bluuebunny/crossref_metadata_2025 huggingface dataset:
Inhibition of the Serotonin (5-Hydroxytryptamine) Transporter Reduces Bone Accrual during Growth
Authors: Warden Stuart J. , Robling Alexander G. , Sanders Megan S. , Bliziotes Michael M. , Turner Charles H.
Published: November 2004

Selective serotonin-reuptake inhibitors (SSRIs) antagonize the serotonin (5-hydroxytryptamine) transporter (5-HTT), and are frequently prescribed to children and adolescents to treat depression. However, recent findings of functional serotonergic pathways in bone cells and preliminary clinical evidence demonstrating detrimental effects of SSRIs on bone growth have raised questions regarding the effects of these drugs on the growing skeleton. The current work investigated the impact of 5-HTT inhibition on the skeleton in: 1) mice with a null mutation in the gene encoding for the 5-HTT; and 2) growing mice treated with a SSRI. In both models, 5-HTT inhibition had significant detrimental effects on bone mineral accrual. 5-HTT null mutant mice had a consistent skeletal phenotype of reduced mass, altered architecture, and inferior mechanical properties, whereas bone mineral accrual was impaired in growing mice treated with a SSRI. These phenotypes resulted from a reduction in bone formation without an increase in bone resorption and were not influenced by effects on skeletal mechanosensitivity or serum biochemistries. These findings indicate a role for the 5-HTT in the regulation of bone accrual in the growing skeleton and point to a need for further research into the prescription of SSRIs to children and adolescents.
SOUTHWORTH AND SERIALITY
Authors: LOOBY CHRISTOPHER
Published: November 2004

E.D.E.N. Southworth's originally massively popular novel, The Hidden Hand (1859), was not published as a book until it had undergone serialization three separate times, over the course of a quarter century, in a weekly story-paper called the New York Ledger. This bare fact about the material form in which it circulated and gained its large and admiring audience has consequences for interpreting the novel that have gone entirely unexamined by scholars. Thus, Southworth's novel offers a good test case for the claim that the material form of publication (in this case, periodical serialization) is a substantively important aspect of the work's meaning: the readers who responded to it so enthusiastically had all read it under the conditions of seriality. In this essay I attempt to take account of the interpretive implications of seriality for understanding Southworth's novel, exploring some of the ways in which it was ideologically embedded in the Ledger and describing the active and canny role it played in that periodical's strident apoliticism. The Hidden Hand embodied the magazine's declared nonpartisanship in, among other things, various forms of generic melding and imaginary scenarios of sectional uni�cation. Critical accounts that have sought to characterize this novel as proslavery or antislavery have all missed the point that Southworth's tale actively ignored such political issues and thus sought to transcend the dire sectional controversies that were unmistakably impending at the time of its publication.
Resistance to Antimicrobial Agents: An Update
Authors: Rybak Michael J.
Published: November 2004

Decades of overuse and misuse of antibiotics have turned the resistance problem into a crisis. Preventive and corrective measures are urgently needed. This article presents a broad overview of the status of antimicrobial resistance. Resistance in key bacterial pathogens such as enterococci, staphylococci, pneumococci, and gram‐negative bacilli; resistance to fluoroquinolones, third‐generation cephalosporins, and the carbapenems; and mechanisms of resistance are discussed. The article also reviews the adverse impact of resistance on outcomes for patients with nosocomial infections. Finally, a brief overview of how the medical community can face its moment of truth is presented.
Treating Serious Infections: Focus on Cefepime
Authors: Wong‐Beringer Annie
Published: November 2004

Antibiotic resistance among medically important pathogens is curtailing the therapeutic value of many of the standard broad‐spectrum antibiotics used for empiric treatment of serious infections. This article presents a brief overview of the etiology of serious infections and the threat of emerging resistance, and reviews the adverse impact of inadequate empiric treatment on patient outcomes and hospital ecology. The treatment of two clinically important infections with cefepime—pneumonia in hospitalized patients and febrile neutropenia—also is discussed.
The Impact of Antibiotic Management on Resistance
Authors: Bosso John A.
Published: November 2004

The misguided presumption that a simple inverse relationship exists between the use of antibiotics and the emergence of bacterial resistance (i.e., increasing antibiotic use equals decreasing susceptibility and vice versa) has handicapped a full understanding of this relationship and perhaps efforts to bring resistance under control. In fact, this relationship is complicated. This article reviews factors that obscure detection of associations between antibiotic use and the emergence of resistance. It also provides a sample of the extensive data on this subject in the hope of encouraging the conduct of more sophisticated studies of the relationship between antibiotic use and the emergence of resistance. Such studies are necessary to provide institutions with the data they need to make informed decisions regarding antibiotic use.
Opitz “C” trigonocephaly‐like syndrome in a patient with terminal deletion of 2p and partial duplication of 17q
Authors: Czakó Márta , Riegel Mariluce , Morava Éva , Bajnóczky Katalin , Kosztolányi György
Published: November 2004

A boy with trigonocephaly, cleft palate, multiple minor anomalies, flexion deformities of elbows, cryptorchidism, and severe muscular hypotonia had an unbalanced karyotype with duplication of the distal 17q and deletion of the tip of 2p. This was derived from a reciprocal translocation in the father, 46,XY,t(2;17)(p25;q24). The propositus had some findings observed in patients with distal dup(17q), while trigonocephaly not found in these patients may be associated with the terminal deletion of 2p including the locus of SOX11 gene. It is proposed that the major clinical findings of this patient are consistent with the phenotype characteristic of the Opitz “C” trigonocephaly syndrome. © 2004 Wiley‐Liss, Inc.
Effects of ultrasonic oscillations on processing behavior and mechanical properties of metallocene‐catalyzed linear low‐density polyethylene/low‐density polyethylene blends
Authors: Wu Hong , Guo Shaoyun , Chen Guangshun , Shi Huaigu
Published: November 2004

