bluuebunny/crossref_metadata_2025 huggingface dataset:
Aromaticity Indices from Magnetic Shieldings
Authors: Chen Zhongfang , Heine Thomas , von Rague Schleyer Paul , Sundholm Dage
Published: March 2005

For Abstract see ChemInform Abstract in Full Text.
Early‐stage carcinoids of the gastrointestinal tract
Authors: Soga Jun
Published: March 2005

BACKGROUND

Gastrointestinal (GI) carcinoids, considered to be endocrine neoplasms with relatively low levels of malignancy, have never been examined in large, statistically reliable series to determine their true aggressive behavior in the early stage of both minute (≤ 5 mm) or small (5.1–10.0 mm) tumors at a depth of invasion restricted to the mucosa and submucosa (sm carcinoids).

METHODS

Of a total number of 1914 cases of GI sm carcinoids selected from the Niigata Registry, 1614 with the tumor size recorded on a millimeter scale were categorized in 5‐mm size intervals and rates of metastases were calculated for those in each size category. Of statistical significance was confirmation that the rectum (n = 849), the stomach (n = 449), the duodenum (n = 349), and the jejunoileum (n = 149) were among the principal growth sites. The Kaplan–Meier method was used to calculate 5‐year‐survival rates (5YSRs) and a comparative study was undertaken.

RESULTS

GI sm carcinoids exhibited a metastasis rate of 16.4% (264 of 1614) as a whole and minute carcinoids (≤ 5 mm) revealed an unexpectedly high metastasis rate of 6.0% (24 of 399) on average, which ranged from 3.7% (8 of 216) in the rectum to 17.2% (5 of 29) in the jejunoileum. Small carcinoids measuring 5.1–10 mm also showed a high metastasis rate of 13.3% (90 of 675) on average, ranging from 9.6% (12 of 125) in the stomach to 41.2% (14 of 34) in the jejunoileum. The combined average metastasis rate for both minute and small carcinoids combined (≤ 10 mm) was as high as 10.6% (114 of 1074). The comparative study confirmed that, in both the stomach and the rectum, the metastasis rate of sm carcinoids was significantly higher than that for ordinary sm carcinomas in tumors > 10 mm. Although most patients (92.8%; 1777 of 1914) underwent an endoscopy and/or a wider resection of the lesions, nonresectable metastases were found in 22 patients (1.1%). Of these, 16 had undergone a laparotomy and 6 had not received surgery. Among 1001 patients with GI sm carcinoids, the 5YSRs after curative resection ranged from 98.3% in the rectum to 89.6% in the stomach (P < 0.05), representing an average of 96.7% for the entire series.

CONCLUSIONS

Unexpectedly high aggressiveness in metastasis rates in both rectal and gastric sm carcinoids > 10 mm exhibiting values significantly higher than those of sm carcinomas were found in 1914 patients suffering from GI sm carcinoids. However, in sm carcinoids at either the minute or small tumor stage (tumors ≦ 10 mm), the metastasis rates were comparable to those of sm carcinomas. It should be emphasized that the 5YSRs for patients with GI sm carcinoids may be comparable to those with sm carcinomas in certain cases. These points should be taken into consideration when treating patients with GI carcinoids, particularly in the early stage, and even with the depth of invasion confined to the submucosa. Cancer 2005. © 2005 American Cancer Society.
Efficacy of allogeneic hematopoietic stem cell transplantation depends on cytogenetic risk for acute myeloid leukemia in first disease remission
Authors: Yanada Masamitsu , Matsuo Keitaro , Emi Nobuhiko , Naoe Tomoki
Published: March 2005

BACKGROUND

The efficacy of allogeneic hematopoietic stem cell transplantation (allo‐HSCT) from a human leukocyte antigen‐identical sibling donor remains controversial for patients with acute myeloid leukemia (AML) in first complete disease remission (CR1). Because the karyotype identified at diagnosis is the most relevant prognostic factor for AML, it should be possible to assess the efficacy more accurately on the basis of cytogenetic risk.

METHODS

The authors performed a metaanalysis of five studies, which employed both natural randomization based on donor availability and intention‐to‐treat analysis, with overall survival as an outcome of interest. Metaregression analysis was then performed to identify the efficacy for patients stratified into the favorable, intermediate, and poor cytogenetic risk groups.

RESULTS

For the entire cohort, there was a statistically significant advantage with allo‐HSCT in terms of overall survival with a summary hazard ratio of 1.15 (95% confidence interval, 1.01–1.32, P = 0.037) for the random‐effect model. Metaregression analysis showed a significant coefficient of +0.24 for the poor cytogenetic risk group, and −0.25 for the favorable cytogenetic risk group, indicating that the benefit of allo‐HSCT was further increased for the former, and lost for the latter. The coefficient for the intermediate cytogenetic risk group was +0.09, and was not statistically significant.

CONCLUSIONS

These findings suggested that the efficacy of allo‐HSCT for patients with AML in CR1 depended on cytogenetic risk. The beneficial effect of allo‐HSCT was yielded for the poor risk group, and probably for the intermediate risk groups, but was absent for the favorable risk group. Cancer 2005. © 2005 American Cancer Society.
Recent advances in understanding the cell death pathways activated by anticancer therapy
Authors: Kim Ryungsa
Published: March 2005

