bluuebunny/crossref_metadata_2025 huggingface dataset:
Men, Women, Job Sprawl, and Journey to Work in the Philadelphia Region
Authors: Weinberger Rachel
Published: March 2007

The observation that increasing dispersion of employment opportunities leads to decreased travel times is reflective of a short-term phenomenon. Census-reported journey-to-work travel time is examined for the greater Philadelphia region, showing that more people are commuting by automobile, a mode usually associated with shorter journey times, but are reporting longer trip times. The finding is counterintuitive as it coincides with a period when new jobs were established in outlying areas and the region experienced a net loss in jobs. The study concludes that as job opportunities disperse into lower density areas, Philadelphia’s existing high-capacity systems are underutilized, and transportation systems throughout the region that were designed for relatively low demand are becoming overwhelmed in time. The net effect is a breakdown of both the urban mass transit systems and the suburban and rural highway networks, the latter because of overuse and the former because of underuse.
An analysis of the variables predicting instant messenger use
Authors: Donghun Chung  , Chang Soo Nam
Published: March 2007

This article focuses on which variables predict instant messenger (IM) use. A model was tested with a sample of 329 undergraduate participants. Results indicated a strong link between internet self-efficacy and perceived usefulness of IM. Subsequently, one's attitude toward using IM was impacted by the perceived usefulness of IM. Also, a peer groups' subjective norm about IM accurately predicted their intention to use IM. However, intention did not predict IM use for users, and attitude toward using IM did not predict intention to use IM for either group. Finally, the data were judged to be inconsistent with the model.
Internet privacy and institutional trust
Authors: Turow Joseph , Hennessy Michael
Published: March 2007

What does the US public believe about the credibility of institutional actors when it comes to protecting information privacy online? Drawing on perspectives of environmental risk, this article addresses the question through a nationally representative telephone survey of 1200 adults who go online at home. A key result is that a substantial percentage of internet users believes that major corporate or government institutions will both help them to protect information privacy and take that privacy away by disclosing information to other parties without permission. This finding and others raise questions about the dynamics of risk-perception and institutional trust on the web.
Read at your own risk
Authors: Baruh Lemi
Published: March 2007

This article discusses how interactive media threaten informational privacy, especially in a legal environment that fails to protect individuals' right to receive and use content without being scrutinized by private and government institutions.The article observes that as information about media consumption habits make up an increasingly large share of the stock of data that institutions can use in order to make inferences about individuals, it becomes increasingly more difficult for individuals to determine which types of behaviors would cause them to be assigned to a high-risk category. In the light of this observation, the article concludes by proposing that in order to address the uncertainty that individuals face in trying to figure out how institutions use personal information to categorize them into different risk groups, a privacy protection scheme that increases the accountability of these automated and manual interpretation processes is needed.
Digital citizenship among ethnic minority youths in the Netherlands and Flanders
Authors: D'Haenens Leen , Koeman Joyce , Saeys Frieda
Published: March 2007

This article deals with ICT availability among ethnic minority groups in the Netherlands and Flanders. The rapid spread of ICT applications has affected various aspects of digital citizenship. The study results suggest that the world of ethnic minority youths in the Netherlands and Flanders, as with other western countries, is being digitized gradually. This is an irreversible evolution with tangible effects in new trends in communication and consumption. Ethnic minority youths orient themselves to the country where they live (bridging between cultures) as well as to their parents' country of origin (bonding of social capital). This article examines whether differences in information and communication technology access and use can be explained by culture-specific characteristics such as ethnocultural position, religion and language proficiency, apart from the usual sociodemographic characteristics (age, sex and socio-economic status). Examining the online activities of ethnic minority
Impact of cytogenetics on outcome of matched unrelated donor hematopoietic stem cell transplantation for acute myeloid leukemia in first or second complete remission
Authors: Tallman Martin S. , Dewald Gordon W. , Gandham Sharavi , Logan Brent R. , Keating Armand , Lazarus Hillard M. , Litzow Mark R. , Mehta Jayesh , Pedersen Tanya , Pérez Waleska S. , Rowe Jacob M. , Wetzler Meir , Weisdorf Daniel J.
Published: March 2007

We compared the treatment-related mortality, relapse rate, disease-free survival (DFS), and overall survival (OS) by cytogenetic risk group of 261 patients with acute myeloid leukemia in first complete remission (CR1) and 299 patients in CR2 in undergoing matched unrelated donor hematopoietic stem cell transplantation (HSCT). For patients in first CR, the DFS and OS at 5 years were similar for the favorable, intermediate, and unfavorable risk groups at 29% (95% confidence interval [CI], 8%-56%) and 30% (22%-38%); 27% (19%-39%) and 29% (8%-56%); and 30% (95% CI, 22%-38%) and 30% (95% CI, 20%-41%), respectively. For patients in second CR, the DFS and OS at 5 years were 42% (95% CI, 33%-52%) and 35% (95% CI, 28%-43%); 38% (95% CI, 23%-54%) and 45% (95% CI, 35%-55%); and 37% (95% CI, 30%-45%) and 36% (95% CI, 21%-53%), respectively. Cytogenetics had little influence on the overall outcome for patients in first CR. In second CR, outcome was modestly, but not significantly, better for patients with favorable cytogenetics. The graft-versus-leukemia effect appeared effective, even in patients with unfavorable cytogenetics. However, treatment-related mortality was high. Matched unrelated donor HSCT should be considered for all patients with unfavorable cytogenetics who lack a suitable HLA-matched sibling donor.
Distinct roles of VEGFR-1 and VEGFR-2 in the aberrant hematopoiesis associated with elevated levels of VEGF
Authors: Huang Yuhui , Chen Xiaolan , Dikov Mikhail M. , Novitskiy Sergey V. , Mosse Claudio A. , Yang Li , Carbone David P.
Published: March 2007

