bluuebunny/crossref_metadata_2025 huggingface dataset:
Large eddy simulation (2D) using diffusion–velocity method and vortex‐in‐cell
Authors: Milane R. E.
Published: February 2004

A large eddy Simulation based on the diffusion‐velocity method and the discrete vortex method is presented. The vorticity‐based and eddy viscosity type subgrid scale model simulating the enstrophy transfer between the large and small scale appears as a convective term in the diffusion‐velocity formulation. The methodology has been tested on a spatially growing mixing layer using the two‐dimensional vortex‐in‐cell method and the Smagorinsky subgrid scale model. The effects on the vorticity contours, momemtum thickness, mean streamwise velocity profiles, root‐mean‐square velocity and vorticity fluctuations and negative cross‐stream correlation are discussed. Comparison is made with experiment and numerical work where diffusion is simulated using random walk. Copyright © 2004 John Wiley & Sons, Ltd.
Numerical analysis of the rotating viscous flow approaching a solid sphere
Authors: Wang Yan‐Xing , Lu Xi‐Yun , Zhuang Li‐Xian
Published: February 2004

A numerical simulation is performed to investigate the flow induced by a sphere moving along the axis of a rotating cylindrical container filled with the viscous fluid. Three‐dimensional incompressible Navier–Stokes equations are solved using a finite element method. The objective of this study is to examine the feature of waves generated by the Coriolis force at moderate Rossby numbers and that to what extent the Taylor–Proudman theorem is valid for the viscous rotating flow at small Rossby number and large Reynolds number. Calculations have been undertaken at the Rossby numbers (Ro) of 1 and 0.02 and the Reynolds numbers (Re) of 200 and 500. When Ro=O(1), inertia waves are exhibited in the rotating flow past a sphere. The effects of the Reynolds number and the ratio of the radius of the sphere and that of the rotating cylinder on the flow structure are examined. When Ro ≪ 1, as predicted by the Taylor–Proudman theorem for inviscid flow, the so‐called ‘Taylor column’ is also generated in the viscous fluid flow after an evolutionary course of vortical flow structures. The initial evolution and final formation of the ‘Taylor column’ are exhibited. According to the present calculation, it has been verified that major theoretical statement about the rotating flow of the inviscid fluid may still approximately predict the rotating flow structure of the viscous fluid in a certain regime of the Reynolds number. Copyright © 2004 John Wiley & Sons, Ltd.
Effect of corner angle on convection enhancement in wavy ducts with trapezoidal cross‐sections
Authors: Savino S. , Comini G. , Nonino C.
Published: February 2004

The effect of corner angle variations on pressure drop and heat transfer characteristics is investigated in the fully developed region of wavy ducts with trapezoidal cross‐sections. The resulting enhancement of convection, with respect to corresponding straight ducts, can be attributed to the formation of longitudinal vortices close to the two parallel surfaces. Numerical simulations show that Nusselt numbers and friction factors increase with the decrease of corner angle from 90 to 60°, before levelling out around 60°. Nusselt numbers and friction factors also increase with the Reynolds number, and the slopes of their representative curves increase above a critical value of the Reynolds number because of the onset of time‐periodic flow oscillations. Copyright © 2004 John Wiley & Sons, Ltd.
Daphnia response to predation threat involves heat‐shock proteins and the actin and tubulin cytoskeleton
Authors: Pijanowska Joanna , Kloc Malgorzata
Published: February 2004

Of all the environmental pressures that all organisms across all kingdoms must face, one of the greatest is the risk of predation. The unpredictability of predation events from the perspective of a single individual is one of the major components of a changing, unstable environment (Gliwicz and Pijanowska, 1989; Lampert, 1987). The panoply of antipredator defenses among terrestrial and aquatic organisms involves a variety of morphological, behavioral, and life‐history adaptations that even if they are not life‐saving, may enable organisms to complete reproduction before predation occurs. Most of these phenotypic changes are directly induced by cues associated with the biotic agent, in the case of aquatic organisms, the chemical compounds (kairomones) released by a predator into the water. Herein we show that exposure of Daphnia to invertebrate and vertebrate kairomones results in changes in motion, behavior, and life history and at the molecular level involves changes in heat‐shock proteins (HSPs) level and the actin and tubulin cytoskeleton. In addition, some of these effects are transgenerational, i.e., they are passed on from the mother to her offspring. genesis 38:81–86, 2004. © 2004 Wiley‐Liss, Inc.
Movement of calmodulin between cells in the ovary and embryo of drosophila
Authors: Andruss Bernard F. , Bolduc Clare , Beckingham Kathy
Published: February 2004

Summary: Calmodulin (CaM) is an essential component of calcium signaling in multicellular organisms. We used null mutations of the Drosophila CaM gene (Cam) in combination with clonal analysis and immunolocalization to examine the effects of loss of Cam function in the ovarian germline and developing embryo. These studies have uncovered unexpected and striking movements of CaM protein within these tissues. In the ovary, evidence for transfer of CaM from an external source, across plasma membranes, into the germline cells was obtained. In late embryogenesis, maternally derived CaM protein relocalizes dramatically within the nervous system of both wildtype and Cam null embryos‐a process that may also involve movement across cell membranes. These findings indicate dynamic, unsuspected elements to the in vivo functions of CaM in the whole organism. genesis 38:93–103, 2004. Published 2004 Wiley‐Liss, Inc.
Elk‐1 knock‐out mice engineered by Flp recombinase‐mediated cassette exchange
Authors: Cesari Francesca , Rennekampff Verena , Vintersten Kristina , Giang Vuong Lam , Seibler Jost , Bode Jürgen , Wiebel Franziska F. , Nordheim Alfred
Published: February 2004

