bluuebunny/crossref_metadata_2025 huggingface dataset:
Ensemble Simulation of the Lightning Flash Variability in a 3D Cloud Model with Parameterizations of Cloud Electrification and Lightning Flashes
Authors: Pinty Jean-Pierre , Barthe Christelle
Published: January 2008

A series of ensemble simulations were performed to study the statistics of flash characteristics produced by an electrification and lightning scheme in the cloud-resolving model Méso-NH. Here, the electrical variability of two storms—one supercellular and one multicellular—results from a random triggering location of the flashes and from a branching algorithm that describes the flash path. The study shows that the electrical model is able to generate several estimates of the total flash number for an identical evolution of the dynamics and microphysics of each storm in the 120 ensemble members. The variability of the flash number spans over three standard deviations taken from the ensemble mean. The simulations produce regularly shaped distributions of flash internal parameters (i.e., number of segments and branching levels per flash). The ensemble simulation shows that the model is stable and self-regulatory as suggested by the limited overshoot on the maximum electric field time series. An application to the production of nitrogen oxides indicates that the two storms produce 200 ± 150 mol of NO per flash on average.
Accounting for Autocorrelation in Detecting Mean Shifts in Climate Data Series Using the Penalized Maximal t or F Test
Authors: Wang Xiaolan L.
Published: January 2008

This study proposes an empirical approach to account for lag-1 autocorrelation in detecting mean shifts in time series of white or red (first-order autoregressive) Gaussian noise using the penalized maximal t test or the penalized maximal F test. This empirical approach is embedded in a stepwise testing algorithm, so that the new algorithms can be used to detect single or multiple changepoints in a time series. The detection power of the new algorithms is analyzed through Monte Carlo simulations. It has been shown that the new algorithms work very well and fast in detecting single or multiple changepoints. Examples of their application to real climate data series (surface pressure and wind speed) are presented. An open-source software package (in R and FORTRAN) for implementing the algorithms, along with a user manual, has been developed and made available online free of charge.
Estimation of Global Ground Heat Flux
Authors: Bennett William B. , Wang Jingfeng , Bras Rafael L.
Published: January 2008

This study investigates the use of a previously published algorithm for estimating ground heat flux (GHF) at the global scale. The method is based on an analytical solution of the diffusion equation for heat transfer in a soil layer and has been shown to be effective at the point scale. The algorithm has several advantageous properties: 1) it only needs a single-level input of surface (skin) temperature, 2) the time-mean GHF can be derived directly from time-mean skin temperature, 3) it has reduced sensitivity to the variability in soil thermal properties and moisture, 4) it does not requires snow depth, and 5) it is computationally effective. A global map of the necessary thermal inertia parameter is derived using reanalysis data as a function of soil type. These parameter estimates are comparable to values obtained from in situ observations. The new global GHF estimates are generally consistent with the reanalysis GHF output simulated using two-layer soil hydrology models. The authors argue that the new algorithm is more robust and trustworthy in regions where they differ. The proposed algorithm offers potential benefits for direct assimilation of observations of surface temperature as well as GHF into the reanalysis models at various time scales.
The Collapse of the Bering Strait Ice Dam and the Abrupt Temperature Rise in the Beginning of the Holocene
Authors: Sandal Cathrine , Nof Doron
Published: January 2008

This paper focuses on the abrupt increase in the oceanic and atmospheric temperature in the Northern Hemisphere at the beginning of the Holocene, approximately 11 000 yr before the present. De Boer and Nof hypothesized that, at that time, the Bering Strait (BS) opened up abruptly because of the breakup of an ice dam (by rising sea levels). It is proposed further here that this sudden opening caused an abrupt increase in the mean temperature of the Northern Hemisphere. An analytical, coupled ocean–atmosphere model is applied to the North Atlantic in an attempt to quantify the temperature change resulting from the opening of the BS. Heat, salt, and mass are all conserved within a box in the North Atlantic. A convection condition allows water to enter the deep layer and the island rule relates the wind field to the mass fluxes.

The conventional approach that the meridional overturning cell (MOC) was not operating during the Younger Dryas because of an overwhelming freshwater flux is adopted here. Opening the BS in the early Holocene allowed these freshwater anomalies to be flushed out into the Pacific, reviving convection and the transport of heat northward. Restarting convection with an open BS increases mean oceanic and atmospheric temperature by 3° and 23°C, respectively. These values are comparable to those found in both the Centre Européen de Recherche et d’Enseignement des Géosciences de l’Environnement (CEREGE) alkenone and Greenland Ice Sheet Project 2 (GISP 2) ice core records. Of course, restarting convection increases the temperature even with a closed BS, but in the closed BS case the oceanic increase is slightly higher (4°C instead of 3°C), whereas the atmospheric is much lower (17.5°C instead of 23°C). This is because, by requiring a continuous sea level around the Americas, an open BS allows the wind field to limit the amount of Southern Ocean water that enters the South Atlantic. This controlled volume flux (8 Sv) is considerably smaller than that allowed into the Atlantic in the no-wind control closed BS case (17 Sv).
The Role of Antiendothelial Cell Antibodies in the Development and Follow-up of Coronary and Peripheral Arterial Diseases
Authors: Aslim Erdal , Hakki Akay Tankut , Bastürk Bilkay , Özkan Suleyman , Gültekin Bahadir , Özcobanoglu Salih , Sirvan Sale , Aslamaci Sait
Published: February 2008

