gravidarum (PG). The purpose of this prospective study was to investigate longitudinally the serum concentration of glutathione

S

–transferase alpha (GSTA, a specific marker of hepatocellular integrity) and to compare this with the temporal profile of conventional liver function markers in women with ICP (n = 63), PG (n = 43), and normal pregnant controls (n = 26). Blood was sampled on at least 3 separate occasions between 16 weeks of gestation and 4 weeks postpartum. Serum concentrations of GSTA increased with gestation in ICP, being significantly higher from 24 (±2) weeks compared with controls (400% difference; 95% CI, 240%-734%;

P

< .001). GSTA was also higher in ICP versus PG (433% difference; 95% CI, 228%–790%;

P

< .001) throughout the gestational period studied. Significant differences in the ICP compared with control and PG groups were also found for total bile acids, alanine aminotransferase, aspartate aminotransferase, γ–glutamyl transpeptidase and alkaline phosphatase.

In conclusion

, the measurement of GSTA provides a test of liver dysfunction that distinguishes women with ICP from those with PG. Additionally, on the basis of this study, reference ranges for biochemical markers of liver function require reevaluation in pregnancy. (Hepatology 2004;40:1406-1414.)
Low–Grade Steatosis and Major Changes in Portal Flow As New Prognostic Factors in Steroid–Treated Alcoholic Hepatitis
Authors: Duvoux Christophe , Radier Catherine , Roudot–Thoraval Françoise , Maille François , Anglade Marie–Christine , Van Nhieu Jeanne Tran , Rosa Isabelle , Hospitel Sylvie , Abd–Alsamad Issam , Sitruk Véronique , Seror Olivier , Ziol Marianne , Blondon Hughes , Dhumeaux Daniel , Richardet Jean–Philippe
Published: November 2004

The aim of this study was to assess the prevalence and prognostic value of major alterations of portal flow in patients with steroid–treated alcoholic hepatitis. Fifty patients with severe, histologically proven alcoholic hepatitis were enrolled. Clinical data, liver test results, and hepatic Doppler ultrasound findings were collected at inclusion and at month 2. Patients were followed for 1 year or until death. Major changes in portal flow were defined as reversed or alternating flow in the portal trunk and/or in intrahepatic portal branches. Changes in portal flow were observed in 24 (48.0%) of 50 and 17 (39.5%) of 43 patients at inclusion and month 2, respectively. Univariate analysis showed that age older than 50 years, steatosis less than 20% on initial liver biopsy, presence of major changes in portal flow, Child–Turcotte–Pugh score higher than 12, factor V level higher than 45%, and hepatofugal splenic blood flow were associated with a lower 1–year survival. Cox regression analysis showed that steatosis < 20% (relative hazard [RH] = 9.3,

P

= .0009) and major changes in portal flow (RH = 3.1,

P

= .04), were independently associated with poor survival.

In conclusion

, major changes in portal flow are frequent in patients with severe alcoholic hepatitis. Altered portal flow and steatosis < 20% are new prognostic factors in steroid–treated alcoholic hepatitis and must be taken into account in patient management. (Hepatology 2004;40:1370–1378).
Irs–2 Mediates the Antiapoptotic Effect of Insulin in Neonatal Hepatocytes
Authors: Valverde Angela M. , Fabregat Isabel , Burks Deborah J. , White Morris F. , Benito Manuel
Published: November 2004