Elk‐1 is a member of the TCF subfamily of Ets proteins. TCFs interact with SRF at serum response elements (SREs) of immediate early genes (IEGs), such as c‐fos and Egr‐1, thereby mediating IEG induction upon extracellular stimulation. We previously generated an Elk‐1 null allele (Elk1‐137) in murine embryonic stem (ES) cells by homologous recombination. In Elk1‐137, the Elk‐1 gene was replaced by a Hygromycin B phosphotransferase – Thymidine Kinase (HygTk) fusion gene, flanked by two nonidentical Flp recombinase recognition (FRT) sites (Cesari et al., [2004] Mol Cell Biol, in press) to allow for the subsequent generation of alternative alleles of interest by recombinase‐mediated cassette exchange (RMCE). Elk1‐deficient mice derived from Elk‐1(137/0) ES cells are viable and do not reveal strong phenotypical abnormalities, apart from male sterility. However, the Elk‐1 locus contains the Tk cassette, which has previously been related to this defect. Therefore, in our first experiment involving the technique of Flp RMCE we chose to remove the HygTk cassette in Elk‐1(137/0) ES cells and to generate Elk‐1(RMCE16/0) and Elk‐1(RMCE16/RMCE16) mice. In so doing, we provide evidence that the sterility of Elk1(137/0) mice was not due to the absence of Elk‐1 but rather the presence of HygTk. This is the first report of mice derived from ES cells which were subjected to Flp RMCE and thus proves that RMCE is a powerful tool for the genetic engineering of previously tagged loci in the mouse genome. genesis 38:87–92, 2004. © 2004 Wiley‐Liss, Inc.
Expression of AmphiCoe, an amphioxus COE/EBF gene, in the developing central nervous system and epidermal sensory neurons
Authors: Mazet Françoise , Masood Samia , Luke Graham N. , Holland Nicholas D. , Shimeld Sebastian M.
Published: February 2004

Summary: The COE/EBF gene family marks a subset of prospective neurons in the vertebrate central and peripheral nervous system, including neurons deriving from some ectodermal placodes. Since placodes are often considered unique to vertebrates, we have characterised an amphioxus COE/EBF gene with the aim of using it as a marker to examine the timing and location of peripheral neuron differentiation. A single COE/EBF family member, AmphiCoe, was isolated from the amphioxus Branchiostoma floridae. AmphiCoe lies basal to the vertebrate COE/EBF genes in molecular phylogenetic analysis, suggesting that the duplications that formed the vertebrate COE/EBF family were specific to the vertebrate lineage. AmphiCoe is expressed in the central nervous system and in a small number of scattered ectodermal cells on the flanks of neurulae stage embryos. These cells become at least largely recessed beneath the ectoderm. Scanning electron microscopy was used to examine embryos in which the ectoderm had been partially peeled away. This revealed that these cells have neuronal morphology, and we infer that they are the precursors of epidermal primary sensory neurons. These characters lead us to suggest that differentiation of some ectodermal cells into sensory neurons with a tendency to sink beneath the embryonic surface represents a primitive feature that has become incorporated into placodes during vertebrate evolution. genesis 38:58–65, 2004. © 2004 Wiley‐Liss, Inc.
Effects of a combined extract of Ginkgo biloba and Bacopa monniera on cognitive function in healthy humans
Authors: Nathan Pradeep J. , Tanner Sally , Lloyd Jenny , Harrison Ben , Curran Leah , Oliver Chris , Stough Con
Published: February 2004

Extracts of Ginkgo biloba and Bacopa monniera have been shown to produce positive effects on cognitive function in healthy subjects. While the exact mechanisms are not known, it has been suggested that antioxidant properties and cholinergic modulation may play a role. In the current study the sub‐chronic (2 weeks) and chronic (4 weeks) effects of an extract containing Ginkgo biloba (120 mg) and Bacopa monniera (300 mg) (Blackmores Ginkgo Brahmi) on cognitive function were examined. The study was a randomized, double‐blind, placebo‐controlled, independent group design in which 85 healthy subjects were allocated to one of two treatment conditions (placebo or combined Ginkgo biloba and Bacopa monniera extract). Testing was conducted at baseline and 2 and 4 weeks post treatment. The results showed that the combined extract relative to placebo did not demonstrate any significant effects on tests investigating a range of cognitive processes including attention, short‐term and working memory, verbal learning, memory consolidation, executive processes, planning and problem solving, information processing speed, motor responsiveness and decision making. These findings suggest that at least within the current treatment duration and doses, an extract containing Ginkgo biloba and Bacopa monniera had no cognitive enhancing effects in healthy subjects. Copyright © 2004 John Wiley & Sons, Ltd.
Sedation, an unpleasant, undesirable and potentially dangerous side‐effect of many psychotropic drugs
Authors: Bourin Michel , Briley Mike
Published: February 2004

Sedation is a property of many psychotropic drugs. It can be defined as a decrease in psychomotor and cognitive performance. Many of the earlier neuroleptic, anxiolytic, antidepressant and antihistamine drugs were extremely sedative and sedation came to be considered as an integral part of the activity of these compounds. Newer, far less sedative, examples of each of these classes have shown that sedation is not required for their efficacy. Sedation is now increasingly considered as an adverse effect which should be avoided rather than a desirable effect especially when treating disorders such as anxiety or depression. This article discusses the sedative properties and mechanisms of different classes of psychotropic drugs. Copyright © 2004 John Wiley & Sons, Ltd.
Effects of Ginkgo biloba on alertness and chemosensory function in healthy adults
Authors: Mattes Richard D. , Pawlik M. Kate
Published: February 2004

