bluuebunny/crossref_metadata_2025 huggingface dataset:
Design of an active roll control system for hybrid four-wheel-drive vehicles
Authors: Yim Seongjin , Yi Kyongsu
Published: August 2012

This paper presents a method for designing an active roll control system, combined with integrated chassis control for hybrid four-wheel-drive vehicles. The active roll control system adopts an active anti-roll bar as an actuator and is designed by model matching control with a roll estimator. To maintain the manoeuvrability of hybrid four-wheel-drive vehicles with an active roll control system, integrated chassis control is adopted. The hybrid four-wheel-drive vehicle consists of a front internal-combustion engine and independent motor-driven rear wheels and is equipped with electronic stability control, active front steering and four-wheel drive. Direct yaw moment control is used to generate a control yaw moment. Weighted pseudo-inverse-based control allocation and simulation-based optimization are proposed to distribute the control yaw moment. Simulations on the vehicle simulation software CarSim® show that the proposed active roll control system with integrated chassis control is effective for controlling the roll motion and the yaw motion of a hybrid four-wheel-drive vehicle.
Formal verification of lateral and temporal safety buffers for state-based conflict detection
Authors: Narkawicz Anthony , Muñoz César , Herencia-Zapana Heber , Hagen George
Published: August 2012

This article presents an analytical definition of lateral and temporal safety buffers to be used in state-based conflict detection algorithms. A lateral buffer is a distance to be added to the minimum lateral separation to accommodate for uncertainty in the surveillance information. A temporal buffer is a time to be added to the lookahead conflict detection time to accommodate for dropped surveillance messages due to signal attenuation. These safety buffers are defined using precise mathematical statements and the main theorems give numerical upper bounds on the probability of a missed alert. A particular case is considered where absolute bounds on the errors in position and velocity information are known. In this case, under well-defined assumptions provided in this article, safety buffers are given that guarantee mathematically that the probability of a missed alert is zero. The results are presented as theorems, which were formally proven using a mechanical theorem prover.
Railing against neoliberalism: Radical political unionism in SUD-Rail and RMT
Authors: Gordon Alex , Upchurch Martin
Published: August 2012

This article responds to the analysis presented by Connolly and Darlington of developments in SUD-Rail in France and RMT in the UK. The authors present the context for understanding the effects of neoliberal marketization of the rail sector in the two countries, and assess radical political unionism as a response. They also reflect on further areas for research.
Design, modeling, and optimization of a thermally activated reconfigurable wing system
Authors: Beblo Richard , Joo James , Smyers Brian , Reich Gregory
Published: August 2012

Reconfigurable structures such as morphing aircraft generally require an on-board energy source to function. At high speeds, however, frictional heating generated at the nose of a morphing aircraft can provide a large amount of thermal energy during a short period of time. This thermal energy can be collected, transferred, and utilized to reconfigure the aircraft. Direct utilization of thermal energy has the ability to significantly decrease or eliminate the losses associated with converting thermal energy to other forms, such as electric. The following work describes possible system designs and components that can be utilized to transfer the thermal energy harvested at the nose of the aircraft to internal components for direct thermal actuation of a reconfigurable wing structure. Previously reported topology optimized heat collectors, vehicle trajectories, and the deployment mechanism are combined with the presented analytical model of a heat pipe for a system level model used to optimize the system based on weight and the desired wing deployment time.
Costs of School-Located Influenza Vaccination Clinics in Maine During the 2009–2010 H1N1 Pandemic
Authors: Cho Bo-Hyun , Asay Garrett R. Beeler , Lorick Suchita A. , Tipton Meredith L. , Dube Nancy L. , Messonnier Mark L.
Published: August 2012

This study retrospectively estimated costs for a convenience sample of school-located vaccination (SLV) clinics conducted in Maine during the 2009–2010 influenza season. Surveys were developed to capture the cost of labor including unpaid volunteers as well as supplies and materials used in SLV clinics. Six nurses from different school districts completed a clinic day survey on staff time; four of the six also provided data for materials and supplies. For all clinics, average per-dose labor cost was estimated at $5.95. Average per-dose material cost, excluding vaccine, was $5.76. From the four complete clinic survey responses, total per-dose cost was estimated to be an average of $13.51 (range = $4.91–$32.39). Use of donated materials and uncompensated volunteer staff could substantially reduce per-dose cost. Average per-dose cost could also be lowered by increasing the number of doses administered in a clinic.
A reputation-based peer-to-peer architecture for semantic service discovery in distributed manufacturing environments
Authors: Zhang Wenyu , Zhang Shuai , Cai Ming , Liu Yanan
Published: August 2012

The rapidly increasing volume of today’s global manufacturing resources is demanding new approaches for resource location or discovery in distributed manufacturing environments. This article presents an ontology-based service-oriented peer-to-peer architecture for semantic discovery of manufacturing services across virtual enterprises in distributed manufacturing environments. Each enterprise exhibits as a peer that publishes sharable manufacturing services through its private service registry. The peers sharing similar ontological interests through ontological directory are clustered together, and the most reputed peer is elected as the super peer through multicriteria decision making among related trust parameters. All super peers form a reputed distributed hash table–based structured peer-to-peer overlay, and the leaf peers are communicated with and controlled by respective super peers. Then, a manufacturing service request can be first routed to the suitable super peer through structured indexing and further to its leaf peer through client/server communication, thus supporting efficient service discovery. The case study of the prototype system is presented to validate the applicability of the proposed approach for industrial application.
The Uses and Abuses of Foreign Aid
Authors: Kono Daniel Yuichi , Montinola Gabriella R.
Published: August 2012

