bluuebunny/crossref_metadata_2025 huggingface dataset:
Origin and evolution of large brains in toothed whales
Authors: Marino Lori , McShea Daniel W. , Uhen Mark D.
Published: October 2004

Toothed whales (order Cetacea: suborder Odontoceti) are highly encephalized, possessing brains that are significantly larger than expected for their body sizes. In particular, the odontocete superfamily Delphinoidea (dolphins, porpoises, belugas, and narwhals) comprises numerous species with encephalization levels second only to modern humans and greater than all other mammals. Odontocetes have also demonstrated behavioral faculties previously only ascribed to humans and, to some extent, other great apes. How did the large brains of odontocetes evolve? To begin to investigate this question, we quantified and averaged estimates of brain and body size for 36 fossil cetacean species using computed tomography and analyzed these data along with those for modern odontocetes. We provide the first description and statistical tests of the pattern of change in brain size relative to body size in cetaceans over 47 million years. We show that brain size increased significantly in two critical phases in the evolution of odontocetes. The first increase occurred with the origin of odontocetes from the ancestral group Archaeoceti near the Eocene‐Oligocene boundary and was accompanied by a decrease in body size. The second occurred in the origin of Delphinoidea only by 15 million years ago. © 2004 Wiley‐Liss, Inc.
D‐methylphenidate and D,L‐methylphenidate are not developmental toxicants in rats and rabbits
Authors: Teo Steve K. , Stirling David I. , Hoberman Alan M. , Christian Mildred S. , Thomas Steve D. , Khetani Vikram D.
Published: October 2004

BACKGROUND: D,L‐threo‐Methylphenidate (D,L‐MPH) is marketed currently for attention deficit hyperactivity disorder in children. D‐threo‐methylphenidate (dexmethylphenidate; D‐MPH) is a refined formulation of D,L‐methylphenidate containing only the active enantiomer and was recently approved in the U.S. for the same condition. D‐Methylphenidate has been shown to be efficacious in patients at half the dose of D,L‐MPH with a potentially improved therapeutic profile. The developmental toxicity of both compounds was determined and compared in rats and rabbits according to current International Conference on Harmonization (ICH) guidelines. METHODS: Groups of pregnant rats were orally dosed twice daily 6 hr apart from Days 7 to 17 of presumed gestation (DG 7–17) for total daily doses of 2, 6 and 20 mg/kg D‐MPH and 40 mg/kg D,L‐MPH. Groups of presumed pregnant rabbits were similarly dosed from DG 6 to 18 for total daily doses of 4, 20 and 100 mg/kg D‐MPH and 200 mg/kg D,L‐MPH. Control groups for both studies were given water vehicle. Comprehensive clinical and developmental measurements were made. Satellite groups of animals were included in the main rat and rabbit studies for toxicokinetic assessment. RESULTS: No drug‐related mortality was seen in the F0 rats and rabbits. The number of rats with repetitive pawing, dilated pupil and aggression was significantly greater for the 40 mg/kg D,L‐MPH compared to the 20 mg/kg D‐MPH dosed rats. Maternal body weight and body weight gain were significantly reduced for both D‐MPH and D,L‐MPH groups compared to control. Maternal reproductive and litter parameters were unaffected by both drugs. No gross external, soft tissue, or skeletal alterations related to both compounds were seen in the fetuses. In rabbits, head‐bobbing and hyperpnea were significantly greater for the 200 mg/kg D,L‐MPH compared to 100 mg/kg D‐MPH. No other maternal or fetal effects related to both compounds were seen. Exposure to D‐MPH (as assessed by AUC) showed no teratogenic effects at exposures of up to 5.6 and 1.7 times for the rat and rabbit respectively compared to children taking the maximum therapeutic dose of 20 mg/day (10 mg twice a day). No teratogenic effects were seen for D,L‐MPH in rat and rabbit at exposures of up to 3.7 to 11.7 times that of the maximum therapeutic pediatric dose of 60 mg/day. CONCLUSIONS: Rats and rabbits dosed with D,L‐MPH exhibited significantly greater incidence of maternal clinical observations at twice the dose of D‐MPH. Both D‐MPH and D,L‐MPH were not teratogenic in rats and rabbits at higher exposure levels compared to humans. © 2003 Wiley‐Liss, Inc.
Microcomputed tomography imaging of skeletal development and growth
Authors: Guldberg Robert E. , Lin Angela S.P. , Coleman Rhima , Robertson Galen , Duvall Craig
Published: October 2004

Skeletogenesis is an exquisitely orchestrated and dynamic process, culminating in the formation of highly variable and complex mineralized structures that are optimized for their function. While cellular and molecular biology studies have provided tremendous recent progress toward understanding how patterns of bone formation are regulated, high resolution imaging techniques such as microcomputed tomography (micro‐CT) can provide complementary quantitative information about the progressive changes in three‐dimensional (3‐D) skeletal morphology and density that occur during early skeletal development and postnatal growth. Furthermore, recently developed in vivo micro‐CT systems promise to be a powerful and efficient tool for noninvasively monitoring normal skeletogenesis, as well as for evaluating the effects of genetic or environmental manipulation. This review focuses on the use of micro‐CT imaging and analysis to better understand normal and abnormal skeletal development and growth. Birth Defects Research (Part C) 72: 250–259, 2004. © 2004 Wiley‐Liss, Inc.
Making the mouse embryo transparent: Identifying developmental malformations using magnetic resonance imaging
Authors: Schneider Jürgen E. , Bhattacharya Shoumo
Published: October 2004

