bluuebunny/crossref_metadata_2025 huggingface dataset:
Role of B-Cell–Activating Factor in Adhesion and Growth of Human Multiple Myeloma Cells in the Bone Marrow Microenvironment
Authors: Tai Yu-Tzu , Li Xian-Feng , Breitkreutz Iris , Song Weihua , Neri Paola , Catley Laurence , Podar Klaus , Hideshima Teru , Chauhan Dharminder , Raje Noopur , Schlossman Robert , Richardson Paul , Munshi Nikhil C. , Anderson Kenneth C.
Published: July 2006

Recent studies have underscored the role of B-cell-activating factor (BAFF), a member of the tumor necrosis factor superfamily, in promoting the survival of malignant B cells, including human multiple myeloma. We here characterized the functional significance of BAFF in the interaction between multiple myeloma and bone marrow stromal cells (BMSC) and further defined the molecular mechanisms regulating these processes. BAFF is detected on BMSCs derived from multiple myeloma patients as evidenced by flow cytometry. BAFF secretion is 3- to 10-fold higher in BMSCs than in multiple myeloma cells, and tumor cell adhesion to BMSCs augments BAFF secretion by 2- to 5-fold, confirmed by both ELISA and immunoblotting. Adhesion of MM1S and MCCAR multiple myeloma cell lines to KM104 BMSC line transfected with a luciferase reporter vector carrying the BAFF gene promoter (BAFF-LUC) significantly enhanced luciferase activity, suggesting that nuclear factor-κB (NF-κB) activation induced by multiple myeloma adhesion to BMSCs mediates BAFF up-regulation. Moreover, BAFF (0-100 ng/mL) increases adhesion of multiple myeloma lines to BMSCs in a dose-dependent manner; conversely, transmembrane activator and calcium modulator and cyclophylin ligand interactor-Ig or B-cell maturation antigen/Fc blocked BAFF stimulation. Using adenoviruses expressing dominant-negative and constitutively expressed AKT as well as NF-κB inhibitors, we further showed that BAFF-induced multiple myeloma cell adhesion is primarily mediated via activation of AKT and NF-κB signaling. Importantly, BAFF similarly increased adhesion of CD138-expressing patient multiple myeloma cells to BMSCs. These studies establish a role for BAFF in localization and survival of multiple myeloma cells in the bone marrow microenvironment and strongly support novel therapeutics, targeting the interaction between BAFF and its receptors in human multiple myeloma. (Cancer Res 2006; 66(13): 6675-82)
Arming Tumor-Reactive T Cells with Costimulator B7-1 Enhances Therapeutic Efficacy of the T Cells
Authors: Zheng Guoxing , Liu Shanrong , Wang Peijie , Xu Ying , Chen Aoshuang
Published: July 2006

T cells ectopically expressing costimulators are pathogenic and contribute to autoimmunity against self-antigens. Given that tumor antigens are often self-antigen or mutated self-antigens, we hypothesize that neoexpressing a costimulator on tumor-reactive T cells may likewise enhance their reactivity to tumor. To test this hypothesis, we have expressed B7-1 on OT-1 CD8+ T-cell receptor transgenic T cells via protein transfer (or protein “painting”). Naïve OT-1 T cells, after being painted with B7-1, can self-costimulate themselves, elicit enhanced proliferative and CTL responses to E.G7-ovalbumin tumor cells (expressing a cognate antigen), and become resistant to CD4+CD25+ regulatory T-cell-mediated suppression. Importantly, these T cells, when coimplanted with E.G7-ovalbumin tumor cells into a syngeneic host, are three to nine times more potent than are control T cells (mock painted with human IgG) in inhibiting tumor growth. Further, on transfer into mice bearing established E.G7-ovalbumin tumors, B7-1-painted ex vivo–amplified OT-1 T cells induced complete tumor regression in 65% of treated mice, whereas the control T cells did so in only 28% of treated mice. Finally, on transfer into mice bearing less immunogenic 4T1 breast tumors, B7-1-painted tumor-reactive CD8+ T cells improved the survival of treated mice to a greater extent than did the control T cells. Hence, this study establishes that arming tumor-reactive T cells with a costimulator can enhance their antitumor efficacy. (Cancer Res 2006; 66(13): 6793-9)
A Novel Role for Human Sulfiredoxin in the Reversal of Glutathionylation
Authors: Findlay Victoria J. , Townsend Danyelle M. , Morris Taylor E. , Fraser Jacob P. , He Lin , Tew Kenneth D.
Published: July 2006

Modification of protein cysteine residues by disulfide formation with glutathione (glutathionylation) is a reversible posttranslational modification of critical importance in controlling cell signaling events following oxidative and/or nitrosative stress. Here, we show that human sulfiredoxin, a small redox protein conserved in eukaryotes, can act as a novel regulator of the redox-activated thiol switch in cells by catalyzing deglutathionylation of a number of distinct proteins in response to oxidative and/or nitrosative stress. Actin and protein tyrosine phosphatase 1B were identified in vitro as targets of sulfiredoxin 1 (Srx1)–dependent deglutathionylation and confirmed in vivo by two-dimensional gel electrophoresis analysis. In addition, we show that Srx1-dependent deglutathionylation is functionally relevant through restoration of phosphatase activity. Human sulfiredoxin contains one cysteine residue (Cys99) that is conserved in all family members. Mutation of the cysteine residue inhibits deglutathionylation but did not affect its capacity to bind intracellular proteins. Furthermore, sulfiredoxin is not an acceptor molecule for the GS− moiety during the reaction process. Using two-dimensional gel electrophoresis, we identified multiple protein targets in vivo that are deglutathionylated by sulfiredoxin following oxidative and/or nitrosative stress. This novel deglutathionylation function of sulfiredoxin suggests it has a central role in redox control with potential implications in cell signaling. (Cancer Res 2006; 66(13): 6800-6)
Inhibition of Tumor Growth and Progression of LNCaP Prostate Cancer Cells in Athymic Mice by Androgen and Liver X Receptor Agonist
Authors: Chuu Chih-pin , Hiipakka Richard A. , Kokontis John M. , Fukuchi Junichi , Chen Rou-Yu , Liao Shutsung
Published: July 2006