Research shows that foreign aid promotes economic development in democracies but not in autocracies. Although explanations for this phenomenon vary, a common theme is that autocracies are more likely to misuse aid. We provide evidence of such misuse, showing that autocracies are more likely than democracies to divert development aid to the military. Theoretically, we build on “selectorate” models in which autocrats respond to aid by contracting civil liberties. Because this strategy requires military capacity, autocracies but not democracies should spend aid on the military. We support this hypothesis empirically, providing further evidence that autocracies misuse foreign aid.
Mean Platelet Volume and Related Factors in Patients at Different Stages of Diabetic Nephropathy
Authors: Turgutalp Kenan , Özhan Onur , Akbay Esen , Tombak Anıl , Tiftik Naci , Ozcan Turkay , Yılmaz Sercan , Helvacı İlter , Kiykim Ahmet
Published: August 2012

Introduction:

Mean platelet volume (MPV) is an independent cardiovascular disease predictor, and characteristics of MPV in patients with diabetic nephropathy (DN) are not well known.

Aim:

To determine the MPV levels in patients at different stages of DN.

Patients and Methods:

The MPV levels were investigated in healthy participants (group 1, n = 157), patients with type 2 diabetes mellitus without complication (group 2, n = 160), diabetic patients with clinical proteinuria (group 3, n = 144), and in patients with chronic kidney disease due to DN (group 4, n = 160).

Findings:

The MPV level was higher in all diabetic patients than that in normal participants ( P < .05). The MPV values had a positive correlation with the serum creatinine and proteinuria, and a negative correlation with the glomerular filtration rate ([GFR] P < .001 for all, r values; .72, and .82, and −.92, respectively).

Conclusion:

The MPV values were higher in diabetic groups than that in normal participants. Both GFR and proteinuria were the most powerful determinants of MPV.
Bivalirudin Utilization in Rats Undergoing Cardiopulmonary Bypass
Authors: Zhang Ruidong , Huang Yue , Zhang Mazhong , Liu Jinfen
Published: August 2012

Objective:

To investigate the impact of bivalirudin alternative treatment on antiheparin/platelet factor 4 antibody levels perioperatively in rats undergoing cardiopulmonary bypass (CPB).

Methods:

Two groups of rats received heparin pretreatment and two groups of rats not, and during CPB all the four groups received either bivalirudin or heparin. Pre-CPB and post-CPB day 7 venous blood samples were used to determine the levels of antiheparin/PF4 antibody immunoglobulin (Ig) G with enzyme-linked immunosorbent assay.

Results:

Preoperative heparin pretreatment increased the antiheparin/PF4 antibody IgG levels ( P < .01), while the administration of heparin further increased this levels ( P < .01). The use of bivalirudin prevented further increase in antiheparin/PF4 antibody IgG levels.

Conclusion:

Bivalirudin, as a direct thrombin inhibitor, could circumvent the increased antiheparin/PF4 antibody level in circulation due to the heparin administration.
The Association of Interleukin 6−634C/G Polymorphism With Left Atrial Thrombus and Severe Spontaneous Echocontrast in Patients With Atrial Fibrillation
Authors: Deng Xin-Tao , Jiang Min-Hui , Zhu Jian-Hua , Ge Li-Jun , Guo Jing , Gao Shu-Ping , Zheng Jin-Guo , Luan Hong , Shi Gui-Liang , Wang Ru-Xing , Shi Hai-Feng , Pan Min
Published: August 2012

Atrial fibrillation (AF) not only is an independent risk factor for death but also confers significant risk of morbidity from stroke associated with left atrial thrombus. The association of interleukin 6 ( IL-6) polymorphism with thrombus in AF has not been investigated before. We carried out a case–control study in Han Chinese. The IL-6 −634C/G genotypes of 31 patients with thrombus and 45 patients without thrombus were detected by polymerase chain reaction and restriction fragment length polymorphism. The frequencies of the IL-6 genotypes (CC, CG, and GG) were 29.03%, 54.54%, and 16.13% for the patients with thrombus, and 55.56%, 40.00%, and 4.44% for the patients without thrombus, respectively ( P = .0391). Compared with the CC genotype, the G allele carriers (CG + GG) had a 2.79-fold increased risk of thrombus or severe spontaneous echocontrast (SEC). These results suggest that IL-6 −634C/G polymorphism is associated with thrombus and severe SEC, and the G allele is an independent risk for thrombus and severe SEC in Han Chinese patients with AF.
The (F)utility of Post-Conviction Polygraph Testing
Authors: Rosky Jeffrey W.
Published: August 2012