Developmental malformations are a major cause of childhood mortality and are typically characterized by lesions that allow survival of the embryo through gestation. The genetics of developmental malformations are powerfully studied by using high‐throughput, phenotype‐driven screens (e.g., following zebrafish or mouse mutagenesis) or by genotype‐driven studies using transgenic or knockout mice. With regard to either approach, the mouse is anatomically and phylogenetically closer to humans than any other genetically tractable model organism. This is particularly important in the cardiovascular and respiratory systems, which have unique mammalian features. The identification of murine models of developmental malformations is, however, hindered by the opacity of the late gestational mouse embryo. In this review, we describe recent advances in magnetic resonance imaging that make it possible to rapidly identify malformations in the developing mouse embryo with high efficiency. Birth Defects Research (Part C) 72:241–249, 2004. © 2004 Wiley‐Liss, Inc.
Molecular imaging of the embryonic heart: Fables and facts on 3D imaging of gene expression patterns
Authors: Ruijter Jan M. , Soufan Alexandre T. , Hagoort Jaco , Moorman Antoon F.M.
Published: October 2004

Molecular imaging, which is the three‐dimensional (3D) visualization of gene expression patterns, is indispensable for the study of the function of genes in cardiac development. The instrumentation, as well as the development of specific contrast agents for molecular imaging, has shown spectacular advances in the last decade. In this review, the spatial resolutions, contrast agents, and applications of these imaging methods in the field of cardiac embryology are discussed. Apart from 3D reconstructions from histological sections, not many of these methods have been applied in embryological research. This review shows that, for most methods, neither the spatial resolutions nor the specificity and applicability of the contrast agents are adequate for the reliable imaging of specific gene expression at the microscopic resolution required for embryological studies of small organs like the developing heart. Although a 3D reconstruction from sections will always suffer from imperfections, the resulting reconstructions meet the aim of most biological studies, especially since the original microscopic images are linked. With respect to imaging of gene expression, only histological sections and laser scanning microscopy provide the required resolution and specificity at the tissue and cellular level. Episcopic fluorescence image capturing and optical projection tomography are being used for microscopic phenotyping and lineage analysis, and both show potential for detailed molecular imaging. Other methods can be used very efficiently in rapid evaluation of biological experiments and high‐throughput screens of large‐scale gene expression profiling efforts when high spatial resolution is not required. Birth Defects Research (Part C) 72:224–240, 2004. © 2004 Wiley‐Liss, Inc.
Current standards of surgery for pancreatic cancer
Authors: Alexakis N , Halloran C , Raraty M , Ghaneh P , Sutton R , Neoptolemos J P
Published: October 2004

Background

Pancreatic cancer carries a dismal prognosis but there has been a vast increase in evidence on its management in the past decade.

Methods

An electronic and manual search was performed for articles on the surgical treatment of pancreatic cancer published in the past 10 years.

Results

Six major areas of advancement were identified. Groups at high risk of developing pancreatic cancer, notably those with chronic pancreatitis and hereditary pancreatitis, have been defined, raising the need for secondary screening. Methods of staging pancreatic cancer for resection have greatly improved but accuracy is still only 85–90 per cent. Pylorus-preserving partial pancreatoduodenectomy without extended lymphadenectomy is the simplest procedure; it does not compromise long-term survival. Adjuvant chemotherapy significantly improves long-term survival. Patients who are free from major co-morbidity have better palliation by surgery (with a double bypass) than by endoscopy. High-volume centres improve the results of surgery for all outcome measures including long-term survival.

Conclusion

The surgical management of pancreatic cancer has undergone a significant change in the past decade. It has moved away from no active treatment. The standard of care can now be defined as potentially curative resection in a specialist centre followed by adjuvant systemic chemotherapy.
Intra-abdominal hypertension and the abdominal compartment syndrome (Br J Surg 2004; 91: 1102–1110)
Authors: Teubner A , Anderson I D , Scott N A , Carlson G L
Published: October 2004

The Editors welcome topical correspondence from readers relating to articles published in the Journal. Responses can be sent electronically via the BJS website (www.bjs.co.uk) or by post. All letters will be reviewed and, if approved, appear on the website. A selection of these will be edited and published in the Journal. Letters must be no more than 250 words in length. Letters submitted by post should be typed on A4-sized paper in double spacing and should be accompanied by a disk.
Triplication of the lesser occipital nerve
Authors: Madhavi C. , Holla S.J.
Published: October 2004

Triplication of the lesser occipital nerve (LON) was observed bilaterally in an adult male cadaver during routine prosection of the posterior triangle. The three LONs were studied to determine the clinical importance of this variation. The origin of one LON was from a nerve to the trapezius that had a common origin with the trunk of the supraclavicular nerve (C3,4) from the cervical plexus. Such a common origin of a LON may explain the pain referred to the shoulder and arm that is experienced by some patients with cervicogenic headache. Another LON ran across the roof of the posterior triangle, passed through the trapezius and was closely related to the point of exit of the greater occipital nerve (GON) from the trapezius. This LON supplied the nape of the neck, back of the scalp and the auricle. The anomalous course taken by this LON through the trapezius may be an explanation for cervicogenic headache precipitated by neck movement. The close relationship of this variant LON to the exit of the GON from the trapezius seems to be relevant to the management of cervicogenic headache. The authors suggest that the reason for the complete pain relief experienced by some patients with cervicogenic headache by anesthetic blockade of the GON may be because both the GON and LON are blocked simultaneously due to their proximity in these patients. Clin. Anat. 17:667–671, 2004. © 2004 Wiley‐Liss, Inc.
Biochemical Association of Poly(ADP‐ribose) Polymerase‐1 and Its Apoptotic Peptide Fragments with DNA Polymerase β
Authors: Confer Nils F. , Kumari Sunitha R. , Alvarez‐Gonzalez Rafael
Published: October 2004

