bluuebunny/crossref_metadata_2025 huggingface dataset:
A comparison of invasive versus noninvasive full-time mechanical ventilation in Duchenne muscular dystrophy
Authors: Soudon P , Steens M , Toussaint M
Published: June 2008

The aim of this study was to compare morbidity and causes of death in a series of 42 Duchenne patients receiving full-time mechanical ventilation either by tracheostomy (TR, n = 16 or by noninvasive methods (noninvasive ventilation [NIV], n = 26). At inclusion for a 5-year observation period (2002–2006), TR and NIV patients were 32.7 and 27 years old, respectively. A program of follow-up with similar ventilation devices, techniques of respiratory physiotherapy, and drugs was applied to all the patients [TR + NIV]. Ages and respiratory characteristics at death and causes of death were comparable between groups. Morbidity was worse in TR compared with NIV patients; mucus hypersecretion and tracheal injuries were more frequent, whereas loss of weight and need for gastric feeding appeared less frequent in the TR group. Because noninvasive techniques avoid the severe complications associated with TR with comparable mortality, the authors support the use of noninvasive interfaces as default choice when assisted ventilation is required for daytime use.
Original Research: Role of phosphodiesterases in modulation of BKCachannels in hypertensive pulmonary arterial smooth muscle
Authors: Shu Zhu  , White Richard E. , Barman Scott A.
Published: June 2008

BKCachannels regulate pulmonary arterial pressure, and protein kinase C (PKC) inhibits BKCachannels, but little is known about PKC-mediated modulation of BKCachannel activity in pulmonary arterial smooth muscle. Studies were carried out to determine mechanisms of PKC modulation of BKCachannel activity in pulmonary arterial smooth muscle cells (PASMC) of the fawn-hooded rat (FHR), an animal model of pulmonary hypertension. Forskolin opened BKCachannels in FHR PASMC, which was blocked by PKC activation, and reversed by the phosphodiesterase (PDE) inhibitors IBMX, milrinone, and zaprinast. PDE inhibition also blocked the vasoconstrictor response to PKC activation in FHR pulmonary arteries. These results indicate that PKC inhibits cAMP-induced activation of BKCachannels and causes pulmonary vasoconstriction in hypertensive pulmonary arterial smooth muscle via PDE, which further suggests PDE inhibitors for treatment of pulmonary hypertension.
Review: Therapeutic perspectives in bronchial vascular remodeling in COPD
Authors: Zanini Andrea , Chetta Alfredo , Olivieri Dario
Published: June 2008

COPD may be characterized by significant changes in airway mucosal blood vessels, which may contribute to bronchial airway remodeling. The airway wall is more vascularized in COPD patients than in healthy subjects, though this phenomenon is less evident than in asthmatic patients. The vascular mucosal changes in the airways of patients with COPD are strictly linked to the inflammatory processes. The cellular mechanisms responsible for the microvascular changes are still unclear, however, pro-angiogenic factors, such as VEGF, TGF- β, FGF, and proteolytic enzymes such as MMPs, may play a role. Up to now, the clinical and functional consequences of this phenomenon and the therapeutic approach have been scarcely investigated. Inhaled corticosteroids seem to have positive effects, by reducing the vascular area and growth factor expression. Specific antagonists to VEGF, TGF- β, FGF, and MMPs could beneficially control chronic airway inflammation and vascular remodeling in COPD as well as slow down the progression of the disease. Several of these growth factor antagonists are being evaluated and some seem to be effective in reducing vascularity, however further studies are required to ascertain whether or not these antagonists may play a role in COPD therapy.
Review: Stem cell therapy: the great promise in lung disease
Authors: Siniscalco Dario , Sullo Nikol , Maione Sabatino , Rossi Francesco , D'Agostino Bruno
Published: June 2008

Lung injuries are leading causes of morbidity and mortality worldwide. Pulmonary diseases such as asthma or chronic obstructive pulmonary disease characterized by loss of lung elasticity, small airway tethers, and luminal obstruction with inflammatory mucoid secretions, or idiopathic pulmonary fibrosis characterized by excessive matrix deposition and destruction of the normal lung architecture, have essentially symptomatic treatments and their management is costly to the health care system.

Regeneration of tissue by stem cells from endogenous, exogenous, and even genetically modified cells is a promising novel therapy. The use of adult stem cells to help with lung regeneration and repair could be a newer technology in clinical and regenerative medicine. In fact, different studies have shown that bone marrow progenitor cells contribute to repair and remodeling of lung in animal models of progressive pulmonary hypertension.

Therefore, lung stem cell biology may provide novel approaches to therapy and could represent a great promise for the future of molecular medicine. In fact, several diseases can be slowed or even blocked by stem cell transplantation.
Integrated computational model to predict mechanical behaviour of spot weld
Authors: Yang Y. P. , Babu S. S. , Orth F. , Peterson W.
Published: June 2008

An integrated computational model was developed by considering microstructural heterogeneity and residual stress of spot welds. The model consists of a resistance spot weld process model and a local mechanical model. The resistance spot weld process model is used to predict residual stress distribution, which is mapped into the local mechanical model. The hardness distribution of a spot weld is measured experimentally, and then converted into the tensile strength which is mapped into the local mechanical model. The local mechanical model is then used to predict the load response functions and failure modes of DP 590 spot welds. The predictions have been compared with DP 590 spot weld experiments.
Paroxysmal nocturnal hemoglobinuria: natural history of disease subcategories
Authors: de Latour Régis Peffault , Mary Jean Yves , Salanoubat Célia , Terriou Louis , Etienne Gabriel , Mohty Mohamad , Roth Sophie , de Guibert Sophie , Maury Sebastien , Cahn Jean Yves , Socié Gerard
Published: June 2008

