bluuebunny/crossref_metadata_2025 huggingface dataset:
pVHL co‐ordinately regulates CXCR4/CXCL12 and MMP2/MMP9 expression in human clear‐cell renal cell carcinoma
Authors: Struckmann K , Mertz KD , Steu S , Storz M , Staller P , Krek W , Schraml P , Moch H
Published: January 2008

Loss of pVHL function, characteristic for clear‐cell renal cell carcinoma (ccRCC), causes increased expression of CXCR4 chemokine receptor, which triggers expression of metastasis‐associated MMP2/MMP9 in different human cancers. The impact of pVHL on MMP2/MMP9 expression and their relationship to CXCR4 and its ligand CXCL12 in ccRCC is unclear. By using reverse transcription PCR, immunofluorescence and immunohistochemistry, strong mRNA and protein expression of CXCR4, CXCL12, MMP2, MMP9 and MMP inhibitors TIMP1 and TIMP2 was found in VHL‐null 786‐O ccRCC cells. Loss of CXCR4/CXCL12 expression after restoration of VHL function in these cells was accompanied by a significant reduction of MMP2 and MMP9 expression, whereas neither TIMP1 nor TIMP2 expression was affected. Using real‐time PCR analysis, higher MMP2 (p = 0.0134) and MMP9 (p = 0.067) mRNA expression levels were detected in primary ccRCC with strong CXCR4 compared to cases with weak CXCR4 expression. There was no association between CXCR4 and TIMP1 or TIMP2 mRNA expression. MMP2 protein expression data obtained by immunohistochemistry on a tissue microarray uncovered positive cytoplasmic staining in 290/380 (76%) primary ccRCCs. Co‐expression of CXCR4 and MMP2 was found in 282 of these tumours (74%). Our in vitro and in vivo data strongly indicate that pVHL coordinately regulates expression of metastasis‐associated genes CXCR4/CXCL12 and MMP2/MMP9 but the exact molecular mechanism of this regulation remains to be determined. Co‐expression of CXCR4 and CXCL12, as demonstrated in VHL‐null 786‐O cells, might enable ccRCC progression and metastatic dissemination by autocrine receptor stimulation, even in the absence of exogenous CXCL12. Copyright © 2008 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Physiotherapy diagnosis in clinical practice: a survey of orthopaedic certified specialists in the USA
Authors: Spoto Marcia Miller , Collins Jennifer
Published: January 2008

Background and Purpose. Diagnosis is a complex process that involves clinical decision‐making along several dimensions, culminating in the assignment of a label or labels which inform(s) treatment decisions. Much of the attention given to physiotherapy diagnosis has been devoted to specific, disparate classification systems for low back pain. The purpose of the present study was to investigate how physiotherapists view and approach diagnosis in clinical practice in the USA. Method. A survey was developed to collect both quantitative and qualitative data related to diagnostic process and classification in orthopaedic practice. Subjects comprised 253 Board‐certified orthopaedic physiotherapy practioners. A total of 850 surveys were administered; 253 surveys were completed, representing a return rate of 30%. Results. Eighty‐four per cent of the respondents report patient care as their primary professional practice area. Seventy‐six per cent of the subjects utilized a diagnostic classification system distinct from the medical diagnosis when managing patients with low back pain. Of those, the largest percentage (38%) utilized a general pathophysiological classification system, 32% utilized the McKenzie system and, in decreasing order of frequency, treatment‐based classification (9%) and movement impairment classification (7%). Qualitative data suggest considerable variation in how orthopaedic specialists view diagnosis in patient management, with several common themes emerging: physiotherapy diagnosis may incorporate the medical diagnosis, but moves beyond it; physiotherapy diagnosis occurs across multiple levels or systems; physiotherapists tend to view diagnosis as being process‐oriented with its primary purpose being to guide treatment decisions. Conclusions. As physiotherapy evolves from a profession that treats by prescription to a doctoring profession it should give serious attention to diagnosis, the foundation of evidence‐based practice. Striving for consensus on the role of diagnosis in patient management should become a priority, as well as developing a more standard taxonomy with consistent terminology. Copyright © 2008 John Wiley & Sons, Ltd.
TNF polymorphisms and prostate cancer risk
Authors: Danforth Kim N. , Rodriguez Carmen , Hayes Richard B. , Sakoda Lori C. , Huang Wen‐Yi , Yu Kai , Calle Eugenia E. , Jacobs Eric J. , Chen Bingshu E. , Andriole Gerald L. , Figueroa Jonine D. , Yeager Meredith , Platz Elizabeth A. , Michaud Dominique S. , Chanock Stephen J. , Thun Michael J. , Hsing Ann W.
Published: January 2008

BACKGROUND

Inflammation has been hypothesized to increase prostate cancer risk. Tumor necrosis factor (TNF) is an important mediator of the inflammatory process, but the relationship between TNF variants and prostate cancer remains unclear.

METHODS

We examined associations between six TNF single nucleotide polymorphisms (SNPs) (rs1799964, rs1800630, rs1799724, rs1800629, rs361525, rs1800610) and prostate cancer risk among 2,321 cases and 2,560 controls from two nested case‐control studies within the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO, n = 2,561, 5 SNPs) and the Cancer Prevention Study II Nutrition Cohort (Nutrition Cohort, n = 2,320, 6 SNPs). Odds ratios and 95% confidence intervals were estimated for individual SNPs and haplotypes in each cohort separately and in pooled analyses.

