bluuebunny/crossref_metadata_2025 huggingface dataset:
A novel animal model to investigate fractionated radiotherapy-induced alimentary mucositis: the role of apoptosis, p53, nuclear factor-κB, COX-1, and COX-2
Authors: Yeoh Ann S.J. , Gibson Rachel J. , Yeoh Eric E.K. , Bowen Joanne M. , Stringer Andrea M. , Giam Kar A. , Keefe Dorothy M.K.
Published: August 2007

Radiation-induced mucositis is a common and serious side effect of radiotherapy. Molecular mechanisms of mucosal injury, however, are still poorly understood and extremely difficult to study in humans. A novel Dark Agouti rat model using fractionated radiotherapy to induce mucositis has been developed to investigate the occurrence of alimentary mucosal injury. Twenty-four Dark Agouti rats were randomly assigned to receive either fractionated radiotherapy or no radiotherapy. The irradiated rats received a fractionated course of abdominal radiotherapy at 45 Gy/18 fractions/6 weeks treating thrice weekly (i.e., at a radiation dose of 2.5 Gy per fraction). After each week of radiation, a group of irradiated rats was killed. Histomorphology and mucin distribution in the alimentary tract was investigated. The terminal deoxynucleotidyl transferase–mediated dUTP nick end labeling assay was used to examine apoptosis in the colon and jejunum, and intestinal morphometry was used to assess villus length, crypt length, and mitotic crypt count. Immunohistochemistry of p53, nuclear factor-κB, cyclooxygenase (COX)-1, and COX-2 was also done. The fractionated radiotherapy course induced alimentary mucositis from week 1, with more severe injury seen in the small intestine. The hallmark appearance of apoptosis was present in the crypts of the small and large intestine. In the jejunum and colon, goblet cell disorganization and degeneration was obvious and crypt mitotic counts were severely depleted throughout the treatment. Expression of p53, nuclear factor-κB, COX-1, and COX-2 was increased in the irradiated intestinal sections. Fractionated radiation-induced alimentary mucositis has been effectively documented in the Dark Agouti rat for the first time. Further studies investigating the molecular mechanisms underlying radiation-induced mucositis are planned to ultimately achieve anti–mucotoxic-targeted therapies. [Mol Cancer Ther 2007;6(8):2319–27]
213Bi-induced death of HSC45-M2 gastric cancer cells is characterized by G2 arrest and up-regulation of genes known to prevent apoptosis but induce necrosis and mitotic catastrophe
Authors: Seidl Christof , Port Matthias , Gilbertz Klaus-Peter , Morgenstern Alfred , Bruchertseifer Frank , Schwaiger Markus , Röper Barbara , Senekowitsch-Schmidtke Reingard , Abend Michael
Published: August 2007

Tumor cells are efficiently killed after incubation with α-emitter immunoconjugates targeting tumor-specific antigens. Therefore, application of α-emitter immunoconjugates is a promising therapeutic option for treatment of carcinomas that are characterized by dissemination of single tumor cells in the peritoneum like ovarian cancer or gastric cancer. In diffuse-type gastric cancer, 10% of patients express mutant d9-E-cadherin on the surface of tumor cells that is targeted by the monoclonal antibody d9MAb. Coupling of the α-emitter 213Bi to d9MAb provides an efficient tool to eliminate HSC45-M2 gastric cancer cells expressing d9-E-cadherin in vitro and in vivo. Elucidation of the molecular mechanisms triggered by α-emitters in tumor cells could help to improve strategies of α-emitter radioimmunotherapy. For that purpose, gene expression of 213Bi-treated tumor cells was quantified using a real time quantitative-PCR low-density array covering 380 genes in combination with analysis of cell proliferation and the mode of cell death. We could show that 213Bi-induced cell death was initiated by G2 arrest; up-regulation of tumor necrosis factor (TNF), SPHK1, STAT5A, p21, MYT1, and SSTR3; and down-regulation of SPP1, CDC25 phosphatases, and of genes involved in chromosome segregation. Together with morphologic changes, these results suggest that 213Bi activates death cascades different from apoptosis. Furthermore, 213Bi-triggered up-regulation of SSTR3 could be exploited for improvement of the therapeutic regimen. [Mol Cancer Ther 2007;6(8):2346–59]
A bifunctional colchicinoid that binds to the androgen receptor
Authors: Sharifi Nima , Hamel Ernest , Lill Markus A. , Risbood Prabhakar , Kane Charles T. , Hossain Md Tafazzal , Jones Amanda , Dalton James T. , Farrar William L.
Published: August 2007

