bluuebunny/crossref_metadata_2025 huggingface dataset:
Glycogen Synthase Kinase-3 regulates IGFBP-1 gene transcription through the Thymine-rich Insulin Response Element
Authors: Finlay David , Patel Satish , Dickson Lorna M , Shpiro Natalia , Marquez Rodolfo , Rhodes Chris J , Sutherland Calum
Published: September 2004

Background

Hepatic expression of several gene products involved in glucose metabolism, including phosphoenolpyruvate carboxykinase (PEPCK), glucose-6-phosphatase (G6Pase) and insulin-like growth factor binding protein-1 (IGFBP-1), is rapidly and completely inhibited by insulin. This inhibition is mediated through the regulation of a DNA element present in each of these gene promoters, that we call the T hymine-rich I nsulin R esponse E lement (TIRE). The insulin signalling pathway that results in the inhibition of these gene promoters requires the activation of phosphatidylinositol 3-kinase (PI 3-kinase). However, the molecules that connect PI 3-kinase to these gene promoters are not yet fully defined. Glycogen Synthase Kinase 3 (GSK-3) is inhibited following activation of PI 3-kinase. We have shown previously that inhibitors of GSK-3 reduce the activity of two TIRE-containing gene promoters (PEPCK and G6Pase), whose products are required for gluconeogenesis.

Results

In this report we demonstrate that in H4IIE-C3 cells, four distinct classes of GSK-3 inhibitor mimic the effect of insulin on a third TIRE-containing gene, IGFBP-1. We identify the TIRE as the minimum requirement for inhibition by these agents, and demonstrate that the target of GSK-3 is unlikely to be the postulated TIRE-binding protein FOXO-1. Importantly, overexpression of GSK-3 in cells reduces the insulin regulation of TIRE activity as well as endogenous IGFBP-1 expression.

Conclusions

These results implicate GSK-3 as an intermediate in the pathway from the insulin receptor to the TIRE. Indeed, this is the first demonstration of an absolute requirement for GSK-3 inhibition in insulin regulation of gene transcription. These data support the potential use of GSK-3 inhibitors in the treatment of insulin resistant states such as Type 2 diabetes mellitus, but suggest that it will be important to identify all TIRE-containing genes to assess potential side effects of these agents.
Coactivators p300 and PCAF physically and functionally interact with the foamy viral trans-activator
Authors: Bannert Helmut , Muranyi Walter , Ogryzko Vasily V , Nakatani Yoshihiro , Flügel Rolf M
Published: September 2004

Background

Foamy virus Bel1/Tas trans-activators act as key regulators of gene expression and directly bind to Bel1 response elements (BRE) in both the internal and the 5'LTR promoters leading to strong transcriptional trans-activation. Cellular coactivators interacting with Bel1/Tas are unknown to date.

Results

Transient expression assays, co-immunoprecipitation experiments, pull-down assays, and Western blot analysis were used to demonstrate that the coactivator p300 and histone acetyltransferase PCAF specifically interact with the retroviral trans-activator Bel1/Tas in vivo. Here we show that the Bel1/Tas-mediated trans-activation was enhanced by the coactivator p300, histone acetyltransferases PCAF and SRC-1 based on the crucial internal promoter BRE. The Bel1/Tas-interacting region was mapped to the C/H1 domain of p300 by co-immunoprecipitation and pull-down assays. In contrast, coactivator SRC-1 previously reported to bind to the C-terminal domain of p300 did not directly interact with the Bel1 protein but nevertheless enhanced Bel1/Tas-mediated trans-activation. Cotransfection of Bel1/Tas and p300C with an expression plasmid containing the C/H1domain partially inhibited the p300C-driven trans-activation.

Conclusions

Our data identify p300 and PCAF as functional partner molecules that directly interact with Bel1/Tas. Since the acetylation activities of the three coactivators reside in or bind to the C-terminal regions of p300, a C/H1 expression plasmid was used as inhibitor. This is the first report of a C/H1 domain-interacting retroviral trans-activator capable of partially blocking the strong Bel1/Tas-mediated activation of the C-terminal region of coactivator p300. The potential mechanisms and functional roles of the three histone and factor acetyltransferases p300, PCAF, and SRC-1 in Bel1/Tas-mediated trans-activation are discussed.
An economic analysis of premarriage prevention of hepatitis B transmission in Iran
Authors: Adibi Peyman , Rezailashkajani Mohammadreza , Roshandel Delnaz , Behrouz Negar , Ansari Shahin , Somi Mohammad Hossein , Shahraz Saeed , Zali Mohammad Reza
Published: September 2004

Background

To assess the economic aspects of HBV (hepatitis B virus) transmission prevention for premarriage individuals in a country with cultural backgrounds like Iran and intermediate endemicity of HBV infection.

Methods

A cost-effectiveness analysis model was used from the health care system and society perspectives. The effectiveness was defined as the number of chronic HBV infections averted owing to one of the following strategies:

1) HBsAg screening to find those would-be couples one of whom is HBsAg positive and putting seronegative subjects on a protection protocol comprising HBV vaccination, single dose HBIG and condom protection.

2) HBsAg screening as above, in addition to performing HBcAb screening in the HBsAg negative spouses of the HBsAg positive persons and giving the protocol only to HBcAb negative ones.

Sensitivity and threshold analyses were conducted.

