bluuebunny/crossref_metadata_2025 huggingface dataset:
Chronic low-dose aspirin therapy attenuates reflex cutaneous vasodilation in middle-aged humans
Authors: Holowatz Lacy A. , Kenney W. Larry
Published: November 2008

Full expression of reflex cutaneous vasodilation is dependent on cyclooxygenase- (COX) and nitric oxide synthase- (NOS) dependent mechanisms. Low-dose aspirin therapy is widely prescribed to inhibit COX-1 in platelets for atherothrombotic prevention. We hypothesized that chronic COX inhibition with daily low-dose aspirin therapy (81 mg) would attenuate reflex vasodilation in healthy human skin. Two microdialysis fibers were placed in forearm skin of seven middle-aged (57 ± 3 yr), normotensive, healthy humans with no preexisting cardiovascular disease, taking daily low-dose aspirin therapy (aspirin: 81 mg), and seven unmedicated, healthy, age-matched control (no aspirin, 55 ± 3 yr) subjects, with one site serving as a control (Ringer) and the other NOS inhibited (NOS inhibited: 10 mM NG-nitro-l-arginine methyl ester). Red cell flux was measured over each site by laser-Doppler flowmetry, as reflex vasodilation was induced by increasing core temperature (oral temperature) 1.0°C using a water-perfused suit. Cutaneous vascular conductance (CVC) was calculated (CVC = flux/mean arterial pressure) and normalized to maximal CVC (CVCmax; 28 mM sodium nitroprusside). CVCmax was not affected by either aspirin or NOS inhibition. The plateau in cutaneous vasodilation during heating (change in oral temperature = 1.0°C) was significantly attenuated in the aspirin group (aspirin: 25 ± 3% CVCmax vs. no aspirin: 50 ± 7% CVCmax, P < 0.001 between groups). NOS inhibition significantly attenuated %CVCmax in both groups (aspirin: 17 ± 2% CVCmax, no aspirin: 23 ± 3% CVCmax; P < 0.001 vs. control), but this attenuation was less in the no-aspirin treatment group ( P < 0.001). This is the first observation that chronic low-dose aspirin therapy attenuates reflex cutaneous vasodilation through both COX- and NOS-dependent mechanisms.
Vascular endothelial senescence: from mechanisms to pathophysiology
Authors: Erusalimsky Jorge D.
Published: November 2008

Most mitotically competent mammalian cell types can react to stress by undergoing a phenotypically distinctive and permanent form of growth arrest called “cellular senescence.” This response has been extensively characterized in cell culture and more recently it has been found to occur also in vivo in a number of tissues. In this review I will present the case for the occurrence of senescence in the vascular endothelium. I will also discuss the mechanisms and factors that modulate endothelial cell replicative capacity and the onset of senescence. Finally, I will examine the senescent phenotype and its possible consequences for the development and progression of vascular diseases.
Identification of differential gene expression during porcine conceptus rapid trophoblastic elongation and attachment to uterine luminal epithelium
Authors: Ross Jason W. , Ashworth Morgan D. , Stein Daniel R. , Couture Oliver P. , Tuggle Christopher K. , Geisert Rodney D.
Published: November 2008

Early embryonic development in the pig is characterized by a rapid elongation of the conceptus trophectoderm on days 11–12 of gestation. Initially, the conceptus trophoblast is morphologically rearranged from a 10-mm sphere into a tubular shape, transitioning into a thin filamentous form >150 mm in length in 2–3 h, followed by continued expansion within the uterine lumen for several days. Conceptus elongation is critical for establishing adequate placental surface area needed for embryo and fetal survival throughout gestation. The objective of this study was to characterize conceptus gene expression during trophoblastic elongation and the early attachment to the uterine endometrium on days 11–14 of gestation with the GeneChip Porcine Genome Array. In all, 3,759 different probe sets were statistically different in at least one comparison [spherical vs. tubular, spherical vs. day 12 filamentous (D12F), spherical vs. day 14 filamentous (D14F), tubular vs. D12F, tubular vs. D14F, and D12F vs. D14F]. When restricted to the spherical vs. D12F and D12F vs. D14F comparisons, 482 and 232 genes, respectively, were statistically different with greater than twofold change in expression. Utilization of k-means clustering, in addition to the Database for Annotation, Visualization, and Integrated Discovery (DAVID), identified genes of interest. Quantitative RT-PCR expression profiles for interferon-γ (IFNG), heat shock protein 27 kDa (HSPB1), angiomotin, B-cell linker (BLNK), chemokine ligand 14 (CXCL14), parathyroid hormone-like hormone (PTHLH), and maspin were supportive of the GeneChip Porcine Genome Array data.
Optimum Design of Organic Electrochemical Type Transistors for Applications in Biochemical Sensing
Authors: Badhwar Shruti , Narayan K. S.
Published: November 2008

This paper addresses the issue of optimizing various performance parameters involved in the design of organic electrochemical type transistors based on the conducting polymer, poly (3,4‐ethylenedioxythiophene): poly(styrene sulfonate)(PEDOT:PSS) for applications in biochemical sensing. We report the effect of device contact geometry, gate to channel length ratio “Lg/L_, and analyte distance from the source electrode “x_, on the device sensitivity and response time.
Weak Forms of Continuity and Associated Properties
Authors: Sarsak Mohammad S.
Published: November 2008

We introduce slightly p‐continuous mapping and almost p‐open mapping and investigate the relationships between these mappings and related types of mappings, and also study some properties of these mappings.
Eigenvalue Asymptotics of the Even‐Dimensional Exterior Landau‐Neumann Hamiltonian
Authors: Persson Mikael
Published: November 2008