The influences of ultrasonic oscillations on rheological behavior and mechanical properties of metallocene‐catalyzed linear low‐density polyethylene (mLLDPE)/low‐density polyethylene (LDPE) blends were investigated. The experimental results showed that the presence of ultrasonic oscillations can increase the extrusion productivity of mLLDPE/LDPE blends and decrease their die pressure and melt viscosity during extrusion. Incorporation of LDPE increases the critical shear rate for sharkskin formation of extrudate, crystallinity, and mechanical properties of mLLDPE. The processing behavior and mechanical properties of mLLDPE/LDPE blends were further improved in the presence of ultrasonic oscillations during extrusion. © 2004 Wiley Periodicals, Inc. J Appl Polym Sci 94: 2522–2527, 2004
Toxicity of two type II ribosome‐inactivating proteins (cinnamomin and ricin) to domestic silkworm larvae
Authors: Wei Guo‐qing , Liu Ren‐Shui , Wang Qiong , Liu Wang‐Yi
Published: November 2004

Cinnamomin and ricin are two type II ribosome‐inactivating proteins. They exhibited a different toxicity to domestic silkworm (Bombyx mori) larvae by oral feeding bioassay. The LC50 of ricin to the silkworm larvae at third instar was much lower than that of cinnamomin. When the isolated 80S ribosome from domestic silkworm pupae was treated separately with the reduced cinnamomin or the reduced ricin, a specific RNA fragment (R‐fragment) was produced as characterized by 8 M urea‐denatured polyacrylamide gel (3.5%) electrophoresis. The purified A‐chains of both cinnamomin and ricin showed a slightly different RNA N‐glycosidase activity to the domestic silkworm pupal ribosome. It was proposed that the difference of their toxicity to domestic silkworm larvae was not related to their A‐chains but to the properties of their B‐chains. It was also found that the vomit obtained from the midgut of domestic silkworm larvae could hydrolyze these two proteins apparently to a similar extent. Arch. Insect Biochem. Physiol. 57:160–165, 2004. © 2004 Wiley‐Liss, Inc.
The mechanism and modes of inhibition of arginine kinase from the cockroach (Periplaneta americana)
Authors: Brown Ashli E. , Grossman Steven H.
Published: November 2004

The kinetic mechanism and evaluation of several potential inhibitors of purified arginine kinase from the cockroach (Periplanta americana) were investigated. This monomeric phosphagen kinase is important in maintaining ATP levels during the rapid energy demands of muscle required for contraction and motility. Analysis reveals the following dissociation constants (mM) for the binary complex: E·Arg˜P → E + Arg˜P, K = 1.0; E·Arg → E + Arg, K = 0.45; E·MgATP → E + MgATP, K = 0.17; E·MgADP → E + MgADP, K = 0.12; and the ternary complex: Arg˜P·E·MgADP → E·MgADP + Arg˜P, K = 0.94; Arg·E·MgATP → E·MgATP + Arg, K = 0.49; MgATP·Enz·Arg → E·Arg +MgATP, K = 0.14; MgADP·E·Arg˜P → E·Arg˜P + MgADP, K = 0.09. For a particular substrate, the ratio of the dissociation constants for the binary to ternary complex is close to one, indicating little, if any, cooperativity in substrate binding for the rapid equilibrium, random addition mechanism. The time course of the arginine kinase reaction exhibits a pronounced curvature, which, as described for enzyme from other sources, is attributed to formation of an inhibitory catalytic dead‐end complex, MgADP·E·Arg. The curvature is accentuated by the addition of monovalent anions, including borate, thiocyanate, and, most notably, nitrite and nitrate. This effect is attributed to stabilization of the dead‐end complex through formation of a transition state analog. However, the substantial decrease in initial velocity (92%) caused by nitrate is due to an additional inhibitory effect, further characterized as non‐competitive inhibition (Ki = 8.0 mM) with the substrate L‐arginine. On the other hand, borate inhibition of the initial velocity is only 30% with significant subsequent curvature, suggesting that this anion functions as an inhibitor mainly by formation of a transition state analog. However, some component of the borate inhibition appears to be mediated by an apparent partial competitive inhibition with L‐arginine. D‐arginine is not a substrate for arginine kinase from the cockroach, but is an effective competitive inhibitor with a Ki = 0.31 mM. L‐Canavanine is a weak substrate for arginine kinase (Km = 6.7 mM) with a Vmax for the pure enzyme that is approximately one‐third that of L‐arginine. However, initial velocity experiments of substrate mixtures suggest that competition between L‐canavanine and L‐arginine may not be a simple summation effect and may involve a structural modification. Sensitivity of arginine kinase activity to D‐arginine as well as nitrate and borate anions, coupled with the fact that L‐arginine is an essential amino acid for the cockroach, suggest that arginine kinase could be a useful chemotherapeutic target for the control of cockroach proliferation. Arch. Insect Biochem. Physiol. 57:166–177, 2004. © 2004 Wiley‐Liss, Inc.
Conveying taxonomy context for topic‐focused Web search
Authors: Pahlevi Said Mirza , Kitagawa Hiroyuki
Published: November 2004

