bluuebunny/crossref_metadata_2025 huggingface dataset:
Altered Frontal and Temporal Brain Function during Olfactory Stimulation in Adult Attention-Deficit/Hyperactivity Disorder
Authors: Schecklmann Martin , Schenk Eva , Maisch Andreas , Kreiker Susanne , Jacob Christian , Warnke Andreas , Gerlach Manfred , Fallgatter Andreas J. , Romanos Marcel
Published: December 2010

Objective: Olfactory processing depends on dopamine metabolism and orbitofrontal cortex functioning, both known to be disturbed in attention-deficit/hyperactivity disorder (ADHD). Some investigations suggested alterations in olfactory processing (identification and sensitivity) in childhood and adult ADHD. Methods: In the present study we investigated olfactory function (Sniffin’ Sticks) of 29 adult patients with ADHD (17 combined, 11 inattentive, and 1 hyperactive/impulsive subtype) and 29 controls matched for sex, handedness, age, intelligence, and education. Additionally, we measured frontal, temporal, and somatosensory cortical activity during olfactory perception. This was performed with functional near-infrared spectroscopy (fNIRS) during presentation of 2-phenylethanol (olfactory stimulant) and linalool (mixed olfactory/trigeminal stimulant) in two concentrations each. Results: Adult patients with ADHD and controls did not differ in sensitivity for and discrimination and identification of olfactory stimuli. Functional brain imaging measures with fNIRS generally revealed diminished activation in olfaction-associated brain regions in patients with ADHD. Only for a high concentration of linalool, oxygenated haemoglobin (O2Hb) concentrations in patients were similar to controls (significant increase in the temporal, somatosensory, and inferior-frontal cortex). O2Hb concentrations in active brain regions positively correlated with ADHD symptoms during childhood and trait impulsivity. These effects were carried for the subgroup with combined subtype. Conclusions: Although we could not replicate altered clinical performance in ADHD, our fNIRS findings suggest an association of cortical olfactory processing with hyperactivity and impulsivity in adult ADHD.
Cardiac Arrhythmogenic Remodeling in a Rat Model of Long-Term Intensive Exercise Training
Authors: Benito Begoña , Gay-Jordi Gemma , Serrano-Mollar Anna , Guasch Eduard , Shi Yanfen , Tardif Jean-Claude , Brugada Josep , Nattel Stanley , Mont Lluis
Published: December 2010

Background—

Recent clinical studies suggest that endurance sports may promote cardiac arrhythmias. The aim of this study was to use an animal model to evaluate whether sustained intensive exercise training induces potentially adverse myocardial remodeling and thus creates a potential substrate for arrhythmias.

Methods and Results—

Male Wistar rats were conditioned to run vigorously for 4, 8, and 16 weeks; time-matched sedentary rats served as controls. Serial echocardiograms and in vivo electrophysiological studies at 16 weeks were obtained in both groups. After euthanasia, ventricular collagen deposition was quantified by histological and biochemical studies, and messenger RNA and protein expression of transforming growth factor-β1, fibronectin-1, matrix metalloproteinase-2, tissue inhibitor of metalloproteinase-1, procollagen-I, and procollagen-III was evaluated in all 4 cardiac chambers. At 16 weeks, exercise rats developed eccentric hypertrophy and diastolic dysfunction, together with atrial dilation. In addition, collagen deposition in the right ventricle and messenger RNA and protein expression of fibrosis markers in both atria and right ventricle were significantly greater in exercise than in sedentary rats at 16 weeks. Ventricular tachycardia could be induced in 5 of 12 exercise rats (42%) and only 1 of 16 sedentary rats (6%;
P
=0.05). The fibrotic changes caused by 16 weeks of intensive exercise were reversed after an 8-week exercise cessation.

Conclusions—

In this animal model, we documented cardiac fibrosis after long-term intensive exercise training, together with changes in ventricular function and increased arrhythmia inducibility. If our findings are confirmed in humans, the results would support the notion that long-term vigorous endurance exercise training may in some cases promote adverse remodeling and produce a substrate for cardiac arrhythmias.
The Wirewalker: A Vertically Profiling Instrument Carrier Powered by Ocean Waves
Authors: Pinkel R. , Goldin M. A. , Smith J. A. , Sun O. M. , Aja A. A. , Bui M. N. , Hughen T.
Published: December 2010

Ocean wave energy is used to drive a buoyant instrument platform down a wire suspended from a surface float. At the lower terminus of the profiling range, the cam that rectifies wave vertical motion is released and the package, termed the Wirewalker, free ascends. No electronic components are used in the profiler, and only a few moving parts are involved. The Wirewalker is tolerant of a broad range of payloads: the ballast is adjusted by adding discrete foam blocks. The Wirewalker profiles 1000–3000 km month−1, vertically, with typical missions lasting from days to months. A description of the profiler is presented along with a discussion of basic profiling dynamics.
Helping or Hurting: Are Adolescent Intervention Programs Minimizing Racial Inequality?
Authors: Walsh Rachael
Published: December 2010