Ginkgo biloba is reported to enhance cognitive function in patients with selected neural disorders. Its effects in healthy, young adults are less well characterized. This work explored whether Ginkgo biloba could ameliorate decrements in alertness post‐prandially and/or enhance chemosensory function. Both are functions that could be influenced by enhanced cerebral blood flow and neuronal metabolism, reported properties of the compound. A double‐blind placebo‐controlled study was conducted with 19 males and 20 females with a mean age of 23.6 ± 5.4 years and mean weight of 70.0 ± 1.9 kg. Participants were supplemented for 13 weeks with either Ginkgo biloba (mean dose 184.5 mg/d (range 130–234 mg/d)) or placebo and administered various alertness, performance, affective state and chemosensory tests at weeks 1, 5, 9 and 13. Participants did experience the post‐prandial affective state decrement (i.e. post‐lunch dip), but not the performance decrement. Performance on the chemosensory tests improved over the 13‐week study. However, Ginkgo biloba was ineffective at alleviating the symptoms of the post‐lunch dip or at enhancing taste and smell function. Copyright © 2004 John Wiley & Sons, Ltd.
Depot antipsychotic use in schizophrenia: an East Asian perspective
Authors: Sim Kang , Su Alex , Ungvari Gabor S , Fujii Senta , Yang Shu‐yu , Chong Mian‐Yoon , Si Tianmei , Chung Eun Kee , Tsang Hin‐Yeung , Chan Yiong Huak , Shinfuku Naotaka , Tan Chay Hoon
Published: February 2004

Aims

Few studies have examined the use of depot antipsychotics in East Asian patients with schizophrenia. This study examined the prevalence of depot antipsychotic use and its clinical correlates.

Methods

Across six East Asian countries and territories, 2399 patients with schizophrenia were surveyed using a standardized protocol.

Results

Depot antipsychotic medications were prescribed in 15.3% (n=368) of the patients, being the most common in Singapore, followed by Taiwan, Japan and China. Being on depot antipsychotic drugs was significantly associated with male gender (particularly in Taiwan and Japan), delusions in Japan, aggression, higher daily CPZ equivalent dose and co‐prescription of anticholinergic drugs but less likely with disorganized speech (particularly in China) and negative symptoms (particularly in Japan and Singapore). On multivariate analysis, the significant associated factors were treatment setting, younger age, longer duration of illness, aggression and the lack of use of an oral, atypical antipsychotic.

Conclusion

There was a wide variation in the prevalence of depot antipsychotic prescription, suggesting that it may not be guided by any recognizable principles and is more likely determined by local traditions and prescription culture. There is a need to re‐examine the risk–benefit profile of each patient before deciding on the initiation or continuation of depot antipsychotic medication. Copyright © 2004 John Wiley & Sons, Ltd.
Breakdown of the regulatory control of pyrimidine biosynthesis in human breast cancer cells
Authors: Sigoillot Frederic D. , Sigoillot Severine M. , Guy Hedeel I.
Published: February 2004

The activity of the de novo pyrimidine biosynthetic pathway in the MCF7 breast cancer cells was 4.4‐fold higher than that in normal MCF10A breast cells. Moreover, while pyrimidine biosynthesis in MCF10A was tightly regulated, increasing as the culture matured and subsequently down‐regulated in confluency, the biosynthetic rate in MCF7 cells remained elevated and invariant in all growth phases. The flux through the pathway is regulated by carbamoyl phosphate synthetase, a component of the multifunctional protein, CAD. The intracellular CAD concentration was 3.5‐ to 4‐fold higher in MCF7 cells, an observation that explains the high rate of pyrimidine biosynthesis but cannot account for the lack of growth‐dependent regulation. In MCF10A cells, up‐regulation of the pathway in the exponential growth phase resulted from MAP kinase phosphorylation of CAD Thr456. The pathway was subsequently down‐regulated by dephosphorylation of P∼Thr456 and the phosphorylation of CAD by PKA. In contrast, the CAD P∼Thr456 was persistently phosphorylated in MCF7 cells, while the PKA site remained unphosphorylated and consequently the activity of the pathway was elevated in all growth phases. In support of this interpretation, inhibition of MAP kinase in MCF7 cells decreased CAD P∼Thr456, increased PKA phosphorylation and decreased pyrimidine biosynthesis. Conversely, transfection of MCF10A with constructs that elevated MAP kinase activity increased CAD P∼Thr456 and the pyrimidine biosynthetic rate. The differences in the CAD phosphorylation state responsible for unregulated pyrimidine biosynthesis in MCF7 cells are likely to be a consequence of the elevated MAP kinase activity and the antagonism between MAP kinase‐ and PKA‐mediated phosphorylations. © 2004 Wiley‐Liss, Inc.
Identification of interleukin‐8 as estrogen receptor‐regulated factor involved in breast cancer invasion and angiogenesis by protein arrays
Authors: Lin Ying , Huang Ruochun , Chen Lipai , Li Shiyong , Shi Qian , Jordan Craig , Huang Ruo‐Pan
Published: February 2004

With the goal of identifying key factors involved in human breast cancer progression, we applied human cytokine antibody arrays we have developed to screen cytokine expression levels in human breast cancer cell lines and identified interleukin (IL)‐8 as a key factor involved in breast cancer invasion and angiogenesis. Elevated expression of IL‐8 in breast cancer cells was associated with breast cancer invasiveness and angiogenesis. Neutralization of antibody against IL‐8 specifically blocked IL‐8‐mediated tumor cell invasion and angiogenesis. Furthermore, IL‐8 levels in human breast cancer cells were closely related to estrogen receptor (ER) status. ER positive cells expressed low levels of IL‐8 whereas ER negative cells expressed high levels of IL‐8. Expression of exogenous ERα substantially inhibited IL‐8 expression. Our findings raise intriguing questions regarding the role of IL‐8 in the development and progression of human breast cancer in association with ER status. © 2004 Wiley‐Liss, Inc.
Loss of p16INK4a expression is associated with vascular endothelial growth factor expression in squamous cell carcinoma of the esophagus
Authors: Takeuchi Hiroya , Ozawa Soji , Shih Chih‐Horng , Ando Nobutoshi , Kitagawa Yuko , Ueda Masakazu , Kitajima Masaki
Published: February 2004