The natural history of paroxysmal nocturnal hemoglobinuria (PNH) clinical subcategories (classic PNH and aplastic anemia [AA]/PNH syndrome) is still unknown. We retrospectively studied 460 PNH patients diagnosed in 58 French hematologic centers from 1950 to 2005. The median (SE) follow-up time was 6.8 (0.5) years. The median survival time (SE) was 22 (2.5) years. We identified 113 patients with classic PNH, 224 patients with AA-PNH syndrome, and 93 (22%) intermediate patients who did not fit within these 2 categories. At presentation, classic PNH patients were older, with more frequent abdominal pain and displayed higher levels of GPI-AP–deficient granulocytes. A time-dependent improved survival was observed. In classic PNH, diagnoses before 1986 (hazard ratio [HR]: 3.6; P = .01) and increasing age (P < .001) were associated with worse survival prognoses, whereas use of androgens within the first year after diagnosis was protective (HR, 0.17; P = .01). Transfusions before 1996 (HR, 2.7; P = .007) led to lower survival rates in patients with AA-PNH syndrome, whereas immunosuppressive treatment was associated with better outcomes (HR, 0.33; P = .03). Evolution to thrombosis affected survival in both subcategories (classic PNH: HR, 7.8 [P < .001]; AA-PNH syndrome: HR, 33.0 [P < .001]). Evolution to bicytopenia or pancytopenia for classic PNH (HR, 7.3, P < .001) and malignancies for AA-PNH syndrome (HR, 48.8; P < .001) were associated with worse outcomes. Although clinical presenta-tion and prognosis factors are different, classic PNH and AA-PNH syndrome present roughly similar outcomes, affected mainly by complications.
Depletion of human regulatory T cells specifically enhances antigen-specific immune responses to cancer vaccines
Authors: Morse Michael A. , Hobeika Amy C. , Osada Takuya , Serra Delila , Niedzwiecki Donna , Lyerly H. Kim , Clay Timothy M.
Published: June 2008

CD4+CD25highFoxP3+ regulatory T (Treg) cells limit antigen-specific immune responses and are a cause of suppressed anticancer immunity. In preclinical and clinical studies, we assessed the immune consequences of FoxP3+ Treg-cell depletion in patients with advanced malignancies. We demonstrated that a CD25high targeting immunotoxin (denileukin diftitox) depleted FoxP3+ Treg cells, decreased Treg-cell function, and enhanced antigen-specific T-cell responses in vitro. We then attempted to enhance antitumor immune responses in patients with carcinoembryonic antigen (CEA)–expressing malignancies by Treg-cell depletion. In a pilot study (n = 15), denileukin diftitox, given as a single dose or repeated dosing, was followed by immunizations with dendritic cells modified with the fowlpox vector rF-CEA(6D)-TRICOM. By flow cytometric analysis, we report the first direct evidence that circulating CD4+CD25highFoxP3+ Treg cells are depleted after multiple doses of denileukin diftitox. Earlier induction of, and overall greater exposure to, the T-cell response to CEA was observed in the multiple-dose group, but not the single-dose group. These results indicate the potential for combining Treg-cell depletion with anticancer vaccines to enhance tumor antigen-specific immune responses and the need to explore dose and schedule of Treg depletion strategies in optimiz-ing vaccine efforts. This trial was registered at www.clinicaltrials.gov as no. NCT00128622.
A unique three-dimensional model for evaluating the impact of therapy on multiple myeloma
Authors: Kirshner Julia , Thulien Kyle J. , Martin Lorri D. , Debes Marun Carina , Reiman Tony , Belch Andrew R. , Pilarski Linda M.
Published: June 2008

Although the in vitro expansion of the multiple myeloma (MM) clone has been unsuccessful, in a novel three-dimensional (3-D) culture model of reconstructed bone marrow (BM, n = 48) and mobilized blood autografts (n = 14) presented here, the entire MM clone proliferates and undergoes up to 17-fold expansion of malignant cells harboring the clonotypic IgH VDJ and characteristic chromosomal rearrangements. In this system, MM clone expands in a reconstructed microenvironment that is ideally suited for testing specificity of anti-MM therapeutics. In the 3-D model, melphalan and bortezomib had distinct targets, with melphalan targeting the hematopoietic, but not stromal com-partment. Bortezomib targeted only CD138+CD56+ MM plasma cells. The localization of nonproliferating cells to the reconstructed endosteum, in contact with N-cadherin–positive stroma, suggested the presence of MM-cancer stem cells. These drug-resistant CD20+ cells were enriched more than 10-fold by melphalan treatment, exhibited self-renewal, and generated clonotypic B and plasma cell progeny in colony forming unit assays. This is the first molecularly verified demonstration of proliferation in vitro by ex vivo MM cells. The 3-D culture provides a novel biologically relevant preclinical model for evaluating therapeutic vulnerabilities of all compartments of the MM clone, including presumptive drug-resistant MM stem cells.
Long-term remission of Philadelphia chromosome–positive acute lymphoblastic leukemia after allogeneic hematopoietic cell transplantation from matched sibling donors: a 20-year experience with the fractionated total body irradiation–etoposide regimen
Authors: Laport Ginna G. , Alvarnas Joseph C. , Palmer Joycelynne M. , Snyder David S. , Slovak Marilyn L. , Cherry Athena M. , Wong Ruby M. , Negrin Robert S. , Blume Karl G. , Forman Stephen J.
Published: June 2008