We study the Schrödinger operator with a constant magnetic field in the exterior of a compact domain in
ℝ2d, d ≥ 1. The spectrum of this operator consists of clusters of eigenvalues around the Landau levels. We
give asymptotic formulas for the rate of accumulation of eigenvalues in these clusters. When the compact is a Reinhardt domain we are able to show a more precise asymptotic formula.
Regulation of Osteoblast Differentiation by Slit2 in Osteoblastic Cells
Authors: Sun Hongli , Dai Kerong , Tang Tingting , Zhang Xiaoling
Published: November 2008

Background/Aims: There is an urgent need to identify the molecular factors involved in osteoblast proliferation and differentiation in order to improve bone formation and treat bone disease. Recent studies demonstrate that many ‘axon guidance’ molecules play important roles in the development and remodeling of bone through their actions regulating osteoblast or osteoclast differentiation. The expressions and roles in bone tissue of the neuron guidance molecules slit and robo have not been reported previously. The objective of the current study is to investigate the expression and the roles of slit and robo in osteoblastic cells. Methods: The mRNAs slit2 and robo were detected in primary cell lines during their osteoblastic differentiation. The role of slit2 was studied using the recombinant proteins slit2 and hemagglutinin (HA)-roboN by transfecting the 293 cells. Results: The data indicated that the mRNAs of slit2, robo1 and robo2 were expressed during the osteoblastic differentiation of rat osteoblasts (calvarial osteoblasts derived from newborn rats), the nontransformed preosteogenic cell line MC3T3-E1, rat marrow stromal cells and the murine mesenchymal progenitor cell line C3H10T1/2. The exogenous slit2 protein inhibited the differentiation of rat osteoblasts and MC3T3-E1. Furthermore, the osteoblastic differentiation was improved when the endogenous slits were antagonized by recombinant HA-roboN, which is the extracellular domain of the rat robo1 protein. The inhibition of slit2 in osteogenic differentiation was independent of the RhoA/ROCK pathway. Conclusion: Slit2 plays a role in regulating in vitro osteoblast differentiation. This has opened a new avenue to understand the molecular events involved in the osteoblastic differentiation.
Evaluation of Animal Models for the Hair-Inducing Capacity of Cultured Human Dermal Papilla Cells
Authors: Inoue Keita , Kato Harunosuke , Sato Takahiro , Osada Aki , Aoi Noriyuki , Suga Hirotaka , Eto Hitomi , Gonda Koichi , Yoshimura Kotaro
Published: November 2008

Background: The dermal papilla (DP) interacts with epithelial cells for folliculogenesis. For translational research on cell therapies for hair regrowth with cultured human DP cells (hDPCs), a model to evaluate the capacity of hDPCs to induce hair formation is inevitable. Methods: Chamber models were constructed by transplanting 4 different combinations of mouse or human epithelial and mesenchymal cells into a silicone chamber implanted onto the back of nude mice. In parallel, 3 types of sandwich constructs were created by inserting hDPCs or human DP tissue between the epidermis and dermis of isolated rat footpad skin or human facial skin, and subcutaneously transplanting the constructs into the back of nude mice. Four to six weeks later, skin sections of each model were histologically examined. Results: Folliculoneogenesis was detected in both chamber and sandwich models, although the induction rate and maturity of the hair follicles varied among cell combination subgroups in each model. The difference in hair induction rate was not statistically significant between 2 representative chamber and sandwich subgroups using cultured hDPCs. The sandwich model, however, required fewer hDPCs, did not require human keratinocytes, and exhibited a higher rate of successful sample collection. Conclusions: Although there is no significant difference in hair induction rate, the sandwich model using cultured hDPCs and the rat sole skin is more feasible than the chamber model using human cultured keratinocytes and hDPCs as a tool to evaluate the hair-inducing capacity of cultured hDPCs.
In Preparation for Adulthood
Authors: Kelly Diann Cameron
Published: November 2008

The inclusion of minorities in the civic affairs of society is critical. Research indicates many of today's youth are less likely to engage in meaningful civic activities and more likely to experience social exclusion because of disparities in educational settings, economic disadvantages, and health disparities. This phenomenon is more likely to occur in communities overcome by crime, drug dealing, and other indicators of diminished quality of life, where there is greater anonymity and suspicion among neighbors and less trust. Social trust is a significant trait for adulthood because social trust promotes individuals' actively engaging in society and seeing themselves as valued members of their communities. Secondary data from the CIRCLE National Youth Survey, comprising 1,000 youths between ages 15 and 25 years, show that youth who trust in others and trust in government are more likely to participate in community service, voting, and political volunteerism, even among young minorities.
Enantioselectivity in the Pharmacokinetic Interaction Between Fluvastatin and Lercanidipine in Healthy Volunteers
Authors: Boralli Vanessa Bergamin , Coelho Eduardo Barbosa , Sampaio Stefânia Amaral , Marques Maria Paula , Lanchote Vera Lucia
Published: November 2008