RESULTS

No TNF SNP was associated with prostate cancer risk in PLCO (P‐trend ≥ 0.16), while in the Nutrition Cohort, associations were significant for 2 highly correlated variants (rs1799724, 1800610, r2 = 0.95; P‐trend = 0.04 and 0.02, respectively). In pooled analyses, no single SNP was associated with prostate cancer risk (P‐trend ≥ 0.08). After adjustment for multiple testing, no SNP was associated with prostate cancer risk in either cohort individually or in the pooled analysis (P‐trend all ≥ 0.10). Haplotypes based on 5 TNF SNPs did not vary by case/control status in PLCO, but showed marginal associations in the Nutrition Cohort (global P = 0.06) and the pooled analysis (global P = 0.05).

CONCLUSIONS

Despite somewhat suggestive haplotype results, overall our study does not support an association between TNF variants and prostate cancer risk. Prostate 68: 400–407, 2008. © 2008 Wiley‐Liss, Inc.
Increased distributional variance of mitochondrial DNA content associated with prostate cancer cells as compared with normal prostate cells
Authors: Mizumachi Takatsugu , Muskhelishvili Levan , Naito Akihiro , Furusawa Jun , Fan Chun‐Yang , Siegel Eric R. , Kadlubar Fred F. , Kumar Udaya , Higuchi Masahiro
Published: January 2008

Background

Mitochondria are key organelles for apoptosis, and mitochondrial DNA (mtDNA) content can regulate cancer progression. Increases in mtDNA mutations and deletions have been reported in cancer; however, a detailed investigation of mtDNA content in cancer cells has not yet been conducted.

Methods

Quantitative real‐time PCR and improved extraction method were established to investigate the mtDNA content in a single prostate cell.

Results

The heterogeneity of mtDNA content was demonstrated between the clones of prostate cancer cell line LNCaP and individual cells in each clone. To investigate whether large distributional variance of mtDNA content is associated with cancer initiation and/or progression, we first compared PZ‐HPV‐7, an HPV‐transformed normal prostate epithelial cell line, with CA‐HPV‐10, transformed from prostate cancer cells derived from the same donor. We found an enhanced distributional variance of mtDNA content in CA‐HPV‐10. Then, we investigated mtDNA content in individual cells in laser microdisssected cancer and adjacent normal cells from prostate cancer tissue specimens using quantitative real‐time PCR method. Results showed that the mtDNA content per cell follows a higher skewed distribution in cancer cells as compared in normal cells. We also observed that mtDNA content was increased in seven of nine (78%) of prostate cancers compared to normal prostate tissue.

Conclusions

These results indicate that prostate carcinogenesis may involve dysregulation of mtDNA content. Prostate 68: 408–417, 2008. © 2008 Wiley‐Liss, Inc.
Hypermethylation of MCAM gene is associated with advanced tumor stage in prostate cancer
Authors: Liu Jun‐Wei , Nagpal Jatin K. , Jeronimo Carmen , Lee Ji Eun , Henrique Rui , Kim Myoung Sook , Ostrow Kimberly L. , Yamashita Keishi , van Criekinge Vim , Wu Guojun , Moon Chu‐So , Trink Barry , Sidransky David
Published: January 2008

BACKGROUND

DNA methylation has emerged as a promising biomarker for prostate cancer detection. In this report, we screened 36 candidate genes generated by a bioinformatic analysis of the human genome, and found that the melanoma cell adhesion molecule (MCAM) was an excellent candidate for cancer‐specific methylation in prostate cancer.

METHODS

Direct sequencing of bisulfite‐treated genomic DNA, conventional methylation‐specific PCR (MSP), real‐time quantitative methylation‐specific PCR, immunohistochemistry, colony formation assay, and statistical analysis.

RESULTS

We found that the melanoma cell adhesion molecule (MCAM) gene promoter was specifically methylated in prostate cancer cell lines and primary prostate cancer (PCa) but not in non‐neoplastic prostate (BPH) tissues by direct sequencing of bisulfite‐treated genomic DNA and conventional methylation‐specific PCR (MSP). Further analysis with quantitative MSP showed greater hypermethylation of the MCAM promoter (80%, 70/88) in primary prostate cancer compared to 12.5% (3/24) in BPH. Prostatic intraepithelial neoplasias (PIN), potential precursors of prostate carcinoma, showed an intermediate methylation rate of 23% (7/30). We further observed that MCAM promoter methylation was directly correlated with tumor stage (pT3+pT4) (P = 0.001) and Gleason score (P = 0.018) in primary prostate carcinoma.

CONCLUSIONS

Our results suggest that MCAM promoter hypermethylation deserves further attention as a potential diagnostic prostatic DNA marker in human prostate cancer. Prostate 68: 418–426, 2008. © 2008 Wiley‐Liss, Inc.
Critical roles for JNK, c‐Jun, and Fas/FasL‐Signaling in vitamin E analog‐induced apoptosis in human prostate cancer cells
Authors: Jia Li , Yu Weiping , Wang Pei , Li Jing , Sanders Bob G. , Kline Kimberly
Published: January 2008

Background

α‐Tocopherol ether‐linked acetic acid (α‐TEA), an analog of vitamin E (RRR‐α‐tocopherol), is a potent pro‐apoptotic agent for human cancer cells in vivo and in vitro.