Androgen-dependent human LNCaP 104-S tumor xenografts progressed to androgen-independent relapsed tumors (104-Rrel) in athymic mice after castration. The growth of 104-Rrel tumors was suppressed by testosterone. However, 104-Rrel tumors adapted to androgen and regrew as androgen-stimulated 104-Radp tumors. Androgen receptor expression in tumors and serum prostate-specific antigen increased during progression from 104-S to 104-Rrel but decreased during transition from 104-Rrel to 104-Radp. Expression of genes related to liver X receptor (LXR) signaling changed during progression. LXRα, LXRβ, ATP-binding cassette transporter A1 (ABCA1), and sterol 27-hydroxylase decreased during progression from 104-S to 104-Rrel. These coordinated changes in LXR signaling in mice during progression are consistent with our previous findings that reduction of ABCA1 gene expression stimulates proliferation of LNCaP cells. To test if attenuation of LXR signaling may enhance prostate cancer progression from an androgen-dependent state to an androgen-independent state, castrated mice carrying 104-S tumors were given the synthetic LXR agonist T0901317 by gavage. T0901317 delayed progression from 104-S to 104-Rrel tumors. Based on our in vivo model, androgen is beneficial for the treatment of androgen-independent androgen receptor–rich prostate cancer and modulation of LXR signaling may be a potentially useful therapy for prostate cancer. (Cancer Res 2006; 66(13): 6482-6)
CD1d-Restricted T Cells License B Cells to Generate Long-Lasting Cytotoxic Antitumor ImmunityIn vivo
Authors: Chung Yeonseok , Kim Byung-Seok , Kim Yeon-Jeong , Ko Hyun-Jeong , Ko Sung-Youl , Kim Dong-Hyeon , Kang Chang-Yuil
Published: July 2006

Although resting B cells are known for being poorly immunogenic and for inducing T-cell tolerance, we have here attempted to test whether their immunogenicity could be enhanced by CD1d-restricted invariant T cells (iNKT) to a point where they could be used in cellular vaccines. We found that the addition of the iNKT ligand α-galactosylceramide (αGalCer) to peptide-loaded B cells overcame peptide-specific T-cell unresponsiveness and allowed for the generation of peptide-specific memory CTL immunity. This CTL was induced independently of CD4 T and natural killer cells but required iNKT and CD8 T cells. B cells directly primed CTL, and the αGalCer and the peptide must be presented on the same cell. Importantly, our B-cell–based vaccine is comparable in efficiency with dendritic cell–based vaccines, inducing similar CTL responses as well as providing an effective regimen for preventing and suppressing s.c. and metastatic tumors. Therefore, with the help of iNKT, peptide-pulsed B cells can establish long-lasting antitumor immunity and so show promise as the basis for an alternative cell-based vaccine. (Cancer Res 2006; 66(13): 6843-50)
Raimon Panikkar's Cosmotheandrism — Theologizing at the Meeting Point of Hinduism and Christianity
Authors: Komulainen Jyri
Published: July 2006

Raimon Panikkar (b. 1918), a Catalan-born Hindu-Christian, is a prominent theorist of interreligious dialogue. This article provides an analysis of his theology of religions. On the basis of the most recent sources available, it appears that even his 'radical pluralism' cannot eschew the inherent problems characteristic of pluralistic theologies of religions.Unlike other pluralists, Panikkar does not subscribe to the Enlightenment tradition. Instead, his plea for the transformation of religions is based on an idiosyncratic 'Cosmotheandrism', which draws on both primordial religious traditions and existentialist philosophy. The prerequisites of interreligious dialogue, as outlined in his work, thus entail commitment to a particular cosmology and mode of consciousness.
Satellite Measurement of Stratospheric Winds and Ozone Using Doppler Michelson Interferometry. Part II: Retrieval Method and Expected Performance
Authors: Rochon Yves J. , Rahnama Peyman , McDade Ian C.
Published: July 2006

This paper is about the retrieval of horizontal wind and ozone number density from measurement simulations for the Stratospheric Wind Interferometer for Transport Studies (SWIFT). This instrument relies on the concept of imaging Doppler Michelson interferometry applied to thermal infrared emission originating from the stratosphere. The instrument and measurement simulations are described in detail in the first of this series of two papers. In this second paper, a summary of the measurement simulations and a data retrieval method suited to these measurements are first presented. The inversion method consists of the maximum a posteriori solution approach with added differential regularization and, when required, iterations performed with the Gauss–Newton method. Inversion characterization and an error analysis have been performed. Retrieval noise estimates have been obtained both from derived covariance matrices and sample inversions. Retrieval noise levels for wind and ozone number density of ∼1–3 m s−1 and <1% have been obtained over the altitude range of 20–45 km with Backus–Gilbert resolving lengths of ∼1.5 km. Retrieval noise levels over the extended altitude range of 15–55 km are less than 10 m s−1 and 2%. The sensitivity to other error sources has been examined through a few sample realizations. The contributions from these other errors can be as important as or more so than retrieval noise. An error budget identifying contributing wind and ozone error levels to total errors of 5 m s−1 and 5% for altitudes of 20–45 km has been prepared relying on the retrieval errors and knowledge of the instrument design.
“If You Know Our Names It Helps!”
Authors: Robertson Joanne
Published: July 2006

