bluuebunny/crossref_metadata_2025 huggingface dataset:
"No Peace" in a Book of Consolation. a Framework for the Book of Isaiah?
Authors: Olley John
Published: August 2004

After an overview of interpretations of the twofold statement of Isa. xlviii 22 and lvii 21 and the concluding lxvi 24 and of evidence from texts and versions, examination of vocabulary provides a basis for considering relationship to the verses' contexts and to the structure and interpretation of Isaiah. Both xlviii 22 and lvii 21 are appropriate to their literary contexts, providing cohesion and flow, and predating the framing provided by chs. i and lxv-lxvi. Irrespective of whether the verses are intended to divide xl-lxvi, the reader sees links and so is drawn to look at the blocks. lxvi 24 forms an inclusio with i 2 for the book as a whole: there is comfort and hope for "rebels", but finally warning to those who persist in rebellion.
A Study of the Elderly People Living in Nursing Homes in Iran with a Specific Focus on Tehran
Authors: Sheykhi Mohammad Taghi
Published: August 2004

In the present research the author has tried to bring together the literature and collected data to examine elderly people's quality of life in Iran. In the exploratory phase, a focused group of elderly people was approached and observed. The paper also is intended for students of social policy and those responsible for the elderly people. The author hopes that the present research would act as a beginning step to expand gerontology, which is less developed in countries like Iran, as a new academic discipline. Older people are particularly interesting to study, not only because they are builders of our past, and what has led to the present, but also more importantly, they constitute the group to which, in due course, most of us will belong.This paper examines the living conditions of the elderly residing at the elderly centers in Iran with special reference to Tehran through an empirical method. In this research, while reviewing the relevant literature, the author has referred to various theories as required to assess the elderly people's quality of life. The paper also explores a perspective of the elderly people in Tehran so far as their needs, expectations, their retirement life, and their health weaknesses are concerned. The survey is carried out in the hope of creating further research drives and incentives among the young social researchers.However, as the number of elderly people is on the rise in Iran due to change in the entire social structure of the country and increase in life expectancy, there is a need for further investments to prevent the likely future challenges.
T cells support osteoclastogenesis in an in vitro model derived from human multiple myeloma bone disease: the role of the OPG/TRAIL interaction
Authors: Colucci Silvia , Brunetti Giacomina , Rizzi Rita , Zonno Antonia , Mori Giorgio , Colaianni Graziana , Del Prete Davide , Faccio Roberta , Liso Arcangelo , Capalbo Silvana , Liso Vincenzo , Zallone Alberta , Grano Maria
Published: August 2004

The development of multiple myeloma (MM) bone disease is mediated by increased number and activity of osteoclasts (OCs). Using an in vitro osteoclastogenesis model consisting of unstimulated and unfractionated peripheral blood mononuclear cells (PBMCs) from patients with MM, we showed that T cells support the formation of OCs with longer survival. Different from T-cell–depleted MM PBMC cultures, exogenous macrophage-colony stimulating factor (M-CSF) and receptor activator of nuclear factor-κB ligand (RANKL) were necessary for the formation of OCs; however, they did not exhibit longer survival. We found up-regulated production of RANKL, osteoprotegerin (OPG), and TNF-related apoptosis-inducing ligand (TRAIL) by fresh MM T cells. Despite high OPG levels, the persistence of osteoclastogenesis can be related to the formation of the OPG/TRAIL complex demonstrated by immunoprecipitation experiments and the addition of anti-TRAIL antibody which decreases OC formation. OCs overexpressed TRAIL decoy receptor DcR2 in the presence of MM T cells and death receptor DR4 in T-cell–depleted cultures. In addition, increased Bcl-2/Bax (B-cell lymphoma-2/Bcl2-associated protein X) ratio, following Bcl-2 up-regulation, was detected in OCs generated in the presence of T cells. Our results highlight that MM T cells support OC formation and survival, possibly involving OPG/TRAIL interaction and unbalanced OC expression of TRAIL death and decoy receptors.
Rac1 is the small GTPase responsible for regulating the neutrophil chemotaxis compass
Authors: Sun Chun Xiang , Downey Gregory P. , Zhu Fei , Koh Adeline L. Y. , Thang Herman , Glogauer Michael
Published: August 2004

Although both of the small Rho guanosine triphosphatases (GTPases) Rac1 and Rac2 have been demonstrated to play a role in chemotaxis, the precise and possible unique roles performed by each of these 2 Rac isoforms in neutrophil chemotaxis have not been defined. To elucidate the specific roles of Rac1 and Rac2 in neutrophils during the process of chemotaxis, we generated mice deficient in Rac1, Rac2, or in both Rac1 and Rac2 in cells of myeloid lineage including neutrophils by mating Rac2 null mice with mice carrying a conditional allele for Rac1 and expressing the Cre recombinase downstream of a specific myeloid promoter, lysozyme M. We demonstrate here that although Rac1 null neutrophils display normal chemokinesis, they are unable to migrate toward the source of the chemoattractant. By contrast, Rac2 null neutrophils can orient toward the chemoattractant source but are unable to migrate efficiently. We show that Rac1 is essential for gradient detection and orientation toward the chemoattractant source through spatially constrained regulation of phosphoinositol-3,4,5-trisphosphate (PIP3) and Akt in the leading edge and confirm that Rac2 is the primary regulator of actin assembly providing the molecular motor for neutrophil translocation during chemotaxis.
Outcomes after alemtuzumab-containing reduced-intensity allogeneic transplantation regimen for relapsed and refractory non-Hodgkin lymphoma
Authors: Morris Emma , Thomson Kirsty , Craddock Charles , Mahendra Prem , Milligan Donald , Cook Gordon , Smith Graeme Murray , Parker Anne , Schey Steve , Chopra Rajesh , Hatton Christopher , Tighe Jane , Hunter Anne , Peggs Karl , Linch David , Goldstone Anthony , Mackinnon Stephen
Published: August 2004