Occlusive lesions in the arterial endothelium are often caused by formation of intimal hyperplasia and fibrinoid necrosis. The objective of this study was to investigate the association between antiendothelial cell antibodies (AECAs) and the development of coronary artery disease (CAD) and peripheral artery disease (PAD). In this study, 94 patients with CAD or PAD and 94 healthy volunteers serving as control subjects were examined. Frozen sections of human umbilical vein endothelial cells and primate smooth muscle cells were used to detect the presence of AECAs, which were found in 52 of 94 patients (55%) and in 15 of 94 controls (16%) ( P < .001). Endothelial structure tissue damage is a major factor in arterial diseases. In the present study, a statistically significant relationship was found between AECAs and the development of CAD and PAD. The presence of AECAs has been identified as a risk factor for these diseases. According to this study, AECAs are reliable prognosticators for the development of CAD and PAD. Further studies with large numbers of serum samples are under way.
The Effects of Self-Regulated Strategy Development on the Writing Performance of Second-Grade Students With Behavioral and Writing Difficulties
Authors: Lane Kathleen Lynne , Harris Karen R. , Graham Steve , Weisenbach Jessica L. , Brindle Mary , Morphy Paul
Published: January 2008

The effects of a secondary academic intervention, embedded in the context of a positive behavior support model, on the writing of second-grade students at risk for emotional and behavioral disorder and writing problems were examined in this study. Students were taught how to plan and draft a story using the self-regulated strategy development model. Results of this multiple-probe design revealed lasting improvements in story completeness, length, and quality for all 6 students. Students and teachers rated the intervention favorably, with some indicating that the intervention exceeded their expectations. Limitations and directions for future research are discussed.
Between Legal and Illegal Tender
Authors: Horesh Niv
Published: January 2008

Using recently declassified archival material pertaining to the Chartered Bank of India Australia and China, this article foregrounds quantitative evidence that sheds new light on the history of British banks in Asia. It shows that Hong Kong came to play a critical role in the bank's note issue strategy after the Straits Settlements had moved off the silver standard in 1906. Locally denominated notes issued on mainland China complemented the Hong Kong issue. However, their circulation volume dropped dramatically during the anti-British boycott that followed the May Thirtieth Incident (1925).
Religion, Modernity, and Urban Space
Authors: Poon Shuk-wah
Published: January 2008

This article examines the impact of the Nationalist regime's modernizing project on the religious landscape and people's public behavior in Republican Guangzhou. In the transformation of the Guangzhou City God Temple, urban space became a place of contest between the government's modernizing project and urban people's religious traditions. In 1931, the municipal government converted the City God Temple into the Native Goods Exhibition Hall, a political space that attempted to foster patriotic consumption among the populace. Yet, beneath the surface, the people of Guangzhou continued to treat the “exhibition hall” as a religious space for expressing their faith in their patron god. While the government was doubtless an important force in modernizing the urban landscape, the city's people managed to inscribe their values onto the urban public space.
Maternal uses of non-object terms in child-directed speech: Color, number and time
Authors: Tare Medha , Shatz Marilyn , Gilbertson Lisa
Published: February 2008

Non-object terms including color, number and time words pose a challenge for word learning due in part to non-obvious word-referent mappings. Finding early word-word knowledge for such terms, Shatz has suggested that exposure to them in varied conversational contexts might facilitate word-word mappings. To address whether input feasibly carries such information, we examined longitudinal transcripts from the CHILDES database for the frequency and uses of subsets of color and number words in mothers' speech to toddlers and of time words to preschoolers. All the mothers studied made varied uses of the terms from these lexical categories. The findings support the argument that varied conversational input provides useful data for children to create early word-word mappings for non-object terms.
Likelihood-Ratio DIF Testing: Effects of Nonnormality
Authors: Woods Carol M.
Published: January 2008

Differential item functioning (DIF) occurs when an item has different measurement properties for members of one group versus another. Likelihood-ratio (LR) tests for DIF based on item response theory (IRT) involve statistically comparing IRT models that vary with respect to their constraints. A simulation study evaluated how violation of the normality assumption about the random latent variable for one or both groups affected IRT-LR-DIF results. Item response data with or without DIF were generated from the two-parameter logistic model and fitted under the assumption that the latent distribution was normal for both groups. Although the IRT-LR-DIF method performed well when latent distributions were normal for both groups, results were distorted when the distribution was skewed for one or both groups. Specifically, Type I error was inflated, differences between reference- and focal-group item parameter estimates were inaccurate, and group differences in the mean and variance of the latent distribution were overestimated.
Novel Epoxy Resin Networks with High Impact Strength and Hardness
Authors: Athawale Anjali A. , Alhousami Mohammed H.M.
Published: February 2008

Novel epoxy resins with high impact strength and hardness have been synthesized by the bulk polymerization method. These materials were modified with styrene, polymethylmethacrylate, methylmethacrylate, and acrylonitrile to obtain both thermoplastic and thermosetting resins. Physical properties of the resulting mixtures were evaluated by measuring the impact strength, hardness and the degree of compression. Thermograms were used to investigate the behavior of different curing agents with resins. Comparison of results of modified epoxy resin with blank epoxy resin reveals that modified resins show remarkably high glass transition temperatures and thermal stability, as well as hardness. These materials exhibit a higher degree of solvent resistance.
Investigation of the Sorption and Tensile Response of Pultruded E-Glass/Vinylester Composites Subjected to Hygrothermal Exposure and Sustained Strain
Authors: Helbling C.S. , Karbhari V.M.
Published: February 2008

