bluuebunny/crossref_metadata_2025 huggingface dataset:
Calendering of Pseudoplastic and Viscoplastic Sheets of Finite Thickness
Authors: Sofou Souzanna , Mitsoulis Evan
Published: October 2004

The lubrication approximation theory (LAT) is used to provide numerical results for calendering sheets with a desired final thickness. The Herschel-Bulkley model of viscoplasticity is used, which reduces with appropriate modifications to the Bingham, the power-law and the Newtonian models. For a desired final sheet thickness, the results give the required thickness of the entering sheet as a function of the dimensionless power-law index (in the case of pseudoplasticity) and the dimensionless yield stress (in the case of viscoplasticity). The corresponding pressure-gradient and pressure distributions are also given. The integrated quantities of engineering interest are calculated. These include the maximum pressure, the roll-separating force, and the power input to the rolls. Both pseudoplasticity and viscoplasticity lead to thicker sheets than the Newtonian model for large entry thickness ratios, while they lead to thinner sheets for small entry thickness ratios. In the case of viscoplastic sheets, the interesting yielded/unyielded regions appear as a function of the dimensionless yield stress. All engineering quantities, given in a dimensionless form, increase substantially with the departure from the Newtonian values. A test case for calendering a plastic sheet with a yield stress is given as an example of implementing the present results.
Cell type–specific regulation of von Willebrand factor expression by the E4BP4 transcriptional repressor
Authors: Hough Christine , Cuthbert Carla D. , Notley Colleen , Brown Christine , Hegadorn Carol , Berber Ergul , Lillicrap David
Published: October 2004

Mechanisms of tissue-restricted patterns of von Willebrand factor (VWF) expression involve activators and repressors that limit expression to endothelial cells and megakaryocytes. The relative transcriptional activity of the proximal VWF promoter was assessed in VWF-producing and -nonproducing cells, and promoter activity was highest in endothelial cells followed by megakaryocytes. Only basal VWF promoter activity was seen in nonendothelial cells. Here we identify a negative response element located at nucleotides (nts) +96/+105 and demonstrate, using chromatin immunoprecipitation (ChIP) analysis, that in vivo this sequence interacts with the E4BP4 transcriptional repressor. Differences in size and relative abundance of nuclear E4BP4 were observed. In HepG2 cells, low levels of larger forms of E4BP4 are present that directly interact with the negative response element. In VWF-expressing cells, high levels of smaller forms predominate with no evidence of direct DNA binding. However, in endothelial cells, mutation of the VWF E4BP4 binding motif not only restores but also further elevates VWF promoter activity, suggesting that E4BP4 may be part of a coordinated binding complex. These observations implicate this binding motif in repressing both activated and basal levels of VWF transcription by different cell type–specific mechanisms, and support the hypothesis that E4BP4 sequesters negative regulators of transcription, thereby enhancing activated gene expression.
15-Deoxy-Δ12,14-prostaglandin J2 induces apoptosis in human malignant B cells: an effect associated with inhibition of NF-κB activity and down-regulation of antiapoptotic proteins
Authors: Piva Roberto , Gianferretti Patrizia , Ciucci Alessandra , Taulli Riccardo , Belardo Giuseppe , Santoro M. Gabriella
Published: October 2004

Cyclopentenone prostaglandins are potent inhibitors of nuclear factor-κB (NF-κB), a transcription factor with a critical role in promoting inflammation and connected with multiple aspects of oncogenesis and cancer cell survival. In the present report, we investigated the role of NF-κB in the antineoplastic activity of the cyclopentenone prostaglandin 15-deoxy-Δ12,14-PGJ2 (15d-PGJ2) in multiple myeloma (MM) and Burkitt lymphoma (BL) cells expressing constitutively active NF-κB. 15d-PGJ2 was found to suppress constitutive NF-κB activity and potently induce apoptosis in both types of B-cell malignancies. 15d-PGJ2-induced apoptosis occurs through multiple caspase activation pathways involving caspase-8 and caspase-9, and is prevented by pretreatment with the pan-caspase inhibitor ZVAD (z-Val-Ala-Asp). NF-κB inhibition is accompanied by rapid down-regulation of NF-κB-dependent antiapoptotic gene products, including cellular inhibitor-of-apoptosis protein 1 (cIAP-1), cIAP-2, X-chromosome-linked inhibitor-of-apoptosis protein (XIAP), and FLICE-inhibitory protein (cFLIP). These effects were mimicked by the proteasome inhibitor MG-132, but not by the peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist troglitazone, suggesting that 15d-PGJ2-induced apoptosis is independent of PPAR-γ. Knockdown of the NF-κB p65-subunit by lentiviral-mediated shRNA interference also resulted in apoptosis induction in malignant B cells with constitutively active NF-κB. The results indicate that inhibition of NF-κB plays a major role in the proapoptotic activity of 15d-PGJ2 in aggressive B-cell malignancies characterized by aberrant regulation of NF-κB. (Blood. 2005;105:1750-1758)
Mechanism by which H-2g, a glucose analog of blood group H antigen, mediates angiogenesis
Authors: Zhu Kui , Amin Mohammed Asif , Zha Yuanyuan , Harlow Lisa A. , Koch Alisa E.
Published: October 2004