Vascular endothelial growth factor (VEGF), a major factor in tumor-host interactions, plays a critical role in the aberrant hematopoiesis observed in cancer-bearing hosts. To dissect the roles of VEGF receptor (VEGFR)-1 and VEGFR-2 in cancer-associated hematopoiesis in vivo, we selectively stimulated VEGFR-1 and VEGFR-2 by continuous infusion of receptor-specific ligands or selective blockade with VEGF receptor-specific antibodies in mice infused with recombinant VEGF at levels observed in tumor-bearing animals. We found that the effect of VEGF on the accumulation of Gr1+CD11b+ cells is mediated by VEGFR-2, but that the 2 receptors have opposite effects on lymphocyte development. Pathophysiologic levels of VEGF strongly inhibit T-cell development via VEGFR-2, whereas VEGFR-1 signaling decreases this inhibition. VEGFR-1, and not VEGFR-2, signaling is responsible for the observed increase of splenic B cells. Both receptors are capable of inhibiting dendritic cell function. These data suggest that most of observed aberrant hematopoiesis caused by excess tumor-derived VEGF is mediated by VEGFR-2, and VEGFR-1 alone has very limited independent effects but clearly both positively and negatively modulates the effects of VEGFR-2. Our findings suggest that selective blockade of VEGFR-2 rather than of both receptors may optimally overcome the adverse hematologic consequences of elevated VEGF levels found in malignancy.
Antibody-drug conjugates targeted to CD79 for the treatment of non-Hodgkin lymphoma
Authors: Polson Andrew G. , Yu Shang-Fan , Elkins Kristi , Zheng Bing , Clark Suzanna , Ingle Gladys S. , Slaga Dionysos S. , Giere Lynne , Du Changchun , Tan Christine , Hongo Jo-Anne , Gogineni Alvin , Cole Mary J. , Vandlen Richard , Stephan Jean-Philippe , Young Judy , Chang Wesley , Scales Suzie J. , Ross Sarajane , Eaton Dan , Ebens Allen
Published: March 2007

Targeting cytotoxic drugs to cancer cells using antibody–drug conjugates (ADCs), particularly those with stable linkers between the drug and the antibody, could be an effective cancer treatment with low toxicity. However, for stable-linker ADCs to be effective, they must be internalized and degraded, limiting potential targets to surface antigens that are trafficked to lysosomes. CD79a and CD79b comprise the hetrodimeric signaling component of the B-cell receptor, and are attractive targets for the use of ADCs because they are B-cell–specific, expressed in non-Hodgkin lymphomas (NHL), and are trafficked to a lysosomal-like compartment as part of antigen presentation. We show here that the stable-linker ADCs anti-CD79b-MCC-DM1 and anti-CD79b-MC-MMAF are capable of target-dependent killing of nonHodgkin lymphoma cell lines in vitro. Further, these 2 ADCs are equally effective as low doses in xenograft models of follicular, mantle cell, and Burkitt lymphomas, even though several of these cell lines express relatively low levels of CD79b in vivo. In addition, we demonstrate that anti-CD79b ADCs were more effective than anti-CD79a ADCs and that, as hypothesized, anti-CD79b antibodies downregulated surface B-cell receptor and were trafficked to the lysosomal-like major histocompatibility complex class II–positive compartment MIIC. These results suggest that anti-CD79b-MCC-DM1 and anti-CD79b-MC-MMAF are promising therapeutics for the treatment of NHL.
Different STAT-3 and STAT-5 phosphorylation discriminates among Ph-negative chronic myeloproliferative diseases and is independent of the V617F JAK-2 mutation
Authors: Teofili Luciana , Martini Maurizio , Cenci Tonia , Petrucci Giovanna , Torti Lorenza , Storti Sergio , Guidi Francesco , Leone Giuseppe , Larocca Luigi Maria
Published: March 2007

The V617F JAK2 mutation reported in Ph-negative myeloproliferative diseases (MPDs) induces the constitutive activation of JAK2, which produces an increased phosphorylation of signal transducer activator of transcription (STAT). In this study, we have analyzed a series of 114 patients (54 with polycythemia vera [PV], 44 with essential thrombocythemia [ET], 12 with idiopathic myelofibrosis [IM], and 4 with myelofibrosis secondary to MPD) for the expression pattern of phosphorylated STAT-3 and STAT-5 (pSTAT-3 and pSTAT-5, respectively) by immunostaining bone marrow biopsies. We found 3 specific patterns of pSTAT-3 and pSTAT-5 expression, significantly different from the normal staining pattern: uniformly increased pSTAT-3 and pSTAT-5 expression in PV, increased pSTAT-3 and reduced pSTAT-5 expression in ET, and uniformly reduced pSTAT-3 and pSTAT-5 expression in IM. A moderate increase of pSTAT-3 and pSTAT-5 expression was observed in secondary forms of erythrocytosis and thrombocytosis. In all evaluated MPDs, the pSTAT-5 and pSTAT-3 expression pattern was not influenced by the presence of V617F JAK2 mutation. These findings underline the importance of bone marrow histology in the differential diagnosis of Ph-negative MPD and support the hypothesis that V617F mutation simply contributes with other molecular defects in allowing the PV, ET, or IM phenotype to emerge.
BRAF V600E Maintains Proliferation, Transformation, and Tumorigenicity of BRAF-Mutant Papillary Thyroid Cancer Cells
Authors: Liu Dingxie , Liu Zhi , Condouris Stephen , Xing Mingzhao
Published: March 2007

Context: Although the BRAF V600E mutant can initiate the formation of papillary thyroid cancer (PTC), it is unclear whether it is required to maintain cell proliferation, transformation, and tumor growth of BRAF mutation-harboring PTC.