Castrate-resistant prostate cancer (CRPC) continues to be dependent on the androgen receptor (AR) for disease progression. We have synthesized and evaluated a novel compound that is a conjugate of colchicine and an AR antagonist (cyanonilutamide) designed to inhibit AR function in CRPC. A problem in multifunctional AR-binding compounds is steric hindrance of binding to the embedded hydrophobic AR ligand-binding pocket. Despite the bulky side chain projecting off of the AR-binding moiety, this novel conjugate of colchicine and cyanonilutamide binds to AR with a Ki of 449 nmol/L. Structural modeling of this compound in the AR ligand-binding domain using a combination of rational docking, molecular dynamics, and steered molecular dynamics simulations reveals a basis for how this compound, which has a rigid alkyne linker, is able to bind to AR. Surprisingly, we found that this compound also binds to tubulin and inhibits tubulin function to a greater degree than colchicine itself. The tubulin-inhibiting activity of this compound increases cytoplasmic AR levels in prostate cancer cells. Finally, we found that this compound has greater toxicity against androgen-independent prostate cancer cells than the combination of colchicine and nilutamide. Together, these data point to several ways of inhibiting AR function in CRPC. [Mol Cancer Ther 2007;6(8):2328–36]
Fertility, Pregnancy and Delivery in Women after Biventricular Repair for Double Outlet Right Ventricle
Authors: Drenthen Willem , Pieper Petronella G. , van der Tuuk Karin , Roos-Hesselink Jolien W. , Hoendermis Elke S. , Voors Adriaan A. , Mulder Barbara J.M. , van Dijk Arie P.J. , Yap Sing C. , Vliegen Hubert W. , Moons Philip , Ebels Tjark , van Veldhuisen Dirk J.
Published: August 2007

Objectives: To investigate outcome of pregnancy and fertility in women with double outlet right ventricle (DORV). Methods: Using 2 congenital heart disease registries, 21 female patients with DORV (aged 18–39 years) were retrospectively identified. Detailed recordings of each patient and their completed (>20 weeks gestation) pregnancies were recorded. Results: Overall, 10 patients had 19 pregnancies, including 3 spontaneous miscarriages (16%). During the 16 live birth pregnancies, primarily (serious) noncardiac complications were observed, e.g. premature labor/delivery (n = 7 and n = 3, respectively), small for gestational age (n = 4), preeclampsia (n = 2) and recurrence of congenital heart disease (n = 2). Except for postpartum endocarditis and deterioration of subpulmonary obstruction, only mild cardiac complication pregnancies were recorded. Two women with children reported secondary female infertility. Several menstrual cycle disorders were reported: secondary amenorrhea (n = 4), primary amenorrhea (n = 3) and oligomenorrhea (n = 2). Conclusion: Successful pregnancy in women with DORV is possible. Primarily noncardiac complications were observed and only few (minor) cardiac complications. Infertility and menstrual cycle disorders appear to be more prevalent.
Long-Term Re-Infection Rate after Helicobacter pylori Eradication in Bangladeshi Adults
Authors: Ahmad Mian Mashhud , Ahmed Dewan Saifuddin , Rowshon A.H.M. , Dhar Swapan Chandra , Rahman Motiur , Hasan Mahmud , Beglinger Christoph , Gyr Niklaus , Khan A.K. Azad
Published: August 2007

Background and Aim: Bangladesh is a developing country with a very high prevalence of Helicobacter pylori infection, which has been ascribed to overcrowding and poor sanitary conditions. It has generally been accepted that the re-infection rate is higher in countries with a high prevalence of H. pylori infection. Short-term follow-up studies support this assumption but no long-term studies are available to confirm or refute this assertion. The present study was aimed to define the long-term H. pylori re-infection rate (6 years after successful eradication) in duodenal ulcer patients. Methods: In a previous study, 90 patients were successfully eradicated for H. pylori and followed-up for 24 months. 17/90 were found to be re-infected (18% re-infection rate per year in the first 12 months) [Gastroenterology 2001;792–798]. The remaining 73 patients were targeted for long-term follow-up. 26/73 were lost to follow-up; 6 symptomatic patients were tested H. pylori positive in the period between 24 and 60 months post-eradication. The remaining 41 patients were evaluated 72 months after successful eradication. The evaluation included clinical history taking, a 13C-urea breath test (UBT), and endoscopy. Results: Of the 41 H. pylori-eradicated patients analyzed after 72 months, 16 were H. pylori-positive. If the 6 patients, who were tested positive between 24 and 60 months, are added, the total re-infection cases amount to 22 subjects in the period between 24 and 72 months. Therefore, an overall annual re-infection rate 6 years after eradication of 5.02% can be calculated. Six of the 23 symptomatic patients had duodenal ulcer relapse, 5/6 were H. pylori re-infected and one was H. pylori-negative at 72 months post-treatment. Conclusion: The long-term annual H. pylori re-infection rate in Bangladeshi adults is markedly higher than in Western countries but lower than anticipated. In this study, duodenal ulcer relapse is clearly related to H. pylori re-infection.
Psychotropic Profile of S 17092, a Prolyl Endopeptidase Inhibitor, Using Quantitative EEG in Young Healthy Volunteers
Authors: Morain P. , Boeijinga P.H. , Demazières A. , De Nanteuil G. , Luthringer R.
Published: August 2007

The central activity of S 17092, a prolyl endopeptidase (PEP) inhibitor, was investigated by quantitative electroencephalography (qEEG) in 48 young healthy men participating in a double-blind, randomized, placebo-controlled, cross-over study. S 17092 (100, 200, 400 or 600 mg) and placebo were administered once daily for 10 days in a rising multiple-dose scheme. EEG recordings were performed before and repeatedly from 0.5 to 24 h after dose on day 1 and day 10. PEP activity in plasma was also measured for the same periods. S 17092 appeared as a potent inhibitor of PEP activity at all doses, after both single and repeated administrations. EEG changes after acute doses were slight and of short duration, mainly characterized by increased relative alpha 1 power, suggesting a vigilance-promoting EEG profile. After repeated doses and more strikingly after a superimposed dose, increases in relative alpha 1 power were still present with additional increase in relative delta power and decreases in absolute fast alpha, fast beta, theta powers and total power at all doses. These EEG findings suggest that S 17092 might possess some mood-stabilizing potential in addition to its cognition-enhancing properties.
Comparison of 11C-choline-PET/CT and whole body-MRI for staging of prostate cancer
Authors: Pfannenberg A. C. , Rieger A. , Aschoff P. , Müller M. , Paulsen F. , Anastasiadis A. , Claussen C. D. , Bares R. , Schlemmer H. P. , Eschmann S. M.
Published: August 2007