The aim of the present research is to provide insights into the sorption behavior and degradation mechanisms of a unidirectional pultruded E-glass/vinylester composite subjected to synergistic hygrothermal exposure and sustained bending strain for exposure times of up to 2 years. Composite specimens were found to follow a Langmuir-type diffusion behavior in all environments, with departure from that behavior attributed either to material leaching-out, chemical breakdown, interfacial debonding, or central delamination. The composite tensile strength decreased with increasing immersion time and temperature, with high sustained strain levels having a more detrimental effect at elevated temperatures. The initial strength loss was associated with matrix plasticization, while later reductions were caused by the occurrence of mechanisms of fiber degradation and interfacial debonding. Changes in tensile strength were largely reversible as a result of immersion in deionized water at 22 °C, but the level of regain decreased substantially at higher immersion temperatures. Finally, failure by delamination was observed to occur in the most severe environments at strength retention levels dependent upon the amount of imposed bending strain.
Market-Based Pay in Action
Authors: Leavitt William M. , Morris John C.
Published: January 2008

The practice of linking the pay of public sector employees to the prevailing labor market, or market-based pay, has been a topic of conversation in many municipalities across the nation. Although much has been written about the use of this pay philosophy, little has been written about the use of market-based pay in local government settings. This article presents the results of in-depth interviews about the use of market-based pay with the human resource directors in the seven Hampton Roads, Virginia, cities. The authors find that although the idea of a market-based pay system is alluring, the difficulties of balancing internal and external equity, political considerations, and economic barriers make full implementation of such a system difficult at best.
Point Counterpoint: The Function of Contradictions on an Interdisciplinary Health Care Team
Authors: Martin Donald R. , O'Brien Jill L. , Heyworth Judith A. , Meyer Nancy R.
Published: January 2008

In this qualitative study we used Dialectical Theory to analyze contradictions occurring between medical doctors (MDs) and nurse practitioners (NPs) working collaboratively on a health care team. The analysis of interview data revealed contradictions in two areas: (1) NPs espouse a need for heightened autonomy in their working associations with medical doctors, whereas conversely, MDs emphasize a need for ongoing connection, and (2) MDs argue that NPs should be more proactive problem solvers and frame their working relationships as educational. However, NPs argue that MDs enact patterns of behavior that limit proactive problem solving and curtail the educational potential of those relationships, thus reinforcing predictable work routines. Both areas of contradiction constitute what dialectical theorist Leslie Baxter refers to as “oppositions.” Examples of these oppositions are provided in the analysis. The study concludes with an assessment of how such contradictions might constitute developmental opportunities for NPs and MDs working in collaboration.
The Caregiving Trajectory Among Poor and Chronically Ill People
Authors: Robles-Silva Leticia
Published: January 2008

This article analyzes the caregiving trajectory for adults and elderly persons who suffer from diabetes. The objective is to develop a conceptual framework for understanding caregiving changes over time. An ethnographic study was conducted in a poor urban neighborhood in Guadalajara, Mexico, in which 21 caregivers were interviewed and followed from 1997 through 2001. The trajectory has a beginning and an end, and moves through three phases: semi-care, care, and dying. The phases differ by the type and timing of actions undertaken, and the degree to which the caregiver takes over the physical functions and social roles of the sick person.
Please Don't give Up On Me: When Faculty Fail To Care
Authors: Hawk Thomas F. , Lyons Paul R.
Published: February 2008

Students in an evening MBA program were given the opportunity to respond to the following four questions: (a) Have you ever had the feeling that a faculty member or instructor had “given up” on you and your learning in a course? (b) What did the faculty member or instructor do or not do to give you that feeling? (d) What did you do as a result of that feeling, perception? and (d) What are ways that a faculty member or instructor can communicate to you that he or she has not given up on his or her commitment to you and your learning in a course? The authors examine the student responses in the context of an ethic of care, pedagogical caring, and pedagogical respect. They conclude with some specific recommendations for improving faculty pedagogical caring.
The Role of Parental Influences on Young Adolescents' Career Development
Authors: Keller Briana K. , Whiston Susan C.
Published: February 2008

The relationship between specific parental behaviors and the career development of young adolescents was assessed. Regression analyses revealed that parental behaviors did relate to the career development of middle school students, after controlling for student grade level and gender. Parental behaviors tended to relate more to career decision-making self-efficacy (CDMSE) than to career maturity, and general psychosocial parenting behaviors appeared to be more salient than career-focused parent behaviors. Five specific behaviors were found to be predictive of participants' career development. The discrepancy between adolescents' and parents' views of family relationships was also shown to relate to the adolescents' career decision-making self-efficacy. The results from the current study further expand on the results from other studies in this area by providing insight into the effects of specific parental behaviors. Implications for research and practice are discussed.
Globalizing Democracy
Authors: Johnson Pauline
Published: January 2008