The 4A11 antigen is a unique cytokine-inducible antigen up-regulated on rheumatoid arthritis (RA) synovial endothelial cells (ECs) compared with normal ECs. Previously, we showed that in soluble form, this antigen, Lewisy-6/H-5-2 (Ley/H) or its glucose analog, 2-fucosyl lactose (H-2g), induced the expression of EC intercellular adhesion molecule-1 (ICAM-1) and leukocyte-endothelial adhesion through the Janus kinase 2 (JAK2)–signal transducer and activator of transcription 3 (STAT3) pathway. Currently, we show that H-2g induces release of EC angiogenic basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF), an effect inhibited by decoy nuclear factor κB (NFκB) oligodeoxynucleotide (ODN). JAK2 and phosphoinositide-3 kinase (PI3K) are 2 upstream kinases of NFκB activated by H-2g, as confirmed by an inhibitor of kappa B kinase (IKKβ) assay. In vitro, H-2g induces vascular sprouting in the rat aortic ring model, whereas blockade of JAK2, PI3K, or NFκB inhibits sprouting. Likewise, in the in vivo mouse Matrigel plug angiogenesis assay, chemical inhibitors and antisense or decoy ODNs of JAK2, PI3K, or NFκB decrease angiogenesis, confirming the importance of these pathways in H-2g–induced EC signaling. The critical role of Ley/H involvement in angiogenesis and its signaling pathways may provide new targets for therapy of diseases characterized by pathologic neovascularization.
Angiopoietins can directly activate endothelial cells and neutrophils to promote proinflammatory responses
Authors: Lemieux Caroline , Maliba Ricardo , Favier Judith , Théorêt Jean-François , Merhi Yahye , Sirois Martin G.
Published: October 2004

Angiopoietin-1 (Ang1) and -2 (Ang2) are endothelial growth factors that bind to the tyrosine kinase receptor Tie2 and contribute to orchestrate blood vessel formation during angiogenesis. Ang1 mediates vessel maturation and integrity by the recruitment of pericytes. In contrast, Ang2 is classically considered as a Tie2 antagonist, counteracting the stabilizing action of Ang1. Inflammation exists in a mutually dependent association with angiogenesis and we have therefore studied the capacity of angiopoietins to modulate proinflammatory activities, namely P-selectin translocation and neutrophil adhesion onto endothelial cells. We observed that both Ang1 and Ang2 increased these biologic activities. Furthermore, combination of Ang1/Ang2 induced an additive effect on neutrophil adhesion but not on P-selectin translocation. In an attempt to clarify this phenomenon, we found that angiopoietins can directly activate neutrophils through Tie2 signaling as well as modulate platelet-activating factor (PAF) synthesis and β2 integrin functional up-regulation. Together, our data demonstrate that angiopoietins could promote acute recruitment of leukocytes, which might contribute to facilitate vascular remodeling and angiogenesis.
Effect of the G-308A polymorphism of the tumor necrosis factor (TNF)-α gene promoter site on plasma levels of TNF-α and C-reactive protein in smokers: a cross-sectional study
Authors: Gander Marie-Louise , Fischer Joachim E , Maly Friedrich E , von Känel Roland
Published: October 2004

Background

Plasma levels of tumor necrosis factor (TNF)-α and of C-reactive protein (CRP) are elevated in smokers. Previous studies failed to show an association between the G-308A polymorphism in the promoter region of the TNF-α gene and coronary artery disease (CAD). We investigated whether smoking would interact with the TNF-α G-308A polymorphism in determining plasma levels of TNF-α and CRP.

Methods

Study participants with a complete data set in terms of smoking and the TNF-α G-308A polymorphism were 300 middle-aged male and female industrial employees. After excluding 24 irregular smokers, analyses were performed on 198 "non-smokers" (life-long non-smokers or subjects who quit smoking >6 months ago) as compared to 78 "regular smokers" (subjects currently smoking >3 cigarettes/day). All subjects had a fasting morning blood draw to measure plasma levels of TNF-α and CRP by high-sensitive enzyme-linked immunosorbent assays.

Results

The cardiovascular risk factor adjusted analysis regressing log-transformed CRP levels against smoking status, genotype, and smoking-status-genotype interaction revealed a significant main effect for smoking status (F1,250 = 5.67, p = .018) but not for genotype (F1,250 = 0.33, p = .57). The interaction-term between genotype and smoking status was not significant (F1,250 = 0.09, p = .76). The fully adjusted model with plasma TNF-α failed to show significant main effects for smoking and genotype, as well as for the smoking-status-genotype interaction.

Conclusions

The findings suggest that the TNF-α G-308A polymorphism does not mediate the effect of smoking on plasma CRP levels. It remains to be seen whether other genetic polymorphisms along the inflammatory pathway may modulate vascular risk in smokers.
Oxytocin and cholecystokinin secretion in women with colectomy
Authors: Ohlsson Bodil , Rehfeld Jens F , Forsling Mary L
Published: October 2004

Background

Cholecystokinin (CCK) concentrations in plasma have been shown to be significantly higher in colectomised subjects compared to healthy controls. This has been ascribed to reduced inhibition of CCK release from colon. In an earlier study CCK in all but one woman who was colectomised, induced release of oxytocin, a peptide present throughout the gastrointestinal (GI) tract. The aim of this study was thus to examine if colectomised women had a different oxytocin response to CCK compared to healthy controls.