Methods

α‐TEA‐induced apoptosis was investigated in LNCaP and PC‐3 human prostate cancer cells. Apoptosis was measured by DAPI‐staining and FACS analyses of the sub‐G1 fraction. Signaling molecules involved in apoptosis were measured by Western immunoblot analyses with or without prior immunoprecipitation, FACS analyses of cell surface membrane expression, RT‐PCR analyses of mRNA levels, and chromatin immunoprecipitation. Functional significance was determined using siRNAs, dominant negative mutant, chemical inhibitor, or neutralizing antibody.

Results

α‐TEA treatment increased Fas and Fas ligand mRNA and protein levels; as well as, levels of cell surface membrane Fas in both cell lines. Blockage of Fas signaling attenuated α‐TEA‐induced apoptosis. α‐TEA treatment also produced prolonged, elevated levels of activated (phosphorylated) c‐Jun N‐terminal kinase (JNK) and its substrate c‐Jun, both of which were demonstrated to be necessary for α‐TEA‐induced apoptosis. Chromatin immunoprecipitation results showed binding of c‐Jun to the promoters of both Fas and FasL in α‐TEA treated cells. Investigations of α‐TEA‐triggered apoptosis showed dual signaling from Fas with essential roles for both FADD and Daxx with FADD initiating the classical pathway mediated by caspase‐8 activation and Daxx initiating an alternate pathway involving activation of JNK, c‐Jun, and increased levels of Fas and FasL.

Conclusions

Collectively, data support critical roles for JNK, c‐Jun, and dual signaling from Fas/FasL via FADD and Daxx in α‐TEA‐induced apoptosis of human prostate cancer cells. Prostate 68: 427–441, 2008. © 2008 Wiley‐Liss, Inc.
Pilot and feasibility study of serum chemokines as markers to distinguish prostatic disease in men with low total serum PSA
Authors: Macoska Jill A. , Begley Lesa A. , Dunn Rodney L. , Siddiqui Javed , Wei John T. , Sarma Aruna V.
Published: January 2008

BACKGROUND

The incidence and prevalence of both benign prostatic hypertrophy (BPH) and prostate cancer (PCa) increase with the aging process. Our laboratory recently showed that the chemokines CXCL5 and CXCL12, which normally function as inflammatory mediators, are secreted at higher levels by aging prostate stromal fibroblasts and elicit proliferative responses from both prostate stromal fibroblast and epithelial cells. Because both CXCL5 and CXCL12 are secreted molecules, we hypothesized that their levels in patient serum might serve as biomarkers to distinguish between BPH and PCa.

METHODS

Serum CXCL5 and CXCL12 levels were determined using sandwich ELISAs for 51 men demonstrating low serum PSA values of ≤10 ng/ml who underwent diagnostic needle biopsy for the detection of PCa. The bivariate relationship of circulating chemokine levels, age, and disease status in the prostate was tested using the Wilcoxon rank‐sum test.

Results

Total serum CXCL12 levels were significantly higher for men who were biopsy positive compared to those who were biopsy negative for cancer and histological prostatitis (P = 0.050). Among men who were biopsy negative for PCa, total serum CXCL5 levels were inversely associated with prostate volume and were significantly higher in men with concomitant BPH and histological prostatitis compared to those without evidence of prostatic disease (P < 0.003).

CONCLUSIONS

The results of this pilot and feasibility study suggest that serum or plasma CXCL5 and CXCL12 levels may potentially distinguish between BPH and PCa among patients presenting with low serum PSA, and may be useful toward facilitating decisions to perform diagnostic needle biopsy in this patient population. Prostate 68: 442–452, 2008. © 2008 Wiley‐Liss, Inc.
Antisense MDM2 enhances the response of androgen insensitive human prostate cancer cells to androgen deprivation in vitro and in vivo
Authors: Mu Zhaomei , Hachem Paul , Hensley Harvey , Stoyanova Radka , Kwon Hae Won , Hanlon Alexandra L. , Agrawal Sudhir , Pollack Alan
Published: January 2008

Background

Antisense MDM2 oligonucleotide (AS‐MDM2) sensitizes androgen sensitive LNCaP cells to androgen deprivation (AD) in vitro and in vivo. In this study, we investigated the effects of AS‐MDM2 combined with AD on androgen resistant LNCaP (LNCaP‐Res) and moderately androgen resistant bcl‐2 overexpressing LNCaP (LNCaP‐BST) cells.

Methods

The LNCaP‐Res cell line was generated by culturing LNCaP cells in medium containing charcoal‐stripped serum for more than 1 year. Apoptosis was quantified in vitro by Annexin V staining and caspase 3 + 7 activity. For the in vivo studies, orthotopic tumor growth was monitored by magnetic resonance imaging (MRI). AS‐MDM2 and the mismatch control were given by i.p. injection at doses of 25 mg/kg per day, 5 days/week for 15 days.

Results

LNCaP‐Res cells expressed high levels of androgen receptor (AR) and bcl‐2, and displayed no growth inhibition to AD. AS‐MDM2 caused significant reductions in MDM2 and AR expression, and increases in p53 and p21 expression in both cell lines. AS‐MDM2 + AD resulted in the highest levels of apoptosis in vitro and tumor growth inhibition in vivo in both cell lines; although, these effects were less pronounced in LNCaP‐BST cells.

