bluuebunny/crossref_metadata_2025 huggingface dataset:
Emergence of insulin resistance in juvenile baboon offspring of mothers exposed to moderate maternal nutrient reduction
Authors: Choi Jaehyek , Li Cun , McDonald Thomas J. , Comuzzie Anthony , Mattern Vicki , Nathanielsz Peter W.
Published: June 2011

Developmental programming of postnatal pancreatic β-cell and peripheral insulin function by maternal nutrient reduction (MNR) has been extensively investigated in rodents and sheep, but no data exist from nonhuman primate offspring of MNR mothers. We hypothesized that moderate levels of MNR would result in developmental programming of postnatal β-cell function and peripheral insulin sensitivity that lead to emergence of a prediabetic state prior to puberty. Prepregnancy phenotype of 18 nonpregnant baboons was matched. During pregnancy and lactation 12 mothers ate chow ad libitum (controls), while six ate 70% of chow consumed by controls (weight-adjusted MNR). Weaned offspring ate normal chow. At 3.5 ± 0.18 yr (mean ± SE) in an intravenous glucose tolerance test, conscious, tethered MNR juvenile offspring (2 females and 4 males) showed increased fasting glucose ( P < 0.04), fasting insulin ( P < 0.04), and insulin area under the curve (AUC; P < 0.01) compared with controls (8 females and 4 males). Insulin AUC also increased following an arginine challenge ( P < 0.02). Baseline homeostatic model assessment insulin β-cell sensitivity was greater in MNR offspring than controls ( P < 0.03). In a hyperinsulinemic, euglycemic clamp, the glucose disposal rate decreased 26% in MNR offspring. Changes observed were not sex dependent. MNR in pregnancy and lactation programs offspring metabolic responses, increasing insulin resistance and β-cell responsiveness, resulting in emergence of an overall phenotype that would predispose to later life type-2 diabetes, especially, should other dietary challenges such as a Westernized diet be experienced.
Effects of Different Salinities on Juvenile Growth ofGammarus aequicauda(Malacostraca: Amphipoda)
Authors: Delgado Lídia , Guerao Guillermo , Ribera Carles
Published: June 2011

Gammarus aequicaudais a euryhaline amphipod that is a common inhabitant of brackish environments of the Mediterranean Sea. In the Ebro delta, the population density ofG. aequicaudais highly variable throughout the year. The main objective of this study is to investigate the effect of salinity on the growth ofG. aequicaudajuveniles.G. aequicaudaembryos and juveniles can survive and grow in the laboratory between 2 psu and 40 psu salinity, depending on the previous acclimation period for the reproductive individuals. Adults acclimated at 34 psu produced embryos and juveniles that survived and developed at salinities between 9 psu and 40 psu; adults acclimated at 9 psu produced embryos and juveniles that could develop in oligohaline conditions. The lower growth rate values were 10.9 μm d−1and 13.5 μm d−1at 40 psu and 2 psu, respectively, with the higher values of 18.0 μm d−1and 18.5 μm d−1at 19 and 34 psu, respectively.
A Model Analysis of Tensile Stress in the Toadfish Vestibular Membranes
Authors: Pender Daniel J.
Published: June 2011

Background. A theoretical model analysis of stress in the vestibular membranes has identified a geometrical stress factor incorporating shape, size, and thickness that can be used to assess peak stress in the various chambers.Methods. Using published measurements of the toadfish vestibular membranes made during surgery, the geometrical stress factor can be evaluated for each chamber based on the model.Results. The mean geometrical stress factor is calculated to be the lowest in the semicircular canal (4.4), intermediate in the ampulla (6.0), and the highest in the utricle (17.4).Conclusions. The model predicts that substantial hoop stress disparities exist in the toadfish vestibular labyrinth. Stress is least in the semicircular canal, which therefore appears to be the structure with greatest stability. The utricle is found to be the most stress prone structure in the vestibular labyrinth and therefore appears to be the chamber most vulnerable to distention and potential modification.
Early Detection of Nasopharyngeal Carcinoma
Authors: Tabuchi Keiji , Nakayama Masahiro , Nishimura Bungo , Hayashi Kentaro , Hara Akira
Published: June 2011

Nasopharyngeal carcinoma (NPC) is a unique disease with a clinical presentation, epidemiology, and histopathology differing from other squamous cell carcinomas of the head and neck. NPC is an Epstein-Barr virus-associated malignancy with a marked racial and geographic distribution. Specifically, it is highly prevalent in southern China, Southeast Asia, and the Middle East. To date, most NPC patients have been diagnosed in the advanced stage, but the treatment results for advanced NPC are not satisfactory. This paper provides a brief overview regarding NPC, with the focus on the early detection of initial and recurrent NPC lesions.
Monte Carlo Simulation of Linear Polymer Thermal Depolymerization under Isothermal and Dynamic Modes
Authors: Bystritskaya Elena V. , Karpukhin Oleg N. , Kutsenova Alla V.
Published: June 2011