Results

The cost of each chronic infection averted was 202$ and 197$ for the strategies 1 and 2, respectively. Sensitivity analysis showed that strategy 2 was always slightly cheaper than strategy 1. The discounted threshold value for the lifetime costs of chronic liver disease, above which the model was cost saving was 2818$ in strategy 1 and 2747$ in strategy 2.

Conclusions

Though premarriage prevention of HBV transmission in the countries with cultural backgrounds similar to Iran seems cost saving, further studies determining precise costs of HBV infection in Iran can lead to a better analysis.
Tuberculosis presenting as immune thrombocytopenic purpura
Authors: Ozkalemkas Fahir , Ali Ridvan , Ozkan Atilla , Ozcelik Tulay , Ozkocaman Vildan , Kunt-Uzaslan Esra , Bahadir-Erdogan Beril , Akalin Halis
Published: September 2004

Background

Although various hematologic abnormalities are seen in tuberculosis, immune thrombocytopenic purpura is a rare event.

Case Presentation

We report a case of a 29 year-old male who was presented with immune thrombocytopenia-induced hemoptysis, macroscopic hematuria and generalized petechiae. The patient was found to have clinical, microbiological and radiological evidence of active pulmonary tuberculosis. The immune thrombocytopenic purpura was successfully treated with anti-tuberculous drugs combined with corticosteroids and high dose immune globulin therapy.

Conclusion

Immune thrombocytopenic purpura can be one of the hematological manifestations of tuberculosis which has a global prevalence with increasing incidence secondary to HIV infection.
A novel epitope of N-CAM defines precursors of human adherent NK cells
Authors: Li Shen , Xu Jun , Makarenkova Valeria P , Tjandrawan Tjendimin , Vakkila Jukka , Reichert Torsten , Gooding William , Lagenaur Carl F , Achim Cristian L , Chambers William H , Herberman Ronald B , Whiteside Theresa L , Vujanovic Nikola L
Published: September 2004

Activated, adherent natural killer (A-NK) cells represent a distinct subpopulation of interleukin (IL)-2-stimulated NK cells, which are selectively endowed with the increased expression of integrins and ability to adhere to solid surfaces, migrate into, infiltrate, and destroy cancerous tissues. The present study defines the phenotype and functions of precursors of A-NK (pre-A-NK) cells in humans. Peripheral blood pre-A-NK cells, in contrast to the rest of NK cells, express a novel epitope of CD56 neuronal cell adhesion molecule, termed ANK-1, and increased cell-surface levels of integrins. Pre-A-NK cells also express low levels of CD56 and CD161, and some express CD162 receptor, do not express CD25 or activation markers, and are effective mediators of NK cytotoxicity. Thus, pre-A-NK cells are generally similar to CD56dim NK cells. However, pre-A-NK cells differ from the main NK cell subpopulation by having a lower expression level of CD16 and a lower ability to mediate redirected antibody-dependent, cell-mediated cytotoxicity. More importantly, pre-A-NK cells are preferentially endowed with the ability to rapidly respond to IL-2 by integrin-mediated adherence to endothelial cells, extracellular matrix, and plastic. This early, specific response of pre-A-NK cells to IL-2 is followed by their activation, vigorous proliferation, and differentiation into phenotypically and functionally similar A-NK cells. Pre-A-NK cells represent only ∼26% of peripheral blood NK cells but encompass the majority of NK cells in normal and cancerous, solid tissues. We conclude that pre-A-NK cells represent a distinct subset of resting, mature NK cells with the characteristics indicative of their ability to migrate and reside in solid tissues.
Rat NKp46 activates natural killer cell cytotoxicity and is associated with FcɛRIγ and CD3ζ
Authors: Westgaard Ingunn H , Berg Siri F , Vaage John T , Wang Lawrence L , Yokoyama Wayne M , Dissen Erik , Fossum Sigbjørn
Published: September 2004

NKp46 has been identified in the human, rat, mouse, monkey, and cattle. We have generated a monoclonal antibody, WEN23, against rat NKp46. By flow cytometry, NKp46 is expressed by all natural killer (NK) cells but not by T cells, B cells, granulocytes, monocytes, dendritic cells, or macrophages. Thus, NKp46/WEN23 is the first NK cell-specific marker in the rat. In a redirected lysis assay, preincubation of the effector cells with WEN23 augmented lysis of the Fc receptor (FcR)+ murine tumor target cells, indicating that NKp46 is an activating NK cell receptor. Moreover, preincubation of the effector cells with WEN23 F(ab′)2 fragments reduced killing of target cells, confirming the activating function of NKp46 and indicating that the mouse tumor target cells express a ligand for rat NKp46. Lysis of FcR− mouse and human tumor target cells was reduced after incubation of effector cells with WEN23, suggesting that rat NKp46 recognizes a ligand that is conserved between primates and rodents. By Western blot and immunoprecipitation using WEN23, NKp46 is expressed as a monomer of ∼47 kDa in interleukin-2-activated NK cells. The immunoreceptor tyrosine-based activation motif bearing adaptor proteins CD3ζ and the γ chain of FcRI for IgE (FcɛRIγ) with NKp46 from lysates of NK cells, indicating that rat NKp46 activates NK cell cytotoxicity by similar pathways as CD16.
Granulocyte chemotactic protein-2 mediates adaptive immunity in part through IL-8Rβ interactions
Authors: Singh Udai P , Singh Shailesh , Boyaka Prosper N , McGhee Jerry R , Lillard James W
Published: September 2004

