bluuebunny/crossref_metadata_2025 huggingface dataset:
Evidence Favoring the Use of an α
2
-Selective Vasopressor Agent for Cardiopulmonary Resuscitation
Authors: Pellis Tommaso , Weil Max Harry , Tang Wanchun , Sun Shijie , Xie Jing , Song Lei , Checchia Paul
Published: November 2003

Background—

Both α
1
- and β-adrenergic agonists increase the severity of global myocardial ischemic injury. We hypothesized that combined β- and α
1
-adrenergic blockade would improve initial resuscitation and postresuscitation myocardial and neurological functions. We further hypothesized that the resulting α
2
-actions of relatively brief duration would favor improved functions compared with the more prolonged effect of nonadrenergic vasopressin.

Methods and Results—

Three groups of 5 male domestic pigs weighing 37±3 kg were investigated. Ventricular fibrillation was untreated for 7 minutes before the start of precordial compression, mechanical ventilation, and attempted defibrillation. Animals were randomized to receive central venous injections of equipressor doses of (1) epinephrine, (2) epinephrine in which both α
1
- and β-adrenergic effects were blocked by previous administration of prazosin and propranolol, and (3) vasopressin during CPR. All but 1 animal were successfully resuscitated. After injection of epinephrine, significantly better cardiac output and fractional area change, together with lesser increases in troponin I, were observed after α
1
- and β-adrenergic blockade. Postresuscitation neurological function was also improved after α
1
- and β-block in comparison with unblocked epinephrine and after vasopressin.

Conclusions—

Equipressor doses of epinephrine, epinephrine after α
1
- and β-adrenergic blockade, and vasopressin were equally effective in restoring spontaneous circulation after prolonged ventricular fibrillation. However, combined α
1
- and β-adrenergic blockade, which represented a predominantly selective α
2
-vasopressor effect, resulted in improved postresuscitation cardiac and neurological recovery.
Clinical Characterization of Left Ventricular Noncompaction in Children
Authors: Pignatelli Ricardo H. , McMahon Colin J. , Dreyer William J. , Denfield Susan W. , Price Jack , Belmont John W. , Craigen William J. , Wu Jen , El Said Howaida , Bezold Louis I. , Clunie Sarah , Fernbach Susan , Bowles Neil E. , Towbin Jeffrey A.
Published: November 2003

Background—

Left ventricular noncompaction (LVNC) is a reportedly uncommon genetic disorder of endocardial morphogenesis with a reportedly high mortality rate. The purpose of this study was to identify the clinical characteristics of children with LVNC.

Methods and Results—

We retrospectively reviewed 36 children with LVNC evaluated at Texas Children’s Hospital (TCH) from January 1997 to December 2002. Five children had associated cardiac lesions. There were 16 girls and 20 boys. The median age at presentation was 90 days (range, 1 day to 17 years). The median duration of follow-up was 3.2 years (range, 0.5 to 12 years). Twenty-seven patients (75%) had ECG abnormalities, most commonly biventricular hypertrophy (10 patients, 28%). Both ventricles were involved in 8 patients (22%) and only the left ventricle in 28 patients (78%). Left ventricular systolic function was depressed in 30 patients (83%), with a median ejection fraction of 30% (range, 15% to 66%) at diagnosis. Nine patients presenting in the first year of life with depressed left ventricular contractility had a transient recovery of function; however, ejection fraction deteriorated later in life, at a median interval of 6.3years (range, 3 to 12 years). Two patients had an “undulating” phenotype from dilated to hypertrophic cardiomyopathy. Two patients (6%) were identified with an underlying
G4.5
gene mutation. Five patients (14%) died during the study.

Conclusions—

LVNC does not have an invariably fatal course when diagnosed in the neonatal period. A significant number of patients have transient recovery of function followed by later deterioration, which may account for many patients presenting as adults, some manifesting an “undulating” phenotype.
Long-Term Treatment With a Specific Rho-Kinase Inhibitor Suppresses Cardiac Allograft Vasculopathy in Mice
Authors: Hattori Tsuyoshi , Shimokawa Hiroaki , Higashi Midoriko , Hiroki Junko , Mukai Yasushi , Kaibuchi Kozo , Takeshita Akira
Published: November 2003

Cardiac allograft vasculopathy (CAV) continues to be a major cause of late graft failure after cardiac transplantation. We have demonstrated that Rho-kinase, an effector of the small GTPase Rho, plays an important role in the pathogenesis of arteriosclerosis. In this study, we examined whether the Rho-kinase–mediated pathway is also involved in the pathogenesis of CAV using a specific Rho-kinase inhibitor and a dominant-negative Rho-kinase. Hearts from AKR mice were heterotopically transplanted to C3H/He (allograft) or AKR mice (isograft), and the effects of long-term oral treatment with fasudil, which is metabolized to a specific Rho-kinase inhibitor hydroxyfasudil, on CAV were examined at 2 and 4 weeks after the transplantation. Coronary remodeling in the allografts characterized by intimal thickening and perivascular fibrosis was dose-dependently suppressed in the fasudil group compared with the control group (
P
<0.01, n=9 to 10). The inhibitory effects of hydroxyfasudil were mimicked by in vivo gene transfer of dominant-negative Rho-kinase (
P
<0.05, n=4). Among the proinflammatory cytokines examined, those of macrophage migration inhibitory factor, interferon-γ, and transforming growth factor-β1 were upregulated in the control group and were dose-dependently inhibited in the fasudil group (
P
<0.01, n=5). Vascular inflammation in the allografts, as evidenced by accumulation of inflammatory cells (macrophages and T cells), was also significantly inhibited in the fasudil group (
P
<0.05, n=5 to 10). These results indicate that long-term treatment with fasudil suppresses CAV in mice, suggesting that Rho-kinase is an important therapeutic target for the prevention of CAV.
Longitudinal Optical Imaging Study for Locomotor Recovery After Stroke
Authors: Miyai Ichiro , Yagura Hajime , Hatakenaka Megumi , Oda Ichiro , Konishi Ichiro , Kubota Kisou
Published: November 2003

Background and Purpose—

We sought to investigate cerebral mechanisms underlying locomotor recovery after stroke.