We have characterized the biochemical association of two DNA damage‐dependent enzymes, poly(ADP‐ribose) polymerase‐1 (PARP‐1) [EC 2.4.2.30] and DNA polymerase β (pol β) [2.7.7.7]. We reproducibly observed that pol β is an efficient covalent target for ADP‐ribose polymers under standard conditions of enzymatically catalyzed ADP‐ribosylation of βNAD+ as a substrate. The efficiency of poly(ADP‐ribosyl)ation increased as a function of the pol β and βNAD+ concentrations. To further characterize the molecular interactions between these two unique polymerases, we also subjected human recombinant PARP‐1 to peptide‐specific enzymatic degradation with either caspase‐3 or caspase‐7 in vitro. This proteolytic treatment, commonly referred to as ‘a hallmark of apoptosis’, generated the two physiologically relevant peptide fragments of PARP‐1, e.g., a 24‐kDa amino‐terminus and an 89‐kDa carboxy‐terminal domain. Interestingly, co‐incubation of the two peptide fragments of PARP‐1 with full‐length pol β resulted in their domain‐specific molecular association as determined by co‐immunoprecipitation and reciprocal immunoblotting. Therefore, our data strongly suggest that, once PARP‐1 is proteolyzed by either caspase‐3 or caspase‐7 during cell death, the specific association of its apoptotic fragments with DNA repair enzymes, such as pol β, may serve a regulatory molecular role in the execution phase of apoptosis.
Understanding Sterol‐Membrane Interactions, Part II: Complete 1H and 13C Assignments by Solid‐State NMR Spectroscopy and Determination of the Hydrogen‐Bonding Partners of Cholesterol in a Lipid Bilayer
Authors: Soubias Olivier , Jolibois Franck , Réat Valérie , Milon Alain
Published: October 2004

The complete assignment of cholesterol 1H and 13C NMR resonances in a lipid bilayer environment (Lα‐dimyristoylphosphatidylcholine/cholesterol 2:1) has been obtained by a combination of 1D and 2D MAS NMR experiments: 13C spectral editing, ge‐HSQC, dipolar HETCOR and J‐based HETCOR. Specific chemical shift variations have been observed for the C1–C6 atoms of cholesterol measured in CCl4 solution and in the membrane. Based on previous work (F. Jolibois, O. Soubias, V. Réat, A. Milon, Chem. Eur. J. 2004, 10, preceding paper in this issue: DOI: 10.1002/chem.200400245) these variations were attributed to local changes around the cholesterol hydroxy group, such as the three major rotameric states of the C3O3 bond and different hydrogen bonding partners (water molecules, carboxy and phosphodiester groups of phosphatidylcholine). Comparison of the experimental and theoretical chemical shifts obtained from quantum‐chemistry calculations of various transient molecular complexes has allowed the distributions of hydrogen bonding partners and hydroxy rotameric states to be determined. This is the first time that the probability of hydrogen bonding occurring between cholesterol's hydroxy group and phosphatidylcholine's phosphodiester has been determined experimentally.
Immunophenotyping is an independent factor for risk stratification in AML
Authors: Repp R. , Schaekel U. , Helm G. , Thiede C. , Soucek S. , Pascheberg U. , Wandt H. , Aulitzky W. , Bodenstein H. , Sonnen R. , Link H. , Ehninger G. , Gramatzki M.
Published: October 2004

Background

Chromosomal abnormalities are one of the most important prognostic factors in acute myeloid leukemia (AML). However, only a limited number of patients have such informative chromosomal abnormalities. The prognostic value of immunophenotyping in this disease is still unclear.

Methods

Seven hundred and eighty‐three newly diagnosed AML patients treated in the German SHG‐AML trials in 1991 and 1996 were analyzed with a panel of 33 antibodies. Expression was correlated to overall survival, complete remission‐rate, and complete remission duration, and tested in a multivariate analysis including other clinical and biological markers.

Results

With a median follow‐up of 4.3 years, patients with AML blasts negative for CD9, CD11b, CD13, CD34, and CD41, or positive for CD15, CD33, CD38, CD64, and MPO had superior overall survival. This effect was associated with a significantly higher complete remission rate (CD13, CD34, CD41, and CD64) or a longer complete remission duration (CD9, CD11b, and CD64). Cox‐regression analysis, including cytogenetic, morphologic, and biologic parameters showed CD9, CD13, CD34, and CD64 as independent factors for overall survival. These markers were used for a prognostic score. Patients were pooled in three groups with highly significant differences of overall survival. The prognostic relevance of this score was confirmed in patients with normal karyotype and/or in younger patients ≤ 60 years.

Conclusions

Immunophenotyping is not only helpful for diagnosis but is of independent significance for prognosis, and may be useful for risk stratification in AML patients. Cytometry Part B (Clin. Cytometry) 53B:11–19, 2003. © 2003 Wiley‐Liss, Inc.
Increased predictive value of parameters by fuzzy logic‐based multiparameter analysis
Authors: Peltri Gregor , Bitterlich Norman
Published: October 2004

Background

A recent study on postoperative effusions and edema was used to demonstrate the potential of fuzzy techniques in multiparameter data analysis. In this study, more than 50 parameters of 75 patients were collected and examined for correlations between some of the parameters and the later development of complications.

Methods

We employed a rule‐based fuzzy‐logic system in order to combine the diagnostic values of single parameters. The advantage of fuzzy sets is that they substitute sharp cut‐off values with a smooth transition from one property to another. Therefore, there is no decision of “either–or” but rather a graded assessment of “more or less”, which is often more suitable for a problem.

Results

The fuzzy combination of parameters led to a large increase of sensitivity and specificity when compared with the best single parameter. This increase was achieved by taking a close look at the parameters. A newly created parameter, relative weight, turned out to be very powerful.