Hypertension and dyslipidemia are independent risk factors for cardiovascular mortality and are frequently present in the same patient. Fluvastatin (FV), used to reduce cholesterol levels, and lercanidipine (LER), used to control blood pressure, are marketed as racemic mixtures. Therapeutic activities are 30‐fold higher for (+)‐3R,5S‐FV and 100‐ to 200‐fold higher for S‐LER compared with their respective antipodes. The present study describes the enantioselective pharmacokinetic interaction between LER and FV in healthy volunteers. A crossover randomized study was conducted in 3 phases on 8 volunteers treated with a single oral racemic dose of LER (20 mg) or FV (40 mg) or LER plus FV. Serial blood samples were collected from 0 to 24 hours. Plasma concentrations of the LER and FV enantiomers were determined by liquid chromatography/tandem mass spectrometry, and pharmacokinetic parameters were evaluated using the WinNonlin software. The Wilcoxon and Mann‐Whitney tests (P<.05) were used to analyze enantiomer ratios and the pharmacokinetic drug interaction. Data are expressed as medians. In monotherapy, the kinetic disposition of both FV and LER was enantioselective. AUC values were significantly higher for (–)‐3S,5R‐FV than for (+)‐3R,5S‐FV (358.20 vs 279.68 ng·h/mL) and for S‐LER compared with R‐LER (13.90 vs 11.88 ng·h/mL). The pharmacokinetic parameters of FV were not enantioselective when combined with LER (AUC: (–)‐3S,5R‐FV: 325.21; (+)‐3R,5S‐FV: 316.44 ng·h/mL). There was a significant reduction in S‐LER (8.06 vs 13.90 ng·h/mL) and R‐LER (6.76 vs 11.88 ng·h/mL) AUC values when FV was coadministered. In conclusion, the interaction between FV‐LER might be clinically relevant because AUC values of (+)‐3R,5S‐FV were increased when LER was coadministered, and AUC values of the 2 LER enantiomers were reduced when FV was coadministered.
CYP2C19 Genotype Is a Major Factor Contributing to the Highly Variable Pharmacokinetics of Voriconazole
Authors: Weiss Johanna , ten Hoevel Magdalena Maria , Burhenne Jürgen , Walter‐Sack Ingeborg , Hoffmann Michael Marcus , Rengelshausen Jens , Haefeli Walter E. , Mikus Gerd
Published: November 2008

In vitro data on the metabolism of the antifungal voriconazole suggest that its pharmacokinetics might be influenced by the activity of CYP2C19, CYP2C9, and CYP3A. To elucidate the genetic influence of polymorphic enzymes on voriconazole metabolism, the authors pooled the pharmacokinetic data from 2 interaction studies in which 35 participants were enrolled according to their CYP2C19 genotype to receive a single 400‐mg oral dose of voriconazole. Nine participants were homozygous for CYP2C19*1/*1, 8 heterozygous for *1/*17, 11 heterozygous for*1/*2, 2 heterozygous for *2/*17, 4 homozygous for *2/*2, and 1 with a double mutation CYP2C19*2/*2*17. Nine (heterozygous) individuals were carriers of the CYP2C9*2 or *3 variant alleles. Twenty‐five participants did not express the CYP3A5 isozyme (*3/*3), whereas in 5 individuals, the *1/*3 combination was present (active enzyme). In addition, the CYP2D6 genotype and 2 variants of the drug transporter MDR1 (C3435T and G2677T) were determined. Multiple regression analysis of voriconazole apparent oral clearance revealed that 49% of its variance can be explained solely by the CYP2C19 polymorphism (P < .0001). Including the other polymorphisms into the regression model did not show any significant contribution. The number of variant CYP2C19 alleles therefore explains a substantial part of the wide variability of voriconazole pharmacokinetics, whereas the presence of functional CYP3A5 and the CYP2C9 genotype had no significant impact on voriconazole exposure. Some minor contribution results from the MDR1 C3435T genotype.
Parenting Styles and Health-Related Behavior in Childhood and Early Adolescence
Authors: Lohaus Arnold , Vierhaus Marc , Ball Juliane
Published: November 2008

This study addresses the development of health-related behavior during childhood and adolescence and the protective influence of an authoritative parenting style. The study is based on two samples followed from Grades 2 through 5 and from Grades 4 through 7. The first sample consisted of 432 second graders with a mean age of 7.9 years at the beginning of the study, while the second sample consisted of 366 fourth graders with a mean age of 10.1 years. Later health behavior showed substantial correlations to previous health behavior over a 3-year interval. Moreover, there was an increase of favorable health behavior during elementary school and a decrease in the subsequent age periods. The slope for negative health behavior showed an inverted pattern. The level of this general trend was significantly affected by the perceived maternal and paternal parenting style and by gender. The significance of the results for health promotion is discussed.
Preoperative Magnetic Resonance Assessment of Patellar Tendon Dimensions for Graft Selection in Anterior Cruciate Ligament Reconstruction
Authors: Chang Chong Bum , Seong Sang Cheol , Kim Tae Kyun
Published: November 2008

Background

A bone patellar tendon bone autograft is one of the standard graft choices for anterior cruciate ligament reconstruction. However, its use can be limited when the patellar tendon is too narrow or too long.

Hypothesis

A preoperative assessment of patellar tendon dimensions using magnetic resonance imaging would be accurate and reliable. Patients undergoing anterior cruciate ligament reconstruction would have wide ranges of patellar tendon dimensions, and a significant proportion of patients would have a too narrow and/or too long patellar tendon as the graft choice. There would be a demographic predictor to identify the patients with inappropriate patellar tendon dimensions.

Study Design

Cohort study (diagnosis); Level of evidence, 3.

Methods

The accuracy and reliability of magnetic resonance assessments of patellar tendon dimensions were assessed by comparing the intraoperative measurements using a ruler in 55 knees and 10 knees, respectively. Data from the magnetic resonance assessments in 147 knees undergoing anterior cruciate ligament reconstruction were used for the normative documentation of the patellar tendon dimensions (width, thickness, and length) and identification of demographic predictors for the dimensions.