Methods

Eleven women, mean age 34.4 ± 2.3 years, who had undergone colectomy because of ulcerative colitis or constipation were studied. Eleven age-matched healthy women served as controls. All subjects were fasted overnight and given 0.2 μg/kg body weight of CCK-8 i.v. in the morning. Samples were taken ten minutes and immediately before the injection, and 10, 20, 30, 45, 60, 90 and 120 min afterwards. Plasma was collected for measurement of CCK and oxytocin concentrations.

Results

The basal oxytocin and CCK concentrations in plasma were similar in the two groups. Intravenous injection of CCK increased the release of oxytocin from 1.31 ± 0.12 and 1.64 ± 0.19 pmol/l to 2.82 ± 0.35 and 3.26 ± 0.50 pmol/l in controls and colectomised women, respectively (p < 0.001). Given the short half-life of CCK-8 in plasma, the increased concentration following injection could not be demonstrated in the controls. On the other hand, in colectomised women, an increase of CCK in plasma was observed for up to 20 minutes after the injection, concentrations increasing from 1.00 ± 0.21 to a maximum of 1.81 ± 0.26 pmol/l (p < 0.002).

Conclusion

CCK stimulates the release of oxytocin in women. There is no difference in plasma concentrations between colectomised and controls. However, colectomy seems to reduce the metabolic clearance of CCK. The hyperCCKemia in patients who had undergone colectomy is consequently not only dependent on CCK release, but may also depend on reduced clearance.
Punica granatum(Pomegranate) juice provides an HIV-1 entry inhibitor and candidate topical microbicide
Authors: Neurath A Robert , Strick Nathan , Li Yun-Yao , Debnath Asim K
Published: October 2004

Background

For ≈ 24 years the AIDS pandemic has claimed ≈ 30 million lives, causing ≈ 14,000 new HIV-1 infections daily worldwide in 2003. About 80% of infections occur by heterosexual transmission. In the absence of vaccines, topical microbicides, expected to block virus transmission, offer hope for controlling the pandemic. Antiretroviral chemotherapeutics have decreased AIDS mortality in industrialized countries, but only minimally in developing countries. To prevent an analogous dichotomy, microbicides should be: acceptable; accessible; affordable; and accelerative in transition from development to marketing. Already marketed pharmaceutical excipients or foods, with established safety records and adequate anti-HIV-1 activity, may provide this option.

Methods

Fruit juices were screened for inhibitory activity against HIV-1 IIIB using CD4 and CXCR4 as cell receptors. The best juice was tested for inhibition of: (1) infection by HIV-1 BaL, utilizing CCR5 as the cellular coreceptor; and (2) binding of gp120 IIIB and gp120 BaL, respectively, to CXCR4 and CCR5. To remove most colored juice components, the adsorption of the effective ingredient(s) to dispersible excipients and other foods was investigated. A selected complex was assayed for inhibition of infection by primary HIV-1 isolates.

Results

HIV-1 entry inhibitors from pomegranate juice adsorb onto corn starch. The resulting complex blocks virus binding to CD4 and CXCR4/CCR5 and inhibits infection by primary virus clades A to G and group O.

Conclusion

These results suggest the possibility of producing an anti-HIV-1 microbicide from inexpensive, widely available sources, whose safety has been established throughout centuries, provided that its quality is adequately standardized and monitored.
A high prevalence of cumulative trauma disorders in Iranian instrumentalists
Authors: Sadeghi Shahram , Kazemi Behrooz , Shooshtari Seyed Mostafa Jazayeri , Bidari Ali , Jafari Peyman
Published: October 2004

Background

Cumulative trauma disorders (CTDs) are common in musicians and their prevalence has been the subject of a number of studies in most western countries. Such studies are scarce in developing countries despite the possibility that CTDs may have a different prevalence in these countries, especially when considering traditional musical instruments and different methods of playing. Although not formally studied before, according to our experience the prevalence of CTDs seemed to be high among Iranian instrumentalists.

We proposed this study to determine the prevalence of CTDs in amateur music students playing one of the two traditional Iranian instruments: Daf and Setar.

Methods

In a prospective cross sectional study, we interviewed and examined the students of three music training centers in Iran. Seventy eight instrumentalists, who were playing Daf or Setar and twelve students who had not started playing yet were regarded as case and control groups respectively. Some of them also underwent electrodiagnostic studies.

Results

Forty-seven percent (17 of 36) of the Setar players and 57% (24 of 42) of the Daf players and fifty-three percent (41 of 78) of the instrumentalists as a whole had CTDs. None of them had carpal tunnel syndrome.

Conclusions

Our study revealed that the prevalence of CTDs in Iranian instrumentalists was unusually high. In addition to age, other variables may be contributory. This needs to be further studied.
Nutrition and cancer: A review of the evidence for an anti-cancer diet
Authors: Donaldson Michael S
Published: October 2004