Conclusions

Fuzzy techniques can increase the discriminating power of classical statistical tools. In addition, results obtained by fuzzy analysis are highly interpretable. A combination of the CLASSIF1 algorithm for the identification of the most relevant parameters, followed by fuzzy analysis, represents a powerful tool for the handling of large amounts of multiparameter data. Cytometry Part B (Clin. Cytometry) 53B:75–77, 2003. © 2003 Wiley‐Liss, Inc.
Development of an Enzymeless/Mediatorless Glucose Sensor Using Ruthenium Oxide‐Prussian Blue Combinative Analogue
Authors: Kumar Annamalai Senthil , Chen Pei‐Yen , Chien Shu‐Hua , Zen Jyh‐Myng
Published: October 2004

Presented in this work is the first step towards an enzymeless/mediatorless glucose sensor. We first observed remarkable electrocatalytic oxidation of glucose using combinative ruthenium oxide (RuOx)‐Prussian blue (PB) analogues (designated as mvRuOx‐RuCN, mv: mixed valent) at ca. 1.1 V (vs. Ag/AgCl) in acidic media (pH 2 Na2SO4/H2SO4). Individual RuOx and PB analogs failed to give any such catalytic response. A high ruthenium oxidation state (i.e., oxy/hydroxy‐RuVII, E°≈1.4 V vs. RHE), normally occurring in strong alkaline conditions at RuOx‐based electrodes, was electrogenerated and stabilized (without any conventional disproportionation reaction) in the mvRuOx‐RuCN matrix for glucose catalysis. Detail X‐ray photoelectron spectroscopic studies can fully support the observation. The catalyst was chemically modified onto a disposable screen‐printed carbon electrode and employed for the amperometric detection of glucose via flow injection analysis (FIA). This system has a linear detection range of 0.3–20 mM with a detection limit and sensitivity of 40 μM (S/N=3) and 6.2 μA/(mM cm2), respectively, for glucose. Further steps towards the elimination of interference and the extendibility to neutral pHs were addressed.
Cytoprotection against oxidative stress‐induced damage of astrocytes by extracellular ATP via P2Y1 receptors
Authors: Shinozaki Youichi , Koizumi Schuichi , Ishida Seiichi , Sawada Jun‐Ichi , Ohno Yasuo , Inoue Kazuhide
Published: October 2004

Oxidative stress is the main cause of neuronal damage in traumatic brain injury, hypoxia/reperfusion injury, and neurodegenerative disorders. Although extracellular nucleosides, especially adenosine, are well known to protect against neuronal damage in such pathological conditions, the effects of these nucleosides or nucleotides on glial cell damage remain largely unknown. We report that ATP but not adenosine protects against the cell death of cultured astrocytes induced by hydrogen peroxide (H2O2). ATP ameliorated the H2O2‐induced decrease in cell viability of astrocytes in an incubation time‐ and concentration‐dependent fashion. Protection by ATP was inhibited by P2 receptor antagonists and was mimicked by P2Y1 receptor agonists but not by adenosine. The expressions of P2Y1 mRNAs and functional P2Y1 receptors in astrocytes were confirmed. Thus, ATP, acting on P2Y1 receptors in astrocytes, showed a protective action against H2O2. The astrocytic protection by the P2Y1 receptor agonist 2‐methylthio‐ADP was inhibited by an intracellular Ca2+ chelator and a blocker of phospholipase C, indicating the involvement of intracellular signals mediated by Gq/11‐coupled P2Y1 receptors. The ATP‐induced protection was inhibited by cycloheximide, a protein synthesis inhibitor, and it took more than 12 h for the onset of the protective action. In the DNA microarray analysis, ATP induced a dramatic upregulation of various oxidoreductase genes. Taken together, ATP acts on P2Y1 receptors coupled to Gq/11, resulting in the upregulation of oxidoreductase genes, leading to the protection of astrocytes against H2O2. © 2004 Wiley‐Liss, Inc.
Human alpha rhythms during visual delayed choice reaction time tasks: A magnetoencephalography study
Authors: Babiloni Claudio , Babiloni Fabio , Carducci Filippo , Cincotti Febo , Del Percio Claudio , Della Penna Stefania , Franciotti Raffaella , Pignotti Sandro , Pizzella Vittorio , Rossini Paolo Maria , Sabatini Elisabetta , Torquati Kathya , Romani Gian Luca
Published: October 2004

Magnetoencephalography (MEG) includes fast and comfortable recording procedures very suitable for the neurophysiological study of cognitive functions in aged people. In this exploratory MEG study in normal young adults, we tested whether very simple short‐term memory (STM) demands induce visible changes in amplitude and latency of surface α rhythms. Two delayed response tasks were used. In the STM condition, a simple cue stimulus (one bit) was memorized along a brief delay period (3.5–5.5 s). In the control (no short‐term memory; NSTM) condition, the cue stimulus remained available along the delay period. To make extremely simple the tasks, the explicit demand was visuospatial but the retention could be also based on phonological and somatomotor coding. Compared to the control condition, the amplitude of the α 1 (6–8 Hz) ERD decreased in the left hemisphere, whereas the amplitude of the α 2 (8–10 Hz) and α 3 (10–12 Hz) event‐related desynchronization (ERD) increased in right and left parietal areas, respectively. Furthermore, the latency of the α ERD peak was slightly but significantly (P < 0.05) later in STM compared to control condition. In conclusion, whole‐head MEG technology and very simple STM demands revealed significant changes of human neuromagnetic α rhythms in normal young adults. Hum. Brain Mapp 24:184–192, 2005. © 2004 Wiley‐Liss, Inc.
Do Valine Side Chains Have an Influence on the Folding Behavior of β‐Substituted β‐Peptides?
Authors: Glättli Alice , Seebach Dieter , van Gunsteren Wilfred F.
Published: October 2004

