bluuebunny/crossref_metadata_2025 huggingface dataset:
Therapeutic Options in Advanced Laryngeal Cancer: An Overview
Authors: Dias Fernando L. , Lima Roberto A. , Kligerman Jacob , Cernea Claudio R.
Published: December 2005

Historically, patients with advanced laryngeal cancer have been treated with radical surgery and adjuvant radiation therapy. Intensive surgical research has allowed surgeons to deal with almost any local extension and to propose an appropriate surgical procedure for each case. Several function-sparing surgical options are available to treat moderately advanced/advanced laryngeal cancer. Better understanding of the anatomy and biology of cancer in this anatomical site has enabled us to devise effective oncological strategies associated with a great effort to preserve laryngeal function. Numerous efforts have been made to augment the therapeutic armamentarium with the addition of chemotherapeutic agents combined with radiation therapy. For advanced laryngeal cancer, the debate is still open between partial/subtotal surgical procedures, which are more efficient but sacrifice parts of the larynx, and radiotherapy/chemoradiation protocols which can preserve the larynx and its function even though it requires radical surgery for salvage. Efforts should be made to select patients properly, in an individual basis, based on tumor characteristics, clinical aspects, patient’s expectations, and the expertise of the head and neck oncologic team for the various therapeutic strategies in order to get better oncological results in association with the preservation of the laryngeal form and function, when possible.
A Centenary of Auscultatory Blood Pressure Measurement: A Tribute to Nikolai Korotkoff
Authors: Paskalev Dobrin , Kircheva Anna , Krivoshiev Stefan
Published: December 2005

In 1905, Dr. Nikolai Korotkoff (1874–1920), a Russian surgeon, discovered a simple and precise technique to measure arterial pressure. He was born on 26th February 1874 in the central Russian city of Kursk. Korotkoff graduated from the Medical Faculty of Moscow University in 1898, but he worked later in the Surgical Clinic at the Imperial Military Medical Academy in St. Petersburg (Russia). Korotkoff served as a military surgeon during the Russo-Japanese War (1904–1905) and his major efforts were to find reliable clinical signs that could predict whether limb flow would be viable after vascular surgery of traumatic aneurysm. He found that after complete compression, the aneurysm of the arm (i.e. distal pulse on a. brachialis) disappeared with Riva-Rocci cuff and then gradually decreasing the pressure, a series of sounds could be heard by stethoscope under the artery distal to the compression. Korotkoff described four distinct phases of sounds: first sound, then compression murmurs, second tone, and disappearance of sounds. Korotkoff was also able to demonstrate the same auscultatory finding in healthy persons. He failed to notice only the muffled second sound, which was demonstrated a little later. These classical observations are now well known as the five different phases of Korotkoff sounds. In November 1905, during a conference of the Imperial Military Medical Academy, he reported his discovery in a short presentation entitled ‘On the issue of the methods for measuring blood pressure’. In 1939, the Joint Committee of the American Heart Association and the Cardiac Society of Great Britain and Ireland recognized officially and accepted worldwide Korotkoff’s method for blood pressure determining.
Individual IGF-I Responsiveness to a Fixed Regimen of Low-Dose Growth Hormone Replacement Is Increased with Less Variability in Obese Compared to Non-Obese Adults with Severe Growth Hormone Deficiency
Authors: Yuen Kevin C.J. , Cook David M. , Rumbaugh Elease E. , Cook Marie B. , Dunger David B.
Published: December 2005

Background/Aims: Decreased GH and IGF-I levels and increased GH responsiveness are frequently reported in obesity. As GH-deficient adults are commonly obese, the role of obesity in affecting hepatic responsiveness of IGF-I generation to GH stimulation is unclear in severe GH-deficient states. To address this question, we challenged a cohort of severely GH-deficient non-obese and obese adults with a fixed low GH dose (0.2 mg/day), and examined the relationship of body mass index (BMI) with IGF-I response. Methods: 12 non-obese (6 males, median BMI 24.7 kg/m2) and 14 obese (7 males, median BMI 45.2 kg/m2) adults with severe GH deficiency were studied for 8 weeks. Blood samples were collected at baseline, and weeks 4 and 8. Results: There was a larger increment and reduced variability of IGF-I levels in obese compared to non-obese GH-deficient adults at week 8, but not at week 4. A similar but smaller increment and less variability was observed with IGFBP-3. Increment IGF-I positively correlated with baseline BMI at weeks 4 (r = 0.49, p < 0.02) and 8 (r = 0.47, p < 0.02). No gender differences were observed with the IGF-I and IGFBP-3 response. Conclusions: This study demonstrates that there is a larger increment and deceased individual variability of IGF-I to the low GH replacement dose in obese compared to non-obese adults with severe GH deficiency, regardless of gender. The positive association of IGF-I increment with BMI implies a greater impact of obesity rather than GH deficiency in enhancing hepatic sensitivity to GH. These findings, thus, question the reliability of interpreting single serum IGF-I levels in non-obese adults with severe GH deficiency treated with low GH replacement doses.
Helicobacter pylori Seroprevalence in Patients with Chronic Obstructive Pulmonary Disease and Its Relation to Pulmonary Function Tests
Authors: Gencer Mehmet , Ceylan Erkan , Yıldız Zeyrek Fadile , Aksoy Nurten
Published: December 2005