It has been estimated that 30–40 percent of all cancers can be prevented by lifestyle and dietary measures alone. Obesity, nutrient sparse foods such as concentrated sugars and refined flour products that contribute to impaired glucose metabolism (which leads to diabetes), low fiber intake, consumption of red meat, and imbalance of omega 3 and omega 6 fats all contribute to excess cancer risk. Intake of flax seed, especially its lignan fraction, and abundant portions of fruits and vegetables will lower cancer risk. Allium and cruciferous vegetables are especially beneficial, with broccoli sprouts being the densest source of sulforophane. Protective elements in a cancer prevention diet include selenium, folic acid, vitamin B-12, vitamin D, chlorophyll, and antioxidants such as the carotenoids (α-carotene, β-carotene, lycopene, lutein, cryptoxanthin). Ascorbic acid has limited benefits orally, but could be very beneficial intravenously. Supplementary use of oral digestive enzymes and probiotics also has merit as anticancer dietary measures. When a diet is compiled according to the guidelines here it is likely that there would be at least a 60–70 percent decrease in breast, colorectal, and prostate cancers, and even a 40–50 percent decrease in lung cancer, along with similar reductions in cancers at other sites. Such a diet would be conducive to preventing cancer and would favor recovery from cancer as well.
Early detection of Pseudomonas aeruginosa – comparison of conventional versus molecular (PCR) detection directly from adult patients with cystic fibrosis (CF)
Authors: Xu Jiru , Moore John E , Murphy Philip G , Millar B Cherie , Elborn J Stuart
Published: October 2004

Background

Pseudomonas aeruginosa (PA) is the most important bacterial pathogen in patients with cystic fibrosis (CF) patients. Currently, routine bacteriological culture on selective/non- selective culture media is the cornerstone of microbiological detection. The aim of this study was to compare isolation rates of PA by conventional culture and molecular (PCR) detection directly from sputum.

Methods

Adult patients (n = 57) attending the regional adult CF centre in Northern Ireland, provided fresh sputum following airways clearance exercise. Following processing of the specimen with sputasol (1:1 vol), the specimen was examined for the presence of PA by plating onto a combination of culture media (Pseudomonas isolation agar, Blood agar & McConkey agar). In addition, from the same specimen, genomic bacterial DNA was extracted (1 ml) and was amplified employing two sequence-specific targets, namely (i) the outer membrane protein (opr L) gene locus and (ii) the exotoxin A (ETA) gene locus.

Results

By sputum culture, there were 30 patients positive for PA, whereas by molecular techniques, there were 35 positive patients. In 39 patients (22 PA +ve & 17 PA -ve), there was complete agreement between molecular and conventional detection and with both PCR gene loci. The opr L locus was more sensitive than the ETA locus, as the former was positive in 10 more patients and there were no patients where the ETA was positive and the opr L target negative. Where a PCR +ve/culture -ve result was recorded (10 patients), we followed these patients and recorded that 5 of these patients converted to being culture-positive at times ranging from 4–17 months later, with a mean lag time of 4.5 months.

Conclusions

This study indicates that molecular detection of PA in sputum employing the opr L gene target, is a useful technique in the early detection of PA, gaining on average 4.5 months over conventional culture. It now remains to be established whether aggressive antibiotic intervention at this earlier stage, based on PCR detection, has any significant benefits on clinical outcome.
Sparse graphical Gaussian modeling of the isoprenoid gene network in Arabidopsis thaliana
Authors: Wille Anja , Zimmermann Philip , Vranová Eva , Fürholz Andreas , Laule Oliver , Bleuler Stefan , Hennig Lars , Prelić Amela , von Rohr Peter , Thiele Lothar , Zitzler Eckart , Gruissem Wilhelm , Bühlmann Peter
Published: October 2004

We present a novel graphical Gaussian modeling approach for reverse engineering of genetic regulatory networks with many genes and few observations. When applying our approach to infer a gene network for isoprenoid biosynthesis in Arabidopsis thaliana, we detect modules of closely connected genes and candidate genes for possible cross-talk between the isoprenoid pathways. Genes of downstream pathways also fit well into the network. We evaluate our approach in a simulation study and using the yeast galactose network.
Human Vγ9/Vδ2 effector memory T cells express the killer cell lectin-like receptor G1 (KLRG1)
Authors: Eberl Matthias , Engel Rosel , Aberle Silke , Fisch Paul , Jomaa Hassan , Pircher Hanspeter
Published: October 2004

The killer cell lectin-like receptor G1 (KLRG1) is expressed in natural killer (NK) cells and effector memory αβ T cells. γδ T cells represent an unconventional lymphocyte population that shares characteristics of NK cells and T cells and links innate and adaptive immunity. Vγ9/Vδ2 T cells comprise the majority of peripheral human γδ T cells and respond to the microbial metabolite (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMB-PP). Here, we demonstrate that KLRG1 is expressed in a significant proportion of Vγ9/Vδ2 T cells in cord blood and in the majority of peripheral Vγ9/Vδ2 T cells from adult donors. KLRG1+ Vγ9/Vδ2 T cells displayed an effector memory phenotype, as KLRG1 was expressed mainly in Vγ9/Vδ2 T cells lacking CD27, CD45RA, CD62L, and CC chemokine receptor 7 (CCR7). Unlike αβ T cells, where possession of KLRG1 identified effector memory cells with impaired proliferative capacity, KLRG1+ Vγ9/Vδ2 T cells were able to proliferate vigorously upon stimulation with HMB-PP in the presence of interleukin-2. Moreover, KLRG1 ligation on Vγ9/Vδ2 T cells by antibodies did not inhibit HMB-PP-induced proliferation and cytokine production nor cytolysis of Daudi cells.
T cell contact-mediated activation of respiratory burst in human polymorphonuclear leukocytes is inhibited by high-density lipoproteins and involves CD18
Authors: Cettour-Rose Philippe , Nguyen Thi Xuan Khanh , Serrander Lena , Kaufmann Marie-Thérèse , Dayer Jean-Michel , Burger Danielle , Roux-Lombard Pascale
Published: October 2004