To assess the role of insulin action and inaction in the liver, immortalized hepatocyte cell lines have been generated from insulin receptor substrate (IRS)–2-/- and wild–type mice. Using this model, we have recently demonstrated that the lack of IRS–2 in neonatal hepatocytes resulted in insulin resistance. In the current study, we show that immortalized neonatal hepatocytes undergo apoptosis on serum withdrawal, with caspase–3 activation and DNA laddering occurring earlier in the absence of IRS–2. Insulin rescued wild–type hepatocytes from serum withdrawal–induced caspase–3 activation and DNA fragmentation in a dose–dependent manner, but it failed to rescue hepatocytes lacking IRS–2. In IRS–2-/- cells, insulin failed to phosphorylate Bad. Furthermore, in these cells, insulin was unable to translocate Foxo1 from the nucleus to the cytosol. Adenoviral infection of wild–type cells with constitutively active Foxo1 (ADA) induced caspase–8 and caspase–3 activities, proapoptotic gene expression, DNA laddering and apoptosis. Dominant negative Foxo1 regulated the whole pathway in an opposite manner. Prolonged insulin treatment (24 hours) increased expression of antiapoptotic genes (Bcl–xL), downregulated proapoptotic genes (Bim and nuclear Foxo1), and decreased caspase–3 activity in wild–type hepatocytes but not in IRS–2-/- cells. Infection of IRS–2-/- hepatocytes with adenovirus encoding IRS–2 reconstituted phosphatidylinositol 3–kinase (PI 3–kinase)/Akt/Foxo1 signaling, restored pro– and antiapoptotic gene expression, and decreased caspase–3 activity in response to insulin, thereby blocking apoptosis.

In conclusion,

IRS–2 signaling is specifically required through PIP3 generation to mediate the survival effects of insulin. Epidermal growth factor, via PIP3/Akt/Foxo1 phosphorylation, was able to rescue IRS–2-/- hepatocytes from serum withdrawal–induced apoptosis, modulating pro– and anti–apoptotic gene expression and downregulating caspase–3 activity.

Supplementary material for this article can be found on the Hepatology website

(
http://interscience.wiley.com/jpages/0270–9139/suppmat/index.html
). (Hepatology 2004;40:1285–1294.)
Validation of A New Prognostic Staging System for Hepatocellular Carcinoma: the Jis Score Compared With the Clip Score
Authors: Kudo Masatoshi , Chung Hobyung , Haji Seiji , Osaki Yukio , Oka Hiroko , Seki Toshihito , Kasugai Hiroshi , Sasaki Yo , Matsunaga Takashi
Published: November 2004

The Japan Integrated Staging score (JIS score), which combines the Child–Turcotte–Pugh classification and tumor–node–metastasis staging, has been proposed as a better prognostic staging system for hepatocellular carcinoma (HCC) than the Cancer of the Liver Italian Program (CLIP) scoring system. In this study, validation was performed among a larger patient population. A total of 4,525 consecutive patients with HCC who had been diagnosed at five institutions were included. Stratification ability, prognostic predictive power, and reproducibility were analyzed and compared with results from the CLIP scoring system. Only 45% (1,951 of 4,525) of all patients were categorized as early stage HCC according to JIS score (0 or 1), whereas 63% (2,878 of 4,525) of the patients were categorized as having a CLIP score of 0 or 1. Significant differences in survival curves were not observed among CLIP scores 3 to 6. In contrast, survival curves showed significant differences among all the JIS scores. The same JIS scoring subgroups showed a similar prognosis, and good internal reproducibility was observed in each of the institutions. Multivariate analysis of the prognosis in all 4,525 patients proved the JIS score to be the best prognostic factor. Furthermore, the Akaike information criteria proved that the JIS scoring system was statistically a better model for predicting outcome than the CLIP scoring system.

In conclusion

, the stratification ability and prognostic predictive power of the JIS score were much better than that of the CLIP score and were simple to obtain and remember. (Hepatology 2004; 40:1396-1405.)
Waning Immunity To Plasma–Derived Hepatitis B Vaccine and the Need for Boosters 15 Years After Neonatal Vaccination
Authors: Lu Chun–Yi , Chiang Bor–Luen , Chi Wei–Kuang , Chang Mei–Hwei , Ni Yen–Hsuan , Hsu Hsu–Mei , Twu Shiing–Jer , Su Ih–Jen , Huang Li–Min , Lee Chin–Yun
Published: November 2004

Neonatal immunization with hepatitis B (HB) vaccine is highly effective; however, more needs to be learned about the duration of protection and indications for boosters. We measured antibody to HB core antigen (anti–HBc), HB surface antigen (HBsAg), and pre– and postbooster titers of HBsAg antibody (anti–HBs) 15 years after primary neonatal immunization with plasma–derived HB vaccines in 2 cohorts of 15–year–old children. Group A consisted of 78 children who were born to HB e antigen-positive HBsAg carrier mothers and had developed protective levels of anti–HBs antibodies (≥10 mIU/mL) following HB immunization. Group B consisted of 113 apparently healthy children whose anti–HBs titers after vaccination were unknown. Anti–HBs was undetectable (antibody titer <10 mIU/mL) in 29.9% in group A and 62.4% in group B (