Background: Chronic obstructive pulmonary disease (COPD) is a slowly progressive condition characterized by poorly reversible airflow limitation that is associated with an abnormal inflammatory response of the lung. It has been shown that there is a seroepidemiological association of Helicobacter pylori (Hp) infection with many inflammatory conditions. Objective: In this study, we aimed to investigate seroprevalence in Hp patients with COPD and to determine whether there is an association between Hp infection and COPD. Methods: Forty-nine voluntary patients with COPD and 50 healthy control subjects of similar age and sex were included in the study. Hp-specific IgG was measured with a commercially available kit from venous blood samples. Results: Serum levels of Hp-specific IgG and Hp IgG seropositivity were significantly higher in the patients with COPD than in the control subjects (p < 0.001 and p = 0.006, respectively). In addition, when the patients with COPD were grouped according to Hp IgG seropositivity, forced expiratory volume in 1 s (FEV1) values were lower in the seropositive patients compared to seronegative patients, and Hp serum IgG levels were correlated with FEV1 values, which indicate the severity of COPD, in the COPD group (r = –0.306, p = 0.032). Conclusion: The results suggest that there is an association between Hp infection and COPD, and Hp IgG levels are correlated with the severity of COPD.
Natural Course of Isolated Pulmonary Langerhans’ Cell Histiocytosis in a Toddler
Authors: Nagy Béla , Soós Györgyike , Nagy Kálmán , Dezső Balázs
Published: December 2005

Isolated pulmonary Langerhans’ cell histiocytosis (LCH) is distinctly rare under the age of 15 years, since the majority of patients are young adult males with heavy smoking habits. Isolated pulmonary involvement suggests that antigens inhaled from cigarette smoke are involved. Here we present a case of LCH restricted to the lungs in a toddler whose parents were heavy smokers. Since LCH was not medically treated for 3 years due to parental refusal, the disease can be regarded as having followed its natural course. During the 3-year follow-up, the disease progressed to severe pulmonary fibrosis resulting in honeycomb lungs. Based on the comparative immunohistochemical analyses of the cells obtained from bronchoalveolar lavages during the disease course, it appears that the evolution of fibrosis is rather a result from the accumulating alveolar macrophages than from the persistence of the Langerhans’ cells. Passive cigarette smoking may be considered a significant risk factor in both the pathogenesis and development of pulmonary LCH in a small child.
Evidence in Teacher Education
Authors: Pecheone Raymond L. , Chung Ruth R.
Published: December 2005

The Performance Assessment for California Teachers (PACT) was developed in response to a California State mandate (SB 2042), requiring teacher preparation programs to use performance assessments as one measure in making credentialing decisions. In this article, results are examined from statewide implementation of the PACT assessments during the first 2 pilot years. Despite the limitation of only 2 years of data, 3 years of implementation experiences have informed participating programs about how they can better support candidate learning and identify areas for examination. In addition, this research suggests that the PACT performance assessment can be used in teacher education as a valid measure of individual teacher competence for the purpose of teacher licensure and as a powerful tool for teacher learning and program improvement.
Do Professional Development Schools (PDSs) Make a Difference? A Comparative Study of PDS and Non-PDS Teacher Candidates
Authors: Castle Sharon , Fox Rebecca K. , Souder Kathleen O'Hanlan
Published: December 2005

This study assesses the impact of professional development schools (PDSs) on preservice teachers, comparing PDS and non-PDS candidates at the point of licensure. Data sources include student teaching evaluations and portfolio presentations. Statistical analyses reveal PDS candidates scored significantly higher than non-PDS candidates on aspects of planning, instruction, management, and assessment. Qualitative analysis of portfolio presentations reveals PDS candidates showed greater ownership of their school and classroom and more sophistication in applying and integrating Interstate New Teacher Assessment and Support Consortium standards. Five differences are discussed: how and why versus what, standards connected versus standards isolated, assessment as driving instruction versus assessment as tools, reflection connected to practice versus reflection not connected to practice, and student focus versus self-focus. Contextual and programmatic differences are used to explain the differences. The case is made that PDS graduates may affect student learning sooner than traditionally trained beginning teachers.
A Systemic Approach to Enhancing Teacher Quality
Authors: Lasley Thomas J. , Siedentop Daryl , Yinger Robert
Published: December 2005

All those responsible for the preparation of teachers agree that having a highly qualified teacher in every classroom is essential to student academic achievement. The research of the past decade by William Sanders and others clearly demonstrates the significance of the teacher in fostering student growth and academic achievement. What researchers and practitioners are having difficulty agreeing on is the essential characteristics of the teachers who create value-added learning and the ways in which professional development experiences need to be structured in order to foster and develop those critical teacher characteristics. The Ohio Teacher Quality Partnership represents one state's approach to better understand the relationship between teacher behaviors and student achievement and how a wide variety of stakeholders are collaborating to create a more vital educational system for P-12 students.
Evidence in Teacher Preparation
Authors: Wineburg Mona S.
Published: December 2005