Over the past two decades, the role of apoptosis in the cytotoxicity of anticancer drugs has become clear. Apoptosis may occur via a death receptor‐dependent (extrinsic) or independent (intrinsic or mitochondrial) pathway. Mitochondria play a central role in cell death in response to DNA damage, and mediate the interaction(s) of various cytoplasmic organelles, including the endoplasmic reticulum, Golgi apparatus, and lysosomes. The mitochondrial pathway of cell death is mediated by Bcl‐2 family proteins, a group of antiapoptotic and proapoptotic proteins that regulate the passage of small molecules, such as cytochrome c, Smac/Diablo, and apoptosis‐inducing factor, which activates caspase cascades, through the mitochondrial transition pore. In addition, apoptosis can induce autophagic cell death via crosstalk between the two pathways upon treatment with anticancer drugs. The current review focused on recent advances surrounding the mechanism(s) of cell death induced by anticancer agents and discussed potential molecular targets for enhancing the chemotherapeutic effect(s) of anticancer agents. Cancer 2005. © 2005 American Cancer Society.
Nuclear survivin predicts recurrence and poor survival in patients with resected nonsmall cell lung carcinoma
Authors: Shinohara Eric T. , Gonzalez Adriana , Massion Pierre P. , Chen Heidi , Li Ming , Freyer Andrea S. , Olson Sandra J. , Andersen Jeremiah J. , Shyr Yu , Carbone David P. , Johnson David H. , Hallahan Dennis E. , Lu Bo
Published: March 2005

BACKGROUND

Survivin, which is a member of the inhibitor of apoptosis protein gene family, regulates both programmed cell death and mitosis. It has been shown that survivin expression and its subcellular localization both have prognostic value for patients with malignant disease. In this study, the authors investigated whether nuclear or cytoplasmic staining of survivin was a prognostic marker for patients with lung carcinoma.

METHODS

Paraffin‐embedded tissue blocks from 144 patients with Stage I and II resected nonsmall cell lung carcinoma (NSCLC) were obtained for immunohistochemical staining. Three specimens from each patient were prepared and stained with a survivin‐specific antibody. Nuclear and cytoplasmic staining was graded from 1 to 3 based on intensity.

RESULTS

Patients who had nuclear staining for survivin had a significantly increased risk of disease recurrence (hazard ratio, 2.95; P = 0.0046) and death (hazard ratio, 2.74; P = 0.0086).

CONCLUSIONS

The nuclear presence of survivin may be an independent biomarker for disease recurrence and overall survival in patients with resected Stage I and II NSCLC. Cancer 2005. © 2005 American Cancer Society.
Prognostic factors in the nonsurgical treatment of esophageal carcinoma with radiotherapy or radiochemotherapy
Authors: Rades Dirk , Schild Steven E. , Bahrehmand Roja , Zschenker Oliver , Alberti Winfried A. , Rudat Volker R.
Published: March 2005

BACKGROUND

The current study was performed to evaluate prognostic factors for overall survival (OS), distant metastasis (DM), and local failure (LF) in patients with Stage II/III esophageal carcinoma.

METHODS

The following potential prognostic factors were retrospectively investigated in 124 patients treated with radiotherapy (RT) alone or with radiochemotherapy: age, gender, performance status, tumor location, tumor length, histology, histologic grade, T classification, N classification, International Union Against Cancer stage, chemotherapy, RT dose, and pre‐RT hemoglobin level.

RESULTS

Using univariate analysis (Kaplan–Meier method), pre‐RT hemoglobin level, RT dose, tumor length, chemotherapy, and performance status were significantly associated with OS. Hemoglobin levels of 12.1–14.0 g/dL were associated with the best OS, followed by ≥ 14.1 g/dL and ≤ 12.0 g/dL. DM was significantly influenced by tumor length, RT dose, N classification, and performance status. LF was significantly influenced by pre‐RT hemoglobin level, RT dose, and tumor length. Using multivariate analysis (Cox proportional hazard model), pre‐RT hemoglobin maintained significance for OS (P < 0.001) and LF (P < 0.001), RT dose for OS (P = 0.001), DM (P = 0.031), and LF (P < 0.001), tumor length for OS (P = 0.003), DM (P = 0.017), and LF (P = 0.033), and chemotherapy for OS (P = 0.027). N classification was of borderline significance for DM (P = 0.054). Performance status lost significance for OS (P = 0.73) and LF (P = 0.22).

CONCLUSIONS

The strongest predictors for outcome in Stage II/III esophageal carcinoma were RT dose, tumor length, pre‐RT hemoglobin level, and chemotherapy. The pre‐RT hemoglobin level was an independent prognostic factor significantly associated with OS and LF. A hemoglobin level of 12.1–14 g/dL resulted in a better prognosis than hemoglobin levels ≥ 14 g/dL and ≤ 12 g/dL. Cancer 2005. © 2005 American Cancer Society.
Increasing use of gonadotropin‐releasing hormone agonists for the treatment of localized prostate carcinoma
Authors: Shahinian Vahakn B. , Kuo Yong‐fang , Freeman Jean L. , Orihuela Eduardo , Goodwin James S.
Published: March 2005

BACKGROUND

The role of androgen deprivation therapy in prostate carcinoma is controversial in earlier stages of disease. The authors examined the time trends and patterns of use for androgen deprivation in the form of gonadotropin‐releasing hormone (GnRH) agonists or orchiectomy, in population‐based tumor registries.

METHODS

Data were obtained from the linked Surveillance, Epidemiology and End Results‐Medicare database. A total of 100,274 men with prostate carcinoma diagnosed from 1991 through 1999 were selected. The main outcome was the proportion of men who received ≥ 1 dose of a GnRH agonist in the first 6 months of diagnosis. This was plotted by year and stratified for age, grade, stage as well as primary versus adjuvant usage. Multiple logistic regression was used to examine predictors of GnRH agonist use in the subset of patients with localized cancer.

RESULTS

There was a consistent increase in GnRH agonist use by year for all ages, stages, and grades. Even in men ≥ 80 years with localized stage and low to moderate grade tumors, primary GnRH agonist use increased over the study period, from 3.7% in 1991 to 30.9% in 1999 (P < 0.001). The multivariable analysis showed that significant variability in GnRH agonist use existed among SEER geographic regions.