P

< .001). Anti–HBc was detected in 33.3 % in group A and 4.4 % in group B (

P

< .001). After a single booster dose of HB vaccine, 2.7% in group A and 3.3% in group B remained anti–HBs-negative. A blunted serological response was noted in approximately 20% in both groups. One HBsAg carrier was detected in group A (1.3%) and 4 in group B (3.5%). Fifteen years after neonatal immunization with plasma–derived HB vaccine, a large proportion of children exhibited waning immunity. This poses the risk of breakthrough infection. A single booster augmented the serological response to the vaccine in most but not all subjects.

In conclusion

, our findings suggest that one or more booster immunizations are needed in seronegative subjects by at least 15 years following neonatal immunization with plasma–derived HB vaccine. (Hepatology 2004;40:1415-1420.)
Sidechain Biology and the Immunogenicity of Pdc–E2, the Major Autoantigen of Primary Biliary Cirrhosis
Authors: Mao Tin K. , Davis Paul A. , Odin Joseph A. , Coppel Ross L. , Gershwin Eric M.
Published: November 2004

The E2 component of mitochondrial pyruvate dehydrogenase complex (PDC–E2) is the immunodominant autoantigen of primary biliary cirrhosis. Whereas lipoylation of PDC–E2 is essential for enzymatic activity and predominates under normal conditions, other biochemical systems exist that also target the lysine residue, including acylation of fatty acids or xenobiotics and ubiquitinylation. More importantly, the immunogenicity can be affected by derivatization of the lysine residue, as the recognition of lipoylated PDC–E2 by patient autoantibodies is enhanced compared with octanoylated PDC–E2. Furthermore, our laboratory has shown that various xenobiotic modifications of a peptide representing the immunodominant region of PDC–E2 are immunoreactive against patient sera. The only purported regulatory system that prevents the accumulation of potentially autoreactive PDC–E2 is glutathionylation, in which the lysine–lipoic acid moiety is further modified with glutathione during apoptosis. Interestingly, this system is found in several cell lines, including HeLa, Jurkat, and Caco–2 cells, but not in cholangiocytes and salivary gland epithelial cells, both of which are targets for destruction in primary biliary cirrhosis. Hence, the failure of this or other regulatory system(s) may overwhelm the immune system with immunogenic PDC–E2 that can initiate the breakdown of tolerance in a genetically susceptible individual. In this review the authors survey the data available on the biochemical life of PDC–E2, with particular emphasis on the lysine residue and its known interactions with machinery involved in various posttranslational modifications. (Hepatology 2004;40:1241-1248.)
Role of Hepatic Fibrin in Idiosyncrasy–Like Liver Injury From Lipopolysaccharide–Ranitidine Coexposure in Rats
Authors: Luyendyk James P. , Maddox Jane F. , Green Christopher D. , Ganey Patricia E. , Roth Robert A.
Published: November 2004

Coadministration of nonhepatotoxic doses of the histamine 2–receptor antagonist ranitidine (RAN) and bacterial lipopolysaccharide (LPS) results in hepatocellular injury in rats, the onset of which occurs in 3 to 6 hours. This reaction resembles RAN idiosyncratic hepatotoxicity in humans. Early fibrin deposition occurs in livers of rats cotreated with LPS/RAN. Accordingly, we tested the hypothesis that the hemostatic system contributes to liver injury in LPS/RAN–treated rats. Rats were given either LPS (44.4 × 106 EU/kg) or its vehicle, then RAN (30 mg/kg) or its vehicle 2 hours later. They were killed 2, 3, 6, 12, or 24 hours after RAN treatment, and liver injury was estimated from serum alanine aminotransferase activity. A modest elevation in serum hyaluronic acid, which was most pronounced in LPS/RAN–cotreated rats, suggested altered sinusoidal endothelial cell function. A decrease in plasma fibrinogen and increases in thrombin–antithrombin dimers and in serum concentration of plasminogen activator inhibitor–1 occurred before the onset of liver injury. Hepatic fibrin deposition was observed in livers from LPS/RAN–cotreated rats 3 and 6 hours after RAN. Liver injury was abolished by the anticoagulant heparin and was significantly attenuated by the fibrinolytic agent streptokinase. Hypoxia, one potential consequence of sinusoidal fibrin deposition, was observed in livers of LPS/RAN–treated rats.