Introducing context to a user query is effective to improve the search effectiveness. In this article we propose a method employing the taxonomy‐based search services such as Web directories to facilitate searches in any Web search interfaces that support Boolean queries. The proposed method enables one to convey current search context on taxonomy of a taxonomy‐based search service to the searches conducted with the Web search interfaces. The basic idea is to learn the search context in the form of a Boolean condition that is commonly accepted by many Web search interfaces, and to use the condition to modify the user query before forwarding it to the Web search interfaces. To guarantee that the modified query can always be processed by the Web search interfaces and to make the method adaptive to different user requirements on search result effectiveness, we have developed new fast classification learning algorithms.
Price discovery in the Texas cash cattle market
Authors: Bessler David A. , Davis Ernest E.
Published: November 2004

Time series methods and directed acyclic graphs are used to uncover the centre of price discovery in 10 weight/gender classes of feeder and fed cattle from cash markets in Texas, U.S.A. Heavy feeder heifers, animals sitting on a margin of feeding for meat or breeding for new stocks, are weakly exogenous in an error correction representation of these prices. Further, contemporaneous price innovations from this class of animals cause price innovations in feeder steers and lighter weight feeder heifers. Innovation accounting shows the prominent role that heavy heifers play in cattle price discovery. Copyright © 2004 John Wiley & Sons, Ltd.
Crown‐Tetrathiafulvalenes Attached to a Pyrrole or an EDOT Unit: Synthesis, Electropolymerization and Recognition Properties
Authors: Trippé Gaëlle , Le Derf Franck , Lyskawa Joël , Mazari Miloud , Roncali Jean , Gorgues Alain , Levillain Eric , Sallé Marc
Published: November 2004

A crown‐tetrathiafulvalene electroactive receptor has been covalently linked to electropolymerizable pyrrole or 3,4‐ethylenedioxythiophene monomers. The synthetic route to the monofonctionalized tetrathiafulvalene (TTF) ligand has been optimized. Two derivatives of pyrrole (N‐ and 3‐substituted) were synthesized. The various substituted monomers have been electropolymerized to produce polypyrrole (PP) and poly(ethylenedioxothiophene) (PEDOT) films bearing the electroactive TTF moiety. The electroactivity of the polymer films is efficiently controlled by the well‐defined two‐step redox behavior of the TTF unit. In the case of PEDOT, an alternative post‐polymerization derivatization strategy has been used, involving the grafting of the crown‐TTF ligand on the previously grown PEDOT backbone. Though chemical derivatization is realized under heterogeneous conditions, in the bulk of the film, this strategy proved to be particularly efficient. These electrodes constitute the first examples of conducting polymer‐based modified electrodes incorporating a TTF electrochemical probe, able to interact with a guest ion, such as Ba2+. The cation recognition properties of these various electrodes have been analyzed by cyclic voltammetry and their electroactivity in water as well as their regeneration capability have been investigated.
Electronic Structure and Chain‐Length Effects in Diplatinum Polyynediyl Complexes trans,trans‐[(X)(R3P)2Pt(CC)nPt(PR3)2(X)]: A Computational Investigation
Authors: Zhuravlev Fedor , Gladysz John A.
Published: November 2004

Structure and bonding in the title complexes are studied using model compounds trans,trans‐[(C6H5)(H3P)2Pt(CC)nPt(PH3)2(C6H5)] (PtCxPt; x=2n=4–26) at the B3LYP/LACVP* level of density functional theory. Conformations in which the platinum square planes are parallel are very slightly more stable than those in which they are perpendicular (ΔE=0.12 kcal mol−1 for PtC8Pt). As the carbon‐chain length increases, progressively longer CC triple bonds and shorter CC single bonds are found. Whereas the triple bonds in HCxH become longer (and the single bonds shorter) as the interior of the chain is approached, the PtCC triple bonds in PtCxPt are longer than the neighboring triple bond. Also, the PtC bonds are shorter at longer chain lengths, but not the HC bonds. Accordingly, natural bond orbital charge distributions show that the platinum atoms become more positively charged, and the carbon chain more negatively charged, as the chain is lengthened. Furthermore, the negative charge is localized at the two terminal CC atoms, elongating this triple bond. Charge decomposition analyses show no significant d–π* backbonding. The HOMOs of PtCxPt can be viewed as antibonding combinations of the highest occupied π orbital of the sp‐carbon chain and filled in‐plane platinum d orbitals. The platinum character is roughly proportional to the Pt/Cx/Pt composition (e.g., x=4, 31 %; x=20, 6 %). The HOMO and LUMO energies monotonically decrease with chain length, the latter somewhat more rapidly so that the HOMO–LUMO gap also decreases. In contrast, the HOMO energies of HCxH increase with chain length; the origin of this dichotomy is analyzed. The electronic spectra of PtC4Pt to PtC10Pt are simulated. These consist of two π–π* bands that redshift with increasing chain length and are closely paralleled by real systems. A finite HOMO–LUMO gap is predicted for PtC∞Pt. The structures of PtCxPt are not strictly linear (average bond angles 179.7°–178.8°), and the carbon chains give low‐frequency fundamental vibrations (x=4, 146 cm−1; x=26, 4 cm−1). When the bond angles in PtC12Pt are constrained to 174° in a bow conformation, similar to a crystal structure, the energy increase is only 2 kcal mol−1. The above conclusions should extrapolate to (CC)n systems with other metal endgroups.
The prognostic significance of bone marrow levels of neurofibromatosis‐1 protein and ras oncogene mutations in patients with acute myeloid leukemia and myelodysplastic syndrome
Authors: Lu Di , Nounou Randa , Beran Miloslav , Estey Elihu , Manshouri Taghi , Kantarjian Hagop , Keating Michael J. , Albitar Maher
Published: November 2004

BACKGROUND

It has been reported that point mutations of the ras gene occur frequently in acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). However, the prognostic significance of ras gene mutations in patients with these disorders has been a controversial issue. Although abnormalities in the neurofibromatosis 1 (NF1) gene, which is a gene involved in the ras pathway, have been observed frequently in patients with juvenile chronic myelogenous leukemia, the role of these abnormalities in adult patients with AML or MDS is not clear.