We report the outcomes after reduced-intensity conditioning allogeneic stem cell transplantation (RIT) for non-Hodgkin lymphoma (NHL) in 88 patients (low-grade NHL [LG-NHL], n = 41; high-grade NHL [HG-NHL], n = 37; mantle cell lymphoma [MCL], n = 10). Thirty-seven patients had previously received autografts, and 21 were in complete remission (CR) at transplantation. Conditioning therapy consisted of alemtuzumab, fludarabine, and melphalan. Sixty-five patients received peripheral blood stem cells (PBSCs) from HLA-identical siblings, and 23 received bone marrow (BM) from matched unrelated donors. Prophylaxis for graft-versus-host disease (GVHD) consisted of cyclosporin A. Grade III-IV acute GVHD developed in 4 patients, and chronic GVHD developed in 6 patients. With a median follow-up of 36 months (range, 18-60 months), the actuarial overall survival (OS) rates at 3 years were 34% for HG-NHL, 60% for MCL, and 73% for LG-NHL (P < .001). The 100-day and 3-year transplant-related mortality (TRM) rates for patients with LG-NHL were 2% and 11%, respectively, and were better (P = .01) than they were for patients with HG-NHL (27% and 38%, respectively). The actuarial current progression-free survival (PFS) rate at 3 years, including the rate for patients who achieved remission after donor lymphocyte infusion (DLI) for progression, was 65% for LG-NHL, 50% for MCL, and 34% for HG-NHL (P = .002). Twenty-one patients underwent DLI for matched related donor (MD)-persistent disease or relapse, and 15 underwent DLI for mixed hematopoietic chimerism. Patients who experienced relapses of LG-NHL and chronic lymphocytic leukemia (CLL) achieved excellent PFS with extremely low TRM and GVHD, even when matched related donors were unavailable. (Blood. 2004;104:3865-3871)
In vivo antitumor effects of the mTOR inhibitor CCI-779 against human multiple myeloma cells in a xenograft model
Authors: Frost Patrick , Moatamed Farhad , Hoang Bao , Shi Yijiang , Gera Joseph , Yan Huajun , Frost Philip , Gibbons Jay , Lichtenstein Alan
Published: August 2004

In vitro studies indicate the therapeutic potential of mTOR inhibitors in treating multiple myeloma. To provide further support for this potential, we used the rapamycin analog CCI-779 in a myeloma xenograft model. CCI-779, given as 10 intraperitoneal injections, induced significant dose-dependent, antitumor responses against subcutaneous growth of 8226, OPM-2, and U266 cell lines. Effective doses of CCI-779 were associated with modest toxicity, inducing only transient thrombocytopenia and leukopenia. Immunohistochemical studies demonstrated the antitumor responses were associated with inhibited proliferation and angiogenesis, induction of apoptosis, and reduction in tumor cell size. Although CCI-779-mediated inhibition of the p70 mTOR substrate was equal in 8226 and OPM-2 tumor nodules, OPM-2 tumor growth was considerably more sensitive to inhibition of proliferation, angiogenesis, and induction of apoptosis. Furthermore, the OPM-2 tumors from treated mice were more likely to show down-regulated expression of cyclin D1 and c-myc and up-regulated p27 expression. Because earlier work suggested heightened AKT activity in OPM-2 tumors might induce hypersensitivity to mTOR inhibition, we directly tested this by stably transfecting a constitutively active AKT allele into U266 cells. The in vivo growth of the latter cells was remarkably more sensitive to CCI-779 than the growth of control U266 cells.
Regulation of platelet membrane levels of glycoprotein VI by a platelet-derived metalloproteinase
Authors: Gardiner Elizabeth E. , Arthur Jane F. , Kahn Mark L. , Berndt Michael C. , Andrews Robert K.
Published: August 2004

Thrombosis can be initiated when activated platelets adhere to injured blood vessels via the interaction of subendothelial collagen with its platelet receptor, glycoprotein (GP) VI. Here we observed that incubation of platelets with convulxin, collagen, or collagen-related peptide (CRP) resulted in GPVI signaling-dependent loss of surface GPVI and the appearance of an approximately 55-kDa soluble fragment of GPVI as revealed by immunoblotting. Ethylenediaminetetraacetic acid (EDTA) or GM6001 (a metalloproteinase inhibitor with broad specificity) prevented this loss. In other receptor systems, calmodulin binding to membrane-proximal cytoplasmic sequences regulates metalloproteinase-mediated ectodomain shedding. In this regard, we have previously shown that calmodulin binds to a positively charged, membrane-proximal sequence within the cytoplasmic tail of GPVI. Incubation of platelets with calmodulin inhibitor W7 (150 μM) resulted in a time-dependent loss of GPVI from the platelet surface. Both EDTA and GM6001 prevented this loss. Surface plasmon resonance demonstrated that W7 specifically blocked the association of calmodulin with an immobilized synthetic peptide corresponding to the calmodulin-binding sequence of GPVI. These findings suggest that disruption of calmodulin binding to receptor cytoplasmic tails by agonist binding to the receptor triggers metalloproteinase-mediated loss of GPVI from the platelet surface. This process may represent a potential mechanism to regulate GPVI-dependent platelet adhesion.
Protein kinase Cδ mediates retinoic acid and phorbol myristate acetate–induced phospholipid scramblase 1 gene expression: its role in leukemic cell differentiation
Authors: Zhao Ke-Wen , Li Xi , Zhao Qian , Huang Ying , Li Dong , Peng Zhen-Gang , Shen Wu-Zhong , Zhao Ji , Zhou Quansheng , Chen Zhu , Sims Peter J. , Wiedmer Therese , Chen Guo-Qiang
Published: August 2004