Conclusions

AS‐MDM2 + AD enhanced apoptotic cell death in vitro and tumor growth inhibition in vivo in androgen resistant cell lines. The action of AS‐MDM2 + AD was influenced somewhat by bcl‐2 expression as an isolated change (LNCaP‐BST cells), but not when accompanied by other molecular changes associated with androgen insensitivity (LNCaP‐Res cells). MDM2 knockdown has promise for the treatment of men with early hormone refractory disease. Prostate 68: 599–609, 2008. © 2008 Wiley‐Liss, Inc.
A kinetic model of fumigant sorption by grain using batch experimental data
Authors: Darby James A
Published: January 2008

BACKGROUND: Most fumigants are adsorbed by grain at differing rates depending on the fumigant or grain type. Sorption can reduce the concentrations of fumigation doses to sublethal levels before grain has been disinfested. A model to predict fumigant losses due to sorption in industrial scenarios is needed.

RESULTS: This work reviews the kinetics of grain fumigant sorption and develops a new alternative model based upon key factors established from the literature and batch experimental results. The novel model accounts for linear mass transfer within the grain, irreversible ‘binding’ and linear partitioning of the fumigant to the grain. Model coefficients were estimated by minimizing the sum of squared residuals between model predictions and experimental data. The model was compared with other options including diffusion into spheres, and results for methyl bromide and phosphine are provided.

CONCLUSION: The model describes the transient changes of fumigant concentrations in both the intergranular air and grain. It provides the capacity to predict fumigant concentrations throughout grain stacks for a wide range of scenarios of industrial importance. Copyright © 2008 CSIRO, Australia. Published by John Wiley & Sons,Ltd.
Interaction of peptides with biomembranes assessed by potential‐sensitive fluorescent probes
Authors: Matos Pedro M. , Gonçalves Sónia , Santos Nuno C.
Published: January 2008

Peptide–membrane interaction is an important step to be evaluated in a study of the activity and mode of action of several bioactive peptides. A variety of methods are available; however, few of them satisfy the criteria of being sensitive, biocompatible, versatile, easy to perform, and allowing real‐time monitoring as the use of potential‐sensitive fluorescent probes. Here we review methods for detecting the effects of membrane‐active peptides, even those that are not intrinsically fluorescent, on the different types of membrane potentials, with a special emphasis on studies conducted with living cells. FPE is a probe sensitive to surface potential and detects electrostatic interactions at the water‐lipid interface. Di‐8‐ANEPPS is sensitive to dipole potential and detects membrane incorporations. Transmembrane potential changes reveal major membrane destabilizations, such as in pore formation. The combination of the information obtained from the three potential variations can lead to a more elucidative picture of the mechanisms of the interaction of relevant peptides with biomembranes. Copyright © 2008 European Peptide Society and John Wiley & Sons, Ltd.
What can light scattering spectroscopy do for membrane‐active peptide studies?
Authors: Domingues Marco M. , Santiago Patrícia S. , Castanho Miguel A. R. B. , Santos Nuno C.
Published: January 2008

Highly charged peptides are important components of the immune system and belong to an important family of antibiotics. Although their therapeutic activity is known, most of the molecular level mechanisms are controversial. A wide variety of different approaches are usually applied to understand their mechanisms, but light scattering techniques are frequently overlooked. Yet, light scattering is a noninvasive technique that allows insights both on the peptide mechanism of action as well as on the development of new antibiotics. Dynamic light scattering (DLS) and static light scattering (SLS) are used to measure the aggregation process of lipid vesicles upon addition of peptides and molecular properties (shape, molecular weight). The high charge of these peptides allows electrostatic attraction toward charged lipid vesicles, which is studied by zeta potential (ζ‐potential) measurements. Copyright © 2008 European Peptide Society and John Wiley & Sons, Ltd.
Effect of magnon–LA phonon interaction on LA phonon excitation at finite temperature
Authors: Cheng Tai‐Min , Li Lin , Shen Long‐hai
Published: January 2008

A magnon–longitudinal acoustic (LA) phonon interaction model is developed on the basis of a two‐dimensional square Heisenberg ferromagnetic system. The LA phonon excitation is studied by Matsubara–Green function theory, and the LA phonon excitation dispersion curves are calculated on the main symmetric lines in Brillouin zone (BZ). It is found that there exists obvious LA phonon hardening. The hardening of LA phonons becomes more evident near the M point of the BZ boundary. The influences of various parameters on LA phonon hardening are also discussed. (© 2008 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)
Investigation of operational characteristics and possibility of obtaining highly detuned GaInNAsSb VCSEL
Authors: Gutowski K. , Sarzała R. P. , Nakwaski W.
Published: January 2008

Comprehensive computer simulation was used to investigate a possibility to highly detune GaInNAsSb VCSEL devices from the wavelength of 1422 nm, corresponding to the highest RT optical gain of their Ga0.62In0.38N0.023As0.95Sb0.027/GaN0.025As0.975 quantum‐well (QW) active regions, to 1500 nm, closer to the wavelength used in the third generation of the fibre optical communication. The RT continuous‐wave (CW) lasing operation of the 1500‐nm VCSEL, with an identical active region to that of the 1422‐nm one and the cavity properly re‐designed for the 1500‐nm wavelength, may be obtained for the active‐region temperature increased by about 94 K over RT which is necessary for a required QW gain shift to longer wavelengths. However, such a temperature‐induced CW RT VCSEL lasing operation at 1500 nm is reached at the expense of an increase in its threshold current density by as much as 10 times as compared to that of the 1422‐nm VCSEL. Detuned devices has different operational characteristics e.g. worse mode selectivity and threshold current decrease with ambient temperature either quantum‐wells number increase. (© 2008 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)
Theory of electronic structure of BGaAs and related alloys
Authors: Lindsay A. , O'Reilly E. P.
Published: January 2008