Allogeneic hematopoietic cell transplantation (HCT) is the only known curative modality for patients with Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ ALL). Sixty-seven patients with HLA-matched sibling donors received fractionated total body irradiation (FTBI) and high-dose VP16, whereas 11 patients received FTBI/VP16/cyclophosphamide, and 1 patient received FTBI/VP16/busulfan. The median age was 36 years. At the time of HCT, 49 patients (62%) were in first complete remission (CR1) and 30 patients (38%) were beyond CR1 (> CR1). The median follow-up was 75 months (range, 14-245 months). The 10-year overall survival for the CR1 and beyond CR1 patients was 54% and 29% (P = .01), respectively, and event-free survival was 48% and 26% (P = .02), respectively. There was no significant difference in relapse incidence (28% vs 41%, P = .28), but nonrelapse mortality was significantly higher in the beyond CR1 patients, (31% vs 54%, P = .03, respectively). By univariate analysis, factors affecting event-free and overall survival were white blood cell count at diagnosis (< 30 × 109/L vs > 30 × 109/L) and disease status (CR1 vs > CR1). The median time to relapse for CR1 and for beyond CR1 patients was 12 months and 9 months, respectively. Our results indicate that FTBI/VP16 with or without cyclophosphamide confers long-term survival in Ph+ ALL patients and that disease status at the time of HCT is an important predictor of outcome.
The GraRS regulatory system controls Staphylococcus aureus susceptibility to antimicrobial host defenses
Authors: Kraus Dirk , Herbert Silvia , Kristian Sascha A , Khosravi Arya , Nizet Victor , Götz Friedrich , Peschel Andreas
Published: June 2008

Background

Modification of teichoic acids with D-alanine by the products of the dlt operon protects Gram-positive bacteria against major antimicrobial host defense molecules such as defensins, cathelicidins, myeloperoxidase or phospholipase. The gra RS regulatory genes have recently been implicated in the control of D-alanylation in Staphylococcus aureus.

Results

To determine the impact of the GraRS regulatory system on resistance to antimicrobial host defense mechanisms and virulence of S. aureus, we compared inactivation of S. aureus SA113 wild type and its isogenic gra RS deletion mutant by the human cathelicidin LL-37 or human neutrophil granulocytes in vitro, and the ability to cause infection in vivo. We show here that gra RS deletion considerably alters bacterial surface charge, increases susceptibility to killing by human neutrophils or the defense peptide LL-37, and attenuates virulence of S. aureus in a mouse infection model.

Conclusion

Our results indicate that S. aureus can regulate its surface properties in order to overcome innate host defenses.
Variation in WNT7A is unlikely to be a cause of familial Congenital Talipes Equinovarus
Authors: Liu Guoqing , Inglis Julie , Cardy Amanda , Shaw Duncan , Sahota Sukhy , Hennekam Raoul , Sharp Linda , Miedzybrodzka Zosia
Published: June 2008

Background

Genetic factors make an important contribution to the aetiology of congenital talipes equinovarus (CTEV), the most common developmental disorder of the lower limb. WNT7A was suggested as a candidate gene for CTEV on the basis of a genome-wide scan for linkage in a large multi-case family. WNT7A is a plausible candidate gene for CTEV as it provides a signal for pattern formation during limb development, and mutation in WNT7A has been reported in a number of limb malformation syndromes.

Methods

We investigated the role of WNT7A using a family-based linkage approach in our large series of European multi-case CTEV families. Three microsatellite markers were used, of which one (D3S2385) is intragenic, and the other two (D3S2403, D3S1252) are 700 kb 5' to the start and 20 kb from the 3' end of the gene, respectively. Ninety-one CTEV families, comprising 476 individuals of whom 211 were affected, were genotyped. LOD scores using recessive and incomplete-dominant inheritance models, and non-parametric linkage scores, excluded linkage.

Results

No significant evidence for linkage was observed using either parametric or non-parametric models. LOD scores for the parametric models remained strongly negative in the regions between the markers, and in the 0.5 cM intervals outside the marker map. No significant lod scores were obtained when the data were analysed allowing for heterogeneity.

Conclusion

Our evidence suggests that the WNT7A gene is unlikely to be a major contributor to the aetiology of familial CTEV.
The diagnostic work up of growth failure in secondary health care; An evaluation of consensus guidelines
Authors: Grote Floor K , Oostdijk Wilma , De Muinck Keizer-Schrama Sabine MPF , van Dommelen Paula , van Buuren Stef , Dekker Friedo W , Ketel Arnoldus G , Moll Henriette A , Wit Jan M
Published: June 2008

Background

As abnormal growth might be the first manifestation of undetected diseases, it is important to have accurate referral criteria and a proper diagnostic work-up. In the present paper we evaluate the diagnostic work-up in secondary health care according to existing consensus guidelines and study the frequency of underlying medical disorders.