Methods—

We measured cortical activities during hemiparetic gait on the treadmill before and after 2 months of inpatient rehabilitation in 8 patients with initial stroke (5 men, 3 women; 4 with right and 4 with left hemiparesis; aged 57 years; 3 months after stroke on average), using an optical imaging system.

Results—

On the initial evaluation, hemiparetic gait was associated with increased oxygenated hemoglobin levels in the medial primary sensorimotor cortex (SMC) that were greater in the unaffected hemisphere than in the affected hemisphere as well as in the premotor cortex (PMC) and supplementary motor area. On the second examination, the asymmetry in SMC activation significantly improved, and there was enhanced PMC activation in the affected hemisphere. Improvement of the asymmetrical SMC activation significantly correlated with improvement of gait parameters.

Conclusions—

Locomotor recovery after stroke may be associated with improvement of asymmetry in SMC activation and enhanced PMC activation in the affected hemisphere.
Induction of chronic lymphocytic leukemia (CLL)–specific CD4- and CD8-mediated T-cell responses using RNA-transfected dendritic cells
Authors: Müller Martin R. , Tsakou Garyfalia , Grünebach Frank , Schmidt Susanne M. , Brossart Peter
Published: November 2003

Recently, it was demonstrated that transfection of dendritic cells (DCs) with tumor-derived RNA can elicit effective T-cell responses. This technique does not require the definition of the tumor antigen or HLA haplotype of the patients. We applied this approach to induce HLA class I– and class II–restricted T-cell responses directed against malignant cells from patients with chronic lymphocytic leukemia (B-CLL). Here, we show that DCs generated from monocytes of patients with B-CLL induce leukemia-specific cytotoxic and proliferative T-cell responses on transfection with total RNA isolated from autologous leukemic B lymphocytes. Standard 51Cr-release assays showed specific major histocompatibility complex (MHC) class I–restricted cytotoxic activity against the autologous leukemic B cells and DCs transfected with CLL-RNA, whereas nonmalignant B cells were spared. The specificity of the cytotoxic T-lymphocyte (CTL) response was confirmed using cold target inhibition assays and by blocking HLA class I molecules. Furthermore, we established a protocol for the amplification of whole B-CLL mRNA. The use of DCs transfected with in vitro amplified B-CLL mRNA elicited specific T-cell responses similar to the results obtained with native mRNA. These data suggest that vaccinations using DCs transfected with RNA might be a potent new strategy in the treatment of CLL.
Janus kinase 3 (JAK3) deficiency: clinical, immunologic, and molecular analyses of 10 patients and outcomes of stem cell transplantation
Authors: Roberts Joseph L. , Lengi Andrea , Brown Stephanie M. , Chen Min , Zhou Yong-Jie , O'Shea John J. , Buckley Rebecca H.
Published: November 2003

We found 10 individuals from 7 unrelated families among 170 severe combined immunodeficiency (SCID) patients who exhibited 9 different Janus kinase 3 (JAK3) mutations. These included 3 missense and 2 nonsense mutations, 1 insertion, and 3 deletions. With the exception of 1 individual with persistence of transplacentally transferred maternal lymphocytes, all infants presented with a T–B+NK– phenotype. The patient mutations all resulted in abnormal B-cell Janus kinase 3 (JAK3)–dependent interleukin-2 (IL-2)–induced signal transducer and activator of transcription-5 (STAT5) phosphorylation. Additional analyses of mutations permitting protein expression revealed the N-terminal JH7 (del58A) and JH6 (D169E) domain mutations each inhibited receptor binding and catalytic activity, whereas the G589S JH2 mutation abrogated kinase activity but did not affect γc association. Nine of the 10 patients are currently alive from between 4 years and 18 years following stem cell transplantation, with all exhibiting normal T-cell function. Reconstitution of antibody function was noted in only 3 patients. Natural killer (NK) function was severely depressed at presentation in the 4 patients studied, whereas after transplantation the only individuals with normal NK lytic activity were patients 1 and 5. Hence, bone marrow transplantation is an effective means for reconstitution of T-cell immunity in this defect but is less successful for restoration of B-cell and NK cell functions.
Series introduction: innate host defense of the respiratory epithelium
Authors: Hiemstra Pieter S , Bals Robert
Published: November 2003

This series overviews the current knowledge of the innate-immune system of the lung. Special emphasis is put on mechanisms used by epithelial cells of the respiratory tract to contribute to host defense. This defense function is important, as the lung is especially prone to microbial exposure. The exchange of oxygen and carbon dioxide requires the ventilation of a large volume of environmental air that may contain respiratory pathogens. Furthermore, the digestive pathway shares with the airways the pharynx, opening another possibility for the uptake of microorganisms into the respiratory tract. Host defense is provided by a multilayered and complex system that aims to avoid colonization and infection of the lung. A classic view separates the inborn, innate-immune system from adaptive mechanisms that involve antigen-specific lymphocytes [1].
Glucocorticoid Receptor Counteracts Tumorigenic Activity of Akt in Skin through Interference with the Phosphatidylinositol 3-Kinase Signaling Pathway
Authors: Leis Hugo , Page Angustias , Ramírez Angel , Bravo Ana , Segrelles Carmen , Paramio Jesús , Barettino Domingo , Jorcano José L. , Pérez Paloma
Published: November 2003