Chemokines constitute a large family of structurally related proteins that play a role in leukocyte migration and differentiation. Indeed, the early expression of human CXC chemokine receptor 1 (hCXCR1) and hCXCR2 [homologous to mouse interleukin (IL)-8Rβ] ligands by the epithelium is a hallmark of the mucosal host defense. Mice lack IL-8; however, granulocyte chemotactic protein-2 (GCP-2)/lipopolysaccharide-induced CXC chemokine, a murine homologue of human GCP-2, has 32% and 61% sequence identity to human IL-8 and GCP-2, respectively, and binds hCXCR1, hCXCR2, and mouse IL-8Rβ. To better understand the role of GCP-2 in adaptive immunity and as a nasal adjuvant, we characterized the exogenous effects of this CXC chemokine on cellular and humoral mucosal immune responses. GCP-2 significantly enhanced serum immunoglobulin G (IgG) and mucosal IgA antibodies through increased cytokine secretion by CD4+ T cells. These alterations in humoral and cellular responses were preceded by an increase in the number of B cells in the nasal tract, a decrease in the number of CD4+ T cells in the nasal tract as well as cervical lymph nodes, and an increase in the number of neutrophils in the nasal tract 12 h after GCP-2 immunization. This chemokine also modulated CD28 expression by CD4+ T cells during CD3ɛ stimulation of wild-type mice. GCP-2 increased CD80 and CD86 expression on B cells during in vitro stimulation in a dose-dependent manner. In contrast, cytokine and costimulatory molecule enhancement by GCP-2 was not induced by lymphocytes from IL-8Rβ−/− mice, suggesting that GCP-2 modulates cellular immunity in part through IL-8Rβ interactions.
Test decisions over time: tracking validity
Authors: Fox Janna
Published: September 2004

This study took a grounded theory approach in investigating the relationship between the criteria indigenously drawn for an English for academic purposes (EAP) test and the outcomes of test decisions over time. Test outcomes were examined across three theoretical samples: (1) an EAP teacher-identified sample of misplaced students; (2) a database-generated sample that matched the key variables in the EAP teachers’ sample; and (3) a random sample of test-takers drawn from a single administration of the test. Although analysis revealed two sources of testing error, namely, under-specification of bands in the writing sub-test scale and an under-valuing of the listening sub-test in the overall weighted average of the test, it also revealed the relationship between key patterns of performance on the test and performance in university classrooms that signposted students at risk. As such, the study provides evidence of the usefulness of inquiry that examines the relationship between EAP test performance and the use of English as a mediating tool in academic performance.
Can placement tests inform instructional decisions?
Authors: Green Anthony B. , Weir Cyril J.
Published: September 2004

Studies of placement tests are typically narrowly concerned with their validation as instruments for the efficient grouping of students. They rarely explore the assumption that placement test content can be related to classroom tasks and so inform instructional decisions. This study focuses on a trial version of the Global Placement Test (GPT), a measure of grammatical knowledge being developed for use in language schools worldwide. The central concern is the extent to which the GPT can enable schools to make valid inferences regarding mastery of the grammatical structures to be taught on the relevant courses and hence guide diagnostic intervention. In this study the GPT, together with another test specifically designed to measure knowledge of grammatical items expressing temporal relations in English, was administered to 1070 EFL (English as a Foreign Language) learners studying in the UK, Greece and Japan. The dimensionality of the GPT as a measurement scale was investigated by IRT and factor-analytic methods. The analysis suggests that item difficulty is affected more by item type than by any inherent linguistic difficulty of the element of grammatical competence being tested. The results cast doubt on whether quick grammar-based placement tests, which traditionally emphasize efficiency and practicality, can provide sufficient information on which to base diagnostic mediation or sequencing of instructional materials.
Stepwise airway management in the trauma patient
Authors: Carley Simon , Gwinnutt CL
Published: September 2004

The importance of establishing and maintaining a patent airway is a well-recognized principle in the resuscitation of all trauma victims. Many currently available guidelines for airway management in trauma patients have been aimed largely at anaesthetists or those with anaesthetic training. Typically they concen trate on either those patients who require intubation, with techniques to use when this fails, or those in whom little intervention beyond facemask oxygen is required. In reality, clinicians with varying degrees of skill will be faced with managing the trauma patient’s airway and many will not be able to safely attempt tracheal intubation. A pragmatic approach to airway assessment and management is presented that recognizes the variation in skills between clinicians. We also suggest that the role of supraglottic airway devices should now be recognized by all clinicians involved with airway management, particularly those not skilled in tracheal intubation and they should become an integral part of airway management.
Minimum haemoglobin in intensive care
Authors: Desai Suneel , Manji Mav
Published: September 2004

Multiple and complex aetiological factors contributes to anaemia in critically ill patients. This article sets out to examine the clinical evidence and physiological rationale for transfusion, traditionally based on an arbitrary haemoglobin trigger of 10 g=dL. Maintenance of haemoglobin concentration level of 10 g=dL or above may benefit only a small group of patients with an acute myocardial infarction, unstable angina or those who have severe coronary artery disease. However, most critically ill patients tolerate anaemia very well due to physiological compen satory mechanisms and clinical studies suggest that there is an increase in adverse outcome if transfusion is carried out using this traditional trigger threshold.
Global trends in trauma
Authors: Leppäniemi AK
Published: September 2004