Methods

Data on growth and additional diagnostic procedures were collected from medical records of new patients referred for short stature to the outpatient clinics of the general paediatric departments of two hospitals (Erasmus MC – Sophia Children's Hospital, Rotterdam and Spaarne Hospital, Haarlem) between January 1998 and December 2002. As the Dutch Consensus Guideline (DCG) is the only guideline addressing referral criteria as well as diagnostic work-up, the analyses were based on its seven auxological referral criteria to determine the characteristics of children who are incorrectly referred and the adequacy of workup of those who are referred.

Results

Twenty four percent of children older than 3 years were inappropriately referred (NCR). Of the correctly referred children 74–88% were short corrected for parental height, 40–61% had a height SDS <-2.5 and 21% showed height deflection (Δ HSDS < -0.25/yr or Δ HSDS < -1). In none of the children a complete detailed routine diagnostic work up was performed and in more than 30% no routine laboratory examination was done at all. Pathologic causes of short stature were found in 27 children (5%).

Conclusion

Existing guidelines for workup of children with suspected growth failure are poorly implemented. Although poorly implemented the DCG detects at least 5% pathologic causes of growth failure in children referred for short stature. New guidelines for referral are required with a better sensitivity and specificity, wherein distance to target height should get more attention. The general diagnostic work up for short stature should include testing for celiac disease in all children and for Turner syndrome in girls.
Bacterial-based systems for expression and purification of recombinant Lassa virus proteins of immunological relevance
Authors: Branco Luis M , Matschiner Alex , Fair Joseph N , Goba Augustine , Sampey Darryl B , Ferro Philip J , Cashman Kathleen A , Schoepp Randal J , Tesh Robert B , Bausch Daniel G , Garry Robert F , Guttieri Mary C
Published: June 2008

Background

There is a significant requirement for the development and acquisition of reagents that will facilitate effective diagnosis, treatment, and prevention of Lassa fever. In this regard, recombinant Lassa virus (LASV) proteins may serve as valuable tools in diverse antiviral applications. Bacterial-based systems were engineered for expression and purification of recombinant LASV nucleoprotein (NP), glycoprotein 1 (GP1), and glycoprotein 2 (GP2).

Results

Full-length NP and the ectodomains of GP1 and GP2 were generated as maltose-binding protein (MBP) fusions in the Rosetta strains of Escherichia coli (E. coli) using pMAL-c2x vectors. Average fusion protein yields per liter of culture for MBP-NP, MBP-GP1, and MBP-GP2 were 10 mg, 9 mg, and 9 mg, respectively. Each protein was captured from cell lysates using amylose resin, cleaved with Factor Xa, and purified using size-exclusion chromatography (SEC). Fermentation cultures resulted in average yields per liter of 1.6 mg, 1.5 mg, and 0.7 mg of purified NP, GP1 and GP2, respectively. LASV-specific antibodies in human convalescent sera specifically detected each of the purified recombinant LASV proteins, highlighting their utility in diagnostic applications. In addition, mouse hyperimmune ascitic fluids (MHAF) against a panel of Old and New World arenaviruses demonstrated selective cross reactivity with LASV proteins in Western blot and enzyme-linked immunosorbent assay (ELISA).

Conclusion

These results demonstrate the potential for developing broadly reactive immunological assays that employ all three arenaviral proteins individually and in combination.
New Horizons for Imaging Lymphatic Function
Authors: Sharma Ruchi , Wendt Juliet A. , Rasmussen John C. , Adams Kristen E. , Marshall Milton V. , Sevick‐Muraca Eva M.
Published: June 2008

In this review, we provide a comprehensive summary of noninvasive imaging modalities used clinically for the diagnosis of lymphatic diseases, new imaging agents for assessing lymphatic architecture and cancer status of lymph nodes, and emerging near‐infrared (NIR) fluorescent optical imaging technologies and agents for functional lymphatic imaging. Given the promise of NIR optical imaging, we provide example results of functional lymphatic imaging in mice, swine, and humans, showing the ability of this technology to quantify lymph velocity and frequencies of propulsion resulting from the contractility of lymphatic structures.
Phenotypic Characterization of Primary Lymphedema
Authors: Connell Fiona , Brice Glen , Mortimer Peter
Published: June 2008

The phenotypic entities of primary lymphedema vary in age of onset, site of edema, associated features, inheritance patterns, and underlying genetic cause. Determining the representative phenotype for different types of genetically determined primary lymphedema has been successfully achieved with Milroy's disease and the lymphedema–distichiasis syndrome. Here we describe and illustrate their well‐delineated phenotypes. Phenotype characterization facilitates the identification of causative genes, as has been demonstrated with VEGFR3 and FOXC2, in Milroy's disease and lymphedema–distichiasis respectively. Other forms of primary lymphedema are discussed.
Lymphatic Vessel Activation in Cancer
Authors: Das Suvendu , Skobe Mihaela
Published: June 2008