In 1965, appalled by the racial disparity with respect to access to higher education, the federal government implemented the Higher Education Act. After more than 40 years of programmatic intervention, gaps persist. As such, this study analyzes two of the three original HEA programs—Upward Bound and Talent Search—focusing on race/ethnicity and socioeconomic status, examining program effectiveness on a national scale. Based on deformed choices ideology and using a nationally representative data set, the National Education Longitudinal Study, event history analysis is employed to determine the effect of Upward Bound and Talent Search with respect to college attendance rates. Both hazard and risk ratios are used to determine the interaction between program participation and race/ethnicity. Program participation significantly benefits low-SES African American and impoverished Hispanic students, providing college attendance opportunities equivalent to that of average-SES White students. Once the school effect on the hazard function was taken into consideration, the benefit of program participation for African American and Hispanic students increased further. Future research is required to ensure effective use of appropriations, while implementation is extended to the masses of low-SES African American and Hispanic students. Directions of future research and policy implications are discussed further.
Building new competencies for government administrators and managers in an era of public sector reforms: the case of Mozambique
Authors: Awortwi Nicholas
Published: December 2010

African public administration today is mixed with elements of the old bureaucratic model continuing alongside the new public management (NPM). The increasing application of the NPM approach has placed public administration and management systems in the spotlight and raised a number of challenges. Among them are the relevance of policy importation and the availability of civil servants with the requisite competence to perform the very critical responsibilities of government that reforms introduce. Using the case of Mozambique, this article shows that implementation of public sector reforms has brought in its trail considerable gaps between reform strategies and the competences needed to execute them. Convinced that competences of public administrators are a vital prerequisite for the success of reforms, the government of Mozambique has instituted a series of training programmes to provide the kind of competences that would reflect the new demands and realities facing the public sector. Though it is too early to expect results, the article concludes that the technical, managerial and leadership skills of public administrators and managers are being improved through better training curricula than were provided in the past.

Points for practitioners

The structure, functions, and processes of public administration and management have undergone remarkable changes as a result of NPM approaches. But as new approaches are being introduced, government managers have found themselves trying very hard to manage using old skills. In almost every profession, new circumstances require the development of new, or a redefinition of existing, skills. Institutionalizing new training curricula to provide technical, managerial and leadership competence for government administrators has become imperative now more than ever before. The caveat is that building new competencies will not necessarily fix all the problems unless other structural problems such as remuneration, promotion and utilization of ex-trainees are also addressed.
Water sector reform in Italy and in the Netherlands: ambitious change with an uncertain outcome versus consensus-seeking moderate change
Authors: Argento Daniela , van Helden G. Jan
Published: December 2010

This article aims at analysing the commonalities and differences in recent water sector reforms in Italy and in the Netherlands. The reforms in both countries are characterized by similar goals of achieving greater transparency and efficiency, and comparable governance ideas regarding the establishment of integrated water companies. However, there appears to be a gap between the reforms as initially intended and the way in which they were realized. Although the reform idea of forming integrated water companies has been maintained in Italy, its realization has been postponed, whereas in the Netherlands this reform idea has been replaced by a bottom-up implementation approach, stimulating cooperation rather than integration projects within the water sector. An assessment of the accomplishment of the reform goals conducted in the Netherlands shows that greater transparency and efficiency have been realized to some extent, whereas in Italy any systematic information on this issue has been unavailable. Our analysis of the reasons for the gaps between the reforms as originally intended and the way in which they have been realized shows some similarities between the two countries in the sense of highly institutionalized practices. There are, however, also substantial differences between these two countries. In Italy, there are no networks of water organizations, which explains the lack of local and regional commitment to the centrally desired changes, resulting in their slow execution. In the Netherlands, these networks are powerful enablers with strong coalitions, which have resisted the compulsory implementation of radical changes.

Points for practitioners

The success of a radical water sector reform, which proposes that the current types of organizations be replaced by new types of organizations, is dependent upon the approval of all powerful stakeholders. However, if radical reform is only supported by some of these powerful stakeholders, it is wise to focus mainly on the relevant goals, and have the stakeholders achieve these goals at their own discretion. The reform implementation will benefit from the involvement of stakeholders at the executive level in both the discussions about the reform content and the processes through which this content can be realized.
Acculturation, Religiosity, and Ethnicity Predict Mothers’ Causal Beliefs About Separation Anxiety Disorder and Preferences for Help-Seeking
Authors: Sood Erica D. , Mendez Julia L. , Kendall Philip C.
Published: December 2010

This study examined causal beliefs about separation anxiety disorder (SAD) and preferences for help-seeking among 117 Indian American, Puerto Rican, and European American mothers. Mothers completed measures of acculturation and strength of religious faith (SORF) and, after reading vignettes describing SAD, made judgments about the etiology of symptoms and the likelihood of various forms of help-seeking for youth SAD symptoms. Hierarchical multiple regressions revealed that acculturation to mainstream American culture and SORF predicted mothers’ causal beliefs and preferences for help-seeking. In addition, Puerto Rican mothers were more likely than European American mothers to attribute symptoms to medical causes after accounting for cultural variables. Results highlight the importance of examining cultural constructs that contribute to ethnic group differences. Implications for future research and clinical practice are discussed.
Identification of Caries Risk Factors in Toddlers
Authors: Fontana M. , Jackson R. , Eckert G. , Swigonski N. , Chin J. , Zandona A. Ferreira , Ando M. , Stookey G.K. , Downs S. , Zero D.T.
Published: December 2010