The apparent utility of the polygraph to work both as a treatment and supervision aid and as a deterrent for future offending is cited as ample justification for its use. This article examines these claims to demonstrate that although post-conviction polygraph testing may have some utility by increasing disclosures of prior offending and, within specific cases, admissions of treatment and supervision violations, the limited evidence accumulated thus far does not adequately ascertain its accuracy nor support its efficacy or effectiveness as a deterrent. The article concludes with recommendations for creating a real evidentiary base beyond polygraph testing’s apparent ability to elicit more information from offenders to evidence that can determine whether it is efficacious and effective in reducing criminality and deviance.
Healthy Foods Thought to Be Unhealthy at First Glance
Authors: Alpert Patricia T.
Published: August 2012

In this highly fat-conscious society, several foods that were traditionally considered to be unhealthy are now proving to be of great health value and can be consumed on a regular basis. In this issue, the health benefits of the foods most commonly perceived as unhealthy are featured in the hopes of raising public consciousness. Consuming these foods in moderation may be protective against some of the chronic diseases.
Potential Role of Poly(ADP-Ribose) Polymerase (PARP) Activation in Methotrexate-Induced Nephrotoxicity and Tubular Apoptosis
Authors: Dalaklioglu Selvinaz , Sahin Pinar , Ordueri Ece Gungor , Celik-Ozenci Ciler , Tasatargil Arda
Published: August 2012

Nephrotoxicity is one of the serious dose-limiting complications of methotrexate (MTX) when used in the treatment of various malignancies and nononcological diseases. The aim of this study was to investigate the role of poly(adenosine diphosphate ribose) polymerase (PARP) activity in MTX-induced nephrotoxicity. Rats were divided into 4 groups as control, MTX treated (MTX, 7 mg/kg per d, intraperitoneally [ip], once daily for 3 consecutive days), MTX plus 1,5-isoquinelinediol (ISO, a PARP inhibitor, 3 mg/kg per d, i.p.) treated, or ISO treated. Histopathology of kidneys was evaluated by light microscopy. Terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling assay was used to analyze apoptosis in kidney sections. Blood urea nitrogen (BUN), serum creatinine, and urinary N-acetyl-β-d-glucosaminidase (NAG) were used as biochemical markers of MTX-induced renal injury. Our results showed that MTX administration significantly increased BUN, serum creatinine, and urinary NAG levels. The PARP-1 and PAR (a product of PARP activity) expression and apoptotic cell death were also markedly increased in renal tubules after MTX administration. The ISO treatment attenuated MTX-induced renal injury, as indicated by BUN and serum creatinine levels, urinary NAG excretion, and renal histology. The PARP inhibitor treatment reduced PARP-1 and PAR expression to levels similar to that of controls. These results revealed that ISO may have a protective effect against the nephrotoxic effects of MTX by inhibiting PARP activation. This is the first study that demonstrates the role of PARP activation in MTX-induced nephrotoxicity and tubular apoptosis.
Bilateral ureteropelvic junction stenosis causing hydronephrosis and renal failure in an adult cat
Authors: Foster Jonathan D , Pinkerton Marie E
Published: August 2012

A 3.5-year-old male neutered cat was presented for investigation of renomegaly appreciated during a routine physical examination. Marked renomegaly due to bilateral hydronephrosis was detected and further testing identified International Renal Interest Society stage 2, non-hypertensive, non-proteinuric chronic kidney disease. Ten months later the cat was evaluated for acute lethargy; severe azotemia with oliguria was documented. Medical therapy failed to result in clinical improvement and the cat was euthanased. Necropsy revealed bilateral marked hydronephrosis secondary to a tortuous proximal ureter consistent with proximal ureteropelvic junction stenosis. This is the first report of this disorder leading to progressive renal failure in a cat.
Cerebral coenurosis in a cat caused by Taenia serialis: neurological, magnetic resonance imaging and pathological features
Authors: Jull Philip , Browne Elizabeth , Boufana Belgees S , Schöniger Sandra , Davies Emma
Published: August 2012

Clinical summary:

A 4-year-old Birman cat was presented with marked obtundation and non-ambulatory tetraparesis. Two well-demarcated, intra-axial T2-hyperintense, T1-hypointense structures, which did not contrast enhance, were evident on magnetic resonance imaging (MRI). Histopathology of the structures revealed metacestodes that were morphologically indicative of larval stages of Taenia species. Polymerase chain reaction amplification of a fragment within the 12S rRNA gene confirmed the subspecies as Taenia serialis.