Previous experiments on Bx Ga1–x As containing a few percent boron show a dramatic increase in electron effective mass, m*e , similar to that observed in many GaNx As1–x samples. By contrast, there is a near‐linear blue‐shift of the energy gap, which can be conventionally described using the virtual crystal approximation. We use a tight‐binding model to show that isolated B atoms have little effect either on the band gap or lowest conduction band dispersion in Bx Ga1–x As. By contrast, B pairs and clusters introduce defect levels close to the conduction band edge (CBE) which, through a weak band‐anticrossing (BAC) interaction, significantly reduce the band dispersion in and around the Γ ‐point, thus accounting for the strong increase in m*e and reduction in mobility observed in these alloys. Calculations show that replacing gallium by aluminium shifts the CBE upwards, leading to a large density of B‐related states in the energy gap. By contrast, indium shifts the band edge downwards, leading eventually to a band edge m*e close to that predicted by the virtual crystal approximation. (© 2008 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)
Characterization of covalent addition products of chlorogenic acid quinone with amino acid derivatives in model systems and apple juice by high‐performance liquid chromatography/electrospray ionization tandem mass spectrometry
Authors: Schilling Susanne , Sigolotto Constance‐Isabelle , Carle Reinhold , Schieber Andreas
Published: January 2008

High‐performance liquid chromatography (HPLC) coupled to electrospray ionization tandem mass spectrometry (ESI‐MSn) was used to study the covalent interactions between chlorogenic acid (CQA) quinone and two amino acid derivatives, tert‐butyloxycarbonyl‐L‐lysine and N‐acetyl‐L‐cysteine. In a model system at pH 7.0, the formation of covalent addition products was demonstrated for both derivatives. The addition product of CQA dimer and tert‐butyloxycarbonyl‐L‐lysine was characterized by LC/MSn as a benzacridine structure. For N‐acetyl‐L‐cysteine, mono‐ and diaddition products at the thiol group with CQA quinone were found. In apple juice at pH 3.6, covalent interactions of CQA quinone were observed only with N‐acetyl‐L‐cysteine. Taking together these results and those reported by other groups it can be concluded that covalent interactions of amino side chains with phenolic compounds could contribute to the reduction of the allergenic potential of certain food proteins. Copyright © 2008 John Wiley & Sons, Ltd.
Raman scattering characterisation of electrochemical growth of CuInSe2 nanocrystalline thin films for photovoltaic applications: Surface and in‐depth analysis
Authors: Izquierdo‐Roca V. , Álvarez‐García J. , Calvo‐Barrio L. , Pérez‐Rodríguez A. , Morante J. R. , Bermudez V. , Ramdani O. , Grand P.‐P. , Kerrec O.
Published: January 2008

A detailed Raman scattering analysis of the electrodeposition process of nanocrystalline CuInSe2 layers for solar cell devices is reported. The correlation of the Raman spectra measured after the growth of the layers with different times has allowed investigating the chemical phases involved in the film formation process and their resulting nanocrystalline structure. The experimental data indicate the presence of elemental Se and CuSe binary compounds as the main secondary phases in the layers, which are directly related to the Se and Cu excess conditions used in the electrodeposition growth. These data show the existence of a high content of elemental Se at the region close to the interface of the layer with the Mo‐coated glass substrate, this being likely related to a lack of incorporation of In at the initial growth stages. Nanoscopic Cu‐deficient domains are also revealed by the presence of a band at the low frequency side of the main CuInSe2 peak. Copyright © 2008 John Wiley & Sons, Ltd.
A rank‐based sample size method for multiple outcomes in clinical trials
Authors: Huang Peng , Woolson Robert F. , O'Brien Peter C.
Published: January 2008

O'Brien (Biometrics 1984; 40:1079–1087) introduced a rank‐sum‐type global statistical test to summarize treatment's effect on multiple outcomes and to determine whether a treatment is better than others. This paper presents a sample size computation method for clinical trial design with multiple primary outcomes, and O'Brien's test or its modified test (Biometrics 2005; 61:532–539) is used for the primary analysis. A new measure, the global treatment effect (GTE), is introduced to summarize treatment's efficacy from multiple primary outcomes. Computation of the GTE under various settings is provided. Sample size methods are presented based on prespecified GTE both when pilot data are available and when no pilot data are available. The optimal randomization ratio is given for both cases. We compare our sample size method with the Bonferroni adjustment for multiple tests. Since ranks are used in our derivation, sample size formulas derived here are invariant to any monotone transformation of the data and are robust to outliers and skewed distributions. When all outcomes are binary, we show how sample size is affected by the success probabilities of outcomes. Simulation shows that these sample size formulas provide good control of type I error and statistical power. An application to a Parkinson's disease clinical trial design is demonstrated. Splus codes to compute sample size and the test statistic are provided. Copyright © 2008 John Wiley & Sons, Ltd.
oDect: an RFID‐based object detection API to support applications development on mobile devices
Authors: Bellotti Francesco , Berta Riccardo , Margarone Massimiliano , De Gloria Alessandro
Published: January 2008