Polymorphonuclear neutrophils (PMN) are recruited to sites of inflammation, where they are in close vicinity with other immune cell types. The present study demonstrates that direct cell–cell contact with stimulated T cells activates PMN respiratory burst. To discard interferences with soluble products, membranes isolated from human T lymphocytes (msT) or the monocytic cell line HUT-78 (msHUT) were used to mimic cellular contact. msT and msHUT induced a dose-dependent production of radical oxygen species (ROS) in PMN, as detected by chemiluminescence. Similar results were obtained with fixed, stimulated T cells, confirming that ROS production was a result of cell-surface molecules and not to soluble products of T cells. ROS production was mainly intracellular, suggesting that ROS may take part in intracellular processes. High-density lipoproteins (HDL), which had previously been shown to inhibit T cell contact-induced cytokine production in monocyte-macrophages, potently reduced ROS production induced in PMN upon contact with stimulated T cells. This supports the emerging role of HDL as immunomodulators in inflammatory diseases. Furthermore, monoclonal antibodies to CD18 inhibited 60% of the PMN respiratory burst induced by msT, suggesting that CD18 contributed to PMN activation. The present results emphasize the importance of direct cell–cell contact with stimulated T cells in inflammatory processes.
The Extent to which Relaxin Promotes Proliferation and Inhibits Apoptosis of Cervical Epithelial and Stromal Cells Is Greatest during Late Pregnancy in Rats
Authors: Lee Hyung-Yul , Zhao Shuangping , Fields P. A. , Sherwood O. D.
Published: October 2004

Relaxin promotes marked growth of the cervix during the second half of rat pregnancy, and this growth is accompanied by an increase in both epithelial and stromal cells. The objective of this study was to test the hypothesis that the extent to which relaxin promotes proliferation and inhibits apoptosis of cervical cells is greatest during late pregnancy in rats. The influence of neutralization of circulating relaxin by iv injection of 5 mg monoclonal antibody against rat relaxin (MCA1) was examined at 3-d intervals throughout the second half of pregnancy. Controls were injected with either 5 mg monoclonal antibody against fluorescein or 0.5 ml PBS vehicle. To evaluate cell proliferation, 5′-bromo-2-deoxyuridine was injected sc 8 h before cervixes were collected. Terminal deoxynucleotidyl transferase-mediated deoxyuridine 5′-triphosphate nick end-labeling and electron microscopy were used to detect apoptotic cells. Neutralization of relaxin with MCA1 decreased the rate of proliferation and increased the rate of apoptosis of cervical cells by d 13. However, the extent to which relaxin influenced these processes was greatest and dramatic by late pregnancy. In MCA1-treated rats on d 22 of pregnancy, the rates of proliferation of both epithelial and stromal cells were less than 20% those in controls, and the rates of apoptosis in epithelial cells and stromal cells were more than 10- and 3-fold, respectively, greater than those in controls. In conclusion, this study provides evidence that the extent to which relaxin promotes proliferation and inhibits apoptosis of cervical epithelial and stromal cells is greatest during late pregnancy.
Bisphenol-A, an Environmental Contaminant that Acts as a Thyroid Hormone Receptor Antagonist in Vitro, Increases Serum Thyroxine, and Alters RC3/Neurogranin Expression in the Developing Rat Brain
Authors: Zoeller R. Thomas , Bansal Ruby , Parris Colleen
Published: October 2004

Considering the importance of thyroid hormone (TH) in brain development, it is of potential concern that a wide variety of environmental chemicals can interfere with thyroid function or, perhaps of greater concern, with TH action at its receptor (TR). Recently bisphenol-A (BPA, 4,4′ isopropylidenediphenol) was reported to bind to the rat TR and act as an antagonist in vitro. BPA is a high production volume chemical, with more than 800 million kg of BPA produced annually in the United States alone. It is detectable in serum of pregnant women and cord serum taken at birth; is 5-fold higher in amniotic fluid at 15–18 wk gestation, compared with maternal serum; and was found in concentrations of up to 100 ng/g in placenta. Thus, the human population is widely exposed to BPA and it appears to accumulate in the fetus. We now report that dietary exposure to BPA of Sprague Dawley rats during pregnancy and lactation causes an increase in serum total T4 in pups on postnatal d 15, but serum TSH was not different from controls. The expression of the TH-responsive gene RC3/neurogranin, measured by in situ hybridization, was significantly up-regulated by BPA in the dentate gyrus. These findings suggest that BPA acts as a TH antagonist on the β-TR, which mediates the negative feedback effect of TH on the pituitary gland, but that BPA is less effective at antagonizing TH on the α-TR, leaving TRα-mediated events to respond to elevated T4.
Computer aided stress analysis of fellow's gear-shaping cutter at different stages of a cutting stroke
Authors: Datta P P , Chattopadhyay T K , Banerjee R N
Published: October 2004

Achieving maximum efficiency (in terms of the quantity of products produced in a stipulated time) with improved accuracy and surface finish through chatter-free high-speed cutting processes are among the challenges of the current gear cutting industry. Modern techniques usually employ generating type of cutters, such as Fellow's gear-shaping cutter, for the production of high-speed low-noise accurate gears. A literature review has indicated that experimental and theoretical methods had been predominantly used in the design of gear cutting tools, compared with computer-aided methods. In this research a gear-shaping cutter for spur gears is modelled using three-dimensional ten-node tetrahedral finite elements. The stress values on the gear-shaping cutter are calculated at different instants of a cutting stroke, assuming different loading conditions. The analysis of stress distribution due to the varying force distribution on the gear cutter edges, for the same cutting and process parameters during the generation process, is believed to be new to the literature.
Predicting flow localization and formability of aluminium alloy sheets
Authors: Aghaie-Khafri M
Published: October 2004