The skin-targeted overexpression of the glucocorticoid receptor (GR) in transgenic mice dramatically impairs the inflammatory responses to tumor promoter agents and suppresses skin tumor development. The antiinflammatory, rapid effects of corticosteroids are partially exerted through interference of GR with the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway in several tissues, a highly relevant pathway in the mouse skin tumor progression process. In this work, we aimed to elucidate whether a cross-talk mechanism between GR and PI3K/Akt occurred in intact skin as well as the biological relevance of this interaction during skin tumorigenesis. We report that, in transgenic mice overexpressing the receptor, GR physically associated with p85α/PI3K in skin, resulting in decreased Akt and IκB kinase activity. GR activation by dexamethasone in normal mouse skin also decreased Akt activity within minutes, whereas cotreatment with the GR antagonist RU486 abolished dexamethasone action. Indeed, GR exerted a nongenomic action because keratinocyte transfection with a transcriptionally defective receptor mutant still decreased PI3K and Akt activity. Moreover, GR coexpression greatly reduced the accelerated growth of malignant tumors and increased Akt activity induced by Akt-transfected keratinocytes, as shown by in vivo tumorigenic assays. Overall, our data strongly indicate that GR/PI3K-Akt cross-talk constitutes a major mechanism underlying the antitumor effect of glucocorticoids in skin.
β-Catenin regulates Cripto- and Wnt3-dependent gene expression programs in mouse axis and mesoderm formation
Authors: Morkel Markus , Huelsken Joerg , Wakamiya Maki , Ding Jixiang , van de Wetering Marc , Clevers Hans , Taketo Makoto M. , Behringer Richard R. , Shen Michael M. , Birchmeier Walter
Published: November 2003

Gene expression profiling of β-catenin, Cripto and Wnt3 mutant mouse embryos has been used to characterise the genetic networks that regulate early embryonic development. We have defined genes whose expression is regulated by β-catenin during formation of the anteroposterior axis and the mesoderm, and have identified Cripto,which encodes a Nodal co-receptor, as a primary target of β-catenin signals both in embryogenesis as well as in colon carcinoma cell lines and tissues. We have also defined groups of genes regulated by Wnt3/β-catenin signalling during primitive streak and mesoderm formation. Our data assign a key role to β-catenin upstream of two distinct gene expression programs during anteroposterior axis and mesoderm formation.
Echinoid synergizes with the Notch signaling pathway inDrosophilamesothorax bristle patterning
Authors: Escudero Luis M. , Wei Shu-Yi , Chiu Wei-Hsin , Modolell Juan , Hsu Jui-Chou
Published: November 2003

echinoid (ed) encodes an immunoglobulin domain-containing cell adhesion molecule that negatively regulates the Egfr signaling pathway during Drosophila photoreceptor development. We show a novel function of Ed, i.e. the restriction of the number of notum bristles that arise from a proneural cluster. Thus, loss-of-function conditions for ed give rise to the development of extra macrochaetae near the extant ones and increase the density of microchaetae. Analysis of ed mosaics indicates that extra sensory organ precursors (SOPs) arise from proneural clusters of achaete-scute expression in a cell-autonomous way. edembryos also exhibit a neurogenic phenotype. These phenotypes suggest a functional relation between ed and the Notch (N) pathway. Indeed,loss-of-function of ed reduces the expression of the N pathway effector E(spl)m8 in proneural clusters. Moreover, combinations of moderate loss-of-function conditions for ed and for different components of the N pathway show clear synergistic interactions manifested as strong neurogenic bristle phenotypes. We conclude that Ed is not essential for, but it facilitates, N signaling. It is known that the N and Egfr pathways act antagonistically in bristle development. Consistently, we find that Ed also antagonizes the bristle-promoting activity of the Egfr pathway, either by the enhancement of N signalling or, similar to the eye, by a more direct action on the Egfr pathway.
In Search of Negative Customer Feedback: The Effect of Expecting to Evaluate on Satisfaction Evaluations
Authors: Ofir Chezy , Simonson Itamar
Published: November 2003

Customers' evaluations of quality and satisfaction are critical inputs in the development of marketing strategies. Given the increasingly common practice of asking for such evaluations, buyers of products (e.g., cars) and services (e.g., hotels, educational programs/courses) often know in advance that they subsequently will be asked to provide their evaluations. In a series of field and laboratory studies, the authors demonstrate that expecting to evaluate leads to less favorable quality and satisfaction evaluations and reduces customers' willingness to purchase and recommend the evaluated services. The negative bias of expected evaluations is observed when actual quality is either low or high, and it persists even when buyers are told explicitly to consider both the positive and negative aspects. The authors examine three possible explanations for this systematic bias, which are referred to as negativity enhancement, role expectation, and vigilant processing. The findings are most consistent with the negativity enhancement account, indicating that unless buyers begin the evaluation task with low expectations, they tend to focus during consumption primarily on negative aspects of product/service quality. The article concludes with a discussion of the theoretical and practical implications of this research.
The Joint Spatial Representation of Multiple Variable Batteries Collected in Marketing Research
Authors: Desarbo Wayne S. , Wu Jianan
Published: November 2003