Results

Preoperative magnetic resonance assessments of the patellar tendon dimensions were accurate and reliable. Korean patients undergoing anterior cruciate ligament reconstruction had wide variations in patellar dimensions, and a significant portion of the patients had an inappropriate patellar tendon (longer than 5 cm in 4.1% and narrower than 27 mm at middle portion in 15.6%) for the graft source. Patient height was the predictor used for patellar tendon width. The mathematical equation used to estimate the width based on patient height was: tendon width at middle portion (mm) = 0.202 × patient height (cm) — 5.07.

Conclusion

Preoperative magnetic resonance assessment of patellar tendon dimensions can be a valuable tool with satisfactory accuracy and reliability when the autologous patellar tendon is considered as the graft source for anterior cruciate ligament reconstruction.
Synthesis and Application of Novel Multi-arm Poly(carboxylic acid)s for Glass-ionomer Restoratives
Authors: Xie Dong , Zhao Jun , Weng Yiming
Published: November 2008

We have developed a novel glass-ionomer cement system composed of multi-arm poly(acrylic acid-co-itaconic acid)s. These polyacids were synthesized via a chain-transfer polymerization reaction using newly synthesized multi-arm chain-transfer agents. The cements formulated with the multi-arm polyacids showed significantly lower viscosities in water as compared to those formulated with the linear polyacids. Due to the lower viscosities, the MW of the polyacids can be significantly increased for enhanced mechanical strengths, while keeping the ease of mixing and handling. The experimental cements showed significantly improved compressive strengths as compared to Fuji II after aged in water for 3 months.
Influence of Automatic Firearms on the Presence of Multiple Victims of Violence
Authors: Libby Nicholas E. , Wright James D.
Published: November 2008

This study investigates the impact of automatic firearm usage on the presence of multiple victims within a violent encounter. In addition, key situational and contextual variables from the criminal events perspective are controlled. Data were collected from the National Incident-Based Reporting System of the Federal Bureau of Investigation. Logistic regression analyses were conducted to determine if automatic firearms, compared to semiautomatic firearms, increased the chance of multiple victims appearing within incidents of serious violence. Results indicate that automatic weapons increase the likelihood of multiple victimization, although various situational and contextual factors such as incident circumstance and victim—offender relationship increase these odds as well.
Endovascular Approaches to Complex Thoracic Aortic Disease
Authors: Hughes G. Chad , Sulzer Christopher F. , McCann Richard L. , Swaminathan Madhav
Published: November 2008

Diseases of the thoracic aorta remain among the most lethal and difficult to treat conditions. In 2005, the US Food and Drug Administration approved the first endoprosthesis for the treatment of aneurysms of the descending thoracic aorta; at present, there are 3 thoracic devices approved by the US Food and Drug Administration. Although approved only for the treatment of descending aneurysms, thoracic endografting has other potential off-label applications, including acute and chronic aortic dissection and traumatic aortic transection. Endovascular repair of thoracic aortic pathology is emerging as the preferred treatment strategy in certain patients, as increasing data suggest that endovascular repair may be performed with lower peri-operative morbidity and mortality rates and similar midterm survival, when compared with standard open repair. However, because of anatomic constraints related to required endograft seal zones, a significant number of patients are excluded from standard endovascular repair. Hybrid techniques, including open aortic arch and thoracoabdominal debranching procedures, have been described to allow creation of proximal and/or distal landing zones for the stent graft seal. This review describes the surgical and anesthetic considerations relevant to thoracic endografting, with an emphasis on hybrid procedures used to treat more complex thoracic aortic pathology. Hybrid techniques may be performed with lower rates of morbidity and mortality than conventional open repair, and they appear to be a safe alternative to open repair for thoracoabdominal and aortic arch aneurysms in properly selected patients with significant comorbidity or prior open aortic surgery.
The Aftermath of Combat-Related PTSD
Authors: Pearrow Melissa , Cosgrove Lisa
Published: November 2008

The number of military personnel who are involved in combat situations continues to increase. As a result, researchers have identified risk factors associated with the development of combat-related posttraumatic stress disorder (PTSD). The authors of this article review some of the characteristics of military personnel involved in these conflicts, factors unique to the current military actions, and symptom presentation and prevalence rates of PTSD among those serving in Iraq and Afghanistan. They discuss mechanisms for the transgenerational transmission of trauma symptoms and identify strategies for interventions.
Portal Vein Thrombosis After Laparoscopic Splenectomy: The Size of the Risk
Authors: Targarona Eduard M.
Published: November 2008

Portal vein thrombosis (PVT) after splenectomy is a potentially life-threatening complication. Clinical symptoms may be insidious, and progression can lead to intestinal infarction and portal hypertension. Interest in PVT has increased as a high incidence has been found in the laparoscopic setting. The higher incidence of PVT found in recent prospective studies of laparoscopically operated patients compared with retrospective reports from the 1990s suggests that PVT may have been underreported. Clinical outcome depends on the extension of the thrombus and the underlying disease. Main risk factors may be myeloproliferative diseases requiring splenectomy and splenomegaly, but PVT may occur after splenectomy for any clinical indication. The extent to which laparoscopy is responsible for PVT remains unclear. Laparoscopic surgeons should be aware of the risk of PVT, and it should be suspected in cases with an atypical outcome after laparoscopic splenectomy. Once diagnosed, prompt anticoagulation therapy may resolve the thrombotic event.
Beyond the Operating Room: A Simulator for Sacroiliac Screw Insertion
Authors: Rush Raphael , Ginsberg Howard J. , Jenkinson Richard , Whyne Cari M.
Published: November 2008