Most cancerous lesions metastasize through the lymphatic system and the status of regional lymph nodes is the most important indicator of a patient's prognosis. The extent of lymph node involvement with cancer is also an important parameter used for determining treatment options. Although the importance of the lymphatic system for metastasis has been well recognized, traditionally, the lymphatic vessels have not been considered actively involved in the metastatic process. Recent evidence, however, indicates that the activation of the lymphatic system is an important factor in tumor progression to metastasis. Tumor lymphangiogenesis has been associated with increased propensity for metastasis, and lymphatic vessel density has emerged as another promising prognostic indicator. More recently, lymphangiogenesis in the sentinel lymph nodes has been shown to contribute to malignant progression. In addition to its role as a transport system for tumor cells, the lymphatic system may also be more actively involved in metastases by directly facilitating tumor cell recruitment into the lymphatic vessels. This review highlights recent advances in our understanding of the mechanisms by which lymphatic vessels participate in metastasis.
Effect of Des-acyl Ghrelin on Adiposity and Glucose Metabolism
Authors: Zhang Weizhen , Chai Biaoxin , Li Ji-yao , Wang Hui , Mulholland Michael W.
Published: June 2008

Ghrelin, a gastric peptide hormone, has been reported to regulate GH secretion and energy homeostasis. Here, we examined the effect of des-acyl ghrelin driven from the fatty acid-binding protein-4 (FABP4) promoter on adiposity and glucose metabolism. A high level of expression of des-acyl ghrelin (692 ± 293 fmol/g fat) in adipose tissue was detected in FABP4-ghrelin transgenic mice, but not in wild-type littermates. Circulating des-acyl ghrelin was significantly higher in FABP4-ghrelin transgenic mice (8409 ± 3390 pm) compared with wild-type mice (513 ± 58 pm). No significant change was observed for plasma acylated ghrelin and obestatin. Epididymal and perirenal fat masses decreased 35 ± 9 and 52 ± 9%, respectively, in FABP4-ghrelin transgenic mice. FABP4-ghrelin transgenic mice are resistant to obesity induced by high-fat diet. Brown fat mass was not affected by overexpression of ghrelin in adipose tissue. Glucose tolerance tests showed glucose levels to be significantly lower in FABP4-ghrelin transgenic mice than in controls after glucose administration. Insulin sensitivity testing showed that FABP4-ghrelin transgenic mice had a 28 ± 5% greater hypoglycemic response to insulin. Our study demonstrates that overexpression of ghrelin from the FABP4 promoter impairs the development of white adipose tissues, and alters glucose tolerance and insulin sensitivity in mice.
The Cloned Equine Thyrotropin Receptor Is Hypersensitive to Human Chorionic Gonadotropin; Identification of Three Residues in the Extracellular Domain Involved in Ligand Specificity
Authors: Royer Julien , Lefevre-Minisini Anne , Caltabiano Gianluigi , Lacombe Thierry , Malthiery Yves , Savagner Frédérique , Pardo Leonardo , Rodien Patrice
Published: June 2008

The receptors for TSH, LH/chorionic gonadotropin (CG), and FSH belong to the same subfamily of G protein-coupled receptors. The specificity of recognition of their cognate hormone involves a limited number of residues in the leucine-rich repeats present in the N-terminal ectodomain of the receptor. It is admitted that receptors of this subfamily coevoluted with their respective ligands. The secretion of CG is restricted to gestation of primates and Equidae. We hypothesized that, facing the challenge of a new hormone, the glycoprotein hormone receptors would have evolved differently in Equidae and human so that distinct residues are involved in hormone specificity. In particular, it is known that equine CG has a dual (FSH and LH) activity when administered to other species. In the present work, we cloned and characterized functionally the equine TSH receptor (TSHR), which shares 89% homology with the human TSHR. The equine TSHR is not responsive to equine CG but is more sensitive to human CG than the human TSHR. Three residues, at positions 60, 229, and 235 of the ectodomain, are responsible for this difference in sensitivity as shown by modelization and targeted mutagenesis, followed by in vitro functional characterization. The phylogenetic approach is a suitable approach to identify determinants of specificity of receptors.
Molecular Characterization, Tissue-Specific Expression, and Regulation of Melanocortin 2 Receptor in Rainbow Trout
Authors: Aluru Neelakanteswar , Vijayan Mathilakath M.
Published: June 2008

ACTH, the primary secretagogue for corticosteroid biosynthesis, binds to melanocortin 2 receptor (MC2R) and activates the signaling cascade leading to steroid biosynthesis in the adrenal cortex. Whereas MC2R regulation has been studied using mammalian models, little is known about the molecular mechanisms involved in ACTH signaling in nonmammalian vertebrates. A full-length cDNA encoding MC2R was sequenced from rainbow trout (Oncorhynchus mykiss) interrenal tissue (analogous to the adrenal cortex in mammals) and showed about 60 and about 44% amino acid sequence similarity to teleosts and humans, respectively. Phylogenetic analysis confirmed that MC2R from all species clustered together and was distant from other MCRs. Quantitative real-time PCR revealed a marked tissue-specific difference in MC2R mRNA abundance, with the highest levels observed in the interrenal tissue, ovary, and testis. Acute ACTH, but not α-MSH or [Nle4, d-Phe7]-MSH, stimulation resulted in a time- and dose-related elevation in MC2R mRNA abundance in the interrenal tissue. This corresponded with higher steroidogenic acute regulatory protein and cytochrome P450 side-chain cleavage enzyme gene expression as well as elevated cortisol production. An acute stressor transiently elevated plasma ACTH and cortisol levels at 1 h, and this was followed by a significant increase in MC2R mRNA abundance at 4 h after stressor exposure. Taken together, our results demonstrate that ACTH regulation of MC2R is highly conserved in vertebrates, whereas the tissue-specific distribution of this receptor transcript level leads us to propose a role for ACTH signaling in the stressor-mediated suppression of sex steroid levels in fish.
β-Catenin has sequential roles in the survival and specification of ventral dermis
Authors: Ohtola Jennifer , Myers John , Akhtar-Zaidi Batool , Zuzindlak Diana , Sandesara Pooja , Yeh Karen , Mackem Susan , Atit Radhika
Published: June 2008