According to many of his critics, Habermas is so preoccupied with `old normative maps' that he cannot really help us chart our options in a fast globalizing world. The following article contests aspects of this familiar critique. The argument is developed in three stages. First, some misapprehensions are targeted. No unreconstructed liberal, Habermas is shown to offer a discriminating interpretation of learning processes that need to guide political democracy in a global context. The far-reaching agenda of Habermas's programme for a globalized and democratized welfare project is underlined. Next, Habermas's attempt to bring forward the normative resources of liberal democratic histories is contrasted with Ulrich Beck's normative avant-gardism. This latter is shown to be a mere semblance of radicalism that serves to legitimate the triumph of one particular axis within modernization processes. Finally, the article explores a dilemma that faces Habermas's attempt to use the potentials of a particular cultural tradition as the normative grounds for a globally extended democracy. Habermas wants to avoid reducing critical theory to the mere affirmation of certain parochial cultural choices and so tries to find grounds for establishing the universal resonance of these normative contents. The last section looks into the ideological character of this attempt and considers an alternative way in which the inter-cultural significance of democratic Enlightenment commitments might be tested.
Should Patients With Contained Rupture of a Descending Aortic Aneurysm Only Receive Unilateral Artificial Ventilation? Case Report of a Death During an Operation
Authors: Hofmann Hans-Stefan , Kroll Heike , Kunze Christian , Bromber Harry
Published: January 2008

The danger of thoracic aneurysm rupture increases with the size of the aneurysm. We report on a 59-year-old man who developed a secondary aneurysm of the descending thoracic aorta within the residual type A dissection that was approximately 9-cm long and in which a contained rupture occurred. The patient died as a result of a massive hemorrhage during the anesthesiological preparation for emergency operation a short time after double-lumen intubation and commencement of controlled artificial ventilation. Autopsy revealed an atelectatic lower pulmonary lobe that had partially fused with the aneurysm. The fusion may have been so substantial that it may have acutely eliminated the covering of the contained rupture during artificial ventilation.
Pseudoaneurysm of the Brachial Artery Following Humeral Fracture
Authors: Moran Deirdre , Roche-Nagle Graham , Ryan Ronan , Brophy David , Quinlan William , Barry Mary
Published: January 2008

The frequency of peripheral artery aneurysms in the upper extremities is less than in the lower extremities. Diagnosis and surgical treatment are important because upper extremity aneurysms can severely compromise the function of a limb and possibly lead to the loss of an arm or fingers. Very rarely, posttraumatic upper extremity pseudoaneurysms show symptoms after a long period of time. Diagnosis can be made on review of the patient's history and a physical examination. Surgical reconstruction is the preferred treatment for such patients. We present a case of a brachial artery pseudoaneurysm following humeral fracture.
A Population-Level Analysis: The Influence of Hospital Type on Trends in Use and Outcomes of Lower Extremity Angioplasty
Authors: Vogel Todd R. , Symons Rebbecca G. , Flum Dave R.
Published: January 2008

Objective The use of infrainguinal percutaneous transluminal angioplasty (PTA) has increased, but patterns of use have not been well studied. Academic institutions (AIs) and nonacademic institutions (NAIs) may have developed different practice patterns and may have different associated outcomes.

Methods A retrospective statewide population-based administrative database was evaluated for patients undergoing PTA (1997-2004).

Results A total of 1718 patients underwent PTA for claudication (51.9%), rest pain (12.1%), and ulceration or gangrene (23.1%). The use of infrainguinal stents (62.4% vs 60.8%), elective procedures (76.3% vs 79.8%), in-hospital death (1.6% vs 2.2%), 30-day mortality (2.1% vs 3.3%), readmission rates (17.1% vs 15.9%), and reintervention rates after readmission (38.5% vs 42.9%) were similar between groups. Increased use of PTA was noted in AIs versus NAIs (239.5% vs 53.9%). AIs were significantly less likely to perform PTA for rest pain (7.5% vs 14.4%, P < .05).

Conclusion AIs had a more recent increase in the use of PTA, but less often used PTA for patients with rest pain compared with NAIs. Both center types had higher than expected 30-day readmission and reintervention rates. Further understanding of the implementation and associated outcomes of PTA is required.
Use of Cryopreserved Femoral Vein for In Situ Replacement of Infected Femorofemoral Prosthetic Artery Bypass
Authors: Dosluoglu Hasan H. , Kittredge Jonathan , Cherr Gregory S.
Published: January 2008

Isolated groin infection following crossover femoral bypass is not uncommon, and its management may be challenging, especially in medically high-risk patients. When an in situ replacement is appropriate, using an autologous vein (femoral or saphenous) would be the preferred method; however, this may not always be feasible. The authors used cryopreserved femoral vein grafts for in situ replacement of femorofemoral bypass grafts with excellent results in 3 high-risk patients who developed early graft infections and failed graft preservation attempts. In situ replacement of infected femorofemoral grafts using a cryopreserved femoral vein graft can be considered as a second-line intervention when an adequately sized autologous vein is unavailable or unusable or is not feasible in high-risk patients.
“Unpredictable” Late Rupture of an Abdominal Aortic Aneurysm After Bifurcated Ancure Endograft Repair
Authors: Rosen Noah A. , Cayne Neal S. , Macari Michael , Jacobowitz Glenn R.
Published: January 2008