The influence of valine side chains on the folding/unfolding equilibrium and, in particular, on the 314‐helical propensity of β3‐peptides were investigated by means of molecular‐dynamics (MD) simulation. To that end, the valine side chains in two different β3‐peptides were substituted by leucine side chains. The resulting four peptides, of which three have never been synthesized, were simulated for 150 to 200 ns at 298 and 340 K, starting from a fully extended conformation. The simulation trajectories obtained were compared with respect to structural preferences and folding behavior. All four peptides showed a similar folding behavior and were found to predominantly adopt 314‐helical conformations, irrespective of the presence of valine side chains. No other well‐defined conformation was observed at significant population in any of the simulations. Our results imply that β3‐peptides show a structural preference for 314‐helices independent of the branching nature of the side chains, in contrast to what has been previously proposed on the basis of circular‐dichroism (CD) measurements.
Probing the Conformational Changes in the Enzymatic Hydrolysis of 2‐Acetamido‐2‐deoxy‐β‐D‐glucopyranosides
Authors: Böhm Matthias , Vasella Andrea
Published: October 2004

The isoquinuclidines 7 and 8 were synthesised and tested as inhibitors of hexosaminidases from jack beans and from bovine kidney. These isoquinuclidines mimick the 1,4B‐conformer of a N‐acetyl‐glucosamine‐derived β‐d‐glucopyranoside; they are competitive inhibitors with Ki values from 0.014 to 0.30 μM. The strong inhibition of these enzymes agrees with the hypothesis that the enzymatic hydrolysis of 2‐acetamido‐2‐deoxy‐β‐d‐glucopyranosides proceeds via a boat‐like conformer with a pseudo‐axial scissile glycosidic bond and a pseudo‐axial acetamido substituent optimally oriented to effect an intramolecular substitution of the aglycon.
Cytotoxic Isoprenylated Flavonoids from the Roots of Sophora flavescens
Authors: Ding Peilan , Chen Daofeng , Bastow Kenneth F. , Nyarko Alexander K. , Wang Xihong , Lee Kuo‐Hsiung
Published: October 2004

Three new flavonoids, which are isoprenylated by fused 2,2‐dimethyl‐3,4‐dihydro‐2H‐pyran moieties, were isolated from the roots of Sophora flavescens and named flavenochromanes A–C (1–3). Their structures were elucidated by spectroscopic methods, including 2D‐NMR techniques. Flavenochromane C (3) showed strong cytotoxic activity against A549 (lung carcinoma), 1A9 (ovarian carcinoma), KB (epidermoid carcinoma of the nasopharynx), and KB‐Vin (drug‐resistant variant KB) cell lines with IC50 values ≤1.7 μM, and significant activity against the MCF‐7 (breast adenocarcinoma) cell line with an IC50 value of 3.6 μM. Flavenochromane B (2) displayed slightly lower inhibitory effects (IC50 3.2–6.9 μM) as compared with 3.
Synthesis and Absolute Configuration at C(8) of ‘p‐Menthane‐3,8,9‐triol’ Derived from (–)‐Isopulegol
Authors: Yuasa Yoshifumi , Yuasa Yoko
Published: October 2004

Two diastereoisomers of the new, potentially insecticidal ‘p‐menthane‐3,8,9‐triol’ (=(2S)‐ and (2R)‐ 2‐[(1R,2R,4R)‐2‐hydroxy‐4‐methylcyclohexyl]propane‐1,2‐diol; (8S)‐ and (8R)‐1), have been synthesized from (–)‐isopulegol by both conventional dihydroxylation and catalytic Sharpless dihydroxylation (Scheme). The absolute configuration at C(8) of the corresponding orthoformate adduct (8S)‐3a was determined by 1H‐NMR and X‐ray crystallographic analysis (Figure).
2,4‐Dioxa‐7‐aza‐, 2,4‐Dioxa‐8‐aza‐, and 2,4‐Dioxa‐9‐aza‐3‐phosphadecalins as Rigid Acetylcholine Mimetics: Syntheses and Characterization
Authors: Furegati Stefan , Ganci Walter , Gorla Fabrizio , Ringeisen Urs , Rüedi Peter
Published: October 2004

Phosphorylation of suitable piperidine precursors yielded a series of novel decalin‐type O,N,P‐heterocycles. The title compounds, P(3)‐axially and P(3)‐equatorially X‐substituted, cis‐ and trans‐configurated 2,4‐dioxa‐7‐aza‐, 2,4‐dioxa‐8‐aza‐, and 2,4‐dioxa‐9‐aza‐3‐phosphabicyclo[4.4.0]decane 3‐oxides (X=Cl, F, 4‐nitrophenoxy, and 2,4‐dinitrophenoxy), are configuratively fixed and conformationally constrained P‐analogues of acetylcholine and as such represent acetylcholine (7‐aza and 9‐aza isomers) or γ‐homo‐acetylcholine mimetics (8‐aza isomers). Being irreversible inhibitors of acetylcholinesterase (AChE), the compounds are considered to be suitable probes for the investigation of the stereochemical course of the inhibition reaction by 31P‐NMR spectroscopy. Moreover, the design of these mimetics will enable studies of molecular interactions with AChE, in particular, the recognition conformation of acetylcholine.
Quantifying the local‐scale uncertainty of estimated actual evapotranspiration
Authors: Hupet F. , Bogaert P. , Vanclooster M.
Published: October 2004

In this study, we quantified the local‐scale uncertainty of the actual evapotranspiration estimated from a water balance approach combining two soil‐water‐content measurement techniques (time‐domain reflectometry and neutron probe sounding). The local‐scale uncertainty was quantified for 28 sampling points located within a small maize cropped field. This was done by determining progressively the expected value and uncertainty on soil‐water content, soil‐water storage, soil‐water storage variation and on bottom flux. This latter term was quantified using two different hydraulic conductivity curves (HCC), derived from a pedotransfer function (PTF) and from field measurements. Results show that uncertainty on a soil water storage estimate for the considered experimental measurements in terms of standard deviation range between 9·72 and 10·37 mm. This uncertainty is related mainly to the calibration of the soil‐water content measurement instruments. For a soil‐water storage variation estimate, the uncertainty is smaller, with values ranging between 3·48 and 5·42 mm. In this case, the main component of the total variance is the instrumental variance and the variance resulting from the technique used to integrate soil‐water‐content measurements. The expected values and uncertainties for the bottom fluxes were significantly different for the two different HCC characterization techniques in some places in the field. For estimated ET fluxes with in situ estimated HCC results show that the uncertainty ranges in terms of standard deviation between 3·82 and 5·97 mm. It should be stressed that these values can be considered as very low and that a better precision is probably very difficult to obtain as all sensitive factors contributing to the ET variance have been determined in a consistent and optimal way. Finally, it is shown that the uncertainties in estimated HCC with PTFs may result in large uncertainties in estimated ET, questioning thereby the use of PTFs in characterizing the field water balance. Copyright © 2004 John Wiley & Sons, Ltd.
Quantification of irreversible benzene sorption in sandy materials
Authors: Kim Dong‐Ju , Choi Nag‐Choul , Kim Song‐Bae
Published: October 2004