The RFID technology is becoming ever more popular in the development of ubiquitous computing applications. A full exploitation of the RFID potential requires the study and implementation of human–computer interaction (HCI) modalities to be able to support wide usability by the target audience. This implies the need for programming methodologies specifically dedicated to support the easy and efficient prototyping of applications to have feedback from early tests with users. On the basis of our field‐working experience, we have designed oDect, a high‐level language and platform‐independent application programming interface (API), ad hoc designed to meet the needs of typical applications for mobile devices (smart phones and PDAs). oDect aims at allowing application developers to create their prototypes focusing on the needs of the final users, without having to care about the low‐level software that interacts with the RFID hardware. Further, in an end‐user developing (EUD) approach, oDect provides specific support for the application end‐user herself to cope with typical problems of RFID applications in detecting objects. We describe in detail the features of the API and discuss the findings of a test with four programmers, where we analyse and evaluate the use of the API in four sample applications. We also present results of an end‐user test, which investigated strengths and weaknesses of the territorial agenda (TA) concept. The TA is an RFID‐based citizen guide that aids—through time‐ and location‐based reminders—users in their daily activities in a city. The TA directly exploits EUD features of oDect, in particular concerning the possibility of linking detected objects with custom actions. Copyright © 2008 John Wiley & Sons, Ltd.
An empirical study on software development with open source components in the chinese software industry
Authors: Chen Weibing , Li Jingyue , Ma Jianqiang , Conradi Reidar , Ji Junzhong , Liu Chunnian
Published: January 2008

Chinese software companies are increasingly using open source software (OSS) components in software development. Development with OSS components faces challenges with respect to component selection, component integration, licensing compliance, and system maintenance. Although these issues have been investigated in the industry in other countries, few similar studies have been performed in China. It is therefore difficult for Chinese software companies to be aware of their special issues and to make the necessary improvements. This article describes a questionnaire‐based survey of software development with OSS components in Chinese software companies. Data from 47 completed development projects in 43 companies were collected. The results show that the main motivation behind using OSS components was their modifiability and low license cost. Using a web search engine was the most common method of locating OSS components. Local acquaintance and compliance requirements were the major decisive factors in choosing a suitable component. To avoid legal exposure, the common strategy was to use components without licensing constraints. The major cost of OSS‐based projects was the cost to learn and understand OSS components. Almost 84% of the components needed bug fixing or other changes to the code. However, close participation with the OSS community was rare. Copyright © 2008 John Wiley & Sons, Ltd.
A component‐based process for modelling and evolving legacy systems
Authors: Kotonya Gerald , Hutchinson John
Published: January 2008

The potential benefits of evolving legacy systems to component‐based system architectures are well documented. These include rapid, non‐intrusive modernization through the use of commercial off‐the‐shelf (COTS) components and significantly reduced post‐maintenance costs. However, the hype has not translated to a corresponding increase in the migration of legacy systems to component‐based architectures. There are two main reasons for this. First, many legacy systems provide adequate core functionality. For this type of system, replacement may not be the most cost‐effective solution. Second, there is a general lack of scalable methods and tools that support component‐based modelling and evolution for legacy systems. The article discusses challenges of evolving legacy systems and proposes COMPonent‐Oriented Software Engineering (COMPOSE), a component‐based approach built on an extensible ADL that provides a framework for modelling, verifying and evolving legacy systems using black‐box components. We also describe our experience of using it to evolve a legacy system. Copyright © 2008 John Wiley & Sons, Ltd.
Effect of Hospital Volume of Thyroidectomies on Outcomes Following Substernal Thyroidectomy
Authors: Pieracci Fredric M. , Fahey Thomas J.
Published: January 2008

Background

Substernal thyroidectomy (ST), as compared to conventional, cervical thyroidectomy, is a technically demanding procedure that is associated with increased morbidity and mortality. We tested the hypothesis that outcomes following ST are improved at centers that perform a high volume of thyroidectomies.

Methods

Patients who underwent ST from 1998 to 2004 were extracted from the New York State Statewide Planning and Research Cooperative System database. Hospital volume of thyroidectomies was divided into low (<33 per year), middle (33–99 per year), and high (≥100 per year) volumes. Outcome variables included hospital length of stay (LOS), recurrent laryngeal nerve (RLN) injury, hypoparathyroidism, postoperative bleeding, respiratory failure, blood transfusion, and mortality.

Results

A total of 1153 STs were analyzed; 372 (32.2%) were performed at low‐volume centers, 388 (33.7%) at middle‐volume centers, and 393 (34.0%) at high‐volume centers. Linear associations were observed between increasing hospital volume of thyroidectomies and decreasing age (p = 0.003), increasing co‐morbidity (p < 0.0001), increased likelihood of total versus subtotal thyroidectomy (p < 0.0001), and increased likelihood of thyroid malignancy (p < 0.0001). Despite this, increasing hospital volume of thyroidectomies predicted a decreased likelihood of overall complications (p = 0.005), postoperative bleeding (p = 0.01), blood transfusion (p = 0.04), respiratory failure (p = 0.04) and mortality (p = 0.004), as well as a trend toward a decreased LOS (p = 0.06). The overall complication rate and the mortality rate remained significantly associated with volume group by multivariate analysis.