Objective: The aim of the study was to investigate whether BRAF V600E is required for the proliferation, transformation, and tumorigenicity of BRAF mutation-harboring PTC cells.

Design: We addressed this issue using BRAF small interference RNA (siRNA) to transfect stably several BRAF mutation-harboring PTC cell lines, isolated clones with stable suppression of BRAF, and assessed their ability to proliferate, transform, and grow xenograft tumors in nude mice.

Results: PTC cell proliferation and transformation were suppressed in specific BRAF siRNA clones, but not in control scrambled siRNA clones. Specifically, taking the advantage of stable BRAF knockdown, we were able to show continued suppression of PTC cell proliferation and transformation, or anchorage-independent colony formation in soft agar, after long-term culture. Moreover, we also demonstrated that in vivo tumorigenicity and growth of tumors from the specific BRAF siRNA cell clones in nude mice were suppressed compared with control clones.

Conclusions: BRAF V600E is not only an initiator of PTC as demonstrated previously but is also a maintainer of proliferation, transformation, and tumorigenicity of PTC cells harboring BRAF mutation, and growth of tumors derived from such cells continues to depend on BRAF V600E. These results provide further support for potentially effective therapy targeted at BRAF for BRAF mutation-harboring PTC.
Interactions among Peroxisome Proliferator Activated Receptor-γ, Insulin Signaling Pathways, and Steroidogenic Acute Regulatory Protein in Human Ovarian Cells
Authors: Seto-Young Donna , Avtanski Dimiter , Strizhevsky Marina , Parikh Grishma , Patel Parini , Kaplun Julia , Holcomb Kevin , Rosenwaks Zev , Poretsky Leonid
Published: March 2007

Context and Objective: Peroxisome proliferator activated receptor-γ (PPAR-γ) agonists thiazolidinediones (TZDs) are thought to ameliorate hyperandrogenism in polycystic ovary syndrome by reducing hyperinsulinemia. However, TZDs also exhibit direct effects in the human ovary. We examined interactions among PPAR-γ, insulin signaling pathways, and steroidogenic acute regulatory (StAR) protein in human ovarian cells.

Materials and Methods: Mixed human ovarian tissue culture that contained granulosa, theca, and stromal cells, and a culture of purified granulosa cells obtained during in vitro fertilization, were established as previously described. Cells were cultured in the presence or absence of insulin, with or without 25 or 50 μm rosiglitazone or pioglitazone. Expression of PPAR-γ, insulin receptor, or insulin receptor substrate (IRS)-1 in both cell systems and of the StAR protein in granulosa cells was measured using immunoprecipitation and immunoblotting.

Results: Rosiglitazone stimulated expression of PPAR-γ, insulin receptor α- and β-subunits, and IRS-1 up to 168% (P < 0.05), 679% (P < 0.006), 290% (P < 0.037), and 323% (P < 0.01) of baseline, respectively. Pioglitazone stimulated expression of PPAR-γ, insulin receptor α- and β-subunits, and IRS-1 up to 222% (P < 0.01), 362% (P < 0.001), 402% (P < 0.029), and 492% (P < 0.03), respectively. Insulin alone stimulated expression of PPAR-γ, α-subunit and β-subunit of insulin receptor, and IRS-1 up to 174% (P < 0.001), 692% (P < 0.014), 275% (P < 0.024), and 431% (P < 0.01), respectively. In purified granulosa cell culture, rosiglitazone stimulated expression of StAR protein up to 540% (P < 0.007), and pioglitazone stimulated expression of StAR protein up to 670% (P < 0.007). Insulin alone stimulated expression of StAR protein up to 600% (P < 0.012).

Conclusions: Insulin and TZDs independently stimulate expression of PPAR-γ, insulin receptor, IRS-1, and StAR protein in human ovarian cells. Thus, PPAR-γ, insulin receptor with its signaling pathways, and StAR protein constitute a novel human ovarian regulatory system with complex interactions among its components.
The Calcium-Sensing Receptor Is a Target of Autoantibodies in Patients with Autoimmune Polyendocrine Syndrome Type 1
Authors: Gavalas Nikos G. , Kemp E. Helen , Krohn Kai J. E. , Brown Edward M. , Watson Philip F. , Weetman Anthony P.
Published: March 2007

Context: Autoimmune polyendocrine syndrome type 1 (APS1) is an autosomal recessive disorder caused by mutations in the autoimmune regulator gene. Hypoparathyroidism occurs in 80% of patients with APS1 and has been suggested to result from an autoimmune reaction against the calcium-sensing receptor (CaSR) on parathyroid cells. However, the detection of CaSR antibodies in APS1 remains controversial, with some studies disputing the relevance of the receptor as an autoantigen.

Objective: The aim of this study was to analyze a defined set of APS1 patient sera for the presence of CaSR antibodies using different assay systems.

Results: APS1 patients and individuals with other autoimmune disorders along with healthy subjects were tested for antibody binding to the CaSR. In an immunoprecipitation assay with the CaSR expressed in human embryonic kidney 293 cells, 12 of 14 (85.7%) APS1 and two of 28 (7.1%) Graves’ disease patients were considered positive for CaSR antibodies. The prevalence of receptor antibodies was significantly greater than that in the cohort of healthy individuals only in the APS1 patient group (P < 0.0001). In a flow cytometry assay, seven of 14 (50.0%) APS1 patient sera showed binding to the extracellular domain of the CaSR. The prevalence of receptor antibodies in the APS1 patient group was significantly greater than that in the group of healthy controls (P = 0.023). No CaSR antibodies could be detected in any patients or controls using a radiobinding assay.