Marketing research studies pertaining to market segmentation, competitive market structure, and product/service positioning often involve the collection of multiple batteries of measurements from the same set of respondents (e.g., preferences, attribute ratings, demographics, proximity judgments). Various multidimensional scaling (MDS) and spatial methods have been used in the analysis of these variable batteries separately but not much effort has been expended in attempting to relate the individually derived spatial structures. The authors propose a new latent structure MDS procedure that is devised to represent jointly the structure in multiple batteries (preferences, proximities, and brand attribute ratings) of variables collected across the same set of respondents. The authors present the technical structure of the proposed maximum likelihood–based model and conceptually compare it with other related spatial MDS models. The authors present an illustration of the procedure with respect to the analysis of published proximity, preference, and brand ratings data collected from consumers who evaluated ten brands of soft drinks.
A Methodology for Linking Customer Acquisition to Customer Retention
Authors: Thomas Jacquelyn S.
Published: November 2003

Customer acquisition and retention are not independent processes. However, because of data limitations, customer management decisions are frequently based only on an analysis of acquired customers. This analysis shows that these decisions can be biased and misleading. The author presents a modeling approach that estimates the length of a customer's lifetime and adjusts for this bias. Using the model, the author shows the financial impact of not accounting for the effect of acquisition on customer retention.
Chronic myelogenous leukemia with e13a3 (b2a3) type of BCR‐ABL transcript having a DNA breakpoint between ABL exons a2 and a3
Authors: Liu Li‐Gen , Tanaka Hideo , Ito Kinro , Kyo Taiichi , Ito Takuo , Kimura Akiro
Published: November 2003

We describe a patient with chronic myelogenous leukemia (CML), in whom the DNA breakpoint in the BCR‐ABL fusion gene was determined to result in a rare e13a3 (b2a3) transcript. The breakpoint in BCR was intron 13, which was 30 bp downstream from exon 13, and the breakpoint in ABL was intron 2, and was 46 bp downstream from exon a2. This case conforms to the mechanism of DNA breakage occurring within ABL intron 2, but not at 5′ to ABL exon a2. With our review of this case and the literature, it seems that CML with the BCR‐a3 fusion product is associated with a low proportion of circulating immature cells, mild or lack of splenomegaly, slow progressiveness, rather resistance to IFN‐α, and good response to imatinib mesylate. This is the first report of BCR‐a3‐type CML in which the exact DNA breakpoint was identified and located between exons a2 and a3 of the ABL gene. Am. J. Hematol. 74:268–272, 2003. © 2003 Wiley‐Liss, Inc.
Extranodal diffuse follicular center lymphoma mimicking mantle cell lymphoma of the intestine
Authors: Tomita Shigeki , Kojima Masaru , Imura Johji , Hori Hiroshige , Ueda Yoshihiko , Koitabashi Ayako , Suzuki Yasunaga , Nakamura Tetsuya , Nakamura Yuichi , Mitani Kinuko , Terano Akira , Ohkura Yasuo , Kawamata Hitoshi , Fujimori Takahiro
Published: November 2003

We report a case of diffuse follicular center lymphoma (FCL), which is a morphological variant of follicular lymphoma, resembling multiple lymphomatous polyposis (mantle cell lymphoma of the intestine). The patient was a 48‐year‐old Japanese man who was found, by colonoscopy, to have numerous small polypoid lesions along the entire large intestine. Abdominal computed tomography revealed hepatosplenomegaly and enlargement of multiple mesenteric lymph nodes. Histologically, the lesion was characterized by diffuse proliferation of small‐ to medium‐sized lymphocytes with cleaved nuclei in the mucosa and submucosa. Immunohistochemical studies showed that the tumor cells were CD20+, CD10+, BCL‐2+, CD5–, surface IgM–, and cyclin D1–. Moreover, a cytogenetic study showed a translocation at (14;18)(q32;q21). Finally, this case was diagnosed as diffuse FCL, although the tumor was mimicking mantle cell lymphoma. Am. J. Hematol. 74:287–289, 2003. © 2003 Wiley‐Liss, Inc.
Proportionate cancer mortality among workers in the Belarussian tanning industry
Authors: Veyalkin Ilya V. , Milyutin Alexander A.
Published: November 2003

Background

The tanning industry involves many occupational exposures. This study evaluates proportionate cancer mortality among workers employed in the Belarussian tanning plant in Minsk.

Methods

A total of 768 workers with seniority of not less than 6 months who were hired after January 1, 1953 and died before December 31, 2000 was investigated. Proportionate mortality ratios (PMRs) were calculated using the population of Minsk to generate expected numbers.

Results

Among women employed in the tannery, there was a significant excess of pancreatic cancer, based on eight deaths (expected = 2.56, PMR = 3.13, 95% CI = 1.35–6.17). Six of the eight pancreatic cancer deaths occurred among women occupied in dyeing–stuffing workshops (expected = 1.64, PMR = 3.67, 95% CI = 1.34–7.97), all among workers hired between 1962 and 1984 (expected = 1.06, PMR = 6.54, 95% CI = 2.6–13.4).

Conclusions

Women in this tanning industry cohort experienced excess mortality of cancer of the pancreas, with suggested increases of corpus and cervix uteri, melanoma, and kidney cancers. For men, an insignificant increase in PMR of oral cavity–pharynx and pancreatic cancers was seen. Further prospective follow‐up of living members of this cohort, will allow more in‐depth analysis of rare cancer sites, latency, and duration of employment, and is warranted. Am. J. Ind. Med. 44:637–642, 2003. © 2003 Wiley‐Liss, Inc.
Psychosocial risk factors for musculoskeletal symptoms among women working in geriatric care
Authors: Gunnarsdottir Holmfridur K. , Rafnsdottir Gudbjoerg L. , Helgadottir Berglind , Tomasson Kristinn
Published: November 2003

Background

Nursing is a stressful, physically demanding occupation and a rush setting for musculoskeletal problems. The aim of this study is to explore the extent of the association between psychosocial work characteristics and musculoskeletal symptoms among women working in geriatric care.