Based on a previous study of the irreversible sorption of benzene in sandy aquifer materials, we further investigated a method to quantify an irreversible sorption coefficient of aqueous benzene. Assuming that the rate of irreversible loss from the solution to the sorption sites followed first‐order kinetics, the irreversible sorption coefficient was derived from a kinetic batch sorption test conducted for an appropriate soil‐to‐solution ratio to reflect the flow conditions imposed on a column test. Simulation results revealed that the irreversible sorption coefficient estimated from the kinetic batch test provided a good agreement with the measured data obtained from the column test, indicating that the method proposed in this study can be used to quantify the irreversible sorption coefficient. Copyright © 2004 John Wiley & Sons, Ltd.
In vivo performance of the Nitinol shape‐memory stapes prosthesis during hearing restoration surgery in otosclerosis: A first report
Authors: Rajan Gunesh P. , Eikelboom Robert H. , Anandacoomaraswamy Keith S. , Atlas Marcus D.
Published: October 2004

The limitations of manual prosthesis crimping in hearing restoration surgery for otosclerosis are thought to have a key role in the occurrence of incomplete postoperative elimination of conductive hearing loss and postoperative recurrences of conductive hearing loss. To eliminate manual crimping, the self‐crimping, shape‐memory alloy Nitinol stapes piston was introduced in nine otosclerosis patients. The results were compared with those in a database of surgeries performed with conventional titanium pistons. The effects of the self‐crimping Nitinol prosthesis on the postoperative elimination of conductive hearing loss and its postoperative variations were investigated. The variations of postoperative residual conductive hearing loss were significantly smaller and the extent of conductive hearing‐loss elimination greater in the Nitinol group. The mean postoperative residual conductive hearing loss was smaller in the Nitinol group. The postoperative stability of conductive hearing loss elimination was similar in both patient groups. Preliminary results suggest that the self‐crimping shape‐memory alloy Nitinol stapes piston overcomes the drawbacks of manual crimping in hearing restoration surgery for otosclerosis. © 2004 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 72B: 305–309, 2005
Hepatoprotection by L‐cysteine‐glutathione mixed disulfide, a sulfhydryl‐modified prodrug of glutathione
Authors: Berkeley Lorelle I. , Cohen Jonathan F. , Crankshaw Daune L. , Shirota Frances N. , Nagasawa Herbert T.
Published: October 2004

L‐Cysteine‐glutathione disulfide, a ubiquitous substance present in mammalian cells, was shown to be highly effective in protecting mice against acetaminophen‐induced hepatotoxicity. Since the corresponding D‐cysteine‐glutathione disulfide was totally ineffective in this regard, an enzymatic mechanism that provides glutathione directly to cells is postulated. © 2003 Wiley Periodicals, Inc. J Biochem Mol Toxicol 17:95–97, 2003; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jbt.10069
siRNA mediated inhibition of MMP‐1 reduces invasive potential of a human chondrosarcoma cell line
Authors: Jiang Xiaoling , Dutton Charyl M. , Qi Wen‐ning , Block Joel A. , Garamszegi Nandor , Scully Sean P.
Published: October 2004

Matrix metalloproteinases (MMPs) play a crucial role in tumor cell invasion and metastasis. Expression of MMP‐1 has been reported as a prognostic predictor of recurrence in human chondrosarcoma, and studies using human chondrosarcoma cell lines indicate that MMP‐1 expression levels correlate with in vitro invasiveness. These observations suggest that MMP‐1 activity has a central role in cell egress from the primary tumor at an early step in the metastatic cascade. In this study, siRNA was used to investigate whether knock down of the MMP‐1 gene could be used to inhibit invasiveness in a human chondrosarcoma cell line. The inhibitory effect of siRNA on endogenous MMP‐1 gene expression and protein synthesis was demonstrated via RT‐PCR, Northern blotting, Western blotting, collagenase activity assay, and an in vitro cell migration assay. The siRNA inhibited MMP‐1 expression specifically, since it did not affect the expression of endogenous glyceraldehyde phosphate dehydrogenase (GAPDH) nor other collagenases. Most importantly, the siRNA mediated reduction in MMP‐1 expression correlated with a decreased ability of chondrosarcoma cells to invade a Type I collagen matrix. The reduction of invasive behavior demonstrated by human chondrosarcoma cells transfected with MMP‐1 siRNA and the specificity of this inhibition supports the hypothesis that this metalloproteinase molecule is involved in initiation of chondrosarcoma metastasis. © 2004 Wiley‐Liss, Inc.
PKC/MAPK signaling suppression by retinal pericyte conditioned medium prevents retinal endothelial cell proliferation
Authors: Kondo Tetsu , Hosoya Ken‐ichi , Hori Satoko , Tomi Masatoshi , Ohtsuki Sumio , Terasaki Tetsuya
Published: October 2004