The goal of endovascular repair of an abdominal aortic aneurysm is to exclude the aneurysm from systemic arterial pressure, thereby preventing rupture. However, the long-term durability of endovascular repair continues to be in question, as aneurysm rupture after endovascular repair continues to be reported. We report the case of an 89-year-old patient who underwent endovascular repair of a 7.1-cm abdominal aortic aneurysm with an Ancure endograft 5 years earlier. Despite close follow-up and a shrinking aneurysm sac on annual contrast-enhanced computed tomography, he presented with aneurysm rupture and a new proximal type I endoleak. The endoleak and rupture were successfully repaired with endovascular placement of a main body extension.
Serum Creatinine Stabilization Following Renal Artery Stenting
Authors: Bates Mark C. , Campbell John E. , Broce Mike , Lavigne Philip S. , Riley Mary A.
Published: January 2008

The impact of renal artery stenting on renal function in a subgroup of consecutive de novo patients with atherosclerotic renal artery stenosis from the single operator, single center, retrospective renal stent trial is defined. Patients with inadequate preprocedure and/or follow-up renal function studies were excluded. Abnormal baseline serum creatinine (sCr) was defined as ≥1.5 mg/dL. Follow-up sCr was improved, unchanged, or worsened if the variance from baseline decreased by >20%, stayed within 20%, or increased >20%, respectively. For the total cohort (194 patients), renal function stabilized or improved in 72% of patients. Plotting 1/sCr demonstrated a decline in renal function before the procedure that stabilized following renal artery stenting. Bilateral renal artery stenting predicted normal follow-up sCr, and baseline sCr >2.1 mg/dL was associated with improvement in sCr long-term. In conclusion, renal artery stenting results in overall stabilization of renal function, and bilateral renal artery stenting seems to have added benefit.
Physician as Hospital Chief Executive Officer
Authors: Falcone Robert E. , Satiani Bhagwan
Published: January 2008

The vast majority of hospitals in the United States today are led by nonphysicians. This is in sharp contrast to the turn of the 20th century, when over a third of the hospitals in the United States were physician led. As the pendulum swings back from lay leader to clinician leader, there is a strong and appropriate opportunity for physicians to reinsert themselves into a leadership role. In fact, the time has perhaps never been more appropriate than today. In a health care system that is complex, troubled, and challenging, the physician CEO brings a unique set of skills to the business of medicine. The successful physician leader, however, must understand the business of medicine as well as or better than he or she understands the practice of medicine. Training, developing, and equipping our future physician leaders with the necessary skill sets will be one of medicines' many challenges as it expands into the 21st century.
The monoclonal anti–VLA-4 antibody natalizumab mobilizes CD34+ hematopoietic progenitor cells in humans
Authors: Zohren Fabian , Toutzaris Diamandis , Klärner Viola , Hartung Hans-Peter , Kieseier Bernd , Haas Rainer
Published: January 2008

We investigated the role of adhesion molecule VLA-4 in CD34+ blood stem-cell mobilization. Therefore, we examined 20 patients with multiple sclerosis (MS) who were treated with the anti–VLA-4 antibody natalizumab. Treated patients had received a median number of 4 natalizumab infusions (range: 2-9 infusions). Blood samples were taken 4 weeks following the last infusion. With a median proportion of 7.6 CD34+ cells/μL (range: 2.2-30.4 cells/μL), these patients had a significantly higher (P = .003) amount of circulating CD34+ cells compared with 5 healthy volunteers (median: 1.4/μL; range: 0.6-2.4/μL) and 5 untreated MS patients (median: 1.0/μL; range: 0.5-1.7/μL) (P = .001). Serial measurements in 4 patients receiving their first natalizumab infusion showed a maximal significant increase in circulating CD34+ cells from 3.3/μL (range: 1.6-4.8/μL) to 10.4/μL (range: 7.5-12.04/μL) 72 hours following natalizumab infusion (P = .001), including pluripotent cells in colony-forming assays. This mobilizing ability of natalizumab might be useful for patients with poor response to granulocyte colony-stimulating factor (G-CSF)–based protocols.
Human skin keratins are the major proteins in exhaled breath condensate
Authors: Hoffmann H. J. , Tabaksblat L. M. , Enghild J. J. , Dahl R.
Published: January 2008

Exhaled breath condensate (EBC) may be an attractive noninvasive alternative to bronchoscopy, bronchoalveolar lavage and induced sputum for diagnosis and monitoring of pulmonary disease. The aim of the present study was to identify proteins in EBC by mass spectrometry. Protein in EBC was characterised by gel electrophoresis of freeze-dried EBC samples, and individual proteins were identified by mass spectrometry.

Saliva, ambient air condensate (AAC) and EBC were collected from normal human volunteers with or without a filter to remove particles from air. In some instances, EBC was condensed by breathing compressed air. Samples were freeze-dried and analysed by SDS-PAGE and peptide mass fingerprinting.

Three major bands were seen in EBC and AAC, and were identified by peptide mass fingerprinting. The probability-based Mowse score was significant only for cytokeratin (CK) 1, CK2 and CK10. In the catalogue of human cytokeratins, CK1, CK2, CK9 and CK10 are described in keratinising epidermis. Saliva did not contain keratin and compressed air EBC contained markedly less keratin. Filtration of inspired air did not remove contaminating keratin.