In conclusion,

the results suggest that the hemostatic system is activated after LPS/RAN cotreatment and that fibrin deposition in liver is important for the genesis of hepatic parenchymal cell injury in this model. (Hepatology 2004;40:1342-1351.)
Cellular Immune Responses Against Hcv: T Cells Take A Diversion in the Liver
Authors: Klenerman Paul , Semmo Nasser , Ward Scott , Jaeschke Hartmut , Mullen Kevin , Moradpour Darius
Published: November 2004

Regulatory T (T(R)) cells consist of phenotypically and functionally distinct CD4+ and CD8+ T–cell subsets engaged both in maintaining self–tolerance and in preventing anti-non-self effector responses (microbial, tumor, transplant, and so on) that may be harmful to the host. Here we propose that the proinflammatory function of virus–specific memory effector CCR7-CD8+ T cells, which are massively recruited in the liver, are inefficient (in terms of IFN–gamma production) in patients with chronic hepatitis C virus (HCV) infection because of the concomitant presence of virus–specific CCR7-CD8+ T(R) cells producing considerable amounts of IL–10. These CD8+ T(R) cells are antigen specific, as they can be stimulated by HCV epitopes and suppress T–cell responses that are in turn restored by the addition of neutralizing anti-IL–10. This study provides direct evidence of the existence of virus–specific CD8+ T(R) cells that infiltrate the livers of patients with chronic HCV infection, identifies IL–10 as a soluble inhibitory factor mediating suppression, and suggests that these cells play a pivotal role in controlling hepatic effector CD8+ T–cell responses.
Agallochaols A and B, Two New Diterpenes from the Chinese Mangrove Excoecaria agallochaL.
Authors: Wang Ji‐Dong , Guo Yue‐Wei
Published: November 2004

Two new ent‐isopimarane diterpenoids, agallochaols A (1) and B (2), were isolated from the dried stems and leaves of the mangrove Excoecaria agallocha L. Their structures were established on the basis of spectroscopic data and chemical evidence.
Rhodium(II)‐Catalyzed Inter‐ and Intramolecular Enantioselective Cyclopropanations with Alkyl‐Diazo(triorganylsilyl)acetates
Authors: Müller Paul , Lacrampe Fabienne
Published: November 2004

The intermolecular cyclopropanation of styrene with ethyl diazo(triethylsilyl)acetate (1a) proceeds at room temperature in the presence of chiral RhII carboxylate catalysts derived from imide‐protected amino acids and affords mixtures of trans‐ and cis‐cyclopropane derivatives 2a in up to 72% yield but with modest enantioselectivities (<54%) (Scheme 1 and Table 1). Protiodesilylation of a diastereoisomer mixture 2a with Bu4NF is accompanied by epimerization at C(1) (→3). The intramolecular cyclopropanation of allyl diazo(triethylsilyl)acetate (8a), in turn, affords optically active 3‐oxabicyclo[3.1.0]hexan‐2‐one (9a) with yields of up to 85% and 56% ee (Scheme 3 and Table 2). Similarly, the (2Z)‐pent‐2‐enyl derivative 8d reacts to 9d in up to 77% yield and 38% ee (Scheme 3 and Table 3). In contrast, the diazo decomposition of (2E)‐3‐phenylprop‐2‐enyl and 2‐methylprop‐2‐en‐1‐yl diazo(triethyl‐silyl)acetates (8b and 8c, resp.) is unsatisfactory and gives very poor yields of substituted 3‐oxabicyclo[3.1.0]hexan‐2‐ones 9b and 9c, respectively (Table 3).
Isolation and Characterization of New Bitter Diterpenoids from the Basidiomycete Sarcodon scabrosus
Authors: Ma Bing‐Ji , Zhu Hua‐Jie , Liu Ji‐Kai
Published: November 2004