This article reports on a survey examining the state of knowledge and practice about how universities provide evidence of the effectiveness of their programs to schools, parents, policy makers, and the public. The project asked three questions: What is happening? What is promising? What is believable? The survey focused on two areas: results and outcomes, and issues in measurement. Data from this study reveal that state colleges and universities are expending extraordinary energy and resources assessing prospective teachers and compiling data about teacher preparation programs. The survey data uncover the myriad issues that confound the data collection process, the difficulties around establishing validity and reliability, and the extraordinary demands placed on programs to produce data for a variety of constituencies. Recommendations are made for the development of a national framework for evidence, guidelines that institutions can use to proactively develop data systems that promote a culture of evidence on their campuses.
Surviving the dragnet: ‘special interest’ detainees in the US after 9/11
Authors: Mathur Shubh
Published: December 2005

Following the 9/11 attacks in the US, thousands of Muslim, South Asian and Middle Eastern men were detained by the FBI, police and immigration officers and held in various prisons in New York and New Jersey. The effect of these detentions on individuals, their families and the wider community is here documented. The purpose of this incarceration, which often endured for months without charges being brought, was not to ensure greater security, but to carry out surveillance on and intimidate what had been designated, via an official and popular discourse of anti-Muslim racism, a ‘suspect community’. While postmodern anthropology may consider human rights part of an ‘outmoded’ discourse, the experience of these detainees proves its continued relevance.
The limits of reform: the Wolfensohn era at the World Bank
Authors: Bello Walden , Guttal Shalmali
Published: December 2005

With the appointment in 1995 of James Wolfensohn to the presidency of the World Bank began an attempt to recast the negative image that the Bank had acquired as a result of its widely criticised structural adjustment programmes, land resettlement schemes and large dam projects in developing countries. ‘Poverty reduction’ and ‘good governance’ were to be the new watchwords, and civil society organisations were invited to engage in a process of dialogue and reform. The various initiatives introduced by the World Bank during Wolfensohn’s ten-year presidency are surveyed here and shown to continue, in effect, the discredited policies of the 1980s, while the promised dialogue with civil society was stillborn.
Europe: ‘speech crime’ and deportation
Authors: Fekete Liz
Published: December 2005

Throughout Europe, reforms to immigration law are being introduced which effectively tie rights to citizenship and residence to limitations on freedom of speech; the penalty for breaching these is, increasingly, deportation. So far, these measures have only been applied to Muslims, usually religious leaders, held to have made inflammatory or offensive statements -! offences which could be dealt with under existing public order law. But the use of immigration legislation to deal with such issues bypasses the need for judicial transparency and overrides the rights of the accused. In the process, a separate, parallel justice system is set up which lacks any checks and balances on state power.
Nurse and Client Perceptions of Home Health Wound Care Effectiveness After a Change in Medicare Reimbursement
Authors: Eaton Melody K.
Published: December 2005

The purpose of this study was to begin to explore client and nurse perceptions related to how a change in a Medicare reimbursement, Prospective Payment System (PPS), affects home health care. The target population included home health clients with stage III or greater decubitus ulcers, age 65 years or older. Six Virginia home health agencies were randomly selected. From those sites, all 39 charts that met population criteria were accessed and analyzed, and then 16 care recipients were purposely selected. In addition, 26 home health nurses with pre- and post-PPS experience were purposefully selected. Semistructured, audiotaped interviews were conducted, transcribed, and analyzed using thematic content analysis. Results demonstrated PPS adaptive behavior and an increase in use of education and family caregivers related to wound care. Themes that emerged included professional competence, caregiver as key, and sense of support. Perceptions emphasize the necessity for resource management, collaboration, and patient advocacy.
Low-Income Housing Policy and Socioeconomic Inequalities in Women’s Health: The Importance of Nursing Inquiry and Intervention
Authors: Welch Dinah , Kneipp Shawn
Published: December 2005

Decent, affordable housing is the building block of healthy neighborhoods. Housing characteristics not only shape the quality of life in communities but also affect individual and family health. The structural and social aspects of housing have a significant impact on the health of individuals and populations. Early public health nursing pioneers such as Lillian Wald and Jane E. Hitchcock understood the adverse impact of substandard housing on population health and incorporated advocacy for housing and other social policy reforms as an integral aspect of their nursing interventions. Contemporary nursing literature, however, is lacking in its critical examination of relationships between housing and health. This article presents historical and current issues in low-income housing policy, discusses how low-income housing policy has contributed to social inequalities in health, and advocates for the importance and inherent value of nursing inquiry and intervention in this area.
The Conceptual Model for Nursing and Health Policy Revisited
Authors: Russell Gail E. , Fawcett Jacqueline
Published: December 2005

A conceptual model of nursing and health policy was proposed by the authors in 2001. Revisions in the model have been made, and the model has been used to guide the evolution of a nursing doctoral program and doctoral dissertation research. The revised model provides a framework for analysis and evaluation of public, organizational, and professional polices influencing the quality, cost, and access to nursing and other health care services, as well as for nursing-discipline specific and health services research at any one of four interacting levels: Level 1—efficacy of nursing practice processes; Level 2—effectiveness of nursing practice processes and effectiveness and efficiency of health care delivery subsystems; Level 3—equity of access to effective and efficient nursing practice processes and efficient nursing practice delivery systems, and equity in distribution of costs and burdens of care delivery; Level 4—justice and the social changes and market interventions addressing equity.
North Carolina Center for Nursing Health Policy Fellowship: A Strategy for Developing Nursing Leaders for the Future
Authors: Cleary Brenda , Hofler Linda , Seamon Judy
Published: December 2005