Practical significance:

This is the first report of MRI findings of cerebral coenurosis caused by T serialis in a cat. Early MRI should be considered an important part of the diagnostic work-up for this rare clinical disease, as it will help guide subsequent treatment and may improve the prognosis.
Simulations on flow and soot deposition in diesel particulate filters
Authors: Yamamoto Kazuhiro , Ohori Shinya
Published: August 2012

To reduce particulate matter, including soot in diesel exhaust gas, a diesel particulate filter has been developed. In the after-treatment of exhaust gas, the filter traps particulate matter when the exhaust gas passes its porous wall. An increase of particulate matter accumulation could cause technological problems due to the higher filter back-pressure. This can result in a subsequent worsening of fuel efficiency and a decrease in engine output. However, it is difficult to experimentally observe the phenomena in diesel particulate filters. In this study, we simulated the flow with soot deposition using the lattice Boltzmann method. To discuss the flow in a real cordierite filter, a tomography-assisted simulation was conducted, and the inner structure of the filter was scanned using a three-dimensional X-ray computed tomography technique. The local velocity and pressure distributions in the filter were clearly visualized. To model the soot deposition, a parameter of soot deposition probability was used. Results show that the pressure drop increases as more soot is deposited. When the soot deposition probability of the parameter of soot deposition is larger, the soot deposition region is limited to the filter wall surface, corresponding to surface filtration. The pressure drop is smaller as the parameter of soot deposition is increased.
The Impact of Weight-Based Discrimination in the Health Care Setting
Authors: Johnston Craig A.
Published: August 2012

Considerable attention has been given to the behaviors that need to be changed in individuals who are overweight and obese. Much less attention has been given to the behaviors that need to be changed in health care professionals who treat these individuals. Specifically, health care professionals, similar to the general population, have been shown to engage in weight-based discrimination. The impact this may have on patients is discussed.
The Legal Strategy of the Cruise Line Industry
Authors: Wilson Robert H.
Published: August 2012

The three dominant North American cruise line companies have developed an effective legal strategy that provides a strategic, competitive advantage involving any dispute or litigation with a guest. All cruise guests are required to sign a contract containing similar terms and conditions that limit the loss for personal property, death, personal injury, emotional stress, and mental anguish; require written notice of claims; require filing of lawsuits within a specified shortened period of time; provide mandatory arbitration for certain claims; and waive class actions. The terms and conditions also take advantage of and conform to legislation affecting the maritime industry. At the heart of the strategy is the identical forum selection clause requiring all guests to initiate all suits in the U.S. District Court for Southern Florida. Because most litigation takes place in the same court, corporate counsel will have the benefit of being able to modify and update their terms and conditions to reflect the court’s most recent decisions, even when they were not parties to the case. The ability of litigating in a location close to their home offices is also a huge convenience factor. Equally important, the forum may be one that is very inconvenient for the guest, a factor that may cause some cases to be settled early. The strategy of an industry-wide, comprehensive, and similar set of terms and conditions, anchored by a forum selection clause, is an effective litigation strategy that might be used as model by lodging companies as part of their online contracts.
Pain as a Comorbidity of Pediatric Obesity
Authors: Hainsworth Keri R. , Miller Lawrence A. , Stolzman Stacy C. , Fidlin Brian M. , Davies W. Hobart , Weisman Steven J. , Skelton Joseph A.
Published: August 2012

The purpose of this study was to document the prevalence and characteristics of physical pain in a sample of severely obese children and adolescents. In this retrospective chart review, primary measures included current and past pain, pain intensity, and pain characteristics during a 5-minute walk test. Pain assessments for 74 patients (mean age 11.7 years; 53% female; 41% African American) were conducted by a physical therapist. Past pain was reported by 73% of the sample, with 47% reporting pain on the day of program enrollment. Although average pain intensity was moderate (M = 5.5/10), alarmingly, 42% of those with current pain reported severe pain (6/10 to 10/10). Overall, pain occurred primarily in the lower extremities and with physical activity. Patients reporting current pain had a significantly higher body mass index than those reporting no pain. These findings suggest that pain is common in severely obese youth, and furthermore, that pain should be recognized as a comorbidity of pediatric obesity. Routinely screening severely obese children and adolescents for pain presence and intensity is recommended.
An Innovative Program to Address Learning Barriers in Small Schools
Authors: Fast Gail Ann , Gray Lorali , Miles-Koehler Mona
Published: August 2012

While all schools in Washington State have had to deal with shrinking financial resources, small, rural school districts, with fewer than 2,000 students, face unique circumstances that further challenge their ability to meet rising student health needs. This article will explore how small districts utilize the services of the Washington State School Nurse Corps (SNC), an innovative program that supports student health and safety while reducing barriers to learning. Through direct registered nursing services and regional nurse administrative consultation and technical assistance, the SNC strengthens rural school districts’ capacity to provide a safe and healthy learning environment. In addition, we will examine current research that links health and learning to discover how the SNC model is successful in addressing health risks as barriers to learning. Lastly, as resources continue to dwindle, partnerships between schools, the SNC, and state and local health and education organizations will be critical in maintaining health services and learning support to small, rural schools.
Neuro Excellence in the ICU
Authors: Peled Harry , Ramos Laura , Katz Micheal
Published: August 2012

There is significant literature showing improved outcomes in patients who are cared for in a specialized neurocritical care unit. The authors propose a model where the key aspects of specialized neurocrticial care can be provided within the framework of an existing ICU in an efficient and effective manner as an alternative to a separate neurocritical care unit. The key aspects of programmatic success are described.
Initial Experience With ImaCor hTEE-Guided Management of Patients Following Transplant and Mechanical Circulatory Support
Authors: Kang Christpher Y. , Hirose Hitoshi , Hastings Harold M. , Cavarocchi Nicholas C.
Published: August 2012