Injuries cause about 10% of all deaths worldwide, with road traffic accidents, self-inflicted injuries, violence and war injuries being the most common causes of traumatic deaths. There is an anticipated increase in all of these categories by the year 2020. In addition to the increasing global incidence of trauma, other major trends in trauma and its management identified in this review include the growing emphasis on prevention and public health aspects of trauma, the globalization of trauma practices due to the rapid access to new information, a critical emphasis on organizational aspects of trauma care and education, the prominent role of efficacious and cost effective management practises, a shift to gentler treatment methods with less interference in the physiological recovery mechanisms, and at the same time, extreme care and the management of its consequences. In order to fight the global epidemic of trauma, it is the duty and the privilege of health care professionals to take the leadership in this task by ‘thinking globally and acting locally’ but most importantly by working together and sharing their expe riences (the successes and the failures) and by knowing that they can make a difference.
Substance abuse and the trauma patient
Authors: Guly Henry
Published: September 2004

Alcohol and other drugs of abuse are often associated with trauma. Alcohol and other drugs have an effect on patients’ behaviour, their vital signs, conscious level and pupils. IV drug abusers may have difficult venous access and may carry blood borne infections. Drug dependent patients are at risk of withdrawal symptoms which need to be recognized and treated. Acute intoxication may make the diagnosis of brain (and other) injuries difficult and chronic alcoholism may be associated with a variety of medical problems which may complicate the management of trauma and which lead to increased mortality. It is important not just to treat the injuries but to recognize the underlying substance abuse so that help can be offered and future injuries avoided.
Doctors and nurses in emergency care: where are the boundaries now?
Authors: Brook Simon , Crouch Robert
Published: September 2004

The current political healthcare economy is blurring traditional professional bound aries, and national agendas are requiring nurses to take on more roles and tasks previously undertaken by doctors. The emergency nurse practitioner’s expanding scope of practice has moved beyond managing the care of patients with minor injuries, to include those with ‘minor’ illnesses and indeed beyond that to the management and care of those with increasingly complex, acute and chronic conditions. The process of conjugation between the two disciplines has been driven by the demands and pressures on the health economy. Given the unprecedented and increasing overlap in practice between the domains of medicine and nursing, it is time to re-examine differences between them and clarify the issues which divide them. There is a need to benchmark infrastructure and standardize the education and development of nurses undertaking advanced practice roles. There is also a need for continued debate on the future of the health care workforce, informed by research, to facilitate correct and cost effective decision making.
Emergency induction of anaesthesia in the prehospital setting: a review of the anaesthetic induction agents
Authors: Easby J , Dodds C
Published: September 2004

The standard of prehospital care is improving in many trauma systems around the world. For patients surviving the primary injury, the optimal prehospital interven tions remain debatable. Current evidence suggests that patients with severe head injury may benefit from advanced airway management, most commonly per formed by rapid sequence induction of anaesthesia and orotracheal intubation. The ‘best choice’ induction agent remains unclear, and choice seems to depend on local preferences and the skill mix of the prehospital care team. In this review we look at the recent evidence for selected hypnotic agents.
Review Management of nonunion in trauma
Authors: Pacheco Ricardo J , Bradbury Martin D , Kasis Ata G , Saleh Michael
Published: September 2004

Treatment of nonunion has radically changed in recent years. We define nonunion as a fracture of bone induced either by trauma or surgery which does not show clinical or radiographic signs of progression to healing within a reasonable time span. The reparative processes are present but inadequate. Fracture healing may be considered to be a balance between repair and breakdown processes at the fracture site. When breakdown exceeds repair, nonunion is the result. Altering the conditions at the fracture site even marginally in favour of repair will eventually lead to bony continuity being restored. Nonunion treatment should follow three principles: a) realignment; b) stabilization; and c) stimulation. Any surgical proce dure should address one or all of these areas. In this article the principles of nonunion management are explained, together with different bone healing stimulation techniques and our clinical results.
Factors Predictive of Tumor-Positive Nonsentinel Lymph Nodes After Tumor-Positive Sentinel Lymph Node Dissection for Melanoma
Authors: Lee Jonathan H. , Essner Richard , Torisu-Itakura Hitoe , Wanek Leslie , Wang Hejing , Morton Donald L.
Published: September 2004

Purpose

Approximately 20% of sentinel node (SN) positive melanoma patients have additional non-SN (NSN) metastasis. The rationale for this study was to identify the factors associated with additional nodal disease, as a method to determine which patients may most benefit from completion lymph node dissection (CLND).

Patients and Methods

During 1990 to 2002, 1,599 patients have undergone SN biopsy at our institute. 19.5% underwent CLND for tumor-positive SN. One hundred ninety-one of these patients had clinicopathologic information available for review. Univariate analyses used χ2 test, Wilcoxson rank sum test, and χ2 test for trend. Multivariate analyses used logistic regression and Wald test.

Results

Forty-six (24%) patients had tumor-positive NSN. Univariate analyses showed that primary thickness (Breslow and Clark), primary site, SN tumor size, and number of tumor-positive SNs were significantly associated with tumor-positive NSN. Multivariate analysis (167 patients), confirmed that Breslow and SN tumor size were independently predictive. Sex, histology, ulceration, mitotic index, and SN basin location were not predictive. Risk stratification by the number of prognostic factors present (Breslow ≥ 3 mm and SN tumor size ≥ 2 mm) showed that probability of finding tumor-positive NSN was 12.3% in the low-risk group (0 factors), 30.9% in the intermediate-risk group (1 factor), and 41.9% in the high-risk group (2 factors).