Little is known about the regulation mechanism of endothelial cell proliferation by retinal pericytes. The purpose of this study was to elucidate the suppression mechanism of retinal capillary endothelial cell growth by soluble factors derived from retinal pericytes. Conditioned medium of retinal pericytes (rPCT1‐CM) suppressed ischemia‐induced retinal neovascularization. The growth and DNA synthesis of TR‐iBRB2 cells, a conditionally immortalized rat retinal capillary endothelial cell line, were suppressed in a concentration‐dependent manner by concentrated rPCT1‐CM. The number of human cultured endothelial cells was also reduced by rPCT1‐CM. These results provide the first evidence that CM from the cultivation of pericytes alone can inhibit retinal neovascularization in vivo and in vitro. Although the growth reduction of TR‐iBRB2 cells was only partly reversed by treatment of rPCT1‐CM with antibodies to transforming growth factor‐β1, it was completely lost by heat‐treatment of rPCT1‐CM, suggesting that anti‐angiogenic factors are soluble proteins. The levels of expression of G1/S‐phase‐related proteins, such as cyclin D1, cyclin‐dependent kinase (cdk)4, cdk6, and proliferating cell nuclear antigen, were reduced and a cdk inhibitor, p21Cip1, was induced in rPCT1‐CM‐treated TR‐iBRB2 cells. Moreover, phosphorylated p44/42 mitogen‐activated protein kinase (p44/42 MAPK) in TR‐iBRB2 cells was reduced by rPCT1‐CM treatment and phosphorylated protein kinase C (PKC)α/βII, which is upstream of p44/42 MAPK, was also suppressed. In conclusion, CM from retinal pericytes suppresses PKC‐p44/42 MAPK signaling, inhibits endothelial cell growth, and prevents retinal neovascularization. Anti‐angiogenic factors derived from retinal pericytes are likely to play a critical role in the regulation of retinal endothelial cell growth. © 2004 Wiley‐Liss, Inc.
Reversal of the silencing of tetracycline‐controlled genes requires the coordinate action of distinctly acting transcription factors
Authors: Pankiewicz Renata , Karlen Yann , Imhof Markus O. , Mermod Nicolas
Published: October 2004

Background

Regulation of genes transferred to eukaryotic organisms is often limited by the lack of consistent expression levels in all transduced cells, which may result in part from epigenetic gene silencing effects. This reduces the efficacy of ligand‐controlled gene switches designed for somatic gene transfers such as gene therapy.

Methods

A doxycycline‐controlled transgene was stably introduced in human cells, and clones were screened for epigenetic silencing of the transgene. Various regulatory proteins were targeted to the silent transgene, to identify those that would mediate regulation by doxycycline.

Results

A doxycycline‐controlled minimal promoter was found to be prone to gene silencing, which prevents activation by a fusion of the bacterial TetR DNA‐binding domain with the VP16 activator. DNA modification studies indicated that the silenced transgene adopts a poorly accessible chromatin structure. Several cellular transcriptional activators were found to restore an accessible DNA structure when targeted to the silent transgene, and they cooperated with Tet‐VP16 to mediate regulation by doxycycline.

Conclusions

Reversal of the silencing of a tetracycline‐regulated minimal promoter requires a chromatin‐remodeling activity for subsequent promoter activation by the Tet‐VP16 fusion protein. Thus, distinct regulatory elements may be combined to obtain long‐term regulation and persistent expression of exogenous genes in eukaryotic cells. Copyright © 2004 John Wiley & Sons, Ltd.
Prenatal stress causes gender‐dependent neuronal loss and oxidative stress in rat hippocampus
Authors: Zhu Zhongliang , Li Xia , Chen Weina , Zhao Yan , Li Hui , Qing Cai , Jia Ning , Bai Zhuanli , Liu Jiankang
Published: October 2004

Our purpose was to investigate the effects of prenatal stress on neuronal changes in the hippocampus and the possible involvement of oxidative stress in female and male rats. Female and male offspring (1‐month‐old), whose dams were restrained in middle or later pregnant stage (MS or LS), were studied to observe changes in the number of hippocampal neurons and the expression of neuronal nitric oxide synthase (nNOS) in the hippocampus. Both MS and LS induced an increase in the number of nNOS‐positive expression in female and male offspring in the hippocampus; however, both MS and LS caused a significant decrease in the number of hippocampal neurons in the female, but not in the male offspring. In addition, significant increases in calcium content and oxidant generation were induced by LS in the hippocampal CA3 region in female rats. These data suggest that prenatal stress can cause oxidative stress and consequent damage to neurons, leading to neuronal loss in the brain of offspring during development. © 2004 Wiley‐Liss, Inc.
Projections from the trigeminal nuclear complex to the cochlear nuclei: A retrograde and anterograde tracing study in the guinea pig
Authors: Zhou Jianxun , Shore Susan
Published: October 2004

In addition to input from auditory centers, the cochlear nucleus (CN) receives inputs from nonauditory centers, including the trigeminal sensory complex. The detailed anatomy, however, and the functional implications of the nonauditory innervation of the auditory system are not fully understood. We demonstrated previously that the trigeminal ganglion projects to CN, with terminal labeling most dense in the marginal cell area and secondarily in the magnocellular area of the ventral cochlear nucleus (VCN). We continue this line of study by investigating the projection from the spinal trigeminal nucleus to CN in guinea pig. After injections of the retrograde tracers FluoroGold or biotinylated dextran amine (BDA) in VCN, labeled cells were found in the spinal trigeminal nuclei, most densely in the pars interpolaris and pars caudalis with ipsilateral dominance. The anterograde tracers Fluoro‐Ruby or BDA were stereotaxically injected into the spinal trigeminal nucleus. Most labeled puncta were found in the marginal area of VCN and the fusiform cell layer of dorsal cochlear nucleus (DCN). A smaller number of labeled puncta was located in the molecular and deep layers of DCN and the magnocellular area of VCN. The trigeminal projection to CN may provide somatosensory information necessary for pursuing a sound source or for vocal production. These projections may have a role in the generation and modulation of tinnitus. © 2004 Wiley‐Liss, Inc.
Exploring the connection between frustration and consumer choice behavior in a dynamic decision environment
Authors: Strebel Judi , O'Donnell Kathleen , Myers John G.
Published: October 2004