The purpose of this study was to identify risk factors to predict caries progression in toddlers in primary-healthcare settings for the cost-effective targeting of preventive and referral strategies. We examined 329 children (26 ± 6 mos old) twice, one year apart, in Indiana, USA. A 107-item structured interview was used to collect information from the primary caregiver and child on factors/beliefs/perceptions/behaviors that could affect caries development, transmission of bacteria, medical-dental health, and access to care. Bacterial levels, gingivitis, dental plaque, and caries experience were assessed. Multiple-variable logistic regression models of caries progression toward cavitation included family caries experience, transmission-related behaviors, dietary factors, health beliefs, and lower income, but differed in selected predictors/predictive power by race/ethnicity. Addition of clinical variables did not significantly improve the prediction.
Encouraging Cognitive Connections and Creativity in the Music Classroom
Authors: Peterson Christopher W. , Madsen Clifford K.
Published: December 2010

The ability to apply knowledge rests at the core of the educational experience and is an important aspect of all teaching. In music education, many experiences are structured so information gained can be related to another activity, but such transfer can be difficult. When students learn to transfer information and knowledge to new situations, they are more likely to retain that knowledge; this retention seems to be enhanced when the information is presented within an activity where creativity is encouraged. There is also evidence to support a technique where the teacher clearly states that transfer is a goal for learning in a “community-of-learners” environment, where the students share verbally their creative connections with the class. This article is an exploration of the concept of transfer and includes strategies for teaching creative thinking through transfer activities in the secondary music classroom or rehearsal setting.
Object associations of early-learned light and heavy English verbs
Authors: Maouene Josita , Laakso Aarre , Smith Linda B.
Published: December 2010

Many of the verbs that young children learn early have been characterized as ‘light.’ However, there is no agreed upon definition of ‘lightness’ and no useable metric that could be applied to a wide array of verbs. This article provides evidence for one metric by which the ‘lightness’ of early-learned verbs might be measured: the number of objects with which they are associated (in adult judgment) or co-occur (in speech to and by children). The results suggest that early-learned light verbs and heavy verbs differ in the breadth of the objects they are associated with: light verbs have weak associations with specific objects, whereas heavy verbs are strongly associated with specific objects. However, there is an indication that verbs have narrower associations to objects in speech to children. The methodological usefulness of this metric is discussed as are the implications of the patterns of distributions for children’s learning of common verbs.
Virtual Reality Versus Computer-Aided Exposure Treatments for Fear of Flying
Authors: Tortella-Feliu Miquel , Botella Cristina , Llabrés Jordi , Bretón-López Juana María , del Amo Antonio Riera , Baños Rosa M. , Gelabert Joan M.
Published: December 2010

Evidence is growing that two modalities of computer-based exposure therapies—virtual reality and computer-aided psychotherapy—are effective in treating anxiety disorders, including fear of flying. However, they have not yet been directly compared. The aim of this study was to analyze the efficacy of three computer-based exposure treatments for fear of flying: virtual reality exposure therapy (VRET), computer-aided exposure with a therapist’s (CAE-T) assistance throughout exposure sessions, and self-administered computer-aided exposure (CAE-SA). A total of 60 participants with flying phobia were randomly assigned to VRET, CAE-T, or CAE-SA. Results indicate that the three interventions were effective in reducing fear of flying at posttreatment and at 1-year follow-up; furthermore, there were no significant differences between them in any of the outcome measure. Large within-group effect sizes were found for all three treatment conditions at both posttreatment and at follow-up. The results suggest that therapist involvement might be minimized during computer-based treatments and that CAE can be as effective as VRET in reducing fear of flying.
Eosinophilic Allergic Polyp
Authors: Jeong Woo‐Jin , Lee Chul Hee , Cho Sang‐Heon , Rhee Chae‐Seo
Published: December 2010

Objective

Tissue eosinophilia is a hallmark of nasal polyposis. However, there is no universally accepted definition for eosinophilic nasal polyp. The aims of this study were to histologically analyze the inflammatory cell population in the nasal polyp and propose the concept of eosinophilic allergic polyp (EAP), a simple and objective concept that would be clinically and practically valuable.

Study Design

A cohort study with histological analysis of tissue sections and chart review.

Setting

A tertiary university hospital.

Subjects and Methods

Nasal polyp tissues were harvested during routine endoscopic sinus surgery from a cohort of 118 patients. Total number of inflammatory cells, including eosinophils, was counted. The presence of allergy and asthma was assessed, which was then correlated with the histologic findings. To determine a criterion for EAP, a receiver operating characteristic curve was used to identify the best cutoff point, which was further validated by comparing the eosinophil proportion in each group with reference to the clinical parameters.

Results

Eosinophil accounted for an average of 18.7% of all inflammatory cells. The proportion of nasal polyps with at least 1 or more eosinophil infiltration accounted for 90.7% of all nasal polyps. When the concept of EAP was applied, a tissue eosinophil count of 11% was found to be significant and clinically most useful. Using this criterion, the proportion of EAP among nasal polyps was 62.7%.