METHODS

In this study, bone marrow specimens that were obtained from previously untreated patients with AML and MDS were examined for ras mutations, and the levels of NF1 protein expression were measured.

RESULTS

Ras point mutations were detected in 16 of 83 patients with AML (19%) and in 21 of 90 patients with MDS (23%). Fourteen of 28 patients with chronic myelomonocytic leukemia (50%) had ras gene mutations. Decreased bone marrow levels of NF1 protein (< 70% of the median level detected in control bone marrow specimens) were observed in 20 of 66 patients with AML (30.3%) and in 8 of 29 patients with MDS (27.6%); none of the patients with ras gene mutations had decreased bone marrow levels of NF1 protein. The presence of a mutant ras gene was associated with a shorter complete remission duration (CRD) in patients with MDS (P = 0.05) but had no effect on survival in patients with AML or MDS. Patients with AML who had decreased NF1 protein levels had a slightly longer CRD compared with patients who had normal NF1 levels (P = 0.07). However, the NF1 level had no significant impact on survival among patients with AML or MDS. When patients with low NF1 levels were grouped with patients who had ras mutations, the patients who had AML had a significantly longer CRD compared with the patients who had MDS (P = 0.02).

CONCLUSIONS

The current results suggest that a reduction in NF1 protein expression and the presence of ras point mutations may complement each other and that they both play a complex role in the biology of AML and MDS. Cancer 2003;97:441–9. © 2003 American Cancer Society.

DOI 10.1002/cncr.11036
Agenesis and microdontia of permanent teeth as late adverse effects after stem cell transplantation in young children
Authors: Hölttä Päivi , Alaluusua Satu , Saarinen‐Pihkala Ulla M. , Peltola Jaakko , Hovi Liisa
Published: November 2004

BACKGROUND

The objective of the current study was to examine the occurrence of tooth agenesis and microdontia in pediatric stem cell transplantation (SCT) recipients.

METHODS

The impact of total body irradiation (TBI) and age at SCT on agenesis and microdontia of permanent teeth was examined in 55 patients from panoramic radiographs. Assessment A1 (for tooth agenesis and microdontia) excluded the third molars, and assessment A2 (for tooth agenesis) included the third molars. Patients were grouped according to TBI status (the TBI group vs. the non‐TBI group) and age at SCT (patients age ≤ 3.0 years [Group Y], patients ages 3.1–5.0 years [Group M], and patients age ≥ 5.1 years [Group O]).

RESULTS

From 1 to 12 teeth were missing in 77%, 40%, and 0% of patients (assessment A1) in Groups Y, M, and O, respectively (Group Y vs. Group M, P = 0.055; Group Y vs. Group O, P < 0.001; and Group M vs. Group O, P = 0.002), increasing to 83%, 78%, and 43%, respectively, when the third molars were included (assessment A2; P values were not significant). Correspondingly, 75%, 60%, and 13%, respectively, of patients had 1–12 microdontic teeth (assessment A1: Group Y vs. Group M, P = 0.306; Group Y vs. Group O, P < 0.001; and Group M vs. Group O, P = 0.003). Recipient age at the time of SCT was found to have a negative correlation with the number of missing teeth (P = 0.001) and microdontic teeth (P = 0.005). TBI appeared to have little effect on the prevalence of tooth agenesis (assessment A1: TBI group, 32%; non‐TBI group, 29%; assessment A2: TBI group, 72%; non‐TBI group, 46%; P values were not significant) or on the prevalence of microdontia (assessment A1: TBI, 41%; non‐TBI, 50%; P value was not significant). A tendency toward an increased number of affected teeth was noticed in the group of patients who received TBI.

CONCLUSIONS

Depending on their age at SCT, 50–100% of pediatric SCT recipients will later present with agenesis and/or microdontia of permanent teeth that may jeopardize occlusal development. Young age (≤ 5.0 years) at SCT was found to be a stronger risk factor than TBI, although TBI caused additive impairment. Cancer, 2005. © 2004 American Cancer Society.
All‐optical analog‐to‐digital conversion based on fiber nonlinearity
Authors: Oda Sho‐ichiro , Mao Xuelong , Maruta Akihiro , Kitayama Ken‐ichi
Published: November 2004

Recently, research on optical analog‐to‐digital (A‐D) conversion not restricted by the operating speed of electronic devices has been carried out extensively. However, the operation in the optical domain is limited up to sampling. Operations subsequent to quantization are carried out by using electronic devices. The authors proposed a method to realize both sampling and quantization in the A‐D conversion simultaneously in the optical domain. In this method, four‐wave mixing in the fiber is used for optical sampling and the soliton effects in a fiber are used for optical quantization. In this paper, the principle of the proposed method is described first. Numerical simulation demonstrates its effectiveness. Further, a proof‐of‐concept experiment is carried out, confirming its realizability. © 2004 Wiley Periodicals, Inc. Electron Comm Jpn Pt 1, 88(3): 53–62, 2005; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/ecja.20149
V‐shaped diversity antenna for microcell station
Authors: Komai Tomohiro , Hori Toshikazu , Cho Keizo , Yamamoto Heiichi , Okada Minoru
Published: November 2004