CONCLUSIONS

The use of GnRH agonists for prostate carcinoma increased dramatically during the 1990s. This increase occurred across all stages and histologic grades of prostate carcinoma, and was greatest in patients ≥ 80 years. Cancer 2005. © 2005 American Cancer Society.
Use of tamoxifen in advanced‐stage hepatocellular carcinoma
Authors: Nowak Anna K. , Stockler Martin R. , Chow Pierce K. H. , Findlay Michael
Published: March 2005

BACKGROUND

Hepatocellular carcinoma (HCC) is the third most common cause of cancer mortality worldwide. Survival is poor for patients with advanced‐stage HCC, and small trials of tamoxifen for patients with this disease have shown conflicting results. The authors conducted a systematic review of randomized clinical trials to compare the effect of a tamoxifen‐containing arm with a nontamoxifen‐containing arm in advanced HCC.

METHODS

Eligible trials were identified from the Cochrane Hepato‐Biliary Group register and other databases. Studies were selected for inclusion and their methodologic quality assessed by three independent reviewers. Hazard ratios (HR) were derived for overall survival where possible. Metaanalysis was performed using a fixed‐effect model.

RESULTS

The authors identified 10 randomized trials with a total of 1709 patients. Use of tamoxifen had no effect on median survival (HR, 1.05; 95% confidence interval, 0.94–1.16; P = 0.4) or tumor response rate. The findings were stable in sensitivity analyses and were not affected by publication bias or inclusion of low‐quality studies or studies reported in abstract form only. Few adverse events or withdrawals were noted.

CONCLUSIONS

There was no support for the therapeutic use of tamoxifen in advanced HCC, nor for its use as a control arm in future clinical trials. Cancer 2005. © 2005 American Cancer Society.
Carcinoma core distribution in patients with palpable and nonpalpable prostate tumors
Authors: Hernandez Javier , Thompson Ian M.
Published: March 2005

Introduction of prostate‐specific antigen (PSA)–based screening for prostate carcinoma has led to a significant increase in the detection of prostate carcinoma. Prostate core needle biopsy remains the gold standard as a diagnostic tool with which to ascertain disease status. In this issue of Cancer, Demura et al. challenge some commonly accepted concepts regarding the zonal distribution of prostate carcinoma and explore the distribution of carcinoma cores within the prostate as well as the potential impact of a systematic, ultrasound‐guided transperineal template biopsy in improving carcinoma detection rates.
Prinzipielle Beobachtungen zu Bauweise und Verfall der Gewölbe in den Tempeln von Angkor in Kambodscha
Authors: Pfefferkorn Stephan , Leisen Hans
Published: March 2005

Während der Blüte der Khmer‐Kultur entstanden in der Zeit von um 800 bis um 1300 n. Chr. auf dem Gebiet des heutigen Kambodscha und Thailand beeindruckende Tempelanlagen. Eine bedeutende Konzentration dieser Bauten stellt das heutige Angkor im Zentrum Kambodschas unweit des Sees Tonle Sap dar. Je nach Stilperiode dominieren als Baumaterial Ziegel, Laterit oder Sandstein. Die zum Teil recht unterschiedlichen Formen der einzelnen Gebäudeteile der Tempelanlagen besitzen eine Gemeinsamkeit. Für den oberen Abschluß ihrer Türme, lang gestreckten Galerien, Bibliotheks‐ und Torbauten wählten deren Baumeister das Prinzip der Kragwölbung. Heute sind große Teile der Gewölbe vor allem der langgestreckten Galerien bereits eingestürzt bzw. stark geschädigt. Die folgenden Untersuchungen sollen diese Bauweise der Khmer näher beleuchten und einen Beitrag dazu leisten, das Tragverhalten der Gewölbe im Zusammenhang mit deren Unterkonstruktionen besser zu verstehen, um die Ursachen der Schäden sicherer herauszufinden und auf sicherer Basis Maßnahmekonzepte zur Sanierung zu entwickeln. Die Grundlage für diese Betrachtungen bildet ein Arbeitsaufenthalt der Autoren in Angkor im Februar 2000, der – thematisch in das vom Auswärtigen Amt Deutschlands finanzierte und von der Fachhochschule Köln geleitete German Apsara Conservation Project (GACP) eingebettet – von der Deutschen Forschungsgemeinschaft unterstützt wurde.
Der Wand‐Decken‐Knoten im Mauerwerksbau: Teil 1: Theoretische und experimentelle Untersuchungen zur Tragfähigkeit
Authors: Jäger Wolfram , Baier Gunar
Published: March 2005

Der Wand‐Decken‐Knoten hat bei der Bemessung von Mauerwerk eine markante Bedeutung, da infolge der Verdrehung der Geschoßdecken in die Wände Biegemomente übertragen werden, die wiederum die Tragfähigkeit der Wand nachhaltig beeinflussen. Um den Arbeitsaufwand für deren Ermittlung in Grenzen zu halten, wird die Berechnung des Rahmensystems aus Wänden und Decken i. d. R. auf Ein‐Knoten‐Systeme zurückgeführt, die jeweils am Kopf und am Fuß der Wand angesetzt werden. Auf diese Weise läßt sich gleichzeitig die Lagerung der Wand an diesen Stellen berücksichtigen. Einer möglichst realitätsnahen Bestimmung der infolge Behinderung der Deckenverdrehungen indizierten Biegemomente und somit der Lastexzentrizität in der Wand kommt eine besondere Bedeutung bei der Bemessung zu. Die Güte der Modellierung und die zugrunde gelegten Annahmen haben Einfluß auf das rechnerische Ergebnis, das mehr oder weniger von dem realen Verhalten und der tatsächlichen Tragfähigkeit abweicht. Es soll auf der sicheren Seite liegen sowie einfach und schnell zu bestimmen sein.