Kinetics of linear polymer thermal depolymerization under isothermal and dynamic TGA modes was simulated by the Monte Carlo method. The simulation was carried out on model arrays having the same initial degree of polymerization and different width (polydispersity index, ) at three constant temperatures and five heating rates. Kinetics of the process in both modes is described by the Avrami equation, the exponent in which decreasing as the distribution width increases. Treatment of the model kinetic curves of degradation using the nonlinear regression method by the Avrami equation, under both isothermal and dynamic modes, gives correct activation energy and pre-exponential factor values independently of the initial PDI. Data obtained in the dynamic mode were also treated by two isoconversion methods, widely applied to kinetic analysis of TGA curves (Flynn-Wall-Ozawa method and Kissinger-Akahira-Sunose (KAS) method).
Functional Inequalities Associated with Cauchy Additive Functional Equation in Non‐Archimedean Spaces
Authors: Ebadian A. , Ghobadipour N. , Rassias Th. M. , Gordji M. Eshaghi
Published: June 2011

We investigate the generalized Hyers‐Ulam stability of the functional inequalities ∥f((x + y + z)/4) + f((3x − y − 4z)/4) + f((4x + 3z)/4)∥≤∥2f(x)∥ and ∥f((y − x)/3) + f((x − 3z)/3) + f((3x + 3z − y)/3)∥≤∥f(x)∥ in non‐Archimedean normed spaces in the spirit of the Th. M. Rassias stability approach.
High Frequency of PIK3R1 and PIK3R2 Mutations in Endometrial Cancer Elucidates a Novel Mechanism for Regulation of PTEN Protein Stability
Authors: Cheung Lydia W.T. , Hennessy Bryan T. , Li Jie , Yu Shuangxing , Myers Andrea P. , Djordjevic Bojana , Lu Yiling , Stemke-Hale Katherine , Dyer Mary D. , Zhang Fan , Ju Zhenlin , Cantley Lewis C. , Scherer Steven E. , Liang Han , Lu Karen H. , Broaddus Russell R. , Mills Gordon B.
Published: June 2011

We demonstrate that phosphatidylinositol 3-kinase (PI3K) pathway aberrations occur in >80% of endometrioid endometrial cancers, with coordinate mutations of multiple PI3K pathway members being more common than predicted by chance. PIK3R1 (p85α) mutations occur at a higher rate in endometrial cancer than in any other tumor lineage, and PIK3R2 (p85β), not previously demonstrated to be a cancer gene, is also frequently mutated. The dominant activation event in the PI3K pathway appears to be PTEN protein loss. However, in tumors with retained PTEN protein, PI3K pathway mutations phenocopy PTEN loss, resulting in pathway activation. KRAS mutations are common in endometrioid tumors activating independent events from PI3K pathway aberrations. Multiple PIK3R1 and PIK3R2 mutations demonstrate gain of function, including disruption of a novel mechanism of pathway regulation wherein p85α dimers bind and stabilize PTEN. Taken together, the PI3K pathway represents a critical driver of endometrial cancer pathogenesis and a novel therapeutic target.

Significance: Our data indicate that the PI3K pathway is targeted in the vast majority of endometrioid endometrial cancers leading to PI3K pathway activation. Frequent oncogenic mutations in PIK3R1 and PIK3R2 provide evidence for their role in endometrial cancer pathophysiology with patient-specific mutations revealing a novel mechanism by which p85α regulates the PI3K pathway through stabilizing PTEN. Cancer Discovery; 1(2); 170–85. ©2011 AACR.

Read the Commentary on this article by Herrero-Gonzalez and Di Cristofano, p. 106

This article is highlighted in the In This Issue feature, p. 91
From Archaic Narcissism to Empathy for the Self
Authors: Gehrie Mark J.
Published: June 2011

The concept of the selfobject was central to Heinz Kohut’s psychology of the self. With an eye to studying the development of narcissism and its implications for the growth of new psychic structure, this concept is reviewed and reassessed. Post-Kohutian complexities regarding its definition and use extend our consideration of the development of narcissism beyond archaic configurations toward further evolution of the self and the nature of mature narcissism. The hypothesis is offered that developing narcissism and the growth of self-regulation impact the acquisition of new structure and new capacities through the emergence of newly potentiated aspects of the self. The implications of these emergent qualities of the self are examined in the context of our understanding of self-esteem regulation, the state of the self, and the goals of psychoanalysis. A clinical example illustrates how technique and process in an analysis may be organized around the development of such new capacities.
Wisdom in the Jewish and Christian Scriptures: Wisdom in the New Testament
Authors: Thiselton Anthony C.
Published: June 2011

Wisdom in James denotes not intellectual cleverness but a practical gift from God for everyday life, especially in the face of trials. Parallels exist in Judaism and Stoicism. In the Gospels wisdom often finds expression in short, pithy aphorisms, particularly in ‘Q’ and in pronouncements following parables. Jesus is more, but not less, than a wisdom-teacher. Examples are considered. In Corinth wisdom had become a status-seeking commodity. Hence Paul speaks of the wisdom of God and of the cross. In the Pauline epistles wisdom has Christological significance.
The lost legacy of Robert DeCourcy Ward in American geographical climatology
Authors: Rohli Robert V. , Bierly Gregory D.
Published: June 2011