Current teaching techniques for orthopedic screw insertions involve “learning by doing” in the operating room. Minimally invasive insertion of sacroilliac (SI) screws is a relatively uncommon operation, providing scant opportunity for training outside of a few major centers. As such, SI screw insertion is a prime candidate for simulator-based training. This work describes the development and implementation of a simulator for minimally invasive SI screw insertion using accurate 3-dimensional (3D) computed tomography (CT)—based visualization of the pelvic and upper sacral anatomy. The simulator was designed in Tool Command Language atop the Amira 3D visualization package. CT images of pelvic regions were automatically segmented to generate 3D surfaces. Using inlet and outlet 3D views, guidewire insertion can be performed followed by an appropriately sized SI screw. The simulator was found to provide a realistic representation of the pelvis, and test users reported increased understanding of the procedure of SI screw insertion following use. The 3D reconstructions of the pelvis allowed for visual correlations between CT slices and inlet and outlet x-ray views. Pilot work with surgical trainees suggests the tool's value in increasing the familiarity of surgical trainees to visualize the pelvis in 3D and perform SI screw insertion.
Mechanical Circular Stapler Device Loaded With Nonabsorbable Titanium Staples for Ileo-prostate Capsuloplasty Following Prostate Capsule Sparing Cystectomy: Initial Experience in Cadavers
Authors: Abreu Sidney C. , Abreu André Luís C. , Araújo Mardhen B. , Neves Marcelo F. , Fonseca Gilvan N.
Published: November 2008

Purpose. Mechanical linear staplers have been safely used in urology with an acceptable 0% to 7.9% rate of stone formation in long-term follow-up. We sought to evaluate the feasibility of using mechanical circular stapler devices to perform ileocapsuloplasty following cystoadenomectomy in cadavers. Material and methods. Three unfrozen cadavers were used in this study. The prostate was enucleated and removed along with the bladder, leaving an ample cavity wherein the 21-mm anvil could be easily accommodated. A 2-0 purse string suture was then placed at the prostate capsule rim and tightly tied around the anvil. Following this, the circular stapler device was introduced into the neobladder through its opened limb and the center rod of the stapler device was passed through an opening made at the most dependent portion of the pouch where another purse string suture was placed and tied around it. Finally, the center rod of the stapler was connected to the anvil and fired, thus completing the anastomosis. Results. The procedure was feasible in all cases and 2 intact rings of prostatic capsule and bowel tissue were obtained, thus attesting the integrity of the anastomoses. Retrograde injection of methylene blue reassured that a watertight anastomosis was achieved whereas cystoscopic and macroscopic examination of the anastomotic site demonstrated a wide patent anastomosis in all cases. Conclusions. Use of mechanical circular stapler to perform ileocapsuloplasty in cadavers is feasible and has potential advantages such as decreased anastomotic time, diminished chances of urinary extravasations, and reduced degree of difficulty.
Cooperation between integrin α5 and tetraspan TM4SF5 regulates VEGF-mediated angiogenic activity
Authors: Choi Suyong , Lee Sin-Ae , Kwak Tae Kyoung , Kim Hyeon Jung , Lee Mi Ji , Ye Sang-Kyu , Kim Sung-Hoon , Kim Semi , Lee Jung Weon
Published: November 2008

Tetraspan TM4SF5 is highly expressed in a diverse number of tumor types. Here we explore the mechanistic roles of TM4SF5 in angiogenesis. We found that TM4SF5 overexpression correlates with vascular endothelial growth factor (VEGF) expression in SNU449 hepatocytes and with vessel formation in clinical hepatocarcinoma samples. Conditioned media from TM4SF5-expressing cells enhanced viability and tube formation of primary human umbilical vein endothelial cells, and outgrowth of endothelial cells from aorta ring segments, which was abolished by treatment with an anti-VEGF antibody. TM4SF5 retained integrin α5 on the cell surface for VEGF induction, and preincubation with anti–integrin α5 antibody abolished TM4SF5-mediated VEGF expression and secretion. TM4SF5-mediated effects required integrin α5, c-Src, and signal transducer and activator of transcription 3 (STAT3). In addition, tumors from nude mice injected with TM4SF5-expressing cells and from clinical human hepatocarcinoma tissues showed enhanced integrin α5 expression, vessel formation, and signaling activity, which were inhibited by administration of anti–integrin α5 or -VEGF antibody. This study suggests that TM4SF5 facilitates angiogenesis of neighboring endothelial cells through VEGF induction, mediated by cooperation between TM4SF5 and integrin α5 of epithelial cells.
Malaria treatment-seeking behaviour and recovery from malaria in a highland area of Kenya
Authors: Sumba Peter O , Wong S Lindsey , Kanzaria Hemal K , Johnson Kelsey A , John Chandy C
Published: November 2008

Background

Malaria epidemics in highland areas of Kenya cause significant morbidity and mortality.

Methods

To assess treatment-seeking behaviour for malaria in these areas, a questionnaire was administered to 117 randomly selected households in the highland area of Kipsamoite, Kenya. Self-reported episodes of malaria occurred in 100 adults and 66 children.

Results

The most frequent initial sources of treatment for malaria in adults and children were medical facilities (66.0% and 66.7%) and local shops (19.0% and 30.3%). Adults and children who initially visited a medical facility for treatment were significantly more likely to recover and require no further treatment than those who initially went to a local shop (adults, 84.9% v. 36.8%, P < 0.0001, and children, 79.6% v. 40.0%, P = 0.002, respectively). Individuals who attended medical facilities recalled receiving anti-malarial medication significantly more frequently than those who visited shops (adults, 100% vs. 29.4%, and children, 100% v. 5.0%, respectively, both P < 0.0001).