The dermis promotes the development and maintains the functional components of skin, such as hair follicles, sweat glands, nerves and blood vessels. The dermis is also crucial for wound healing and homeostasis of the skin. The dermis originates from the somites, the lateral plate mesoderm and the cranial neural crest. Despite the importance of the dermis in the structural and functional integrity of the skin, genetic analysis of dermal development in different parts of the embryo is incomplete. The signaling requirements for ventral dermal cell development have not been established in either the chick or the mammalian embryo. We have shown previously that Wnt signaling specifies the dorsal dermis from the somites. In this study, we demonstrate that Wnt/β-catenin signaling is necessary for the survival of early ventral dermal progenitors. In addition, we show that, at later stages,Wnt/β-catenin signaling is sufficient for ventral dermal cell specification. Consistent with the different origins of dorsal and ventral dermal cells, our results demonstrate both conserved and divergent roles ofβ-catenin/Wnt signaling in dermal development.
Location of the vortex formation threshold at suction inlets near ground planes by computational fluid dynamics simulation
Authors: Jermy M , Ho W H
Published: June 2008

Vortices can develop in the intakes of turbojet and turbofan aero engines during high power operation near solid surfaces such as during takeoff or ground tests. These vortices can stall the compressor and cause significant damage. The factors determining the formation of the vortex include engine thrust, distance from ground, and ambient vorticity. A computational fluid dynamics study was conducted to determine whether these effects could be predicted numerically, and the results were compared to previous wind-tunnel studies. This is the first reported study of numerical predictions of the vortex formation threshold. Two factors, which had not been previously studied either experimentally or numerically, were investigated: the effects of increasing the size of the suction inlet and increasing the thickness of the ground boundary layer. Both were found to encourage vortex formation. The threshold of vortex formation predicted numerically agrees with previous wind-tunnel studies, within the scatter of the experimental data. The numerical results reproduce all trends identified in the experimental studies. The minimum shear required to form a vortex was found, lying between 0.001 and 0.05/s (Rossby number of the order of 105).
Satellite attitude control using solar radiation pressure based on non-linear sliding mode control
Authors: Patel T R , Kumar K D , Behdinan K
Published: June 2008

The paper proposes the use of solar radiation pressure for satellite attitude control using non-linear sliding mode control (SMC). The system comprises a satellite with two-oppositely placed solar flaps. A non-linear SMC approach has been adopted to develop control law for suitably rotating the solar flaps to achieve desired satellite attitude performance. The detailed numerical simulation of the governing non-linear system equation of motion including the effects of various system parameters on the controller performance, establishes the feasibility of the proposed control strategy. The numerical simulation matches with the analytical results. Furthermore, the proposed controller is found to be robust against external disturbances and its performance is superior in comparison to feedback linearization control. Thus, the robustness of the proposed control strategy makes it attractive for future space applications.
Influence of tab geometry and its orientation on under-expanded sonic jets
Authors: Thanigaiarasu S , Jayaprakash S , Elangovan S , Rathakrishnan E
Published: June 2008

The effect of tab geometry and its orientation placed at the nozzle exit on the evolution of an axi-symmetric sonic under-expanded and fully expanded jet was investigated experimentally. The tab used was a hollow semi-circular tube. The near jet flow field was studied for two configurations of the tab, namely, the concave surface facing the flow exiting nozzle (arc-tab facing-in) and convex surface facing the flow (arc-tab facing-out) for three different protrusions of the tab corresponding to blockages of 3.82, 7.64, and 11.46 per cent ( z1, z2, and z3, respectively). The results were compared with that obtained for a plain rectangular tab of the same blockage and a plain circular nozzle. The jet was found to decay at a faster rate in the case of arc-tab facing-in configuration at all blockage levels as compared with the other two configurations. With arc-tab facing-in, the core length was reduced by 80 per cent and the corresponding reduction was 40 per cent for the jet with arc-tab facing-out and rectangular tabs. For the under-expanded sonic jet at the nozzle pressure ratio (NPR) 2, 3, and 5, the arc-tab facing-in configuration was found to reduce the potential core length and weaken the shock structure significantly as compared with the other two configurations as indicated by the lesser amplitude in pitot pressure variations. The shadowgraph pictures showed that the shock-cell structure was significantly perturbed and length of the cells was reduced considerably. This effect was found to be more pronounced at higher blockages. The iso-baric contours indicate that the jet spread is faster and wider in the direction normal to the tab revealing that the streamwise vortices shed by the tabs cause an inward indentation of the ambient air into the jet core and outward ejection of the jet core to the ambient. The geometry and orientation of the tab along with the level of blockage seem to have a profound influence on the development of the jet in the near field.
Intramedullary application of bone morphogenetic protein in the management of a major bone defect after an Ilizarov procedure
Authors: Burkhart K. J. , Rommens P. M.
Published: June 2008

We describe a patient with insufficient bone regeneration of the tibia after bone transport over an intramedullary nail, in whom union was ultimately achieved after exchange nailing and intramedullary application of rh-bone morphogenetic protein-7 at the site of distraction.
Disorders of the sternoclavicular joint
Authors: Robinson C. M. , Jenkins P. J. , Markham P. E. , Beggs I.
Published: June 2008