The purpose of this narrative is to explore students’ perceptions of exemplary and effective teachers, contextualized within contemporary conversations about “evidence-based” instruction and school reform. A brief overview of audience performance texts and their implications for teacher education programs is first provided, followed by the role-play of a panel discussion among students, educators, and policy makers. The text highlights the relationship between students’ perceptions and the research regarding optimal teaching strategies and learning environments.
An Ojibwe American Indian View of Adult Learning in the Workplace
Authors: Grover Linda LeGarde , Keenan Karen M.
Published: July 2006

The problem and the solution. Human resource development professionals have, in recent years, given increasing attention to fostering diversity and epistemological, or “world view” inclusiveness in the workplace. However, although research exists on many diverse groups, little exists on the management and development of American Indian workers. Various cultural aspects of the ways in which American Indians view existence affecting learning, of knowledge sharing, developing skills, and applying skill and knowledge to task, are unfamiliar to many Westerners. Many HRD professionals would likely benefit from knowledge of and familiarity with American Indian culture and worldview, knowledge that would surely enhance their ability to (a) communicate effectively with and within those communities and (b) include some aspects of American Indian epistemology that might complement or intersect with their own lives and work. This article focuses on the Ojibwe Indians of the North Central United States and southern Canada.
Ubuntu Worldview: A Traditional African View of Adult Learning in the Workplace
Authors: Nafukho Fredrick Muyia
Published: July 2006

The problem and the solution. In traditional African society, adult learning was viewed as holistic learning for life and work and formed the foundation of many African societies. It was used as a process of breaking down barriers and of combating social exclusion. With the current transitions taking place in Africa, less emphasis is being placed on adult learning. The issue of how adults learn in different societies and the philosophy that guides the adult-learning process in the workplace is an important theme for adult education and human resource development scholars and practitioners. This article seeks to bridge the existing gap in terms of the contribution of the African ubuntuism paradigm to adult learning in the workplace.
Rethinking Adult Learning in the Workplace
Authors: McLean Gary N.
Published: July 2006

The problem and the solution. Adult learning is a core concept in support of basic human resource development concepts, such as performance improvement, continuous quality improvement, knowledge management, organizational learning, change management, learning organizations, and a myriad of other initiatives. Yet adult learning is not understood very well. In spite of decades of research, adult educators and HRD practitioners still have imperfect understandings of adult learning, and researchers continue to search for a unitary theory of adult learning. This issue of Advances makes clear that how adults learn is, at least in part, influenced by their worldview. This realization, along with the extensive diversity of worldviews, calls for a new perspective about adult learning in the workplace, among practitioners, theoreticians, and researchers.
Video Computer-Assisted Self-Administered Interviews for Deaf Respondents
Authors: Gerich Joachim , Lehner Roland
Published: July 2006

As sign language is the primary communication channel for the vast majority of deaf persons, options for survey research with this population are limited. A video computerassisted self-administered interview (CASI) instrument developed for deaf respondents is introduced. With the help of a case study involving 234 deaf persons in Austria, the impact of multimedia-supported CASI methods for special populations is discussed.
The Cathedral Is Alive: Animating Biomimetic Architecture
Authors: Dollens Dennis
Published: July 2006

The Cathedral as an animation with implications for genetic architecture and strategies for design-biomimetics, this article argues (with experimental illustrations) for the use of animation in architectural research that is consistent with software visualization and fully capable of contributing to the design-thinking process. Repudiating the use of animation as merely a medium for architectural presentation and affirming the coupling of animation and design-biomimetics, Dollens considers how animation can stimulate and develop architectural ideas, forms, and design through the digital revisualization of natural elements evolving from plants, shells, and skeletons.
Clay mineralogy of the Tertiary onshore and offshore strata of the British Isles
Authors: Huggett J. M. , Knox R. W. O'B.
Published: July 2006

Tertiary sediments are of restricted occurrence in the onshore British Isles but occur extensively offshore, attaining thicknesses of ~4 km in the Faroe—Shetland Basin and ~3 km in the North Sea Basin. Clay mineral stratigraphic studies of the North Sea Paleocene to Lower Miocene successions show a dominance of smectite (and smectite-rich illite-smectite) with minor illite, kaolin and chlorite. Abundant smectite in the Paleocene and Eocene reflects alteration of volcanic ash derived from pyroclastic activity associated with the opening of the North Atlantic between Greenland and Europe. However, the persistence of high smectite into the Oligocene and Middle Miocene indicates that smectite-rich soils on adjacent land areas may also have been an important source of detrital clays. An upwards change to illite-dominated assemblages in the Middle Miocene reflects higher rates of erosion and detrital clay supply, with a subsequent increase in chlorite reflecting climatic cooling. The persistence of smectite-rich assemblages to depths of >3000 m in the offshore indicates little burial-related diagenesis within the mudstone succession, possibly as a consequence of over-pressuring. Despite the importance of Paleocene and Eocene sandstones as hydrocarbon reservoirs in the North Sea and Faroe-Shetland basins, there are few published details of the authigenic clays. The principal clay cements in these sandstones are kaolin and chlorite, with only minor illite reported.