Methods

The participants were female employees of all geriatric nursing homes and geriatric hospital wards in Iceland having a staff of 10 or more. A total of 1,886 questionnaires were distributed. The response rate was 80%.

Results

Finding the job mentally difficult, mental exhaustion after one's shift, dissatisfaction with supervisors or the flow of information, insufficient influence at work, dissatisfaction with the hierarchy, intense time pressure, lack of solidarity, dissatisfaction with the job, harassment, violence or threats at work; all of the aforementioned gave crude odds ratios (OR) two or above for one or more musculoskeletal symptoms. Mental exhaustion and harassment, violence, and threats were the factors connected with symptoms from all the body regions studied.

Conclusions

The extent of the association of work‐related psychosocial factors and musculoskeletal symptoms among the geriatric female nursing staff is substantial and needs to be taken into account by occupational health services and others involved in preventive work. Am. J. Ind. Med. 44:679–684, 2003. © 2003 Wiley‐Liss, Inc.
Starting the protein synthesis machine: eukaryotic translation initiation
Authors: Preiss Thomas , W. Hentze Matthias
Published: November 2003

The final assembly of the protein synthesis machinery occurs during translation initiation. This delicate process involves both ends of eukaryotic messenger RNAs as well as multiple sequential protein–RNA and protein–protein interactions. As is expected from its critical position in the gene expression pathway between the transcriptome and the proteome, translation initiation is a selective and highly regulated process. This synopsis summarises the current status of the field and identifies intriguing open questions. BioEssays 25:1201–1211, 2003 © 2003 Wiley Periodicals, Inc.
Perpetuating the double helix: molecular machines at eukaryotic DNA replication origins
Authors: Méndez Juan , Stillman Bruce
Published: November 2003

The hardest part of replicating a genome is the beginning. The first step of DNA replication (called “initiation”) mobilizes a large number of specialized proteins (“initiators”) that recognize specific sequences or structural motifs in the DNA, unwind the double helix, protect the exposed ssDNA, and recruit the enzymatic activities required for DNA synthesis, such as helicases, primases and polymerases. All of these components are orderly assembled before the first nucleotide can be incorporated. On the occasion of the 50th anniversary of the discovery of the DNA structure, we review our current knowledge of the molecular mechanisms that control initiation of DNA replication in eukaryotic cells, with particular emphasis on the recent identification of novel initiator proteins. We speculate how these initiators assemble molecular machines capable of performing specific biochemical tasks, such as loading a ring‐shaped helicase onto the DNA double helix. BioEssays 25:1158–1167, 2003. © 2003 Wiley Periodicals, Inc.
Move it on over: getting proteins across biological membranes
Authors: Eichler Jerry , Irihimovitch Vered
Published: November 2003

The translocation of proteins across membranes is a central problem in biology. Regardless of the system in question, delivering proteins across a given membrane relies on many of the same basic themes. At the same time, however, each membrane translocation system, beit signal‐gated or signal‐assembled, makes use of components unique to that system. The latest findings on protein translocation across a variety of biological membranes have been presented in a recent review article.1 BioEssays 25:1154–1157, 2003. © 2003 Wiley Periodicals, Inc.
Absolute configuration of the thyroid hormone analog KAT‐2003 as determined by the 1H NMR anisotropy method with a novel chiral auxiliary, MαNP acid
Authors: Nishimura Toshihiro , Taji Hiromi , Harada Nobuyuki
Published: November 2003

The absolute configuration of the chiral thyroid hormone analog KAT‐2003 (+)‐2, showing hypocholesterolemic activities, decreases of hepatic triglyceride contents with lowering cardiac side effects, and significant inhibitory effect for the second primary hepatocellular carcinoma, was determined as S by the 1H NMR anisotropy method using a novel chiral auxiliary, 2‐methoxy‐2‐(1‐naphtyl)propionic acid (MαNP acid). Chirality 16:13–21, 2004. © 2003 Wiley‐Liss, Inc.
Chiral aldehydes in hydrocarbons: diastereoselective nucleophilic addition, NMR, and CD spectroscopy reveal dynamic solvation effects
Authors: Cainelli Gianfranco , Galletti Paola , Pieraccini Silvia , Quintavalla Arianna , Giacomini Daria , Piero Spada Gian
Published: November 2003

Temperature‐dependent studies on the diastereoselective nucleophilic addition of n‐ BuLi to α‐chiral aldehydes as (S)‐O‐(t‐butyl‐dimethylsilyl)lactal, (S)‐O‐(t‐butyl‐dimethylsilyl) mandelic aldehyde, and (R)‐2‐phenylpropanal in n‐decane and n‐dodecane reveal dynamic solvation phenomena with the presence of inversion temperatures (Tinv) in the Eyring plots of ln (anti/syn) vs. 1/ T. These dynamic solvent effects were disclosed by temperature‐dependent studies of the 13C NMR, CD, and UV spectra of the starting aldehydes in solution of n‐decane and n‐dodecane. The concomitant presence of three peculiar temperatures TCD, TUV, and TNMR, whose values are identical and match Tinv, clearly confirms our earlier interpretation of the solvent‐dependent nature of Tinv. The inversion temperature, as well as TCD, TUV, and TNMR represents the interconversion temperature of two different solvation clusters which act as two different supramolecules with different stereoselectivities. Chirality 16:50–56, 2004. © 2003 Wiley‐Liss, Inc.
Multidimensional viscous shocks II: The small viscosity limit
Authors: Guès Olivier , Métivier Guy , Williams Mark , Zumbrun Kevin
Published: November 2003

In this paper we prove the existence of curved, multidimensional viscous shocks and also justify the small‐viscosity limit.