Vascular endothelial growth factor (VEGF) expression has been suggested to correlate with intratumoral microvessel density, tumor advancement and prognosis in esophageal squamous cell carcinoma (ESCC). Previous studies have showed that disruption of cell cycle regulator p16 is related to oncogenesis and tumor progression in ESCC. We hypothesized that VEGF expression in ESCC is reflected by abnormalities in the p16INK4a gene. To clarify the regulatory role of p16INK4a in VEGF expression in vitro, we transferred the p16INK4a gene into a p16INK4a‐deleted ESCC cell line and observed changes in VEGF expression. Furthermore, we immunohistochemically assessed the expression of the cell cycle regulators (p16, p53 and RB) and VEGF in 90 surgically resected specimens of ESCC. Introduction of p16INK4a cDNA by the p16 expression vector significantly suppressed cell proliferation in the p16INK4a‐deleted cell line TE8 (p < 0.0001). VEGF secretion by TE8 cells transfected with the p16INK4a vector was significantly suppressed as compared to non‐transfected TE8 cells (p < 0.0001) and TE8 cells transfected with a control vector (p = 0.0015). The immunohistochemical studies of ESCC primary tumor specimens showed that loss of p16 expression was significantly correlated with VEGF‐positive expression (p = 0.0004). The cumulative postoperative survival rate in the group with p16‐positive and VEGF‐negative expression was significantly higher than in the other groups. Neither p53 nor RB expression had any impact on outcome. Aberrant p53 expression tended to be associated with VEGF expression, but the trend did not reach statistical significance. Our study demonstrated that VEGF expression was correlated with p16 expression in ESCC. Our results suggest that p16 may have a regulatory role in VEGF expression in ESCC. © 2004 Wiley‐Liss, Inc.
Tumor skewing of CD34+ progenitor cell differentiation into endothelial cells
Authors: Young M. Rita I.
Published: February 2004

Tumor production of granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) results in the mobilization of CD34+ progenitor cells into the peripheral blood and tumor tissue. Using the Lewis lung carcinoma (LLC) model, in vitro studies showed that LLC cells could chemoattract CD34+ cells predominantly through tumor production of VEGF. Addition of LLC‐conditioned medium to CD34+ cells that were cultured under conditions that support myeloid lineage cells skewed the differentiation of these precursor cells toward endothelial cells expressing CD31 and CD144. This differentiation of CD34+ cells toward endothelial cells was attributed predominantly to angiopoietin‐1 in the tumor‐conditioned medium. The CD34+ cells expressed the angiopoietin receptor Tie‐2 and their differentiation into endothelial cells was blocked with neutralizing angiopoietin‐1 antibodies. In vivo studies showed that infusion of lacZ+ CD34+ cells from the bone marrow of transgenic mice into wild‐type mice bearing LLC tumors resulted in the accumulation of lacZ+ cells within the tumor mass, particularly at the tumor's periphery. That these infused CD34+ progenitor cells could develop into endothelial cells of the tumor vasculature was supported by their acquisition of the endothelial cell markers CD31 or CD144 within the tumor tissue. These studies demonstrate the capacity of tumor to attract CD34+ cells to the tumor site and to direct the differentiation of these CD34+ cells into endothelial cells that can become a component of the tumor vasculature. © 2004 Wiley‐Liss, Inc.
Combined 90Yttrium‐DOTA‐labeled PAM4 antibody radioimmunotherapy and gemcitabine radiosensitization for the treatment of a human pancreatic cancer xenograft
Authors: Gold David V. , Modrak David E. , Schutsky Keith , Cardillo Thomas M.
Published: February 2004

We have examined the application of 90Y‐DOTA‐cPAM4, anti‐MUC1 IgG, in combination with the front‐line drug gemcitabine as a potential therapeutic for pancreatic cancer. Athymic nude mice bearing CaPan1 human pancreatic cancer xenografts were administered 2 mg of gemcitabine on days 0, 3, 6, 9 and 12 with concurrent 90Y‐DOTA‐cPAM4 (100 μCi) provided on day 0. A second group of mice received a second cycle of treatment 5 weeks after the start of the first cycle. Control groups of mice included those that received either treatment arm alone, the combined modality treatment employing a nontargeting control antibody (hLL2, anti‐B‐cell lymphoma) and a final group that was left untreated. Gemcitabine administered as a single agent provided no antitumor effect. A single cycle of the combined 90Y‐DOTA‐cPAM4 and gemcitabine treatment provided greater inhibition of tumor growth than was observed for any of the other treatment procedures. Tumor growth was delayed for a period of 7 weeks. Two cycles of gemcitabine with concomitant 90Y‐DOTA‐cPAM4 yielded significant tumor regression and increased median survival to 21 weeks vs. 12 weeks for mice receiving a single cycle of therapy (p<0.024). Median tumor volume doubling‐times were 18 weeks in mice treated with 2‐cycles of therapy vs. 7 weeks in mice given only 1‐cycle (p<0.001), and 3.5 weeks for the group that received 2‐cycles of gemcitabine concomitant with equitoxic nontargeting 90Y‐DOTA‐hLL2 (p<0.001). These data suggest that addition of 90Y‐DOTA‐cPAM4 RAIT to a gemcitabine treatment regimen may provide enhanced antitumor efficacy for the treatment of pancreatic cancer. © 2004 Wiley‐Liss, Inc.
Combined effects of cyclooxygenase‐1 and cyclooxygenase‐2 selective inhibitors on intestinal tumorigenesis in adenomatous polyposis coli gene knockout mice
Authors: Kitamura Tomohiro , Itoh Masaki , Noda Tetsuo , Matsuura Mamoru , Wakabayashi Keiji
Published: February 2004