As a charter member of the Association of American Geographers and a well-respected scholar in academic meteorology, Robert DeCourcy Ward was an important figure in the earth sciences tradition of early American academic geography. The purpose of this paper is twofold: (1) to elaborate on the contributions of Ward to modern geographical climatology; and (2) to examine some of his writing beyond scientific topics as likely cause for the lack of attention to his geographical work today. Ward’s work across a range of spatial scales from local thunderstorm events to sea breeze circulations to global climatic classification represented a ‘bridge’ between scholars in the meteorology and geography communities. His emphasis on the conceptual understanding of climate as a dynamic rather than static entity represented a paradigm shift for which he has not been credited. He was a true and early advocate for study of the relationship between people and the environment. A thorough review of Ward’s works suggests that his environmental deterministic philosophy and writings on topics outside of physical geography, particularly immigration reform and eugenics, may have contributed to his current obscurity as an important early practitioner of our discipline. We suggest that, in general, the lessons of history, both triumphant and tragic, should never be forgotten, and it is in this framework that we believe that Ward should be remembered.
Application of material flow analysis to estimate the efficiency of e-waste management systems: the case of Lithuania
Authors: Gurauskienė Inga , Stasiškienė Žaneta
Published: June 2011

Electrical and electronic equipment (EEE) has penetrated everyday life. The EEE industry is characterized by a rapid technological change which in turn prompts consumers to replace EEE in order to keep in step with innovations. These factors reduce an EEE life span and determine the exponential growth of the amount of obsolete EEE as well as EEE waste (e-waste). E-waste management systems implemented in countries of the European Union (EU) are not able to cope with the e-waste problem properly, especially in the new EU member countries. The analysis of particular e-waste management systems is essential in evaluation of the complexity of these systems, describing and quantifying the flows of goods throughout the system, and all the actors involved in it. The aim of this paper is to present the research on the regional agent based material flow analysis in e-waste management systems, as a measure to reveal the potential points for improvement. Material flow analysis has been performed as a flow of goods (EEE). The study has shown that agent-based EEE flow analysis incorporating a holistic and life cycle thinking approach in national e-waste management systems gives a broader view to the system than a common administrative one used to cover. It helps to evaluate the real efficiency of e-waste management systems and to identify relevant impact factors determining the current operation of the system.
A Sensitive Diffusion Tensor Imaging Quantification Method to Detect Language Laterality in Children
Authors: Tiwari Vijay Narayan , Jeong Jeong-Won , Asano Eishi , Rothermel Robert , Juhasz Csaba , Chugani Harry T.
Published: June 2011

Using diffusion tensor imaging tractography and color-coded anisotropy map quantification, we investigated asymmetry of the arcuate fasciculus to determine language laterality in children and compared it with the Wada test. Arcuate fasciculus volume and fractional anisotropy were measured after tractography. We also quantified the fiber orientation distribution in the arcuate fasciculus region, ie, the fraction of arcuate fasciculus fibers oriented in the anteroposterior and mediolateral directions. A Laterality Index was calculated for each of the measured parameters. Volumetric analysis of the arcuate fasciculus showed asymmetry favoring the language dominant hemisphere ( P = .02), while fractional anisotropy showed no significant asymmetry ( P = .07). The mean anteroposterior and mediolateral components on the language dominant side were significantly higher than on the nondominant side ( P = .003 and .002, respectively). The Laterality Index values were concordant with the Wada test results except for 1 case. Fractional anisotropy also falsely lateralized language in 1 case.
Spontaneous Resolution of Atraumatic Intrauterine Ping-Pong Fractures in Newborns Delivered by Cesarean Section
Authors: Basaldella Luca , Marton Elisabetta , Bekelis Kimon , Longatti Pierluigi
Published: June 2011

Two cases of spontaneous intrauterine ping-pong fractures are reported in newborns delivered by cesarean section. Skull fractures occurred with no evidence of extrinsic trauma or cephalopelvic disproportion. Subsequent clinical follow-up at 6 and 12 months revealed normal skull reshaping and growth, with no associated neurological deficits. Spontaneous intrauterine ping-pong fractures in newborns delivered by cesarean section is a distinctly rare condition. These 2 cases demonstrate that, even without complicated spontaneous vaginal delivery or history of external trauma, congenital ping-pong fracture of the skull can occur. The existence of this clinical condition and its spontaneous resolution is important knowledge that can assist in the prepartum and postpartum management of children with this pathology.
Fatigue performance of aircraft panels with novel skin buckling containment features
Authors: Quinn D , Murphy A , Cervi L
Published: June 2011

To increase structural efficiency of stiffened panels in an aircraft, it is plausible to introduce skin buckling containment features to increase the local skin stability and thus static strength performance. Introducing buckling containment features may also significantly influence the fatigue crack growth performance of the stiffened panel. This study focuses on the experimental demonstration of panel durability with skin bay buckling containment features. Through a series of fatigue crack growth tests on integrally machined aluminium alloy stiffened panels, the potential to simultaneously improve static strength performance and crack propagation behaviour is demonstrated. The introduction of prismatic buckling containment features which have yielded significant static strength performance gains have herein demonstrated potential fatigue life gains of up to + 63 per cent.
Non-Newtonian and flow pulsatility effects in simulation models of a stented intracranial aneurysm
Authors: Cavazzuti M , Atherton M A , Collins M W , Barozzi G S
Published: June 2011