Conclusion: The CaSR is an autoantigen in APS1, but detection of antibodies against the receptor appears to be influenced by the assay system used.
Age of Onset of Type 1 Diabetes in Children and Carotid Intima Medial Thickness
Authors: Dalla Pozza Robert , Bechtold Susanne , Bonfig Walter , Putzker Stefanie , Kozlik-Feldmann Rainer , Netz Heinrich , Schwarz Hans-Peter
Published: March 2007

Context: Cardiovascular disease due to atherosclerosis is a major cause of morbidity and mortality in adult diabetic patients. In children, signs of subclinical atherosclerosis such as increased intima-media thickness (IMT) of the common carotid arteries have been detected in several studies. However, concerns may arise about the different analyzing methods used because measurements in patients and controls differ significantly.

Patients and Methods: We studied 208 children [150 patients with diabetes mellitus type 1, mean age (±sd) 13.9 ± 2.8 yr, 66 males, mean glycosylated hemoglobin (±sd) 7.8 ± 1.4%, and 58 healthy controls, mean age (±sd) 14.1 ± 3.1 yr, 32 males] and used normal IMT values published recently for comparison of the results.

Results: Of 150 patients, 37 had an increased IMT [mean IMT (±sd) 1.6 ± 0.6], whereas healthy controls had nearly normal IMT values [mean IMT (±sd) 0.3 ± 0.1; P < 0.001]. Age at onset of diabetes, mean daily insulin dosage, systolic blood pressure, and total cholesterol level were significantly related to IMT in a multilinear regression model. A total of 25 diabetic patients were hypertensive and had a significantly increased IMT (mean IMT 0.475 ± 0.03 mm) compared to the remaining patients (mean IMT 0.459 ± 0.02 mm; P < 0.05).

Conclusions: The IMT measurement detected subclinical atherosclerosis in a large cohort of diabetic children. Systolic blood pressure, total cholesterol level, insulin dosage, and age at onset of the disease were significantly related to the IMT. Longitudinal measurements may help to identify patients at special risk for atherosclerotic changes and cardiovascular disease.
Mechanisms of the HRSL3 tumor suppressor function in ovarian carcinoma cells
Authors: Nazarenko Irina , Schäfer Reinhold , Sers Christine
Published: March 2007

HRSL3 (also known as H-REV107-1) belongs to a class II tumor suppressor gene family and is downregulated in several human tumors including ovarian carcinomas. To unravel the mechanism of HRSL3 tumor suppressor action, we performed a yeast two-hybrid screen and identified the α-isoform of the regulatory subunit A of protein phosphatase 2A (PR65α) as a new interaction partner of HRSL3. Interaction between HRSL3 and PR65α was confirmed in vitro and by co-immunoprecipitation in mammalian cells. We demonstrate that HRSL3 binds to the endogenous PR65α, thereby partially sequestering the catalytic subunit PR36 from the PR65 protein complex, and inhibiting PP2A catalytic activity. Furthermore, binding of HRSL3 to PR65 induces apoptosis in ovarian carcinoma cells in a caspase-dependent manner. Using several mutant HRSL3 constructs, we identified the N-terminal proline-rich region within the HRSL3 protein as the domain that is relevant for both binding of PR65α and induction of programmed cell death. This suggests that the negative impact of HRSL3 onto PP2A activity is important for the HRSL3 pro-apoptotic function and indicates a role of PP2A in survival of human ovarian carcinomas. The analysis of distinct PP2A target molecules revealed PKCζ as being involved in HRSL3 action. These data implicate HRSL3 as a signaling regulatory molecule, which is functionally involved in the oncogenic network mediating growth and survival of ovarian cancer cells.
Comparative roles of Twist-1 and Id1 in transcriptional regulation by BMP signaling
Authors: Hayashi Masanori , Nimura Keisuke , Kashiwagi Katsunobu , Harada Taku , Takaoka Kunio , Kato Hiroyuki , Tamai Katsuto , Kaneda Yasufumi
Published: March 2007

Basic helix-loop-helix (bHLH) transcription factors are known as key regulators for mesenchymal differentiation. The present study showed that overexpression of Twist-1, a bHLH transcription factor, suppresses bone morphogenetic protein (BMP)-induced osteoblast differentiation, and downregulation of endogenous Twist-1 enhances BMP signaling. Maximal inhibition of BMP signaling was observed when Twist-1 was bound to E47, which markedly enhanced the stability of Twist-1. Co-immunoprecipitation assays revealed that Twist-1 formed a complex with Smad4 and histone deacetylase (HDAC) 1 in MC3T3-E1 cells stably expressing Twist-1. With trichostatin, an HDAC inhibitor, osteogenic factors such as alkaline phosphatase, Runx2 and osteopontin increased. Those results suggested that Twist-1 inhibited BMP signaling by recruiting HDAC1 to Smad4.