As with cyclooxygenase (COX)‐2, genetic disruption of COX‐1 gene or pharmacologic inhibition of its activity has been shown to decrease the number of intestinal polyps in Apc gene‐deficient mice. The present study was designed to investigate the combined effects of COX‐1 and COX‐2 selective inhibitors on spontaneous polyp formation in APC1309 female mice. The animals were treated with 300 or 600 ppm mofezolac (a COX‐1 selective inhibitor) alone, 200 or 400 ppm nimesulide (a COX‐2 selective inhibitor) alone, 300 ppm mofezolac plus 200 ppm nimesulide, 600 ppm mofezolac plus 400 ppm nimesulide, or 10 ppm indomethacin (a dual‐COX inhibitor) in the diet from 7 weeks of age for 4 weeks. Percentage inhibition of polyp area in the intestine was 17% with 600 ppm mofezolac alone and 25% with 400 ppm nimesulide alone, their sum of 42% being almost equal to the 37% observed for the combination treatment. Administration of 300 ppm mofezolac plus 200 ppm nimesulide also significantly decreased polyp area in the intestine by 30%. Moreover, the numbers of polyps more than 2.5 mm in diameter were markedly decreased by combined treatment of both COX inhibitors. With 10 ppm indomethacin, the dual inhibitor, polyp area was also clearly reduced by 46%. Our results indicate that COX‐1 and COX‐2 may to some extent contribute to polyp formation independently and inhibitor combination treatment thus has particular potential for chemoprevention of colon carcinogenesis. © 2004 Wiley‐Liss, Inc.
Site‐specific familial aggregation of prostate cancer
Authors: Verhage Bas A.J. , Aben Katja K.H. , Witjes J. Alfred , Straatman Huub , Schalken Jack A. , Kiemeney Lambertus A.L.M.
Published: February 2004

Over the last decade, epidemiologic evidence has accumulated in favor of a significant but heterogeneous hereditary component in prostate cancer (PC) susceptibility. In order to map and clone PC susceptibility genes, stratification of PC families into genetically homogeneous groups appears to be a key issue. Subset definition based on age at diagnosis, presumed mode of inheritance, number of affecteds per family and coaggregation of PC with other cancers has already proven successful in some studies. Previously, the finding of the coaggregation of malignancies of the central nervous system within PC families helped to link a prostate‐brain cancer susceptibility gene (CAPB) to chromosome 1p36. In this study, we evaluate the risk of PC and malignancies at other sites among first‐degree relatives of a large population‐based group of Dutch PC patients. A population‐based family case‐control study was initiated that included Caucasian PC patients newly diagnosed between July 1996 and December 1999. Information on 12,575 first‐degree relatives of 704 PC patients and 1,371 controls was collected through postal questionnaires and telephone interviews. All reported PC in first‐degree relatives was verified through medical records. In our population, PC has a strong familial component that is reflected by a 2.9‐fold increased risk (95% CI = 2.2–3.9) of PC for first‐degree relatives of PC patients. This familial risk was somewhat higher among brothers (hazard ratio = 3.9; 95% CI = 2.4–6.4) compared to fathers (hazard ratio = 2.5; 95% CI = 1.7–3.6). Cancers at other sites did not coaggregate with PC. Our data suggest that familial PC, at least in this Western European population, is site‐specific, not part of an inherited cancer syndrome. © 2004 Wiley‐Liss, Inc.
Smoking, drinking and colorectal cancer in Hong Kong Chinese: A case‐control study
Authors: Ho Judy Wai‐Chu , Lam Tai‐Hing , Tse Chun‐Wah , Chiu Leo Kai‐Ming , Lam Hoi‐San , Leung Pik‐Fung , Ng Ka‐Chun , Ho Sai‐Yin , Woo Jean , Leung Sophie Suk‐Fong , Yuen Siu‐Tsan
Published: February 2004

Expert opinions differ on the causal role of cigarettes and alcohol in colorectal cancer. This study investigates such associations in Hong Kong Chinese. A hospital‐based case‐control study was conducted from April 1998 to March 2000. Newly diagnosed colorectal adenocarcinoma and sex‐ and age‐matched inpatient controls without gastrointestinal and malignant conditions were included. Structured interviews were conducted using a validated questionnaire to study any association of smoking, drinking and the lifelong extent of such exposures with colorectal cancer risk. We successfully interviewed 822 cases and 926 controls. Current regular cigarette smokers had an increased rectal cancer risk (adjusted OR = 1.44; 95% CI = 1.001–2.06). Increasing tertiles of smoking duration in ever smokers was also associated with increased rectal cancer risk (p trend = 0.038). An increased risk of colorectal cancer was found in current drinkers (adjusted OR = 1.42; 95% CI = 1.09–1.85) and in those who drank ≥ 4 days (current and ex‐drinkers) or > 4 units (ever and ex‐drinkers) weekly. Moreover, colorectal cancer risk was found to decrease with increasing duration of drinking abstention (p trend = 0.006). This is the first report of a positive association between cigarette smoking and rectal cancer risk in a Chinese population. Current drinkers and those who drank regularly and heavily had increased colorectal cancer risk. Moreover, this study is the first to show that drinking cessation could be effective in reversing such increased risk in a duration‐dependent manner. These new findings are important for cancer prevention and healthcare promotion. © 2004 Wiley‐Liss, Inc.
Inhibition of in vitro angiogenesis by 2‐methoxy‐ and 2‐ethyl‐estrogen sulfamates
Authors: Newman Simon P. , Leese Mathew P. , Purohit Atul , James David R.C. , Rennie Catherine E. , Potter Barry V.L. , Reed Michael J.
Published: February 2004