In the midst of ongoing concern about succession planning to develop the next generation of nursing leaders, the profession cannot afford to overlook succession planning in regard to the next generation of nurse leaders in health policy. This article describes a project of the North Carolina Center for Nursing that provides a fellowship in state-level health policy for North Carolina nurses who have completed a graduate level health policy course. Policy fellows are exposed to health policy analysis through the public policy arena, regulatory and administrative arenas, and organizational and institutional arenas. As part of this journey, all major state stakeholders in health policy are involved in the mentoring process. The North Carolina Center for Nursing Health Policy Fellowship is described here as a potential model related to policy initiatives in other states.
Performative Writing as Scholarship: An Apology, an Argument, an Anecdote
Authors: Pelias Ronald J.
Published: December 2005

The article, divided into three sections, argues for the methodological power of performative writing. Part 1 borrows from the literary tradition by offering an apology on behalf of performative writing as it links the poetic and the performative. Part 2 continues the argument by structuring its claims in the form of a logical proof. Part 3 completes the case by offering a short story of how performative writing has functioned within the academy. The essay enacts the performative writing method as it calls for its use.
Differential regulation of endothelial exocytosis of P-selectin and von Willebrand factor by protease-activated receptors and cAMP
Authors: Cleator John H. , Zhu Wen Qin , Vaughan Douglas E. , Hamm Heidi E.
Published: December 2005

Thrombin-mediated endothelial-cell release of von Willebrand factor (VWF) and P-selectin functionally links protease-activated receptors (PARs) to thrombosis and inflammation. VWF release can be stimulated by both Ca2+ and cAMP, and, although both VWF and P-selectin are found in Weibel-Palade bodies (WPBs), we found that their release could be differentially regulated. In these studies, human umbilical vein endothelial cells stimulated with cAMP or PAR2-AP led to a delayed release of VWF and significantly less P-selectin release compared with histamine, thrombin, or PAR1-AP. Dose-response studies revealed that PAR2-AP was significantly less efficacious in promoting the release of P-selectin compared with VWF. PAR2-AP–induced robust stimulation of intracellular Ca2+ coupled with a significantly greater inhibitory effect of calcium chelation on release of VWF compared with cell-surface expression of P-selectin, suggests an additional Ca2+-independent pathway involved in release of P-selectin. PAR2-AP failed to increase global cAMP levels; however, inhibition of protein kinase A led to a significant attenuation of PAR2-AP–mediated release of VWF. Confocal microscopy studies revealed that PAR2 and forskolin caused preferential release of a population of Weibel-Palade bodies (WPBs) consisting of only VWF. Thus, WPBs are pharmacologically and morphologically heterogeneous, and distinct granule populations are susceptible to differential regulation.
Enhanced engraftment of hematopoietic stem/progenitor cells by the transient inhibition of an adaptor protein, Lnk
Authors: Takizawa Hitoshi , Kubo-Akashi Chiyomi , Nobuhisa Ikuo , Kwon Sang-Mo , Iseki Masanori , Taga Tetsuya , Takatsu Kiyoshi , Takaki Satoshi
Published: December 2005

Hematopoietic stem cells (HSCs) are the key elements responsible for maintaining blood-cell production throughout life and for lymphohematopoietic reconstitution following bone marrow (BM) transplantation. Enhancement of the engrafting potential and expansion capabilities of HSCs as well as hematopoietic progenitor cells (HPCs) has been a long-time desire as a means of reducing the risks and difficulties that accompany BM transplantation. The ability of HSCs/HPCs to reconstitute the hematopoietic system of irradiated hosts is negatively regulated by an intracellular adaptor protein, Lnk. Here we have identified the functional domains of Lnk and developed a dominant-negative (DN) Lnk mutant that inhibits the functions of Lnk endogenously expressed in the HSCs/HPCs and thereby potentiates the HSCs/HPCs for engraftment. Importantly, even transient expression of DN-Lnk in HSCs/HPCs facilitated their engraftment under nonmyeloablative conditions and fully reconstituted the lymphoid compartments of immunodeficient host animals. HPCs expressing DN-Lnk were efficiently trapped by immobilized vascular cell adhesion molecule-1 (VCAM-1) in a transwell migration assay, suggesting involvement of Lnk in the regulation of cell mobility or cellular interaction in microenvironments. Transient inhibition of Lnk or Lnk-mediated pathways could be a potent approach to augment engraftment of HSCs/HPCs without obvious side effects.
Persistence of naive CD45RA+ regulatory T cells in adult life
Authors: Seddiki Nabila , Santner-Nanan Brigitte , Tangye Stuart G. , Alexander Stephen I. , Solomon Michael , Lee Soon , Nanan Ralph , de Saint Groth Barbara Fazekas
Published: December 2005