Although phospholipid scramblase 1 (PLSCR1) was originally identified based on its capacity to promote transbilayer movement of membrane phospholipids, subsequent studies also provided evidence for its role in cell proliferation, maturation, and apoptosis. In this report, we investigate the potential role of PLSCR1 in leukemic cell differentiation. We show that all-trans retinoic acid (ATRA), an effective differentiation-inducing agent of acute promyelocytic leukemic (APL) cells, can elevate PLSCR1 expression in ATRA-sensitive APL cells NB4 and HL60, but not in maturation-resistant NB4-LR1 cells. ATRA- and phorbol 12-myristate 13-acetate (PMA)–induced monocytic differentiation is accompanied by increased PLSCR1 expression, whereas only a slight or no elevation of PLSCR1 expression is observed in U937 cells differentiated with dimethyl sulfoxide (DMSO), sodium butyrate, or vitamin D3. Cell differentiation with ATRA and PMA, but not with vitamin D3 or DMSO, results in phosphorylation of protein kinase Cδ (PKCδ), and the PKCδ-specific inhibitor rottlerin nearly eliminates the ATRA- and PMA-induced expression of PLSCR1, while ectopic expression of a constitutively active form of PKCδ directly increases PLSCR1 expression. Finally, decreasing PLSCR1 expression with small interfering RNA inhibits ATRA/PMA-induced differentiation. Taken together, these results suggest that as a protein induced upon PKCδ activation, PLSCR1 is required for ATRA- and PMA-triggered leukemic cell differentiation.
The γ-carboxyglutamic acid domain of anticoagulant protein S is involved in activated protein C cofactor activity, independently of phospholipid binding
Authors: Saller François , Villoutreix Bruno O. , Amelot Aymeric , Kaabache Tahar , Le Bonniec Bernard F. , Aiach Martine , Gandrille Sophie , Borgel Delphine
Published: August 2004

We expressed 2 chimeras between human protein S (PS) and human prothrombin (FII) in which the prothrombin γ-carboxyglutamic acid (Gla) domain replaced the PS Gla domain in native PS (GlaFII-PS) or in PS deleted of the thrombin-sensitive region (TSR) (GlaFII-ΔTSR-PS). Neither PS/FII chimera had activated protein C (APC) cofactor activity in plasma clotting assays or purified systems, but both bound efficiently to phospholipids. This pointed to a direct involvement of the PS Gla domain in APC cofactor activity through molecular interaction with APC. Using computational methods, we identified 2 opposite faces of solvent-exposed residues on the PS Gla domain (designated faces 1 and 2) as potentially involved in this interaction. Their importance was supported by functional characterization of a PS mutant in which the face 1 and face 2 PS residues were reintroduced into GlaFII-PS, leading to significant APC cofactor activity, likely through restored interaction with APC. Furthermore, by characterizing PS mutants in which PS face 1 and PS face 2 were individually replaced by the corresponding prothrombin faces, we found that face 1 was necessary for efficient phospholipid binding but that face 2 residues were not strictly required for phospholipid binding and were involved in the interaction with APC.
Evaluation of the suitability of free-energy minimization using nearest-neighbor energy parameters for RNA secondary structure prediction
Authors: Doshi Kishore J , Cannone Jamie J , Cobaugh Christian W , Gutell Robin R
Published: August 2004

Background

A detailed understanding of an RNA's correct secondary and tertiary structure is crucial to understanding its function and mechanism in the cell. Free energy minimization with energy parameters based on the nearest-neighbor model and comparative analysis are the primary methods for predicting an RNA's secondary structure from its sequence. Version 3.1 of Mfold has been available since 1999. This version contains an expanded sequence dependence of energy parameters and the ability to incorporate coaxial stacking into free energy calculations. We test Mfold 3.1 by performing the largest and most phylogenetically diverse comparison of rRNA and tRNA structures predicted by comparative analysis and Mfold, and we use the results of our tests on 16S and 23S rRNA sequences to assess the improvement between Mfold 2.3 and Mfold 3.1.

Results

The average prediction accuracy for a 16S or 23S rRNA sequence with Mfold 3.1 is 41%, while the prediction accuracies for the majority of 16S and 23S rRNA structures tested are between 20% and 60%, with some having less than 20% prediction accuracy. The average prediction accuracy was 71% for 5S rRNA and 69% for tRNA. The majority of the 5S rRNA and tRNA sequences have prediction accuracies greater than 60%. The prediction accuracy of 16S rRNA base-pairs decreases exponentially as the number of nucleotides intervening between the 5' and 3' halves of the base-pair increases.

Conclusion

Our analysis indicates that the current set of nearest-neighbor energy parameters in conjunction with the Mfold folding algorithm are unable to consistently and reliably predict an RNA's correct secondary structure. For 16S or 23S rRNA structure prediction, Mfold 3.1 offers little improvement over Mfold 2.3. However, the nearest-neighbor energy parameters do work well for shorter RNA sequences such as tRNA or 5S rRNA, or for larger rRNAs when the contact distance between the base-pairs is less than 100 nucleotides.
Estimates of statistical significance for comparison of individual positions in multiple sequence alignments
Authors: Sadreyev Ruslan I , Grishin Nick V
Published: August 2004

Background

Profile-based analysis of multiple sequence alignments (MSA) allows for accurate comparison of protein families. Here, we address the problems of detecting statistically confident dissimilarities between (1) MSA position and a set of predicted residue frequencies, and (2) between two MSA positions. These problems are important for (i) evaluation and optimization of methods predicting residue occurrence at protein positions; (ii) detection of potentially misaligned regions in automatically produced alignments and their further refinement; and (iii) detection of sites that determine functional or structural specificity in two related families.