The novel cyathane‐type diterpenoids scabronine G and H (1 and 2, resp.) were isolated from the fruiting bodies of the basidiomycete Sarcodon scabrosus together with four known compounds, allocyathin B2 (3), sarcodonin A (4), sarcodonin G (5), and scabronine F (6). Their structures were determined by spectroscopic means, including 2D‐NMR (HMBC, HMQC, ROESY, 1H,1H‐COSY).
Vanadium induces apoptosis and modulates the expressions of metallothionein, Ki‐67 nuclear antigen, and p53 during 2‐acetylaminofluorene‐induced rat liver preneoplasia
Authors: Chakraborty Tridib , Samanta Shaonly , Ghosh Balaram , Thirumoorthy N. , Chatterjee Malay
Published: November 2004

Our previous studies have shown that vanadium, a dietary micronutrient, has an inhibitory effect against experimentally induced rat hepatocarcinogenesis. In this study, we evaluated the role of vanadium on some potential protein expression markers of carcinogenesis, such as metallothionein (MT), an intracellular metal‐binding protein linked with cell proliferation and apoptosis, Ki‐67 nuclear antigen, and p53 tumor suppressor during 2‐acetylaminofluorene (2‐AAF)‐induced (0.05% in basal diet) rat liver preneoplasia. In a short‐term regimen, supplementation of vanadium at a dose of 0.5 ppm effectively suppressed the formation of DNA ‘comets’ (29.55%; P < 0.02), thereby indicating its nongenotoxicity at this particular dose. Vanadium administration throughout the study reduced relative liver weight (RLW), nodular incidence (57.15%), total number, and multiplicity (48.45%) with restoration of hepatic zinc (Zn), magnesium (Mg), selenium (Se), copper (Cu), iron (Fe), and calcium (Ca) contents when compared to the carcinogen control. Moreover, treatment with vanadium significantly abated the expressions of MT and Ki‐67, studied at four sequential time points. An increased immunopositivity of p53 protein (1.03 ± 0.23%; P < 0.02) was found in vanadium‐treated rat liver with an elevated apoptotic‐labeling index (AI; P < 0.001) as documented by TUNEL assay. Furthermore, a positive correlation between MT expression and Ki‐67 labeling along with a strong negative correlation between MT immunoreactivity and AI (r = −0.9000, P = 0.0004 at week 24) at various time intervals suggest that, vanadium‐mediated suppression of MT and Ki‐67 expressions may be associated with induction of apoptosis. The results thus provide evidence for the first time in support of the potential role of vanadium on induction of p53 and apoptosis with concurrent suppression of MT and Ki‐67 in order to have an understanding, in part, of the chemopreventive mechanism of this trace element in limiting neoplastic transformation in a defined model of experimental rat hepatocarcinogenesis. © 2004 Wiley‐Liss, Inc.
SWI/SNF chromatin remodeling complex is obligatory for BMP2‐induced, Runx2‐dependent skeletal gene expression that controls osteoblast differentiation
Authors: Young Daniel W. , Pratap Jitesh , Javed Amjad , Weiner Brian , Ohkawa Yasuyuki , van Wijnen Andre , Montecino Martin , Stein Gary S. , Stein Janet L. , Imbalzano Anthony N. , Lian Jane B.
Published: November 2004