The sternoclavicular joint is vulnerable to the same disease processes as other synovial joints, the most common of which are instability from injury, osteoarthritis, infection and rheumatoid disease. Patients may also present with other conditions, which are unique to the joint, or are manifestations of a systemic disease process. The surgeon should be aware of these possibilities when assessing a patient with a painful, swollen sternoclavicular joint.
The maximum priority index method for severely constrained item selection in computerized adaptive testing
Authors: Cheng Ying , Chang Hua‐Hua
Published: June 2008

This paper introduces a new heuristic approach, the maximum priority index (MPI) method, for severely constrained item selection in computerized adaptive testing. Our simulation study shows that it is able to accommodate various non‐statistical constraints simultaneously, such as content balancing, exposure control, answer key balancing, and so on. Compared with the weighted deviation modelling method, it leads to fewer constraint violations and better exposure control while maintaining the same level of measurement precision.
The role of efficacy and moral outrage norms in creating the potential for international development activism through group‐based interaction
Authors: Thomas Emma F. , McGarty Craig A.
Published: June 2008

This paper adopts an intergroup perspective on helping as collective action to explore the ways to boost motivation amongst people in developed countries to join the effort to combat poverty and preventable disease in developing countries. Followingvan Zomeren, Spears, Leach, and Fischer's (2004)model of collective action, we investigated the role of norms about an emotional response (moral outrage) and beliefs about efficacy in motivating commitment to take action amongst members of advantaged groups. Norms about outrage and efficacy were harnessed to an opinion‐based group identity (Bliuc, McGarty, Reynolds, & Muntele, 2007) and explored in the context of a novel group‐based interaction method. Results showed that the group‐based interaction boosted commitment to action especially when primed with an (injunctive) outrage norm. This norm stimulated a range of related effects including increased identification with the pro‐international development opinion‐based group, and higher efficacy beliefs. Results provide an intriguing instantiation of the power of group interaction (particularly where strengthened with emotion norms) to bolster commitment to positive social change.
There is nothing either good or bad but thinking makes it so: Informational support and cognitive appraisal of the work‐family interface
Authors: van Steenbergen Elianne F. , Ellemers Naomi , Haslam S. Alexander , Urlings Femke
Published: June 2008

This paper examines whether cognitive appraisals regarding work‐family role combination can be influenced by providing informational support. We conducted an experiment among female employees with young children working in a financial services organization (N=149). Participants received information communicating either a scarcity or an expansion perspective on human energy, prior to completing a survey. In support of our predictions, results showed that employees appraised the task of combining their work and family roles more positively after exposure to an expansion rather than a scarcity message. This research offers new theoretical insights into the role of cognitive appraisal in work‐family research and offers scope for designing intervention programs that help employees to view role‐combining more positively.
Germanachandachsoin repair uptake: Resources to sustain or remove epistemic asymmetry
Authors: Golato Andrea , Betz Emma
Published: June 2008

Using conversation analytic methodology, this article examines the use of the German tokensach‘oh’ andachso‘oh I see’ in the uptake of repair. Whileachsohas been studied from a functional-pragmatic perspective, no contrastive study ofachandachsoexists. We investigate two questions: Do different forms ofachoccur in the same sequential position? Are they associated with different interactional functions?

The paper shows that in sequentially third position, repairs are receipted withachorachso. The different tokens have different interactional import. While ach receipts new informational content (claiming a change-of-state, similar to Englishoh; Heritage 1984), it does not mark understanding.Achso, by contrast, serves as a receipt for informationandprior action, claiming that speakers now share the same epistemic level and thus marking a successful repair resolution.Achsomakes sequence closure relevant and is followed by a shift in action and/or topic while anach-turn makes more talk relevant, specifically next turn confirmation.

The paper concludes by discussing the component tokensachandsoseparately and outlining implications for the study of epistemics through ‘little words.’
Embryonic Stem Cell-Derived Neurons as a Cellular System to Study Gene Function: Lack of Amyloid Precursor Proteins APP and APLP2 Leads to Defective Synaptic Transmission
Authors: Schrenk-Siemens Katrin , Perez-Alcala Siro , Richter Jens , Lacroix Emmanuel , Rahuel Joseph , Korte Martin , Müller Ulrike , Barde Yves-Alain , Bibel Miriam
Published: June 2008

The in vitro generation of uniform populations of neurons from mouse embryonic stem cells (ESCs) provides a novel opportunity to study gene function in neurons. This is of particular interest when mutations lead to lethal in vivo phenotypes. Although the amyloid precursor protein (APP) and its proteolysis are regarded as key elements of the pathology of Alzheimer's disease, the physiological function of APP is not well understood and mice lacking App and the related gene Aplp2 die early postnatally without any obvious histopathological abnormalities. Here we show that glutamatergic neurons differentiated from ESCs lacking both genes reveal a decreased expression of the vesicular glutamate transporter 2 (VGLUT2) both at the mRNA and protein level, as well as a reduced uptake and/or release of glutamate. Blocking γ-secretase cleavage of APP in wild-type neurons resulted in a similar decrease of VGLUT2 expression, whereas VGLUT2 levels could be restored in App−/−Aplp2−/− neurons by a construct encompassing the C-terminal intracellular domain of APP. Electrophysiological recordings of hippocampal organotypic slice cultures prepared from corresponding mutant mice corroborated these observations. Gene expression profiling and pathway analysis of the differentiated App−/−Aplp2−/− neurons identified dysregulation of additional genes involved in synaptic transmission pathways. Our results indicate a significant functional role of APP and amyloid precursor-like protein 2 (APLP2) in the development of synaptic function by the regulation of glutamatergic neurotransmission. Differentiation of ESCs into homogeneous populations thus represents a new opportunity to explore gene function and to dissect signaling pathways in neurons.