Conclusion

Thicker primary and larger SN tumor size are factors that correlate best with tumor-positive NSN. Although none of these factors are absolutely predictive of residual nodal disease, these factors must be strongly considered if the SN contains metastasis, as they provide enhanced risk assessment for NSN tumor-positivity.
Serum Cardiac Troponins and N-Terminal Pro-Brain Natriuretic Peptide: A Staging System for Primary Systemic Amyloidosis
Authors: Dispenzieri Angela , Gertz Morie A. , Kyle Robert A. , Lacy Martha Q. , Burritt Mary F. , Therneau Terry M. , Greipp Philip R. , Witzig Thomas E. , Lust John A. , Rajkumar S. Vincent , Fonseca Rafael , Zeldenrust Steven R. , McGregor Christopher G.A. , Jaffe Allan S.
Published: September 2004

Purpose

Primary systemic amyloidosis (AL) is a multisystemic disorder resulting from an underlying plasma cell dyscrasia. There is no formal staging system for AL, making comparisons between studies and treatment centers difficult. Our group previously identified elevated serum cardiac troponin T (cTnT) as the most powerful predictor of overall survival. Others have reported that N-terminal pro-brain natriuretic peptide (NT-proBNP) is a valuable prognostic marker. We sought to develop a staging system for patients with AL.

Patients and Methods

Two hundred forty-two patients with newly diagnosed AL who were seen at the Mayo Clinic between April 1979 and November 2000, and who had echocardiograms and stored serum samples at presentation were eligible for this retrospective review. NT-proBNP measurements were performed on 242 patients in whom cTnT and cardiac troponin I (cTnI) had been previously run. Two prognostic models were designed using threshold values of NT-proBNP and either cTnT or cTnI (NT-proBNP < 332 ng/L, cTnT < 0.035 μg/L, and cTnI < 0.1 μg/L). Depending on whether NT-proBNP and troponin levels were both low, were high for only one level, or were both high, patients were classified as stage I, II, or III, respectively.

Results

Using the cTnT+NT-proBNP model 33%, 30%, and 37% of patients were stages I, II, and III, respectively, with median survivals of 26.4, 10.5, and 3.5 months, respectively. The alternate cTnI+NT-proBNP model predicted median survivals of 27.2, 11.1, and 4.1 months, respectively.

Conclusion

Stratification of AL patients into three stages is possible with two readily available and reproducible tests setting the stage for more consistent and reliable cross comparisons of therapeutic outcomes.
Telomerase Expression Predicts Unfavorable Outcome in Osteosarcoma
Authors: Sanders Robert P. , Drissi Rachid , Billups Catherine A. , Daw Najat C. , Valentine Marcus B. , Dome Jeffrey S.
Published: September 2004

Purpose

Osteosarcoma is distinct from most cancers in that the majority of osteosarcomas lack telomerase expression and use the alternative lengthening of telomeres (ALT) mechanism to maintain telomeres. Laboratory studies suggest that compared with ALT, telomerase expression is associated with increased tumor aggressiveness. We evaluated the clinical significance of telomerase expression in human osteosarcoma.

Patients and Methods

Fifty-six osteosarcomas from 51 patients treated at St Jude Children's Research Hospital between 1982 and 2003 were evaluated for telomerase enzyme activity, mRNA expression of the catalytic component of telomerase (TERT), and presence of the ALT pathway.

Results

Outcome analysis was based on TERT mRNA expression in the primary tumor samples from 44 patients. Fourteen primary tumors expressed TERT mRNA (32%; eight TERT only, six TERT and ALT) and 30 did not express TERT mRNA (68%; 29 ALT, one no ALT). Progression-free survival (PFS) was inferior in the TERT-positive group compared with the TERT-negative group (3-year estimates, 21.4% ± 9.5% v 63.7% ± 11.1%; P = .014). Likewise, overall survival was inferior in the TERT-positive group compared with the TERT-negative group (3-year estimates, 42.9% ± 12.2% v 70.0% ± 9.9%; P = .031). Among 31 patients with nonmetastatic disease at diagnosis, PFS was lower in the TERT-positive group compared with the TERT-negative group (3-year estimates, 33.3% ± 13.6% v 72.0% ± 11.5%; P = .092).

Conclusion

Telomerase expression in primary tumor samples is associated with decreased PFS and OS in patients with osteosarcoma. Additional studies are warranted to better define the clinical utility of this molecular marker.
Autologous Hematopoietic Stem-Cell Transplantation for Children With Acute Myeloid Leukemia in First or Second Complete Remission: A Prognostic Factor Analysis
Authors: Godder Kamar , Eapen Mary , Laver Joseph H. , Zhang Mei-Jie , Camitta Bruce M. , Wayne Alan S. , Gale Robert Peter , Doyle John J. , Yu Lolie C. , Chen Allen R. , Garvin James H. , Sandler Eric S. , Yeager Andrew M. , Edwards John R. , Horowitz Mary M.
Published: September 2004

Purpose

To determine prognostic factors correlated with outcomes after autologous hematopoietic stem-cell transplantation (HSCT) in children with acute myeloid leukemia (AML).