Conclusion

The authors suggest a tissue eosinophil proportion of more than 11% as a criterion for EAP, a clinically useful concept of nasal polyp that bears good correlation with asthma and allergy.
Aortic arch replacement with moderate hyperthomia and a modified 3-pump circuit
Authors: Charumathi Dasarathan , Vaijyanath Prashanth , Sekhar Lavanya , Kotturathu Mammen Cherian
Published: December 2010

A strategy employing moderate hypothermia for replacement of the aortic arch is proposed to avoid the complications of profound hypothermic circulatory arrest. Two patients underwent complete replacement of the aortic arch using three pumps (Figure 1a — one to perfuse the brain, one for the thoracoabdominal aorta and the third for the heart). There were no complications and the patients were extubated uneventfully. The method preserves autoregulation of cerebral blood flow without high vascular resistances.
Providers’ Reported and Actual Use of Coaching Strategies in Natural Environments
Authors: Salisbury Christine , Cambray-Engstrom Elizabeth , Woods Juliann
Published: December 2010

This case study examined the agreement between reported and actual use of coaching strategies based on home visit data collected on a diverse sample of providers and families. Paired videotape and contact note data of and from providers during home visits were collected over a six month period and analyzed using structured protocols. Results of both descriptive and correlation analyses indicated providers used a range of coaching strategies, tended to underreport (under-represent) their efforts on contact notes, and demonstrated practices that were primarily collaborative and family-centered. Agreement between actual and reported use of coaching strategies was variable and did not support our anticipated finding. Implications for future research and practice are discussed.
Can the Reparability of Meniscal Tears Be Predicted With Magnetic Resonance Imaging?
Authors: Bernthal Nicholas M. , Seeger Leanne L. , Motamedi Kambiz , Stavrakis Alexandra I. , Kremen Thomas J. , McAllister David R. , Motamedi Ali R.
Published: December 2010

Background: Historically, magnetic resonance imaging (MRI) has been very useful in diagnosing meniscal tears but not as valuable in predicting whether a meniscal tear is reparable. Given that several recent studies suggested that MRI can be used to predict tear reparability, the topic has resurfaced as a controversy in the orthopaedic and radiology literatures.

Hypothesis: Experienced musculoskeletal radiologists can use MRI to predict the reparability of meniscal tears with good to excellent accuracy using the same arthroscopic criteria used by surgeons intraoperatively.

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

Methods: Fifty-eight patients with meniscal tears treated with repair were matched by age and sex with 61 patients with tears treated with meniscectomy. Two senior musculoskeletal radiologists independently and blindly reviewed preoperative MRI of these 119 meniscal tears. Using established arthroscopic criteria, the radiologists were asked to grade each tear 0 to 4, with 1 point for each of the following: a tear larger than 10 mm, within 3 mm of the meniscosynovial junction, greater than 50% thickness, and with an intact inner meniscal fragment. Only a tear with a score of 4 would be predicted to be reparable.

Results: The 2 radiologists’ ability to correctly estimate reparability was poor, with 58.0% and 62.7% correct predictions (κ = 0.155 and 0.250, respectively). Interrater reliability assessment showed that the raters agreed on a score of 4 (reparable) versus <4 (not reparable) 73.7% of the time (κ = 0.434) but came to identical scores only 38.1% of the time (κ = 0.156). Determining the status of the inner fragment was the most predictive individual criterion and the only one to reach statistical significance (χ2 = 14.9, P <.001).

Conclusion: Magnetic resonance imaging is not an effective or efficient predictor of reparability of meniscal tears with the current arthroscopic criteria.
Metabolic profiles in serum of mouse after chronic exposure to drinking water
Authors: Yan Zhang  , Bing Wu  , Xuxiang Zhang  , Aimin Li  , Shupei Cheng
Published: December 2010

The toxicity of Nanjing drinking water on mouse (Mus musculus) was detected by 1H nuclear magnetic resonance (NMR)-based metabonomic method. Three groups of mice were fed with drinking water (produced by Nanjing BHK Water Plant), 3.8 μg/L benzo(a)pyrene as contrast, and clean water as control, respectively, for 90 days. It was observed that the levels of lactate, alanine, and creatinine in the mice fed with drinking water were increased and that of valine was decreased. The mice of drinking water group were successfully separated from control. The total concentrations of polycyclic aromatic hydrocarbons (PAHs), phthalates (PAEs), and other organic pollutants in the drinking water were 0.23 μg/L, 4.57 μg/L, and 0.34 μg/L, respectively. In this study, Nanjing drinking water was found to induce distinct perturbations of metabolic profiles on mouse including disorders of glucose-alanine cycle, branched-chain amino acid and energy metabolism, and dysfunction of kidney. This study suggests that metabonomic method is feasible and sensitive to evaluate potential toxic effects of drinking water.
Research Recruitment in Home Care in an Era of Scams and Advocacy
Authors: Macdonald Marilyn
Published: December 2010

Recruitment is the cornerstone of research involving human beings. Most of what has been written involved institutional recruitment, yet the past two decades have seen an exponential rise in the delivery of home care. This shift has been accompanied by an increase in the volume of research conducted in homecare, and the majority of home care recipients are elderly. The elderly experience a disproportionate occurrence of consumer fraud and are increasingly reluctant to give strangers access to their homes. Advocacy groups have made formidable contributions to raising the awareness among older persons of risks to their person and finances. The aim of this article is to raise awareness of the importance of recruitment in the home care community and to recommend to researchers that they partner with community agencies and advocacy groups to inform citizens of the value of their participation in research in home care, and the benefits.
Weight Management in Overweight and Obese Patients with Type 2 Diabetes Mellitus
Authors: Kyrou Ioannis , Kumar Sudhesh
Published: December 2010