In conclusion, skin keratin in exhaled breath condensate derives from ambient air and not from the respiratory tract.
Outcomes for COPD pharmacological trials: from lung function to biomarkers
Authors: Cazzola M. , MacNee W. , Martinez F. J. , Rabe K. F. , Franciosi L. G. , Barnes P. J. , Brusasco V. , Burge P. S. , Calverley P. M. A. , Celli B. R. , Jones P. W. , Mahler D. A. , Make B. , Miravitlles M. , Page C. P. , Palange P. , Parr D. , Pistolesi M. , Rennard S. I. , Rutten-van Mölken M. P. , Stockley R. , Sullivan S. D. , Wedzicha J. A. , Wouters E. F.
Published: January 2008

The American Thoracic Society/European Respiratory Society jointly created a Task Force on “Outcomes for COPD pharmacological trials: from lung function to biomarkers” to inform the chronic obstructive pulmonary disease research community about the possible use and limitations of current outcomes and markers when evaluating the impact of a pharmacological therapy. Based on their review of the published literature, the following document has been prepared with individual sections that address specific outcomes and markers, and a final section that summarises their recommendations.
Towards an automatic classification of protein structural domains based on structural similarity
Authors: Sam Vichetra , Tai Chin-Hsien , Garnier Jean , Gibrat Jean-Francois , Lee Byungkook , Munson Peter J
Published: January 2008

Background

Formal classification of a large collection of protein structures aids the understanding of evolutionary relationships among them. Classifications involving manual steps, such as SCOP and CATH, face the challenge of increasing volume of available structures. Automatic methods such as FSSP or Dali Domain Dictionary, yield divergent classifications, for reasons not yet fully investigated. One possible reason is that the pairwise similarity scores used in automatic classification do not adequately reflect the judgments made in manual classification. Another possibility is the difference between manual and automatic classification procedures. We explore the degree to which these two factors might affect the final classification.

Results

We use DALI, SHEBA and VAST pairwise scores on the SCOP C class domains, to investigate a variety of hierarchical clustering procedures. The constructed dendrogram is cut in a variety of ways to produce a partition, which is compared to the SCOP fold classification.

Ward's method dendrograms led to partitions closest to the SCOP fold classification. Dendrogram- or tree-cutting strategies fell into four categories according to the similarity of resulting partitions to the SCOP fold partition. Two strategies which optimize similarity to SCOP, gave an average of 72% true positives rate (TPR), at a 1% false positive rate. Cutting the largest size cluster at each step gave an average of 61% TPR which was one of the best strategies not making use of prior knowledge of SCOP. Cutting the longest branch at each step produced one of the worst strategies.

We also developed a method to detect irreducible differences between the best possible automatic partitions and SCOP, regardless of the cutting strategy. These differences are substantial. Visual examination of hard-to-classify proteins confirms our previous finding, that global structural similarity of domains is not the only criterion used in the SCOP classification.

Conclusion

Different clustering procedures give rise to different levels of agreement between automatic and manual protein classifications. None of the tested procedures completely eliminates the divergence between automatic and manual protein classifications. Achieving full agreement between these two approaches would apparently require additional information.
A novel method to quantify local CpG methylation density by regional methylation elongation assay on microarray
Authors: Zhang Dingdong , Wang Yan , Bai Yunfei , Ge Qinyu , Qiao Yingjuan , Luo Junfeng , Jia Chao , Lu Zuhong
Published: January 2008

Background

DNA methylation based techniques are important tools in both clinical diagnostics and therapeutics. But most of these methods only analyze a few CpG sites in a target region. Indeed, difference of site-specific methylation may also lead to a change of methylation density in many cases, and it has been found that the density of methylation is more important than methylation of single CpG site for gene silencing.

Results

We have developed a novel approach for quantitative analysis of CpG methylation density on the basis of microarray-based hybridization and incorporation of Cy5-dCTP into the Cy3 labeled target DNA by using Taq DNA Polymerase on microarray. The quantification is achieved by measuring Cy5/Cy3 signal ratio which is proportional to methylation density. This methylation-sensitive technique, termed RMEAM (regional methylation elongation assay on microarray), provides several advantages over existing methods used for methylation analysis. It can determine an exact methylation density of the given region, and has potential of high throughput. We demonstrate a use of this method in determining the methylation density of the promoter region of the tumor-related gene MLH1, TERT and MGMT in colorectal carcinoma patients.

Conclusion

This technique allows for quantitative analysis of regional methylation density, which is the representative of all allelic methylation patterns in the sample. The results show that this technique has the characteristics of simplicity, rapidness, specificity and high-throughput.
Dimerization of the transmembrane domain of amyloid precursor proteins and familial Alzheimer's disease mutants
Authors: Gorman Paul M , Kim Sanguk , Guo Meng , Melnyk Roman A , McLaurin Joanne , Fraser Paul E , Bowie James U , Chakrabartty Avijit
Published: January 2008

Background

Amyloid precursor protein (APP) is enzymatically cleaved by γ-secretase to form two peptide products, either Aβ40 or the more neurotoxic Aβ42. The Aβ42/40 ratio is increased in many cases of familial Alzheimer's disease (FAD). The transmembrane domain (TM) of APP contains the known dimerization motif GXXXA. We have investigated the dimerization of both wild type and FAD mutant APP transmembrane domains.