Regulatory T cells (TREGs) constitutively expressing CD4, CD25, and the transcription factor Foxp3 can prevent a wide range of experimental and spontaneous autoimmune diseases in mice. In humans, CD4+CD25bright T cells, predominantly within the CD45RO+ activated/memory subset in adults and the CD45RA+ naive T-cell subset in infants, are considered to be the equivalent subset. Using novel combinations of monoclonal antibodies (mAbs), we examined expression of CD25 in human infant thymus, cord blood, adult peripheral blood, lymph node, and spleen. In addition to the CD4+CD25bright T cells, subfractionation on the basis of CD45 splice variants indicated that all samples contained a second distinct population of cells expressing a slightly lower level of CD25. In adult peripheral blood, this population expressed a naive CD45RA+ phenotype. The corresponding population in lymph node, spleen, and cord blood showed some evidence of activation, and expressed markers characteristic of TREGs, such as cytotoxic T lymphocyte-associated antigen 4 (CTLA-4). Sorted CD4+CD25+CD45RA+ T cells from both cord and adult blood expressed very high levels of mRNA for Foxp3 and manifested equivalent suppressive activity in vitro, indicating that they are bone fide members of the regulatory T-cell lineage. Targeting naive TREGs in adults may offer new means of preventing and treating autoimmune disease.
IL-10 can induce the expression of EBV-encoded latent membrane protein-1 (LMP-1) in the absence of EBNA-2 in B lymphocytes and in Burkitt lymphoma- and NK lymphoma-derived cell lines
Authors: Kis Lorand L. , Takahara Miki , Nagy Noemi , Klein George , Klein Eva
Published: December 2005

EBV-positive nasopharyngeal carcinoma and Hodgkin, T, and natural killer (NK) lymphomas express EBNA-1 and the latent membrane proteins (LMP1-2; type II latency). In contrast to type III EBV-transformed lymphoblastoid cell lines, in these cells the LMPs are expressed in the absence of EBNA-2. We have previously reported that exposure to CD40 ligand and IL-4 could induce LMP-1 in an in vitro EBV-infected Hodgkin lymphoma-derived cell line, which expressed only EBNA-1. We show now that both human and EBV-encoded IL-10 can induce LMP-1 in the absence of EBNA-2 in the Daudi, P3HR1, and other BL cell lines. Interestingly, induction of LMP-1 was not accompanied by the downregulation of BCL-6. IL-10 could also induce LMP-1 in the conditional lymphoblastoid cell line ER/EB2-5 where EBNA-2 was downregulated in the absence of estrogen. Moreover, IL-10 could induce the expression of LMP-1 in tonsillar B cells infected with the nontransforming, EBNA-2-deficient EBV strain P3HR1 and enhance LMP-1 expression in 2 EBV-positive NK lymphoma lines. The demonstration that IL-10 can induce the expression of LMP-1 in an EBNA-2-independent manner shows that the major transforming EBV gene LMP-1 can be induced by extracellular signals in lymphoid cells, and IL-10 might contribute to the establishment of type II EBV latency.
Mutations in dyskeratosis congenita: their impact on telomere length and the diversity of clinical presentation
Authors: Vulliamy Tom J. , Marrone Anna , Knight Stuart W. , Walne Amanda , Mason Philip J. , Dokal Inderjeet
Published: December 2005

The two genes mutated in the bone marrow failure syndrome dyskeratosis congenita (DC) both encode components of the telomerase complex responsible for maintaining the ends of chromosomes in stem cells and in the germ line. In reviewing the mutation profile that is found in DC, we describe 9 novel mutations in the DKC1 gene and 3 novel TERC mutations responsible for the X-linked and autosomal dominant forms of the disease, respectively, but find that two thirds of the families do not have mutations in either of these genes. In a significant subset of these uncharacterized families, the index case presents with severe disease previously defined as the Hoyeraal Hreidarsson (HH) syndrome. The diverse clinical phenotype seen in patients with X-linked DC is not explained by the different amino acid substitutions: Presentation of the recurrent A353V substitution ranges from classic DC to the severe HH variant. However, we do see that patients with HH have significantly shorter telomeres than those with a relatively mild presentation. In the new families described with TERC mutations, there is further evidence of disease anticipation associated with shorter telomeres in the younger generations. This study highlights the considerable genetic and phenotypic diversity of DC.
Posttranscriptional regulation of Fas (CD95) ligand killing activity by lipid rafts
Authors: Nachbur Ueli , Kassahn Daniela , Yousefi Shida , Legler Daniel F. , Brunner Thomas
Published: December 2005

Fas (CD95/Apo-1) ligand-mediated apoptosis induction of target cells is one of the major effector mechanisms by which cytotoxic lymphocytes (T cells and natural killer cells) kill their target cells. In T cells, Fas ligand expression is tightly regulated at a transcriptional level through the activation of a distinct set of transcription factors. Increasing evidence, however, supports an important role for posttranscriptional regulation of Fas ligand expression and activity. Lipid rafts are cholesterol- and sphingolipid-rich membrane microdomains, critically involved in the regulation of membrane receptor signaling complexes through the clustering and concentration of signaling molecules. Here, we now provide evidence that Fas ligand is constitutively localized in lipid rafts of FasL transfectants and primary T cells. Importantly, disruption of lipid rafts strongly reduces the apoptosis-inducing activity of Fas ligand. Localization to lipid rafts appears to be predominantly mediated by the characteristic cytoplasmic proline-rich domain of Fas ligand because mutations of this domain result in reduced recruitment to lipid rafts and attenuated Fas ligand killing activity. We conclude that Fas ligand clustering in lipid rafts represents an important control mechanism in the regulation of T cell–mediated cytotoxicity.
Quantitative assessment of molecular remission after high-dose therapy with autologous stem cell transplantation predicts long-term remission in mantle cell lymphoma
Authors: Pott Christiane , Schrader Carsten , Gesk Stefan , Harder Lana , Tiemann Markus , Raff Thorsten , Brüggemann Monika , Ritgen Matthias , Gahn Benedikt , Unterhalt Michael , Dreyling Martin , Hiddemann Wolfgang , Siebert Reiner , Dreger Peter , Kneba Michael
Published: December 2005