Conclusion

A significant proportion of this highland population chooses local shops for initial malaria treatment and receives inappropriate medication at these localshops, reslting in delay of effective treatment. Shopkeeper education has the potential to be a component of prevention or containment strategies for malaria epidemics in highland areas.
A rapid 3% polyacrylamide slab gel electrophoresis method for high through put screening of LDL phenotype
Authors: Singh Yogendra , Lakshmy Ramakrishnan , Gupta Ruby , Kranthi Vemparala
Published: November 2008

Background

Small dense LDL is reported to be associated with increased coronary artery disease risk by various epidemiological studies. The gold standard for separation and identification of LDL subtypes in plasma is ultracentrifugation which is a lengthy procedure and difficult to perform. Various other methods like NMR, HPLC, gradient gel electrophoresis (GGE) have been reported for LDL sub fractionation all of which require specialized equipments and expertise. We report here a high throughput 3% polyacrylamide slab gel electrophoresis method (PASGE) for sub fractionation of LDL which was compared with GGE, a commonly used method for LDL sub fractionation.

Results

The 3% PASGE method compared well with the GGE method There was a good correlation between LDL particle diameter identified by the PASGE and GGE (Pearson correlation coefficient = 0.950). A 100% concordance was found when samples were classified as per LDL phenotypes in subjects with A and B phenotype by the two methods with the concordance being 66% in subjects with intermediate (I) phenotype. The electrophoresis apparatus was optimized and designed for running twenty eight samples at a time compared to twelve to fourteen by the conventional PASGE and eight to twelve by disc electrophoresis.

Conclusion

The rapid 3% polyacrylamide slab gel electrphoresis method developed is simple to perform, cost-effective and can be used for the identification LDL sub fractionation and phenotyping in large epidemiological studies.
Genetic variation in stromal proteins decorin and lumican with breast cancer: investigations in two case-control studies
Authors: Kelemen Linda E , Couch Fergus J , Ahmed Shahana , Dunning Alison M , Pharoah Paul DP , Easton Douglas F , Fredericksen Zachary S , Vierkant Robert A , Pankratz V Shane , Goode Ellen L , Scott Christopher G , Rider David N , Wang Xianshu , Cerhan James R , Vachon Celine M
Published: November 2008

Introduction

The stroma is the supportive framework of biologic tissue in the breast, consisting of various proteins such as the proteoglycans, decorin and lumican. Altered expression of decorin and lumican is associated with breast tumors. We hypothesized that genetic variation in the decorin (DCN) and lumican (LUM) genes may contribute to breast cancer.

Methods

We investigated associations of 14 common polymorphisms in the DCN and LUM genes with 798 breast cancer cases and 843 controls from Mayo Clinic, MN, USA. One polymorphism per gene with the strongest risk association in the Mayo Clinic sample was genotyped in 4,470 breast cancer cases and 4,560 controls from East Anglia, England (Studies of Epidemiology and Risk Factors in Cancer Heredity (SEARCH)).

Results

In the Mayo Clinic sample, six polymorphisms were associated with breast cancer risk (Ptrend ≤ 0.05). The association with LUM rs2268578, evaluated further in SEARCH, was positive, although the odds ratios (OR) were weaker and not statistically significant. ORs were 1.4 (95% confidence interval [CI], 1.1 to 1.8) for heterozygotes and 2.2 (95% CI, 1.1 to 4.3; P2 df = 0.002) for homozygotes in the Mayo Clinic sample, and were 1.1 (95% CI, 0.9 to 1.2) for heterozygotes and 1.4 (95% CI, 1.0 to 2.1; P2 df = 0.13) for homozygotes in the SEARCH sample. In combined analyses, the ORs were 1.1 (95% CI, 1.0 to 1.2) for heterozygotes and 1.6 (95% CI, 1.2 to 2.3; P2 df = 0.005) for homozygotes. Positive associations for this polymorphism were observed for estrogen receptor-positive tumors in both the Mayo Clinic sample (OR for heterozygotes = 1.5, 1.1 to 1.9 and OR for homozygotes = 2.5, 1.2 to 5.3;P2 df = 0.001) and the SEARCH sample (OR for heterozygotes = 1.0, 0.9 to 1.1 and OR for homozygotes = 1.6, 1.0 to 2.5; P2 df = 0.10). In combined analyses, the ORs were 1.1 (95% CI, 0.9 to 1.2) for heterozygotes and 1.9 (95% CI, 1.3 to 2.8; P2 df = 0.001) for homozygotes.

Conclusions

Although LUM rs2268578 was associated with breast cancer in the Mayo Clinic study, particularly estrogen receptor-positive breast cancer, weaker and modest associations were observed in the SEARCH sample. These modest associations will require larger samples to adequately assess the importance of this polymorphism in breast cancer.
Impact of Body Mass Index and Weight Change After Treatment on Cancer Recurrence and Survival in Patients With Stage III Colon Cancer: Findings From Cancer and Leukemia Group B 89803
Authors: Meyerhardt Jeffrey A. , Niedzwiecki Donna , Hollis Donna , Saltz Leonard B. , Mayer Robert J. , Nelson Heidi , Whittom Renaud , Hantel Alexander , Thomas James , Fuchs Charles S.
Published: November 2008

Purpose

Obesity is a risk factor for the development of colon cancer. However, the influence of body mass index (BMI) on the outcome of patients with established colon cancer remains uncertain. Moreover, the impact of change in body habitus after diagnosis has not been studied.

Patients and Methods

We conducted a prospective, observational study of 1,053 patients who had stage III colon cancer and who were enrolled on a randomized trial of adjuvant chemotherapy. Patients reported on height and weight during and 6 months after adjuvant chemotherapy. Patients were observed for cancer recurrence or death.