Results

For problems (1) and (2), we propose analytical estimates of P-value and apply them to the detection of significant positional dissimilarities in various experimental situations. (a) We compare structure-based predictions of residue propensities at a protein position to the actual residue frequencies in the MSA of homologs. (b) We evaluate our method by the ability to detect erroneous position matches produced by an automatic sequence aligner. (c) We compare MSA positions that correspond to residues aligned by automatic structure aligners. (d) We compare MSA positions that are aligned by high-quality manual superposition of structures. Detected dissimilarities reveal shortcomings of the automatic methods for residue frequency prediction and alignment construction. For the high-quality structural alignments, the dissimilarities suggest sites of potential functional or structural importance.

Conclusion

The proposed computational method is of significant potential value for the analysis of protein families.
Co-transcriptional folding is encoded within RNA genes
Authors: Meyer Irmtraud M , Miklós István
Published: August 2004

Background

Most of the existing RNA structure prediction programs fold a completely synthesized RNA molecule. However, within the cell, RNA molecules emerge sequentially during the directed process of transcription. Dedicated experiments with individual RNA molecules have shown that RNA folds while it is being transcribed and that its correct folding can also depend on the proper speed of transcription.

Methods

The main aim of this work is to study if and how co-transcriptional folding is encoded within the primary and secondary structure of RNA genes. In order to achieve this, we study the known primary and secondary structures of a comprehensive data set of 361 RNA genes as well as a set of 48 RNA sequences that are known to differ from the originally transcribed sequence units. We detect co-transcriptional folding by defining two measures of directedness which quantify the extend of asymmetry between alternative helices that lie 5' and those that lie 3' of the known helices with which they compete.

Results

We show with statistical significance that co-transcriptional folding strongly influences RNA sequences in two ways: (1) alternative helices that would compete with the formation of the functional structure during co-transcriptional folding are suppressed and (2) the formation of transient structures which may serve as guidelines for the co-transcriptional folding pathway is encouraged.

Conclusions

These findings have a number of implications for RNA secondary structure prediction methods and the detection of RNA genes.
Epidemiology of the human immunodeficiency virus in Saudi Arabia; 18-year surveillance results and prevention from an Islamic perspective
Authors: Madani Tariq A , Al-Mazrou Yagob Y , Al-Jeffri Mohammad H , Al Huzaim Naser S
Published: August 2004

Background

data on HIV epidemiology and preventive measures in Islamic countries is limited. This study describes the results of 18-year of HIV surveillance in Saudi Arabia (SA) and the preventive measures implemented from an Islamic perspective.

Methods

surveillance for HIV has been underway in SA since 1984. Indications for HIV testing include clinical suspicion, screening of contacts of HIV-infected patients, and routine screening of blood and organ donors, prisoners, intravenous drug users, patients with other sexually transmitted infections, and expatriates pre-employment. This is a case series descriptive study of all confirmed HIV infections diagnosed in SA from 1984 through 2001.

Results

a total of 6046 HIV infections were diagnosed, of which 1285 (21.3%) cases were Saudi citizens. Over the 18-year surveillance period the number of HIV infections diagnosed annually among Saudi citizens gradually increased and, over the period 1997–2001, it reached to 84 to 142 cases per year. The number of cases per 100,000 population varied widely between regions with a maximum of 74 cases and a minimum of 2 cases. The infection was most common in the age group 20–40 years (74.6%) and predominantly affected men (71.6%). The modes of transmission among Saudi citizens and expatriates, respectively, were as follows: heterosexual contact, 487 (37.9%) and 1352 (28.4%) cases; blood transfusion, 322 (25.0%) and 186 (3.9%) cases; perinatal transmission, 83 (6.5%) and 19 (0.4%) cases; homosexual contact, 32 (2.5%) and 38 (0.8%) cases; intravenous drug use, 17 (1.3%) and 33 (0.7%) cases; bisexual contact, 10 (0.8%) and 14 (0.3%) cases; unknown, 334 (26.0%) and 3119 (65.5%) cases. The number of HIV infections transmitted by blood or blood products transfusion declined to zero by year 2001 and all such infections occurred due to transfusions administered before 1986. At HIV diagnosis, 4502/6046 (74.5%) patients had no symptoms, 787 (13.0%) patients had non-AIDS defining manifestations, and 757 (12.5%) patients had AIDS. A total of 514/1285 (40%) Saudi patients died by year 2001.

Conclusions

the number of HIV cases in SA is limited with heterosexual contact being the main mode of transmission. From an Islamic perspective, preventive strategies include prevention of non-marital sex and intravenous drug use with encouragement of "safe sex" through legal marriage.
The oncogenic fusion protein RUNX1-CBFA2T1 supports proliferation and inhibits senescence in t(8;21)-positive leukaemic cells
Authors: Martinez Natalia , Drescher Bettina , Riehle Heidemarie , Cullmann Claire , Vornlocher Hans-Peter , Ganser Arnold , Heil Gerhard , Nordheim Alfred , Krauter Jürgen , Heidenreich Olaf
Published: August 2004

Background

The fusion protein RUNX1-CBFA2T1 associated with t(8;21)-positive acute myeloid leukaemia is a potent inhibitor of haematopoetic differentiation. The role of RUNX1-CBFA2T1 in leukaemic cell proliferation is less clear. We examined the consequences of siRNA-mediated RUNX1-CBFA2T1 depletion regarding proliferation and clonogenicity of t(8;21)-positive cell lines.