Three models of different stent designs implanted in a cerebral aneurysm, originating from the Virtual Intracranial Stenting Challenge’07, are meshed and the flow characteristics simulated using commercial computational fluid dynamics (CFD) software in order to investigate the effects of non-Newtonian viscosity and pulsatile flow. Conventional mass inflow and wall shear stress (WSS) output are used as a means of comparing the CFD simulations. In addition, a WSS distribution is presented, which clearly discriminates in favour of the stent design identified by other groups. It is concluded that non-Newtonian and pulsatile effects are important to include in order to avoid underestimating WSS, to understand dynamic flow effects, and to discriminate more effectively between stent designs.
Evolution or revolution? The impact of unions on workplace performance in Britain and France
Authors: Bryson Alex , Forth John , Laroche Patrice
Published: June 2011

We use nationally representative workplace surveys to examine the relationship between unionization and workplace financial performance in Britain and France. We find that union bargaining is detrimental to workplace performance in both countries. However, in Britain the effect is confined to the declining proportion of unionized workplaces where there is active collective bargaining. In the French case, the effect is confined to the minority of cases where unions have high density and to unions with a reputation for militancy.
Francisella asiatica as the causative agent of piscine francisellosis in cultured tilapia (Oreochromis sp.) in the United States
Authors: Soto Esteban , Baumgartner Wes , Wiles Judy , Hawke John P.
Published: June 2011

Francisella asiatica is a Gram-negative, pleomorphic, facultative intracellular, bacterial pathogen that causes acute to chronic disease in a wide variety of warm-water cultured and wild fish species. Outbreaks of francisellosis in warm water fish have been documented in Taiwan, Japan, United Kingdom, Hawaii, and Latin America (including Costa Rica) but the organism has only been reported from the United States on one occasion from hybrid striped bass in California. In 2010, the bacterium was detected from diseased tilapia by culture on cystine heart agar supplemented with hemoglobin and by utilizing an F. asiatica–specific real-time polymerase chain reaction assay. The tilapia ( Oreochromis niloticus) were cultured in an indoor, closed, recirculating aquaculture facility in the Midwest of the United States. The identity of isolates recovered from diseased fish was confirmed as F. asiatica by amplification and sequence comparison of the 16S ribosomal RNA and intracellular growth locus C ( iglC) gene. Gross and microscopic examination of affected tissues revealed the presence of marked anterior renomegaly and splenomegaly with severe granulomatous disease.
Federal Policy on Disproportionality in Special Education
Authors: Albrecht Susan Fread , Skiba Russell J. , Losen Daniel J. , Chung Choong-Geun , Middelberg Laura
Published: June 2011

Monitoring requirements in the 1997 amendments to and 2004 reauthorization of the Individuals with Disabilities Education Act (IDEA) acknowledged the existence and extent of racial/ethnic disproportionality in special education, especially when, in 2004, Congress designated this concern among the top three priority areas for monitoring and enforcement of the law. However, federal interpretations of the 2004 requirements have created confusion at the State (SEA) and Local Education Agency (LEA) levels. This article analyzes data from state Annual Performance Reports to assess the progress made in identifying disproportionality. Though high levels of disproportionality remain, an increasing number of states are finding no LEAs with disproportionality when it must be shown that the disproportionality was caused by inappropriate identification. The analyses provided suggest that federal interpretations of IDEA 2004 have not been effective in addressing disproportionate representation in special education. Recommendations for improving policy to remedy this serious problem are provided.
Quality and Antioxidant Properties of Fresh-cut Apple Wedges from 10 Cultivars During Modified Atmosphere Packaging Storage
Authors: Röβle C. , Gormley T.R. , Brunton N. , Butler F.
Published: June 2011

Antioxidant activity and quality parameters of skin-on apple wedges from 10 cultivars were examined during chill storage and over two growing seasons. Storage of fresh-cut apple wedges had a significant impact on quality parameter indices such as browning index (p < 0.001) and texture firmness (p < 0.001). Headspace gas analysis indicated that the degree of browning negatively correlated to oxygen (-0.69) and positively (0.70) correlated to carbon dioxide levels. Antioxidant capacity as assessed by three in vitro methods (DPPH, FRAP and ORAC) decreased significantly for 9 of the 10 cultivars after 5 days of storage at 3 ± 1 °C (p < 0.001). These indices increased in case of Shampion apples over the same storage period for all three assays. With regard to antioxidant capacity and quality parameters, the cultivars Gloster, Alwa, Idared and Jonica were the best performing overall and could therefore be recommended as a core ingredient in fresh-cut fruit products.
The “10 Keys” to Healthy Aging
Authors: Robare Joseph F. , Bayles Constance M. , Newman Anne B. , Williams Kathy , Milas Carole , Boudreau Robert , McTigue Kathleen , Albert Steven M. , Taylor Christopher , Kuller Lewis H.
Published: June 2011