The offshore successions provide a valuable background to the interpretation of the more intensively studied, but stratigraphically less complete, onshore Tertiary successions. The most extensive onshore successions occur in the London and Hampshire basins where sediments of Paleocene to earliest Oligocene age are preserved. Here clay assemblages are dominated by illite and smectite with subordinate kaolin and chlorite. The relatively large smectite content of these successions is also attributed primarily to the alteration of volcanic ash. Associated non-smectitic clays are largely detrital in origin and sourced from areas to the west, with reworking of laterites and “china clay” deposits developed over Cornish granites. Authigenic clays include glauconite (sensu lato), early diagenetic kaolin that has replaced muscovite (principally in the London Clay Formation of the London Basin) and smectite that has replaced ash. Pedogenesis has extensively modified the assemblages in the Reading Formation and Solent Group. Tertiary sediments are largely missing from onshore northern and western Britain, but clays and sands of Eocene and Oligocene age are locally preserved in small fault-bounded basins. Here, clay assemblages are dominated by kaolin with minor illite.
Complete genome sequence of Shigella flexneri 5b and comparison with Shigella flexneri 2a
Authors: Nie Huan , Yang Fan , Zhang Xiaobing , Yang Jian , Chen Lihong , Wang Jing , Xiong Zhaohui , Peng Junping , Sun Lilian , Dong Jie , Xue Ying , Xu Xingye , Chen Shuxia , Yao Zhijian , Shen Yan , Jin Qi
Published: July 2006

Background

Shigella bacteria cause dysentery, which remains a significant threat to public health. Shigella flexneri is the most common species in both developing and developed countries. Five Shigella genomes have been sequenced, revealing dynamic and diverse features. To investigate the intra-species diversity of S. flexneri genomes further, we have sequenced the complete genome of S. flexneri 5b strain 8401 (abbreviated Sf8401) and compared it with S. flexneri 2a (Sf301).

Results

The Sf8401 chromosome is 4.5-Mb in size, a little smaller than that of Sf301, mainly because the former lacks the SHI-1 pathogenicity island (PAI). Compared with Sf301, there are 6 inversions and one translocation in Sf8401, which are probably mediated by insertion sequences (IS). There are clear differences in the known PAIs between these two genomes. The bacteriophage SfV segment remaining in SHI-O of Sf8401 is clearly larger than the remnants of bacteriophage SfII in Sf301. SHI-1 is absent from Sf8401 but a specific related protein is found next to the pheV locus. SHI-2 is involved in one intra-replichore inversion near the origin of replication, which may change the expression of iut/iuc genes. Moreover, genes related to the glycine-betaine biosynthesis pathway are present only in Sf8401 among the known Shigella genomes.

Conclusion

Our data show that the two S. flexneri genomes are very similar, which suggests a high level of structural and functional conservation between the two serotypes. The differences reflect different selection pressures during evolution. The ancestor of S. flexneri probably acquired SHI-1 and SHI-2 before SHI-O was integrated and the serotypes diverged. SHI-1 was subsequently deleted from the S. flexneri 5b genome by recombination, but stabilized in the S. flexneri 2a genome. These events may have contributed to the differences in pathogenicity and epidemicity between the two serotypes of S. flexneri.
Relationship between resident workload and self-perceived learning on inpatient medicine wards: a longitudinal study
Authors: Haney Elizabeth M , Nicolaidis Christina , Hunter Alan , Chan Benjamin KS , Cooney Thomas G , Bowen Judith L
Published: July 2006

Background

Despite recent residency workload and hour limitations, little research on the relationship between workload and learning has been done. We sought to define residents' perceptions of the optimal patient workload for learning, and to determine how certain variables contribute to those perceptions. Our hypothesis was that the relationship between perceived workload and learning has a maximum point (forming a parabolic curve): that either too many or too few patients results in sub-optimal learning.

Methods

Residents on inpatient services at two academic teaching hospitals reported their team and individual patient censuses, and rated their perception of their learning; the patient acuity; case variety; and how challenged they felt. To estimate maximum learning scores, linear regression models with quadratic terms were fit on learning score.

Results

Resident self-perceived learning correlated with higher acuity and greater heterogeneity of case variety. The equation of census versus learning score, adjusted for perception of acuity and case mix scores, showed a parabolic curve in some cases but not in others.

Conclusion

These data suggest that perceived resident workload is complex, and impacted by additional variables including patient acuity and heterogeneity of case variety. Parabolic curves exist for interns with regard to overall census and for senior residents with regard to new admissions on long call days.
Effect of Letrozole Versus Placebo on Bone Mineral Density in Women With Primary Breast Cancer Completing 5 or More Years of Adjuvant Tamoxifen: A Companion Study to NCIC CTG MA.17
Authors: Perez Edith A. , Josse Robert G. , Pritchard Kathleen I. , Ingle James N. , Martino Silvana , Findlay Brian P. , Shenkier Tamara N. , Tozer Richard G. , Palmer Michael J. , Shepherd Lois E. , Liu Shifang , Tu Dongsheng , Goss Paul E.
Published: July 2006

Purpose

Aromatase inhibition depletes estrogen levels and may be associated with accelerated bone resorption. The National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) study MA.17B evaluated bone turnover markers and bone mineral density (BMD) in postmenopausal women randomly assigned to MA.17, a placebo-controlled trial of letrozole after standard adjuvant tamoxifen.

Patients and Methods

Eligible women had a baseline BMD T score of at least 2.0 in either the hip or L2-4 spine; all received calcium 500 mg and vitamin D 400 U daily. Percentage change in BMD (L2-L4 spine and hip) at 12 and 24 months, rate of osteoporosis, and change in markers of bone formation (serum bone alkaline phosphatase) and resorption (serum C-telopeptide and urine N-telopeptide) at 6, 12, and 24 months were compared.