Patients and Methods

We studied 219 children who received autologous HSCT for AML in first complete remission (CR) and 73 children in second CR and who were reported to the Autologous Blood and Marrow Transplant Registry. Among 29 of 73 patients who underwent transplantation in second CR, duration of first CR was ≥ 12 months.

Results

Three-year cumulative incidences of relapse were 37% (95% CI, 31% to 44%), 60% (95% CI, 41% to 74%), and 36% (95% CI, 20% to 53%) for children in first CR, second CR after a short (< 12 months) first CR, and second CR after a long (≥ 12 months) first CR, respectively. Corresponding 3-year probabilities of leukemia-free survival were 54% (95% CI, 47% to 60%), 23% (95% CI, 10% to 39%), and 60% (95% CI, 42% to 75%). In multivariate analyses, risks of relapse, mortality, and treatment failure (relapse or death, inverse of leukemia-free survival) were higher for patients in second CR after a short first CR than for the other two groups. Transplant-related mortality, treatment failure, and overall mortality rates were higher in older (> 10 years) children.

Conclusion

Duration of first CR seems to be the most important determinant of outcome. Results in children who experience treatment failure with conventional chemotherapy support the use of autologous transplantation as salvage therapy if such patients achieve a subsequent CR.
The role ofSEUSSin auxin response and floral organ patterning
Authors: Pfluger Jennifer , Zambryski Patricia
Published: September 2004

Genetic and physiological analyses implicate auxin flux in patterning,initiation and growth of floral organs. Within the Arabidopsisflower, the ETTIN/ARF3 transcription factor responds to auxin to effect perianth organ number and reproductive organ differentiation. This work describes a modifier of ettin that causes filamentous, mispositioned outer whorl organs and reduced numbers of malformed stamens in the double mutant. The modifier was discovered to be a new allele of the seuss(seu) mutant. SEU encodes a novel protein that is predicted to transcriptionally co-repress the AGAMOUS floral organ identity gene. The effects of seu on ett are shown to be independent of the SEU-AG pathway. Furthermore, morphological, physiological and genetic evidence implicate SEU in auxin-regulated growth and development. seu has a pleiotropic phenotype that includes reductions in several classic auxin responses such as apical dominance, lateral root initiation, sensitivity to exogenous auxin and activation of the DR5 auxin response reporter. seu displays a synergistic interaction with the auxin response mutant pinoid, producing flowers with few outer whorl organs. Collectively, these data suggest that SEU is a novel factor affecting auxin response. A model is proposed in which SEU functions jointly with ETT in auxin response to promote floral organ patterning and growth.
Sp8andSp9, two closely relatedbuttonhead-like transcription factors, regulateFgf8expression and limb outgrowth in vertebrate embryos
Authors: Kawakami Yasuhiko , Esteban Concepción Rodríguez , Matsui Takaaki , Rodríguez-León Joaquín , Kato Shigeaki , Belmonte Juan Carlos Izpisúa
Published: September 2004

Initiation and maintenance of signaling centers is a key issue during embryonic development. The apical ectodermal ridge, a specialized epithelial structure and source of Fgf8, is a pivotal signaling center for limb outgrowth. We show that two closely related buttonhead-like zinc-finger transcription factors, Sp8 and Sp9, are expressed in the AER, and regulate Fgf8 expression and limb outgrowth. Embryological and genetic analyses have revealed that Sp8and Sp9 are ectodermal targets of Fgf10 signaling from the mesenchyme. We also found that Wnt/β-catenin signaling positively regulates Sp8, but not Sp9. Overexpression functional analyses in chick unveiled their role as positive regulators of Fgf8expression. Moreover, a dominant-negative approach in chick and knockdown analysis with morpholinos in zebrafish revealed their requirement for Fgf8 expression and limb outgrowth, and further indicate that they have a coordinated action on Fgf8 expression. Our study demonstrates that Sp8 and Sp9, via Fgf8, are involved in mediating the actions of Fgf10 and Wnt/β-catenin signaling during vertebrate limb outgrowth.
Dpp gradient formation by dynamin-dependent endocytosis: receptor trafficking and the diffusion model
Authors: Kruse Karsten , Pantazis Periklis , Bollenbach Tobias , Jülicher Frank , González-Gaitán Marcos
Published: September 2004

Developing cells acquire positional information by reading the graded distribution of morphogens. In Drosophila, the Dpp morphogen forms a long-range concentration gradient by spreading from a restricted source in the developing wing. It has been assumed that Dpp spreads by extracellular diffusion. Under this assumption, the main role of endocytosis in gradient formation is to downregulate receptors at the cell surface. These surface receptors bind to the ligand and thereby interfere with its long-range movement. Recent experiments indicate that Dpp spreading is mediated by Dynamin-dependent endocytosis in the target tissue, suggesting that extracellular diffusion alone cannot account for Dpp dispersal. Here, we perform a theoretical study of a model for morphogen spreading based on extracellular diffusion, which takes into account receptor binding and trafficking. We compare profiles of ligand and surface receptors obtained in this model with experimental data. To this end, we monitored directly the pool of surface receptors and extracellular Dpp with specific antibodies. We conclude that current models considering pure extracellular diffusion cannot explain the observed role of endocytosis during Dpp long-range movement.
Neural crest cell plasticity and its limits
Authors: Le Douarin Nicole M. , Creuzet Sophie , Couly Gérard , Dupin Elisabeth
Published: September 2004