Results

Using synthetic peptides derived from the APP-TM domain, we show that this segment is capable of forming stable transmembrane dimers. A model of a dimeric APP-TM domain reveals a putative dimerization interface, and interestingly, majority of FAD mutations in APP are localized to this interface region. We find that FAD-APP mutations destabilize the APP-TM dimer and increase the population of APP peptide monomers.

Conclusion

The dissociation constants are correlated to both the Aβ42/Aβ40 ratio and the mean age of disease onset in AD patients. We also show that these TM-peptides reduce Aβ production and Aβ42/Aβ40 ratios when added to HEK293 cells overexpressing the Swedish FAD mutation and γ-secretase components, potentially revealing a new class of γ-secretase inhibitors.
COX-2 and PPARγ expression are potential markers of recurrence risk in mammary duct carcinoma in-situ
Authors: Kulkarni Swati , Patil Deepa B , Diaz Leslie K , Wiley Elizabeth L , Morrow Monica , Khan Seema A
Published: January 2008

Background

In women with duct carcinoma in-situ (DCIS) receiving breast conservation therapy (BCT), in-breast recurrences are seen in approximately 10%, but cannot be accurately predicted using clinical and histological criteria. We performed a case-control study to identify protein markers of local recurrence risk in DCIS.

Methods

Women treated for DCIS with BCT, who later developed in-breast recurrence (cases) were matched by age and year of treatment to women who remained free of recurrence (controls).

Results

A total of 69 women were included in the study, 31 cases and 38 controls. Immunohistochemical evaluation of DCIS tissue arrays was performed for estrogen receptor, progesterone receptor, HER-2/neu, cyclin D1, p53, p21, cycloxygenase-2 (COX-2) and peroxisome proliferator activated receptor γ (PPARγ). Two markers were significantly different between cases and controls on univariate analysis: strong COX-2 expression was associated with increased risk of recurrence, with 67% vs. 24% positivity in cases and controls p = 0.006; and nuclear expression of PPARγ was associated with protection from recurrence with 4% vs. 27% positivity in cases and controls, p = 0.024. In a multivariate model which included size, grade, COX-2 and PPARγ positivity, we found COX-2 positivity to be a strong independent risk factor for recurrence (OR 7.90, 95% CI 1.72–36.23)., whereas size and grade were of borderline significance. PPARγ expression continued to demonstrate a protective trend, (OR 0.14, 95% CI 0.06–1.84).

Conclusion

Our findings suggest that COX-2 and PPARγ should be investigated further as biologic markers to predict DCIS recurrence, particularly since they are also potential therapeutic targets.
Development of fragment-specific osteopontin antibodies and ELISA for quantification in human metastatic breast cancer
Authors: Plumer Alicia , Duan Hongyi , Subramaniam Sripriya , Lucas F Lee , Miesfeldt Susan , Ng Ah-Kau , Liaw Lucy
Published: January 2008

Background

Osteopontin (OPN) is associated with human cancers, and circulating blood OPN may have diagnostic or prognostic value in clinical oncology.

Methods

To evaluate OPN as a cancer biomarker, we generated and characterized five novel mouse monoclonal antibodies against the human full-length OPN (fl-OPN). Epitopes recognized by four antibodies (2C5, 2F10, 2H9, and 2E11) map to N-terminal OPN (aa1-166); one (1F11) maps to C-terminal OPN (aa167-314). These antibodies recognize recombinant and native OPN by ELISA and immunoblot, cross reacting with human and mouse OPN. Two of these novel antibodies (2F10 and 1F11) were used to develop a quantitative enzyme linked immunosorbent assay (ELISA) for fl-OPN.

Results

In comparison with commercially available ELISAs, our assay had high accuracy in measuring fl-OPN standards, and high sensitivity. Specifically, our ELISA has a linear dose response between 0.078 ng/ml-10 ng/ml, with a sensitivity of 13.9 pg/ml. We utilized this assay to quantify fl-OPN in the plasma of healthy volunteers in comparison with patients with metastatic breast cancer. The average circulating plasma fl-OPN in healthy volunteers was 1.2 ng/ml, compared to 4.76 ng/ml in patients with metastatic breast cancer (p = 0.0042). Although the increase in fl-OPN in cancer patients is consistent with previous studies, the measured quantity varied greatly between all existing fl-OPN ELISAs.

Conclusion

Because OPN is a complex molecule with diversity from alternative splicing, post-translational modification, extracellular proteolytic modification, and participation in protein complexes, we suggest that further understanding of specific isoform recognition of multiple OPN species is essential for future studies of OPN biomarker utility.
Intracellular gold nanoparticles enhance non-invasive radiofrequency thermal destruction of human gastrointestinal cancer cells
Authors: Gannon Christopher J , Patra Chitta Ranjan , Bhattacharya Resham , Mukherjee Priyabrata , Curley Steven A
Published: January 2008

Background

Novel approaches to treat human cancer that are effective with minimal toxicity profiles are needed. We evaluated gold nanoparticles (GNPs) in human hepatocellular and pancreatic cancer cells to determine: 1) absence of intrinsic cytotoxicity of the GNPs and 2) external radiofrequency (RF) field-induced heating of intracellular GNPs to produce thermal destruction of malignant cells. GNPs (5 nm diameter) were added to 2 human cancer cell lines (Panc-1, Hep3B). 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and propidium iodide-fluorescence associated cell sorting (PI-FACS) assessed cell proliferation and GNP-related cytotoxicity. Other GNP-treated cells were exposed to a 13.56 MHz RF field for 1, 2, or 5 minutes, and then incubated for 24 hours. PI-FACS measured RF-induced cytotoxicity.