In the present investigation, limit strains are calculated on the basis of the yield criterion proposed by Hosford for sheets having planar isotropy in conjunction with the Vocé, the Tian-Zhang and the power-law material constitutive equations. The model is capable of predicting the limit strains achievable during a uniaxial tension test and also the left-hand side of forming limit curves. Therefore it can be only applied to deformation mode in which one in-plane strain is compressive and the other is tensile. Results from this analysis are compared with the experimental data for AA3105 and AA8011 aluminium alloys. The results indicate good predictions of limit strains for the two alloys when stress-strain data from tensile tests are fitted to the Vocé and the Tian-Zhang equations.
Analysis of surface roughness for parts formed by computer numerical controlled incremental forming
Authors: Hagan E , Jeswiet J
Published: October 2004

Surface roughness tests were performed on computer numerical controlled (CNC) incrementally formed sheet metal parts using various tool depth increments and spindle speeds. A non-contact method using white light interferometry was selected to avoid scratching the material surface. All parts were formed from annealed Al 3003 sheet to a shape with a flat 45° wall section for testing. A relationship was defined between peak-to-valley roughness and depth increment, which was then compared to theory for shear forming. The surface quality of modern incremental methods and shear forming was shown to depend on similar settings, and the defined relationship allows for knowledgeable control of surface roughness in future work on such applications as reflective surfaces.
Feasibility study of friction stir welding of 6061-T6 aluminium alloy with AISI 1018 steel
Authors: Jiang W H , Kovacevic R
Published: October 2004

The present work demonstrates that friction stir welding (FSW) is a feasible route for joining 6061 aluminium (Al) alloy to AISI 1018 steel. The weld has a good weld quality and is free of cracks and porosity. The tensile failure happened at the boundary between the nugget and thermomechanically affected zone of the base Al alloy, indicating that the weld has a higher joining strength. Despite the fact that the hardness fluctuates strongly within the nugget, the average hardness of the nugget is substantially higher than that of the base Al alloy. During FSW, localized melting of the Al alloy in the nugget occurred, and the molten Al alloy reacted strongly with steel pieces spread through the nugget, which resulted in the formation of the Al-Fe intermetallic compounds, Al13Fe4 and Al5Fe2. The nugget consists of secondary phases including coarse steel pieces and Al-Fe intermetallic compounds, and an Al alloy matrix. These secondary phases contribute to the hardness of the weld.
An innovative methodology to improve the design and the performance of direct injection diesel engines
Authors: de Risi A , Donateo T , Laforgia D
Published: October 2004

The present investigation aims at defining a new methodology to analyse the effect of combustion chamber shape and injection strategy on diesel engine emissions and to find an optimized configuration to reduce NOx, soot and HC without significantly decreasing engine performance. This was achieved by using a multistep optimization process based on genetic algorithms. The first step was related to the optimization of combustion chamber shape for a fixed injection strategy. The optimization was firstly performed with respect to a single-pulse injection strategy and a six-hole injector design. Then the process was repeated for an innovative injection strategy characterized by the injection of a relevant quantity of fuel far from top dead centre (large early injection) and a seven-hole injector. The combustion chamber shape was defined according to five geometric parameters, whose ranges of variation were very wide. For all the investigated configurations, the bowl volume and squish-bowl volume ratio were kept constant so that the compression ratio was the same for all the investigated chambers. The spray injection angle was also considered as a variable parameter. The optimization was simultaneously performed for different engine operating conditions, i.e. load and speed values, weighted according to their occurrence in the European Driving Test. From the results of this step, an optimized chamber configuration was selected and, at the same time, the effect of each geometric characteristic on NOx and soot emissions was underlined. In the second step, the combustion chamber shape was kept constant and the optimization process was aimed at identifying an optimized injection strategy for a fixed engine operating mode. Injection pressure, pilot and main advances and pilot energizing time were considered as input for the second step of the optimization process.

The numerical tools used in the investigation include a modified version of the KIVA-3V code and a multiobjective genetic algorithm. The code capability to simulate engine performance was assessed by comparing numerical results with experimental data available for the baseline engine configuration. Three fitness functions were defined according to engine emission levels (soot, NOx and HC) and a penalty function was used to account for engine performance and fuel consumption.
Measuring Factors Underlying Intendedness Of Women's First and Later Pregnancies
Authors: Speizer Ilene S. , Santelli John S. , Afable‐Munsuz Aimee , Kendall Carl
Published: October 2004

CONTEXT: Unintended pregnancy is associated with poor health outcomes for mothers and infants, and is indicative of gaps in family planning services. Conventional measures of pregnancy intendedness do not reflect the multiple factors affecting a woman's pregnancy‐related intentions and attitudes

METHODS: Data collected between March 2002 and February 2003 from 701 women in a public family planning clinic and 671 women in a public prenatal clinic in New Orleans were analyzed to examine factors underlying intendedness (including attitudes toward pregnancy and motivations to achieve or avoid pregnancy)