Obesity is recognised as an important risk factor for type 2 diabetes, inducing insulin resistance and pancreatic beta-cell dysfunction. These obesity-related defects tend to progress following weight gain and can eventually lead to worsening hyperglycaemia over time. Thus, effective weight management is crucial for glycaemic control in overweight and obese patients with type 2 diabetes. Current standard strategies for weight management in these patients include lifestyle interventions and pharmacotherapy. Bariatric surgery has become a promising new option for the treatment of obese patients with type 2 diabetes and in recent years incretin-based therapies have become available, which exhibit favourable effects on body weight. Herein, the efficacy of available weight loss interventions is assessed and the role of newer antidiabetic agents examined, focusing on incretin-based therapies.
The Role of Higher Education Associations in Shaping Policy That Connects Immigration to Educational Opportunity: A Social Capital Framework
Authors: Ortega Noe
Published: December 2010

This study utilizes social capital theory to examine the collective agency available to national higher education associations and better understand the power of the collectivity to influence policy. The analysis draws on a specific issue, the Development, Relief, and Education for Alien Minors Act, and investigates letters and statements submitted by associations to members of Congress in support of this policy between 2006 and 2009. The findings suggest that characteristics unique to this community enhance their ability to influence educational policy.
Practitioner Perceptions of Juvenile Transfer in Pennsylvania
Authors: Myers David L. , Lee Daniel , Giever Dennis , Gilliam Jay
Published: December 2010

Consistent with virtually all other states in the nation, in the mid-1990s legislation was enacted in Pennsylvania to address increasing concerns about serious and violent juvenile offending. This legislation included provisions for facilitating the transfer of violent juvenile offenders to adult criminal court. The current study examines contemporary practitioner perceptions of juvenile transfer to adult court, with regard to the number of juveniles transferred, the effectiveness of this practice, and the appropriate minimum age for transfer to occur. Utilizing statewide survey data, comparisons are made between juvenile court judges, probation officers, prosecutors, and public defenders, and other predictors are assessed. The findings indicate modest overall support for transferring juveniles to adult court, with various significant differences across practitioner groups. Policy implications are discussed.
Language Planning, Language Ideology and Entextualization: War Naming Practices
Authors: Makoni Busi , Makoni Sinfree , Pfukwa Charles
Published: December 2010

AbstractThis article examines the relationship between language and war by investigating naming practices through three prisms: language planning, language ideology and entextualization. The article focuses on names assigned to combatants during the War of Liberation for Zimbabwe's independence. In African cultures, names often address a kaleidoscope of issues which may include the collective history and life experiences of the individual name bearer and the people surrounding him or her. In most African contexts changes in an individual's personal circumstances are marked by a name change, which suggests that names are variable and are not immutable. Entering the guerilla movement in Zimbabwe was a significant transformation which, in accordance with African cultural practices, required a new name to be assigned to signify the entry into a new phase of life. The names assigned reflect a “discourse” about the hopes and aspirations of the combatants. However, it appears that the underlying principles of naming in war are not significantly different from those during peacetime. In addition, war naming practices have implications for language planning from below, language ideologies and entextualization.
Margarete and Sulamith under the Swastika: Girls' Names in Nazi Germany
Authors: Laversuch I.M.
Published: December 2010

AbstractPast research has well established that the personal name a woman carries can have a significant impact upon the way she is perceived by her surrounding environment. The power of this impact may be significantly increased during periods of sociopolitical unrest. Using the techniques of corpus linguistics, this paper traces diachronic variations in the twenty most popular girls' names chosen by German parents between 1934 and 1950. To supplement this empirical analysis, historical information is provided on onomastic legislation which not only affected societal preferences in female names, but also the individual lives of the women who carried them.
Esterified eicosanoids are acutely generated by 5-lipoxygenase in primary human neutrophils and in human and murine infection
Authors: Clark Stephen R. , Guy Christopher J. , Scurr Martin J. , Taylor Philip R , Kift-Morgan Ann P. , Hammond Victoria J. , Thomas Christopher P. , Coles Barbara , Roberts Gareth W. , Eberl Matthias , Jones Simon A. , Topley Nicholas , Kotecha Sailesh , O'Donnell Valerie B.
Published: December 2010