Results

GNPs had no impact on cellular proliferation by MTT assay. PI-FACS confirmed that GNPs alone produced no cytotoxicity. A GNP dose-dependent RF-induced cytotoxicity was observed. For Hep3B cells treated with a 67 μM/L dose of GNPs, cytotoxicity at 1, 2 and 5 minutes of RF was 99.0%, 98.5%, and 99.8%. For Panc-1 cells treated at the 67 μM/L dose, cytotoxicity at 1, 2, and 5 minutes of RF was 98.5%, 98.7%, and 96.5%. Lower doses of GNPs were associated with significantly lower rates of RF-induced thermal cytotoxicity for each cell line (P < 0.01). Cells not treated with GNPs but treated with RF for identical time-points had less cytotoxicity (Hep3B: 17.6%, 21%, and 75%; Panc-1: 15.3%, 26.4%, and 39.8%, all P < 0.01).

Conclusion

We demonstrate that GNPs 1) have no intrinsic cytotoxicity or anti-proliferative effects in two human cancer cell lines in vitro and 2) GNPs release heat in a focused external RF field. This RF-induced heat release is lethal to cancer cells bearing intracellular GNPs in vitro.
Data mining of plasma peptide chromatograms for biomarkers of air contaminant exposures
Authors: Karthikeyan Subramanian , Kumarathasan Premkumari , Vincent Renaud
Published: January 2008

Background

Interrogation of chromatographic data for biomarker discovery becomes a tedious task due to stochastic variability in retention times arising from solvent and column performance. The difficulty is further compounded when the effects of exposure (e.g. to environmental contaminants) and biological variability result in varying numbers and intensities of peaks among chromatograms.

Results

We developed a software tool to correct the stochastic time shifts in chromatographic data through iterative selection of landmark peaks and isometric interpolation to improve alignment of all chromatographic peaks. To illustrate application of the tool, plasma peptides from Fischer rats exposed for 4 h to clean air or Ottawa urban particles (EHC-93) were separated by HPLC with autofluorescence detection, and the retention time shifts between chromatograms were corrected (dewarped). Both dewarped and non-dewarped datasets were then mined for models containing peptide peaks that best discriminate among the treatment groups using ClinproTools™. In general, models generated by dewarped datasets were able to better classify test sample chromatograms into either clean air or EHC-93 exposure groups, and 0 or 24 h post-recovery time groups. Peak areas of peptides in a model that produced the best discrimination of treatment groups were analyzed by two-way ANOVA with exposure (clean air, EHC-93) and recovery time (0 h, 24 h) as factors. Statistically significant (p < 0.05) time-dependent and exposure-dependent increases and decreases were noted establishing these as biomarker candidates for further validation.

Conclusion

Our software tool provides a simple and portable approach for alignment of chromatograms with complex, bi-directional retention time shifts prior to data mining. Reliable biomarker discovery can be achieved through chromatographic dewarping using our software followed by pattern recognition by commercial data mining applications.
Akt inhibitors as an HIV-1 infected macrophage-specific anti-viral therapy
Authors: Chugh Pauline , Bradel-Tretheway Birgit , Monteiro-Filho Carlos MR , Planelles Vicente , Maggirwar Sanjay B , Dewhurst Stephen , Kim Baek
Published: January 2008

Background

Unlike CD4+ T cells, HIV-1 infected macrophages exhibit extended life span even upon stress, consistent with their in vivo role as long-lived HIV-1 reservoirs.

Results

Here, we demonstrate that PI3K/Akt inhibitors, including clinically available Miltefosine, dramatically reduced HIV-1 production from long-living virus-infected macrophages. These PI3K/Akt inhibitors hyper-sensitize infected macrophages to extracellular stresses that they are normally exposed to, and eventually lead to cell death of infected macrophages without harming uninfected cells. Based on the data from these Akt inhibitors, we were able to further investigate how HIV-1 infection utilizes the PI3K/Akt pathway to establish the cytoprotective effect of HIV-1 infection, which extends the lifespan of infected macrophages, a key viral reservoir. First, we found that HIV-1 infection activates the well characterized pro-survival PI3K/Akt pathway in primary human macrophages, as reflected by decreased PTEN protein expression and increased Akt kinase activity. Interestingly, the expression of HIV-1 or SIV Tat is sufficient to mediate this cytoprotective effect, which is dependent on the basic domain of Tat – a region that has previously been shown to bind p53. Next, we observed that this interaction appears to contribute to the downregulation of PTEN expression, since HIV-1 Tat was found to compete with PTEN for p53 binding; this is known to result in p53 destabilization, with a consequent reduction in PTEN protein production.

Conclusion

Since HIV-1 infected macrophages display highly elevated Akt activity, our results collectively show that PI3K/Akt inhibitors may be a novel therapy for interfering with the establishment of long-living HIV-1 infected reservoirs.