Sulfamoylation of 2‐methoxyestrone (2‐MeOE1) was shown previously to enhance its potency as an anti‐proliferative agent against breast cancer cells. We have examined the ability of a series of 2‐methoxyestradiol (2‐MeOE2) and 2‐ethylestradiol (2‐EtE2) sulfamates to inhibit angiogenesis in vitro. 2‐MeOE2 bis‐sulfamate and 2‐EtE2 sulfamate were potent inhibitors of human umbilical vein endothelial cell (HUVEC) proliferation with IC50 values of 0.05 μM and 0.01 μM, respectively. A novel co‐culture system, in which endothelial cells were cultured in a matrix of human dermal fibroblasts, was also used to assess the anti‐angiogenic potential of these drugs. In this system endothelial cells proliferate and migrate through the culture matrix to form tubule structures. Whereas 2‐MeOE2 (1.0 μM) caused a small reduction in tubule formation, both 2‐MeOE2 bis‐sulfamate (0.1 μM) and 2‐EtE2 sulfamate (0.1 μM) almost completely abolished tubule formation. 2‐MeOE2 bis‐sulfamate and 2‐EtE2 sulfamate both induced BCL‐2 phosphorylation, p53 protein expression and apoptosis in HUVECs. Microarray analysis of a limited number of genes known to be involved in the angiogenic process did not show any gross changes in cells treated with the 2‐substituted estrogens. The sulfamoylated derivatives of 2‐MeOE2 and 2‐EtE2 are potent inhibitors of in vitro angiogenesis and both compounds should have therapeutic potential. © 2004 Wiley‐Liss, Inc.
Genotoxicity assessment of oxirane‐based dental monomers in mammalian cells
Authors: Kostoryz Elisabet L. , Wetmore Lori A. , Brockmann William G. , Yourtee David M. , Eick J. David
Published: February 2004

The potential use of oxirane (epoxy) monomers in dental composite development raises the concern to test their genetic safety. Oxiranes can interact with DNA resulting in DNA damage, mutations, and possibly carcinogenesis. Our objective was to evaluate DNA damage and cell‐cycle disruption in mammalian cells after exposure to epoxy monomers. The experimental oxiranes were Araldite™ GY 281, Cyracure™ UVR 6105 and 1,3‐dioxane‐2,2′‐1,3‐dioxane‐5′,4′‐bicyclo[4.1.0] heptane (DECHE‐TOSU). L929 fibroblast cells were incubated with the monomer for 7 and 24 h at 37°C/5% CO2. After incubation, cells were subjected to DNA damage alkaline unwinding assay and flow cytometry cell‐cycle analysis. Lack of DNA damage and cell‐cycle effects were observed with DECHE‐TOSU. Exposure to subtoxic doses of Araldite™ GY 281 or Cyracure™ UVR 6105 caused DNA damage and cell cycle disruption. A significant (p < 0.01) effect for Araldite™ GY 281 was observed with cell populations in G1 and G2/M when compared to DMSO solvent control. Similar comparisons revealed significant differences in G2/M cell cycle population after 24‐h exposure to 100 μM Cyracure™ UVR 6105. For comparison, BISGMA was evaluated to produce DNA damage but without cell‐cycle effects suggesting DNA repair mechanisms were effective. Our findings with DECHE‐TOSU, Araldite™ GY 281 and Cyracure™ UVR 6105 indicated cell‐cycle disruption followed DNA damage. © 2004 Wiley Periodicals, Inc. J Biomed Mater Res 68A: 660–667, 2004
Effect of soft‐segment chemistry on polyurethane biostability during in vitro fatigue loading
Authors: Wiggins Michael J. , MacEwan Matt , Anderson James M. , Hiltner Anne
Published: February 2004

The effect of soft‐segment chemistry on biostability of polyurethane elastomers was studied with a diaphragm‐type film specimen under conditions of static and dynamic loading. During testing, the films were exposed to an H2O2/CoCl2 solution, which simulated the oxidative component of the in vivo environment. Films treated for up to 24 days were evaluated by IR spectroscopy and by optical and scanning electron microscopy. Biostability of a poly(ether urethane) (PEU), which is known to undergo oxidative degradation, was compared with biostability of a poly(carbonate urethane) (PCU), which is thought to be more resistant to oxidation than PEU. Materials similar to PEU and PCU, in which the polyether or polycarbonate soft segment was partially replaced with poly(dimethylsiloxane) (PDMS), were also tested with the expectation that PDMS would improve soft‐segment biostability. Oxidative degradation of the polyether soft segment of PEU was manifest chemically as chain scission and cross‐linking and physically as surface pitting. Biaxial fatigue accelerated chemical degradation of PEU and eventually caused brittle stress cracking. In comparison, the polycarbonate soft segment was more stable to oxidation; there was minimal chemical or physical degradation of PCU, even in biaxial fatigue. Partial substitution of the polyether soft segment with PDMS enhanced oxidative stability of PEU. Although both strategies for modifying soft‐segment chemistry improved the resistance to oxidative degradation, the outstanding mechanical properties of PEU were compromised to some extent. © 2004 Wiley Periodicals, Inc. J Biomed Mater Res 68A: 668–683, 2004
Effect of water structure on blood compatibility— thermal analysis of water in poly(meth)acrylate
Authors: Tanaka Masaru , Mochizuki Akira
Published: February 2004