This study reviews an initial experience using a miniaturized transesophageal echocardiography (TEE) probe (ImaCor, Garden City, NY) with 3 patients in whom Imacor hTEE intervention was used as a point-of-care device to manage extracorporeal membrane oxygenation cannula placement, cardiac hemodynamics, and postoperative cardiac pathophysiology. The management of transplant or mechanical circulatory support (MCS) patients is especially challenging: Transplanted hearts pose unique pathophysiological challenges, and MCS significantly alters pressure–volume–flow relationships. Real-time “hemodynamic” TEE (hTEE) can help provide effective management by direct visualization of cardiac filling and function and help guide hemodynamic management. In the authors’ initial experience, hTEE can provide point-of-care management following transplant or MCS.
Management of High-Energy Acetabular Fractures in the Elderly Individuals
Authors: Hill Brian W. , Switzer Julie A. , Cole Peter A.
Published: August 2012

Acetabular fractures in the elderly individuals are increasing in prevalence. Although there is evidence in the literature that acetabular fractures in elderly patients sustained as a result of low-energy mechanisms can be well treated by nonoperative management, open reduction and internal fixation, or even acute arthroplasty, almost no literature exists that may appropriately guide the treatment of elderly acetabular fractures that occur as a result of high-energy mechanisms. In spite of this lack of evidence, specific principles for providing the best care in adult trauma patients may reasonably be adopted. These principles include aggressive resuscitation and medical optimization; surgical care that focuses on a patient’s survival but does not sacrifice skeletal stability; and early mobilization. Best practices that guide the care of hip fracture patients, such as a team approach to care, the use of protocols to guide treatment, and the timing of surgery to occur as soon as is safely possible also should be employed to guide care in patients who have sustained acetabular fractures. Opportunity exists to better study these higher energy fractures and to, thereby, affect outcomes in patients who have sustained them.
Inhibition of hedgehog signaling for the treatment of murine sclerodermatous chronic graft-versus-host disease
Authors: Zerr Pawel , Palumbo-Zerr Katrin , Distler Alfiya , Tomcik Michal , Vollath Stefan , Munoz Luis E. , Beyer Christian , Dees Clara , Egberts Friederike , Tinazzi Ilaria , Del Galdo Francesco , Distler Oliver , Schett Georg , Spriewald Bernd M. , Distler Jörg H. W.
Published: August 2012

Chronic graft-versus-host disease (cGVHD) is a prognosis limiting complication of allogeneic stem cell transplantation. The molecular mechanisms underlying cGVHD are incompletely understood, and targeted therapies are not yet established for clinical use. Here we examined the role of the hedgehog pathway in sclerodermatous cGVHD. Hedgehog signaling was activated in human and murine cGVHD with increased expression of sonic hedgehog and accumulation of the transcription factors Gli-1 and Gli-2. Treatment with LDE223, a highly selective small-molecule antagonist of the hedgehog coreceptor Smoothened (Smo), abrogated the activation of hedgehog signaling and protected against experimental cGVHD. Preventive therapy with LDE223 almost completely impeded the development of clinical and histologic features of sclerodermatous cGVHD. Treatment with LDE223 was also effective, when initiated after the onset of clinical manifestations of cGVHD. Hedgehog signaling stimulated the release of collagen from cultured fibroblasts but did not affect leukocyte influx in murine cGVHD, suggesting direct, leukocyte-independent stimulatory effects on fibroblasts as the pathomechanism of hedgehog signaling in cGVHD. Considering the high morbidity of cGVHD, the current lack of efficient molecular therapies for clinical use, and the availability of well-tolerated inhibitors of Smo, targeting hedgehog signaling might be a novel strategy for clinical trials in cGVHD.
Microfluidic kit-on-a-lid: a versatile platform for neutrophil chemotaxis assays
Authors: Sackmann Eric K. , Berthier Erwin , Young Edmond W.K. , Shelef Miriam A. , Wernimont Sarah A. , Huttenlocher Anna , Beebe David J.
Published: August 2012

Improvements in neutrophil chemotaxis assays have advanced our understanding of the mechanisms of neutrophil recruitment; however, traditional methods limit biologic inquiry in important areas. We report a microfluidic technology that enables neutrophil purification and chemotaxis on-chip within minutes, using nanoliters of whole blood, and only requires a micropipette to operate. The low sample volume requirements and novel lid-based method for initiating the gradient of chemoattractant enabled the measurement of human neutrophil migration on a cell monolayer to probe the adherent and migratory states of neutrophils under inflammatory conditions; mouse neutrophil chemotaxis without sacrificing the animal; and both 2D and 3D neutrophil chemotaxis. First, the neutrophil chemotaxis on endothelial cells revealed 2 distinct neutrophil phenotypes, showing that endothelial cell-neutrophil interactions influence neutrophil chemotactic behavior. Second, we validated the mouse neutrophil chemotaxis assay by comparing the adhesion and chemotaxis of neutrophils from chronically inflamed and wild-type mice; we observed significantly higher neutrophil adhesion in blood obtained from chronically inflamed mice. Third, we show that 2D and 3D neutrophil chemotaxis can be directly compared using our technique. These methods allow for new avenues of research while reducing the complexity, time, and sample volume requirements to perform neutrophil chemotaxis assays.
Impact of hydroxyurea on clinical events in the BABY HUG trial
Authors: Thornburg Courtney D. , Files Beatrice A. , Luo Zhaoyu , Miller Scott T. , Kalpatthi Ram , Iyer Rathi , Seaman Phillip , Lebensburger Jeffrey , Alvarez Ofelia , Thompson Bruce , Ware Russell E. , Wang Winfred C.
Published: August 2012