Furthermore, the inhibitory effects of Twist-1 on BMP signaling were overcome by Id1 through induction of Twist-1 degradation. These findings suggest that Twist-1 can act as an inhibitor of BMP signaling, and Id1 can regulate BMP signaling through a positive feedback loop repressing Twist-1 function. These two molecules may therefore regulate differentiation of mesenchymal cells into progeny such as osteoblasts by controlling BMP signaling.
Mechanism and biological role of profilin-Srv2/CAP interaction
Authors: Bertling Enni , Quintero-Monzon Omar , Mattila Pieta K. , Goode Bruce L. , Lappalainen Pekka
Published: March 2007

Profilin and cyclase-associated protein (CAP, known in yeast as Srv2) are ubiquitous and abundant actin monomer-binding proteins. Profilin catalyses the nucleotide exchange on actin monomers and promotes their addition to filament barbed ends. Srv2/CAP recycles newly depolymerized actin monomers from ADF/cofilin for subsequent rounds of polymerization. Srv2/CAP also harbors two proline-rich motifs and has been suggested to interact with profilin. However, the mechanism and biological role of the possible profilin-Srv2/CAP interaction has not been investigated. Here, we show that Saccharomyces cerevisiae Srv2 and profilin interact directly (KD ∼1.3 μM) and demonstrate that a specific proline-rich motif in Srv2 mediates this interaction in vitro and in vivo. ADP-actin monomers and profilin do not interfere with each other's binding to Srv2, suggesting that these three proteins can form a ternary complex. Genetic and cell biological analyses on an Srv2 allele (srv2-201) defective in binding profilin reveals that a direct interaction with profilin is not essential for Srv2 cellular function. However, srv2-201 causes a moderate increase in cell size and partially suppresses the cell growth and actin organization defects of an actin binding mutant profilin (pfy1-4). Together these data suggest that Srv2 is an important physiological interaction partner of profilin.
Hsp90 is required to localise cyclin B and Msps/ch-TOG to the mitotic spindle inDrosophilaand humans
Authors: Basto Renata , Gergely Fanni , Draviam Viji M. , Ohkura Hiroyuki , Liley Kathryn , Raff Jordan W.
Published: March 2007

During mitosis, cyclin B is extremely dynamic and although it is concentrated at the centrosomes and spindle microtubules (MTs) in organisms ranging from yeast to humans, the mechanisms that determine its localisation are poorly understood. To understand how cyclin B is targeted to different locations in the cell we have isolated proteins that interact with cyclin B in Drosophila embryo extracts. Here we show that cyclin B interacts with the molecular chaperone Hsp90 and with the MT-associated protein (MAP) Mini spindles (Msps; the Drosophila orthologue of XMAP215/ch-TOG). Both Hsp90 and Msps are concentrated at centrosomes and spindles, and we show that Hsp90, but not Msps, is required for the efficient localisation of cyclin B to these structures. We find that, unlike what happens with other cell cycle proteins, Hsp90 is not required to stabilise cyclin B or Msps during mitosis. Thus, we propose that Hsp90 plays a novel role in regulating the localisation of cyclin B and Msps during mitosis.
Cell adhesion to fibrillin-1: identification of an Arg-Gly-Asp-dependent synergy region and a heparin-binding site that regulates focal adhesion formation
Authors: Bax Daniel V. , Mahalingam Yashithra , Cain Stuart , Mellody Kieran , Freeman Lyle , Younger Kerri , Shuttleworth C. Adrian , Humphries Martin J. , Couchman John R. , Kielty Cay M.
Published: March 2007

We have defined the molecular basis of cell adhesion to fibrillin-1, the major structural component of extracellular microfibrils that are associated with elastic fibres. Using human dermal fibroblasts, and recombinant domain swap fragments containing the Arg-Gly-Asp motif, we have demonstrated a requirement for upstream domains for integrin-α5β1-mediated cell adhesion and migration. An adjacent heparin-binding site, which supports focal adhesion formation, was mapped to the fibrillin-1 TB5 motif. Site-directed mutagenesis revealed two arginine residues that are crucial for heparin binding, and confirmed their role in focal adhesion formation. These integrin and syndecan adhesion motifs juxtaposed on fibrillin-1 are evolutionarily conserved and reminiscent of similar functional elements on fibronectin, highlighting their crucial functional importance.
Signaling by ALK5 mediates TGF-β-induced ET-1 expression in endothelial cells: a role for migration and proliferation
Authors: Castañares Cristina , Redondo-Horcajo Mariano , Magán-Marchal Noemi , ten Dijke Peter , Lamas Santiago , Rodríguez-Pascual Fernando
Published: March 2007

Endothelin-1 (ET-1) is a potent endothelial-derived 21-amino-acid vasoconstrictor peptide and its expression is potently regulated by the cytokine transforming growth factor-β (TGF-β). Most cell types contain a TGF-β type I receptor form known as activin receptor-like kinase 5 (ALK5). However, endothelial cells coexpress an additional type I receptor named ALK1. These forms do not constitute redundant receptors with the same function, but they activate different Smad-mediated expression programmes leading to specific endothelial phenotypes. The aim of our study was to characterize the TGF-β-induced pathway leading to ET-1 expression in endothelial cells and the contribution of the TGF-β-mediated enhancement of ET-1 to the regulation of the endothelial cell migration and proliferation capacity. Our experiments indicate that TGF-β induces ET-1 expression preferentially through the ALK5/Smad3 pathway. Specific ALK5 inhibition totally blocked the anti-angiogenic effect of TGF-β. Antagonism of ET receptors partially reverted the effect of TGF-β, indicating that a significant portion of the anti-migratory and anti-proliferative actions of this cytokine is mediated by ET-1 acting in an autocrine manner on endothelial cells.
Organizing Pneumonia and Pulmonary Eosinophilic Infiltration Associated with Daptomycin
Authors: Cobb Elizabeth , Kimbrough Robert C , Nugent Kenneth M , Phy Michael P
Published: March 2007

Objective:

To report a case of organizing pneumonia with pulmonary eosinophilic infiltrates in a patient receiving daptomycin.