Conclusion

Despite more extensive surgery on patients with greater co‐morbidity, LOS, morbidity, and mortality were all decreased when ST occurred at hospitals that perform a high volume of thyroidectomies.
The Ecumenical Patriarchate as a Beacon of Hope: Insights Into the Role of Religion in a Changing World
Authors: Bartholomeos Patriarch
Published: January 2008

Religion is not only a feature of the past, but is of the utmost importance to the majority of the world's population today. When traditional social, economical, national and collective roles are challenged by a globalised world, religion is the single most important stabilising factor both for individuals and in the political arena. But while globalisation means that some borders have ceased to exist, others have been created. His All Holiness the Ecumenical Patriarch calls us as individuals to work for individual freedom, take responsibility for the environment and to ensure that all regions and nations benefit from the globalisation process.
Aggregatibacter actinomycetemcomitans lipopolysaccharide affects human gingival fibroblast cytoskeletal organization
Authors: Gutiérrez‐Venegas Gloria , Contreras‐Marmolejo Luis Arturo , Román‐Alvárez Patricia , Barajas‐Torres Carolina
Published: January 2008

The cytoskeleton is a dynamic structure that plays a key role in maintaining cell morphology and function. This study investigates the effect of bacterial wall lipopolysaccharide (LPS), a strong inflammatory agent, on the dynamics and organization of actin, tubulin, vimentin, and vinculin proteins in human gingival fibroblasts (HGF). A time‐dependent study showed a noticeable change in actin architecture after 1.5 h of incubation with LPS (1 μg/ml) with the formation of orthogonal fibers and further accumulation of actin filament at the cell periphery by 24 h. When 0.01–10 μg/ml of LPS was added to human gingival fibroblast cultures, cells acquired a round, flat shape and gradually developed cytoplasmic ruffling. Lipopolysaccharides extracted from Aggregatibacter actinomycetemcomitans periodontopathogenic bacteria promoted alterations in F‐actin stress fibres of human gingival cells. Normally, human gingival cells have F‐actin fibres that are organized in linear distribution throughout the cells, extending along the cell's length. LPS‐treated cells exhibited changes in cytoskeletal protein organization, and F‐actin was reorganized by the formation of bundles underneath and parallel to the cell membrane. We also found the reorganization of the vimentin network into vimentin bundling after 1.5 h of treatment. HGF cells exhibited diffuse and granular γ‐tubulin stain. There was no change in LPS‐treated HGF. However, vinculin plaques distributed in the cell body diminished after LPS treatment.

We conclude that the dynamic and structured organization of cytoskeletal filaments and actin assembly in human gingival fibroblasts is altered by LPS treatment and is accompanied by a decrease in F‐actin pools.
β‐Amyloid peptides 1–40βA and 25–35βA suppress human amylin‐mediated death of RINm5F islet β‐cells with distinct actions on fibril formation
Authors: Bai Ji‐Zhong
Published: January 2008

Amyloid deposition is a common feature of Alzheimer's disease and type 2 diabetes related to β‐amyloid peptides (βA) and human amylin (hA), respectively. Both βA and hA form aggregates and fibrils and kill cultured cells. To investigate whether βA and hA display peptide‐specific toxicity on cultured islet β‐cells, we examined the effects of 1–40βA and 25–35βA peptides on hA‐mediated cell death and [125I‐Tyr37]hA precipitation. Synthetic hA aggregated in solution and evoked both conformation‐ and sequence‐dependent cell death. While neither 1–40βA nor 25–35βA was toxic to islet β‐cells, they suppressed hA‐evoked cell death in a concentration‐dependent and saturable manner. Only 1–40βA, but not 25–35βA, showed trophic effects on cultured islet β‐cells and inhibited the precipitation of [125I]hA caused by hA. These results suggest that 25–35βA does not interfere with hA‐mediated fibril formation. Suppression of hA‐evoked death of cultured pancreatic islet β‐cells by the βA peptides is likely to occur through a competing interaction at these cells.
Sexually dimorphic effects of neonatal immune system activation with lipopolysaccharide on the behavioural response to a homotypic adult immune challenge
Authors: Tenk Christine M. , Kavaliers Martin , Ossenkopp Klaus‐Peter
Published: January 2008

Research has shown that acute immune activation during the early postnatal period with the Gram‐negative endotoxin, lipopolysaccharide (LPS), alters a variety of physiological and behavioural processes in the adult animal. For example, neonatal LPS exposure affects disease susceptibility later in life, though these effects appear to be modulated by time of exposure, sex, and immune stimulus. The current study examined sex differences in the effect of neonatal LPS treatment on the locomotor activity response to adult LPS administration. Male and female Long‐Evans rats were treated systemically with either LPS (50 μg/kg) or saline (0.9%) on postnatal days 3 and 5. Later in adulthood (postnatal day 92), all animals were subjected to an adult LPS challenge and were injected (i.p.) with 200 μg/kg LPS. Two hours after injection, animals were placed in a non‐novel open‐field and locomotor activity was assessed for 30 min. Body weights were determined both at the time of injection and 24 h later to examine LPS‐induced weight loss. Adult males treated neonatally with LPS exhibited significantly less horizontal and vertical activity in response to the LPS challenge relative to males treated neonatally with saline. This effect was not observed in females. Thus, the current study provides important evidence of sexual dimorphism in the long‐term effects of neonatal LPS exposure on the responses to an adult homotypic immune challenge in rats. These findings have potential clinical significance given that neonatal exposure to pathogens is a fairly common occurrence and Gram‐negative bacteria are a common cause of neonatal bacterial infections.
Optimizing phase II of drug development for disease‐modifying compounds
Authors: Cummings Jeffrey L.
Published: January 2008