Aim of this study was to compare the diagnostic accuracy of positron emission tomography and computed tomography with 11C-Choline (Cho-PET/CT) and whole body magnetic resonance imaging (WB-MRI) for diagnostic work-up of prostate cancer. Patients, methods: We evaluated retrospectively 42 patients with untreated prostate cancer (n = 17), or increasing levels of prostate-specific antigen (PSA) after curative therapy (n = 25) who had been investigated by both Cho-PET/CT and WB-MRI. MRI, CT, and PET images were separately analyzed by experienced radiologists or nuclear medicine experts, followed by consensus reading. Validation was established by histology, follow-up, or consensus reading. Results: 88/103 detected lesions were considered as malignant: 44 bone metastases, 22 local tumor, 15 lymph node metastases, 3 lung, and 3 brain metastases. One further lesion was located in the adrenal gland, which was a second tumor. Overall sensitivity, specificity and accuracy for Cho-PET/CT were 96.6%, 76.5%, and 93.3%, resp., and for WB-MRI 78.4%, 94.1%, and 81.0%, resp. 3 vertebral metastases had initially been missed by Cho-PET/CT and were found retrospectively. MRI identified 2 bone metastases and 1 lymph node metastasis after being informed about the results of Cho-PET/CT. Conclusions: Cho-PET/CT and WB-MRI both presented high accuracy in the detection of bone and lymph node metastases. The strength of MRI is excellent image quality providing detailed anatomical information whereas the advantage of Cho-PET/CT is high image contrast of pathological foci.
Procedure guideline for iodine-131 whole-body scintigraphy for differentiated thyroid cancer (version 3)
Authors: Dressler J. , Eschner W. , Grünwald F. , Lassmann M. , Leisner B. , Luster M. , Reiners C. , Schicha H. , Schober O. , Dietlein M.
Published: August 2007

Version 3 of the procedure guideline for 131I whole-body scintigraphy (WBS) is the counterpart to the procedure guideline for radioiodine therapy (version 3) and specify the interdisciplinary guideline for thyroid cancer of the Deutsche Krebsgesellschaft concerning the nuclear medicine part. 131I WBS 3–6 months after 131I ablation remains a standard procedure in an endemic area for thyroid nodules and the high frequency of subtotal surgical procedures. Follow-up without 131I WBS is only justified if the following preconditions are fulfilled: low-risk group pT1–2, pN0 M0 with histopathologically confirmed pN0, 131I uptake <2%, 131I WBS during ablation without any suspicious lesion, stimulated thyroglobulin (Tg)-level 3–6 months after ablation <2 ng/mL, and absence of anti-thyroglobulin- antibodies with normal recovery-testing. If patients from the low-risk group show normal 131I WBS 3–6 months after ablation and stimulated Tg is of <2 ng/mL, there will be no need for additional routine 131I WBS. If patients from the high-risk group show normal 131I WBS and stimulated Tg-level of <2 ng/mL 3–6 months after ablation, the follow- up care should include repeated stimulated Tgmeasurements. If the Tg-level remains below 2 ng/mL, an additional 131I WBS will be not necessary. The recommended intervals for stimulated Tg-testing are adapted to the prior intervals for 131I WBS-testing in the high-risk group. Increased anti-thyroglobulin-antibodies or incomplete recovery-testing make an individual strategy of follow- up care necessary, which include 131I WBS.
Comparison of Bulk and Bin Warm-Rain Microphysics Models Using a Kinematic Framework
Authors: Morrison Hugh , Grabowski Wojciech W.
Published: August 2007

This paper discusses the development and testing of a bulk warm-rain microphysics model that is capable of addressing the impact of atmospheric aerosols on ice-free clouds. Similarly to previous two-moment bulk schemes, this model predicts the mixing ratios and number concentrations of cloud droplets and drizzle/raindrops. The key elements of the model are the relatively sophisticated cloud droplet activation scheme and a comprehensive treatment of the collision–coalescence mechanism. For the latter, three previously published schemes are selected and tested, with a detailed (bin) microphysics model providing the benchmark. The unique aspect of these tests is that they are performed using a two-dimensional prescribed-flow (kinematic) framework, where both advective transport and gravitational sedimentation are included. Two quasi-idealized test cases are used, the first mimicking a single large eddy in a stratocumulus-topped boundary layer and the second representing a single shallow convective cloud. These types of clouds are thought to be the key in the indirect aerosol effect on climate. Two different aerosol loadings are considered for each case, corresponding to either pristine or polluted environments. In general, all three collision–coalescence schemes seem to capture key features of the bin model simulations (e.g., cloud depth, droplet number concentration, cloud water path, effective radius, precipitation rate, etc.) for the polluted and pristine environments, but there are detailed differences. Two of the collision–coalescence schemes require specification of the width of the cloud droplet spectrum, and model results show significant sensitivity to the specification of the width parameter. Sensitivity tests indicate that a one-moment version of the bulk model for drizzle/rain, which predicts rain/drizzle mixing ratio but not number concentration, produces significant errors relative to the bin model.
On the Dynamic Interpretation of the Virtual Temperature
Authors: Monteiro Eva , Torlaschi Enrico
Published: August 2007