Results

In this cohort of patients with stage III cancer, 35% of patients were overweight (BMI, 25 to 29.9 kg/m2), and 34% were obese (BMI ≥ 30 kg/m2). Increased BMI was not significantly associated with a higher risk of colon cancer recurrence or death (P trend = .54). Compared with normal-weight patients (BMI, 21 to 24.9 kg/m2), the multivariate hazard ratio for disease-free survival was 1.00 (95% CI, 0.72 to 1.40) for patients with class I obesity (BMI, 30 to 34.9 kg/m2) and 1.24 (95% CI, 0.84 to 1.83) for those with class II to III obesity (BMI ≥ 35 kg/m2) after analysis was adjusted for tumor-related prognostic factors, physical activity, tobacco history, performance status, age, and sex. Similarly, after analysis was controlled for BMI, weight change (either loss or gain) during the time period between ongoing adjuvant therapy and 6 months after completion of therapy did not significantly impact on cancer recurrence and/or mortality.

Conclusion

Neither BMI nor weight change was significantly associated with an increased risk of cancer recurrence and death in patients with colon cancer.
Phase I Study of Adenovirus p53 Administered by Bronchoalveolar Lavage in Patients With Bronchioloalveolar Cell Lung Carcinoma: ECOG 6597
Authors: Keedy Vicki , Wang Wei , Schiller Joan , Chada Sunil , Slovis Bonnie , Coffee Keith , Worrell John , Thet Lyn A. , Johnson David H. , Carbone David P.
Published: November 2008

Purpose

This pilot phase I trial evaluated the safety and maximum-tolerated dose of p53 gene transfer using an adenovirus vector (Ad-p53) delivered via bronchoalveolar lavage (BAL) to patients with bronchioloalveolar lung carcinoma (BAC).

Patients and Methods

Patients were initially administered two treatments of Ad-p53 to a single involved lobe, beginning at 2 × 109 viral particles (vp) per dose and escalated to a maximum of 2 × 1012 vp. If a clinical benefit was seen and the treatment was well tolerated, additional doses could be administered to additional lobes.

Results

Twenty-five patients were treated at doses between 2 × 109 and 2 × 1012 vp. At 2 × 1012 vp, one patient experienced grade 4 pulmonary toxicity, and one patient died 25 days after his second cycle; therefore, a cohort of 10 patients was treated at the recommended phase II dose of 5 × 1011 vp, with no grade 4 toxicity observed. The most frequent toxicities included low-grade fever, hypoxia, and dyspnea. Of the 23 assessable patients, 16 had stable disease as their best response. Subjective improvement in breathing was noted in eight patients. Limited distribution of vector was observed, with transient detection in patient sputum for 1 to 2 days after administration.

Conclusion

Ad-p53 can be administered safely by BAL at 5 × 1011 vp with repeated dosing. Stabilization of disease and symptomatic improvement may warrant further studies of Ad-p53 or other adenoviruses administered by BAL in patients with BAC.
The Utility of Oral Glucose Tolerance Testing for Diagnosis and Assessment of Treatment Outcomes in 166 Patients with Acromegaly
Authors: Carmichael John D. , Bonert Vivien S. , Mirocha James M. , Melmed Shlomo
Published: November 2008

Context: GH suppression after oral glucose load [oral glucose tolerance test (OGTT)] and normal age- and gender-matched IGF-I levels reflect biochemical control of acromegaly. The OGTT is the gold standard for determining control of GH secretion at diagnosis and after surgical treatment, but the usefulness of performing an OGTT in patients treated with medical therapy has not been determined.

Objective: Our objective was to assess relationships between basal GH levels (basal GH), GH responses to OGTT [GH nadir (GHn)], and IGF-I levels.

Design: This was a retrospective electronic database review.

Setting: This study was performed at a tertiary outpatient pituitary center.

Patients: A total of 166 patients with acromegaly (79 females, 87 males) were included in the study. Four categories of testing were performed: diagnosis, postoperative assessment without medication, testing during somatostatin analog (SA) therapy, and testing during dopamine agonist (DA) therapy.

Main Outcome Measures: Basal serum GH and IGF-I levels and GH levels 2 h after 75 g OGTT were measured.

Results: A total of 482 simultaneous OGTT and IGF-I measurements were observed from 1985–2008. Discordant results of oral glucose tolerance testing (GHn and IGF-I) were observed 33, 48, and 18% in postoperative assessment without medication, SA, and DA categories, respectively. In the SA category, 42% of tests were discordant with normal IGF-I and nonsuppressed GHn. In contrast, 4% of tests were discordant with normal IGF-I and nonsuppressed GH in those treated with DA. No significant differences in discordance were observed when basal GH was used.

Conclusions: Both basal and GHn levels are highly discordant with IGF-I levels during medical therapy with SAs. The OGTT is not useful in assessing biochemical control in these subjects.
Managed Care and Private Health Insurance in a Global Context
Authors: Weiner Jonathan P. , Famadas Joanna Case , Waters Hugh R. , Gikic Djordje
Published: November 2008

This article provides an overview of the current role of private health insurance and private care management organizations around the globe. We describe past experiences and challenges associated with the export of U.S.-style managed care. We provide a framework for understanding the potential opportunities within a national health system for expanding managed care approaches and also private health insurance more generally. This article is relevant to both the United States and members of the international community.
Job Satisfaction and Motivation among Physicians in Academic Medical Centers: Insights from a Cross-National Study
Authors: Janus Katharina , Amelung Volker E. , Baker Laurence C. , Gaitanides Michael , Schwartz Friedrich W. , Rundall Thomas G.
Published: November 2008