Development of bone tissue requires maturation of osteoblasts from mesenchymal precursors. BMP2, a member of the TGFβ superfamily, and the Runx2 (AML3/Cbfa1) transcription factor, a downstream BMP2 effector, are regulatory signals required for osteoblast differentiation. While Runx2 responsive osteogenic gene expression has been functionally linked to alterations in chromatin structure, the factors that govern this chromatin remodeling remain to be identified. Here, we address the role of the SWI/SNF chromatin remodeling enzymes in BMP2‐induced, Runx2‐dependent development of the osteoblast phenotype. For these studies, we have examined calvarial cells from wild‐type (WT) mice and mice that are homozygous for the Runx2 null allele, as well as the C2C12 model of BMP2‐induced osteogenesis. By the analysis of microarray data, we find that several components of the SWI/SNF complex are regulated during BMP2‐mediated osteoblast differentiation. Brg1 is an essential DNA dependent ATPase subunit of the SWI/SNF complex. Thus, functional studies were carried out using a fibroblast cell line that conditionally expresses a mutant Brg1 protein, which exerts a dominant negative effect on SWI/SNF function. Our findings demonstrate that SWI/SNF is required for BMP2‐induced expression of alkaline phosphatase (APase), an early marker reflecting Runx2 control of osteoblast differentiation. In addition, Brg1 is expressed in cells within the developing skeleton of the mouse embryo as well as in osteoblasts ex vivo. Taken together these results support the concept that BMP2‐mediated osteogenesis requires Runx2, and demonstrates that initiation of BMP2‐induced, Runx2‐dependent skeletal gene expression requires SWI/SNF chromatin remodeling complexes. © 2004 Wiley‐Liss, Inc.
BH4 (tetrahydrobiopterin)‐dependent activation, but not the expression, of inducible NOS (nitric oxide synthase)‐2 in proinflammatory cytokine‐stimulated, cultured normal human astrocytes is mediated by MEK–ERK kinases
Authors: Chiarini Anna , Dal Pra Ilaria , Gottardo Rossella , Bortolotti Federica , Whitfield James F. , Armato Ubaldo
Published: November 2004

Nitric oxide (NO) from astrocytes is one of the signalers used by the brain's extensive glial‐neuronal‐vascular network, but its excessive production by pro‐inflammatory cytokine‐stimulated glial cells can be cytodestructive. Here, we show how three pro‐inflammatory cytokines (IL‐1β, TNF‐α, and IFN‐γ) together stimulated the activation, but not the prior expression, of NOS‐2 protein via a mechanism involving MEK–ERKs protein kinases in astrocytes from adult human cerebral temporal cortex. The cytokines triggered a transient burst of p38 MAPK activity and the production of NOS‐2 mRNA which were followed by bursts of MEK–ERK activities, synthesis of the NOS‐2 co‐factor tetrahydrobiopterin (BH4), a build‐up of NOS‐2 protein and from it active NOS‐2 enzyme. Selectively inhibiting MEK1/MEK2, but not the earlier burst of p38 MAPK activity, with a brief exposure to U0126 between 24 and 24.5 h after adding the cytokine triad affected neither NOS‐2 expression nor NOS‐2 protein accumulation but stopped BH4 synthesis and the assembly of the NOS‐2 protein into active NOS‐2 enzyme. The complete blockage of active NOS‐2 production by the brief exposure to U0126 was bypassed by simply adding BH4 to the culture medium. Therefore, this cytokine triad triggered two completely separable, tandem operating mechanisms in normal human astrocytes, the first being NOS‐2 gene expression and accumulation of NOS‐2 protein and the second being the synthesis of the BH4 factor needed to dimerize the NOS‐2 protein into active, NO‐making NOS‐2 enzyme. © 2004 Wiley‐Liss, Inc.
Effects of chronic administered guanosine on behavioral parameters and brain glutamate uptake in rats
Authors: Vinadé Elsa R. , Schmidt André P. , Frizzo Marcos E.S. , Portela Luis V. , Soares Félix A. , Schwalm Fábio D. , Elisabetsky Elaine , Izquierdo Ivan , Souza Diogo O.
Published: November 2004