Results

Two hundred twenty-six patients (122 letrozole, 104 placebo) were enrolled. Baseline characteristics were similar in the two groups, including BMD, median age of 60.7 years (81% < 70 years), and median follow-up of 1.6 years. At 24 months, patients receiving letrozole had a significant decrease in total hip BMD (−3.6% v −0.71%; P = .044) and lumbar spine BMD (−5.35% v −0.70%; P = .008). Letrozole increased urine N-telopeptide at 6, 12, and 24 months (P = .054, < .001, and .016, respectively). No patient went below the threshold for osteoporosis in total hip BMD, whereas at the L2-L4 (posteroanterior view), more women became osteoporotic by BMD while receiving letrozole (4.1% v 0%; P = .064).

Conclusion

After 5 years of adjuvant tamoxifen, subsequent letrozole causes a modest increase in bone resorption and reduction in bone mineral density in the spine and hip compared to placebo. Further follow-up is necessary to evaluate the long-term clinical implications of this difference.
Reproductive Outcome of Women with 21-Hydroxylase-Deficient Nonclassic Adrenal Hyperplasia
Authors: Moran C. , Azziz R. , Weintrob N. , Witchel S. F. , Rohmer V. , Dewailly D. , Marcondes J. A. M. , Pugeat M. , Speiser P. W. , Pignatelli D. , Mendonca B. B. , Bachega T. A. S. , Escobar-Morreale H. F. , Carmina E. , Fruzzetti F. , Kelestimur F.
Published: July 2006

Context: Because many women with 21-hydroxylase (21-OH)-deficient nonclassic adrenal hyperplasia (NCAH) carry at least one allele affected by a severe mutation of CYP21, they are at risk for giving birth to infants with classic adrenal hyperplasia (CAH).

Objective: Our objective was to determine the frequency of CAH and NCAH infants born to mothers with 21-OH-deficient NCAH.

Design and Setting: We conducted an international multicenter retrospective/prospective study.

Patients and Methods: The outcome of 203 pregnancies among 101 women with 21-OH-deficient NCAH was reviewed. The diagnosis of 21-OH-deficient NCAH was established by a basal or post-ACTH-stimulation 17-hydroxyprogesterone level of more than 10 ng/ml (30.3 nmol/liter). When possible, genotype analyses were performed to confirm CAH or NCAH in the offspring.

Results: Of the 203 pregnancies, 138 (68%) occurred before the mother’s diagnosis of NCAH and 65 (32%) after the diagnosis. Spontaneous miscarriages occurred in 35 of 138 pregnancies (25.4%) before the maternal diagnosis of NCAH, and in only four of 65 pregnancies (6.2%) after the diagnosis (P < 0.002). Four (2.5%; 95% confidence interval, 0.7–6.2%) of the 162 live births were diagnosed with CAH. To date, 24 (14.8%; 95% confidence interval, 9.0–20.6%) children, 13 girls and 11 boys, have been diagnosed with NCAH. The distribution of NCAH children and their mothers varied significantly by ethnicity (P < 0.0001, for both).

Conclusions: The risk of a mother with 21-OH-deficient NCAH for giving birth to a child affected with CAH is 2.5%; at least 14.8% of children born to these mothers have NCAH.
Proteome Analysis of Cultured Fibroblasts from Type 1 Diabetic Patients and Normal Subjects
Authors: Puricelli Lucia , Iori Elisabetta , Millioni Renato , Arrigoni Giorgio , James Peter , Vedovato Monica , Tessari Paolo
Published: July 2006

Context: Protein profiling of diabetic tissues could provide useful biomarkers for early diagnosis, therapeutic targets, and disease response markers. Cultured fibroblasts are a useful in vitro model for proteome analysis and study of the molecular mechanisms involved in diabetes.

Objective: The objective of the study was to isolate and characterize the proteins of cultured fibroblasts, obtained by skin biopsy, from long-term type 1 diabetic patients without complications and age- and sex-matched normal subjects as controls.

Design: Proteins were separated by two-dimensional electrophoresis (2-DE), and the gel images were qualitatively and quantitatively analyzed. Protein identification was performed by matrix-assisted laser desorption/ionization mass spectrometry.

Results: Reproducible protein maps of fibroblasts from diabetic and healthy subjects were obtained. A total of 125 protein spots were isolated and identified, among them 27 proteins not previously reported in published human fibroblast 2-DE maps, including 20 proteins never reported previously in the literature in human skin fibroblasts. Quantitative analyses revealed six protein spots differentially expressed in the fibroblasts from the diabetic vs. the control subjects (P < 0.05), representing glycolytic enzymes and structural proteins. An increase of triosephosphate I isomerase of two splice isoforms of pyruvate kinase and α-actinin 4 and a decrease of tubulin-β2 and splice isoform 2 of tropomyosin β-chain were detected.

Conclusions: We generated 2-DE reference maps of the proteome of human skin fibroblasts from both normal and uncomplicated type 1 diabetic patients. Differences in glycolytic enzymes and structural proteins were found. The functional implications of the identified proteins are discussed.
A Limited Set of Human MicroRNA Is Deregulated in Follicular Thyroid Carcinoma
Authors: Weber Frank , Teresi Rosemary E. , Broelsch Christoph E. , Frilling Andrea , Eng Charis
Published: July 2006

Context: Although the pathogenesis of follicular thyroid carcinoma (FTC) and its relation to follicular adenoma (FA) remains unclear, detailed understanding of FTC carcinogenesis would facilitate addressing the scientific and clinical challenges, given that there are morphological and molecular similarities between FTC and the frequently occurring FA. Micro-RNAs (miRNAs) are a new class of small, noncoding RNAs implicated in development and cancer and may lend novel clues to FTC genesis. For the latter process, a deregulated miRNA can orchestrate the aberrant expression of several hundred target genes.