In microcell systems such as PHS in which the antenna height is low and the cell radius is small, many antennas are installed on the street so that they are easily seen. Hence, the antenna shapes must be adapted to the aesthetics of urban areas. Also, the handsets are often used indoors, so that the radio waves reach the antenna after several reflections by buildings, and many cross polarization components are present. As an optimum diversity antenna taking account of such propagation characteristics, a bar‐shaped diversity antenna of V shape is proposed. In this paper, based on an analysis of the antenna radiation characteristics by the method of moments and simulation of the diversity effect, a configuration of a V‐shaped diversity antenna suitable for microcell systems is demonstrated. The antenna gain is improved in the direction of antenna inclination. Since many cross polarization components are contained in urban propagation, the diversity effect considering this situation is clarified. It is found that the diversity gain exceeds that for the conventional collinear antenna and that an improvement of more than 3 dB can be attained with a diversity reception level of 1%. Hence, the characteristics are found to be suitable for street microcell configurations. © 2004 Wiley Periodicals, Inc. Electron Comm Jpn Pt 1, 88(3): 11–20, 2005; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/ecja.20179
Elimination of interference due to IQ imbalance for OFCDM direct conversion receiver
Authors: Yuba Tadaaki , Sanada Yukitoshi
Published: November 2004

Recently, with a view to reducing the size and power consumption of wireless receivers, research on direct conversion schemes has been carried out extensively. One of the problems in the direct conversion receiver is IQ imbalance. In the direct conversion receiver, a π/2 phase shifter for RF is required. However, it is difficult to operate a phase shifter with an accurate phase shift value over a broad bandwidth. As a result, the IQ balance of the demodulated signals varies. In the case of OFCDM signals, this IQ imbalance affects the demodulated signals as intercarrier interference (ICI). In the present paper, correction of the IQ imbalance by signal processing is considered for reduction of the effect. © 2004 Wiley Periodicals, Inc. Electron Comm Jpn Pt 1, 88(3): 1–10, 2005; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/ecja.20182
Absence of genotoxicity of a phytotherapeutic extract from Stryphnodendron adstringens (Mart.) Coville in somatic and germ cells of Drosophila melanogaster
Authors: de Sousa Neila Coelho , de Carvalho Salvador , Spanó Mário Antônio , Graf Ulrich
Published: November 2004

Stryphnodendron adstringens (Mart.) Coville, a medicinal plant that grows in the “cerrados” (a savanna ecosystem) of Brazil, popularly known as “Barbatimão,” is an important source of tannins (polyphenols). In Brazil, it is used in industry (mainly as vegetable tanning) and also in traditional medicine for the treatment of various diseases. In the present study, a phytotherapeutic extract from S. adstringens stem bark was evaluated for mutagenic and recombinagenic effects using the wing spot test of Drosophila melanogaster (somatic mutation and recombination test, SMART), and for chromosome damage in germ cells using the Drosophila sex‐chromosome loss test (ring‐X loss). For SMART, the standard as well as the high bioactivation fly crosses were used; the latter cross is characterized by a high sensitivity to promutagens and procarcinogens. Third‐instar larvae from these two crosses were treated for 48 hr with different concentrations (66%, 75%, and 100%) of the phytotherapeutic extract. The wings of the emerging adults were analyzed for the occurrence of different types of mutant spots. No statistically significant differences in spot frequencies between controls and treated series were observed. For the ring‐X loss test, adult males were fed with the same concentrations of the extract as in the wing spot test. No statistically significant increases in ring‐X losses were observed. The results of our experiments suggest that the phytotherapeutic extract from S. adstringens stem bark is not genotoxic in somatic and germ cells of D. melanogaster. Environ. Mol. Mutagen. 41:293–299, 2003. © 2003 Wiley‐Liss, Inc.
Loss of heterozygosity analysis of mouse pulmonary adenomas induced by coal tar
Authors: Benavides Fernando , Conti Claudio J. , LaCava Margaret , Flores Mónica , Glasscock Edward , Sternik Gabriel , Gimenez‐Conti Irma B. , Johnston Dennis A. , Dunsford Harold A. , Goldstein Lawrence S. , Rodriguez Lewis V.
Published: November 2004

Manufactured gas plant (MGP) residues, commonly known as coal tars, were generated several decades ago as a byproduct of residential and industrial gas production from the distillation of coal. Previous short‐term exposure studies have shown MGP residues to be tumorigenic in mouse liver and lung. In order to gain further insight into carcinogenesis by complex mixtures of environmental chemicals containing known carcinogenic polycyclic aromatic hydrocarbons, we investigated mouse pulmonary tumors for loss of heterozygosity (LOH) as a result of multiple exposure to MGP residues. Twenty mouse lung adenomas produced in (C57BL/6 × C3H)F1 hybrid mice and manually microdissected were selected to examine genome‐wide allelic losses at 58 microsatellite loci. Regions of chromosomes 1, 4, 5, 8, and 11 were affected in 30–40% of tumors. The elevated rates of allelic imbalance in these chromosomes may indicate the location of unknown tumor suppressor genes significant to neoplastic transformation in mouse lung tissues. Laser capture microdissection‐based LOH analysis of pulmonary adenomas showed that contamination of nonneoplastic tissues was not masking the allelic losses in the manually microdissected tumor analysis. The low frequency of chromosome instability in these tumors, measured by means of inter‐simple sequence repeat PCR, suggests the presence of discrete regions of LOH instead of extensive structural rearrangements. Environ. Mol. Mutagen. 41:300–308, 2003. © 2003 Wiley‐Liss, Inc.
A recurrent duodenal gastrointestinal stromal tumor with a frameshift mutation resulting in a stop codon in KIT exon 13
Authors: Vu Hoang Anh , Xinh Phan Thi , Kikushima Makoto , Zhu Yi , Tokuhara Makoto , Tani Masayoshi , Shimizu Toshio , Saito Kiyoshi , Tokunaga Katsushi , Sato Yuko
Published: November 2004