The neural crest (NC) yields pluripotent cells endowed with migratory properties. They give rise to neurons, glia, melanocytes and endocrine cells,and to diverse `mesenchymal' derivatives. Experiments in avian embryos have revealed that the differentiation of the NC `neural' precursors is strongly influenced by environmental cues. The reversibility of differentiated cells(such as melanocytes or glia) to a pluripotent precursor state can even be induced in vitro by a cytokine, endothelin 3. The fate of `mesenchymal' NC precursors is strongly restricted by Hox gene expression. In this context,however, facial skeleton morphogenesis is under the control of a multistep crosstalk between the epithelia (endoderm and ectoderm) and NC cells.
What level of friction guarantees adhesion in a complete contact?
Authors: Hills D A , Dini D
Published: September 2004

The Williams' solution for the state of stress near the apex of an elastic wedge is used to study the traction distribution adjacent to the tip of a complete contact. Assuming that the surfaces remain in contact during loading, the coefficient of friction needed to ensure local adhesion is found. This is compared with that predicted by an analysis of an elastic rectangle clamped between elastic halfplanes and is shown to be consistent. The results are appropriate to all complete contacts between elastically similar components.
Innovative manufacturing technologies for the disassembly of consumer goods
Authors: Uhlmann E , Elbing F , Dittberner J
Published: September 2004

Ecological harmless disposal of used technical consumer products will become mandatory for producers and importing companies. This disposal policy will focus on product and material loops; used products will be disassembled and the parts and materials then recycled. Owing to environmental and legislative reasons, the importance of disassembly as a step in the process of recycling is steadily rising. The article presents developed technologies and tools for the disassembly of consumer goods. The aim is to recover materials and reusable components within a semiautomatic pilot disassembly system. Different destructive processes were optimized to disassemble washing machines.
A temperature-controlled complementary metal oxide semiconductor camera
Authors: Harvey S G P , Bähr J L
Published: September 2004

In recent years, complementary metal oxide semiconductor (CMOS) imaging sensors have been replacing charge-coupled device (CCD) imagers in consumer and industrial markets. Their low cost and high peripheral integration on chip gives new opportunities to those who have not adopted CCD technology due to cost or technical concerns. This paper describes the design of a prototype CMOS camera for use in spectral experiments with noise reduction techniques to improve image quality. We use a Peltier device to cool the sensor, a synchronous dynamic random access memory (SDRAM) frame buffer for storage and a universal serial bus (USB) interface to transfer the data at a high speed.
Using HADRIAN for eliciting virtual user feedback in ‘design for all’
Authors: Marshall R , Case K , Porter J M , Sims R , Gyi D E
Published: September 2004

‘Design for all’ is an approach to product, environment or service design that aims to maximize the usability of a particular design. However, a key concept of this approach is not to tailor designs to the user in a bespoke fashion, but rather to provide a single solution that accommodates the needs of all users, including those who are older or are disabled.

In order to support the designer/design team in ‘design for all’ a computer aided design and analysis tool has been developed. The tool, known as HADRIAN, has been developed to address two critical factors. The first factor is the provision of accurate and applicable data on the target users, including a broad spectrum of size, shape, age and ability. The second factor is an efficient and effective means of utilizing the data for ergonomics evaluations during the concept stages of design. HADRIAN's database and task analysis tool work in combination with the existing human modelling system SAMMIE. The system as a whole allows assessment of a design against the population in the database, providing a means to elicit some of the feedback that might be gained by real user trials at a stage in the design process when physical mock-ups and user group selection would be prohibitively time consuming and expensive.
Pressure control for constant-pressure masks
Authors: Chan H , Al-Jumaily A M , D'Arcy A E , Makinson D
Published: September 2004

This research focuses on developing an automatic control scheme to maintain a constant pressure in a mask which is normally used in respiratory devices to help patients with breathing difficulties. The problem of dead time associated with fluid flow in relatively long tubes conveying air is resolved using a feedforward compensation scheme. This compensation includes adding additional electronic components between the system and the controller. Appropriate transfer functions are developed and the system is simulated using Simulink in a Matlab environment. The compensation scheme has demonstrated an effective control, a more stable system and a reduced time delay. The theoretical response is validated experimentally.
The prediction of the non-linear dynamics of a squeeze-film damped aero-engine rotor housed in a flexible support structure
Authors: Bonello P , Brennan M J , Holmes R
Published: September 2004

This paper shows how the non-linear dynamics of a rotor running in unsupported squeeze-film dampers (SFDs) housed in a flexible support structure can be efficiently modelled using an integrated analytical technique and a standard model for the SFDs. A test rig that reproduces, to a limited extent, the essential dynamic features of an aero-engine gas turbine is considered and the aim of the analysis is to assess the ability to predict and interpret the observed non-linear vibrations as indicated by amplitude-speed plots, frequency spectra, orbital motion plots and Poincaré maps. The solution process starts with the application of a fast harmonic balance method that uses receptance functions to determine periodic solutions. A modal-based approach is then used for the analysis of the stability and bifurcation of these solutions, as well as the analysis of aperiodic motion. The simulation correctly predicts the overall performance, including subharmonic motion, combination frequencies and subcritical superharmonic resonances.
Force appropriation for flight flutter testing
Authors: Desforges M J , Cooper J E , Wright J R
Published: September 2004