The Pediatric Hydroxyurea Phase 3 Clinical Trial (BABY HUG) was a phase 3 multicenter, randomized, double-blind, placebo-controlled clinical trial of hydroxyurea in infants (beginning at 9-18 months of age) with sickle cell anemia. An important secondary objective of this study was to compare clinical events between the hydroxyurea and placebo groups. One hundred and ninety-three subjects were randomized to hydroxyurea (20 mg/kg/d) or placebo; there were 374 patient-years of on-study observation. Hydroxyurea was associated with statistically significantly lower rates of initial and recurrent episodes of pain, dactylitis, acute chest syndrome, and hospitalization; even infants who were asymptomatic at enrollment had less dactylitis as well as fewer hospitalizations and transfusions if treated with hydroxyurea. Despite expected mild myelosuppression, hydroxyurea was not associated with an increased risk of bacteremia or serious infection. These data provide important safety and efficacy information for clinicians considering hydroxyurea therapy for very young children with sickle cell anemia. This clinical trial is registered with the National Institutes of Health (NCT00006400, www.clinicaltrials.gov).
Monitoring chronic lymphocytic leukemia progression by whole genome sequencing reveals heterogeneous clonal evolution patterns
Authors: Schuh Anna , Becq Jennifer , Humphray Sean , Alexa Adrian , Burns Adam , Clifford Ruth , Feller Stephan M. , Grocock Russell , Henderson Shirley , Khrebtukova Irina , Kingsbury Zoya , Luo Shujun , McBride David , Murray Lisa , Menju Toshi , Timbs Adele , Ross Mark , Taylor Jenny , Bentley David
Published: August 2012

Chronic lymphocytic leukemia is characterized by relapse after treatment and chemotherapy resistance. Similarly, in other malignancies leukemia cells accumulate mutations during growth, forming heterogeneous cell populations that are subject to Darwinian selection and may respond differentially to treatment. There is therefore a clinical need to monitor changes in the subclonal composition of cancers during disease progression. Here, we use whole-genome sequencing to track subclonal heterogeneity in 3 chronic lymphocytic leukemia patients subjected to repeated cycles of therapy. We reveal different somatic mutation profiles in each patient and use these to establish probable hierarchical patterns of subclonal evolution, to identify subclones that decline or expand over time, and to detect founder mutations. We show that clonal evolution patterns are heterogeneous in individual patients. We conclude that genome sequencing is a powerful and sensitive approach to monitor disease progression repeatedly at the molecular level. If applied to future clinical trials, this approach might eventually influence treatment strategies as a tool to individualize and direct cancer treatment.
Phase 2 study of the lenalidomide and azacitidine combination in patients with higher-risk myelodysplastic syndromes
Authors: Sekeres Mikkael A. , Tiu Ramon V. , Komrokji Rami , Lancet Jeffrey , Advani Anjali S. , Afable Manuel , Englehaupt Ricki , Juersivich Joyce , Cuthbertson David , Paleveda Jennifer , Tabarroki Ali , Visconte Valeria , Makishima Hideki , Jerez Andres , Paquette Ronald , List Alan F. , Maciejewski Jaroslaw P.
Published: August 2012

Lenalidomide and azacitidine each have activity in myelodysplastic syndromes (MDS) patients, where both microenvironment and cell-regulatory mechanisms contribute to disease pathogenesis. The objective of this multicenter, phase 2 expansion trial was to determine the efficacy and safety of combination therapy with azacitidine (75 mg/m2/d for 5 days) and lenalidomide (10 mg/d for 21 days; 28-day cycle) in patients with higher-risk MDS. Among 36 patients enrolled (18 phase 1, 18 phase 2), median age was 68 years (range, 47-78 years) and follow-up was 12 months (range, 3-55 years). IPSS categories included intermediate-1 (n = 5 patients with excess blasts), intermediate-2 (20), and high (11). Common grade 3/4 nonhematologic adverse events included febrile neutropenia (22% of patients), other infection (11%), pulmonary (11%), cardiac (11%), constitutional (11%), and dermatologic (11%). The overall response rate (per modified MDS International Working Group criteria) was 72%: 16 patients (44%) achieved a complete response (CR), and 10 (28%) had hematologic improvement. Median CR duration was 17+ months (range, 3-39+); median overall survival was 37+ months (range, 7-55+) for CR patients, and 13.6 months for the entire cohort (range, 3-55). TET2/DNMT3A/IDH1/2 mutational status was associated with response in a limited number of patients. The lenalidomide/azacitidine combination is well-tolerated and highly active in treating greater-risk MDS. This study is registered at http://www.clinicaltrials.gov as NCT00352001.
Melanoma incidence trends in Limburg after screening and prevention campaigns
Authors: Vanstraelen D , Deleu H , Van Robays J , Dhollander D , Cloes E , Lousberg D , Kuipers G , Adriaens B , Mebis J , Mathei C , Buntinx F
Published: August 2012

Background

Malignant melanoma is a skin cancer of which the incidence is said to be raising in recent years. Prevention may result in decrease of the incidence. Early detection may result in the detection of earlier stages of the disease. In Limburg a combined campaign of prevention and screening has been performed in recent years and its effects should be evaluated.