Gastrointestinal stromal tumors (GISTs) are a specific and rare subset of human gastrointestinal tract tumors. Most GISTs show gain‐of‐function mutations of KIT, mainly in exon 11, that always maintain the reading frame. We report on data from a 43‐year‐old Japanese man with recurrent duodenal GIST and a frameshift mutation in KIT exon 13 together with an in‐frame deletion in KIT exon 11 detected by genomic DNA sequencing. Deletion of 48 base pairs of KIT exon 11, which preserved the reading frame, was identified in both primary and recurrent tumors, whereas deletion of one nucleotide of codon 642 of KIT exon 13, which changed the reading frame and induced a novel stop codon at amino acid 644, was found only in the recurrent tumor. The predicted protein resulting from the latter would lack part of the kinase domain. To the best of our knowledge, this is the first documentation of a GIST with a frameshift mutation of KIT. © 2004 Wiley‐Liss, Inc.
Ganciclovir treatment of hepatitis B virus infection in liver transplant recipients
Authors: Gish R G , Lau J Y , Brooks L , Fang W S J , Steady S L , Imperial J C , Garcia-Kennedy R , Esquivel C O , Keeffe E B
Published: November 2004

To determine the safety and efficacy of ganciclovir treatment of hepatitis B virus (HBV) infection after liver transplantation, nine patients (seven males, two females; mean age, 38 years) with posttransplant HBV infection were treated with ganciclovir for 3 to 10 months. Ganciclovir was administered intravenously at an initial dose of 5 mg/kg/d and then increased to 10 mg/kg/d. Immunosuppressive drug therapy was maintained at low levels. There were no major side effects of ganciclovir therapy. Serum HBV DNA levels decreased by a mean of 90% (range, 42% to 100%), and four of nine patients had no measurable HBV DNA at the completion of therapy. Mean serum alanine aminotransferase levels decreased by 83%. Hepatic expression of HBV antigens and HBV DNA was assessed before and after therapy in six patients and found to be reduced in three patients. The histology activity index was also stabilized or improved in all patients. After discontinuation of therapy, four of nine patients underwent retreatment for 4- to 12-fold elevation of serum HBV DNA and/or biochemical and clinical relapse, that was severe in one patient. This pilot study shows the safety and efficacy of ganciclovir therapy for reducing HBV replication in patients with HBV infection after liver transplantation.
Autoantibodies from patients with primary biliary cirrhosis recognize a region within the nucleoplasmic domain of inner nuclear membrane protein LBR
Authors: Lin F , Noyer C M , Ye Q , Courvalin J , Worman H J
Published: November 2004

Autoantibodies from rare patients with primary biliary cirrhosis (PBC) recognize LBR, or lamin B receptor, an integral membrane protein of the inner nuclear membrane. Human LBR has a nucleoplasmic, amino-terminal domain of 208 amino acids followed by a carboxyl-terminal domain with eight putative transmembrane segments. Autoantibodies against LBR from four patients with PBC recognized the nucleoplasmic, amino-terminal domain but not the carboxyl-terminal domain. Immunoblotting of smaller fusion proteins demonstrated that these autoantibodies recognized a conformational epitope(s) contained within the stretch of amino acids from 1 to 60. These results, combined with those of previous studies, show that autoepitopes of nuclear membrane proteins are located within their nucleocytoplasmic domains and that autoantibodies from patients with PBC predominantly react with one domain of a protein antigen. This work also provides further characterization of anti-LBR antibodies that have found utility as reagents in cell biology research.
In vivo infusion of growth factors enhances the mitogenic response of rat hepatic ductal (oval) cells after administration of 2-acetylaminofluorene
Authors: Nagy P , Bisgaard H C , Santoni-Rugiu E , Thorgeirsson S S
Published: November 2004

Expression of several growth factors is elevated in rat liver, after induction of oval cell proliferation by chemical carcinogens. However, the exact roles played by individual factors are not defined. We infused and examined the effects of epidermal growth factor (EGF) and hepatocyte growth factor (HGF) on the proliferation of ductal and periductal cells after their activation with 2-acetylaminofluorene (2- AAF). Furthermore, we included studies on urokinase-type plasminogen activator (uPA), because Northern blot analysis showed a strong coincidence of uPA expression with oval cell proliferation. Low doses of 2-AAF were used to activate ductal and periductal cells, whereafter growth factors were infused. Infusion of EGF, HGF, uPA, or any combination thereof for up to 7 days resulted in increased numbers of [3H]thymidine-labeled ductal and periductal cells expanding into the liver acinus. Although the growth factors all increased the number of labeled cells, they preferentially acted on different cell populations. Although exposure to 2-AAF alone or combined with infusion of HGF resulted in proliferation of almost equal numbers of ductal and Ito cells, infusion of EGF and any combination hereof resulted in 75% to 80% of labeled cells having a ductal phenotype. Also, infusion of EGF and HGF resulted in decreased numbers of cells undergoing apoptosis in response to 2-AAF. Our results demonstrate that, although 2-AAF acts as a mitogenic stimulus for ductal and periductal cells, growth factors are necessary for survival, motility, and expansion of these cells into the liver acini.
Bacterial translocation in acute liver injury induced by d- galactosamine
Authors: Kasravi F B , Wang L , Wang X , Molin G , Bengmark S , Jeppsson B
Published: November 2004