5-Lipoxygenase (5-LOX) plays key roles in infection and allergic responses. Herein, four 5-LOX–derived lipids comprising 5-hydroxyeicosatetraenoic acid (HETE) attached to phospholipids (PLs), either phosphatidylethanolamine (PE) or phosphatidylcholine (18:0p/5-HETE-PE, 18:1p/5-HETE-PE, 16:0p/5-HETE-PE, and 16:0a/5-HETE-PC), were identified in primary human neutrophils. They formed within 2 minutes in response to serum-opsonized Staphylococcus epidermidis or f-methionine-leucine-phenylalanine, with priming by lipopolysaccharide, granulocyte macrophage colony-stimulating factor, or cytochalasin D. Levels generated were similar to free 5-HETE (0.37 ± 0.14 ng vs 0.55 ± 0.18 ng/106 cells, esterified vs free 5-HETE, respectively). They remained cell associated, localizing to nuclear and extranuclear membrane, and were formed by fast esterification of newly synthesized free 5-HETE. Generation also required Ca2+, phospholipase C, cytosolic and secretory phospholipase A2, 5-LOX activating protein, and mitogen-activated protein kinase/extracellular signal-regulated kinase kinase 1. 5-HETE-PLs were detected in murine S epidermidis peritonitis, paralleling neutrophil influx, and in effluent from Gram-positive human bacterial peritonitis. Formation of neutrophil extracellular traps was significantly enhanced by 5-LOX inhibition but attenuated by HETE-PE, whereas 5-HETE-PE enhanced superoxide and interleukin-8 generation. Thus, new molecular species of oxidized PL formed by human neutrophils during bacterial infection are identified and characterized.
Excellent Outcome With Reduced Treatment in Infants With Nonmetastatic and Unresectable Neuroblastoma Without MYCN Amplification: Results of the Prospective INES 99.1
Authors: Rubie Hervé , De Bernardi Bruno , Gerrard Mary , Canete Adela , Ladenstein Ruth , Couturier Jérôme , Ambros Peter , Munzer Caroline , Pearson Andrew D.J. , Garaventa Alberto , Brock Penelope , Castel Victoria , Valteau-Couanet Dominique , Holmes Keith , Di Cataldo Andrea , Brichard Bénédicte , Mosseri Véronique , Marquez Catalina , Plantaz Dominique , Boni Luca , Michon Jean
Published: December 2010

Purpose

To evaluate the efficacy of low-dose chemotherapy in infants with nonmetastatic and unresectable neuroblastoma (NB) without MYCN amplification.

Patients and Methods

Infants with localized NB and no MYCN amplification were eligible in the SIOPEN Infant Neuroblastoma European Study 99.1 study. Primary tumor was deemed unresectable according to imaging defined risk factors. Diagnostic procedures and staging were carried out according to International Staging System recommendations. Children without threatening symptoms received low-dose cyclophosphamide (5 mg/kg/d × 5 days) and vincristine (0.05 mg/kg at day 1; CyV), repeated once to three times every 2 weeks until surgical excision could be safely performed. Children with either one threatening symptom or insufficient response to CyV were given carboplatin and etoposide (CaE), sometimes followed by vincristine, cyclophosphamide, and doxorubicin. No postoperative treatment was to be administered.

Results

Between December 1999 and April 2004, 120 infants were included in the study. Eighty-eight had no threatening symptoms and 79 received CyV. CaE was given to 49 of them because of insufficient response. Thirty-two children had threatening symptoms, 30 of whom received CaE. Anthracyclines were given to 46 children. Surgery was attempted in 102 patients, leading to gross surgical excision in 93. Relapse occurred in 12 patients (nine local and three metastatic). Five-year overall and event-free survivals were 99% ± 1% and 90% ± 3%, respectively, with a median follow-up of 6.1 years (range, 1.6 to 9.1).

Conclusion

Low-dose chemotherapy without anthracyclines is effective in 62% of infants with an unresectable NB and no MYCN amplification, allowing excellent survival rates without jeopardizing their long-term outcome.
Phase II Study of the Antibody Drug Conjugate Trastuzumab-DM1 for the Treatment of Human Epidermal Growth Factor Receptor 2 (HER2) –Positive Breast Cancer After Prior HER2-Directed Therapy
Authors: Burris Howard A. , Rugo Hope S. , Vukelja Svetislava J. , Vogel Charles L. , Borson Rachel A. , Limentani Steven , Tan-Chiu Elizabeth , Krop Ian E. , Michaelson Richard A. , Girish Sandhya , Amler Lukas , Zheng Maoxia , Chu Yu-Waye , Klencke Barbara , O'Shaughnessy Joyce A.
Published: December 2010

Purpose

The antibody-drug conjugate trastuzumab-DM1 (T-DM1) combines the biologic activity of trastuzumab with targeted delivery of a potent antimicrotubule agent, DM1, to human epidermal growth factor receptor 2 (HER2) –overexpressing cancer cells. Based on results from a phase I study that showed T-DM1 was well tolerated at the maximum-tolerated dose of 3.6 mg/kg every 3 weeks, with evidence of efficacy, in patients with HER2-positive metastatic breast cancer (MBC) who were previously treated with trastuzumab, we conducted a phase II study to further define the safety and efficacy of T-DM1 in this patient population.

Patients and Methods

This report describes a single-arm phase II study (TDM4258g) that assessed efficacy and safety of intravenous T-DM1 (3.6 mg/kg every 3 weeks) in patients with HER2-positive MBC who had tumor progression after prior treatment with HER2-directed therapy and who had received prior chemotherapy.