Objectives

To study time trends of malignant melanoma incidence and the evolution of stages of detected melanomas and to relate them to interventions in previous years.

Methods

An ongoing multi-faceted intervention, including information as well as screening invitations (Euromelanoma project) was implemented in 1999. Time trends of malignant melanoma were studied on the basis of data from the Limburg Cancer Registry (LIKAR) of 1996-2005. Stages were studied on the basis of an additional clinical registration completed by pathologists and dermatologists.

Results

Over the years 1996-2005, the crude incidence rate of malignant melanoma was 6.8/100,000 patient-years in males and 11.6 in females, with a European standardized incidence rate (ESR) of 6.4 in males and 10.5 in females. The incidence progressively increased with age.

In males, the ESR initially decreased, followed by a significant increase from 3.0 in 1998 to 7.6 in 2005. On average this is a yearly increase of 0.5 per 100,000 persons (p= 0.04). In females the curve fluctuates, resulting in almost similar rates in 1996 and 2004 (p = 0.85), but with a sudden increase from 9.2 to 15.8 between 2004 and 2005.

Neither the Breslow nor the Clarck classification showed any significant change over the registration period. The proportion of lymph node invasion, metastasis and ulcerations did not change.

Discussion

With the exception of a small and clinically irrelevant increase in ESR in males, no changes over time were detected in incidence or stage distribution. The effect of the intervention seems limited.
Distribution of events of positive selection and population differentiation in a metabolic pathway: the case of asparagine N-glycosylation
Authors: Dall’Olio Giovanni Marco , Laayouni Hafid , Luisi Pierre , Sikora Martin , Montanucci Ludovica , Bertranpetit Jaume
Published: August 2012

Background

Asparagine N-Glycosylation is one of the most important forms of protein post-translational modification in eukaryotes. This metabolic pathway can be subdivided into two parts: an upstream sub-pathway required for achieving proper folding for most of the proteins synthesized in the secretory pathway, and a downstream sub-pathway required to give variability to trans-membrane proteins, and involved in adaptation to the environment and innate immunity. Here we analyze the nucleotide variability of the genes of this pathway in human populations, identifying which genes show greater population differentiation and which genes show signatures of recent positive selection. We also compare how these signals are distributed between the upstream and the downstream parts of the pathway, with the aim of exploring how forces of population differentiation and positive selection vary among genes involved in the same metabolic pathway but subject to different functional constraints.

Results

Our results show that genes in the downstream part of the pathway are more likely to show a signature of population differentiation, while events of positive selection are equally distributed among the two parts of the pathway. Moreover, events of positive selection are frequent on genes that are known to be at bifurcation points, and that are identified as being in key position by a network-level analysis such as MGAT3 and GCS1.

Conclusions

These findings indicate that the upstream part of the Asparagine N-Glycosylation pathway has lower diversity among populations, while the downstream part is freer to tolerate diversity among populations. Moreover, the distribution of signatures of population differentiation and positive selection can change between parts of a pathway, especially between parts that are exposed to different functional constraints. Our results support the hypothesis that genes involved in constitutive processes can be expected to show lower population differentiation, while genes involved in traits related to the environment should show higher variability. Taken together, this work broadens our knowledge on how events of population differentiation and of positive selection are distributed among different parts of a metabolic pathway.
Effects of starting hemodialysis with an arteriovenous fistula or central venous catheter compared with peritoneal dialysis: a retrospective cohort study
Authors: Coentrão Luis , Santos-Araújo Carla , Dias Claudia , Neto Ricardo , Pestana Manuel
Published: August 2012

Background

Although several studies have demonstrated early survival advantages with peritoneal dialysis (PD) over hemodialysis (HD), the reason for the excess mortality observed among incident HD patients remains to be established, to our knowledge. This study explores the relationship between mortality and dialysis modality, focusing on the role of HD vascular access type at the time of dialysis initiation.

Methods

A retrospective cohort study was performed among local adult chronic kidney disease patients who consecutively initiated PD and HD with a tunneled cuffed venous catheter (HD-TCC) or a functional arteriovenous fistula (HD-AVF) in our institution in the year 2008. A total of 152 patients were included in the final analysis (HD-AVF, n = 59; HD-TCC, n = 51; PD, n = 42). All cause and dialysis access-related morbidity/mortality were evaluated at one year. Univariate and multivariate analysis were used to compare the survival of PD patients with those who initiated HD with an AVF or with a TCC.