RESULTS: In factor analyses, variables measuring pregnancy intendedness were represented by a single latent factor, pregnancy desirability. For first pregnancy, variables that best captured desirability were those measuring happiness, effort in achieving the pregnancy, extent of looking forward to telling friends, whether the pregnancy was intended (i.e., came at the right time or later), and whether the woman wanted to have a baby with her partner. For last or current pregnancies that were second or higher order ones, they were happiness, pregnancy wantedness, effort in achieving the pregnancy, whether the pregnancy was planned and whether the woman wanted to have a baby with her partner. Among women younger than 18 at first pregnancy, happiness and whether a woman wanted a baby with her partner were the only items that captured pregnancy desirability

CONCLUSIONS Future surveys on pregnancy intendedness could reduce the number of questions used to capture pregnancy desirability. This should help standardize surveillance systems and permit better assessment of trends in pregnancy desirability over time
Operomics: Molecular Analysis of Tissues from DNA to RNA to Protein
Authors: Hanash Samir M.
Published: October 2004

The identification of coding sequences in a number of species, including human in the near future, has ushered in the post-genome era. In this era, technologies are becoming available that allow the profiling of tissues and cell populations at the genomic, transcriptomic and proteomic levels. The molecular analysis of tissues at all three levels has been referred to as operomics. This review covers some basic technologies for operomics and their application to some lymphoid disorders. It is proposed that no one type of analysis is fully informative and that information that can be derived from the different compartments encompassed in operomics is complementary. Prospects for introducing such profiling technologies into the clinical laboratory will depend on their robustness, their user friendliness and the clinical relevance of the added information they provide, which cannot be captured through other technologies in use in the clinical laboratory.
Idiosyncratic Reactions to Drugs: Can Medicine Response Profiles Provide a Dynamic Drug Surveillance System?
Authors: Roses Allen D.
Published: October 2004

Over the next few years it will be possible to use advances
in single nucleotide polymorphism map technology
to correlate information from patients' DNA
with their response to medicines. This provides significant
opportunities to enhance current drug surveillance
systems by collecting data that would enable
rare serious adverse events to be predicted in subsequent
patients before the medicine is prescribed. Reasonable
discussion regarding perceived or real barriers
to this surveillance concept is required to realize the
significant patient benefits which will accrue from this
system.
Familial Studies on the Genetics of Cardiovascular Diseases: the Stanislas Cohort
Authors: Visvikis Sophie , Sass Catherine , Pallaud Celine , Grow Michael A. , Zannad Faiez , Siest Gérard , Erlich Henry A. , Cheng Suzanne
Published: October 2004

In a given individual, the level of cardiovascular risk results
from the combination of and interactions between
genetic and environmental components. We
choose to investigate segregation analysis of intermediate
phenotypes in healthy nuclear families, belonging
to the Stanislas cohort, a large familial cohort
composed of 1006 families, which will be followed for
10 years. We developed a panel of 35 genetic markers
including genes involved in lipid metabolism, regulation
of blood pressure, thrombosis, platelet function,
and endothelial cell adhesion. The allele frequencies of
the studied polymorphisms were in agreement with
those reported in other Caucasian populations. As an
example of segregation analysis, we investigated
carotid intima-media thickness (CIMT) variability in a
subset sample of the Stanislas cohort. We found that
about 30% of CIMT variability was attributable to genetic
factors. Associations between CIMT and polymorphisms
in apo CIII, cholesteryl ester transfer protein,
methylene tetrahydrofolate reductase, and
fibrinogen genes were observed and explained about
20% of CIMT variability in men. Furthermore, as another
example of association studies, we investigated
the relations between E-selectin polymorphisms and
blood pressure interindividual variability and longitudinal
changes in unrelated adults of this familial population.
The E-selectin Phe554 allele was found associated
with lower systolic blood pressure and diastolic
blood pressure.
Quantitative PCR
Authors: Jung Roman , Soondrum Krishna , Neumaier Michael
Published: October 2004

The classic molecular biology methods like Northern
or Southern blot analyse non-amplified DNA or RNA,
but need large amounts of nucleic acids, in many instances
from tissues or cells that are heterogeneous.
In contrast, polymerase chain reaction (PCR)-based
techniques allow us to obtain genetic information
through the specific amplification of nucleic acid sequences
starting with a very low number of target
copies. These reactions are characterized by a logarithmic
amplification of the target sequences i.e. increase
of PCR copies followed by a plateau phase
showing a rapid decrease to zero of copy number increment
per cycle. Accordingly, the amount of specific
DNA product at the end of the PCR run bears no correlation
to the number of target copies present in the
original specimen. However, many applications in
medicine or research require quantification of the
number of specific targets in the specimen. This has
generated a rapidly increasing need for the development
of quantitative PCR techniques. Prominent examples
are the determination of viral load in blood
specimens for the diagnosis of HIV or HCV infections,
the determination of changes in gene dosage through
amplification or deletion e.g. of MDR-1, erb-B2, c-myc
or the loss of heterozygosity in general. Finally, the
analysis of gene expression on the mRNA level does
require quantitative approaches to reverse transcriptase
PCR, e.g. for studies in morphogenesis or the profiling
of cancer cells. Recent advances in technology allow
detection of the increment per cycle of a
specifically generated PCR product in “real-time
mode”. Together with the new powerful methods to
dissect heterogeneous tissues or fractionate bodily
fluids, this now sets the stage for a detailed analysis
not only of the genes and genetic changes within a single
cell, but also of the use such cell makes of its genes
e.g. in pharmacogenomics. Examples of recent developments
of the technology and their applications will
be given.
Apolipoprotein E Polymorphisms and Concentration in Chronic Diseases and Drug Responses
Authors: Siest Gérard , Bertrand Philippe , Herbeth Bernard , Vincent-Viry Monique , Schiele Françoise , Sass Catherine , Visvikis Sophie
Published: October 2004