Results

With a follow-up of ≥ 12 months among 112 treated patients, the objective response rate by independent assessment was 25.9% (95% CI, 18.4% to 34.4%). Median duration of response was not reached as a result of insufficient events (lower limit of 95% CI, 6.2 months), and median progression-free survival time was 4.6 months (95% CI, 3.9 to 8.6 months). The response rates were higher among patients with confirmed HER2-positive tumors (immunohistochemistry 3+ or fluorescent in situ hybridization positive) by retrospective central testing (n = 74). Higher response rates were also observed in patients whose tumors expressed ≥ median HER2 levels by quantitative reverse transcriptase polymerase chain reaction for HER2 expression, compared with patients who had less than median HER2 levels. T-DM1 was well tolerated with no dose-limiting cardiotoxicity. Most adverse events (AEs) were grade 1 or 2; the most frequent grade ≥ 3 AEs were hypokalemia (8.9%), thrombocytopenia (8.0%), and fatigue (4.5%).

Conclusion

T-DM1 has robust single-agent activity in patients with heavily pretreated, HER2-positive MBC and is well tolerated at the recommended phase II dose.
Improved Prognosis for Older Adolescents With Acute Lymphoblastic Leukemia
Authors: Pui Ching-Hon , Pei Deqing , Campana Dario , Bowman W. Paul , Sandlund John T. , Kaste Sue C. , Ribeiro Raul C. , Rubnitz Jeffrey E. , Coustan-Smith Elaine , Jeha Sima , Cheng Cheng , Metzger Monika L. , Bhojwani Deepa , Inaba Hiroto , Raimondi Susana C. , Onciu Mihaela , Howard Scott C. , Leung Wing , Downing James R. , Evans William E. , Relling Mary V.
Published: December 2010

Purpose

The prognosis for older adolescents and young adults with acute lymphoblastic leukemia (ALL) has been historically much worse than that for younger patients. We reviewed the outcome of older adolescents (age 15 to 18 years) treated in four consecutive Total Therapy studies to determine if recent improved treatment extended to this high-risk group.

Patients and Methods

Between 1991 and 2007, 963 pediatric patients, including 89 older adolescents, were enrolled on Total Therapy studies XIIIA, XIIIB, XIV, and XV. In the first three studies, treatment selection was based on presenting clinical features and leukemic cell genetics. In study XV, the level of residual disease was used to guide treatment, which featured intensive methotrexate, glucocorticoid, vincristine, and asparaginase, as well as early triple intrathecal therapy for higher-risk ALL.

Results

The 89 older adolescents were significantly more likely to have T-cell ALL, the t(4;11)(MLL-AF4), and detectable minimal residual disease during or at the end of remission induction; they were less likely to have the t(12;21)(ETV6-RUNX1) compared with younger patients. In the first three studies, the 44 older adolescents had significantly poorer event-free survival and overall survival than the 403 younger patients. This gap in prognosis was abolished in study XV: event-free survival rates at 5 years were 86.4% ± 5.2% (standard error) for the 45 older adolescents and 87.4% ± 1.7% for the 453 younger patients; overall survival rates were 87.9% ± 5.1% versus 94.1% ± 1.2%, respectively.

Conclusion

Most older adolescents with ALL can be cured with risk-adjusted intensive chemotherapy without stem-cell transplantation.
“I'm already in a sort of tomb”: A Reply to Philip Scheffner's The Halfmoon Files
Authors: Gordon Avery F.
Published: December 2010

This essay is an illustrated montage of some points of engagement with Philip Scheffner's 2007 film, The Halfmoon Files, about the Halfmoon prisoner of war camp in Wünsdorf, Germany. The camp was an important site for anthropometric research and propaganda during World War I. The film is a ghost story and conjures a number of connections to related stories and to questions of racism, imprisonment, and war that my essay offers in response. My title—“I'm already in a sort of tomb”—is taken from Victor Serge's fictionalized autobiography, Men in Prison, whose contemporaneous account of being in prison during World War I serves as a guide along the way.
The Enemy He Wants
Authors: Dumm Thomas L.
Published: December 2010

President Barack Obama seems to have abandoned his left base in order to rule in a bipartisan manner. In this essay, I suggest that his strategy has not been to govern from the center, even if that is the result of his strategy. Instead, by focusing attention on his conflicts with the Right he has managed to make his left base acquiescent, while illuminating the intransigence of his right opposition. In short, he has chosen the enemy he wants.
The State of the Left, AOE
Authors: Walker Kelley
Published: December 2010

This essay explores the varied reactions of several activists to the first two years of Barack Obama's administration. While their responses vary from resignation to despair to anger, none engages in a spirited defense of the administration. What unites them is a shared assumption that leftists have failed. Rather than complain about or defend an administration they feel they cannot defend, they tend to blame themselves for failing to become the “subject of history”—a subject that haunts and paralyzes left thought and action.
What's Going On? What Is to Be Done?
Authors: Horne Gerald
Published: December 2010

This essay seeks to place in context discontent on the left with the Barack Obama administration by focusing on the remarkable fact that for decades the Euro-American majority has voted consistently for the Republican Party, while minorities—particularly the most consistent anticonservative force, African Americans—are subjected to voter suppression to dampen turnout. This has created a structural right-wing bias within the United States. To escape this conundrum, this essay suggests emulation of our historical predecessors—for example, during the abolitionist struggle and the anti–Jim Crow campaign—who relied heavily on the international community for success.
Hindbrain patterning requires fine-tuning of early krox20 transcription by Sprouty 4
Authors: Labalette Charlotte , Bouchoucha Yassine Xavier , Wassef Michel Adam , Gongal Patricia Anne , Le Men Johan , Becker Thomas , Gilardi-Hebenstreit Pascale , Charnay Patrick
Published: December 2010