The concept of virtual temperature is reviewed and extended into the definition of the dynamic virtual temperature, which is the temperature that a parcel of dry air should have in order to experience the same acceleration as a parcel of cloud air. It is obtained from the equations of motion and depends on the water content in the three thermodynamic states: vapor, liquid, and solid. The scale analysis of the equation of the dynamic virtual temperature shows that the terms due to the acceleration and phase transitions of the particles are negligible with respect to the terms depending on gravity. Therefore, even though conceptually more adequate, the approximate mathematical expression of the dynamic virtual temperature is practically identical to the conventional definition of virtual temperature accounting for water loading.
A Physics-Based Parameterization of Air–Sea Momentum Flux at High Wind Speeds and Its Impact on Hurricane Intensity Predictions
Authors: Moon Il-Ju , Ginis Isaac , Hara Tetsu , Thomas Biju
Published: August 2007

A new bulk parameterization of the air–sea momentum flux at high wind speeds is proposed based on coupled wave–wind model simulations for 10 tropical cyclones that occurred in the Atlantic Ocean during 1998–2003. The new parameterization describes how the roughness length increases linearly with wind speed and the neutral drag coefficient tends to level off at high wind speeds. The proposed parameterization is then tested on real hurricanes using the operational Geophysical Fluid Dynamics Laboratory (GFDL) coupled hurricane–ocean prediction model. The impact of the new parameterization on the hurricane prediction is mainly found in increased maximum surface wind speeds, while it does not appreciably affect the hurricane central pressure prediction. This helps to improve the GFDL model–predicted wind–pressure relationship in strong hurricanes. Attempts are made to provide physical explanations as to why the reduced drag coefficient affects surface wind speeds but not the central pressure in hurricanes.
The Diurnal and Seasonal Variation of the Northern Australian Dryline
Authors: Arnup Sarah J. , Reeder Michael J.
Published: August 2007

The diurnal and seasonal variations of the northern Australian dryline are examined by constructing climatologies of low-level dynamic and thermodynamic variables taken from the high-resolution Australian Bureau of Meteorology’s Limited Area Prediction Scheme (LAPS) forecasts from 2000 to 2003. The development of the dryline is analyzed within the framework of the frontogenesis function applied to the mixing ratio and the airstream diagnostics of Cohen and Schultz. A case study of 12–13 October 2002 illustrating the airmass boundaries over the Australian region is also examined. Daytime surface heating produces sea-breeze circulations around the coast and a large inland heat trough that extends east–west along northern Australia. At night, air parcels accelerate toward low pressure, increasing convergence and deformation within the heat trough. This sharpens the moisture gradient across the tropical and continental airmass boundary into a dryline. This is different than the dryline of the Great Plains in the United States, which generally weakens overnight. The Australian dryline is strongest in spring just poleward of the Gulf of Carpentaria, where the moisture gradient across the heat trough is enhanced by the coast, and the axis of dilatation is closely aligned with mixing ratio isopleths. The dryline is weakest in winter, when the heat trough is weak. The LAPS 3-h forecasts are in good agreement with observations obtained from the Automatic Weather Station network. The 3-h forecasts capture the observed diurnal and seasonal cycle of the airmass boundaries. However, the sea-breeze circulation and ageostrophic flow into the surface heat trough is limited by the model resolution. The LAPS 3-h forecasts may therefore underestimate the nocturnal intensification of the dryline, especially since the inland moisture content is overestimated.
Duplicate VegfA genes and orthologues of the KDR receptor tyrosine kinase family mediate vascular development in the zebrafish
Authors: Bahary Nathan , Goishi Katsutoshi , Stuckenholz Carsten , Weber Gerhard , LeBlanc Jocelyn , Schafer Christopher A. , Berman Sarah S. , Klagsbrun Michael , Zon Leonard I.
Published: August 2007

Vascular endothelial growth factor A (VEGFA) and the type III receptor tyrosine kinase receptors (RTKs) are both required for the differentiation of endothelial cells (vasculogenesis) and for the sprouting of new capillaries (angiogenesis). We have isolated a duplicated zebrafish VegfA locus, termed VegfAb, and a duplicate RTK locus with homology to KDR/FLK1 (named Kdrb). Morpholino-disrupted VegfAb embryos develop a normal circulatory system until approximately 2 to 3 days after fertilization (dpf), when defects in angiogenesis permit blood to extravasate into many tissues. Unlike the VegfAa121 and VegfAa165 isoforms, the VegfAb isoforms VegfAb171 and VegfAb210 are not normally secreted when expressed in mammalian tissue culture cells. The Kdrb locus encodes a 1361–amino acid transmembrane receptor with strong homology to mammalian KDR. Combined knockdown of both RTKs leads to defects in vascular development, suggesting that they cooperate in mediating the vascular effects of VegfA in zebrafish development. Both VegfAa and VegfAb can individually bind and promote phosphorylation of both Flk1 (Kdra) and Kdrb proteins in vitro. Taken together, our data support a model in the zebrafish, in which duplicated VegfA and multiple type III RTKs mediate vascular development.
The Uridine Diphosphate Glucuronosyltransferase 2B15 D85Y and 2B17 Deletion Polymorphisms Predict the Glucuronidation Pattern of Androgens and Fat Mass in Men
Authors: Swanson Charlotte , Mellström Dan , Lorentzon Mattias , Vandenput Liesbeth , Jakobsson Jenny , Rane Anders , Karlsson Magnus , Ljunggren Östen , Smith Ulf , Eriksson Anna-Lena , Bélanger Alain , Labrie Fernand , Ohlsson Claes
Published: August 2007

Context: Previous in vitro studies have demonstrated that the UDP glucuronosyltransferase (UGT)2B15 and UGT2B17 glucuronidate androgens and their metabolites.