Case Summary:

An 84-year-old man developed bilateral, irregularly shaped nodules and infiltrates in the mid and peripheral lung and multiple mediastinal lymph nodes following treatment with intravenous daptomycin for infection of his left knee prosthesis. His other symptoms included decreased appetite, weight loss (6.8 kg over 4–6 wk), malaise, and generalized weakness after 4 weeks of daptomycin therapy. Transthoracic needle biopsy revealed organizing pneumonia with scattered eosinophils. His symptoms and results of computed tomography (CT) scan improved in the month following discontinuation of daptomycin. The Naranjo probability scale indicated a probable reaction to daptomycin.

Discussion:

Pulmonary reactions have been reported with numerous drugs and have a wide range of clinical and radiographic presentations. Clinical trials have shown that daptomycin is well tolerated and has an adverse effect profile similar to that of vancomycin and the semisynthetic penicillins. This case report suggests that chronic use of daptomycin caused organizing pneumonia with eosinophilic infiltrates in a patient treated for an infected knee prosthesis. A definite mechanism for this reaction is not known. We speculate that the chronic administration of daptomycin allowed drug accumulation in surfactant in the alveolar spaces. This may result in higher concentrations of drug near the alveolar epithelial surface, which could injure the epithelium, resulting in organizing pneumonia.

Conclusions:

Development of new pulmonary infiltrates in patients treated with chronic daptomycin therapy should alert healthcare workers to this potential association.
Quetiapine and Breast Feeding
Authors: Rampono Jonathan , Kristensen Judith H , Ilett Kenneth F , Hackett L Peter , Kohan Rolland
Published: March 2007

Objective:

To quantify the relative infant dose of quetiapine during breast feeding, describe the milk:plasma (M:P) ratio, and determine the well-being of the exposed infant.

Case Summary:

A 26-year-old mother and her 3-month-old son were studied over a 24 hour quetiapine dose interval at steady-state. Quetiapine concentrations were quantified by high-performance liquid chromatography. Infant exposure was calculated as the concentration in milk multiplied by an estimated milk production of 0.15 L/kg/day and normalized to the weight-adjusted maternal dose. The average concentration in milk was 41 μg/L, the M:P ratio (measured using average concentrations in the elimination phase) was 0.29, and the relative infant dose was 0.09% of the maternal weight-adjusted dose (7273 μg/kg/day). The infant plasma concentration of 1.4 μg/L was some 6% of the corresponding maternal plasma concentration. No adverse effects were noted in the infant.

Discussion:

Our findings of an infant exposure to quetiapine of less than 0.1% of the maternal dose and a lack of adverse effects confirm and extend the findings of 2 previous studies.

Conclusions:

Although limited, the data shown here support the prescription of quetiapine to a breast-feeding mother following a careful individual risk/benefit analysis. We suggest regular monitoring of infant progress and occasional measurement of quetiapine in the infant's plasma.
Interstitial Nephritis Secondary to Bevacizumab Treatment in Metastatic Leiomyosarcoma
Authors: Barakat Ruchdi K , Singh Navneet , Lal Rajiv , Verani Regina R , Finkel Kevin W , Foringer John R
Published: March 2007

Objective:

To report a case of interstitial nephritis associated with the administration of bevacizumab.

Case Summary:

A 26-year-old man diagnosed with metastatic rectal leiomyosarcoma was treated with intravenous bevacizumab 5 mg/kg and received a total of 3 doses at 2 week intervals. His creatinine had increased from 1.0 mg/dL at baseline to 1.6 mg/dL after 2 doses of bevacizumab and to 4.7 mg/dL after the third dose, prompting admission. Acute renal failure was diagnosed, and hemodialysis was initiated. A renal biopsy revealed interstitial nephritis. Renal failure resolved with cessation of the drug, and the patient did not require further hemodialysis.

Discussion:

Bevacizumab is a recombinant humanized monoclonal immunoglobulin G antibody to vascular endothelial growth factor. Bevacizumab has shown efficacy in treatment of patients with renal cell carcinoma and colorectal cancer and has been approved by the Food and Drug Administration as a first-line treatment for metastatic colorectal cancer. Our patient had no other confounding factors that might have caused renal failure. The presence of primary glomerular disease was excluded by biopsy. According to the Naranjo probability scale, bevacizumab was the probable cause of acute renal failure in this patient.

Conclusions:

Bevacizumab can cause acute renal failure by inducing interstitial nephritis. Renal function should be monitored during bevacizumab therapy.
Hospital Policies for Treatment of Acute Decompensated Heart Failure
Authors: Vats Vikrant , Didomenico Robert J , Wojtynek Jeffrey E , Theobald John C , Schumock Glen T
Published: March 2007

Background:

It is unclear to what extent hospitals use guidelines or protocols in treating acute decompensated heart failure (ADHF) and whether nesiritide is included in these guidelines or protocols.

Objective:

To assess the formulary status of currently used drugs, therapeutic guidelines, and perceptions about the appropriateness of treatment of ADHF in community hospitals.

Methods:

A Web-based survey of pharmacy directors at community hospitals that were part of a national group purchasing organization was conducted.

Results:

One hundred seven hospitals participated in the survey (response rate 47.1%). Diuretics such as furosemide and bumetanide were more commonly included (100% and 94.4%, respectively) on hospital formularies than was torsemide (69.2%). Dopamine and dobutamine were more common (94.4% each) on the formulary than was milrinone (68.2%), Nitroprusside and nitroglycerin were listed on the formularies of more than 90% of participating institutions, while nesiritide was listed on the formularies in only 48.6% of hospitals and was placed on restricted status in 36.4% of hospitals. Guidelines for care of patients with ADHF were used in the emergency department (ED), inpatient care units, and outpatient clinics in 18.6%, 43.0%, and 8.5% of hospitals, respectively. Overall, ADHF care, including general treatment as well as specific use of nesiritide, was deemed appropriate in the majority of patients, but nearly twice as many respondents perceived the management of ADHF and specific use of nesiritide as inappropriate in the ED compared with inpatient treatment. Only 41.1% of the respondents reported following Braunwald recommendations for the use of nesiritide.