To evaluate the prognostic impact of minimal residual disease (MRD), quantitative real-time polymerase chain reaction (RQ-PCR) of clonal IGH rearrangements was performed in 29 patients with mantle cell lymphoma (MCL) treated with high-dose radiochemotherapy and autologous stem cell transplantation (ASCT). Fourteen of 27 patients evaluable for MRD after ASCT achieved complete clinical and molecular remission, whereas 13 patients had detectable MRD within the first year after ASCT. Molecular remission after ASCT was strongly predictive for improved outcome, with a median progression-free survival (PFS) of 92 months in the MRD-negative group compared with 21 months in the MRD-positive group (P < .001). Median overall survival (OS) was 44 months in the MRD-positive group and has not been reached in the MRD-negative group (P < .003). In multivariate analysis, molecular remission and bulky disease were independent prognostic factors for PFS (P = .001 and P = .021, respectively). While cyclophosphamide, doxorubicin, vincristine, prednisolone (CHOP)–like cytoreduction had only modest influence, ara-C–containing mobilization and myeloablative radiochemotherapy significantly reduced MRD. Quantitative MRD measured in the stem cell products of 27 patients was not predictive for molecular remission. We conclude that sequential quantitative monitoring of residual disease after ASCT is a powerful indicator for treatment outcome in MCL and defines subgroups of patients with a significantly different prognosis.
Scientific and clinical opportunities for modeling blood disorders with embryonic stem cells
Authors: Lensch M. William , Daley George Q.
Published: December 2005

Our considerable wealth of data concerning hematologic processes has come despite difficulties working with stem and progenitor cells in vitro and their propensity to differentiate. Key methodologies that have sought to overcome such limitations include transgenic/knock-out animals and in vitro studies using murine embryonic stem cells, because both permit investigation of the formation of hematopoietic tissue from nonhematopoietic precursors. Although there have been many successful studies in model animals for understanding hematopoietic-cell development, differences between lower vertebrates and humans have left gaps in our understanding. Clearly, human-specific strategies to study the onset of hematopoiesis, particularly the earliest events leading to the specification of both normal and abnormal hematopoietic tissue, could bring an investigational renaissance. The recent availability of human embryonic stem (hES) cells suggests that such a system is now at hand. This review highlights the potential of hES cells to model human hematologic processes in vitro with an emphasis on disease targets.
Hyperresponsiveness to inhaled but not intravenous methacholine during acute respiratory syncytial virus infection in mice
Authors: Collins Rachel A , Gualano Rosa C , Zosky Graeme R , Atkins Constance L , Turner Debra J , Colasurdo Giuseppe N , Sly Peter D
Published: December 2005

Background

To characterise the acute physiological and inflammatory changes induced by low-dose RSV infection in mice.

Methods

BALB/c mice were infected as adults (8 wk) or weanlings (3 wk) with 1 × 105 pfu of RSV A2 or vehicle (intranasal, 30 μl). Inflammation, cytokines and inflammatory markers in bronchoalveolar lavage fluid (BALF) and airway and tissue responses to inhaled methacholine (MCh; 0.001 – 30 mg/ml) were measured 5, 7, 10 and 21 days post infection. Responsiveness to iv MCh (6 – 96 μg/min/kg) in vivo and to electrical field stimulation (EFS) and MCh in vitro were measured at 7 d. Epithelial permeability was measured by Evans Blue dye leakage into BALF at 7 d. Respiratory mechanics were measured using low frequency forced oscillation in tracheostomised and ventilated (450 bpm, flexiVent) mice. Low frequency impedance spectra were calculated (0.5 – 20 Hz) and a model, consisting of an airway compartment [airway resistance (Raw) and inertance (Iaw)] and a constant-phase tissue compartment [coefficients of tissue damping (G) and elastance (H)] was fitted to the data.

Results

Inflammation in adult mouse BALF peaked at 7 d (RSV 15.6 (4.7 SE) vs. control 3.7 (0.7) × 104 cells/ml; p < 0.001), resolving by 21 d, with no increase in weanlings at any timepoint. RSV-infected mice were hyperresponsive to aerosolised MCh at 5 and 7 d (PC200 Raw adults: RSV 0.02 (0.005) vs. control 1.1 (0.41) mg/ml; p = 0.003) (PC200 Raw weanlings: RSV 0.19 (0.12) vs. control 10.2 (6.0) mg/ml MCh; p = 0.001). Increased responsiveness to aerosolised MCh was matched by elevated levels of cysLT at 5 d and elevated VEGF and PGE2 at 7 d in BALF from both adult and weanling mice. Responsiveness was not increased in response to iv MCh in vivo or EFS or MCh challenge in vitro. Increased epithelial permeability was not detected at 7 d.