The purpose of this report was to evaluate a prevention program to reduce risk factors for common diseases among older individuals in a lower income community. This randomized community-based study enrolled older adults into a Brief Education and Counseling Intervention or a Brief Education and Counseling Intervention plus a physical activity and (for those with hypertension) a dietary sodium intervention. Outcomes were collected on 389 adults with a mean age of 73.9 years over 24 months. Adherence to the “10 Keys” improved significantly in the proportion meeting goals for low-density lipoprotein cholesterol (+14%), bone mineral density testing (+11%), pneumonia vaccination (+11%), colonoscopy (+14%), and adherence to antihypertensive medication (+9%). This program resulted in significant reductions in key risk factors, increases in immunizations, and adherence to established prevention guidelines over 2 years. Further research is needed to refine the use of community health counselors for translating prevention knowledge into community settings. A major limitation of these studies is the low participation percentage.
Working memory in simultaneous interpreters: Effects of task and age
Authors: Signorelli Teresa M. , Haarmann Henk J. , Obler Loraine K.
Published: June 2011

This study examines whether interpreters have better working memory (WM) than non-interpreters, taking into account different WM components and the potential modulatory influence of age. Younger and older interpreters and non-interpreters were tested on reading span, nonword repetition, and order- and category-cued recall, using English, second-language materials. Articulation rate was also assessed. Interpreters outperformed non-interpreters in reading span and nonword repetition, but not cued recall and articulation rate. These results suggest that interpreters have better ability to manipulate information in working memory and process or store sub-lexical phonological representations, but have no advantage in short-term retention of words and their meaning. Compared to the other tested groups, younger interpreters were marginally better in nonword repetition and cued recall, suggesting that future studies on WM advantages in interpreters should consider the age factor.
Can a connectionist model explain the processing of regularly and irregularly inflected words in German as L1 and L2?
Authors: Strobach Tilo , Schönpflug Ute
Published: June 2011

The connectionist model is a prevailing model of the structure and functioning of the cognitive system of the processing of morphology. According to this model, the morphology of regularly and irregularly inflected words (e.g., verb participles and noun plurals) is processed in the same cognitive network. A validation of the connectionist model of the processing of morphology in German as L2 has yet to be achieved. To investigate L2-specific aspects, we compared a group of L1 speakers of German with speakers of German as L2. L2 and L1 speakers of German were assigned to their respective group by their reaction times in picture naming prior to the central task. The reaction times in the lexical decision task of verb participles and noun plurals were largely consistent with the assumption of the connectionist model. Interestingly, speakers of German as L2 showed a specific advantage for irregular compared with regular verb participles.
Game over? Negotiating modern capitalism in virtual game worlds
Authors: Harambam Jaron , Aupers Stef , Houtman Dick
Published: June 2011

Johan Huizinga’s claim that commercialization threatens the self-enclosed ‘magic circle’ of free play still permeates many contemporary games studies. Critiquing such generalizing and essentialistic assumptions, this article distinguishes four different ‘orders of commercialization’ that impinge on online game worlds and studies empirically how each of these is evaluated and negotiated by players themselves. Based on an analysis of World of Warcraft and Second Life, it demonstrates that some orders of commercialization — that is, the game itself as a commodity and the construction of its world as a virtual marketplace — are compatible with free play since they enhance players’ in-game agency. Other orders of commercialization — that is, ‘real money trading’ and the colonization of the game world by multinationals — are experienced as commodifying and undermine the spirit of play. Contextualization is called for: while some orders of commercialization threaten the ‘magic circle’ of free play, others stimulate or facilitate it.
Dose-finding design for multi-drug combinations
Authors: Wages Nolan A , Conaway Mark R , O'Quigley John
Published: June 2011

Background Most of the current designs used for Phase I dose finding trials in oncology will either involve only a single cytotoxic agent or will impose some implicit ordering among the doses. The goal of the studies is to estimate the maximum tolerated dose (MTD), the highest dose that can be administered with an acceptable level of toxicity. A key working assumption of these methods is the monotonicity of the dose–toxicity curve.

Purpose Here we consider situations in which the monotonicity assumption may fail. These studies are becoming increasingly common in practice, most notably, in phase I trials that involve combinations of agents. Our focus is on studies where there exist pairs of treatment combinations for which the ordering of the probabilities of a dose-limiting toxicity cannot be known a priori.

Methods We describe a new dose-finding design which can be used for multiple-drug trials and can be applied to this kind of problem. Our methods proceed by laying out all possible orderings of toxicity probabilities that are consistent with the known orderings among treatment combinations and allowing the continual reassessment method (CRM) to provide efficient estimates of the MTD within these orders. The design can be seen to simplify to the CRM when the full ordering is known.

Results We study the properties of the design via simulations that provide comparisons to the Bayesian approach to partial orders (POCRM) of Wages, Conaway, and O'Quigley. The POCRM was shown to perform well when compared to other suggested methods for partial orders. Therefore, we comapre our approach to it in order to assess the performance of the new design.

Limitations A limitation concerns the number of possible orders. There are dose-finding studies with combinations of agents that can lead to a large number of possible orders. In this case, it may not be feasible to work with all possible orders.