The purpose of this study is to clarify the main factor causing excellent blood compatibility of poly(2‐methoxyethyl acrylate)(PMEA) by the comparison between PMEA and seven PMEA analogous polymers. The polymers have a typical functional group as ester side chains such as methoxyethyl, hydroxyethyl, phenoxyethyl, and alkyl groups. The properties of the polymers relating to water were investigated in terms of contact angle, equilibrium water content (EWC), and thermal analysis by differential scanning calorimetry. The water in PMEA could be classified into three types: nonfreezing water, freezing bound water, and free water while the water in the analogous polymers was classified into just two types: free and nonfreezing waters, regardless of the chemical structure of the side chain. The surface property represented by the contact angle of water corresponded to the content of the bound water (nonfreezing water + freezing bound water). The platelet compatibility in vitro did not depend on the contents of these waters, or on the contact angle. On the basis of the results of this work and the previous work on the platelet compatibility of poly(MEA‐co‐HEMA) (Tanaka et al. Biomacromolecules 2002;3;36–41), the main factor causing the excellent compatibility of PMEA is discussed. © 2004 Wiley Periodicals, Inc. J Biomed Mater Res 68A: 684–695, 2004
Overestimating hybrid layer quality in polished adhesive/dentin interfaces
Authors: Wang Yong , Spencer Paulette
Published: February 2004

The most popular techniques for determining the quality of the hybrid layer (HL) have relied on morphologic characterization of the polished adhesive/dentin (a/d) interfaces before and after acid‐bleach chemical treatment. Using these techniques, the existence of smooth, acid‐resistant layers has been consistently reported for most adhesive systems. The purpose of this study was to determine whether popular specimen preparation techniques that include polishing and acid‐bleach treatment modify the a/d interface, mask the complexity of the HL, and lead to inaccurate assessment of the quality of the HL. To understand the impact of specimen preparation techniques on the morphology of the resin–dentin interface, polished and unpolished specimens from the same tooth were closely compared after different acid‐bleach chemical treatment procedures. Two one‐bottle adhesives, that is, 3M Single Bond and Pulpdent UNO, exhibiting distinct differences in hydrophilic/hydrophobic composition, were used in this investigation. Using specimens from the same tooth, the effect of chemical treatments on the morphology of the resin–dentin interdiffusion zone and the differences in the morphology of polished and unpolished specimens after these same treatments were studied with scanning electron microscopy. It was shown that conventional specimen preparation techniques that include polishing and acid‐bleach treatment can adversely affect and even obscure the structural detail of the a/d interface in specimens that possess a porous HL. The results indicated that the Pulpdent UNO/dentin interface had better quality than the 3M Single Bond/dentin interface. The difference in the quality of HL can be attributed to factors such as compositional differences that impact the adhesive interaction with water, that is present within the substrate during wet bonding. The inability of the conventional acid‐bleach procedure to reveal the differences in the scanning electron microscopy interfacial morphology was overcome in this investigation by using a multistep technique. © 2004 Wiley Periodicals, Inc. J Biomed Mater Res 68A: 735–746, 2004
Comparison of bone graft matrices for human mesenchymal stem cell‐directed osteogenesis
Authors: Harris C. T. , Cooper L. F.
Published: February 2004

Scaffolds to support cell‐based tissue engineering are critical determinants of clinical efforts to regenerate and repair the body. Bone tissue engineering requires materials that are biocompatible, well vascularized, mechanically suited for bone function, integrated with the host skeleton, and support osteoinduction of the implanted cells that form new bone. The aim of this study was to compare the osteogenic potential of bone marrow‐derived, culture expanded human mesenchymal stem cells (hMSCs) adherent to different scaffolds composed of various calcium phosphates. Cells were loaded onto 2 × 2 mm cubes of coral calcium carbonate‐derived apatite, bovine bone‐derived apatite, synthetic hydroxyapatite (HA)/tricalcium phosphate (TCP) (60:40%), or synthetic HA/TCP (20:80%) and placed into the dorsum of SCID mice for 5 weeks. Subsequent histomorphometric analysis of bone formation within the cubes revealed the absence of bone formation within the coral‐derived apatite and the bovine bone‐derived apatite. Bone formation within synthetic HA/TCP scaffolds was measured to be 8.8% (±2.7%) and 13.8% (±3.6%) of the total tissue present for the 60:40% and 20:80% materials, respectively. Minimal resorption was observed at this early time point. Scanning electron microscopy evaluation of loaded scaffolds indicates that cell loading was not a variable affecting the different bone formation outcomes in these four scaffolds. In this ectopic model, different apatite‐containing scaffolds of similar morphology and porosity demonstrated marked differences in their ability to support osteoinduction by implanted hMSCs. The necessary induction of hMSCs along the osteoblastic lineage may be dependent, in part, on the local microenvironment established by the scaffold chemistry and interactions with the host. © 2004 Wiley Periodicals, Inc. J Biomed Mater Res 68A: 747–755, 2004
The effect of superoxide dismutase deficiency on cadmium stress
Authors: Adamis Paula D. B. , Gomes Débora Silva , Pereira Marcos Dias , de Mesquita Joelma Freire , Pinto Maria Lucia Couto C. , Panek Anita D. , Eleutherio Elis C. A.
Published: February 2004

Saccharomyces cerevisiae mutant strains deficient in superoxide dismutase (Sod), an antioxidant enzyme, were used to analyze cadmium absorption and the oxidation produced by it. Cells lacking the cytosolic Sod1 removed twice as much cadmium as the control strain, while those deficient in the mitochondrial Sod2 exhibited poor metal absorption. Interestingly, the sod1 mutant did not become more oxidized after exposure to cadmium, as opposed to the control strain. We observed that the deficiency of Sod1 increases the expression of both Cup1 (a metallothionein) and Ycf1 (a vacuolar glutathione S‐conjugate pump), proteins involved with protection against cadmium. Furthermore, when sod1 cells were exposed to cadmium, the ratio glutathione oxidized/glutathione reduced did not increase as expected. We propose that a high level of metallothionein expression would relieve glutathione under cadmium stress, while an increased level of Ycf1 expression would favor compartmentalization of this metal into the vacuole. Both conditions would reduce the level of glutathione‐cadmium complex in cytosol, contributing to the high capacity of absorbing cadmium by the sod1 strain. Previous results showed that the glutathione‐cadmium complex regulates cadmium uptake. These results indicate that, even indirectly, metallothionein also regulates cadmium transport. © 2004 Wiley Periodicals, Inc. J Biochem Mol Toxicol 18:12–17, 2004; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jbt.20000
Protein expression pattern of P–glycoprotein along the gastrointestinal tract of the yucatan micropig
Authors: Tang Huadong , Pak Yvonne , Mayersohn Michael
Published: February 2004