Conclusion

Infection with 1 × 105 pfu RSV induced extreme hyperresponsiveness to aerosolised MCh during the acute phase of infection in adult and weanling mice. The route-specificity of hyperresponsiveness suggests that epithelial mechanisms were important in determining the physiological effects. Inflammatory changes were dissociated from physiological changes, particularly in weanling mice.
Genetic interaction motif finding by expectation maximization – a novel statistical model for inferring gene modules from synthetic lethality
Authors: Qi Yan , Ye Ping , Bader Joel S
Published: December 2005

Background

Synthetic lethality experiments identify pairs of genes with complementary function. More direct functional associations (for example greater probability of membership in a single protein complex) may be inferred between genes that share synthetic lethal interaction partners than genes that are directly synthetic lethal. Probabilistic algorithms that identify gene modules based on motif discovery are highly appropriate for the analysis of synthetic lethal genetic interaction data and have great potential in integrative analysis of heterogeneous datasets.

Results

We have developed Genetic Interaction Motif Finding (GIMF), an algorithm for unsupervised motif discovery from synthetic lethal interaction data. Interaction motifs are characterized by position weight matrices and optimized through expectation maximization. Given a seed gene, GIMF performs a nonlinear transform on the input genetic interaction data and automatically assigns genes to the motif or non-motif category. We demonstrate the capacity to extract known and novel pathways for Saccharomyces cerevisiae (budding yeast). Annotations suggested for several uncharacterized genes are supported by recent experimental evidence. GIMF is efficient in computation, requires no training and automatically down-weights promiscuous genes with high degrees.

Conclusion

GIMF effectively identifies pathways from synthetic lethality data with several unique features. It is mostly suitable for building gene modules around seed genes. Optimal choice of one single model parameter allows construction of gene networks with different levels of confidence. The impact of hub genes the generic probabilistic framework of GIMF may be used to group other types of biological entities such as proteins based on stochastic motifs. Analysis of the strongest motifs discovered by the algorithm indicates that synthetic lethal interactions are depleted between genes within a motif, suggesting that synthetic lethality occurs between-pathway rather than within-pathway.
An SVM-based system for predicting protein subnuclear localizations
Authors: Lei Zhengdeng , Dai Yang
Published: December 2005

Background

The large gap between the number of protein sequences in databases and the number of functionally characterized proteins calls for the development of a fast computational tool for the prediction of subnuclear and subcellular localizations generally applicable to protein sequences. The information on localization may reveal the molecular function of novel proteins, in addition to providing insight on the biological pathways in which they function. The bulk of past work has been focused on protein subcellular localizations. Furthermore, no specific tool has been dedicated to prediction at the subnuclear level, despite its high importance. In order to design a suitable predictive system, the extraction of subtle sequence signals that can discriminate among proteins with different subnuclear localizations is the key.

Results

New kernel functions used in a support vector machine (SVM) learning model are introduced for the measurement of sequence similarity. The k-peptide vectors are first mapped by a matrix of high-scored pairs of k-peptides which are measured by BLOSUM62 scores. The kernels, measuring the similarity for sequences, are then defined on the mapped vectors. By combining these new encoding methods, a multi-class classification system for the prediction of protein subnuclear localizations is established for the first time. The performance of the system is evaluated with a set of proteins collected in the Nuclear Protein Database (NPD). The overall accuracy of prediction for 6 localizations is about 50% (vs. random prediction 16.7%) for single localization proteins in the leave-one-out cross-validation; and 65% for an independent set of multi-localization proteins. This integrated system can be accessed at http://array.bioengr.uic.edu/subnuclear.htm.

Conclusion

The integrated system benefits from the combination of predictions from several SVMs based on selected encoding methods. Finally, the predictive power of the system is expected to improve as more proteins with known subnuclear localizations become available.
A novel Dictyostelium RasGEF required for chemotaxis and development
Authors: Arigoni Maddalena , Bracco Enrico , Lusche Daniel F , Kae Helmut , Weeks Gerald , Bozzaro Salvatore
Published: December 2005

Background

Ras proteins are guanine-nucleotide-binding enzymes that couple cell surface receptors to intracellular signaling pathways controlling cell proliferation and differentiation, both in lower and higher eukaryotes. They act as molecular switches by cycling between active GTP and inactive GDP-bound states, through the action of two classes of regulatory proteins: a) guanine nucleotide exchange factor (GEFs) and b) GTP-ase activating proteins (GAPs). Genome wide analysis of the lower eukaryote Dictyostelium discoideum revealed a surprisingly large number of Ras Guanine Nucleotide Exchange Factors (RasGEFs). RasGEFs promote the activation of Ras proteins by catalyzing the exchange of GDP for GTP, thus conferring to RasGEFs the role of main activator of Ras proteins. Up to date only four RasGEFs, which are all non-redundant either for growth or development, have been characterized in Dictyostelium. We report here the identification and characterization of a fifth non-redundant GEF, RasGEFM.