Conclusions:

A sizable percentage of responding community hospitals do not have guidelines for treatment of ADHF despite the existence of such guidelines in the literature. There are opportunities for improvement in the general treatment of ADHF as well as for the use of nesiritide in ADHF, especially in the ED or observation unit versus inpatient units.
Educational psychology and the effectiveness of inclusive education/mainstreaming
Authors: Lindsay Geoff
Published: March 2007

Background. Inclusive education/mainstreaming is a key policy objective for the education of children and young people with special educational needs (SEN) and disabilities.

Aims. This paper reviews the literature on the effectiveness of inclusive education/mainstreaming. The focus is on evidence for effects in terms of child outcomes with examination also of evidence on processes that support effectiveness.

Samples. The review covers a range of SEN and children from pre‐school to the end of compulsory education.

Method. Following an historical review of evidence on inclusive education/mainstreaming, the core of the paper is a detailed examination of all the papers published in eight journals from the field of special education published 2001‐2005 (N=1373): Journal of Special Education, Exceptional Children, Learning Disabilities Research and Practice, Journal of Learning Disabilities, Remedial and Special Education, British Journal of Special Education, European Journal of Special Needs Education, and the International Journal of Inclusive Education. The derived categories were: comparative studies of outcomes: other outcome studies; non‐comparative qualitative studies including non‐experimental case studies; teacher practice and development; teacher attitudes; and the use of teaching assistants.

Results. Only 14 papers (1.0%) were identified as comparative outcome studies of children with some form of SEN. Measures used varied but included social as well as educational outcomes. Other papers included qualitative studies of inclusive practice, some of which used a non‐comparative case study design while others were based on respondent's judgements, or explored process factors including teacher attitudes and the use of teaching assistants.

Conclusions. Inclusive education/mainstreaming has been promoted on two bases: the rights of children to be included in mainstream education and the proposition that inclusive education is more effective. This review focuses on the latter issue. The evidence from this review does not provide a clear endorsement for the positive effects of inclusion. There is a lack of evidence from appropriate studies and, where evidence does exist, the balance was only marginally positive. It is argued that the policy has been driven by a concern for children's rights. The important task now is to research more thoroughly the mediators and moderators that support the optimal education for children with SEN and disabilities and, as a consequence, develop an evidence‐based approach to these children's education.
Lhx6Activity Is Required for the Normal Migration and Specification of Cortical Interneuron Subtypes
Authors: Liodis Petros , Denaxa Myrto , Grigoriou Marirena , Akufo-Addo Cynthia , Yanagawa Yuchio , Pachnis Vassilis
Published: March 2007

The cerebral cortex contains two main neuronal cell populations, the excitatory glutamatergic (pyramidal) neurons and the inhibitory interneurons, which synthesize GABA and constitute 20–30% of all cortical neurons. In contrast to the mostly homogeneous population of projection neurons, cortical interneurons are characterized by remarkable morphological, molecular, and functional diversity. Among the markers that have been used to classify cortical interneurons are the calcium-binding proteins parvalbumin and calretinin and the neuropeptide somatostatin, which in rodents identify mostly nonoverlapping interneuron subpopulations. Pyramidal neurons are born during embryogenesis in the ventricular zone of the dorsal telencephalon, whereas cortical interneurons are generated in the subpallium and reach the cortex by tangential migration. On completion of tangential migration, cortical interneurons switch to a radial mode of migration and enter the cortical plate. Although the mechanisms that control the generation of interneuron diversity are currently unknown, it has been proposed that their site of origin in the ventral forebrain determines their specification into defined neurochemical subgroups. Here, we show thatLhx6, a gene induced in the medial ganglionic eminence and maintained in parvalbumin- and somatostatin-positive interneurons, is required for the specification of these neuronal subtypes in the neocortex and the hippocampus. We also show thatLhx6activity is required for the normal tangential and radial migration of GABAergic interneurons in the cortex.
5-Hydroxytryptamine Induces a Protein Kinase A/Mitogen-Activated Protein Kinase-Mediated and Macromolecular Synthesis-Dependent Late Phase of Long-Term Potentiation in the Amygdala
Authors: Huang Yan-You , Kandel Eric R.
Published: March 2007

The amygdala is a critical site for the acquisition of learned fear memory in mammals, and the formation and long-term maintenance of fear memories are thought to be associated with changes of synaptic strength in the amygdala. Here we report that serotonin (5-hydroxytryptamine; 5-HT), a modulatory neurotransmitter known to be linked to learned fearful and emotional behavior, has dual effects on excitatory synaptic transmission in the basolateral amygdala. There is an early depression of synaptic transmission lasting 30–50 min, mediated by 5-HT1A, and a late, long-lasting facilitation lasting >5 h in slice recordings, mediated by the 5-HT4receptor. 5-HT late phase long-term potentiation (L-LTP) is blocked by inhibitors of either protein kinase A (PKA) and/or mitogen-activated kinase (MAPK) and requires new protein synthesis and gene transcription. Moreover, the 5-HT-induced L-LTP in neurons of amygdala is blocked by the actin inhibitor cytochalasin D, suggesting that 5-HT stimulates a cytoskeletal rearrangement. These results show, for the first time, that 5-HT can produce long-lasting facilitation of synaptic transmission in the amygdala and provides evidence for the possible synaptic role of 5-HT in long-term memory for learned fear.
Thyroid Hormone Deficiency Affects Postnatal Spiking Activity and Expression of Ca2+and K+Channels in Rodent Inner Hair Cells
Authors: Brandt Niels , Kuhn Stephanie , Münkner Stefan , Braig Claudia , Winter Harald , Blin Nikolaus , Vonthein Reinhard , Knipper Marlies , Engel Jutta
Published: March 2007