This research proposes that frustration during the purchase process for high‐technology durable goods has a significant effect on the probability that consumers will commit to a technology and make a purchase. In order to explore the effects of consumer frustration on the purchase process, a scale is developed that reveals that frustration in high‐technology decision environments is composed of two dimensions, processing frustration and frustration with the pace of technological change. These dimensions of frustration have a significant effect on consumer choice behavior. While processing frustration significantly reduces the probability of commitment to a technology, the probability of making a decision is significantly lower when consumers are frustrated with the pace of technological change. © 2004 Wiley Periodicals, Inc.
Reibungs‐ und Verschleißverhalten von chemisch gekoppelten PTFE‐PA‐6.6‐Materialien
Authors: Lehmann D. , Hupfer B. , Staudinger U. , Häußler L. , Jehnichen D. , Janke A. , Kunze K. , Franke R. , Haase I.
Published: October 2004

Mit der Entwicklung der chemisch gekoppelten PTFE‐Polyamid‐Materialien (PTFE‐PA) steht eine neue Werkstoffgeneration für tribologische Einsatzgebiete zur Verfügung. Es werden Ergebnisse zum Materialsystem eines chemisch gekoppelten PTFE‐PA‐6.6 vorgestellt, in dem die sehr guten Material‐ und Verarbeitungseigenschaften des PA‐6.6 mit den Gleiteigenschaften des PTFE kombiniert sind. Die Herstellung erfolgt über reaktive Extrusion auf einem Doppelschneckenextruder unter Polyamidverarbeitungsbedingungen. Die Besonderheit dieser Materialien ist das sehr gute Reibungs‐ und Verschleißverhalten. Im Mittelpunkt stehen die Einflüsse der Verarbeitung, d. h. der Ver‐ und Zerteilung der PTFE‐Mikropulver in der PA‐6.6‐Matrix und der Feuchteaufnahme der PA‐6.6‐Matrix auf die tribologischen Eigenschaften. Es konnte gezeigt werden, dass keine wesentlichen Unterschiede festgestellt wurden, ob das PTFE‐Mikropulver mit einer wenig scherenden Schneckenkonfiguration in eine PA‐6.6‐Spritzgusstype (niedrige Schmelzeviskosität) oder mit einer stark scherenden, intensiv mischenden Schnecke in eine PA‐6.6‐Extrusionstype (hohe Schmelzeviskosität) eingearbeitet wird. Eine weitere wesentliche Aussage ist, dass der Feuchtegehalt des Materials keinen Einfluss auf die tribologischen Eigenschaften hat.
Neue PVD‐Schichtkonzepte für hoch beanspruchte Werkzeuge für umweltverträgliche Fertigungsprozesse
Authors: Bobzin K. , Lugscheider E. , Piñero C.
Published: October 2004

In der laufenden Projektphase des SFB 442 wurde für das Bohren und Drehen von 42CrMo4V und das Bohren von X5CrNi18‐10 der Multilayer TiAlN + amorphes‐Al2O3 entwickelt. Der abrasive Verschleiß bei der Zerspanung von 42CrMo4V konnte behoben werden. Die Tribooxidation an der Nebenschneide beim Drehen wurde gänzlich unterbunden. Gleichzeitig wurde der Kerbverschleiß an der Nebenschneide auch beim Drehen von X5CrNi18‐10 minimiert und die Standzeiten erhöht. Für TiAlN + amorphes‐Al2O3 hat sich ein 40‐lagiger Multilayer als optimal herausgestellt. Um beim Drehen von X5CrNi18‐10 und Inconel 718 den Adhäsionswiderstand zu verbessern, ist geplant, diesen Multilayer mit kristallinem γ‐Al2O3 aufzubauen. Kristallines α‐Al2O3 (CVD) zeigte bei Drehversuchen gegen Inconel 718 sehr gute Ergebnisse bezüglich des Adhäsionswiderstands. In dieser Versuchsreihe konnte gezeigt werden, dass der Adhäsionswiderstand mit der Oberflächenenergie der Schichtsysteme korreliert. α‐Al2O3 besitzt hier die niedrigsten Werte für die Oberflächenenergie und die kleinsten polaren Anteile. Mittlerweile ist es prozesstechnisch möglich, kristallines γ‐Al2O3 auch mit gepulsten MSIP‐Prozessen abzuscheiden.

Verringert man die Einzelschichtdicken von Multilayern bis hin zu Nanolayer‐Schichtsystemen, erhält man so genannte Superlattice‐Strukturen, die sich durch eine extreme Härte auszeichnen. Im Schichtsystem Ti,Hf,CrN wurden zunächst Monolayer entwickelt; schon bald stellte sich heraus, dass die Eigenschaften der Schicht durch Abscheiden von Multilayern (bis zu 80 Lagen) aus TiHfN + CrN die mechanischen Eigenschaften, insbesondere die Duktilität, deutlich verbessern, ohne die entscheidende Warmfestigkeit und Oxidationsstabilität zu verschlechtern. Mit der Entwicklung von Superlattice‐Strukturen konnte eine weitere Härtesteigerung um 32 % erzielt werden. Im Reibprüfstand erwies sich das Superlattice‐Schichtsystem mit einer jeweiligen Schichtdicke der Nanolayer von 10 nm als am günstigsten, da es das beste Verhältnis von Härte zu E‐Modul besitzt. Dieses Schichtsystem wurde beim Napfrückwärtsfließpressen von 16MnCr5 eingesetzt und zeigte nach 100 Hüben ohne Einsatz von Schmierstoff keine Schäden. Dieses hervorragende Ergebnis wurde bisher nur mit diesem Superlattice‐Schichtsystem erreicht.