Objective: The objective of the study was to identify deregulated miRNAs in FTC.

Design: We used two high-density expression arrays to identify miRNAs and their target genes that are differentially expressed between FTC and FA. Validation was done by quantitative RT-PCR. We further functionally characterized the effect of deregulated miRNAs in vitro using HEK293T, FTC133, and K5 cell lines.

Patients: In total, 45 primary thyroid samples (23 FTC, 20 FA, four normal control thyroid) were analyzed.

Results: Two specific miRNAs, miR-197 and miR-346, were significantly overexpressed in FTC. In vitro overexpression of either miRNA induced proliferation, whereas inhibition led to growth arrest. Overexpression of miR-197 and miR-346 repressed the expression of their predicted target genes in vitro and in vivo.

Conclusions: Our observations show that miR-197 and miR-346 contribute to FTC carcinogenesis. Both miRNAs and their target genes might potentially provide for novel molecular markers and act as novel targets for treatment by interference, which could potentially normalize the deregulated profile of many downstream target genes.
Intraoperative Language Localizationin Multilingual Patients With Gliomas
Authors: Bello Lorenzo , Acerbi Francesco , Giussani Carlo , Baratta Pietro , Taccone Paolo , Songa Valeria
Published: July 2006

OBJECTIVE

Intraoperative localization of speech is problematic in patients that are fluent with different languages. Previous studies have generated various results depending on the series of patients studied, the type of language and the sensitivity of the tasks applied. It is not clear if languages are mediated by multiple and separate cortical areas, or shared by common areas. Globally considered, previous studies recommended performing a multiple intra-operative mapping for all the languages the patient is fluent for. Aim of this work was to study the feasibility of performing an intra-operative multiple language mapping in a group of multilingual patients with a glioma undergoing awake craniotomy for tumor removal, to describe the intraoperative cortical and subcortical findings in the area of craniotomy, with the final goal to maximally preserve their functional language.

METHODS

Seven late highly proficient multilingual patients with a left frontal glioma were submitted pre-operatively to a battery of tests to evaluate oral language production, comprehension, and repetition. Each language was tested serially starting from the first acquired language. Items which were correctly named during these tests were used to build personalized blocks to be used intraoperatively. Language mapping was undertaken during awake craniotomies, by the use of a Ojemann cortical stimulator during counting and oral naming tasks. Subcortical stimulation by using the same current threshold was applied during tumor resection, in a back and forth fashion, and the same tests.

RESULTS

Cortical sites essential for oral naming were found in 87.5% of patients, those for the first acquired language in 1 to 4 sites, those for the other languages in 1 to 3 sites. Sites for each language were distinct and separate. Number and location of sites were not predictable, being randomly and widely distributed in the cortex around or less frequently over the tumor area. Subcortical stimulations found tracts for the first acquired language in 4 patients, and for the other languages in 3 patients. Three of these patients decreased their fluency immediately after surgery, affecting the first acquired language, which fully recovered in two patients and partially in one. The procedure was agile and well tolerated by the patients.

CONCLUSION

These findings show that multiple cortical and subcortical language mapping during awake craniotomy for tumor removal is a feasible procedure. They support the concept that intraoperative mapping should be performed for all the languages the patient is fluent for to preserve functional integrity.
Low Morbidity Associated With the Use of Nbca Liquid Adhesive for Preoperative Transarterial Embolization of Central Nervous System Tumors
Authors: Kim Louis J. , Albuquerque Felipe C. , Aziz-Sultan Ali , Spetzler Robert F. , McDougall Cameron G.
Published: July 2006

OBJECTIVE

To determine the safety and efficacy of preoperative embolization of central nervous system (CNS) tumors with n-butyl cyanoacrylate (NBCA) liquid adhesive.

METHODS

Over a 6-yr period, 35 consecutive patients (12 women, 23 men; mean age, 42 yr; range, 6 mo to 75 yr) with a CNS tumor underwent preoperative embolization with NBCA. Tumor type, location, endovascular and surgical treatment, percent of tumor embolization, estimated blood loss, and neurological deficits related to embolization were evaluated retrospectively.

RESULTS

One hundred feeding arteries were embolized (mean, 3 vessels/patient). In only one case (3%) a normal artery was inadvertently occluded by the embolization. During follow-up the resulting neurological deficit resolved completely. There were no neurological deficits or inadvertent embolization events in the remaining 34 cases. The mean percent of tumor embolized was 68%, but did not significantly correlate with operative blood loss (Pearson's correlation coefficient, r = 0.049).