Methods

The t(8;21)-positive cell line Kasumi-1 was electroporated with RUNX1-CBFA2T1 or control siRNAs followed by analysis of proliferation, colony formation, cell cycle distribution, apoptosis and senescence.

Results

Electroporation of Kasumi-1 cells with RUNX1-CBFA2T1 siRNAs, but not with control siRNAs, resulted in RUNX1-CBFA2T1 suppression which lasted for at least 5 days. A single electroporation with RUNX1-CBFA2T1 siRNA severely diminished the clonogenicity of Kasumi-1 cells. Prolonged RUNX1-CBFA2T1 depletion inhibited proliferation in suspension culture and G1-S transition during the cell cycle, diminished the number of apoptotic cells, but induced cellular senescence. The addition of haematopoetic growth factors could not rescue RUNX1-CBFA2T1-depleted cells from senescence, and could only partially restore their clonogenicity.

Conclusions

RUNX1-CBFA2T1 supports the proliferation and expansion of t(8;21)-positive leukaemic cells by preventing cellular senescence. These findings suggest a central role of RUNX1-CBFA2T1 in the maintenance of the leukaemia. Therefore, RUNX1-CBFA2T1 is a promising and leukaemia-specific target for molecularly defined therapeutic approaches.
Association study of polymorphisms in the excitatory amino acid transporter 2 gene (SLC1A2) with schizophrenia
Authors: Deng Xiangdong , Shibata Hiroki , Ninomiya Hideaki , Tashiro Nobutada , Iwata Nakao , Ozaki Norio , Fukumaki Yasuyuki
Published: August 2004

Background

The glutamatergic dysfunction hypothesis of schizophrenia suggests that genes involved in glutametergic transmission are candidates for schizophrenic susceptibility genes. We have been performing systematic association studies of schizophrenia with the glutamate receptor and transporter genes. In this study we report an association study of the excitatory amino acid transporter 2 gene, SLC1A2 with schizophrenia.

Methods

We genotyped 100 Japanese schizophrenics and 100 controls recruited from the Kyushu area for 11 single nucleotide polymorphism (SNP) markers distributed in the SLC1A2 region using the direct sequencing and pyrosequencing methods, and examined allele, genotype and haplotype association with schizophrenia.The positive finding observed in the Kyushu samples was re-examined using 100 Japanese schizophrenics and 100 controls recruited from the Aichi area.

Results

We found significant differences in genotype and allele frequencies of SNP2 between cases and controls (P = 0.013 and 0.008, respectively). After Bonferroni corrections, the two significant differences disappeared. We tested haplotype associations for all possible combinations of SNP pairs. SNP2 showed significant haplotype associations with the disease (P = 9.4 × 10-5, P = 0.0052 with Bonferroni correction, at the lowest) in 8 combinations. Moreover, the significant haplotype association of SNP2-SNP7 was replicated in the cumulative analysis of our two sample sets.

Conclusion

We concluded that at least one susceptibility locus for schizophrenia is probably located within or nearby SLC1A2 in the Japanese population.
The significance of controlled conditions in lentiviral vector titration and in the use of multiplicity of infection (MOI) for predicting gene transfer events
Authors: Zhang Bing , Metharom Pat , Jullie Howard , Ellem Kay AO , Cleghorn Geoff , West Malcolm J , Wei Ming Q
Published: August 2004

Background

Although lentiviral vectors have been widely used for in vitro and in vivo gene therapy researches, there have been few studies systematically examining various conditions that may affect the determination of the number of viable vector particles in a vector preparation and the use of Multiplicity of Infection (MOI) as a parameter for the prediction of gene transfer events.

Methods

Lentiviral vectors encoding a marker gene were packaged and supernatants concentrated. The number of viable vector particles was determined by in vitro transduction and fluorescent microscopy and FACs analyses. Various factors that may affect the transduction process, such as vector inoculum volume, target cell number and type, vector decay, variable vector – target cell contact and adsorption periods were studied. MOI between 0–32 was assessed on commonly used cell lines as well as a new cell line.

Results

We demonstrated that the resulting values of lentiviral vector titre varied with changes of conditions in the transduction process, including inoculum volume of the vector, the type and number of target cells, vector stability and the length of period of the vector adsorption to target cells. Vector inoculum and the number of target cells determine the frequencies of gene transfer event, although not proportionally. Vector exposure time to target cells also influenced transduction results. Varying these parameters resulted in a greater than 50-fold differences in the vector titre from the same vector stock. Commonly used cell lines in vector titration were less sensitive to lentiviral vector-mediated gene transfer than a new cell line, FRL 19. Within 0–32 of MOI used transducing four different cell lines, the higher the MOI applied, the higher the efficiency of gene transfer obtained.

Conclusion

Several variables in the transduction process affected in in vitro vector titration and resulted in vastly different values from the same vector stock, thus complicating the use of MOI for predicting gene transfer events. Commonly used target cell lines underestimated vector titre. However, within a certain range of MOI, it is possible that, if strictly controlled conditions are observed in the vector titration process, including the use of a sensitive cell line, such as FRL 19 for vector titration, lentivector-mediated gene transfer events could be predicted.
Origin of Aldosterone in the Rat Heart
Authors: Gomez-Sanchez Elise P. , Ahmad Naveed , Romero Damian G. , Gomez-Sanchez Celso E.
Published: August 2004