Oral and intraperitoneal administration of the nucleoside guanosine have been shown to prevent quinolinic acid‐ (QA) and α‐dendrotoxin‐induced seizures, impair memory, and impair anxiety in rats and mice. We investigated the effect of 2‐weeks ad lib orally administered guanosine (0.5 mg/ml) on seizures induced by QA, inhibitory avoidance memory, and locomotor performance in rats. We also studied the mechanism of action of guanosine through the measurement of its concentration in the cerebrospinal fluid (CSF) and its effect on glutamate uptake in cortical slices of rats. QA produced seizures in 85% of rats, an effect partially prevented by guanosine (53% of seizures; P = 0.0208). Guanosine also impaired retention on the inhibitory avoidance task (P = 0.0278) and decreased locomotor activity on the open field test (P = 0.0101). The CSF guanosine concentration increased twofold in the treated group compared to that in the vehicle group (P = 0.0178). Additionally, QA promoted a 30% decrease in glutamate uptake as compared to that with intracerebroventricular saline administration, an effect prevented by guanosine in animals protected against QA‐induced seizures. Altogether, these findings suggest a potential role of guanosine for treating diseases involving glutamatergic excitotoxicity such as epilepsy. These effects seem to be related to modulation of glutamate uptake. © 2004 Wiley‐Liss, Inc.
Prognostic significance of the age factor in the thyroid cancer: Statistical analysis
Authors: Falvo Laura , Catania Antonio , Sorrenti Salvatore , D'Andrea Vito , Berni Alberto , Stefano Matteo De , Antoni Enrico De
Published: November 2004

Background and Objectives

To determine whether thyroid carcinoma in elderly patients presents any peculiar characteristics, whether the greater biological aggressiveness of the neoplasm modifies the surgical treatment selected, and whether age greater than 70 years represents an independent prognostic factor.

Methods

Retrospective analysis of case histories from the Department of Surgery of “La Sapienza” University of Rome; 403 patients subjected to total thyroidectomy between 1993 and 1999, with a minimum follow‐up period of 3 years subdivided into three groups: group I (patients aged between 20 and 50 years), group II (patients aged between 51 and 70 years) and group III (patients aged >70 years). The surgical and postoperative treatment is uniform in all study groups.

Results

Age greater than 70 years entails a significant increase in mortality; the mortality rate in the three groups was found to be 3%, 9% and 54%, respectively. Prognosis is significantly worse in the elderly patients group (group III) than in group I (P ≤ 0.001) and in group II (P ≤ 0.001); group II mortality was significantly higher than that of group I (P = 0.005); in group III, the neoplasm displays features of greater biological aggressiveness (greater incidence of undifferentiated forms, presence of lymph nodes at diagnosis and vascular invasion, locally advanced forms, greater incidence of stage IV).

Conclusions

Statistical analysis shows that the greater biological aggressiveness of the neoplasm in elderly patients worsens the prognosis, although an age exceeding 70 years itself represents an unfavourable prognostic factor; total thyroidectomy does not present any counter‐indications in elderly patients. J. Surg. Oncol. 2004;88:217–222. © 2004 Wiley‐Liss, Inc.
Simultaneous repair of abdominal aortic aneurysm and resection of unexpected, associated abdominal malignancies
Authors: Illuminati Giulio , Calio' Francesco G. , D'Urso Antonio , Lorusso Riccardo , Ceccanei Gianluca , Vietri Francesco
Published: November 2004

Background and Objectives

The management of unexpected intra‐abdominal malignancy, discovered at laparotomy for elective treatment of an abdominal aortic aneurysm (AAA), is controversial. It is still unclear whether both conditions should be treated simultaneously or a staged approach is to be preferred. To contribute in improving treatment guidelines, we retrospectively reviewed the records of patients undergoing laparotomy for elective AAA repair.

Methods

From January 1994 to March 2003, 253 patients underwent elective, trans‐peritoneal repair of an AAA. In four patients (1.6%), an associated, unexpected neoplasm was detected at abdominal exploration, consisting of one renal, one gastric, one ileal carcinoid, and one ascending colon tumor. All of them were treated at the same operation, after aortic repair and careful isolation of the prosthetic graft.

Results

The whole series' operative mortality was 3.6%. None of the patients simultaneously treated for AAA and tumor resection died in the postoperative period. No graft‐related infections were observed. Simultaneous treatment of AAA and tumor did not prolong significantly the mean length of stay in the hospital, compared to standard treatment of AAA alone.

Conclusions

Except for malignancies of organs requiring major surgical resections, simultaneous AAA repair and resection of an associated, unexpected abdominal neoplasm can be safely performed, in most of the patients, sparing the need for a second procedure. Endovascular grafting of the AAA can be a valuable tool in simplifying simultaneous treatment, or in staging the procedures with a very short delay. J. Surg. Oncol. 2004;88:234–239. © 2004 Wiley‐Liss, Inc.