Thyroid hormone (TH) is essential for the development of hearing. Lack of TH in a critical developmental period from embryonic day 17 to postnatal day 12 (P12) in rats and mice leads to morphological and functional deficits in the organ of Corti and the auditory pathway. We investigated the effects of TH on inner hair cells (IHCs) using patch-clamp recordings, capacitance measurements, and immunocytochemistry in hypothyroid rats and athyroidPax8−/−mice. Spontaneous and evoked Ca2+action potentials (APs) were present in control IHCs from P3–P11 rats and vanished in parallel with the expression of a rapidly activating Ca2+- and voltage-activated K+(BK) conductance. IHCs of hypothyroid rats and athyroidPax8−/−mice displayed APs until the end of the third postnatal week because of threefold elevated Ca2+currents and missing expression of BK currents. After the fourth postnatal week, some IHCs showed BK currents whereas adjacent IHCs did not, demonstrated by electrophysiology and immunocytochemistry. To test whether the prolonged spiking activity during TH deficiency may be transmitted at IHC synapses, capacitance measurements were performed in parallel to analysis of otoferlin expression, a protein thought to play an essential role in exocytosis of IHCs. Strikingly, otoferlin was absent from IHCs of hypothyroid rats but not ofPax8−/−mice, although both cell types showed exocytosis with an efficiency typical for immature IHCs. These results demonstrate for the first time a TH-dependent control of IHC spiking activity before the onset of hearing attributable to effects of TH on Ca2+and BK channels. Moreover, they question an indispensable role of otoferlin for exocytosis in IHCs.
Minocycline Reduces Microglial Activation and Improves Behavioral Deficits in a Transgenic Model of Cerebral Microvascular Amyloid
Authors: Fan Rong , Xu Feng , Previti Mary Lou , Davis Judianne , Grande Alicia M. , Robinson John K. , Van Nostrand William E.
Published: March 2007

Cerebral microvascular amyloid β protein (Aβ) deposition and associated neuroinflammation is increasingly recognized as an important component leading to cognitive impairment in Alzheimer's disease and related cerebral amyloid angiopathy disorders. Transgenic mice expressing the vasculotropic Dutch/Iowa (E693Q/D694N) mutant human Aβ precursor protein in brain (Tg-SwDI) accumulate abundant cerebral microvascular fibrillar amyloid deposits and exhibit robust neuroinflammation. In the present study, we investigated the effect of the anti-inflammatory drug minocycline on Aβ accumulation, neuroinflammation, and behavioral deficits in Tg-SwDI mice. Twelve-month-old mice were treated with saline or minocycline by intraperitoneal injection every other day for a total of 4 weeks. During the final week of treatment, the mice were tested for impaired learning and memory. Brains were then harvested for biochemical and immunohistochemical analysis. Minocycline treatment did not alter the cerebral deposition of Aβ or the restriction of fibrillar amyloid to the cerebral microvasculature. Similarly, minocycline-treated Tg-SwDI mice exhibited no change in the levels of total Aβ, the ratios of Aβ40 and Aβ42, or the amounts of soluble, insoluble, or oligomeric Aβ compared with the saline-treated control Tg-SwDI mice. In contrast, the numbers of activated microglia and levels of interleukin-6 were significantly reduced in minocycline-treated Tg-SwDI mice compared with saline-treated Tg-SwDI mice. In addition, there was a significant improvement in behavioral performance of the minocycline-treated Tg-SwDI mice. These finding suggest that anti-inflammatory treatment targeted for cerebral microvascular amyloid-induced microglial activation can improve cognitive deficits without altering the accumulation and distribution of Aβ.
A Mechanism Intrinsic to the Vesicle Fusion Machinery Determines Fast and Slow Transmitter Release at a Large CNS Synapse
Authors: Wölfel Markus , Lou Xuelin , Schneggenburger Ralf
Published: March 2007

Heterogeneity of release probabilitypbetween vesicles in the readily releasable pool (RRP) is expected to strongly influence the kinetics of depression at synapses, but the underlying mechanism(s) are not well understood. To test whether differences in the intrinsic Ca2+sensitivity of vesicle fusion might cause heterogeneity ofp, we made presynaptic Ca2+-uncaging measurements at the calyx of Held and analyzed the time course of transmitter release by EPSC deconvolution. Ca2+uncaging, which produced spatially homogeneous elevations of [Ca2+]i, evoked a fast and a slow component of release over a wide range of [Ca2+]i, showing that mechanism(s) intrinsic to the vesicle fusion machinery cause fast and slow transmitter release. Surprisingly, the number of vesicles released in the fast component increased with Ca2+-uncaging stimuli of larger amplitudes, a finding that was most obvious below ∼10 μm[Ca2+]iand that we call “submaximal release” of fast-releasable vesicles. During trains of action potential-like presynaptic depolarizations, submaximal release was also observed as an increase in the cumulative fast release at enhanced release probabilities. A model that assumes two separate subpools of RRP vesicles with different intrinsic Ca2+sensitivities predicted the observed Ca2+dependencies of fast and slow transmitter release but could not fully account for submaximal release. Thus, fast and slow transmitter release in response to prolonged [Ca2+]ielevations is caused by intrinsic differences between RRP vesicles, and an “a posteriori” reduction of the Ca2+sensitivity of vesicle fusion after the onset of the stimulus might cause submaximal release of fast-releasable vesicles and contribute to short-term synaptic depression.