Objective: Our objective was to determine in vivo whether the UGT2B15 D85Y and the UGT2B17 deletion polymorphisms predict androgen glucuronidation and body composition.

Participants: Two population-based cohorts including young adult (n = 1068; age = 18.9 yr) and elderly (n = 1001; age = 75.3 yr) men were included in the study.

Main Outcome Measures: Serum and urine levels of testosterone (T) and dihydrotestosterone (DHT) were measured by gas chromatography-mass spectrometry, and serum levels of the major glucuronidated androgen metabolites androstane-3α,17β-diol(androstanediol)-3-glucuronide, androstanediol-17-glucuronide, and androsterone-glucuronide were measured by liquid chromatography-tandem mass spectrometry. Body composition was measured by dual-energy x-ray absorptiometry.

Results: Both the UGT2B15 D85Y and the UGT2B17 deletion polymorphisms were associated with serum levels of androstanediol-17-glucuronide (P < 0.001) but not with levels of androstanediol-3-glucuronide or androsterone-glucuronide in both cohorts. Glucuronidation of T and DHT was associated with the UGT2B17 deletion but not with the UGT2B15 D85Y polymorphism, suggested by strong associations between the deletion polymorphism and urine levels of these two hormones. Both polymorphisms were associated with several different measures of fat mass (P < 0.01). The UGT2B17 deletion polymorphism was associated with insulin sensitivity (P < 0.05) as indicated by the homeostasis model assessment index.

Conclusions: The UGT2B15 D85Y and the UGT2B17 deletion polymorphisms are both predictors of the glucuronidation pattern of androgens/androgen metabolites. Our findings indicate that UGT2B17 is involved in 17-glucuronidation of mainly T but also of DHT and androstanediol and that UGT2B15 is involved in the 17-glucuronidation of androstanediol. Furthermore, these two polymorphisms are predictors of fat mass in men.
Application of 188Rhenium as an Alternative Radionuclide for Treatment of Prostate Cancer after Tumor-Specific Sodium Iodide Symporter Gene Expression
Authors: Willhauck Michael J. , Sharif Samani Bibi-Rana , Gildehaus Franz-Josef , Wolf Ingo , Senekowitsch-Schmidtke Reingard , Stark Hans-Jürgen , Göke Burkhard , Morris John C. , Spitzweg Christine
Published: August 2007

Context: We reported recently the induction of iodide accumulation in prostate cancer cells (LNCaP) by prostate-specific antigen promoter-directed sodium iodide symporter (NIS) expression that allowed a significant therapeutic effect of 131iodine (131I). These data demonstrated the potential of the NIS gene as a novel therapeutic gene, although in some extrathyroidal tumors, therapeutic efficacy may be limited by rapid iodide efflux due to a lack of iodide organification.

Objective: In the current study, we therefore studied the potential of 188rhenium (188Re), as an alternative radionuclide, also transported by NIS, with a shorter half-life and higher energy β-particles than 131I.

Results: NIS-transfected LNCaP cells (NP-1) concentrated 8% of the total applied activity of 188Re as compared with 16% of 125I, which was sufficient for a therapeutic effect in an in vitro clonogenic assay. γ-Camera imaging of NP-1 cell xenografts in nude mice revealed accumulation of 8–16% injected dose (ID)/g 188Re (biological half-life 12.9 h), which resulted in a 4.7-fold increased tumor absorbed dose (450 mGy/MBq) for 188Re as compared with 131I. After application of 55.5 MBq 131I or 188Re, smaller tumors showed a similar average volume reduction of 86%, whereas in larger tumors volume reduction was significantly increased from 73% after 131I treatment to 85% after application of 188Re.

Conclusion: Although in smaller prostate cancer xenografts both radionuclides seemed to be equally effective after prostate-specific antigen promoter-mediated NIS gene delivery, a superior therapeutic effect has been demonstrated for 188Re in larger tumors.
TheDrosophilahomolog of the Exo84 exocyst subunit promotes apical epithelial identity
Authors: Blankenship J. Todd , Fuller Margaret T. , Zallen Jennifer A.
Published: August 2007