Our study assesses how work-related monetary and nonmonetary factors affect physicians' job satisfaction at three academic medical centers in Germany and the United States, two countries whose differing health care systems experience similar problems in maintaining their physician workforce. We used descriptive statistics and factor and correlation analyses to evaluate physicians' responses to a self-administered questionnaire. Our study revealed that German physician respondents were less satisfied overall than their U.S. counterparts. In both countries, participation in decision making that may affect physicians' work was an important correlate of satisfaction. In Germany other important factors were opportunities for continuing education, job security, extent of administrative work, collegial relationships, and access to specialized technology. In the U.S. sample, job security, financial incentives, interaction with colleagues, and cooperative working relationships with colleagues and management were important predictors of overall job satisfaction. The implications of these findings for the development of policies and management tactics to increase physician job satisfaction in German and U.S. academic medical centers are discussed.
EGFR-dependent migration of glial cells is mediated by reorganisation of N-cadherin
Authors: Rappl Anne , Piontek Guido , Schlegel Jürgen
Published: November 2008

Receptor tyrosine kinases of the EGFR family exert their various effects on cellular function through the formation of different dimeric receptor complexes. To investigate the functional impact of EGFR-HER2 heterodimers on migration of glial tumour cells, we stably transfected different HER2 constructs, including a constitutively active (HER2VE) and a dominant-negative (HER2VEKA) receptor, in the EGFR-overexpressing human glioma cell line LN18. Interference of EGFR activation through HER2VEKA inhibited cellular migration, whereas EGFR activation through HER2VE increased migration. These results were corroborated by inhibition of EGFR-HER2 signalling with tyrosine kinase inhibitors, because only the blocking of both receptors in HER2VE-cells with the bi-specific inhibitor AEE788 downregulated migration to levels comparable with those in HER2VEKA cells. The non-migratory phenotype was mediated through upregulation of N-cadherin and its recruitment to the cell membrane in HER2VEKA cells; downregulation of N-cadherin by RNAi restored migration in HER2VEKA cells and N-cadherin was also downregulated in migrating HER2VE-cells. Downregulation of N-cadherin levels in the plasma membrane was accompanied by a direct interaction of the EGFR-HER2 and N-cadherin–β-catenin complexes, leading to tyrosine phosphorylation of β-catenin. These results indicate that HER2 affects glial-cell migration by modulating EGFR-HER2 signal transduction, and that this effect is mediated by N-cadherin.
Molecular reorganization of Cx43, Zo-1 and Src complexes during the endocytosis of gap junction plaques in response to a non-genomic carcinogen
Authors: Gilleron Jérome , Fiorini Céline , Carette Diane , Avondet Christiane , Falk Matthias M. , Segretain Dominique , Pointis Georges
Published: November 2008

The gap junction protein connexin 43 (Cx43) exhibits dynamic trafficking that is altered in most tumor cells and in response to carcinogen exposure. A number of connexin (Cx)-binding proteins are known to be involved in endocytic internalization of gap junctions. Here, we analyzed the discrete molecular interactions that occur between Src, ZO-1 and Cx43 during Cx43 internalization in response to the non-genomic carcinogen γ-hexachlorocyclohexane (HCH). Internalization of the Cx43 gap junction plaque was significantly accelerated in Cx43-GFP transfected 42GPA9 Sertoli cells that were exposed to the carcinogen. HCH induced the rapid recruitment of Src to the plasma membrane, activation of Src within 3 minutes and the efficient inhibition of gap junctional coupling, but had no effect in the presence of the Src inhibitor PP2. Immunoprecipitation experiments demonstrated that HCH increased Cx43-Src interaction and concomitantly decreased Cx43–ZO-1 association. ZO-1 was detected on both sides of the gap junction plaques in untreated cells, but appeared to be mainly localized on one side during HCH-induced internalization. The dissociation of ZO-1 from Cx43 appears to occur specifically on the side of the plaque to which Src was recruited. These findings provide mechanistic evidence by which internalization of the Cx43 gap junction plaque might be initiated, suggesting that Src-mediated dissociation of ZO-1 from one side of the plaque initiates endocytic internalization of gap junctions and that this process is amplified in response to exposure to HCH.
The adaptor complex AP-2 regulates post-endocytic trafficking through the non-clathrin Arf6-dependent endocytic pathway
Authors: Lau Alan W. , Chou Margaret M.
Published: November 2008

The ADP-ribosylation factor 6 (Arf6) GTPase functions as a key regulator of endocytic trafficking, participating in clathrin-independent endocytosis in most cell types. Unexpectedly, we found that siRNA-mediated depletion of clathrin or of adaptor protein 2 (AP-2)-complex subunits alters trafficking of Arf6 pathway cargo proteins, such as major histocompatibility complex class I (MHCI) and β1 integrin. Internalization of these cargoes from the plasma membrane was not affected in cells depleted of clathrin, but was modestly delayed in cells lacking AP-2. Furthermore, depletion of clathrin or AP-2 altered the intracellular distribution of MHCI and β1 integrin, inducing clustering in a perinuclear region. Despite this altered localization in both depleted populations, enhanced lysosomal targeting of MHCI was observed uniquely in cells that lack AP-2. Total levels of MHCI were modestly but consistently reduced in AP-2-depleted cells, and restored by the lysosomal inhibitor bafilomycin A. Furthermore, the half-life of surface-derived MHCI was reduced in AP-2-depleted cells. Consistent with enhanced degradative sorting, colocalization of Arf6 cargo with the late endosome and lysosome markers CD63 and Lamp1 was increased in cells depleted of AP-2 but not clathrin. These studies indicate a role for AP-2 in maintaining normal post-endocytic trafficking through the Arf6-regulated, non-clathrin pathway, and reveal pervasive effects of clathrin and AP-2 depletion on the endosomal and lysosomal system.