Aldosterone has been demonstrated in the perfusate of the ex situ rat heart and heart homogenates; however, the origin of aldosterone in the heart is controversial, with some reporting a primary role for extraadrenal synthesis within the heart, and others finding that all of the aldosterone in the heart is sequestered from the circulation. In an attempt to resolve this controversy, we measured the aldosterone and corticosterone contents of plasma and hearts of rats on a normal salt (NS), low salt (LS), or high salt (HS) diet, adrenalectomized (ADX+HS), and ADX with aldosterone replacement or deoxycorticosterone excess (ADX+HS+DOC) before tissue harvest. The sodium content of the diet had no significant effect on corticosterone levels in the plasma or heart. LS significantly increased, whereas HS decreased the aldosterone content of plasma and heart compared with NS. Corticosterone levels in both plasma and heart and aldosterone levels in plasma of ADX-HS rats were undetectable in most individuals and were extremely low in very few. Although plasma aldosterone was undetectable, aldosterone was measurable in 30% of the hearts of 84 ADX+HS rats, albeit at low levels. The aldosterone and corticosterone contents of the hearts of ADX+HS+DOC were similar to those of ADX+HS, indicating that aldosterone synthase and 11β-hydroxylase, not substrate, are the limiting factors for extraadrenal synthesis of corticosteroids in the heart. In conclusion, we found that the level of aldosterone content in the healthy rat heart in vivo is significantly lower than that reported elsewhere and reflects plasma levels in intact rats.
Effect of Interferon-τ on Prostaglandin Biosynthesis, Transport, and Signaling at the Time of Maternal Recognition of Pregnancy in Cattle: Evidence of Polycrine Actions of Prostaglandin E2
Authors: Arosh J. A. , Banu S. K. , Kimmins S. , Chapdelaine P. , MacLaren L. A. , Fortier M. A.
Published: August 2004

Recognition and establishment of pregnancy involve several molecular and cellular interactions among the conceptus, uterus, and corpus luteum (CL). In ruminants, interferon-τ (IFNτ) of embryonic origin is recognized as the pregnancy recognition signal. Endometrial prostaglandin F2α (PGF2α) is the luteolysin, whereas PGE2 is considered a luteoprotective or luteotrophic mediator at the time of establishment of pregnancy. The interplay between IFNτ and endometrial PGs production, transport, and signaling at the time of maternal recognition of pregnancy (MRP) is not well understood. We have studied the expression of enzymes involved in metabolism of PGE2 and PGF2α, cyclooxygenase-1 (COX-1) and COX-2, PG synthases (PGES and PGFS), PG 15-dehydrogenase, and PG transporter as well as PGE2 (EP2 and EP3) and PGF2α receptors. IFNτ influences cell-specific expression of COX-2, PGFS, EP2, and EP3 in endometrium, myometrium, and CL in a spatio-temporal and tissue-specific manner, whereas it does not alter COX-1, PGES, PG 15-dehydrogenase, PG transporter, or PGF2α receptor expression in any of these tissues. In endometrium, IFNτ decreases PGFS in epithelial cells and increases EP2 in stroma. In myometrium, IFNτ decreases PGFS and increases EP2 in smooth muscle cells. In CL, IFNτ increases PGES and decreases EP3. Together, our results show that IFNτ directly or indirectly increases PGE2 biosynthesis and EP2-associated signaling in endometrium, myometrium, and CL during MRP. Thus, PGE2 may play pivotal roles in endometrial receptivity, myometrial quiescence, and luteal maintenance, indicating polycrine (endocrine, exocrine, paracrine, and autocrine) actions of PGE2 at the time of MRP. Therefore, the establishment of pregnancy may depend not only on inhibition of endometrial PGF2α, but also on increased PGE2 production in cattle.
Application of artificial neural networks in engine modelling
Authors: He Y , Rutland C J
Published: August 2004

A study was conducted to develop an accurate simulation tool with a small computer resource footprint for engine design. The modelling approach uses artificial neural networks (ANNs) based on multilayer perceptrons (MLPs). The ANN is used to represent engine in-cylinder processes by training the ANN to approximate computational fluid dynamics (CFD) simulation results of the engine. The ANN approach was applied to model a turbo-charged direct injection (DI) diesel engine over a wide range of operating conditions. Seven primary diesel engine control parameters were varied over their possible ranges: engine speed, engine load, start of injection, injection pressure, mass in the first injection pulse of a split injection, boost pressure and exhaust gas recirculation (EGR). The model output includes five quantities: cylinder pressure, cylinder temperature, cylinder wall heat transfer, NOX emission and soot emission (the elemental carbon fraction of particulate matters). The cylinder pressure, temperature and heat transfer are crank angle resolved, while the emissions are cycle resolved. In total 71 engine steady state operating conditions were simulated with CFD, and five MLPs were trained individually to approximate the five engine output parameters as a function of the seven engine control parameters. The testing results showed that the five trained MLPs achieved satisfactory capabilities of predicting engine responses and representing the characteristics of the engine over a wide range of operating conditions. Additionally, the ANN modelling accuracy was improved by incorporating prior knowledge into the ANN design and using a committee of networks instead of the best single network to make predictions.
Diesel autogignition at elevated in-cylinder pressueres
Authors: Crua C , Kennaird D A , Sazhin S S , Heikal M R , Gold M R
Published: August 2004

The autoignition of diesel sprays at in-cylinder pressures from 5 to 9 MPa and injection pressures from 100 to 160 MPa was investigated. A pseudo three-dimensional view was obtained by using two high-speed video cameras recording the autoignition process simultaneously from two different viewpoints, so that the positional ambiguity of the ignition sites may be removed. The autoignition recordings were related to spray liquid core and vapour phase video recordings reported previously, in order to obtain a detailed understanding of the structure of the sprays. The autoignition delay was found to decrease with an increase of in-cylinder pressure up to 7 MPa. However, contrary to common belief, a reverse in this trend was observed at higher pressures, with a rapid increase in the delay at in-cylinder pressures above 7 MPa. This effect was related to a decrease in spray penetration, a decrease of diffusion coefficient and an increase in chemical delay.
Fourier Transform Infrared Spectroscopic Investigation of the Electric-Field-Induced Reorientation of the Nematic 7CPB with Different Prealignment
Authors: Klimov E. , Siesler H. W.
Published: August 2004