The polarized architecture of epithelial tissues involves a dynamic balance between apical and basolateral membrane domains. Here we show that epithelial polarity in the Drosophila embryo requires the exocyst complex subunit homolog Exo84. Exo84 activity is essential for the apical localization of the Crumbs transmembrane protein, a key determinant of epithelial apical identity. Adherens junction proteins become mislocalized at the cell surface in Exo84 mutants in a pattern characteristic of defects in apical, but not basolateral, components. Loss of Crumbs from the cell surface precedes the disruption of Bazooka and Armadillo localization in Exo84 mutants. Moreover, Exo84 mutants display defects in apical cuticle secretion that are similar to crumbs mutants and are suppressed by a reduction in the basolateral proteins Dlg and Lgl. In Exo84 mutants at advanced stages of epithelial degeneration, apical and adherens junction proteins accumulate in an expanded recycling endosome compartment. These results suggest that epithelial polarity in the Drosophila embryo is actively maintained by exocyst-dependent apical localization of the Crumbs transmembrane protein.
Overexpressing the Glucocorticoid Receptor in Forebrain Causes an Aging-Like Neuroendocrine Phenotype and Mild Cognitive Dysfunction
Authors: Wei Qiang , Hebda-Bauer Elaine K. , Pletsch Amy , Luo Jie , Hoversten Mary T. , Osetek Andrew J. , Evans Simon J. , Watson Stanley J. , Seasholtz Audrey F. , Akil Huda
Published: August 2007

Repeated stress enhances vulnerability to neural dysfunction that is cumulative over the course of the lifespan. This dysfunction contributes to cognitive deficits observed during aging. In addition, aging is associated with dysregulation of the limbic–hypothalamic–pituitary–adrenal (LHPA) axis, leading to a delayed termination of the stress response. This delay, in turn, increases exposure to glucocorticoids and exacerbates the likelihood of neural damage. Here we asked whether similar effects could emerge at an early age as a result of genetic variations in the level or function of the brain glucocorticoid receptor (GR). We investigated the effect of forebrain-specific overexpression of GR on LHPA axis activity. Transgenic mice with GR overexpression in forebrain (GRov) display normal basal circulating adrenocorticotropic hormone and corticosterone levels. However, young GRov mice exhibit a number of LHPA alterations, including a blunted initial response to acute restraint stress followed by a delayed turn-off of the stress response. This deficit in negative feedback is paradoxical in the face of elevated GR levels, resembles the stress response in aged animals, and continues to worsen as GRov mice age. The neuroendocrine dysregulation in young GRov mice is coupled with a mild cognitive deficit, also consistent with the accelerated aging hypothesis. The molecular basis of this phenotype was examined using microarray analysis of the hippocampus, which revealed a broad downregulation of glutamate receptor signaling in GRov mice. Thus, even in the absence of chronic stress, elevation of GR gene expression can lead to an increased allostatic load and result in an “aging-like” phenotype in young animals.
Progressive Motor Neuronopathy: A Critical Role of the Tubulin Chaperone TBCE in Axonal Tubulin Routing from the Golgi Apparatus
Authors: Schaefer Michael K. E. , Schmalbruch Henning , Buhler Emmanuelle , Lopez Catherine , Martin Natalia , Guénet Jean-Louis , Haase Georg
Published: August 2007

Axonal degeneration represents one of the earliest pathological features in motor neuron diseases. We here studied the underlying molecular mechanisms in progressive motor neuronopathy (pmn) mice mutated in the tubulin-specific chaperone TBCE. We demonstrate that TBCE is a peripheral membrane-associated protein that accumulates at the Golgi apparatus. Inpmnmice, TBCE is destabilized and disappears from the Golgi apparatus of motor neurons, and microtubules are lost in distal axons. The axonal microtubule loss proceeds retrogradely in parallel with the axonal dying back process. These degenerative changes are inhibited in a dose-dependent manner by transgenic TBCE complementation that restores TBCE expression at the Golgi apparatus. In cultured motor neurons, thepmnmutation, interference RNA-mediated TBCE depletion, and brefeldin A-mediated Golgi disruption all compromise axonal tubulin routing. We conclude that motor axons critically depend on axonal tubulin routing from the Golgi apparatus, a process that involves TBCE and possibly other tubulin chaperones.
Failure to Regulate: Counterproductive Recruitment of Top-Down Prefrontal-Subcortical Circuitry in Major Depression
Authors: Johnstone Tom , van Reekum Carien M. , Urry Heather L. , Kalin Ned H. , Davidson Richard J.
Published: August 2007

Although depressed mood is a normal occurrence in response to adversity in all individuals, what distinguishes those who are vulnerable to major depressive disorder (MDD) is their inability to effectively regulate negative mood when it arises. Investigating the neural underpinnings of adaptive emotion regulation and the extent to which such processes are compromised in MDD may be helpful in understanding the pathophysiology of depression. We report results from a functional magnetic resonance imaging study demonstrating left-lateralized activation in the prefrontal cortex (PFC) when downregulating negative affect in nondepressed individuals, whereas depressed individuals showed bilateral PFC activation. Furthermore, during an effortful affective reappraisal task, nondepressed individuals showed an inverse relationship between activation in left ventrolateral PFC and the amygdala that is mediated by the ventromedial PFC (VMPFC). No such relationship was found for depressed individuals, who instead show a positive association between VMPFC and amygdala. Pupil dilation data suggest that those depressed patients who expend more effort to reappraise negative stimuli are characterized by accentuated activation in the amygdala, insula, and thalamus, whereas nondepressed individuals exhibit the opposite pattern. These findings indicate that a key feature underlying the pathophysiology of major depression is the counterproductive engagement of right prefrontal cortex and the lack of engagement of left lateral-ventromedial prefrontal circuitry important for the downregulation of amygdala responses to negative stimuli.
The Sources of Variability in Saccadic Eye Movements
Authors: van Beers Robert J.
Published: August 2007