The purpose of this study is to characterize the distribution pattern of P–gp protein levels along the entire GI tract in the Yucatan micropig, which is being developed as a model for human drug bioavailability. Small and large intestines were freshly obtained and divided into about 37 segments and 10 segments, respectively (ca., 1 foot/segment). Epithelial cells from the small intestine were obtained by an elution method; whereas, a scraping method was applied to the large intestine. Total cellular protein was isolated from the epithelial cells. Western blot analysis using P–gp antibody showed that the amount of P–gp protein increased distally from the duodenum to the ileum over approximately a 10–fold range. P–gp protein in the large intestine was present at a higher level in the central portion, but the absolute amount was much less than what was found in the small intestine. © 2004 Wiley Periodicals, Inc. J Biochem Mol Toxicol 18:18–22, 2004; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jbt.20001
Organophosphorous and organochlorine pesticides affect human placental phosphoinositides metabolism and PI‐4 kinase activity
Authors: Souza María S. , de Potas Gladis Magnarelli , de D'Angelo Ana M. Pechén
Published: February 2004

The objective of this work was to describe the effect of organophosphorous and organochlorine pesticides on phosphoinositides metabolism in human placenta. Pesticides concentration (10 μM) was used for in vitro incubations of cell‐free homogenates labelled with 32P orthophosphate. Heptachlor (HC) and dichloro‐diphenyl‐trichloroethane (o‐p′ DDT) increased phosphatidyl‐inositol, phosphatidylinositolphosphate, and phosphatidyl‐inositolbiphosphate phosphorylation while azinphosmethyl (AM) increased phosphatidylinositolbiphosphate labeling. Decreased 32P incorporation in phosphatidylinositol was found with phosmet (PM), AM, and chlorpyriphos (CHL).

The effects of these xenobiotics on PI4‐kinase activity using different subcellular fractions were also examined. Both type of pesticides affected the postmembrane supernatant enzyme activity. A biphasic effect on membrane and nuclear PI4‐kinase activity was seen with HC. The strongest effect found was seen with o‐p′ DDT in nuclear kinase activity while substantial changes were also observed in membrane.

These data demonstrate the sensitivity of human placental PI4‐kinase to pesticides currently found in human tissues and suggest deleterious consequences in different processes regulated by 4‐phosphoinositides. © 2004 Wiley Periodicals, Inc. J Biochem Mol Toxicol 18:30–36, 2004; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jbt.20003
Differential oxidant potential of carcinogenic and weakly carcinogenic estrogens: Involvement of metabolic activation and cytochrome P450
Authors: Patel Molini M. , Bhat Hari K.
Published: February 2004

Different estrogens vary in their carcinogenic potential despite having similar hormonal potencies; however, mechanisms of estrogen‐induced carcinogenesis remain to be fully elucidated. It has been hypothesized that generation of reactive estrogen‐quinones and oxidative stress, both of which result from metabolic activation of estrogens, play an essential role in estrogen‐induced carcinogenesis. This hypothesis was tested using the estrogen‐receptor (ER)‐α‐positive hamster kidney tumor (H301) and the human breast cancer (MCF‐7) cell lines. Estrogens with differing carcinogenic potentials were compared in terms of their capacities to induce 8‐iso‐prostaglandin F2α (8− iso‐PGF2α), a marker of oxidative stress. Tumor cells were treated with either 17β‐estradiol (E2), a carcinogenic estrogen or 17‐α‐ethinylestradiol (EE), a weakly‐carcinogenic estrogen. Tumor cells were also treated with α‐naphthoflavone, a cytochrome P450 inhibitor, or a combination of α‐naphthoflavone and E2 to study the effect of metabolic activation of E2 on E2‐induced oxidative stress. H301 cells treated with E2 displayed time‐ and dose‐dependent increases in 8‐iso‐PGF2α, compared to controls; treatment with 10 nM E2 resulted in a maximal 4‐fold induction following 48 h of treatment. In contrast, H301 cells treated with EE did not display an increase in 8‐iso‐PGF2α compared with controls. In H301 cells cotreated with α‐naphthoflavone and E2, α‐naphthoflavone inhibited the E2‐induced increase in 8‐iso‐PGF2α. These data indicate that a carcinogenic estrogen shows strong oxidant potential, whereas a weakly‐carcinogenic estrogen shows poor oxidant potential. Furthermore, inhibiting metabolic activation of a carcinogenic estrogen blocks its oxidant potential. Our data support the hypothesis that metabolic activation and subsequent generation of oxidative stress may play critical roles in estrogen‐induced carcinogenesis. © 2004 Wiley Periodicals, Inc. J Biochem Mol Toxicol 18:37–42, 2004; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jbt.20005
Scandals rock mutual funds: Time to jump ship?
Authors: Evensky Harold R.
Published: February 2004

Wealth management guru Harold Evensky is often quoted by the financial and business press. The wealthy and
powerful seek out his investment advice. So what is he telling his exclusive clients about the latest mutual fund
scandals? How should you protect yourself? © 2003 Evensky, Brown &
Katz.
Cost and performance management tactics used by learning organizations
Authors: Stenzel Catherine , Stenzel Joe
Published: February 2004

In learning organizations, people continuously learn better ways to deliver a product or service; they then
immediately transfer their new learning insights into the process. It's a virtuous circle: Smarter people build
smarter processes that produce better products and services, and so on. © 2004 Wiley Periodicals,
Inc.