Time-resolved Fourier transform infrared (FT-IR) polarization spectroscopy was employed to study the electric-field-induced reorientation of nematic p-cyanophenyl- p-n-heptylbenzoate (7CPB) in the bulk of the cell and near (within 1 μm) the surface of the electrodes. The initial orientation of 7CPB on the germanium electrodes was varied in order to obtain information concerning the behavior of the liquid crystalline molecules in the boundary region. Model systems containing the 7CPB on rubbed polyimide and poly(vinyl alcohol), non-rubbed polyimide and poly(vinyl alcohol), and blank germanium were prepared and investigated.
Interference Effects in Photoacoustic and Reflectance Spectroscopies on TiO2/Si Structures and TiO2 Band Gap
Authors: Conde-Gallardo A. , Cruz-Orea A. , Tomas S. A.
Published: August 2004

Experimental results of photoacoustic (PAS) and reflectance (RS) spectroscopies of titanium dioxide thin films (TiO2), deposited on Si substrates, are compared in a wide optical range including transparent and absorbent regions of TiO2. Due to the fact that the light modulation frequency f used in the photoacoustic experiments was so low that the thermal diffusion length of the TiO2 (μ = 100 μm) is always larger than the thickness of the studied films, the PAS turns out to be complementary to RS over the entire range. The presence of multiple reflection interference effects makes difficult a direct evaluation of the TiO2 band gap from the PAS signal. However, by employing k(λ) values, obtained from transmission experiments on equivalent TiO2 films deposited on transparent fused quartz substrates, the PAS spectra for the films deposited on silicon are reconstructed by using those theoretical models that consider multiple reflections. The reasonable agreement of the simulated and experimental PAS spectra allows one to obtain reliable Eg values for the TiO2 films deposited on opaque silicon substrates.
Contribution of Semi-Quantum Dielectric Function Models to the Analysis of Infrared Spectra
Authors: De Sousa Meneses Domingos , Brun Jean-Francois , Echegut Patrick , Simon Patrick
Published: August 2004

A new approach to modeling using semi-quantum dielectric function models is proposed for the retrieval of the optical functions from infrared spectra. The powerful points of the method are shown throughout the analysis of two semitransparent materials, MgO and KBr. All the results are discussed in light of those obtained with classical techniques. This type of model is able to retrieve, for example, the extinction index in a range that covers at least six orders of magnitude and gives access to highly valuable information about high-order phonon processes.
Evaluating Sandwich Immunoassays in Microarray Format in Terms of the Ambient Analyte Regime
Authors: Saviranta Petri , Okon Ryan , Brinker Achim , Warashina Masaki , Eppinger Joerg , Geierstanger Bernhard H
Published: August 2004

Background: Conceptionally, antibody microarrays are simply multiplexed sandwich immunoassays in a miniaturized format. However, from the amounts of capture antibodies used, it is not apparent whether such assays are ambient analyte (Ekins. Clin Chem 1998;44:2015–30) or mass-sensing devices (Silzel et al. Clin Chem 1998;44:2036–43). We evaluated multiplexed microarray sandwich assays for 24 mouse serum proteins in these terms within the boundaries of our experimental setup and based on theoretical considerations of the law of mass action.

Methods: Capture antibodies for 24 mouse serum proteins were printed on planar microarray substrates. After incubation with mixtures of purified antigens for 1 or 18 h, mixtures of biotinylated detection antibodies were used. High assay sensitivity was achieved by use of resonance-light-scattering particles for signal generation. Titration curves were generated for assay volumes of 20, 40, and 80 μL, and detection limits were calculated and compared. The assays were modeled theoretically based on the amounts of capture antibodies and the assay volumes used.

Results: As predicted, experimental variations of the assay volume by up to fourfold did not appreciably affect detection. Even for the most sensitive assay, <2% of the analyte molecules present in the sample were captured and generated signal at the detection limit. However, increasing the sample incubation time from 1 to 18 h on average lowered the detection limit threefold.

Conclusions: In our experimental setup, all 24 sandwich microarray assays fulfill the criteria of the “ambient analyte” regime because depletion of analyte molecules from the assay volume is insignificant.
Lipid Disorders and Mutations in the APOB Gene
Authors: Whitfield Amanda J , Barrett P Hugh R , van Bockxmeer Frank M , Burnett John R
Published: August 2004

Background: Plasma lipoproteins are important determinants of atherosclerosis. Apolipoprotein (apo) B is a large, amphipathic glycoprotein that plays a central role in human lipoprotein metabolism. Two forms of apoB are produced from the APOB gene by a unique posttranscriptional editing process: apoB-48, which is required for chylomicron production in the small intestine, and apoB-100, required for VLDL production in the liver. In addition to being the essential structural component of VLDL, apoB-100 is the ligand for LDL-receptor-mediated endocytosis of LDL particles.

Content: The study of monogenic dyslipidemias has revealed important aspects of metabolic pathways. In this review, we discuss the regulation of apoB metabolism and examine how APOB gene defects can lead to both hypo- and hypercholesterolemia. The key clinical, metabolic, and genetic features of familial hypobetalipoproteinemia and familial ligand-defective apoB-100 are described.