Our movements are variable, but the origin of this variability is poorly understood. We examined the sources of variability in human saccadic eye movements. In two experiments, we measured the spatiotemporal variability in saccade trajectories as a function of movement direction and amplitude. One of our new observations is that the variability in movement direction is smaller for purely horizontal and vertical saccades than for saccades in oblique directions. We also found that saccade amplitude, duration, and peak velocity are all correlated with one another. To determine the origin of the observed variability, we estimated the noise in motor commands from the observed spatiotemporal variability, while taking into account the variability resulting from uncertainty in localization of the target. This analysis revealed that uncertainty in target localization is the major source of variability in saccade endpoints, whereas noise in the magnitude of the motor commands explains a slightly smaller fraction. In addition, there is temporal variability such that saccades with a longer than average duration have a smaller than average peak velocity. This noise model has a large generality because it correctly predicts the variability in other data sets, which contain saccades starting from very different initial locations. Because the temporal noise most likely originates in movement planning, and the motor command noise in movement execution, we conclude that uncertainty in sensory signals and noise in movement planning and execution all contribute to the variability in saccade trajectories. These results are important for understanding how the brain controls movement.
Constitutive Excitation by Gly90Asp Rhodopsin Rescues Rods from Degeneration Caused by Elevated Production of cGMP in the Dark
Authors: Woodruff Michael L. , Olshevskaya Elena V. , Savchenko Andrey B. , Peshenko Igor V. , Barrett Ronald , Bush Ronald A. , Sieving Paul A. , Fain Gordon L. , Dizhoor Alexander M.
Published: August 2007

Previous experiments indicate that congenital human retinal degeneration caused by genetic mutations that change the Ca2+sensitivity of retinal guanylyl cyclase (retGC) can result from an increase in concentration of free intracellular cGMP and Ca2+in the photoreceptors. To rescue degeneration in transgenic mouse models having either the Y99C or E155G mutations of the retGC modulator guanylyl cyclase-activating protein 1 (GCAP-1), which produce elevated cGMP synthesis in the dark, we used the G90D rhodopsin mutation, which produces constitutive stimulation of cGMP hydrolysis. The effects of the G90D transgene were evaluated by measuring retGC activity biochemically, by recording single rod and electroretinogram (ERG) responses, by intracellular free Ca2+measurement, and by retinal morphological analysis. Although the G90D rhodopsin did not alter the abnormal Ca2+sensitivity of retGC in the double-mutant animals, the intracellular free cGMP and Ca2+concentrations returned close to normal levels, consistent with constitutive activation of the phosphodiesterase PDE6 cascade in darkness. G90D decreased the light sensitivity of rods but spared them from severe retinal degeneration in Y99C and E155G GCAP-1 mice. More than half of the photoreceptors remained alive, appeared morphologically normal, and produced electrical responses, at the time when their siblings lacking the G90D rhodopsin transgene lost the entire retinal outer nuclear layer and no longer responded to illumination. These experiments indicate that mutations that lead to increases in cGMP and Ca2+can trigger photoreceptor degeneration but that constitutive activation of the transduction cascade in these animals can greatly enhance cell survival.
Vulnerability of Korean water resources to climate change and population growth
Authors: Chang H. , Franczyk J. , Im E.-S. , Kwon W.-T. , Bae D.-H. , Jung I.-W.
Published: August 2007

Freshwater availability is affected by changes in climate and growth. We assessed the freshwater vulnerability for five major Korean river basins for 2015 and 2030. We used a regional climate model based on the IPCC SRES A2 scenario, US Geological Survey's Precipitation Rainfall Simulation Model, and population and industrial growth scenarios for impact assessment. The model simulation results suggest increasing spatial and temporal variations of water stress for the basins that are already developed. While freshwater is more vulnerable to growth scenarios than the climate change scenario, climate change alone could decrease mean annual runoff by 10% in four major river basins by 2030. As the first national assessment of climate change, we suggest possible adaptive water resource management and policy strategies for reducing climate related risks in Korea.
From optimal to practical safety standards for dike-ring areas
Authors: Eijgenraam C.J.J.
Published: August 2007

After the flood disaster in 1953 in the southwestern part of the Netherlands, Van Dantzig tried to solve the economic decision problem concerning the optimal height of dikes. His solution has a fixed probability of flooding after each investment. However, when there is economic growth, not the probability of flooding but the expected yearly loss by flooding is the key variable in the real optimal safety strategy. Under some conditions, it is optimal to keep this expected loss within a constant interval. Therefore, when the potential damage increases by economic growth, the flooding probability has to decline in the course of time in order to keep the expected loss between the fixed boundaries. The purpose of the paper is to show the implications of the optimal solution in case there are differences between costs and benefits among dike-ring areas. Further, the paper focuses on the translation of the theoretical results into new legal standards that can work well in practice.
CFD Simulation of Fine Particle Gravity Separation in Hindered-settling Bed Separators
Authors: Xia Y. K.
Published: August 2007

In the modeling of hindered-settling bed separators, the published separation mechanisms are based on differences of particle density and size distributions, without the details of the complexity of particles-liquid interactions. A fluid dynamic model for the separator is developed using the Euler-Lagrangian approach of Computational Fluid Dynamics (CFD). Fluid motion is obtained from solving the movement of liquid governing equations. The damping effect on flow patterns caused by the movement of particles resulting in liquid-particle coupling is included in the models. Effects of particle size, particle density compositions, feed rate, feed water flow rate, and upward fluidizing water flow rate, etc., are simulated in the 2-D separation model. Flow pattern effects on the separation of fine particles in the separators with center downward-flow and side cross-flow feed systems are investigated.
Sliding-mode Observer for Uncertainty Estimation in a Class of Chemical Reactor: A Differential-Algebraic Approach
Authors: Aguilar-López Ricardo
Published: August 2007