Das Verhalten des Wand‐Decken‐Knotens ist mit besonderem Bezug zum Eurocode 6 theoretisch, experimentell und numerisch untersucht worden, um ggf. vorhandene Reserven beim Übergang auf das neue Sicherheitskonzept offenlegen und ausnutzen zu können. Die wesentlichen Ergebnisse werden nachfolgend dargestellt.
Zur Einführung der DIN 1053‐100: Mauerwerk – Berechnung auf der Grundlage des semiprobabilistischen Sicherheitskonzepts
Authors: Jäger Wolfram
Published: March 2005

Im August 2004 ist die DIN 1053‐100 [1] zur Berechnung von Mauerwerk nach dem neuen Sicherheitskonzept erschienen. Sie gestattet die Berechnung und Bemessung von Mauerwerksbauten mit Hilfe von Teilsicherheitsfaktoren. Dabei wurden die Nachweise von der Spannungs‐ auf die Kraftebene umgestellt. Im Zuge der Endfassung sind gegenüber bisherigen Veröffentlichungen aus der Erarbeitungsphase (s. [2] u. [3]) noch Veränderungen vorgenommen worden. Die Aufnahme in die Musterliste der Technischen Baubestimmungen [4] soll im Februar 2005 erfolgen, wobei eine Einschränkung hinsichtlich der Größe der zugelassenen Außermittigkeit im Gebrauchszustand unter vertikaler Belastung ergänzt wird. Der Beitrag stellt die wesentlichen Veränderungen vor und informiert über deren Hintergründe.
Mauermörtel und Putzmörtel nach europäischer Norm
Authors: Riechers Hans‐Joachim
Published: March 2005

Heute werden in den Bereichen “Mauermörtel” und “Putzmörtel” praktisch ausschließlich Werkmörtel eingesetzt. Diese Mörtel unterliegen bei der Herstellung einer strengen Qualitätskontrolle. Verantwortlich dafür ist der Hersteller selbst. Daran ändern Normen und Festlegungen des Bauordnungsrechts nichts. Die Normen legen jedoch Begriffe, Bezeichnungen und Klasseneinteilungen fest, mit denen die Kommunikation zwischen Planern, Herstellern und Bauausführenden erleichtert wird. Deshalb ist es wichtig, daß alle am Mauerwerksbau Beteiligten über den neuesten Stand informiert sind. Die Umstellung auf europäische Normen hat zu einigen Änderungen geführt, die im folgenden – in Kurzform – erläutert werden.
Bemessung von horizontal beanspruchtem Mauerwerk nach prEN 1996‐1‐1 mit Hilfe modifizierter Momentenverteilungszahlen
Authors: Jäger Wolfram , Thieme Mike
Published: March 2005

Horizontal beanspruchte Wände treten im Mauerwerksbau in Deutschland in Form von Ausfachungswänden mit Windbelastung bzw. Kellerwänden mit Erddruckbelastung auf. Diese werden nach DIN 1053‐1 [1] bisher mit Hilfe von Tabelle 9 auf ihre zulässige Größe hin überprüft. Bei Kellerwänden kann ein ausführlicher, rechnerischer Nachweis entfallen, wenn über einen Grenzlastvergleich das angenommene Bogenmodell sichergestellt ist.

In der aktuellen Fassung des EC 6 [2] werden für die Bemessung von Mauerwerk bei Plattenbeanspruchung zwei Rechenmodelle angeboten, das Bogenmodell und das Plattenmodell. Ersteres läßt sich nur bei zutreffenden Randbedingungen, die die Ableitung des Bogenschubs garantieren, anwenden. Bei dem Plattenmodell wird die Momentenverteilung in Anlehnung an die Bruchlinientheorie des Stahlbetonbaus bestimmt und der Biegenachweis unter Ansatz der Elastizitätstheorie geführt. Die Vorteile dieses Bemessungsmodells gegenüber DIN 1053‐1 sind die einfache Berücksichtigung baustofflicher und geometrischer Gegebenheiten und die genauere Nachweisführung.

Bei Untersuchungen zur Einführung des EC 6 in Deutschland wurde festgestellt, daß in bestimmten Parameterbereichen die in ENV 1996‐1‐3 [4] bisher zu findenden Momentenverteilungszahlen eine ungenügende Übereinstimmung mit Wandversuchen zeigen und ein Sicherheitsrisiko bei der Anwendung darstellen. Auf der Basis numerischer Analysen und begleitender Versuche zur Kalibrierung konnten die bestehenden Diskrepanzen beseitigt und modifizierte Momentenverteilungszahlen erarbeitet werden [4]. Der Beitrag informiert über die durchgeführten Untersuchungen und die ereichten Ergebnisse.
HPRT mutations, TCR gene rearrangements, and HTLV‐1 integration sites define in vivo T‐cell clonal lineages
Authors: Allegretta Mark , Ardell Stephanie K. , Sullivan Linda M. , Jacobson Steven , Mortreux Franck , Wattel Eric , Albertini Richard J.
Published: March 2005

HPRT mutations in vivo in human T‐lymphocytes are useful probes for mechanistic investigations. Molecular analyses of isolated mutants reveal their underlying mutational changes as well as the T‐cell receptor (TCR) gene rearrangements present in the cells in question. The latter provide temporal reference points for other perturbations in the in vivo clones as well as evidence of clonal relationships among mutant isolates. Immunological studies and investigations of genomic instability have benefited from such analyses. A method is presented describing a T‐cell lineage analysis in a patient with HTLV‐1 infection. Lineage reconstruction of an in vivo proliferating HPRT mutant clone allows timing of the integration event to a postthymic differentiated cell prior to the occurrence of HPRT mutations. Environ. Mol. Mutagen., 2005. © 2005 Wiley‐Liss, Inc.
Role of infectious diseases in human carcinogenesis
Authors: Herrera Luis A. , Benítez‐Bribiesca Luis , Mohar Alejandro , Ostrosky‐Wegman Patricia
Published: March 2005