Starting with a curved, multidimensional (inviscid) shock solution to a system of hyperbolic conservation laws, we show that the shock can be obtained as a small‐viscosity limit of solutions to an associated parabolic problem (viscous shocks). The two main hypotheses are a natural Evans function assumption on the viscous profile, together with a restriction on how much the shock can deviate from flatness. The main tools are a conjugation lemma that removes xN/ϵ dependence from the linearization of the parabolic problem about the viscous profile, new degenerate Kreiss‐type symmetrizers used to prove an L2 estimate for the linearized problem, and a finite‐regularity calculus of semiclassical and mixed type (classical‐semiclassical) pseudodifferential operators. © 2003 Wiley Periodicals, Inc.
GADD34 induces p53 phosphorylation and p21/WAF1 transcription
Authors: Yagi Ayako , Hasegawa Yoshinori , Xiao Hengyi , Haneda Masataka , Kojima Eiji , Nishikimi Akihiko , Hasegawa Tadao , Shimokata Kaoru , Isobe Ken‐Ichi
Published: November 2003

Recently, others and we have shown that one of the functions of GADD34 is a recovery from a shutoff of protein synthesis induced by endoplasmic reticulum stress. GADD34 has been shown to induce growth arrest and apoptosis. Main protein of apoptosis is p53, especially phosphorylation of p53. And one of the main proteins of growth arrest is p21/WAF1. Here we analyzed the effects of GADD34 on p53 phosphorylation and p21/WAF1 transcription. Transfected Myc‐tagged p53 was dose‐dependently phosphorylated at Ser15 by increasing the amount of GADD34. Transfection of GADD34 also induced the endogenous phosphorylation of p53 and enhanced p21 protein expression. Transfection of GADD34 induced p21/WAF1 promoter activity. This activity was dependent on p53, because GADD34 transfection to p53‐deficient cells produced only a slight increase of p21/WAF1 promoter activity. The p21/WAF1 promoter activity was greatly enhanced by the transfection of p53. Both GADD34 and p53 transfection induced much higher p21/WAF1 promoter activity. The promoter activity of p21/WAF1 was very low in GADD34 deficient MEF. The transfection of GADD34 increased the p21/WAF1 promoter activity in GADD34 deficient MEF. © 2003 Wiley‐Liss, Inc.
Inositol 1,4,5‐trisphosphate receptor (type 1) phosphorylation and modulation by Cdc2
Authors: Malathi Krishnamurthy , Kohyama Shinya , Ho Michael , Soghoian Damien , Li Xiaogui , Silane Michael , Berenstein Alejandro , Jayaraman Thottala
Published: November 2003

Calcium (Ca2+) release from the endoplasmic reticulum (ER) controls numerous cellular functions including proliferation, and is regulated in part by inositol 1,4,5‐trisphosphate receptors (IP3Rs). IP3Rs are ubiquitously expressed intracellular Ca2+‐release channels found in many cell types. Although IP3R‐mediated Ca2+ release has been implicated in cellular proliferation, the biochemical pathways that modulate intracellular Ca2+ release during cell cycle progression are not known. Sequence analysis of IP3R1 reveals the presence of two putative phosphorylation sites for cyclin‐dependent kinases (cdks). In the present study, we show that cdc2/CyB, a critical regulator of eukaryotic cell cycle progression, phosphorylates IP3R1 in vitro and in vivo at both Ser421 and Thr799 and that this phosphorylation increases IP3 binding. Taken together, these results indicate that IP3R1 may be a specific target for cdc2/CyB during cell cycle progression. © 2003 Wiley‐Liss, Inc.
Biochemical and functional changes of rat liver spheroids during spheroid formation and maintenance in culture: II. nitric oxide synthesis and related changes
Authors: Xu Jinsheng , Ma Mingwen , Purcell Wendy M.
Published: November 2003

Liver cells isolated from intact tissue can reaggregate to form three‐dimensional, multicellular spheroids in vitro. During this process, cells undergo a histological and environmental change. How cells respond biochemically to this change has not been studied in detail previously. We have investigated some biochemical changes in rat liver cells during the formation and maintenance of spheroids. Liver cells were isolated from male Sprague rats and spheroids cultured by a gyrotatory‐mediated method. Liver cells were shown to respond to the isolation procedure and the formation of spheroids triggered histological environmental changes that increased arginine uptake, nitric oxide (NO) and urea syntheses, as well as raised levels of GSH, GSSG, glutamic acid and aspartic acid secretion within the first couple of days after cell isolation. Levels were maintained at a relatively stable level in the mature spheroids (>5 days) over the 3 week period of observation. P450 1A1 activity was lost in the first 2 days and gradually recovered thereafter. This study, for the first time, shows that liver cells after isolation and during spheroid formation actively uptake arginine and increase NO and urea syntheses. A high level of NO is likely to play an important role in modulating a series of biochemical changes in liver cells. It is considered that liver cells actively respond to the ‘challenge’ induced by the isolation procedure and subsequent histological environmental changes, and biochemical modulation and instability result. The stable cell–cell contacts and histological environment in mature spheroids permit and support functional recovery and maintenance in vitro. This period of stability permits the use of spheroids in toxicity studies to establish acute and chronic paradigms. © 2003 Wiley‐Liss, Inc.
Induction of GADD gene expression by phenethylisothiocyanate in human colon adenocarcinoma cells
Authors: Powolny Anna , Takahashi Keiko , Hopkins Robin G. , Loo George
Published: November 2003