Acute liver injury is associated with a high rate of infectious and septic complications. Most of these infections are produced by gram negative enteric bacteria. We evaluated bacterial translocation, intestinal permeability, blood flow, portal pressure, and intestinal microflora after induction of liver injury and 70% liver resection in the rat. The rate of translocation to both portal and arterial blood was 100% at 24 hours and 50% at 48 hours after liver resection compared with 83% to portal vein and 50% to aortic blood at both time points after acute liver injury. Translocation to intraabdominal organs (liver, spleen, and mesenteric lymph nodes) was 100% in both groups at both 24 and 48 hours. The rate of translocation increased after liver injury at 48 hours with progression of the liver injury but was decreased in the 70% liver resection group with improvement of liver function. “Total aerobic” and “total anaerobic” bacterial counts in small intestine and cecum were not affected. Pulmonary, distal small intestine, and cecal blood flow were decreased in both groups, whereas blood flow in the proximal small intestine was unaffected. Portal pressure and flow were increased after 70% liver resection, but they were decreased in acute liver injury. After acute liver injury, permeability of both distal small intestine and cecum increased, but after liver resection only cecal permeability increased. The results of this experiment show that bacterial translocation occurs in experimental acute liver injury and that its dynamic, pattern and fate are different from that observed after liver resection, which is a reversible surgical model of liver insufficiency.
Identification of the 37-kd rat liver protein that forms an acetaldehyde adduct in vivo as Δ 4-3-ketosteroid 5β-reductase
Authors: Zhu Y , Fillenwarth M J , Crabb D , Lumeng L , Lin R C
Published: November 2004

Acetaldehyde, the first product of alcohol metabolism, is highly reactive. Several proteins have been shown to be covalently modified by acetaldehyde in vivo. We have previously reported the detection of a cytosolic 37-kd protein-acetaldehyde adduct (-AA) in the liver of alcohol-fed rats. The liver extract from an alcohol-fed rat was subjected to 2-dimensional (2D) sodium dodecylsulfate (SDS)-polyacrylamide gel electrophoresis (PAGE), transferred to polyvinylidene difluoride (PVDF) membrane, and the 37-kd protein-AA spot was digested with trypsin and sequenced for amino acids. Degenerate oligonucleotides corresponding to a peptide sequence of the protein-AA were used as the probe to screen a λ gt11 rat liver complementary DNA (cDNA) library. A clone that extended to a potential ATG start codon was identified. The open reading frame was 978 nucleotides long, encoding 326 amino acid residues. The sequence matched that of rat liver Δ 4-3-ketosteroid 5β-reductase. The cloned cDNA was expressed in Escherichia coli using pGEX-KG as the vector. The expressed protein was found to be of correct molecular weight. It reacted with an antibody that recognized the unmodified liver 37-kd protein by Western blotting. Peptide profiles of tryptic- digested recombinant protein and the purified rat liver 37-kd protein were similar and yielded the same peptide sequence. Δ 4-3-ketosteroid 5β-reductase catalyzes the reduction of key intermediates during bile acid biosynthesis. Whether modification of the 5β-reductase by acetaldehyde affects the enzyme activity and bile acid synthesis remains to be studied.
Prostaglandins modulate the responsiveness of the gastric microcirculation of sodium nitroprusside in cirrhotic rats
Authors: Geraldo J , Ferraz P , Wallace J L
Published: November 2004

Cirrhotic rats have an increased susceptibility to ethanol-induced gastric injury, related to an inability to mount a defensive gastric hyperemic response to luminal irritants, and associated with an impaired reactivity of the gastric microcirculation to nitric oxide (NO)/cyclic guanosine monophosphate (cGMP)-dependent vasodilators. Whether this hyporesponsiveness is in some way related to depressed prostaglandin synthesis by the stomach of cirrhotic rats is not clear. The aims of this study were to evaluate the role of NO and prostaglandins in the regulation of the gastric microcirculation under resting conditions and in response to administration of sodium nitroprusside, as well as to investigate the mechanisms of the hyporesponsiveness of the gastric microcirculation to nitrovasodilators. Cirrhosis was induced in rats by bile duct ligation, and controls had sham-operation. NG-nitro-l-arginine-methyl-ester (l- NAME) and indomethacin administration produced a greater reduction in gastric blood flow in cirrhotic rats than controls. Indomethacin pretreatment almost completely abolished the responsiveness to sodium nitroprusside (NaNP) in cirrhotic rats, while not affecting controls. Long-term administration of misoprostol to cirrhotic rats restored to normal the responsiveness to NaNP, whereas long-term administration of aspirin to healthy rats resulted in a hyporesponsiveness of the gastric microcirculation to NaNP similar to that seen in cirrhotic rats. We conclude that there are interactions between NO and prostaglandins in regulating gastric blood flow in both healthy and cirrhotic rats. The hyporesponsiveness of the gastric microcirculation of cirrhotic rats to a nitrovasodilator may occur as a consequence of prolonged depression of gastric prostaglandin synthesis.
Mesenteric vasodilator responses in cirrhotic rats: A role for nitric oxide
Authors: Mathie R T , Ralevic V , Moore K P , Burnstock G
Published: November 2004