The burden of human infectious diseases remains a public health problem worldwide. At least 2 billion people are affected by viral infections, and a similar number by bacteria or helminths. The long‐term effects of these maladies have raised particular concern since some infectious agents have been associated with chronic human diseases, especially cancer. It is estimated that 13–20% of the world cancer cases are associated with some virus, bacteria, or helminth, e.g., human papillomavirus,Helicobacter pylori, andSchistosoma haematobiumthat cause cervical, stomach, and urinary bladder cancer, respectively. Certain associations between infection and malignancy are strong and irrefutable; others are still speculative. This article reviews the infectious agents that have been associated with cancer and current knowledge about the mechanisms underlying these associations. Environ. Mol. Mutagen., 2005. © 2005 Wiley‐Liss, Inc.
Is the hippocampal theta rhythm related to cognition in a non‐locomotor place recognition task?
Authors: Kelemen Eduard , Morón Ignacio , Fenton André A.
Published: March 2005

The possible correlation of 4–12 Hz hippocampal field oscillations (theta rhythm) with motor and cognitive behavior was studied by recording the hippocampal electroencephalogram in non‐locomoting rats as they solved a hippocampus‐dependent place recognition task. The electroencephalogram (EEG) during the place recognition task was compared with the EEG during a control task, which had the same motor demands but did not require place recognition. In the place recognition task, the rat was passively transported on the periphery of a circular rotating arena, operant responses (lever pressing in Experiment 1 and licking in Experiment 2) emitted in a 60° reward sector of the arena trajectory were reinforced. As expected the theta rhythm was observed during “voluntary” movements such as walking and lever pressing. During walking and lever pressing, when prominent theta was observed, the frequency increased within the first 10 min of a session. When the rats were not moving, during licking or staying motionless, both the theta amplitude and frequency were lower compared with the EEG during walking. There were no correlations between any theta characteristics and cognitive demand of the tasks. © 2005 Wiley‐Liss, Inc.
Tetrodotoxin infusions into the dorsal hippocampus block non‐locomotor place recognition
Authors: Klement Daniel , Pašt'alková Eva , Fenton André A.
Published: March 2005

The hippocampus is critical for navigation in an open field. One component of this navigation requires the subject to recognize the target place using distal cues. The experiments presented in this report tested whether blocking hippocampal function would impair open field place recognition. Hungry rats were trained to press a lever on a feeder for food. In Experiment 1, they were passively transported with the feeder along a circular trajectory. Lever pressing was reinforced only if the feeder was passing through a 60°‐wide sector. Thus, rats preferentially lever pressed in the vicinity of the reward sector indicating that they recognized its location. Tetrodotoxin (TTX) infusions aimed at the dorsal hippocampi caused rats to substantially increase lever pressing with no preference for any region. The aim of Experiment 2 was to determine whether the TTX injections caused a loss of place recognition or a general increase of lever pressing. A separate group of rats was conditioned in a stationary apparatus to press the lever in response to a light. The TTX injections did not abolish preferential lever pressing in response to light. Lever pressing increased less than half as much as the TTX‐induced increase in Experiment 1. When these animals with functional hippocampi could not determine the rewarded period because the light was always off, lever pressing increased much more and was similar to the TTX‐induced increase in Experiment 1. We conclude that the TTX inactivation of the hippocampi impaired the ability to recognize the reward place. © 2005 Wiley‐Liss, Inc.
Hippocampal neurogenesis is not enhanced by lifelong reduction of glucocorticoid levels
Authors: Brunson Kristen L. , Baram Tallie Z. , Bender Roland A.
Published: March 2005

Neurogenesis of dentate gyrus granule cells is generally considered to be negatively regulated by glucocorticoids. We tested the hypothesis that exposure to low plasma corticosteroid levels starting in the early postnatal period enhances granule cell proliferation rate during adulthood. Rat pups were adrenalectomized (ADX) on postnatal day 10 and were then “clamped” throughout life at low corticosterone levels via oral supplementation. Neurogenesis was determined using BrdU immunochemistry at 3 and 12 months in clamped rats as compared with age‐matched, sham‐operated controls. Rate of neurogenesis did not differ between the groups at either 3 or 12 months. It was significantly lower in 12‐month‐old compared with 3‐month‐old rats, despite the presence of an age‐dependent increase of plasma corticosterone only in the sham‐ADX rats. Granule cell layer volume, granule cell density, and granule cell degeneration (determined using apoptotic markers) were indistinguishable in the two groups, further supporting the comparable rate of neurogenesis under differing chronic glucocorticoid levels. In addition, whereas acute deprivation of plasma glucocorticoids (adrenalectomy) in adult rats evoked a burst of granule cell neurogenesis, complete elimination of these hormones (by stopping hormone supplementation) in adult, early‐life ADX/clamped rats did not. These data do not support a simple inverse relationship between chronic plasma glucocorticoid levels and granule cell neurogenesis. Specifically, chronic modulation of glucocorticoid levels commencing early in life evokes additional, adaptive, and compensatory mechanisms that contribute to the regulation of granule cell proliferation. © 2005 Wiley‐Liss, Inc.
Mouse models of impaired fear memory exhibit deficits in amygdalar LTP
Authors: Schimanski Lesley A. , Nguyen Peter V.
Published: March 2005