Phenethylisothiocyanate (PEITC), a potential cancer chemopreventive agent, induces colon cancer cell death, but the mechanism is not entirely clear. Therefore, the aim of this study was to further clarify the molecular effects of PEITC in causing death of human colon adenocarcinoma cells. When incubated with PEITC, HCT‐116 colonocytes showed morphological features characteristic of apoptosis, such as irregular cell shape, translocation of plasma membrane phosphatidylserine, and also chromatin condensation and fragmentation. These changes occurred after single‐strand breaks in DNA were detected, suggesting that PEITC induced irreparable DNA damage, which in turn triggered the process of apoptosis. DNA macroarray analysis of a selected small cluster of apoptosis‐related genes revealed noticeably higher expression of only GADD45, which was confirmed by gene‐specific relative RT‐PCR analysis. This led to investigation of other GADD gene members possibly affected by PEITC. Whereas GADD34 mRNA expression increased just slightly, there was an appreciable elevation of the mRNA for GADD153, which is recognized as a pro‐apoptotic gene. The effect of PEITC on GADD153 was attenuated by either actinomycin D or N‐acetylcysteine, suggesting that PEITC‐induced upregulation of GADD153 mRNA expression was partly at the level of transcriptional activation involving reactive oxygen species. Additionally, PEITC‐induced upregulation of GADD153 mRNA expression did not appear to require p53, based on the observation that PEITC also increased GADD153 mRNA expression in HCT‐15 colonocytes, which are known to express mutant p53. These findings suggest that PEITC creates an oxidative cellular environment that induces DNA damage and GADD153 gene activation, which in turn helps trigger apoptosis. © 2003 Wiley‐Liss, Inc.
Human heme oxygenase: Cell cycle‐dependent expression and DNA microarray identification of multiple gene responses after transduction of endothelial cells
Authors: Abraham N.G. , Scapagnini G. , Kappas A.
Published: November 2003

The purpose of the present study was to examine the role of human heme oxygenase (human HO‐1) in cell cycle progression following exposure to heme or human HO‐1 gene transfer and to identify target genes associated with human HO‐1‐meditated increases in cell cycle progression using cDNA microarray technology. Heme‐induced robust human HO‐1 expression in quiescent human microvessel endothelial cells cultured in 1% FBS and the levels of human HO‐1 expression progressively declined without a change in the cell cyclin. To identify genes regulated by human HO‐1 in the cell cycle, human endothelial cells were transduced with a retroviral vector encoded with human HO‐1 gene or an empty vector. Transgene expression and functionality of the recombinant protein were assessed by Western blotting, enzyme activity, carbon monoxide, cGMP production, and cell cycle analysis. Human cDNA gene array and quantitative real‐time RT‐PCR were used to identify both known and novel differentially expressed genes in cells overexpressing human HO‐1. Major findings were upregulation of several genes associated with cell cycle progression, including cyclin E and D; downregulation of cyclin‐dependent kinase inhibitors p21 and p27, cyclin‐dependent kinases 2, 5, and 6, and monocyte chemoattractant protein‐1; and upregulation of growth factors, including vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor I (VEGFRI), endothelial growth factor (EGF) and hepatic‐derived growth factor (HDGF). These findings identify an array of gene responses to overexpression of human HO‐1 and elucidate new aspects of human HO‐1 signaling involved in cell growth. © 2003 Wiley‐Liss, Inc.
Onset and duration of cytomegalovirus immediate early 1 mRNA expression in the blood of renal transplant recipients
Authors: Goossens Valère J. , Christiaans Maarten H.L. , Blok Marinus J. , Terporten Peter H.W. , Sillekens Peter , Lukacsi Angela , Van Hooff Johannes P. , Bruggeman Cathrien A.
Published: November 2003

Human cytomegalovirus (CMV) messenger (m) RNA expression in circulating leukocytes reflects directly viral activity in the human host. In this study, sixty‐nine patients were monitored prospectively for CMV infection and mRNA expression during the first year after renal transplantation. Of the 69 recipients, 58 (84%) recipients were positive for CMV immediate early 1 (IE1) mRNA as detected by nucleic acid sequence‐based amplification. The median onset of IE1 expression started at day 22 after transplantation and continued for a median duration of 82 days. IE1 mRNA expression started significantly earlier in recipients who developed an active CMV infection (P = 0.001) and in mycophenolate mofetil (MMF) treated recipients (P = 0.002). The duration of IE1 mRNA expression was significantly longer in recipients that had previously an early onset of IE1 mRNA expression (P = 0.001) and in recipients with active CMV infection (P = 0.007). Remarkably, longer prednisolone intake was correlated with a significantly (P = 0.02) shorter duration of IE1 expression compared to a longer duration of IE1 expression in recipients with only a short prednisolone intake. In recipients infected with glycoprotein B (gB) type 1 CMV strains, the duration of IE1 expression was significantly (P = 0.04) shorter compared to recipients infected with non‐gB type 1 CMV strains (64 days vs. 150 days). The study indicates that multiple factors play a role in the onset and/or duration of CMV IE1 mRNA expression, for example, MMF treatment, prednisolone intake, and gB type of the specific CMV strain. The clinical significance of these correlations remains to be studied in more detail. J. Med. Virol. 72:94–101, 2004. © 2004 Wiley‐Liss, Inc.
Changing seroepidemiology of hepatitis B, C, and D virus infections in high‐risk populations
Authors: Huo Teh‐Ia , Wu Jaw‐Ching , Wu Shiow‐Ing , Chang An‐Lung , Lin Shih‐Ku , Pan Chun‐Hung , Huang Yi‐Hsiang , Chang Full‐Young , Lee Shou‐Dong
Published: November 2003