Results

RasGEFM is a multi-domain protein containing six poly-proline stretches, a DEP, RasGEFN and RasGEF catalytic domain. The rasGEFM gene is differentially expressed during growth and development. Inactivation of the gene results in cells that form small, flat aggregates and fail to develop further. Expression of genes required for aggregation is delayed. Chemotaxis towards cAMP is impaired in the mutant, due to inability to inhibit lateral pseudopods. Endogenous cAMP accumulates during early development to a much lower extent than in wild type cells. Adenylyl cyclase activation in response to cAMP pulses is strongly reduced, by contrast guanylyl cyclase is stimulated to higher levels than in the wild type. The actin polymerization response to cAMP is also altered in the mutant. Cyclic AMP pulsing for several hours partially rescues the mutant. In vitro experiments suggest that RasGEFM acts downstream of the cAMP receptor but upstream of the G protein.

Conclusion

The data indicate that RasGEFM is involved in the establishment of the cAMP relay system. We propose that RasGEFM is a component of a Ras regulated pathway, which integrate signals acting as positive regulator for adenylyl cyclase and negative regulator for guanylyl cyclase. Altered guanylyl cyclase, combined with defective regulation of actin polymerization, results in altered chemotaxis.
Common themes and cell type specific variations of higher order chromatin arrangements in the mouse
Authors: Mayer Robert , Brero Alessandro , von Hase Johann , Schroeder Timm , Cremer Thomas , Dietzel Steffen
Published: December 2005

Background

Similarities as well as differences in higher order chromatin arrangements of human cell types were previously reported. For an evolutionary comparison, we now studied the arrangements of chromosome territories and centromere regions in six mouse cell types (lymphocytes, embryonic stem cells, macrophages, fibroblasts, myoblasts and myotubes) with fluorescence in situ hybridization and confocal laser scanning microscopy. Both species evolved pronounced differences in karyotypes after their last common ancestors lived about 87 million years ago and thus seem particularly suited to elucidate common and cell type specific themes of higher order chromatin arrangements in mammals.

Results

All mouse cell types showed non-random correlations of radial chromosome territory positions with gene density as well as with chromosome size. The distribution of chromosome territories and pericentromeric heterochromatin changed during differentiation, leading to distinct cell type specific distribution patterns. We exclude a strict dependence of these differences on nuclear shape. Positional differences in mouse cell nuclei were less pronounced compared to human cell nuclei in agreement with smaller differences in chromosome size and gene density. Notably, the position of chromosome territories relative to each other was very variable.

Conclusion

Chromosome territory arrangements according to chromosome size and gene density provide common, evolutionary conserved themes in both, human and mouse cell types. Our findings are incompatible with a previously reported model of parental genome separation.
Molecular dating of caprines using ancient DNA sequences of Myotragus balearicus, an extinct endemic Balearic mammal
Authors: Lalueza-Fox Carles , Castresana Jose , Sampietro Lourdes , Marquès-Bonet Tomàs , Alcover Josep Antoni , Bertranpetit Jaume
Published: December 2005

Background

Myotragus balearicus was an endemic bovid from the Balearic Islands (Western Mediterranean) that became extinct around 6,000-4,000 years ago. The Myotragus evolutionary lineage became isolated in the islands most probably at the end of the Messinian crisis, when the desiccation of the Mediterranean ended, in a geological date established at 5.35 Mya. Thus, the sequences of Myotragus could be very valuable for calibrating the mammalian mitochondrial DNA clock and, in particular, the tree of the Caprinae subfamily, to which Myotragus belongs.

Results

We have retrieved the complete mitochondrial cytochrome b gene (1,143 base pairs), plus fragments of the mitochondrial 12S gene and the nuclear 28S rDNA multi-copy gene from a well preserved Myotragus subfossil bone. The best resolved phylogenetic trees, obtained with the cytochrome b gene, placed Myotragus in a position basal to the Ovis group. Using the calibration provided by the isolation of Balearic Islands, we calculated that the initial radiation of caprines can be dated at 6.2 ± 0.4 Mya. In addition, alpine and southern chamois, considered until recently the same species, split around 1.6 ± 0.3 Mya, indicating that the two chamois species have been separated much longer than previously thought.

Conclusion

Since there are almost no extant endemic mammals in Mediterranean islands, the sequence of the extinct Balearic endemic Myotragus has been crucial for allowing us to use the Messinian crisis calibration point for dating the caprines phylogenetic tree.
The odorant receptor repertoire of teleost fish
Authors: Alioto Tyler S , Ngai John
Published: December 2005

Background

Vertebrate odorant receptors comprise three types of G protein-coupled receptors: the OR, V1R and V2R receptors. The OR superfamily contains over 1,000 genes in some mammalian species, representing the largest gene superfamily in the mammalian genome.

Results

To facilitate an informed analysis of OR gene phylogeny, we identified the complete set of 143 OR genes in the zebrafish genome, as well as the OR repertoires in two pufferfish species, fugu (44 genes) and tetraodon (42 genes). Although the genomes analyzed here contain fewer genes than in mammalian species, the teleost OR genes can be grouped into a larger number of major clades, representing greater overall OR diversity in the fish.

Conclusion

Based on the phylogeny of fish and mammalian repertoires, we propose a model for OR gene evolution in which different ancestral OR genes or gene families were selectively lost or expanded in different vertebrate lineages. In addition, our calculations of the ratios of non-synonymous to synonymous codon substitutions among more recently expanding OR subgroups in zebrafish implicate residues that may be involved in odorant binding.