Conclusions The proposed design demonstrates the ability to effectively estimate MTD combinations in partially ordered dosefinding studies. Because it relaxes the monotonicity assumption, it can be considered a multivariate generalization of the CRM. Hence, it can serve as a link between single and multiple-agent dosefinding trials.
Unusual asthma syndromes and their management
Authors: Morjaria Jaymin B. , Kastelik Jack A.
Published: June 2011

Asthma usually presents with symptoms of wheeze, dyspnoea and cough. However, clinicians should be aware of atypical presentation of this disorder when cough is the main or only symptom in conditions such as cough-variant asthma, nonasthmatic eosinophilic bronchitis and atopic cough. Early diagnosis and treatment of these conditions with inhaled corticosteroids improves symptoms in the majority of patients. Up to 10% of patients with asthma remain poorly controlled in spite of optimal standard therapy. These patients have been encompassed under the term ‘treatment-refractory asthma’ (TRA), have the greatest morbidity and are responsible for more than 50% of healthcare costs. In this review we discuss investigations, management and pathophysiology of the various phenotypes of atypical presentations of asthma as well as novel biological agents licensed and those that have been reported in clinical trials in terms of their efficacy and safety in TRA.
Relating age and micro-architecture with apparent-level elastic constants: a micro-finite element study of female cortical bone from the anterior femoral midshaft
Authors: Donaldson F E , Pankaj P , Cooper D M L , Thomas C D L , Clement J G , Simpson A H R W
Published: June 2011

Homogenized elastic properties are often assumed for macro-finite element (FE) models used in orthopaedic biomechanics. The accuracy of material property assignments may have a strong effect on the ability of these models to make accurate predictions. For cortical bone, most macro-scale FE models assume isotropic elastic material behaviour and do not include variation of material properties due to bone micro-architecture. The first aim of the present study was to evaluate the variation of apparent-level (homogenized) orthotropic elastic constants of cortical bone with age and indices of bone micro-architecture. Considerable age-dependent differences in porosity were noted across the cortical thickness in previous research. The second aim of the study was to quantify the resulting differences in elastic constants between the periosteum and endosteum. Specimens were taken from the anterior femoral midshaft of 27 female donors (age 53.4 ± 23.6 years) and micro-FE (µFE) analysis was used to derive orthotropic elastic constants. The variation of orthotropic elastic constants (Young’s moduli, shear moduli, and Poisson’s ratios) with various cortical bone micro-architectural indices was investigated. The ratio of canal volume to tissue volume, Ca.V/TV, analogous to porosity, was found to be the strongest predictor ( r ave2 = 0.958) of the elastic constants. Age was less predictive ( r ave2 = 0.385) than Ca.V/TV. Elastic anisotropy increased with increasing Ca.V/TV, leading to lower elastic moduli in the transverse, typically less frequently loaded, directions. Increased Ca.V/TV led to a more substantial reduction in elastic constants at the endosteal aspect than at the periosteal aspect. The results are expected to be most applicable in similar midshaft locations of long bones; specific analysis of other sites would be necessary to evaluate elastic properties elsewhere. It was concluded that Ca.V/TV was the most predictive of cortical bone elastic constants and that considerable periosteal–endosteal variations in these constants can develop with bone loss.
Early death rate in acute promyelocytic leukemia remains high despite all-trans retinoic acid
Authors: Park Jae H. , Qiao Baozhen , Panageas Katherine S. , Schymura Maria J. , Jurcic Joseph G. , Rosenblat Todd L. , Altman Jessica K. , Douer Dan , Rowe Jacob M. , Tallman Martin S.
Published: June 2011

The incidence of early death in a large population of unselected patients with acute promyelocytic leukemia (APL) remains unknown because of the paucity of outcome data available for patients treated outside of clinical trials. We undertook an epidemiologic study to estimate the true rate of early death with data from the Surveillance, Epidemiology, and End Results (SEER) program. A total of 1400 patients with a diagnosis of APL between 1992 and 2007 were identified. The overall early death rate was 17.3%, and only a modest change in early death rate was observed over time. The early death rate was significantly higher in patients aged ≥ 55 years (24.2%; P < .0001). The 3-year survival improved from 54.6% to 70.1% over the study period but was significantly lower in patients aged ≥ 55 years (46.4%; P < .0001). This study shows that the early death rate remains high despite the wide availability of all-trans retinoic acid and appears significantly higher than commonly reported in multicenter clinical trials. These data highlight a need to educate health care providers across a wide range of medical fields, who may be the first to evaluate patients with APL, to have a major effect on early death and the cure rate of APL.
Human teneurin-1 is a direct target of the homeobox transcription factor EMX2 at a novel alternate promoter
Authors: Beckmann Jan , Vitobello Antonio , Ferralli Jacqueline , Brož Daniela Kenzelmann , Rijli Filippo M , Chiquet-Ehrismann Ruth
Published: June 2011

Background

Teneurin-1 is a member of a family of type II transmembrane proteins conserved from C.elegans to vertebrates. Teneurin expression in vertebrates is best studied in mouse and chicken, where the four members teneurin-1 to -4 are predominantly expressed in the developing nervous system in area specific patterns. Based on their distinct, complementary expression a possible function in the establishment of proper connectivity in the brain was postulated. However, the transcription factors contributing to these distinctive expression patterns are largely unknown. Emx2 is a homeobox transcription factor, known to be important for area specification in the developing cortex. A study of Emx2 knock-out mice suggested a role of Emx2 in regulating patterned teneurin expression.

Results

5'RACE of human teneurin-1 revealed new alternative untranslated exons that are conserved in mouse and chicken. Closer analysis of the conserved region around the newly identified transcription start revealed promoter activity that was induced by EMX2. Mutation of a predicted homeobox binding site decreased the promoter activity in different reporter assays in vitro and in vivo in electroporated chick embryos. We show direct in vivo binding of EMX2 to the newly identified promoter element and finally confirm that the endogenous alternate transcript is specifically upregulated by EMX2.