Vertebrate hindbrain segmentation is an evolutionarily conserved process that involves a complex interplay of transcription factors and signalling pathways. Fibroblast growth factor (FGF) signalling plays a major role, notably by controlling the expression of the transcription factor Krox20 (Egr2), which is required for the formation and specification of two segmental units: rhombomeres (r) 3 and 5. Here, we explore the molecular mechanisms downstream of FGF signalling and the function of Sprouty 4 (Spry4), a negative-feedback regulator of this pathway, in zebrafish. We show that precise modulation of FGF signalling by Spry4 is required to determine the appropriate onset of krox20 transcription in r3 and r5 and, ultimately, rhombomere size in the r3-r5 region. FGF signalling acts by modulating the activity of krox20 initiator enhancer elements B and C; in r5, we show that this regulation is mediated by direct binding of the transcription factor MafB to element B. By contrast, FGF signalling does not control the krox20 autoregulatory element A, which is responsible for amplification and maintenance of krox20 expression. Therefore, early krox20 transcription sets the blueprint for r3-r5 patterning. This work illustrates the necessity for fine-tuning in a common and fundamental patterning process, based on a bistable cell-fate choice involving the coupling of an extracellular gradient with a positive-feedback loop. In this mode of patterning, precision and robustness can be achieved by the introduction of a negative-feedback loop, which, in the hindbrain, is mediated by Spry4.
Connective tissue fibroblasts and Tcf4 regulate myogenesis
Authors: Mathew Sam J. , Hansen Jody M. , Merrell Allyson J. , Murphy Malea M. , Lawson Jennifer A. , Hutcheson David A. , Hansen Mark S. , Angus-Hill Melinda , Kardon Gabrielle
Published: December 2010

Muscle and its connective tissue are intimately linked in the embryo and in the adult, suggesting that interactions between these tissues are crucial for their development. However, the study of muscle connective tissue has been hindered by the lack of molecular markers and genetic reagents to label connective tissue fibroblasts. Here, we show that the transcription factor Tcf4 (transcription factor 7-like 2; Tcf7l2) is strongly expressed in connective tissue fibroblasts and that Tcf4GFPCre mice allow genetic manipulation of these fibroblasts. Using this new reagent, we find that connective tissue fibroblasts critically regulate two aspects of myogenesis: muscle fiber type development and maturation. Fibroblasts promote (via Tcf4-dependent signals) slow myogenesis by stimulating the expression of slow myosin heavy chain. Also, fibroblasts promote the switch from fetal to adult muscle by repressing (via Tcf4-dependent signals) the expression of developmental embryonic myosin and promoting (via a Tcf4-independent mechanism) the formation of large multinucleate myofibers. In addition, our analysis of Tcf4 function unexpectedly reveals a novel mechanism of intrinsic regulation of muscle fiber type development. Unlike other intrinsic regulators of fiber type, low levels of Tcf4 in myogenic cells promote both slow and fast myogenesis, thereby promoting overall maturation of muscle fiber type. Thus, we have identified novel extrinsic and intrinsic mechanisms regulating myogenesis. Most significantly, our data demonstrate for the first time that connective tissue is important not only for adult muscle structure and function, but is a vital component of the niche within which muscle progenitors reside and is a critical regulator of myogenesis.
Visualizing dynamic cytoplasmic forces with a compliance-matched FRET sensor
Authors: Meng Fanjie , Sachs Frederick
Published: December 2010

Mechanical forces are ubiquitous modulators of cell activity but little is known about the mechanical stresses in the cell. Genetically encoded FRET-based force sensors now allow the measurement of local stress in specific host proteins in vivo in real time. For a minimally invasive probe, we designed one with a mechanical compliance matching that of many common cytoskeleton proteins. sstFRET is a cassette composed of Venus and Cerulean linked by a spectrin repeat. The stress sensitivity of the probe was measured in solution using DNA springs to push the donor and acceptor apart with 5–7 pN and this produced large changes in FRET. To measure cytoskeletal stress in vivo we inserted sstFRET into α-actinin and expressed it in HEK and BAEC cells. Time-lapse imaging showed the presence of stress gradients in time and space, often uncorrelated with obvious changes in cell shape. The gradients could be rapidly relaxed by thrombin-induced cell contraction associated with inhibition of myosin II. The tension in actinin fluctuated rapidly (scale of seconds) illustrating a cytoskeleton in dynamic equilibrium. Stress in the cytoskeleton can be driven by macroscopic stresses applied to the cell. Using sstFRET as a tool to measure internal stress, we tested the prediction that osmotic pressure increases cytoskeletal stress. As predicted, hypotonic swelling increased the tension in actinin, confirming the model derived from AFM. Anisotonic stress also produced a novel transient (~2 minutes) decrease in stress upon exposure to a hypotonic challenge, matched by a transient increase with hypertonic stress. This suggests that, at rest, the stress axis of actinin is not parallel to the stress axis of actin and that swelling can reorient actinin to lie more parallel where it can absorb a larger fraction of the total stress. Protein stress sensors are opening new perspectives in cell biology.