CONCLUSION

In experienced hands, CNS tumors can be embolized with NBCA liquid adhesive with a high degree of safety and efficacy. We believe that adroit embolization technique with NBCA and other embolisates should be part of the contemporary neuroendovascular armamentarium.
Chiral Ruthenium(II)–Bis(2-oxazolin-2-yl)pyridine Complexes. Asymmetric Catalytic Cyclopropanation of Olefins and Diazoacetates
Authors: Nishiyama Hisao , Itoh Yoshiki , Sugawara Yuji , Matsumoto Hideki , Aoki Katsuyuki , Itoh Kenji
Published: July 2006

A chiral ruthenium(II)–bis(2-oxazolin-2-yl)pyridine catalyst prepared in situ from optically active bis(2-oxazolin-2-yl)pyridine (Pybox-ip) (2) and [RuCl2(p-cymene)]2 (1) exhibited efficient activity for the asymmetric cyclopropanation (ACP) of styrene and several diazoacetates to give the corresponding trans- and cis-2-phenylcyclopropane-1-carboxylates (3 and 4) in good yields (66—87%). A mixture of 1 and 2 in an atmosphere of ethylene produced the trans-RuCl2(Pybox-ip)(ethylene) complex (5), which also proved to be a powerful catalyst for ACP. The stereoselectivity of the trans- and cis-cyclopropanes were from 90 : 10 up to 98 : 2, and their enantioselectivities reached 97%. A catalytic system with 5 could be used for several olefins and internal olefins. A concerted mechanism of ACP with the Ru–Pybox catalyst was postulated on the basis of the stereospecificity with deuterated styrene. Other substituents, such as ethyl, s-butyl, benzyl, and phenyl on the oxazoline rings of Pybox in place of the isopropyl group were also examined, and were found to exhibit a similar high trans-stereoselection and a high enantioselectivity of the cyclopropane products; ex. with Ru–Pybox-ethyl 91 : 9 of 3 : 4 and 82% ee for 3. The non-chiral Ru–Pybox-dihydro catalyst exhibited asymmetric induction with 39% ees of 3 with d- and l-menthyl diazoacetates, and kept a high trans- and cis-stereoselection of 97 : 3.
Cation Sensitivity of a Polypyrrole/Polyanion Composite Film Electrode
Authors: Momma Toshiyuki , Komaba Shin-ichi , Osaka Tetsuya , Nakamura Sadako , Takemura Yoshiko
Published: July 2006

Polypyrrole (PPy)/polyanion composite films were formed electrochemically in coexistence with a polymer electrolyte (poly(sodium 4-styrenesulfonate) (PSS) or poly(acrylic acid) (PAA)) in the polymerizing solution. The potential response behaviors of the PPy/PSS and PPy/PAA composites to cation activities were investigated, and the PPy/PSS electrode showed a better Nernstian response than that of the PPy/PAA electrode. The selection of incorporated polyanions and the polymerizing conditions, which were determined in this paper, affected the response behavior. The resultant PPy/PSS electrode showed a good Nernstian response only to monovalent cations with 58 mV/decade. The electrode indicated the equilibrium potential in a few seconds at the change of cation activity. It was found that the potential response was influenced by both the electroactivity of PPy and the PSS content in the PPy matrix.
Practical Synthesis of a C-Glycosyl Flavonoid via O → C Glycoside Rearrangement
Authors: Kumazawa Toshihiro , Ohki Kazuhito , Ishida Mitsuo , Sato Shingo , Onodera Jun-ichi , Matsuba Shigeru
Published: July 2006

The C-glycosylation of 2,3,4,6-tetra-O-benzyl-α-d-glucopyranosyl fluoride and 2-acetylphloroglucinol 3,5-bis(alkyl ether) in the presence of boron trifluoride etherate as an activator stereoselectively gave the β-C-glucoside in a good yield via O → C glycoside rearrangement. Subsequently, aldol condensation of the C-glucoside with benzaldehyde afforded the corresponding β-C-glucosyl chalcone in a good yield.
Syntheses of Azulene Analogues of Triphenylmethyl Cation: Extremely Stable Hydrocarbon Carbocations and the First Example of a One-Ring Flip as the Threshold Rotation Mechanism for Molecular Propellers
Authors: Ito Shunji , Morita Noboru , Asao Toyonobu
Published: July 2006

A series of azulene analogues of triphenylmethyl cation (tri(1-azulenyl)methyl, di(1-azulenyl)phenylmethyl, and (1-azulenyl)diphenylmethyl hexafluorophosphates) were synthesized by hydride abstraction from the corresponding methane derivatives with DDQ. In order to examine the effect of substituents on the cations, and to enhance their stabilities, a series of cations bearing 3-methyl, 3-methoxycarbonyl, 3,6-di-t-butyl, 6-t-butyl, or 3-t-butyl groups on each of the azulene rings were also synthesized. Their pKR+ values showed that the stabilities of these cations dramatically increase with the number of azulene rings. Tris(3,6-di-t-butyl-1-azulenyl)methyl cation showed the highest pKR+ value (14.3) ever observed. The high stabilities of these cations were attributed to a large conjugative effect between the central cation and the azulene ring(s). The dynamic stereochemistry of these cations was also studied based on the temperature-dependent 1H NMR spectra, which were analyzed by a flip mechanism. Low-temperature NMR studies indicated that tri(1-azulenyl)methyl cations exist in two types of propeller conformations (symmetrical and unsymmetrical propellers, which have C3 (A) and C1(B) symmetries, respectively), and at higher temperature the NMR reflect the rapid isomerization. The lower activation energy of the process B → (or → A), compared with that of B → , indicates that the threshold rotation mechanism for the cation is a one-ring flip. This is the first example of a molecular propeller with a threshold rotation mechanism comprising a one-ring flip.
Synapse Formation and Function Is Modulated by the Amyloid Precursor Protein
Authors: Priller Christina , Bauer Thomas , Mitteregger Gerda , Krebs Bjarne , Kretzschmar Hans A. , Herms Jochen
Published: July 2006