Phase II proof of concept (POC) (IIa) and dose‐finding (IIb) studies represent major challenges in drug development. Prolonged development times delay effective therapies from reaching patients in need and adversely affect industry goals of decreasing time to market. Biomarkers including magnetic resonance imaging, cerebrospinal fluid tau and amyloid β, and amyloid positron emission tomography have been considered as alternative outcomes to clinical measures. None of these is yet validated. Population enrichment is another possible solution to POC studies. More rapid progression to prespecified milestones can be achieved by enriching the population with risk factors. Conclusions based on enriched populations must be extrapolated with caution. Clinical measures with greater sensitivity than standard trial instruments might represent another strategy applicable to POC studies. Adaptive dose‐response designs are being considered as a means of shortening phase IIb studies and creating a seamless interface with phase III. None of these strategies have been validated in a successful drug development program; all have some promise for reforming phase II and answering the central question of “how much information is sufficient to proceed to phase III without excessive risk for failure?”
Prognosis of Alzheimer's disease today: A two‐year prospective study in 686 patients from the REAL‐FR Study
Authors: Cortes Frédéric , Nourhashémi Fati , Guérin Olivier , Cantet Christelle , Gillette-Guyonnet Sophie , Andrieu Sandrine , Ousset Pierre-Jean , Vellas Bruno ,   REAL-FR Group
Published: January 2008

Background

The aim of the present study was to describe the long‐term evolution of Alzheimer's disease (AD) in a prospective cohort of patients under treatment with a close follow‐up.

Methods

Six hundred eighty‐six AD patients from the French Network on AD (REAL‐FR) were followed up and assessed every 6 months for 2 years. Cognitive, functional, behavioral, nutritional, and global status were evaluated by using Mini‐Mental State Examination (MMSE), cognitive subscale of AD Assessment Scale (ADAS‐cog), Activities of Daily Living scale (ADL), Neuropsychiatric Inventory (NPI), Mini‐Nutritional Assessment (MNA), and Clinical Dementia Rating (CDR).

Results

There were 85.13% of patients who were specifically treated for AD during their participation in the study. We observed significant changes (P < .0001) on MMSE, –4.57 ± 0.23; ADAS‐cog, 7.11 ± 0.41; ADL, –1.32 ± 0.07; NPI, 2.94 ± 0.77; MNA, –0.81 ± 0.17; and sum of boxes of the CDR (CDR‐SB), 4.17 ± 0.17. After 2 years, 10.79% (95% confidence interval [CI], 8.47 to 13.11) of the patients evolved twice as rapidly as the mean of the whole cohort on MMSE (loss, ≥9 points), 65.89% (95% CI, 62.34 to 69.44) reported a loss of 3 to 9 points, and 23.32% (95% CI, 20.16 to 26.46) were stable or improved (loss of –2 points maximum). Annual incidences for institutionalization, hospitalization, and death were 11.84% (95% CI, 9.76 to 13.92), 26.13% (95% CI, 22.52 to 29.74), and 5.95% (95% CI, 4.56 to 7.34), respectively.

Conclusions

In a recent large AD cohort mostly under treatment, AD evolution appeared to be variable, with high incidences for death or institutionalization and with 11.84% of the patients exhibiting a rapid cognitive decline, whereas one fourth of the cohort appeared in relatively stable condition, and two thirds had a moderate but significant evolution of the disease. More studies are needed to better understand these variations in patients’ evolution.
On the Society and History of CSSH
Authors: Grew Raymond
Published: January 2008

My knowledge of the inner workings of CSSH began when the journal had completed its sixth year and was already well known and widely circulated. A few years before, Sylvia L. Thrupp had brought it with her when she moved to Michigan from the University of Chicago. When I joined the Michigan faculty, its presence was one of the attractions. I had been become aware of CSSH in its first year, pointed to it by Robert R. Palmer, who was working on the second volume of his Age of the Democratic Revolution. As we talked about his project, I expressed surprise that more was not being done with historical comparison, and he mentioned, rather skeptically I thought, that there was a new journal I might be interested in. I found the first issues in the library and mentioned them to another Princeton colleague who commented, “When historians don't know enough to write about one place, they write on two.” So I learned from the first that the venture was controversial. In contrast, Joseph R. Strayer told me he thought the new journal very promising, largely because of the woman who had founded it. (Much later, I learned that he had persuaded Princeton to make a small contribution to the journal's founding, and some twenty-five years after that conversation, when both were in their eighties, Joseph Strayer married Sylvia Thrupp).
Being Editor
Authors: Trautmann Thomas R.
Published: January 2008

Having brought my editorship to an end just before the CSSH fiftieth birthday—having, you might say, just stepped out of the maelstrom—it might be worthwhile to seize the occasion to analyze, in tranquility, what at the time was just too intense, too difficult but also too deeply satisfying an experience to put into words. Without a doubt, being editor of CSSH was the most gratifying job I ever had, but why? How to bottle the maelstrom?
The Embryography of Alice B. Toklas
Authors: Morgan Lynn M.
Published: January 2008

When Gertrude Stein (1874–1946) was a medical student at Johns Hopkins in Baltimore, she spent the autumn of 1901 constructing an anatomical model of a young human brain. Most accounts call it an “embryo” brain, although as we shall see it likely belonged to a fetus or infant. The assignment was her final opportunity to obtain the medical degree after failing four classes in the spring of her senior year. Her anatomy professor, Franklin Paine Mall (1982–1917), offered her a second chance to graduate if she would finish her brain model and write an accompanying manuscript. Stein eventually produced sixty-three drawings and “roughly twenty-five pages of text,” in addition to the model itself (Meyer 2001: 89). She submitted the work in January 1902, but Mall judged it as inept and threw it away. Stein set off for Europe, leaving medicine behind forever. She settled in Paris where she became an avant-garde writer most notably known for her book supposedly chronicling the life of Alice Babette Toklas (1877–1967), who was Stein's longtime lover, secretary, editor, cook, and companion. The book, published in 1933, narrated the life of the inimitable Gertrude Stein, although it was playfully titledThe Autobiography of Alice B. Toklas.