Results

Compared with PD patients, both HD-AVF and HD-TCC patients were more likely to be older (p<0.001) and to have a higher frequency of diabetes mellitus (p = 0.017) and cardiovascular disease (p = 0.020). Overall, HD-TCC patients were more likely to have clinical visits (p = 0.069), emergency room visits (p<0.001) and hospital admissions (p<0.001). At the end of follow-up, HD-TCC patients had a higher rate of dialysis access-related complications (1.53 vs. 0.93 vs. 0.64, per patient-year; p<0.001) and hospitalizations (0.47 vs. 0.07 vs. 0.14, per patient-year; p = 0.034) than HD-AVF and PD patients, respectively. The survival rates at one year were 96.6%, 74.5% and 97.6% for HD-AVF, HD-TCC and PD groups, respectively (p<0.001). In multivariate analysis, HD-TCC use at the time of dialysis initiation was the important factor associated with death (HR 16.128, 95%CI [1.431-181.778], p = 0.024).

Conclusion

Our results suggest that HD vascular access type at the time of renal replacement therapy initiation is an important modifier of the relationship between dialysis modality and survival among incident dialysis patients.
Elevated levels of serum amyloid A indicate poor prognosis in patients with esophageal squamous cell carcinoma
Authors: Wang Jun-Ye , Zheng Yu-Zhen , Yang Juan , Lin Yue-Hao , Dai Shu-Qin , Zhang Ge , Liu Wan-Li
Published: August 2012

Background

Increase of Serum amyloid A (SAA) level has been observed in patients with a variety of cancers. The objective of this study was to determined whether SAA level could be used as a prognostic parameter in patients with esophageal squamous cell carcinoma (ESCC).

Methods

SAA levels were measured by rate nephelometry immunoassay in 167 healthy controls and 167 ESCC patients prior to surgical resection. Statistical associations between clinicopathological observations and SAA levels were determined using the Mann–Whitney U test. The clinical value of SAA level as a prognostic parameter was evaluated using the Cox’s proportional hazards model.

Results

SAA levels were significantly higher in patients with ESCC compared to levels in healthy controls (13.88 ± 15.19 mg/L vs. 2.26 ± 1.66 mg/L, P < 0.001). Elevation of SAA levels (≥ 8.0 mg/L) was observed in 54.5% (91/167) of patients with ESCC but not in healthy controls. SAA levels were associated with tumor size (P < 0.001), histological differentiation (P = 0.015), T classification (P < 0.001), clinical stage (P < 0.001), lymph node metastasis (P < 0.001) and distant metastasis (P < 0.001), but not with the age and gender of the patients or tumor location. Multivariate analysis revealed that patients with an elevated level of SAA (≥ 8.0 mg/L) had significantly lower 5-year survival rate than those with non-elevated SAA (< 8.0 mg/L, log-rank P < 0.0001).

Conclusions

An elevated level of preoperative SAA was found to associate with tumor progression and poor survival in patients with ESCC.
Vaccinia virus-mediated intra-tumoral expression of matrix metalloproteinase 9 enhances oncolysis of PC-3 xenograft tumors
Authors: Schäfer Simon , Weibel Stephanie , Donat Ulrike , Zhang Qian , Aguilar Richard J , Chen Nanhai G , Szalay Aladar A
Published: August 2012

Background

Oncolytic viruses, including vaccinia virus (VACV), are a promising alternative to classical mono-cancer treatment methods such as surgery, chemo- or radiotherapy. However, combined therapeutic modalities may be more effective than mono-therapies. In this study, we enhanced the effectiveness of oncolytic virotherapy by matrix metalloproteinase (MMP-9)-mediated degradation of proteins of the tumoral extracellular matrix (ECM), leading to increased viral distribution within the tumors.

Methods

For this study, the oncolytic vaccinia virus GLV-1h255, containing the mmp-9 gene, was constructed and used to treat PC-3 tumor-bearing mice, achieving an intra-tumoral over-expression of MMP-9. The intra-tumoral MMP-9 content was quantified by immunohistochemistry in tumor sections. Therapeutic efficacy of GLV-1h255 was evaluated by monitoring tumor growth kinetics and intra-tumoral virus titers. Microenvironmental changes mediated by the intra-tumoral MMP-9 over-expression were investigated by microscopic quantification of the collagen IV content, the blood vessel density (BVD) and the analysis of lymph node metastasis formation.

Results

GLV-1h255-treatment of PC-3 tumors led to a significant over-expression of intra-tumoral MMP-9, accompanied by a marked decrease in collagen IV content in infected tumor areas, when compared to GLV-1h68-infected tumor areas. This led to considerably elevated virus titers in GLV-1h255 infected tumors, and to enhanced tumor regression. The analysis of the BVD, as well as the lumbar and renal lymph node volumes, revealed lower BVD and significantly smaller lymph nodes in both GLV-1h68- and GLV-1h255- injected mice compared to those injected with PBS, indicating that MMP-9 over-expression does not alter the metastasis-reducing effect of oncolytic VACV.

Conclusions

Taken together, these results indicate that a GLV-1h255-mediated intra-tumoral over-expression of MMP-9 leads to a degradation of collagen IV, facilitating intra-tumoral viral dissemination, and resulting in accelerated tumor regression. We propose that approaches which enhance the oncolytic effect by increasing the intra-tumoral viral load, may be an effective way to improve therapeutic outcome.