Inbred mouse strains have different genetic backgrounds that can result in impairments of synaptic plasticity and memory. They are valuable models for probing the mechanisms of memory impairments. We examined fear memory in several inbred strains, along with synaptic plasticity that may underlie fear memory. Long‐term potentiation (LTP) is a form of activity‐dependent synaptic plasticity that is a candidate cellular mechanism for some forms of learning and memory. Strains with impaired contextual or cued fear memory may have selective LTP deficits in different hippocampal subregions, or in the amygdala. We measured fear memory and its extinction in five inbred strains: C57BL/6NCrlBR (B6), A/J, BALB/cByJ (BALB), C57BL/10J (B10), and SM/J (SM). We also measured LTP in the basolateral amygdala and in the hippocampal Schaeffer collateral–commissural (SC) and medial perforant pathways (MPP). All strains exhibited intact contextual fear memory 24 h post‐training, but cued fear memory was impaired in strains A/J, BALB, and SM. At 1 h post‐training, both contextual and cued fear memory deficits were more widespread: all strains except for B6 and B10 showed impairments of both types of memory. Contextual fear extinction was impaired in BALB and SM. We found that amygdalar LTP was reduced in strains A/J and BALB, but SC LTP was intact in all strains (except for a selective multi‐train LTP impairment in BALB). MPPLTP was similar in all five strains. Thus, reduced amygdalar LTP is correlated with impaired cued fear memory in strains A/J and BALB. Also, hippocampal SC LTP is more strongly correlated with 24‐h (long‐term) than with 1‐h (short‐term) contextual fear memory. In this first conjoint study of amygdala‐dependent memory and amygdalar LTP in inbred mice, we identified specific hippocampal and amygdalar LTP deficits that correlate with fear memory impairments. These deficits should be considered when selecting inbred strains for genetic modification. © 2005 Wiley‐Liss, Inc.
Regulation of manganese accumulation in perinatally exposed rat pups
Authors: Kostial Krista , Blanuša Maja , Piasek Martina
Published: March 2005

The risk of manganese (Mn)‐related ill effects in the neonate has been the topic of several investigations because in formula‐fed infants Mn intake is much higher than in breast‐fed infants. In the young, when Mn homeostasis is not yet developed, increased Mn intake might pose a neurotoxic risk. Our work aimed at collecting new data on Mn accumulation during the perinatal period by using an experimental rat model in pups whose mothers were exposed orally to Mn in drink (as manganese chloride; dose of 2000 ppm Mn) throughout pregnancy and 11 days of lactation. Pups were cross‐fostered at birth and placental and mammary transfer of Mn at birth and at the age of 11 days was evaluated. The total pup body burden of Mn was analysed by atomic absorption spectrometry. Concentrations of iron (Fe), zinc (Zn) and calcium (Ca) also were analysed at the end of the experiment.

The concentration of Mn in perinatally exposed pups was 6–8 times higher than in controls, irrespective of the period and duration of exposure. After cessation of exposure, the Mn concentration decreased almost to control levels. Concentrations of other essential elements (Fe, Zn, Ca) were not affected by Mn exposure. Our results indicate the existence of an accurate regulation of Mn accumulation in pups exposed to Mn during the perinatal period. Copyright © 2005 John Wiley & Sons, Ltd.
Etoposide‐induced cytogenotoxicity in mouse spermatogonia and its potential transmission
Authors: Palo Anil K. , Sahu Prajyoti , Choudhury Ramesh C.
Published: March 2005

As cancer chemotherapeutic agents are cytogenotoxic but not target‐specific during systemic treatment, they affect all the encountered cells including the non‐cancerous ones and consequently lead to the recurrence of second malignancy in post‐chemotherapeutic cancer survivors. The effects would be persistent if the stem cells were affected. These drugs also may affect germline cells during therapeutic treatments. There is every chance that the effects are transmitted through the germline cells to the gametes and to the next generation if the gonadal mother cells are affected. Such transmission of effects from the post‐chemotherapeutic childhood cancer survivors is of serious concern but very little attention has been given so far to such studies.

Etoposide (VP‐16) — a semi‐synthetic epipodophyllotoxin derivative, a DNA non‐intercalating agent and a topoisomerase II inhibitor — is prescribed frequently for the treatment of various types of cancers. It is a potent clastogen inducing chromosomal damage both in vitro and in vivo. Its clastogenic effect is indirect through inhibition of the catalytic activity of topoisomerase II enzymes, which maintain the topology of DNA during replication, recombination, transcription, etc. by forming a ‘cleavable complex’ and facilitate the cleaving and re‐ligation of the cleaved DNA to relieve the torsional stress during such events. Transient stabilization of the cleavable complex by etoposide leads to illegitimate ligation of the cleaved DNA. Consequently, single‐ and double‐strand breaks occur.

In the present study, the clastogenic potential of three different doses of etoposide (10, 15 and 20 mg kg−1) in the male germline of mice was assessed from the dividing spermatogonia after a single exposure for one cell cycle duration at 24 h post‐treatment. Transmission of such effects was assessed from the frequency of aberrant primary spermatocytes at week 4 post‐treatment and of abnormal sperm at week 8 post‐treatment.

All three doses of etoposide were found to be clastogenic to the dividing spermatogonia of mice, and mostly chromatid breaks were induced. The effects also were transmitted through the male germline of mice, which was evident from the prevalence of statistically significant increased percentages of aberrant primary spermatocytes at week 4 posttreatment and the higher percentages of abnormal sperm at week 8 post‐treatment. Thus, there is every chance that the cytogenotoxic effects of etoposide are transmitted to the next generation through the male germline of post‐chemotherapeutic cancer survivors, therefore it is essential to make etoposide target‐specific or modulate its effects. Copyright © 2005 John Wiley & Sons, Ltd.
Comparison of different test models for the assessment of cytotoxicity of composite resins
Authors: Cao Tong , Saw Tzuen Yih , Heng Boon Chin , Liu Hua , Yap Adrian U Jin , Ng Mah Lee
Published: March 2005