Apolipoprotein (apo) E is an important circulating and
tissue protein involved in cholesterol homeostasis and
many other functions. The common polymorphism in
the coding region of the gene, four polymorphisms in
the promoter region, other additional single nucleotide
polymorphisms, as well as several apo E variants
have been identified. The common coding polymorphism
strongly influences the lipid metabolism
and the circulating concentration of apo E itself. This
polymorphism is at the origin of the implication of apo
E in cardiovascular and neurodegenerative diseases,
but also of the relation of apo E with longevity. Probably
due to its many metabolic and functional consequences,
apo E polymorphism has been shown to influence
the responses of patients to several drugs
(fibrates, statins, hormone replacement therapy, anti-Alzheimer drugs) or environmental interventions
(black tea, alcohol, diet). Apo E genotyping may be
clinically helpful in defining the risk of patients and
their responses to therapeutics. Finally, circulating apo
E concentration appears to be altered in diseases and
can be modulated by some of the drugs cited above.
This parameter can thus also give interesting clinical
information and could be a therapeutic target, providing
it is validated. At the present time, we cannot exclude
that apo E concentration may be the most
prominent apo E parameter to be considered in health
and disease, while apo E polymorphisms would represent
only secondary parameters influencing apo E concentration.
Angiotensin I-Converting Enzyme Gene Polymorphism and Drug Response
Authors: Baudin Bruno
Published: October 2004

An insertion/deletion (I/D) polymorphism of the angiotensin
I-converting enzyme (ACE) gene has been
described in chromosome 17q23 of the human
genome. Subjects with the genotype DD have
markedly higher plasma ACE levels than those with
genotype II; although ACE concentration in plasma is
not rate-limiting for the production of angiotensin II, it
has been suggested that the renin-angiotensin system
may have an enhanced role in cardiovascular homeostasis
in subjects with DD genotype or D allele. Metaanalysis
confirmed the association of the D allele with
an increased risk of myocardial infarction and stroke,
but these relations are still uncertain with longevity
and renal deterioration. Otherwise, I allele seems to be
related with an improved response to physical training.
The I/D polymorphism of the ACE gene is not a
marker for any form of hypertension, though some
conflicting results have been described. Nevertheless
this polymorphism may have an influence on the antihypertensive
response, particularly when using ACE
inhibitors (ACEI). For example, blood pressure normalization
with captopril in patients suffering from cardiac
failure would be more effective in II genotype;
conversely, both regression in left ventricular hypertrophy
and improvement in diastolic filling would be
greater after long-term treatment with enalapril in patients
with essential hypertension and DD genotype.
Conflicting results were also described using ACEI as a
renoprotective therapy. This review therefore supports
the justification for further evaluation in appropriately
powered studies.
Database Analysis and Gene Discovery in Pharmacogenetics
Authors: Board Philip , Tetlow Natasha , Blackburn Anneke , Chelvanayagam Gareth
Published: October 2004

The global genome research effort has resulted in the creation of extensive DNA and protein sequence databases that are a valuable resource for the identification of new genes and polymorphic variants of enzymes of pharmacogenetic interest. Previously undescribed members of gene families with novel functions and substrate specificities can be identified by database searching and sequence alignment strategies. Since the expressed sequence tag (EST) database contains sequences from many individuals, it can be searched for evidence of polymorphisms that can significantly influence enzyme function. The different approaches to these forms of analysis are reviewed and illustrated with examples from the glutathione transferase gene family.
Polymorphisms in UDP Glucuronosyltransferase Genes: Functional Consequences and Clinical Relevance
Authors: Mackenzie Peter I. , Miners John O. , McKinnon Ross A.
Published: October 2004

As glucuronidation is a major process for the metabolism
and removal of lipophilic chemicals, polymorphic
variations in genes encoding the enzymes involved in
this process, the UDP glucuronosyltransferases (UGT),
may have a significant impact on our capacity to
detoxify and eliminate drugs and toxins. Although 24
human UGT genes have been identified to date, only
polymorphisms in five UGTs, viz. UGT1A1, UGT1A6,
UGT2B4, UGT2B7 and UGT2B15 have been described.
Polymorphisms in UGT1A1, the major bilirubin-glucuronidating
form, often result in a decreased capacity
to glucuronidate bilirubin, such as observed in Gilbert
Syndrome and some forms of perinatal jaundice. The
frequencies of individual UGT1A1 polymorphisms
show extensive variability across ethnic groups. Two
variants of UGT1A6 and UGT2B4 and one variant of
UGT2B7 and UGT2B15 have been identified. However,
the clinical significance of these variants is unclear.
More UGT polymorphisms will undoubtedly be discovered
when the human genome is sequenced. However,
unless the UGT in question is responsible for the
exclusive metabolism of a particular drug or chemical
(e.g. UGT1A1 and bilirubin) or is the predominant or
only UGT present in the cell, it is unlikely that these
polymorphisms will be of major clinical significance.