Summary: Missense mutations in the LDL-receptor-binding domain of apoB cause familial ligand-defective apoB-100, characterized by hypercholesterolemia and premature coronary artery disease. Other mutations in APOB can cause familial hypobetalipoproteinemia, characterized by hypocholesterolemia and resistance to atherosclerosis. These naturally occurring mutations reveal key domains in apoB and demonstrate how monogenic dyslipidemias can provide insight into biologically important mechanisms.
The good, the bad, and the mad: making up (abnormal) people in Indian country, 1900-30
Authors: King C. Richard
Published: August 2004

This essay examines the concept of the modern self as applied to First Nation Americans in the late nineteenth and early twentieth centuries. In particular, it examines the way in which social projects and psychological discourses engaged with the notion of the ‘Indian individual’
in the period 1900-30.
Book Reviews
Authors: Borhi László , Murphy Mary , Degrelle P. , Bennett G.H. , Bennett G.H. , Kaplan George
Published: August 2004

Tibor Frank, Ethnicity, Propaganda, Myth-Making: Studies on Hungarian Connections to Britain and America
, Budapest: Akadémiai Kiadó, 1999, 391 pp., ISBN 9630576597 (hardback) $40.00

Ben Giamo, Kerouac, The Word and the Way: Prose Artist as
Spiritual Quester
, Carbondale: Southern Illinois University Press, 2001, 272 pp., ISBN 0809324318 (paperback) £15.95

Edward Ashbee, American Society Today
, Manchester: Manchester University Press, 2002, 160 pp., ISBN 0719060214 (hardback) £45.00, 0719060222
(paperback) £13.99

Martin Folly, The United States and World War II
, Edinburgh: Edinburgh University Press, 2002, 187 pp., ISBN 07748615261 (paperback) £12.99

Christopher Hewitt, Understanding Terrorism in America: From The Klan to Al Qaeda
, London
and New York: Routledge, 2002, 176 pp., ISBN 0415277663 (paperback) £14.99

Christopher Sandars, America’s Overseas Garrisons: The Leasehold Empire
, Oxford: Oxford University Press, 2000, 354 pp., ISBN 0198296878 (hardback) £45.00
Book Reviews
Authors: Borges Marcelo J. , Brookshaw David , Queiroz de Campos Luísa , Dowling Andrew , Evans Michael J. , Lambert Frances , Newitt Malyn , Raitt Lia Correia , Rix Rob , Rollin Hilary , Willis Clive , Willis Clive
Published: August 2004

Eulália Maria Lahmeyer Lobo, Imigração Portuguesa no Brasil
São Paulo: Hucitec, 2001, 367 pp., ISBN 85-271-0566-7

Gilda Santos (ed.), Brasil e Portugal: 500 anos de enlaces e desenlaces
Rio de Janeiro: Real Gabinete Português
de Leitura, 2 vols., special numbers 17 and 18 of the review Convergência Lusíada, 2000/2001, 407 and 365 pp., ISSN 1414-0381

John F. Laidlar, Portugal, World Bibliographical Series, Volume 71 Oxford: ABC-CLIO Ltd., 2000, lv + 295 pp., ISBN 1-85109-331-1

Daniele
Conversi, The Basques, the Catalans and Spain: Alternative Routes to Nationalist Mobilisation
London: Hurst, 1997, xx + 312 pp., ISBN 1-85065-268-6. Paperback edition, Reno: University of Nevada, 2000, ISBN 0-87417-362-0

Michael T. Newton and Graham J. Shields, Studying
and Working in Spain
Manchester and New York: Manchester University Press, 2001, xviii + 300 pp., ISBN 0-7190-5472-9 (hardback), 0-7190-5473-7 (paperback)

Herbert R. Southworth, Conspiracy and the Spanish Civil War: The Brainwashing of Francisco Franco
London and New
York: Routledge, 2002, xviii + 249 pp., ISBN 0415-22781-X

Fernando Rosas (ed.), Portugal e a Transição para a Democracia (1974-1976)
Lisboa: Edições Colibri, 1999, 373 pp., ISBN 972-772-107-9

Paul Buck, Lisbon: A Cultural and Literary Companion,
Foreword by Jean-Pierre Faye, Cities of the Imagination series Oxford: Signal Books, 2002, 246 pp., ISBN 1-902669-34-7 (hardback), ISBN 1-902669-35-5 (paperback)

Shelley Godsland and Anne M. White (eds.), Cultura popular: Studies in Spanish and Latin American Popular Culture

Berne: Peter Lang AG, 2002, 295 pp., ISBN 3-906766-96-9

Ann McFall and Kent Sproule, Interpreting Spanish: Advanced Language Skills
London: Routledge, 2001; student handouts, 143 pp., ISBN 0-415-24684-9; tutor’s book, 137 pp., ISBN 0-415-24682-2; book, handouts and cassettes
ISBN 0-415- 12561-8

Heloísa Paulo, ‘Aqui Também é Portugal’: A Colónia Portuguesa do Brasil e o Salazarismo
Coimbra: Quarteto, 2000, 624 pp. ISBN 972-8535-42-2

António Costa Pinto, O Fim do Império Português

Lisbon: Horizonte, 2001, 112 pp., ISBN 972-24-1147-0
Alternative Routes of Drug Administration—Advantages and Disadvantages (Subject Review)
Authors:   Committee on Drugs
Published: August 2004

This Policy Statement was retired May 2011.

During the past 20 years, advances in drug formulations and innovative routes of administration have been made. Our understanding of drug transport across tissues has increased. These changes have often resulted in improved patient adherence to the therapeutic regimen and pharmacologic response. The administration of drugs by transdermal or transmucosal routes offers the advantage of being relatively painless.12 Also, the potential for greater flexibility in a variety of clinical situations exists, often precluding the need to establish intravenous access, which is a particular benefit for children.

This statement focuses on the advantages and disadvantages of alternative routes of drug administration. Issues of particular importance in the care of pediatric patients, especially factors that could lead to drug-related toxicity or adverse responses, are emphasized.