This study compared the use of different test models to assess the cytotoxicity of a dental composite. The cytotoxicity of a composite polymerized using two halogen‐based light‐curing units (LCUs) (Max LC and Astralis) and two light‐emitting diode LCUs (E‐light and Freelight) served as the basis of comparison. Disk‐shaped specimens (7 mm diameter, 2 mm high) were fabricated using the four different light sources. The specimens were used in several cytotoxicity test models: direct and indirect contact tests as well as an extract test with an established cell line L‐929. The cells were stained with neutral red after cell‐material contact for 48 h. Neutral red‐stained areas (in mm2, for direct and indirect tests) and absorbance readings (for extract tests) were analysed statistically using ANOVA and the Tukey post hoc test, with P < 0.05 considered to be significantly different. Good correlation between direct and indirect contact tests (r = 0.903) was found. The extract test was the least correlated among the three tests. It was found that the E‐light + Freelight‐cured composite elicited cytotoxicity from the correlated studies. Uncured specimens were most detrimental to the cells in all tests. Our data demonstrated that composite cured with light‐emitting diode LCUs were cytotoxic to L‐929 cells. Different test models were found to give rise to different findings. Thus, a good cell‐material contact method would replicate more closely the physiological situation in vivo. This in turn would give more clinically relevant results. Copyright © 2005 John Wiley & Sons, Ltd.
Lead‐induced changes in human erythrocytes and lymphocytes
Authors: Slobozhanina E. I. , Kozlova N. M. , Lukyanenko L. M. , Oleksiuk O. B. , Gabbianelli R. , Fedeli D. , Caulini G. C. , Falcioni G.
Published: March 2005

In the present work we studied, by chemiluminescence measurements, the influence of lead on the production of reactive oxygen species (ROS) in haemolysates obtained from human erythrocytes incubated in the presence of different concentrations of lead acetate. Moreover, we evaluated the modification of proteins and lipids in human erythrocyte and lymphocyte membranes by using the fluorescence probes N‐(1‐pyrene)maleimide (PM), laurdan and pyrene. No significant changes in chemiluminescence were detected for erythrocytes incubated with 1–10 µM lead acetate for 3 h at 37 °C. By increasing the lead acetate concentration in cell suspensions up to 50 µM for the same incubation time, the percentage of chemiluminescence inhibition was ca. 20%. It was shown that, after incorporating fluorescence probes in the membrane lipid bilayer of erythrocytes and lymphocytes treated with 10 and[sol ]or 50 µM lead acetate, the total fluorescence intensity and the excimer to monomer intensity ratio of PM decreased and the generalized fluorescence polarization of laurdan decreased by 10–15%. The pyrene excimerization coefficient (κex) increased by 20% (in comparison with a magnitude of κex for white membranes isolated from intact erythrocytes) with 6–10 µM lead acetate for 3 h at 37 °C.

The data obtained suggest that the effect of low concentrations of lead acetate does not cause production of ROS in erythrocytes in vitro, but can change the physicochemical state of proteins and lipids in erythrocyte and lymphocyte membranes. This effect is important because it influences the enzymatic activity and the functionality of receptors and channels present at the plasma membrane level, thus modulating the molecular composition of the intracellular space and cell functions. Copyright © 2005 John Wiley & Sons, Ltd.
Novel approach for classifying chemicals according to skin sensitizing potency by non‐radioisotopic modification of the local lymph node assay
Authors: Takeyoshi Masahiro , Iida Kenji , Shiraishi Keiji , Hoshuyama Satsuki
Published: March 2005

The murine local lymph node assay (LLNA) is currently recognized as a stand‐alone sensitization test for determining the sensitizing potential of chemicals, and it has the advantage of yielding a quantitative endpoint that can be used to predict the sensitization potency of chemicals. The ec3 has been proposed as a parameter for classifying chemicals according to the sensitization potency. We previously developed a non‐radioisotopic endpoint for the LLNA based on 5‐bromo‐2′‐deoxyuridine (BrdU) incorporation (non‐RI LLNA), and we are proposing a new procedure to predict the sensitization potency of chemicals based on comparisons with known human contact allergens. Nine chemicals (i.e. diphencyclopropenone, p‐phenylenediamine, glutaraldehyde, cinnamicaldehyde, citral, eugenol, isopropyl myristate, propyleneglycol and hexane) categorized as human contact allergen classes 1–5 were tested by the non‐RI LLNA with the following reference allergens: 2,4‐dinitrochlorobenzene (DNCB) as a class 1 human contact allergen, isoeugenol as a class 2 human contact allergen and α‐hexylcinnamic aldehyde (HCA) as a class 3 human contact allergen. Consequently, nine test chemicals were almost assigned to their correct allergen class. The results suggested that the new procedure for non‐RI LLNA can provide correct sensitization potency data. Sensitization potency data are useful for evaluating the sensitization risk to humans of exposure to new chemical products. Accordingly, this approach would be an effective modification of LLNA with regard to its experimental design. Moreover, this procedure can be applied also to the standard LLNA with radioisotopes and to other modifications of the LLNA. Copyright © 2005 John Wiley & Sons, Ltd.
Benefits of combining the sexes when evaluating data from toxicological studies
Authors: Wiklund Stig Johan , Svens Karin , Palm Maud , Holland Tom
Published: March 2005

In the assessment of the safety of a new drug, a large battery of toxicological studies is performed. In toxicological studies it is common practice to analyse the data from the sexes separately. We argue that this is not best practice and that much is to be gained from combining data from both sexes when evaluating studies. The main benefits and arguments in favour of combining the data are:

(i) Improved efficiency, allowing fewer test animals and[sol ]or better precision.

(ii) Other phases of drug development, clinical trials in particular, combine sexes.

(iii) Most substances act similarly on both sexes and most drugs are prescribed without sex differentiation.

(iv) If sex differences are of interest, combined data facilitates the quantification of the difference.

(v) Reduced number of false positive and false negative findings.

Although there might be some grounds to analysing the sexes separately, we argue that these are comparatively minor.