The amyloid precursor protein (APP) is critical in the pathogenesis of Alzheimer's disease. The question of its normal biological function in neurons, in which it is predominantly located at synapses, is still unclear. Using autaptic cultures of hippocampal neurons, we demonstrate that hippocampal neurons lacking APP show significantly enhanced amplitudes of evoked AMPA- and NMDA-receptor-mediated EPSCs. The size of the readily releasable synaptic vesicle pool was also increased in neurons lacking APP, whereas the release probability was not affected. In addition, the analysis of spontaneous miniature synaptic currents revealed an augmented frequency in neurons lacking APP, whereas the amplitude of miniature synaptic currents was not found to be altered. Together, these findings strongly indicate that lack of APP increases the number of functional synapses. This hypothesis is further supported by morphometric immunohistochemical analysis revealing an increase of synaptophysin-positive puncta per cultured APP knock-out neuron. In conclusion, lack of APP affects synapse formation and transmission in cultured hippocampal neurons.
Pharmacological Activation of mGlu4 Metabotropic Glutamate Receptors Reduces Nigrostriatal Degeneration in Mice Treated with 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine
Authors: Battaglia Giuseppe , Busceti Carla L. , Molinaro Gemma , Biagioni Francesca , Traficante Anna , Nicoletti Ferdinando , Bruno Valeria
Published: July 2006

We examined whether selective activation of mGlu4 metabotropic glutamate receptors attenuates 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced nigrostriatal damage in mice. C57BL mice were treated with a single dose of MPTP (30 mg/kg, i.p.) preceded, 30 min earlier, by a systemic injection of the mGlu4 receptor enhancerN-phenyl-7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxamide (PHCCC). PHCCC was injected either subcutaneously in cremophor EL or intraperitoneally in saline containing 50% DMSO. PHCCC treatment (3 or 10 mg/kg) significantly reduced MPTP toxicity, as assessed by measurements of the striatal levels of dopamine and its metabolites and by tyrosine hydroxylase, dopamine transporter, and glial fibrillary acidic protein immunostaining in the corpus striatum and substantia nigra. In another set of experiments, a higher cumulative dose of MPTP (80 mg/kg divided into four injections with 2 h of interval) was injected tomGlu4−/−mice and their Sv129/CD1 wild-type controls. A higher dose was used in these experiments because Sv129/CD1 mice are less sensitive to MPTP toxicity. Systemic administration of PHCCC was protective in wild-type mice but failed to affect nigrostriatal damage inmGlu4−/−mice. Finally, unilateral infusion of PHCCC in the external globus pallidus protected the ipsilateral nigrostriatal pathway against MPTP toxicity. These data support the view that mGlu4 receptors are potential targets for the experimental treatment of parkinsonism.
Histamine and Its Receptors Modulate Temperature-Preference Behaviors inDrosophila
Authors: Hong Sung-Tae , Bang Sunhoe , Paik Donggi , Kang Jongkyun , Hwang Seungyoon , Jeon Keunhye , Chun Bumkoo , Hyun Seogang , Lee Youngseok , Kim Jaeseob
Published: July 2006

Temperature profoundly influences various life phenomena, and most animals have developed mechanisms to respond properly to environmental temperature fluctuations. To identify genes involved in sensing ambient temperature and in responding to its change, >27,000 independent P-element insertion mutants ofDrosophilawere screened. As a result, we found that defects in the genes encoding for proteins involved in histamine signaling [histidine decarboxylase (hdc), histamine-gated chloride channel subunit 1 (hisCl1), ora transientless (ort)] cause abnormal temperature preferences. The abnormal preferences shown in these mutants were restored by genetic and pharmacological rescue and could be reproduced in wild type using the histamine receptor inhibitors cimetidine and hydroxyzine. Spatial expression of these genes was observed in various brain regions including pars intercerebralis, fan-shaped body, and circadian clock neurons but not indTRPA1-expressing neurons, an essential element for thermotaxis. We also found that the histaminergic mutants showed reduced tolerance for high temperature and enhanced tolerance for cold temperature. Together, these results suggest that histamine signaling may have important roles in modulating temperature preference and in controlling tolerance of low and high temperature.
Neurodevelopmental Outcomes of Preterm Infants in Bangladesh
Authors: Khan Naila Z. , Muslima Humaira , Parveen Monowara , Bhattacharya Mallika , Begum Nasreen , Chowdhury Selim , Jahan Moshrat , Darmstadt Gary L.
Published: July 2006

OBJECTIVES. The purpose of this work was to determine neurodevelopmental outcomes of preterm infants followed by a multidisciplinary team in a tertiary hospital in Bangladesh.

METHODS. Infants <33 weeks' gestational age were serially assessed for neurodevelopment by physicians and developmental psychologists. An estimate of “low,” “moderate,” or “high” risk for neurodevelopmental impairments was made at the first visit. At later assessments, neurodevelopmental impairments were graded by severity as “none,” “mild,” or “serious.”

RESULTS. Of the 159 enrolled children, 65% survived, 16% died, and 19% were lost to follow-up. Family income was lowest among those who died, and maternal and paternal literacy was highest among the survivors. At a mean age of 31 months, developmental status of the 85 children followed-up for ≥12 months was normal in 32%; 45% had mild and 23% had serious neurodevelopmental impairments. Cognitive impairment was the most common deficit (60%). Final outcome was significantly better than estimated initially. Most serious (85%) but fewer mild (37%) problems were identified independently by both child health physicians and psychologists.

CONCLUSIONS. Parental education and family income had significant influence on postdischarge mortality. Two thirds of infants demonstrated neurodevelopmental impairments. Most mild cognitive impairments would have been missed had either physicians or psychologists alone done the assessments. Preterm infants in this low-resource setting are at high risk for neurodevelopmental impairments, which need to be identified early, preferably by a multidisciplinary team of professionals.