Conclusions

We found that human teneurin-1 is directly regulated by EMX2 at a newly identified and conserved promoter region upstream of the published transcription start site, establishing teneurin-1 as the first human EMX2 target gene. We identify and characterize the EMX2 dependent promoter element of human teneurin-1.
Anti-hLAMP2-antibodies and dual positivity for anti-GBM and MPO-ANCA in a patient with relapsing pulmonary-renal syndrome
Authors: Etter Christoph , Gaspert Ariana , Regenass Stephan , Wüthrich Rudolf P , Kistler Thomas , Kain Renate , Cohen Clemens D
Published: June 2011

Background

Pulmonary-renal syndrome associated with anti-glomerular basement membrane (GBM) antibodies, also known as Goodpasture's syndrome, is a rare but acute and life-threatening condition. One third of patients presenting as anti-GBM antibody positive pulmonary-renal syndrome or rapidly progressive glomerulonephritis are also tested positive for anti-neutrophil cytoplasmic antibodies (ANCA). Whilst anti-GBM disease is considered a non-relapsing condition, the long-term course of double-positive patients is less predictable.

Case Presentation

We report a patient with such dual positivity, who presented with pulmonary hemorrhage, crescentic glomerulonephritis and membranous nephropathy. Plasmapheresis in combination with immunosuppresive therapy led to a rapid remission but the disease relapsed after two years. The serum of the patient was tested positive for antibodies to human lysosomal membrane protein 2 (hLAMP2), a novel autoantigen in patients with active small-vessel vasculitis (SVV). The anti-hLAMP2 antibody levels correlated positively with clinical disease activity in this patient.

Conclusion

We hypothesize that this antibody may indicate a clinical course similar to ANCA-associated vasculitis in double-positive patients. However, this needs to be confirmed on comprehensive patient cohorts.
ER stress drives Lipocalin 2 upregulation in prostate cancer cells in an NF-κB-dependent manner
Authors: Mahadevan Navin R , Rodvold Jeffrey , Almanza Gonzalo , Pérez Antonio Fernández , Wheeler Matthew C , Zanetti Maurizio
Published: June 2011

Background

Tumor cells adapt to endoplasmic reticulum (ER) stress through a set of conserved intracellular pathways, as part of a process termed the unfolded protein response (UPR). The expression of UPR genes/proteins correlates with increasing progression and poor clinical outcome of several tumor types, including prostate cancer. UPR signaling can activate NF-κB, a master regulator of transcription of pro-inflammatory, tumorigenic cytokines. Previous studies have shown that Lipocalin 2 (Lcn2) is upregulated in several epithelial cancers, including prostate cancer, and recently Lcn2 was implicated as a key mediator of breast cancer progression. Here, we hypothesize that the tumor cell UPR regulates Lcn2 production.

Methods

We interrogated Lcn2 regulation in murine and human prostate cancer cells undergoing pharmacological and physiological ER stress, and tested UPR and NF-κB dependence by using pharmacological inhibitors of these signaling pathways.

Results

Induction of ER stress using thapsigargin (Tg), a canonical pharmacologic ER stress inducer, or via glucose deprivation, a physiologic ER stressor present in the tumor microenvironment, upregulates LCN2 production in murine and human prostate cancer cells. Inhibition of the UPR using 4-phenylbutyric acid (PBA) dramatically decreases Lcn2 transcription and translation. Inhibition of NF-κB in prostate cancer cells undergoing Tg-mediated ER stress by BAY 11-7082 abrogates Lcn2 upregulation.

Conclusions

We conclude that the UPR activates Lcn2 production in prostate cancer cells in an NF-κB-dependent manner. Our results imply that the observed upregulation of Lipocalin 2 in various types of cancer cells may be the direct consequence of concomitant UPR activation, and that the ER stress/Lipocalin 2 axis is a potential new target for intervention in cancer progression.
Renal denervation in an animal model of diabetes and hypertension: Impact on the autonomic nervous system and nephropathy
Authors: Dias Lucinara D , Casali Karina R , Leguisamo Natalia M , Azambuja Felipe , Souza Martina S , Okamoto Maristela , Machado Ubiratan F , Irigoyen Maria Cláudia , Schaan Beatriz D
Published: June 2011

Background

The effects of renal denervation on cardiovascular reflexes and markers of nephropathy in diabetic-hypertensive rats have not yet been explored.

Methods

Aim: To evaluate the effects of renal denervation on nephropathy development mechanisms (blood pressure, cardiovascular autonomic changes, renal GLUT2) in diabetic-hypertensive rats. Forty-one male spontaneously hypertensive rats (SHR) ~250 g were injected with STZ or not; 30 days later, surgical renal denervation (RD) or sham procedure was performed; 15 days later, glycemia and albuminuria (ELISA) were evaluated. Catheters were implanted into the femoral artery to evaluate arterial pressure (AP) and heart rate variability (spectral analysis) one day later in conscious animals. Animals were killed, kidneys removed, and cortical renal GLUT2 quantified (Western blotting).