The problem of the on-line estimation of the reaction heat in a continuous stirred tank reactor from temperature measurements is addressed in this paper. The proposed uncertainty observer is based on differential algebraic techniques, such that the algebraic observability condition of the uncertainty from noisy temperature measurements is easily verified and the observer structure is very simple, which lead to feasible implementation. The observer proposed is robust against noisy measurements and sustained disturbances. The good performance of the observer is shown by means of numerical simulations and is compared with a nonlinear Luenberger-type observer.
Forces in the Presence of Ceramic Versus Stainless Steel Brackets with Unconventional vs Conventional Ligatures
Authors: Baccetti Tiziano , Franchi Lorenzo , Camporesi Matteo
Published: August 2007

Objective: To compare the forces resulting from four types of bracket/ligature combinations: ceramic brackets and stainless steel brackets combined with unconventional elastomeric ligatures (UEL) and conventional elastomeric ligatures (CEL) during the leveling and aligning phases of orthodontic therapy.

Materials and Methods: The testing model consisted of five 0.022-inch preadjusted brackets (second premolar, first premolar, canine, lateral incisor, and central incisor) for each of the two bracket types. The canine bracket was welded to a sliding bar that allowed for different amounts of offset in the gingival direction. The forces generated by a 0.014-inch superelastic nickel titanium wire in the presence of either the UEL or CEL bracket/ligature systems at different amounts of upward canine misalignment (1.5 mm, 3 mm, 4.5 mm, and 6 mm) were recorded.

Results: Significant differences were found between UEL and CEL systems for all tested variables (P < .01) with the exception of the canine misalignment of 1.5 mm. The average amount of recorded force in the presence of CEL was negligible with 3.0 mm or greater of canine misalignment. On the contrary, during alignment, a force available for tooth movement was recorded in the presence of both ceramic and stainless steel brackets when associated with UEL.

Conclusions: The type of ligature used influenced the actual amount of force released by the orthodontic system significantly more than the type of bracket used (stainless steel vs ceramic).
Accelerated Aging Effects on Surface Hardness and Roughness of Lingual Retainer Adhesives
Authors: Ramoglu Sabri Ilhan , Usumez Serdar , Buyukyilmaz Tamer
Published: August 2007

Objective: To test the null hypothesis that accelerated aging has no effect on the surface microhardness and roughness of two light-cured lingual retainer adhesives.

Materials and Methods: Ten samples of light-cured materials, Transbond Lingual Retainer (3M Unitek) and Light Cure Retainer (Reliance) were cured with a halogen light for 40 seconds. Vickers hardness and surface roughness were measured before and after accelerated aging of 300 hours in a weathering tester. Differences between mean values were analyzed for statistical significance using a t-test. The level of statistical significance was set at P < .05.

Results: The mean Vickers hardness of Transbond Lingual Retainer was 62.8 ± 3.5 and 79.6 ± 4.9 before and after aging, respectively. The mean Vickers hardness of Light Cure Retainer was 40.3 ± 2.6 and 58.3 ± 4.3 before and after aging, respectively. Differences in both groups were statistically significant (P < .001). Following aging, mean surface roughness was changed from 0.039 μm to 0.121 μm and from 0.021 μm to 0.031 μm for Transbond Lingual Retainer and Light Cure Retainer, respectively. The roughening of Transbond Lingual Retainer with aging was statistically significant (P < .05), while the change in the surface roughness of Light Cure Retainer was not (P > .05).

Conclusions: Accelerated aging significantly increased the surface microhardness of both light-cured retainer adhesives tested. It also significantly increased the surface roughness of the Transbond Lingual Retainer.
Effects of preadoption counseling for owners on house-training success among dogs acquired from shelters
Authors: Herron Meghan E. , Lord Linda K. , Hill Lawrence N. , Reisner Ilana R.
Published: August 2007

Objective—To determine the effect of preadoption counseling for owners on house-training success among dogs acquired from shelters.

Design—Prospective study.

Sample Population—113 dog owners.

Procedures—Participants were randomly assigned to a treatment (n = 54) or a control (59) group. Dog owners in the treatment group received counseling (5 minutes' duration) regarding house-training. Owners in the control group did not receive counseling, but all other adoption procedures were otherwise identical to those applied to the treatment group. All participants were contacted by telephone 1 month after adoption of a dog for assessment of house-training status and related issues by use of a standardized survey method; data were compared between groups.

Results—Most shelter dogs were considered successfully house-trained by their owners 1 month after adoption. Furthermore, dogs were considered house-trained by significantly more owners who received preadoption counseling than control group owners (98.1% vs 86.4%). Owners who received counseling used verbal punishment on their dogs during house-training less frequently and applied enzymatic cleaners to urine- or feces-soiled areas more frequently than owners in the control group.

Conclusions and Clinical Relevance—Results have suggested that brief preadoption counseling for owners enhances successful house-training of dogs adopted from shelters. Counseling owners at the time of pet acquisition may thus have beneficial effects in the prevention of inappropriate elimination behaviors. Veterinarians and animal care staff should be encouraged to devote time to counsel new pet owners on successful house-training, as well as other healthcare and behavioral needs.