Needle‐sharing and sexual contact are important transmission routes of hepatitis B, C, and D virus (HBV, HCV, HDV) infection. This study aimed to investigate the current status of these viral infections among high‐risk populations including prostitutes and intravenous (i.v.) drug users, compared with the prevalence rate reported previously to examine the changing seroepidemiology. Of the 916 female prostitutes, 79 (9%) were positive for antibody to HCV (anti‐HCV), 111 (12%) were positive for HBV surface antigen (HBsAg), and 5 (5%) had antibody to HDV (anti‐HDV). The prevalence rate was significantly lower compared to that in 1989–1991 (12%, P = 0.037) for HCV infection, and to that in 1988 (59%) and 1996 (40%) (P < 0.0001) for HDV infection. Of the 494 i.v. drug users, 87 (18%) patients were HBsAg carriers and 12 (14%) were anti‐HDV‐positive. The prevalence rate of HDV infection was significantly lower than that reported in 1985 (79%, P < 0.0001). Among the 443 tested i.v. drug users, 182 (41%) were anti‐HCV‐positive, significantly lower than that in 1985 (53%, P = 0.026). Of the 263 male prostitutes, 11 (4%) were anti‐HCV‐positive, 45 (17%) were HBsAg‐positive, and 7 (16%) were anti‐HDV‐positive. Of the 129 illegal immigrant prostitutes, 7 (5%) were anti‐HCV‐positive, 15 (12%) were HBsAg‐positive and none were positive for anti‐HDV. In conclusion, the findings indicate a declining prevalence of HCV and HDV infections among drug users and prostitutes over the past 16 years. Male prostitutes and immigrant prostitutes are new “high‐risk” populations and may become a reservoir for disease transmission. J. Med. Virol. 72:41–45, 2004. © 2004 Wiley‐Liss, Inc.
Genetic heterogeneity of the precore and the core promoter region of genotype C hepatitis B virus during lamivudine therapy
Authors: Kuwahara Reiichiro , Kumashiro Ryukichi , Murashima Shiro , Ogata Kei , Tanaka Kazuo , Hisamochi Akiko , Hino Teruko , Ide Tatsuya , Tanaka Eisuke , Koga Yuriko , Sata Michio
Published: November 2003

It has been reported that spontaneous or interferon (IFN)‐induced hepatitis B e (HBe) seroconversion has usually been associated with the development of a stop codon in the precore region. However, the difference between lamivudine‐induced seroconversion and spontaneous or IFN‐induced seroconversion is not known. The aim of this study was to investigate the correlation between the evolution of the precore and core promoter mutations and lamivudine‐induced seroconversion. Forty‐five patients with chronic hepatitis B virus (HBV) infection who were treated with lamivudine for more than 1 year were enrolled. The nucleotide sequence of the precore and core promoter region was determined before and after treatment with lamivudine for 1 year. Among 29 patients who were hepatitis B e antigen (HBeAg)‐positive before treatment, 12 (41.3%) lost HBeAg during the course of treatment for 1 year. Of these, eight patients (66.7%) still had precore wild type HBV after 1 year. After 1 year, reversion to precore wild type HBV was detected in 11 (64.7%) of 17 patients who had precore mutant HBV before treatment. Twelve (70.6%) of 17 patients who were persistently HBeAg‐positive had precore wild type HBV before and after treatment for 1 year. Despite the loss of HBeAg, two thirds of the patients still had precore wild type HBV after the 1‐year treatment. It is suggested that lamivudine‐induced seroconversion differs from spontaneous or IFN‐induced seroconversion in the change of nucleotides in the precore region. The reversion in the precore region may be caused by the difference of drug‐susceptibility to lamivudine. The antiviral effect of lamivudine may be more effective in the precore mutant HBV than in the precore wild type HBV. J. Med. Virol. 72:26–34, 2004. © 2004 Wiley‐Liss, Inc.
Distribution of TT virus genomic groups 1–5 in Brazilian blood donors, HBV carriers, and HIV‐1‐infected patients
Authors: Devalle Sylvie , Niel Christian
Published: November 2003

Human isolates of the highly prevalent TT virus (TTV) have been classified into five major genomic groups (1–5). The geographical distribution of the groups throughout the world is not well known. Five different PCR assays were developed in an attempt to amplify specifically TTV DNAs of each genomic group. Serum samples collected from 72 Brazilian adults (24 voluntary blood donors, 24 hepatitis B virus (HBV) carriers, and 24 human immunodeficiency virus type 1 (HIV‐1)‐infected patients) were tested. TTV DNA from at least one genomic group was detected in 11 (46%) blood donors, 13 (54%) HBV carriers, and 24 (100%) HIV‐1 patients. All five genomic groups were detected in the three populations, with the exception of group 2 in blood donors. Some samples, negative with all five specific assays, were positive with the commonly used untranslated region (UTR) PCR system. On the other hand, TTV DNA was detected in some samples by using specific assays but not with the UTR PCR. Mixed infections with 2–5 TTV isolates from different groups were detected in 21% blood donors, 29% HBV carriers, and 71% HIV‐1 patients. Fifteen PCR products (three obtained with each assay) were sequenced. Most sequences showed high (>86%) homology with those of TTV isolates belonging to their presumed groups. However, three sequences had low homology with all TTV sequences available from the DNA databanks. In conclusion, TTV isolates belonging to all five known genomic groups circulate in Brazil, and the results suggest the existence of new and as yet uncharacterised major genomic groups. J. Med. Virol. 72:166–173, 2004. © 2004 Wiley‐Liss, Inc.