Results

Higher glycemia (p < 0.05) and lower mean AP were observed in diabetics vs. nondiabetics (p < 0.05). Heart rate was higher in renal-denervated hypertensive and lower in diabetic-hypertensive rats (384.8 ± 37, 431.3 ± 36, 316.2 ± 5, 363.8 ± 12 bpm in SHR, RD-SHR, STZ-SHR and RD-STZ-SHR, respectively). Heart rate variability was higher in renal-denervated diabetic-hypertensive rats (55.75 ± 25.21, 73.40 ± 53.30, 148.4 ± 93 in RD-SHR, STZ-SHR- and RD-STZ-SHR, respectively, p < 0.05), as well as the LF component of AP variability (1.62 ± 0.9, 2.12 ± 0.9, 7.38 ± 6.5 in RD-SHR, STZ-SHR and RD-STZ-SHR, respectively, p < 0.05). GLUT2 renal content was higher in all groups vs. SHR.

Conclusions

Renal denervation in diabetic-hypertensive rats improved previously reduced heart rate variability. The GLUT2 equally overexpressed by diabetes and renal denervation may represent a maximal derangement effect of each condition.
Identification of maturation and protein synthesis related proteins from porcine oocytes during in vitro maturation
Authors: Kim Jumi , Kim Ji-Su , Jeon Young-Joo , Kim Dong-Wook , Yang Tae-Ho , Soh Yunjo , Lee Hak Kyo , Choi Nag-Jin , Park Soo-Bong , Seo Kang Seok , Chung Hyung Min , Lee Dong-Seok , Chae Jung-Il
Published: June 2011

Background

In vitro maturation (IVM) of mammalian oocytes is divided into the GV (germinal vesicle stage), MI (metaphase I stage) and MII (metaphase II stage) stages, and only fully mature oocytes have acquired the ability to be fertilized and initiate zygotic development. These observations have been mostly based on morphological evaluations, but the molecular events governing these processes are not fully understood.

The aim of the present study was to better understand the processes involved in the molecular regulation of IVM using 2-DE analysis followed by mass spectrometry to identify proteins that are differentially expressed during oocyte IVM.

Result

A total of 16 up-regulated and 12 down-regulated proteins were identified. To investigate the IVM process, we specifically focused on the proteins that were up-regulated during the MII stage when compared with the GV stage, which included PRDX 2, GST, SPSY, myomegalin, PED4D, PRKAB 1, and DTNA. These up-regulated proteins were functionally involved in redox regulation and the cAMP-dependent pathway, which are essential for the intracellular signaling involved in oocyte maturation. Interestingly, the PDE4D and its partner, myomegalin, during the MII stage was consistently confirmed up-regulation by western blot analyses.

Conclusion

These results could be used to better understand some aspects of the molecular mechanisms underlying porcine oocyte maturation. This study identified some regulatory proteins that may have important roles in the molecular events involved in porcine oocyte maturation, particularly with respect to the regulation of oocyte meiotic resumption, MII arrest and oocyte activation. In addition, this study may have beneficial applications not only to basic science with respect to the improvement of oocyte culture conditions but also to mammalian reproductive biotechnology with potential implications.
Porous anodic alumina on galvanically grown PtSi layer for application in template-assisted Si nanowire growth
Authors: Michelakaki Irini , Nassiopoulou Androula G , Stavrinidou Eleni , Breza Katerina , Frangis Nikos
Published: June 2011

We report on the fabrication and morphology/structural characterization of a porous anodic alumina (PAA)/PtSi nano-template for use as matrix in template-assisted Si nanowire growth on a Si substrate. The PtSi layer was formed by electroless deposition from an aqueous solution containing the metal salt and HF, while the PAA membrane by anodizing an Al film deposited on the PtSi layer. The morphology and structure of the PtSi layer and of the alumina membrane on top were studied by Scanning and High Resolution Transmission Electron Microscopies (SEM, HRTEM). Cross sectional HRTEM images combined with electron diffraction (ED) were used to characterize the different interfaces between Si, PtSi and porous anodic alumina.
Liao ning virus in China
Authors: Lu Zhi , Liu Hong , Fu Shihong , Lu Xinjun , Dong Qiang , Zhang Song , Tong Suxiang , Li Minghua , Li Wenjuan , Tang Qing , Liang Guodong
Published: June 2011

Background

Liao ning virus is in the genus Seadornavirus within the family Reoviridae and has a genome composed of 12 segments of double-stranded RNA (dsRNA). It is transmitted by mosquitoes and only isolated in China to date and it is the only species within the genus Seadornavirus which was reported to have been propagated in mammalian cell lines. In the study, we report 41 new isolates from northern and southern Xinjiang Uygur autonomous region in China and describe the phylogenetic relationships among all 46 Chinese LNV isolates.

Findings

The phylogenetic analysis indicated that all the isolates evaluated in this study can be divided into 3 different groups that appear to be related to geographic origin based on partial nucleotide sequence of the 10th segment which is predicted to encode outer coat proteins of LNV. Bayesian coalescent analysis estimated the date of the most recent common ancestor for the current Chinese LNV isolates to be 318 (with a 95% confidence interval of 30-719) and the estimated evolutionary rates is 1.993 × 10-3 substitutions per site per year.

Conclusions

The results indicated that LNV may be an emerging virus at a stage that evaluated rapidly and has been widely distributed in the north part of China.