The contribution of nitric oxide to mesenteric arterial vasodilator responses was investigated in the isolated perfused mesenteric arterial bed of cirrhotic rats (carbon tetrachloride/phenobarbitone; n = 6). Age- matched (n = 9) and phenobarbitone-treated rats (n = 9) served as controls. Responses to the endothelium-dependent dilators acetylcholine and adenosine 5′-triphosphate (ATP) and the smooth muscle dilator (NO donor) sodium nitroprusside were investigated after tone was raised by continuous infusion of methoxamine, before and during infusion of the NO synthesis inhibitor NG-nitro-l-arginine methyl ester (l-NAME; 30 μmol/L) ± l-arginine (1 mmol/L). A significant hyporesponsiveness to methoxamine infusion in cirrhotic preparations (P < .05) was not fully corrected by l-NAME. There was no difference in the percentage vasodilator response to acetylcholine in the cirrhotic group compared with controls; l-NAME significantly and reversibly inhibited the dilator response in all groups. ATP elicited dose-dependent vasodilation that, in the absence of l-NAME, did not differ between the groups. By contrast, in the presence of l-NAME, ATP (5 × 10-8 mol) produced pronounced, reversible vasoconstriction only in cirrhotic animals (P < .02). Vasodilatation attributable to sodium nitroprusside (5 × 10-8 mol) was significantly attenuated in cirrhotic rats. The methoxamine data support the concept of mesenteric hyposensitivity to vasoconstrictor agents in cirrhosis that may be at least partly NO mediated. Increased NO activity in smooth muscle leading to decreased guanylate cyclase availability may account for the diminished vasodilator responses to sodium nitroprusside in cirrhotic preparations. The unchanged responsiveness to vasodilatation by acetylcholine (ACh) and the vasoconstriction to ATP observed during NO blockade in cirrhotic animals indicate that mesenteric endothelial NO is unchanged or possibly diminished.
Direct measurement of hepatic indocyanine green clearance with near-infrared spectroscopy: Separate evaluation of uptake and removal
Authors: Shinohara H , Tanaka A , Kitai T , Yanabu N , Inomoto T , Satoh S , Hatano E , Yamaoka Y , Hirao K
Published: November 2004

We continuously measured hepatic absorbance of indocyanine green (ICG) using near-infrared (NIR) spectroscopy after intravenous bolus injection in rabbits. Hepatic ICG concentration was obtained by subtracting out the absorbance of hemoglobin and other pigments within the liver. Two exponential rate constants, the first reflecting the dye uptake from plasma to the hepatocytes, and the second representing the dye removal from the liver by cytoplasmic transport and biliary excretion, were determined by fitting the time-course curve of hepatic ICG concentration to a two-compartment model with irreversible transfer between the two compartments, as defined by the double-exponential equation: [ICG]liver(t) = -A exp(-α t) + B exp(-β t). The results showed that treatment with bilirubin, a competitive inhibitor of ICG uptake, caused a decrease in α. Treatment with either colchicine, which is toxic to microtubules, or with ouabain, an inhibitor of Na+,K+-ATPase, caused a decrease in β. These results were compatible with the kinetic model. This new method was then used in liver-injured rabbits inflicted with hemorrhagic shock and ischemia-reperfusion, to show that the first rate constant is primarily affected by hepatic microcirculatory condition, and the second refers closely to parenchymal liver damage. In another series of partial liver ischemia- reperfusions, it was possible to simultaneously and separately monitor the ICG profiles of post-ischemic and nonischemic areas. Thus, the kinetic analysis of hepatic ICG concentration curves, as directly measured by NIR spectroscopy, led to the separate evaluation of different clearance process of ICG in the liver, suggesting the advanced utility as a comprehensive liver function test.
Appearance of oval cells in the liver of rats after long-term exposure to ethanol
Authors: Smith P G , Tee L B , Yeoh G C
Published: November 2004

Epidemiological studies show an increased risk of developing liver cancer among alcoholics. There is some agreement that ethanol itself is not carcinogenic, but it may enhance the tumorigenic process by inducing drug-metabolizing enzymes, suppression of the immune system or by affecting DNA repair enzymes. Precisely how ethanol predisposes or promotes the development of hepatoma is unknown. Hepatocarcinogenesis induced by a choline-deficient, ethionine-supplemented (CDE) diet produces extensive alteration of the liver architecture with the emergence and rapid proliferation of oval cells. This study examines whether chronic alcohol consumption induces the proliferation of oval cells. Oval cells induced in rats maintained on a 5% ethanol liquid diet (ELD) for up to 24 months, or fed a CDE diet for up to 4 weeks, are compared using a panel of liver-specific markers. In CDE-treated rats, oval cells staining positively for α-fetoprotein (AFP), π-class glutathione S-transferase (π GST), and the embryonic form of pyruvate kinase (M2-PK) are observed after 1 week. Similar cells are seen in ELD-treated rats after 2 months. Their numbers increase with time, and incorporation of [3H]thymidine confirms they are a dividing population. Acute damage induced by partial hepatectomy and CCI4 poisoning did not induce the appearance of oval cells. We conclude that chronic ethanol consumption induces oval cell proliferation. We suggest that, in addition to other proposed mechanisms, an alteration in cellular composition of the liver be considered as an explanation for the increased incidence of liver cancer among alcoholics.