In this paper, the multivariate mode indicator function (MMIF) method has been applied to simulated flutter test data in order to evaluate the potential application of normal mode force appropriation to flight flutter testing where there are many close modes and noise levels are severe. It is seen that the approach is capable of estimating accurate modal frequencies and force patterns from corrupted test data, for use in the appropriation of particular modes. Damping ratios are accurately estimated from a decay response following a resonance dwell. The complex mode indicator function (CMIF) has also been considered. The practical limitations of in-flight force appropriation are discussed, and the effects of the limited excitation possibilities are demonstrated by simulation. The number and position of exciters used are arguably the most important factors in determining the success of this technique. The application of force appropriation to flight flutter testing may well depend on the availability of small detachable vanes which allow direct excitation of all areas of the aircraft structure.
Modern developments in computational aeroelasticity
Authors: Bendiksen O O
Published: September 2004

A survey of the main challenges in computational aeroelasticity is presented and recent ideas and developments are discussed. Advances over the past 25 years have to a large extent been paced by the required developments in computational fluid dynamics (CFD). The fluid-structure coupling problem remains of central importance and must be addressed in a rational manner in order to obtain accurate and reliable flutter solutions. In the direct Eulerian-Lagrangian computational scheme, a consistent and efficient fluid-structure coupling is obtained by modelling and integrating the fluid-structure system as a single dynamical system, without introducing normal or assumed modes, or an artificial “virtual surface” at the boundary. This computational approach effectively eliminates the phase integration errors associated with classical methods, where the fluid and the structure are integrated sequentially using different schemes. Numerical results are presented to contrast the efficacy of the various schemes in non-linear aeroelastic and aeroservoelastic calculations.
Aeroelastic behaviour of a solar-powered high-altitude long endurance unmanned air vehicle (HALE-UAV) slender wing
Authors: Frulla G
Published: September 2004

A preliminary dynamic and aeroelastic investigation is performed in a simplified equivalent configuration derived from the HELIPLAT HAVE-UAV (high-altitude very-long endurance unmanned air vehicle) wing structure. The presence of slender wing structures introduces in the structural design a certain degree of non-linearity, forcing the designer to deal with specific phenomena, one of which is described. A simple dynamic system is used to point out the important effect due to the inclusion of the deformed equilibrium configuration into the dynamic behaviour of the system. A modified wing structure configuration is used to point out this effect in the flutter behaviour of slender structures. Some interesting design indications are presented.
A review of analytical methods for aircraft structures subjected to high-intensity random acoustic loads
Authors: Cunningham P R , White R G
Published: September 2004

A review of the acoustic fatigue design process for aircraft structures is presented in this paper, together with the current design guides, which are used to predict the stresses that an acousticallly loaded aircraft structure may experience in service. These methods are based on linear theory and use the single-degree-of-freedom approximation method. A recent programme of research which uses this method together with the finite element method to predict the root mean square strains experienced by acoustically excited, doubly curved sandwich panels is briefly discussed. Recent developments in prediction methods based on the non-linear dynamic response of thermoacoustic loaded structures are reviewed, and suggestions are made as to possible future directions in the area of acoustic fatigue research
State-of-the-art dynamic analysis for non-linear gas turbine structures
Authors: Petrov E P , Ewins D J
Published: September 2004

An accurate and robust method has been developed for the general multiharmonic analysis of forced periodic vibrations of bladed discs subjected to abrupt changes of elastic and damping properties at contact nodes located on the interfaces of the components. The approach is based on an analytical formulation of friction contact interface elements which provides exact expressions for multiharmonic forces and stiffness matrices of the elements. The analytical formulation overcomes the numerical difficulties associated with searching for a solution of the non-linear equations, which have been inherent so far for the considered systems, and provides a breakthrough in the analysis of the non-linear forced response of bladed discs and other structures with gaps and friction interfaces. An effective reduction method is reported that allows the size of the resolving equations to be decreased to the number of DOFs (degrees of freedom) at the contact surfaces, while preserving completeness and accuracy of the whole large-scale model.

Numerical investigations demonstrate the outstanding properties of the proposed approach with respect to computational speed, accuracy and stability of calculations for practical gas-turbine structures.
Efficient Formation of a Nitrosyl(protoporphyrinato)iron(II) Complex on Magnesium Oxide Powder
Authors: Noda Hiroyuki , Ohya Hiroaki , Kamada Hitoshi
Published: September 2004

We have investigated the reaction between the system of hydroxo(protoporphyrinato)iron(III) (Heme) complex adsorbed on magnesium oxide (MgO) powder in the presence of cysteine (Cys) (Heme/MgO/Cys) and the nitrite ion (NO2−), using a Clark-type oxygen electrode and an ESR method. The nitrite ion acted as an inhibitor on the oxygen consumption by the Heme/MgO/Cys. This inhibition was not observed on the system of Heme aqueous solution (Hemeaq) in the presence of cysteine (Hemeaq/Cys) and NO2−, where the oxygen consumption was caused. The formation of a nitrosyl(protoporphyrinato)iron(II) complex in the reaction mixture of the Heme/MgO/Cys and NO2− was confirmed by the measurement of an ESR spectrum. This result suggests that the formation of the nitrosyl(protoporphyrinato)iron(II) complex during the reduction of NO2− to nitrogen monoxide (NO) plays a key role on the inhibitory action of NO2−. A possible mechanism for the formation of the nitrosyl(protoporphyrinato)iron(II) complex on the reaction between the Heme/MgO/Cys and NO2− is discussed, as a characteristic feature of our heterogeneous system.