Disclosure of potential conflicts of interest is found at the end of this article.
Osteopontin Promotes the Development of Natural Killer Cells from Hematopoietic Stem Cells
Authors: Chung Jin Woong , Kim Mi Sun , Piao Zheng-Hao , Jeong Mira , Yoon Suk Ran , Shin Nara , Kim Sang Yong , Hwang Eun Sook , Yang Young , Lee Young Ho , Kim Young Sang , Choi Inpyo
Published: June 2008

The detailed mechanisms driving the development of natural killer (NK) cells from hematopoietic stem cells remain to be clearly elucidated. Here, we show that osteopontin (OPN) is a key factor for NK development. OPN-deficient mice evidenced severe impairments of NK development in bone marrow (BM) and spleen in which the NK populations that express CD122 and NK cell receptors were reduced. However, the absence of intrinsic OPN expression did not affect NK development, whereas the absence of OPN in the microenvironment caused a significant reduction in NK population. The expression of OPN was induced by interleukin (IL)-15 in BM stromal cells, and the defect in NK differentiation in IL-15−/− hematopoietic precursor cells (HPC) was recovered by addition of recombinant OPN, suggesting that the microenvironmental OPN may be a key factor in IL-15-mediated NK differentiation. In addition, OPN-driven NK maturation was reduced in T-bet-deficient HPC, suggesting that T-bet is required for OPN-mediated NK development. Collectively, these results show that paracrine OPN signaling drives NK-lineage commitment, thus ultimately promoting NK cell development.

Disclosure of potential conflicts of interest is found at the end of this article.
Adventures in time and space
Authors: Danner Norman , Royer James S.
Published: June 2008

This paper investigates what is essentially a call-by-value version of PCF
under a complexity-theoretically motivated type system. The programming
formalism, ATR, has its first-order programs characterize the polynomial-time
computable functions, and its second-order programs characterize the type-2
basic feasible functionals of Mehlhorn and of Cook and Urquhart. (The ATR-types
are confined to levels 0, 1, and 2.) The type system comes in two parts, one
that primarily restricts the sizes of values of expressions and a second that
primarily restricts the time required to evaluate expressions. The
size-restricted part is motivated by Bellantoni and Cook's and Leivant's
implicit characterizations of polynomial-time. The time-restricting part is an
affine version of Barber and Plotkin's DILL. Two semantics are constructed for
ATR. The first is a pruning of the naive denotational semantics for ATR. This
pruning removes certain functions that cause otherwise feasible forms of
recursion to go wrong. The second semantics is a model for ATR's time
complexity relative to a certain abstract machine. This model provides a
setting for complexity recurrences arising from ATR recursions, the solutions
of which yield second-order polynomial time bounds. The time-complexity
semantics is also shown to be sound relative to the costs of interpretation on
the abstract machine.
Coinductive Proof Principles for Stochastic Processes
Authors: Kozen Dexter
Published: June 2008

We give an explicit coinduction principle for recursively-defined stochastic
processes. The principle applies to any closed property, not just equality, and
works even when solutions are not unique. The rule encapsulates low-level
analytic arguments, allowing reasoning about such processes at a higher
algebraic level. We illustrate the use of the rule in deriving properties of a
simple coin-flip process.
Lambda-RBAC: Programming with Role-Based Access Control
Authors: Jagadeesan Radha , Jeffrey Alan , Pitcher Corin , Riely James
Published: June 2008

We study mechanisms that permit program components to express role
constraints on clients, focusing on programmatic security mechanisms, which
permit access controls to be expressed, in situ, as part of the code realizing
basic functionality. In this setting, two questions immediately arise: (1) The
user of a component faces the issue of safety: is a particular role sufficient
to use the component? (2) The component designer faces the dual issue of
protection: is a particular role demanded in all execution paths of the
component? We provide a formal calculus and static analysis to answer both
questions.
Generative Unbinding of Names
Authors: Pitts Andrew M. , Shinwell Mark R.
Published: June 2008

This paper is concerned with the form of typed name binding used by the
FreshML family of languages. Its characteristic feature is that a name binding
is represented by an abstract (name,value)-pair that may only be deconstructed
via the generation of fresh bound names. The paper proves a new result about
what operations on names can co-exist with this construct. In FreshML the only
observation one can make of names is to test whether or not they are equal.
This restricted amount of observation was thought necessary to ensure that
there is no observable difference between alpha-equivalent name binders. Yet
from an algorithmic point of view it would be desirable to allow other
operations and relations on names, such as a total ordering. This paper shows
that, contrary to expectations, one may add not just ordering, but almost any
relation or numerical function on names without disturbing the fundamental
correctness result about this form of typed name binding (that object-level
alpha-equivalence precisely corresponds to contextual equivalence at the
programming meta-level), so long as one takes the state of dynamically created
names into account.