We do not promote simply pooling the data and neglecting the existence of two sexes when comparing treatment groups. Rather, the analysis of combined data should allow for sex differences, for instance by using stratified procedures or by including a sex factor in a statistical model. We illustrate from real study data where the approach we propose has substantial benefits over traditional methods. A theoretical illustration is provided to quantify mathematically the potential gains and the corresponding sample size reduction, i.e. a reduction of animal use of ca. 50%, that would be possible without impairing the precision of studies. Copyright © 2005 John Wiley & Sons, Ltd.
Legal issues of addiction assessment: the experience with hair testing in Greece
Authors: Savvopoulos M. A. , Pallis E. , Tzatzarakis M. N. , Dialyna I. A. , Tzanakakis G. N. , Tsatsakis A. M.
Published: March 2005

The purpose of this paper is to present Greek law and legislation for crimes and felonies regarding drugs of abuse and the interpretation of hair testing results with respect to Greek law. Details (such as the process, the decision and the competence of the Court, the police record, the indictment, the expert reports, the defendant's individuality, the crimes and the penal confrontal and many others) from legal cases related to toxicomany and its judicial verification were collected and analysed. Laboratory data of cases concerning the laboratory evaluation of toxicomany in addicts and also occasionally the legal course of cases with addict defendants are presented. In four representative cases segmental hair analysis proved that, for as long as the individuals were imprisoned, findings with drug substances corresponding to that period were lesser or practically absent compared with samples corresponding to the time out of prison, which showed increased drug abuse. Hair analysis provides information on chronic exposure rather than acute poisoning. Its detection window varies from some days to months or even years. The procedure that the law lays down in many cases is insufficient and in most cases impossible to abide by. When the medical examiner is not able to decide if the claim of toxicomany is real, segmental hair analysis may be the only way to prove it. In other cases where the medical examiner is able to diagnose the addiction, a segmental hair analysis is necessary because it can show long‐term drug abuse. Copyright © 2005 John Wiley & Sons, Ltd.
Effect of β‐naphthoflavone and phenobarbital on the nephrotoxicity of chlorotrifluoroethylene and 1,1‐dichloro‐2,2‐difluoroethylene in the rat
Authors: Morel Georges , Ban Masarin , Bonnet Pierre , Zissu Danièle , Brondeau Marie‐Thérèse
Published: March 2005

The role of cytochrome P450 activity in the nephrotoxicity of chlorotrifluoroethylene (CTFE) and 1,1‐dichloro‐2,2‐difluoroethylene (DCDFE) was investigated in the male rat. Hepatic cytochrome P450 1A1 and principally P450 2B1[sol ]2 were induced by β‐naphthoflavone and phenobarbital, respectively. Nephrotoxicity was evaluated by investigating urine biochemical parameters, kidney histochemistry and histopathological modifications.

Both CTFE and DCDFE induce severe nephrotoxicity in rats after 4 h of exposure to 200 and 100 ppm, respectively. Compared with controls, activity levels of γ‐glutamyltranspeptidase (γGT), aspartate aminotransferase (AST), alkaline phosphatase (ALP) and N‐acetyl‐β‐d‐glucosaminidase (NAG) in 24‐h urine were increased similarly, but urinary excretion of glucose, proteins and β2‐microglobulin (β2‐m) and serum urea and creatinine levels were increased. Histopathological and histochemical examinations of kidney sections of CTFE‐ and DCDFE‐exposed rats revealed cellular necrosis and tubular lesions 24 h after exposure.

β‐Naphthoflavone‐pretreated rats were afforded some protection against the nephrotoxicity of CTFE and DCDFE. Phenobarbital did not modify DCDFE nephrotoxicity but afforded some protection against CTFE nephrotoxicity. In conclusion, CTFE and DCDFE are strong nephrotoxins. Cytochrome P450 1A1 is implicated in CTFE and DCDFE metabolism and one or several cytochromes induced by phenobarbital are implicated in CTFE metabolism. The P450 cytochromes involved in CTFE and DCDFE metabolism probably constitute detoxication metabolic pathways. The nephrotoxicity of CTFE and DCDFE is therefore subordinated to the cytochrome P450 activity involved in their metabolism. Copyright © 2005 John Wiley & Sons, Ltd.
Pro‐inflammatory effects of Dunkerque city air pollution particulate matter 2.5 in human epithelial lung cells (L132) in culture
Authors: Dagher Zeina , Garçon Guillaume , Gosset Pierre , Ledoux Frédéric , Surpateanu Georgiana , Courcot Dominique , Aboukais Antoine , Puskaric Emile , Shirali Pirouz
Published: March 2005

Exposure to urban airborne particulate matter (PM) has been associated with adverse health effects. The majority of research articles published on air pollution PM relate to PM10. However, increasing emphasis and stringent regulations have been placed on PM2.5. The mechanisms for PM‐induced adverse health effects are not well understood, but inflammation seems to be of importance. We focused our attention also on the capacity of air pollution PM2.5 to induce cytotoxic and inflammatory responses in human epithelial lung cells (L132) in culture. Particulate matter was collected in Dunkerque, a French seaside city characterized by the proximity of industrial activity and heavy motor vehicle traffic. Size distribution results showed that the cumulative frequency of PM2.5 was 92.15% and their specific surface area was 1 m2 g−1. Inorganic and organic chemicals usually associated with the natural environment but also so‐called anthropogenic elements were found in PM, suggesting that much of the PM was derived from wind‐borne dust from the industrial complex and the heavy diesel motor vehicle. We observed PM concentration‐dependent cytotoxic effects in L132 cells (lc10 = 18.84 µg PM ml−1; lc50 = 75.36 µg PM ml−1). We showed that exposure to Dunkerque City's PM2.5 induced significant increases (in a concentration‐ and time‐dependent manner) in protein secretion and[sol ]or gene expression of inflammatory cytokines (i.e. TNF‐α, IL‐1β, IL‐8, GM‐CSF, IL‐6, TGF‐β1). We hypothesized also that the occurrence of the acute inflammatory response might rely on the capacity of such air pollutants to generate oxidative species, which have been implicated in the stringent regulation of the cytokine network. Hence, we suggest that the development of inflammatory effects that worsen over time stems from the cytotoxicity in Dunkerque City's PM2.5‐exposed L132 cells in culture. Copyright © 2005 John Wiley & Sons, Ltd.